胚胎早期发育过程中主要信号通路的作用机制

胚胎发育始于受精卵,后者经过多次卵裂,胚胎的形态发生变化的同时,内部细胞也向不同谱系分化,为随后原肠胚的形成奠定基础。在胚胎早期发育过程中,多种信号通路参与了精细调控,如Hippo信号通路的差异性激活导致了滋养外胚层（trophectoderm,TE）和内细胞群（inner cell mass,ICM）的分化;成纤维细胞生长因子/细胞外信号调节激酶（fibroblast growth factor/extracellular signal-regulated kinase,FGF/ERK）信号通路使ICM进一步分化为原始内胚层（primitive endoderm,PE）和外胚层（epiblast,EPI）;骨形态发生蛋白（bone morphogenetic protein,BMP）信号通路及经典Wnt信号通路不仅与胚胎细胞的多能性相关,还在胚轴的建立中发挥重要作用;Notch信号通路和Nodal信号通路主要参与了胚胎左右不对称的形成等。综述胚胎发育早期的几条主要信号通路的作用,为深入了解胚胎早期发育及其调控提供参考。     

Notch信号通路在哮喘及T淋巴细胞调节中的作用研究进展

Notch信号通路参与多种组织细胞的分化、成熟过程,尤其在T 淋巴细胞的分化过程中起了决定性作用。近年来,大量研究表明,Notch 信号通路参与支气管哮喘（BA）发病的整个病理过程,包括气道炎症、气道高反应、气道重塑及气道血管重塑。笔者拟就 Notch 信号通路在 BA和 T淋巴细胞调节中的作用,进行综述如下。     

Silk peptides inhibit adipocyte differentiation through modulation of the Notch pathway in C3H10T1/2 cells

Silk protein is a biocompatible material that has been used in many biotechnological applications and exhibits body fat-lowering effects. Recent studies have shown that silk peptides increase expression of osteogenic markers in osteoblast-like cells. Because osteogenic and adipogenic differentiation from common mesenchymal progenitor cells are inverse processes and often regulated reciprocally, we hypothesized that silk peptides might suppress adipocyte differentiation. We therefore endeavored to evaluate the effects of silk peptides on adipocyte differentiation in C3H10T1/2 cells. We find that silk peptides inhibit lipid accumulation and morphological differentiation in these cells. Molecular studies show that silk peptides block expression of adipocyte-specific genes such as peroxisome proliferator-activated receptor γ and its targets, including aP2, Cd36, CCAAT enhancer binding proteinα. Silk peptides appear to inhibit adipogenesis by suppression of the Notch pathway, repressing the Notch target genes Hes-1 and Hey-1. In addition, these peptides inhibit endogenous Notch activation, as shown by a reduction in generation of Notch intracellular domain. N-[N-(3.5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butylester, compound E, and WPE-III-31C, which are all known Notch signaling inhibitors, block adipocyte differentiation to an extent similar to silk peptides. Together, our data demonstrate that silk peptides can modulate adipocyte differentiation through inhibition of the Notch signaling and further suggest potential future strategies for treating obesity and its related metabolic diseases.     

microRNAs参与toll样受体介导内毒素耐受的研究进展

Toll样受体（Toll-Like Receptor,TLR）配体脂多糖（Lipopolysaccharide, LPS）,能诱导机体产生免疫耐受（或交叉耐受）,其信号途径受到多种机制的精密调控,在天然免疫中扮演重要角色。microRNAs是Toll样受体通路中常见信号分子IL-1受体相关激酶（IRAK1、IRAK2）和肿瘤坏死相关因子6（TRAF6）的关键靶向元件,参与了免疫耐受（或交叉耐受）的建立及维持。本综述主要讨论了Toll样受体介导耐受形成的机制,并阐述其配体诱导的microRNAs的调节功能,看是否影响Toll 样受体信号途径的激活以及内毒素耐受的建立、维持,对抗炎症疾病治疗的具有重要指导意义。     

生育三烯酚抑制结肠癌细胞增殖中Notch信号蛋白的表达及意义

目的探讨δ-生育三烯酚对人结肠癌细胞SW620细胞增殖抑制作用,研究Notch信号通路中关键蛋白在δ-生育三烯酚抑制结肠癌细胞增殖中的表达及意义。方法以终浓度分别为5、10、15、20、25、30μmol/L的δ-生育三烯酚培养SW620细胞,应用噻唑蓝（MTT）试验观察δ-生育三烯酚抑制结肠癌细胞增殖的作用,计算细胞存活率。应用免疫细胞化学方法检测Notch信号通路关键蛋白Notch、Jagged的表达变化。观察浓度为1μg/ml放线菌酮（CHX）对生育三烯酚抑制结肠癌细胞增殖作用的影响。结果随着δ-生育三烯酚浓度的增加,SW620细胞的存活率逐渐降低,差异有统计学意义（P〈0.05）。Notch信号通路关键蛋白Notch1、Jagged1在溶剂对照组结肠癌细胞中表达量最高,随着加入生育三烯酚剂量的增加,表达量逐渐降低。经CHX干预过的细胞,再加入δ-生育三烯酚,作用24 h后,细胞存活率（83.33%）较单独加入生育三烯酚作用的细胞存活率（28.51%）显著增高,差异有统计学意义（P〈0.05）。结论生育三烯酚抑制人结肠癌细胞增殖并诱导其死亡的方式可能为paraptosis样死亡,Notch信号通路中关键蛋白参与了这一过程。     

姜黄素通过Notch途径抑制人宫颈癌细胞株HeLa细胞增殖

目的:探讨姜黄素对人宫颈癌细胞株HeLa细胞体外增殖抑制及凋亡诱导作用及相关机制。方法:MTT法检测不同浓度姜黄素对HeLa细胞的增殖抑制作用;RT-PCR法检测HeLa细胞Notch1、Notch2、Jagged1、Bcl-2、Bax基因表达情况。结果:姜黄素对HeLa细胞具有增殖抑制作用,且呈时间-剂量依赖性。随着姜黄素剂量的增加,Notch1、Notch2、Bcl-2mRNA的表达逐渐下降,Bax mRNA的表达逐渐升高,Bcl-2/Bax亦逐渐减小,Jagged1mRNA无明显变化。结论:姜黄素可能通过Notch信号途径改变凋亡蛋白的表达,抑制HeLa细胞增殖。     

γ-分泌酶抑制剂对人脐静脉内皮细胞系增殖凋亡的影响

目的探讨Notch信号特异性阻断剂γ-分泌酶抑制剂（DAPT）对正常人脐静脉内皮细胞系增殖凋亡的影响。方法分别用不同浓度DAPT（15、30、45、60μM/L）处理体外培养的人脐静脉内皮细胞（HUVECs）12h、24h和48h,MTT法测定内皮细胞活力;粘附实验测定处理24h后细胞粘附率;TUNEL法检测处理24h后细胞凋亡率;Western法检测Notch信号通路受体Notch1的表达。结果 MTT检测显示DAPT显著抑制HUVECs存活（P〈0.01）,并呈浓度时间依赖性;粘附实验结果显示DAPT（24h）可以显著减弱HUVECs粘附能力（P〈0.01）;TUNEL检测显示DAPT（24h）可以显著增加HUVECs凋亡率（P〈0.01）;Westernblot结果显示DAPT使HUVECs中Notch1表达显著下降（P〈0.01）。结论 DAPT可阻断Notch信号通路,抑制正常人脐静脉内皮细胞的增殖,促进细胞凋亡。     

儿童支原体肺炎的Th17/Treg细胞平衡变化及Notch信号通路作用研究

目的探究儿童支原体肺炎的辅助型T细胞17/调节型T细胞(help T cell 17/T regular cell,Th17/Treg)平衡变化及Notch信号通路作用。方法选取2017年1月-2019年2月新乡市中心医院收治的肺炎支原体肺炎患儿50例,根据肺部是否出现哮鸣音,分为喘息组23例和非喘息组27例,以及同期于该医院体检的健康儿童30名作为对照组。抽取所有研究对象的空腹静脉血5 ml,采用流式细胞术检测Th17/Treg细胞比例;采用酶联免疫吸附法(ELISA)检测白细胞介素-10(Interleukin-10,IL-10)、白细胞介素-17(Interleukin-17,IL-17)水平;采用荧光定量PCR(Real-time PCR,RT-PCR法)检测Notch信号通路分子(Notch1、Hes1)及Th17/Treg转录因子(Foxp3、RORγt)的表达情况;比较三组研究对象的肺功能指标水平1秒用力呼气容积(1 second forced expiratory volume,FEV1)、用力肺活量(Forced vital capacity,FVC)、峰值呼气流量(Peak expiratory flow,PEF)及肺活量为25%、50%、75%时的最大呼气流速(V25、V50、V75)。结果喘息组的Th17、Th17/Treg比例高于非喘息组和对照组,Treg比例低于非喘息组和对照组(P<0.05);喘息组的Foxp3表达及IL-10水平低于非喘息组和对照组,RORγt表达及IL-17水平高于非喘息组和对照组(P<0.05);喘息组的Notch1、Hes1表达高于非喘息组和对照组(P<0.05);喘息组的FEV1、FEV1/FVC、PEF、V25、V50、V75等肺功能指标水平低于非喘息组和对照组(P<0.05)。结论支原体肺炎患儿体内Th17/Treg细胞比例失衡,Notch信号通路相关分子水平升高,导致患儿肺功能下降,Notch信号通路可能通过干预Th17/Treg细胞分化,影响相应细胞因子水平,参与支原体肺炎发生进展。     

mTOR信号通路及其在宫颈癌研究中的进展

哺乳动物雷帕霉素靶蛋白(mTOR)信号通路由于处于生长调节的中心环节而倍受关注,其在细胞生长、增殖、分化及细胞周期调控等多个方面起到重要作用。mTOR信号通路复杂且涉及广泛,其中多个元素的调控异常均与肿瘤的发生密切相关。近年来研究显示,宫颈癌中mTOR信号通路过度表达,表明宫颈癌的发生发展与mTOR信号通路存在紧密内在联系。这可为寻找阻断此通路的特异性靶向治疗药物提供依据。但其具体机制仍需深入研究。本文就mTOR信号转导通路的组成与功能、调节及其与宫颈癌发生发展的相关性进行综述。     

Induction of cancer cell death by isoflavone: the role of multiple signaling pathways

Soy isoflavones have been documented as dietary nutrients broadly classified as "natural agents" which plays important roles in reducing the incidence of hormone-related cancers in Asian countries, and have shown inhibitory effects on cancer development and progression in vitro and in vivo, suggesting the cancer preventive or therapeutic activity of soy isoflavones against cancers. Emerging experimental evidence shows that isoflavones could induce cancer cell death by regulating multiple cellular signaling pathways including Akt, NF-κB, MAPK, Wnt, androgen receptor (AR), p53 and Notch signaling, all of which have been found to be deregulated in cancer cells. Therefore, homeostatic regulation of these important cellular signaling pathways by isoflavones could be useful for the activation of cell death signaling, which could result in the induction of apoptosis of both pre-cancerous and/or cancerous cells without affecting normal cells. In this article, we have attempted to summarize the current state-of-our-knowledge regarding the induction of cancer cell death pathways by isoflavones, which is believed to be mediated through the regulation of multiple cellular signaling pathways. The knowledge gained from this article will provide a comprehensive view on the molecular mechanism(s) by which soy isoflavones may exert their effects on the prevention of tumor progression and/or treatment of human malignancies, which would also aid in stimulating further in-depth mechanistic research and foster the initiation of novel clinical trials.     

Folic acid enhances Notch signaling, hippocampal neurogenesis, and cognitive function in a rat model of cerebral ischemia

Increasing neurogenesis may restore cognitive functions that are impaired in ischemia stroke. Folic acid has been reported to play an important role in neuronal development and reduce the risk of ischemic stroke in primary prevention. Folic acid supplementation stimulates Notch signaling and cell proliferation in neural progenitor cells cultured from neonatal brain. The present study determined whether folic acid supplementation stimulates Notch signaling and neurogenesis and improves cognitive function after ischemic stroke in adult brain. Rats were randomly assigned to four groups: sham operation plus vehicle (Sham), middle cerebral artery occlusion plus vehicle (MCAO), MCAO plus low-dose folic acid (4 mg/(kg day)), and MCAO plus high folic acid (12 mg/(kg day)). The vehicle and folic acid were administered by oral gavage for 28 days prior to sham or MCAO operation and up to 14 days after surgery. Newborn hippocampal neurons were detected at 3, 7, and 14 days post-MCAO. Cognitive function (learning and memory in Y-maze tests) and the protein expression levels of components of the Notch signaling system (Notch1, Hes1, and Hes5) were measured at 7 days post-MCAO. The results showed that MCAO impaired Y-maze performance and stimulated Notch signaling and hippocampal neurogenesis in brain. Folic acid prevented the impairment of Y-maze performance. The nutrient also increased further the expression of Notch1, Hes1, and Hes5 and the number of the newborn hippocampal neurons. Folic acid enhances the stimulation by ischemia of Notch signaling and hippocampal neurogenesis in adult brain and lessens the impairment of cognitive function that occurs after experimental stroke.     

肝癌细胞中抑制Galectin-3基因表达对细胞增殖及侵袭能力的影响及机制研究

目的 探讨Galectin-3基因在肝癌细胞中的表达及抑制其表达对肝癌细胞增殖和侵袭能力的影响及机制。 方法 RT-PCR检测人肝癌细胞MHCC-97H、HepG2、SMCC-7721及人正常肝细胞HL-7702中Galectin-3基因的mRNA表达;Control、NC-siRNA、Galectin-3-siRNA转染HepG2细胞,48 h后Western blot检测各组细胞中Galectin-3、MMP-2、MMP-9、Notch1、Hes1的蛋白表达;CCK8实验和流式细胞仪分别检测细胞的增殖和侵袭能力。 结果 MHCC-97H、HepG2、SMCC-7721细胞中Galectin-3的mRNA表达均显著高于正常肝细胞HL-7702中的Galectin-3的mRNA表达,差异有统计学意义(P<0.01),Galectin-3在HepG2细胞中的表达最高,选择作为后续的研究对象;转染siRNA后能显著抑制Galectin-3基因的表达;Galectin-3-siRNA组细胞存活率、细胞侵袭数及MMP-2、MMP-9、Notch1、Hes1蛋白表达均低于对照组和NC-siRNA组,差异有统计学意义(P<0.01)。 结论 抑制肝癌细胞中Galectin-3基因表达能显著降低癌细胞的增殖及侵袭能力,其机制与Notch1信号通路的调控有关。     

肺动脉高压大鼠肺组织Notch信号的改变

目的探讨肺动脉高压（pulmonary hypertension，PH）大鼠肺组织Notch受体的改变。方法构建肺切除＋野百合碱PH大鼠模型，与正常大鼠比较肺血管重构指标的改变。进行肺组织免疫组化Notch 1-Notch4受体染色和实时荧光定量PCR（RT—PCR）检测（Notch 1-Notch4）mRNA。结果肺切除＋野百合碱组大鼠平均肺动脉压力（mPAP）、右心指数[fulton index，RV／（LV＋S）]、肺小动脉中膜厚度百分比（WT，％）、非肌性小动脉肌化程度、管壁细胞增殖度，明显高于正常大鼠，差异有显著意义（P〈0．05），有新生内膜形成。肺组织免疫组织化染色，肺切除＋野百合碱组和正常对照组大鼠肺动脉均有Notch1，Notch3，Notch4受体表达，未见Notch2受体表达。Notch1表达于血管内皮细胞和平滑肌细胞，Notch3主要表达于平滑肌细胞，Notch4主要表达于内皮细胞。肺切除＋野百合碱组肺组织（Notch1～Notch4）mRNA水平高于正常对照组。结论Notch1，Notch3，Notch4表达于肺动脉，随着PH肺血管重构的发生，表达上调。Notch信号很可能参与了PH肺血管重构过程。     

Notch3在大鼠肝癌中的表达及其意义

目的 研究Notch3在大鼠肝癌发生发展中的动态变化.方法 二乙基亚硝胺诱导大鼠肝细胞癌的发生,于4周、8周、12周、16周时取肝脏标本,免疫组化和Western blot法检测标本中Notch3的表达.结果 随着肝组织损伤加剧,Notch3表达逐渐升高.与正常组相比,肝损伤组、肝硬化组和肝癌组的Notch3蛋白明显表达增加(P＜0.05).结论 Notch3参与了大鼠肝癌发生的全过程,并且随着肝损伤的不断加剧,其表达也逐渐上升.Notch3信号的激活可能是肝癌发生的一项重要机制.     

Insulin/insulin-like growth factor-I hybrid receptor abundance decreases with development in suckling pigs

The activation of the insulin signaling pathway that leads to translation initiation is enhanced in skeletal muscle of neonates, and decreases with development in parallel with the developmental decline in muscle protein synthesis. Because the elevated expression of insulin receptor (IR)/insulin-like growth factor-I receptor (IGF-IR) hybrids has been associated with insulin resistance in some studies, we hypothesized that IR/IGF-IR hybrid abundance and binding affinity increase with development. To test this hypothesis, we determined the abundances and binding affinities of the IR, IGF-IR and hybrid receptor in skeletal muscle of 7- and 26-d-old pigs. We found that the abundances of IR, IGF-IR and hybrid receptor were higher in muscle of 7- than 26-d-old pigs. However, the relative proportions of hybrid receptor abundance compared with IR abundance and IGF-IR abundance were similar at both ages. The binding affinities of the IR, IGF-IR and hybrid receptor also were similar at both ages. Overall, the results suggest that insulin/IGF-I hybrid receptor abundance and binding affinity do not contribute to the developmental decline in the activation of the insulin signaling pathway.     

TGF-β/Smad信号通路在骨关节炎中作用的研究进展

骨关节炎(OA)是一种由多因素导致的骨关节疾病,严重威胁人类健康,其主要表现为关节疼痛、功能障碍,严重者可致畸形。OA的机制尚不十分明确,且缺少有效的治疗药物;针对OA病因、发病机制及预防措施的探索一直是该领域的重要研究方向。有研究发现,转化生长因子-β(TGF-β)/Smad信号通路在OA的发生和发展过程中起着关键作用。本文就近年来国内外关于TGF-β/Smad信号通路在OA中作用的研究进展进行综述。     

HES1与ICN1、Notch1在胃癌组织中的表达及其意义

目的:探讨Notch1信号通路主要分子在人胃癌组织中的表达及意义。方法:免疫组化SP法观察HES1、ICN1、Notch1在胃癌组织、癌旁萎缩性胃炎、癌旁浅表性胃炎、胃镜浅表性胃炎中的表达,分析三者表达与胃癌临床病理特征的关系以及胃癌组织中三者表达的相关性。结果:(1)HES1在胃癌组织的表达高于癌旁浅表性胃炎和胃镜浅表性胃炎(P<0.05);HES1表达与胃癌浸润深度、淋巴转移和肿瘤分期相关(P<0.01)。(2)Notch1、ICN1在胃癌组织的表达低于癌旁萎缩性胃炎(P<0.001);Notch1、ICN1的表达与胃癌分化程度相关(P<0.05)。(3)胃癌组织中Notch1、ICN1的表达呈正相关(P<0.01),HES1与Notch1、ICN1的表达无显著相关性。结论:HES1促进胃癌的发生发展并可能主要由其他通路调控;Notch1与胃癌的分化有关。     

胚胎植入的相关信号通路

胚胎植入及胎儿发育是母胎相互识别、相互适应的过程,该过程蕴含复杂的分子机制,至今尚未阐明。胚胎植入失败是不明原因性不孕、早期流产和反复种植失败的重要原因之一。胚胎植入与子宫内膜容受性密切相关,胚胎植入过程中机体分泌的各种细胞因子可以调控子宫内膜容受性,有效改善妊娠结局。目前研究已发现Notch、Janus激酶-信号转导及转录活化因子、Wnt/β-连环蛋白、丝裂原活化蛋白激酶和核因子κB等信号通路与胚胎植入息息相关。综述这些胚胎植入相关的信号通路及其研究进展,探讨胚胎着床机制,并为改善妊娠结局提供理论依据。     

Oncogenic role of leptin and Notch interleukin-1 leptin crosstalk outcome in cancer

Obesity is a global pandemic characterized by high levels of body fat (adiposity) and derived-cytokines (i.e., leptin). Research shows that adiposity and leptin provide insight on the link between obesity and cancer progression. Leptin’s main function is to regulate energy balance. However, obese individuals routinely develop leptin resistance, which is the consequence of the breakdown in the signaling mechanism controlling satiety resulting in the accumulation of leptin. Therefore, leptin levels are often chronically elevated in human obesity. Elevated leptin levels are related to higher incidence, increased progression and poor prognosis of several human cancers. In addition to adipose tissue, cancer cells can also secrete leptin and overexpress leptin receptors. Leptin is known to act as a mitogen, inflammatory and pro-angiogenic factor that induces cancer cell proliferation and tumor angiogenesis. Moreover, leptin signaling induces cancer stem cells, which are involved in cancer recurrence and drug resistance. A novel and complex signaling crosstalk between leptin, Notch and interleukin-1 (IL-1) [Notch, IL-1 and leptin crosstalk outcome (NILCO)] seems to be an important driver of leptin-induced oncogenic actions. Leptin and NILCO signaling mediate the activation of cancer stem cells that can affect drug resistance. Thus, leptin and NILCO signaling are key links between obesity and cancer progression. This review presents updated data suggesting that adiposity affects cancer incidence, progression, and response to treatment. Here we show data supporting the oncogenic role of leptin in breast, endometrial, and pancreatic cancers.