Notch信号通路在成人EB病毒感染所致传染性单核细胞增多症中的作用

目的:观察成人传染性单核细胞增多症(IM)患者Notch信号通路分子和Th22细胞的变化,检测抑制Notch信号通路对Th22细胞的调控作用。方法:纳入42例IM患者和21例健康对照者,采集外周血,分离血浆和外周血单个核细胞,酶联免疫吸附试验检测血浆白细胞介素(IL)-17和IL-22水平,流式细胞术检测CD3+CD4+IL-17+Th17细胞和CD3+CD4+IL-22+Th22细胞比例,实时定量PCR法检测Th17转录因子维甲酸相关孤独核受体γt(RORγt)、Th22转录因子芳香烃受体(AhR)及Notch信号通路分子(包括Notch受体、Notch配体、Notch下游分子)mRNA相对表达量。纯化CD4+T细胞,使用γ-分泌酶抑制剂(GSI)刺激培养,检测GSI刺激后细胞增殖、Th17和Th22细胞比例、IL-17和IL-22分泌、转录因子mRNA相对表达量变化。结果:IM组外周血单个核细胞中Notch1和Notch2 mRNA的相对表达量分别为13.58±3.18、4.73±1.16,均明显高于对照组的1.09±0.12、1.07±0.15(均P<0.001),而Notch3和Notch4 mRNA相对表达量在IM组和对照组之间的差异无统计学意义(P>0.05)。IM组Notch配体DLL1和Jagged1 mRNA相对表达量、Notch信号下游分子Hes1、Hes5和Hey1 mRNA相对表达量均高于对照组(均P<0.001)。IM患者Th17和Th22细胞比例分别为5.03%±1.15%、4.48%±1.29%,均高于对照组的4.36%±0.82%、3.83%±0.55%(均P<0.05);血浆IL-17和IL-22水平分别为(301.1±53.82)pg/ml、(101.2±16.45)pg/ml,均高于对照组的(237.2±72.18)pg/ml、(84.75±11.83)pg/ml(均P<0.001);RORγt和AhR mRNA相对表达量分别为1.25±0.22、1.21±0.12,均高于对照组的0.99±0.15、1.04±0.11(均P<0.001)。CD4+T细胞增殖水平、Th17细胞比例、IL-17分泌和RORγt mRNA相对表达量在无GSI刺激组和经GSI刺激组之间的差异无统计学意义(P>0.05)。经GSI刺激后Th22细胞比例、IL-22分泌和AhR mRNA相对表达量较无GSI刺激降低(均P<0.05)。结论:Notch信号通路通过AhR调控IM患者CD4+T细胞分泌IL-22,Notch-AhR-Th22细胞通路可能参与IM发病。

Notch3/DLL4信号通路对颈部淋巴水囊瘤后淋巴管发育的影响

目的:探究Notch3/DLL4信号通路对颈部淋巴水囊瘤(CH)后淋巴管成熟发育的影响。方法:选取C57BL/6小鼠和C57BL/6背景Notch3基因敲入小鼠,将两种小鼠分为正常组(对照组)和Notch3基因敲入组(突变组)。选取F2代小鼠处死,取小鼠颈部淋巴结分别进行HE染色、Masson染色、RT-qPCR、Western blot、免疫组化检测。结果:HE及Masson染色结果显示,与对照组比,突变组小鼠的淋巴结构被显著破坏,细胞纤维化严重。RT-qPCR结果显示,与对照组比,突变组小鼠淋巴结中DLL4、Hes1和VEGFR3 mRNA表达显著下降(P<0.05)。Western blot结果显示,与对照组比,突变组小鼠淋巴结中DLL4、Hes1和VEGFR3蛋白表达显著下降(P<0.05)。免疫组化结果显示,与对照组相比,突变组小鼠淋巴结中DLL4、Hes1、Ang2、VEGFA和VEGFR3染色较浅,蛋白表达水平下降(P<0.05)。结论:Notch3/DLL4信号通路能够调控小鼠颈部CH的形成,其机制可能与淋巴管发育有关。

miR-145通过Notch通路调节免疫功能及炎症反应介导创伤性脑损伤的神经保护

目的:探讨miR-145对创伤性脑损伤(TBI)后炎症反应和免疫调节的作用。方法:将雄性C57BL/6小鼠随机分为假手术组(Sham)、模型组(TBI)、TBI+NC agomir组、TBI+miR-145 agomir组。改良神经损伤严重程度评分(mNSS)用于评估创伤后神经功能;MWM测试评估TBI后小鼠的神经认知功能;流式细胞术检测各组小鼠脑组织中Tregs数量;ELISA检测各组小鼠海马中炎症细胞因子表达;免疫组化检测各组小鼠海马中活化的小胶质细胞/巨噬细胞Iba-1表达;RT-qPCR检测M1/M2小胶质细胞/巨噬细胞标志物基因iNOS、CD11b、CD206和Arg1表达;TUNEL染色和神经元细胞核免疫荧光标记(NeuN)的双重染色检测神经元凋亡。结果:与Sham组比较,TBI组小鼠海马组织中miR-145表达显著降低,神经功能损伤增加,脑组织中Tregs在CD4+T细胞群中百分比降低,海马组织中IL-1β、IL-6、TNF-α、IL-4、IL-10和TGF-β表达显著升高,活化的小胶质细胞/巨噬细胞Iba-1数量增多,iNOS、CD11b、CD206和Arg1表达水平显著升高,神经元凋亡升高,Notch1、p21和Hes1 mRNA和蛋白水平均显著升高(P<0.05);与TBI+NC agomir组比较,TBI+miR-145 agomir组小鼠海马中miR-145表达显著升高,神经功能损伤减轻,脑组织中Tregs在CD4+T细胞群中的百分比显著升高,海马中促炎因子IL-1β、IL-6、TNF-α表达显著降低,抗炎因子IL-4、IL-10和TGF-β表达显著升高,活化的小胶质细胞/巨噬细胞Iba-1数量显著减少,iNOS和CD11b表达降低,CD206和Arg1表达水平显著升高,神经元凋亡减少,Notch1、p21和Hes1 mRNA和蛋白水平均显著降低(均P<0.05)。结论:miR-145过表达通过提高Tregs水平,促进小胶质细胞M2极化,调节创伤后神经炎症反应及改善行为功能障碍,这一机制可能通过Notch信号通路介导。

LHPP通过调控NOX2/SHP2通路活性抑制结直肠癌的增殖、侵袭和转移

目的探讨组氨酸磷酸酶(LHPP)通过氧化应激通路对结直肠癌增殖、侵袭和迁移的影响,并初步阐明其作用机制。方法使用Liposome3000进行细胞转染操作。将质粒OE-NC、OE-LHPP和寡核苷酸片段si-NC、si-LHPP分别转染进SW480细胞中,通过Western Blot检测LHPP、NOX2、p-SHP2的蛋白表达量;将质粒OE-NC、OE-LHPP组转染进SW480细胞中并同时使用NCA刺激,通过Western Blot检测NOX2、p-SHP2、p-PI3K、p-ERK1/2、MMP-9、Cyclin D1的蛋白表达量;将质粒OE-NC、OE-LHPP转染进SW480和SW620细胞中,并同时使用NAC刺激,通过划痕实验检测细胞的迁移距离,Transwell实验检测通过孔的细胞数量,克隆形成实验检测细胞的增殖能力。结果SW480细胞中OE-LHPP组LHPP和NOX2蛋白表达水平明显高于OE-NC组(P<0.05),但p-SHP2蛋白表达水平明显低于OE-NC组(P<0.01);SW480细胞中si-Si-LHPP组LHPP和NOX2蛋白表达水平明显低于OE-NC组(P<0.01),但p-SHP2蛋白表达水平明显高于si-NC组。与OE-NC组相比,SW480细胞中OE-LHPP的NOX2蛋白表达水平明显升高(P<0.01),但p-SHP2、p-PI3K、p-ERK1/2、MMP-9、Cyclin D1蛋白表达水平明显降低(P<0.01),SW480和SW680细胞迁移距离缩短、穿过孔的细胞数量减少和细胞克隆形成数量减少;加入NAC干预后,消除了SW480和SW680细胞中OE-NC组和OE-LHPP组在NOX2、p-SHP2、p-PI3K、p-ERK1/2、MMP-9、Cyclin D1的差异,也消除了细胞划痕、细胞侵袭和细胞增殖的差异。结论LHPP通过促进氧化应激抑制SHP2、PI3K和ERK通路活性进而抑制结直肠癌细胞的增殖、侵袭和迁移的影响进而缓解结直肠癌的进展。

川楝素调节Notch信号通路对甲状腺癌细胞增殖、迁移和侵袭的影响

目的 研究川楝素通过调节Notch信号通路对甲状腺癌细胞增殖、迁移和侵袭的影响。方法 体外培养人甲状腺癌细胞8505C,CCK-8法检测不同剂量川楝素对8505C细胞存活率的影响;将8505C细胞分为对照组、川楝素-L、M、H组、川楝素+DAPT(Notch信号通路抑制剂)组;EDU法检测8505C细胞增殖;Transwell检测8505C细胞迁移与侵袭能力;RT-PCR检测不同8505C细胞组Notch1、HES1、HEY1、Ki67、MMP-2的mRNA水平;western blot检测不同8505C细胞组Notch1、HES1、HEY1、Ki67、MMP-2的蛋白水平。结果 与对照组相比,川楝素-L、M、H组8505C细胞EDU阳性细胞率、迁移与侵袭细胞数、Ki67、MMP-2的mRNA以及蛋白水平均显著性降低,Notch1、HES1、HEY1的mRNA以及蛋白水平显著性升高,且呈剂量依赖性(P<0.05);与川楝素-H组相比,川楝素+DAPT组EDU阳性细胞率、迁移与侵袭细胞数、Ki67、MMP-2的mRNA以及蛋白水平均显著性升高,Notch1、HES1、HEY1的mRNA以及蛋白水平显著性降低(P<0.05)。结论 川楝素可能通过激活Notch信号通路,抑制甲状腺癌细胞8505C增殖、迁移和侵袭。

牛蒡子苷元调控Notch/Hes-1信号通路对口腔鳞状细胞癌HSC-3细胞增殖、凋亡和侵袭的影响

目的:探究牛蒡子苷元(ARC)通过调控Notch/Hes-1信号通路对口腔鳞状细胞癌(OSCC)HSC-3细胞增殖、凋亡和侵袭的影响及其机制。方法:使用不同质量浓度的ARC处理人HSC-3细胞,CCK-8法检测ARC对细胞增殖活力的影响,以选择适宜的药物浓度。将HSC-3细胞分为对照组、ARC-L组(10 mg/L ARC)、ARC-M组(20 mg/L ARC)、ARC-H组(40 mg/L ARC)和ARC-H+Jagged1/FC组(40 mg/L ARC+1.2μg/mL Jagged1/FC)。采用EdU法检测细胞增殖能力,划痕愈合实验、Transwell实验和流式细胞术分别检测细胞的迁移、侵袭能力及细胞周期和细胞凋亡率,WB法检测增殖(c-Myc、cyclin D1)、凋亡(BAX、Bcl-2、survivin)、EMT(E-cadherin、vimentin、Snail)及Notch/Hes-1通路(Notch 1、Hes-1、NICD)相关蛋白的表达水平。结果:与0 mg/L相比,10~80 mg/L的ARC均能显著降低HSC-3细胞增殖活力(均P<0.05)。与对照组相比,ARC-L组、ARC-M组和ARC-H组HSC-3细胞EdU阳性率、划痕愈合率、侵袭细胞数、S期和G2/M期细胞占比及c-Myc、cyclin D1、Bcl-2、survivin、vimentin、Snail、Notch 1、Hes-1和NICD蛋白表达均显著降低(均P<0.05),细胞凋亡率、G0/G1期细胞占比及BAX、E-cadherin的蛋白表达均显著升高(均P<0.05),且呈浓度梯度依赖性。同时使用Notch激动剂Jagged1/FC,则可部分逆转ARC对HSC-3细胞增殖、迁移、侵袭、凋亡及相关蛋白表达的作用(均P<0.05)。结论:ARC可能通过抑制Notch/Hes-1信号通路抑制OSCC细胞HSC-3增殖和侵袭并促进细胞凋亡。

秋水仙碱通过激动PI3K/AKT/eNOS信号通路对急性心肌梗死大鼠心功能的影响

目的:探究秋水仙碱通过调节磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B(AKT)/内皮型一氧化氮合酶(eNOS)信号通路对急性心肌梗死(AMI)大鼠心功能的影响。方法:78只大鼠中随机选取12只作为假手术组,剩余大鼠构建AMI模型,造模成功大鼠分为模型组、秋水仙碱组[4 mg/(kg·d)]、秋水仙碱[4 mg/(kg·d)]+LY294002(20 mg/mL)组、秋水仙碱[4 mg/(kg·d)]+MK-2206(60μg/mL)组、秋水仙碱[4 mg/(kg·d)]+L-NAME(1.6 mg/mL)组,每组12只。超声心动图检测大鼠左心室舒张末期内径(LVEDD)、左心室收缩末期内径(LVESD)、射血分数(EF)及短轴缩短率(FS)。处死大鼠,苏木素-伊红(HE)染色检测大鼠心肌组织石蜡切片病理学变化;末端脱氧核苷酸转移酶介导的dUTP缺口末端标记(TUNEL)法检测心肌细胞凋亡率;酶联免疫吸附实验(ELISA)测定大鼠血清肿瘤坏死因子α(TNF-α)、白细胞介素-6(IL-6)、肌酸激酶同工酶(CK-MB)以及心肌组织匀浆中超氧化物歧化酶(SOD)、丙二醛(MDA)、过氧化氢酶(CAT)水平;免疫印迹法(Western Blot)测定大鼠心肌组织PI3K/AKT/eNOS通路蛋白表达。结果:与假手术组相比,模型组大鼠LVESD、LVEDD,血清CK-MB、TNF-α、IL-6水平,心肌匀浆MDA、心肌细胞凋亡率升高,EF、FS水平,心肌匀浆SOD、CAT,心肌组织磷酸化PI3K(p-PI3K)/PI3K、磷酸化AKT(p-AKT)/AKT、磷酸化eNOS(p-eNOS)/eNOS降低(P<0.05);与模型组相比,秋水仙碱组大鼠LVESD、LVEDD,血清CK-MB、TNF-α、IL-6水平,心肌匀浆MDA、心肌细胞凋亡率降低,EF、FS水平,心肌匀浆SOD、CAT,心肌组织p-PI3K/PI3K、p-AKT/AKT、p-eNOS/eNOS升高(P<0.05);与秋水仙碱组相比,秋水仙碱+LY294002组、秋水仙碱+MK-2206组、秋水仙碱+L-NAME组大鼠LVESD、LVEDD,血清CK-MB、TNF-α、IL-6水平,心肌匀浆MDA、心肌细胞凋亡率升高,EF、FS水平,心肌匀浆SOD、CAT,心肌组织p-PI3K/PI3K、p-AKT/AKT、p-eNOS/eNOS降低(P<0.05)。结论:秋水仙碱可能通过激活PI3K/AKT/eNOS信号通路对AMI大鼠发挥心功能保护作用。

黄芩总黄酮对支气管哮喘大鼠的治疗作用及miR-133a-3p/NOX4/NLRP3信号轴表达的影响

目的黄芩总黄酮对支气管哮喘大鼠的治疗作用及miR-133a-3p/NOX4/NLRP3信号轴表达的影响。方法清洁级SD大鼠100只分为正常对照组、模型组、地塞米松组(200 mg/kg)、黄芩总黄酮低剂量组(100 mg/kg)、黄芩总黄酮高剂量组(200 mg/kg),每组20只。除正常对照组外,模型组、地塞米松组、黄芩总黄酮低高剂量组通过卵清蛋白(OVA)建立支气管哮喘模型,并予以相应药物干预。实验结束后,检测肺泡灌洗液淋巴细胞百分比、中性粒细胞百分比、白细胞计数,以及肺/体比值、肺损伤评分、动脉血氧分压(PaO_(2))水平;反逆转录聚合酶链反应(RT-PCR)及蛋白印迹法检测肺支气管组织微小RNA-133a-3p(miR-133a-3p)、NADPH氧化酶4(NOX4)、NOD样受体热蛋白结构域相关蛋白3(NLRP3)水平。结果与正常对照组比较,模型组肺泡灌洗液淋巴细胞百分比、中性粒细胞百分比、白细胞计数、肺/体比值、肺损伤评分,以及支气管组织中NOX4、NLRP3蛋白和mRNA表达水平升高,PaO_(2)水平、支气管组织中miR-133a-3p表达水平降低,差异有统计学意义(P<0.05);与模型组比较,地塞米松组、黄芩总黄酮低剂量组和黄芩总黄酮高剂量组肺泡灌洗液淋巴细胞百分比、中性粒细胞百分比、白细胞计数、肺/体比值、肺损伤评分,以及支气管组织中NOX4、NLRP3蛋白和mRNA表达水平降低,PaO_(2)水平、支气管组织中miR-133a-3p表达水平升高,差异有统计学意义(P<0.05)。与地塞米松组比较,黄芩总黄酮低剂量组、黄芩总黄酮高剂量组肺泡灌洗液淋巴细胞百分比、中性粒细胞百分比、白细胞计数、肺/体比值、肺损伤评分,以及支气管组织中NOX4、NLRP3蛋白和mRNA表达水平升高,PaO_(2)水平、支气管组织中miR-133a-3p表达水平降低,差异有统计学意义(P<0.05)。与黄芩总黄酮低剂量组比较,黄芩总黄酮高剂量组肺泡灌洗液淋巴细胞百分比、中性粒细胞百分比、白细胞计数、肺/体比值、肺损伤评分,支气管组织中NOX4、NLRP3蛋白和mRNA表达水平升高,PaO_(2)水平、支气管组织中miR-133a-3p表达水平降低,差异有统计学意义(P<0.05)。结论黄芩总黄酮对大鼠支气管哮喘具有明显治疗作用,其机制可能与黄芩总黄酮促进miR-133a-3p的表达进而抑制NOX4/NLRP3信号轴的激活相关。

Notch信号通路与骨质疏松症及中医药防治

背景:近年研究表明,Notch信号通路对骨质疏松症有不同程度的影响,深入该方向的研究对骨质疏松的防治具有重要意义。目前,中医药以其多角度、多层次和不良反应小的明显优势在缓解骨质疏松方面发挥显著作用,已成为当今社会研究的重点。目的:分析、整理国内外文献,进一步了解Notch信号通路与骨质疏松症的联系,阐明中医药调控Notch信号通路防治骨质疏松症的作用机制。方法:以“Notch、骨质疏松症、成骨细胞、破骨细胞、骨髓间充质干细胞、信号通路、中药、丸、实验”等为中文检索词,检索中国知网、万方、维普数据库;以“Notch、osteoporosis、Osteoblasts、Osteoclasts、Mesenchymal stem cells、Signal pathway、traditional Chinese medicine、pill、experiment”等为英文检索词,检索PubMed、Nature、Embase数据库,选择各数据库建库至2022年10月的相关文献。结果与结论:Notch信号通路通过参与调控间充质干细胞、成骨细胞和破骨细胞的分化、增殖,从而在不同程度上影响骨质疏松症的发生和进展;Notch信号通路通过直接或间接调控Notch1、Jagged1、Hes、Hey、巨噬细胞集落刺激因子、核因子κB受体活化因子配体等关键细胞因子调节间充质干细胞、成骨细胞和破骨细胞的增殖、分化,进而对骨形成起到促进或抑制的作用,最终对骨质疏松症起到一定的防治效果。中药活性成分大多从补肾类中药提取,如淫羊藿、杜仲、补骨脂、刺五加、女贞子等,且中药复方及制剂都具有补肾强骨的功效,这为后续研究Notch信号通路向防治骨质疏松症提供更多的中药选择和方向。目前中药的研究多为活性成分和单味药提取物,中药复方及制剂的临床实验研究相对较少;关于针灸、推拿、中西医结合等疗法调控Notch信号通路防治骨质疏松症的研究较少,未来还需继续探索中医技术类疗法及中西医结合等疗法对Notch信号通路的调控和对骨质疏松治疗的作用机制。

Hypoglycemic mechanism of Tegillarca granosa polysaccharides on type 2 diabetic mice by altering gut microbiota and regulating the PI3K-akt signaling pathwaye

Type 2 diabetes mellitus(T2DM)is a complex metabolic disease threatening human health.We investigated the effects of Tegillarca granosa polysaccharide(TGP)and determined its potential mechanisms in a mouse model of T2DM established through a high-fat diet and streptozotocin.TGP(5.1×10^(3) Da)was composed of mannose,glucosamine,rhamnose,glucuronic acid,galactosamine,glucose,galactose,xylose,and fucose.It could significantly alleviate weight loss,reduce fasting blood glucose levels,reverse dyslipidemia,reduce liver damage from oxidative stress,and improve insulin sensitivity.RT-PCR and Western blotting indicated that TGP could activate the phosphatidylinositol-3-kinase/protein kinase B signaling pathway to regulate disorders in glucolipid metabolism and improve insulin resistance.TGP increased the abundance of Allobaculum,Akkermansia,and Bifidobacterium,restored the microbiota abundance in the intestinal tracts of mice with T2DM,and promoted short-chain fatty acid production.This study provides new insights into the antidiabetic effects of TGP and highlights its potential as a natural hypoglycemic nutraceutical.

Antibacterial mechanism of kojic acid and tea polyphenols against Escherichia coli O157:H7 through transcriptomic analysis

Escherichia coli O157:H7 is one of the major foodborne pathogenic bacterial that cause infectious diseases in humans.The previous found that a combination of kojic acid and tea polyphenols exhibited better activity against E.coli O157:H7 than using either alone.This study aimed to explore responses underlying the antibacterial mechanisms of kojic acid and tea polyphenols from the gene level.The functional enrichment analysis by comparing kojic acid and tea polyphenols individually or synergistically against E.coli O157:H7 found that acid resistance systems in kojic acid were activated,and the cell membrane and genomic DNA were destructed in the cells,resulting in“oxygen starvation”.The oxidative stress response triggered by tea polyphenols inhibited both sulfur uptake and the synthesis of ATP,which affected the bacteria's life metabolic process.Interestingly,we found that kojic acid combined with tea polyphenols hindered the uptake of iron that played an essential role in the synthesis of DNA,respiration,tricarboxylic acid cycle.The results suggested that the iron uptake pathways may represent a novel approach for kojic acid and tea polyphenols synergistically against E.coli O157:H7 and provided a theoretical basis for bacterial pathogen control in the food industry.

ANO1介导肿瘤恶性生物学行为的机制探讨

ANO1又称为TMEM16A,其作为钙激活的电压依赖性氯通道的分子基础之一,广泛分布于体内多种组织器官,介导了支气管腺体分泌、痛觉、肠道慢波形成等多种生理功能;同时ANO1参与了多种病理过程的发生、发展,如恶性肿瘤、炎症等。多项报导证实了恶性肿瘤发病过程中通过多种信号通路引起ANO1的高表达,继而高表达的ANO1激活不同的下游信号通路提高了肿瘤细胞的恶性生物学行为。本文主要探讨恶性肿瘤中高表达的ANO1提高肿瘤细胞恶性生物学行为的可能机制。

Impact of STAT-signaling pathway on cancer-associated fibroblasts in colorectal cancer and its role in immunosuppression

Colorectal cancer(CRC)remains one of the most commonly diagnosed and deadliest types of cancer worldwide.CRC displays a desmoplastic reaction(DR)that has been inversely associated with poor prognosis;less DR is associated with a better prognosis.This reaction generates excessive connective tissue,in which cancer-associated fibroblasts(CAFs)are critical cells that form a part of the tumor microenvironment.CAFs are directly involved in tumorigenesis through different mechanisms.However,their role in immunosuppression in CRC is not well understood,and the precise role of signal transducers and activators of transcription(STATs)in mediating CAF activity in CRC remains unclear.Among the myriad chemical and biological factors that affect CAFs,different cytokines mediate their function by activating STAT signaling pathways.Thus,the harmful effects of CAFs in favoring tumor growth and invasion may be modulated using STAT inhibitors.Here,we analyze the impact of different STATs on CAF activity and their immunoregulatory role.

Total flavonoids of Astragalus membranaceus protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in mice by inhibiting ferroptosis through SLC7A11/GPX-4 signaling pathway

Parkinson’s disease(PD)is a common neurodegenerative disorder with no cure.Astragalus membranaceus is used in Chinese culture as a food supplement to boost immunity.The present study aimed to explore the neuroprotective effects of total flavonoids extracted from A.membranaceus(TFA)and their protective mechanisms.TFA offered neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)in the mouse model of Parkinsonism,by improving behavior performance in the gait analysis and pole test,and inhibiting the decline of tyrosine hydroxylase(TH)positive neurons and TH protein expression in substantia nigra of mice.TFA also prevented 1-methyl-4-phenylpyridinium(MPP+)induced neurotoxicity in SHSY5Y cells,by increasing GSH and GSH/GSSG ratio,and reducing reactive oxygen species.In addition,the neuroprotective effects of TFA were associated with its ability to restore MPTP/MPP+induced downregulation of SLC7A11 and glutathione peroxidase 4(GPX-4).In conclusion,we demonstrated that TFA exerted significant neuroprotection against MPTP/MPP+induced neurodegeneration by inhibiting ferroptosis through the regulation of SLC7A11/GPX-4 axis,suggesting the use of TFA as a possible food supplement in the prevention of PD.

Adaptive Bistable Stochastic Resonance Based Weak Signal Reception in Additive Laplacian Noise

Weak signal reception is a very important and challenging problem for communication systems especially in the presence of non-Gaussian noise,and in which case the performance of optimal linear correlated receiver degrades dramatically.Aiming at this,a novel uncorrelated reception scheme based on adaptive bistable stochastic resonance(ABSR)for a weak signal in additive Laplacian noise is investigated.By analyzing the key issue that the quantitative cooperative resonance matching relationship between the characteristics of the noisy signal and the nonlinear bistable system,an analytical expression of the bistable system parameters is derived.On this basis,by means of bistable system parameters self-adaptive adjustment,the counterintuitive stochastic resonance(SR)phenomenon can be easily generated at which the random noise is changed into a benefit to assist signal transmission.Finally,it is demonstrated that approximately 8dB bit error ratio(BER)performance improvement for the ABSR-based uncorrelated receiver when compared with the traditional uncorrelated receiver at low signal to noise ratio(SNR)conditions varying from-30dB to-5dB.

一种概率-Voronoi自适应高维模型表达的新能源电力系统小干扰失稳风险评估方法

电力系统中新能源和负荷的不确定性给小干扰稳定性带来挑战。鉴此,该文中提出一种概率-Voronoi自适应采样的高维模型表达方法用于新能源电力系统小干扰失稳风险评估。首先,简要介绍基于高维模型表达的小干扰失稳风险评估步骤和方法,分析模型求解和配点选择对高维模型表达建模精度的影响;然后,基于移动最小二乘法的求解特性分析,提出动态半径选择方法,提高计算准确度和求解效率;而后,改进自适应-Voronoi采样方法,将其和概率思想结合,得到概率-Voronoi采样方法,提高风险评估建模采样的高效性。结合动态半径移动最小二乘法和概率-Voronoi采样法,建立小干扰失稳风险评估的高维模型表达。最后,多个新能源电力系统为例,对比分析所提方法的准确性与高效性,并结合实际源荷不确定数据与电网结构,验证研究的实用性。

Inhibition of Ehrlich ascites carcinoma growth by melatonin:Studies with micro-CT

Melatonin is a versatile indolamine synthesized and secreted by the pineal gland in response to the photoperiodic information received by the retinohypothalamic signaling pathway.Melatonin has many benefits,such as organizing circadian rhythms and acting as a powerful hormone.We aimed to show the antitumor effects of melatonin in both in vivo and in vitro models through the mammalian target of rapamycin(mTOR)signaling pathway and the Argyrophilic Nucleolar Regulatory Region(AgNOR),using the Microcomputed Tomography(Micro CT).Ehrlich ascites carcinoma(EAC)cells were administered into the mice by subcutaneous injection.Animals with solid tumors were injected intraperitoneally with 50 and 100 mg/kg melatonin for 14 days.Volumetric measurements for the taken tumors were made with micro-CT imaging,immunohistochemistry(IHC),real-time polymerase chain reaction(PCR)and AgNOR.Statistically,the tumor tissue volume in the Tumor+100 mg/kg melatonin group was significantly lower than that in the other groups in the data obtained from micro-CT images.In the IHC analysis,the groups treated with Tumor+100 mg/kg melatonin were compared when the mTOR signaling pathway and factor 8(F8)expression were compared with the control group.It was determined that there was a significant decrease(p<0.05).Significant differences were found in the total AgNOR area/nuclear area(TAA/NA)ratio in the treatment groups(p<0.05).Furthermore,there were significant differences between the amount of mTOR mRNA for the phosphatidylinositol 3-kinase(PI3K),AKT Serine/Threonine Kinase(PKB/AKT)genes(p<0.05).Cell apoptosis was evaluated with Annexin V in an in vitro study with different doses of melatonin;It was observed that 100µg/mL melatonin dose caused an increase in the apoptotic cell death.In this study,we have reported anti-tumor effects of melatonin in cell culture studies as well as in mice models.Comprehensive characterization of the melatonin-mediated cancer inhibitory effects will be valuable in advancing our fundamental molecular understanding and translatability of pre-clinical findings to earlier phases of clinical trials.

Insights into genetic diversity and phenotypic variations in domestic geese through comprehensive population and pan-genome analysis

Background Domestic goose breeds are descended from either the Swan goose(Anser cygnoides)or the Greylag goose(Anser anser),exhibiting variations in body size,reproductive performance,egg production,feather color,and other phenotypic traits.Constructing a pan-genome facilitates a thorough identification of genetic variations,thereby deepening our comprehension of the molecular mechanisms underlying genetic diversity and phenotypic variability.Results To comprehensively facilitate population genomic and pan-genomic analyses in geese,we embarked on the task of 659 geese whole genome resequencing data and compiling a database of 155 RNA-seq samples.By constructing the pan-genome for geese,we generated non-reference contigs totaling 612 Mb,unveiling a collection of 2,813 novel genes and pinpointing 15,567 core genes,1,324 softcore genes,2,734 shell genes,and 878 cloud genes in goose genomes.Furthermore,we detected an 81.97 Mb genomic region showing signs of genome selection,encompassing the TGFBR2 gene correlated with variations in body weight among geese.Genome-wide association studies utilizing single nucleotide polymorphisms(SNPs)and presence-absence variation revealed significant genomic associations with various goose meat quality,reproductive,and body composition traits.For instance,a gene encoding the SVEP1 protein was linked to carcass oblique length,and a distinct gene-CDS haplotype of the SVEP1 gene exhibited an association with carcass oblique length.Notably,the pan-genome analysis revealed enrichment of variable genes in the“hair follicle maturation”Gene Ontology term,potentially linked to the selection of feather-related traits in geese.A gene presence-absence variation analysis suggested a reduced frequency of genes associated with“regulation of heart contraction”in domesticated geese compared to their wild counterparts.Our study provided novel insights into gene expression features and functions by integrating gene expression patterns across multiple organs and tissues in geese and analyzing population variation.Conclusion This accomplishment originates from the discernment of a multitude of selection signals and candidate genes associated with a wide array of traits,thereby markedly enhancing our understanding of the processes underlying domestication and breeding in geese.Moreover,assembling the pan-genome for geese has yielded a comprehensive apprehension of the goose genome,establishing it as an indispensable asset poised to offer innovative viewpoints and make substantial contributions to future geese breeding initiatives.

白藜芦醇抑制Notch1信号通路对抗小鼠急性T淋巴细胞白血病

目的:观察白藜芦醇(Res)对急性T淋巴细胞白血病(T-ALL)小鼠的影响,并进一步探讨其对Notch1信号通路的作用机制。方法:将25只6-8周龄雌性C57BL/6小鼠随机分为正常对照组、T-ALL组和Res组,其中Res组又进一步分为low-Res(L-Res)、middle-Res(M-Res)和high-Res(H-Res)3个浓度给药组。应用流式细胞术和瑞氏-吉姆萨染色法检测外周血及脾细胞悬液中白血病细胞百分比,HE染色法观察脾脏和骨髓组织病理形态,RT-q PCR法检测脾脏组织中Notch1、Hes-1、c-Myc、mi R-19b和PTEN m RNA表达水平,Western blot法检测Notch1、Hes-1、c-Myc、p-PTEN和PTEN蛋白表达水平。结果:与对照组相比,T-ALL组小鼠外周血中白血病细胞明显增多,脾脏及骨髓组织中白血病细胞弥漫性浸润,脾脏中Notch1、Hes-1、c-Myc、mi R-19b m RNA表达水平和Notch1、Hes-1、c-Myc蛋白表达水平均明显增高(P<0.01),PTEN m RNA及其蛋白水平显著降低(P<0.01),经白藜芦醇处理后,H-Res组以上各项指标较T-ALL组均获得逆转。结论:白藜芦醇具有抗小鼠T-ALL的作用,其机制可能通过抑制Notch1信号通路发挥作用。

Barley Protein LFBEP-C1 from Lactiplantibacillus plantarum dy-1 Fermented Barley Extracts by Inhibiting Lipid Accumulation in a Caenorhabditis elegans Model

Objective This study aimed to investigate the lipid-lowering activity of LFBEP-C1 in high glucose-fed Caenorhabditis elegans(C.elegans).Methods In this study,the fermented barley protein LFBEP-C1 was prepared and tested for its potential anti-obesity effects on C.elegans.The worms were fed Escherichia coli OP50(E.coli OP50),glucose,and different concentrations of LFBEP-C1.Body size,lifespan,movement,triglyceride content,and gene expression were analyzed.The results were analyzed using ANOVA and Tukey's multiple comparison test.Results Compared with the model group,the head-swing frequency of C.elegans in the group of LFBEP-C1 at 20μg/mL increased by 33.88%,and the body-bending frequency increased by 27.09%.This indicated that LFBEP-C1 improved the locomotive ability of C.elegans.The average lifespan of C.elegans reached 13.55 days,and the body length and width of the C.elegans decreased after LFBEP-C1 intake.Additionally,LFBEP-C1 reduced the content of lipid accumulation and triglyceride levels.The expression levels of sbp-1,daf-2,and mdt-15 significantly decreased,while those of daf-16,tph-1,mod-1,and ser-4 significantly increased after LFBEP-C1 intake.Changes in these genes explain the signaling pathways that regulate lipid metabolism.Conclusion LFBEP-C1 significantly reduced lipid deposition in C.elegans fed a high-glucose diet and alleviated the adverse effects of a high-glucose diet on the development,lifespan,and exercise behavior of C.elegans.In addition,LFBEP-C1 regulated lipid metabolism mainly by mediating the expression of genes in the sterol regulatory element-binding protein,insulin,and 5-hydroxytryptamine signaling pathways.