瘦素:一种潜在的胃肠道激素

瘦素是体内调节食欲和体重的重要物质，主要由白色脂肪组织分泌，它反映了体内脂肪的贮积量。胃肠道瘦素和瘦素受体的发现，提示瘦素可能作为新的胃肠道激素在调节胃肠道功能中发挥重要的作用。本文简要介绍瘦素的基本生理生化及其与胃肠功能和胃肠道肿瘤的关系。     

瘦素及其信号通路促肝纤维化机制研究进展

多种慢性肝病能导致肝纤维化,肝纤维化是发展为肝硬化的中间阶段。肝星状细胞的激活在肝纤维化的发生发展中起关键作用。在各种炎症刺激下,体内促肝纤维化因子激活其信号转导通路,使肝星状细胞的形态和功能发生变化,引起胶原沉积。瘦素作为一种促肝纤维化因子,通过其信号转导机制在肝纤维化发生发展中发挥重要作用。     

瘦素信号转导系统对卵巢功能的影响

通过卵巢交互移植,构建实验小鼠的瘦素长受体(LR)基因型组合分别为A(躯体LR+,卵巢LR-)、B(躯体LR+,卵巢LR+)、C(躯体LR-,卵巢LR+)、D(躯体LR-,卵巢LR-)共4组(A组n=10、余皆n=5).与A、B组比较,C、D组糖脂代谢水平及卵巢功能各项指标之间均存在显著差异.证实卵巢内存在完整的瘦素信号转导系统;卵巢局部瘦素信号转导缺失并小影响卵巢自身的生殖功能.     

瘦素的信号环路——杰出科学成就奖获奖演说介绍

2010年的美国糖尿病协会(ADA)年会上,Martin G Myers教授获得杰出科学成就奖.会上Myers教授作了题为剖析瘦素:从信号通路到信号环路的演讲.瘦素信号通过脑部细胞调节糖代谢、能量平衡和神经内分泌功能.现对其系统研究的结果作一综述,包括:(1)瘦素受体信号转导的细胞机制及其对能量平衡与糖代谢稳态的作用是什么.(2)瘦素作用于脑的哪种神经元细胞来发挥以上作用.     

瘦素对人脐静脉内皮细胞血管内皮生长因子表达的影响

目的:探讨瘦素对人脐静脉内皮细胞(HUVECs)血管内皮生长因子(VEGF)表达的影响。方法:用不同浓度的瘦素刺激原代培养的HUVECs,检测HUVECs表达VEGF的情况。结果:在相同作用时间下,随着瘦素浓度的升高,VEGF蛋白及VEGF mRNA的表达也随之升高,经统计学检验有相关性;在相同瘦素浓度下, 随着作用时间的延长,VEGF蛋白及VEGFmRNA的表达也随之升高,且有相关性。结论:瘦素可以刺激HU- VECs表达VEGF而且呈时间和剂量相关性。     

SOCS—3与瘦素信号转导的关系

瘦素（leptin）是一种ob基因编码的主要由脂肪细胞分泌的循环激素，与肥胖症之间存在复杂的关系。细胞因子信号转导抑制因子-3(SOCS-3)是新近发现的SOCS家族的主要成因之一，对调节leptin的作用具有重要意义。研究发现，leptin专一地诱导SOCS-3基因的表达，而诱导产生的SOCS-3对leptin的信号转导发挥负反馈抑制作用，因此，SOCS-3可能介导了中枢和外周的leptin抵抗，可能是未来肥胖症基因治疗的新靶点。文中介绍了SOCS-3的分子结构、作用机制及其与leptin信号转导的关系。     

SOCS-3与瘦素信号转导的关系

瘦素 (leptin)是一种ob基因编码的主要由脂肪细胞分泌的循环激素 ,与肥胖症之间存在复杂的关系。细胞因子信号转导抑制因子 3(SOCS 3)是新近发现的SOCS家族的主要成员之一 ,对调节leptin的作用具有重要意义。研究发现 ,leptin专一地诱导SOCS 3基因的表达 ,而诱导产生的SOCS 3对leptin的信号转导发挥负反馈抑制作用 ,因此SOCS 3可能介导了中枢和外周的leptin抵抗 ,可能是未来肥胖症基因治疗的新靶点。文中介绍了SOCS 3的分子结构、作用机制及其与leptin信号转导的关系。     

瘦素及其受体与消化系统肿瘤

瘦素(Leptin)是肥胖基因(Ob)的编码产物,Ob-R是其受体,在体内分布于多种组织器官。Leptin与其受体结合后,通过不同的信号转导途径,具有促进多种细胞增殖与分化的作用,可能与肿瘤相关。近来,学者们对Leptin及其受体与消化系统肿瘤的关系进行了深入的研究。发现Leptin及其受体在某些消化系统肿瘤的发生发展过程中存在一定的作用。     

瘦素、肿瘤坏死因子α与脑梗死

脑梗死发病过程中，与瘦素相互作用，主要通过Jak/STAT信号转导途径，导致瘦素抵抗与胰岛素抵抗，影响胰岛素分泌，血压增高、血脂与血糖代谢紊乱等，促进脑梗死发病。     

老年代谢综合征与瘦素及胰岛素样生长因子-1水平的相关性

目的 探索不同瘦素及(IGF)-1水平对老年代谢综合征(MS)的影响及临床意义.方法 选择2011年1月至2011年12月在该院接受治疗的30例代谢综合征的老年患者为MS组,同期健康体检的35人为对照组.对照分析对照组和MS组一般资料及各生长指标,多元回归分析MS组患者各相关生长指标与瘦素及IGF-1水平相关性.结果 MS组患者体重、BMI、WC、SBP、DBP、FBG、2hPG、FINS、TG、HDL-C、IR及瘦素水平显著高于对照组(P＜0.05),而IGF-1水平显著低于对照组(P＜0.05).瘦素水平与体重、BMI、WC、SBP、DBP、FBG、2 hPG、FINS、TG及IR水平呈正相关,而与HDL-C水平呈负相关(P＜0.05);IGF-1水平与BMI、WC、SBP、FBG、TG、TC及IR测定值呈负相关(P＜0.05).结论老年MS患者瘦素水平显著增加,存在不同程度的瘦素抵抗,且抵抗程度与胰岛素抵抗呈正相关;而IGF-1呈现低水平表达,且与胰岛素抵抗呈明显负相关.以二者为干预老年MS发病的靶点,改善胰岛素抵抗程度,对预防此类人群心血管事件的发生具有重要意义.     

Leptin as a cardiac hypertrophic factor: a potential target for therapeutics

The satiety factor leptin has received extensive attention especially in terms of its potential role in appetite suppression and regulation of energy expenditure. Once considered to be solely derived from adipose tissue, which accounts for the greatly increased levels observed in obese subjects, it is now apparent that leptin can be produced by a multiplicity of tissues, including the heart, where it appears to function in an autocrine and paracrine manner. Plasma leptin concentrations are also elevated in patients with heart disease including those with congestive heart failure. Leptin exerts its biological effects via a family of receptors termed Ob-R. In cardiac cells, one of leptin's primary actions is to produce cardiomyocyte hypertrophy through multifaceted cell signaling mechanisms including stimulation of mitogen-activated protein kinase and activation of the RhoA/Rho kinase (ROCK) pathway. The hypertrophic effect of leptin suggests that it may contribute to myocardial remodeling after cardiac injury and offers the potential targeting of the leptin system as a novel cardiac therapy.     

Salivary Fusobacterium nucleatum serves as a potential diagnostic biomarker for gastric cancer

BACKGROUNDAs one of the most common tumors, gastric cancer (GC) has a high mortality rate, since current examination approaches cannot achieve early diagnosis. Fusobacterium nucleatum (Fn) primarily colonized in the oral cavity, has been reported to be involved in the development of gastrointestinal tumor. Until now, little is known about the relationship between salivary Fn and GC.AIMTo determine whether salivary Fn could be a biomarker to diagnose GC and explore the influence of Fn on GC cells.METHODSThe abundance of Fn in saliva was quantified by droplet digital polymerase chain reaction in 120 GC patients, 31 atrophic gastritis (AG) patients, 35 non-AG (NAG) patients, 26 gastric polyp (GP) patients, and 20 normal controls (NC) from Qilu Hospital of Shandong University from January 2019 to December 2020. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic value of Fn as well as traditional serum tumor markers, including carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19-9, and CA72-4. Transwell assay and wound-healing assay were conducted to assess the influence of Fn infection on GC cells. The expression of epithelial-mesenchymal transition (EMT) markers was detected using western blot assay.RESULTSWe found that the level of salivary Fn in GC patients was significantly increased compared with those in AG, NAG, and GP patients and NC (P < 0.001). ROC curve analysis showed a favorable capability of Fn (73.33% sensitivity; 82.14% specificity; area under the curve: 0.813) in GC diagnosis, which was superior to that of CEA, CA19-9, CA72-4, ferritin, and sialic acid. The Fn level in saliva of GC patients was increased as the TNM stage increased. GC patients with lymph node metastasis had higher Fn levels than those without metastasis. Both transwell and wound-healing assays indicated that Fn infection promoted the migration and invasion of GC cells. Western blot analysis showed that Fn infection decreased the expression of E-cadherin and increased the expressions of N-cadherin, vimentin, and snail.CONCLUSIONFn abundance in saliva could be used as a promising biomarker to diagnose GC, and Fn infection could promote GC metastasis by accelerating the EMT process.     

MicroRNAs as a potential prognostic factor in gastric cancer

AIM:To compare the microRNA (miR) profiles in the primary tumor of patients with recurrent and non-recurrent gastric cancer.METHODS:The study group included 45 patients who underwent curative gastrectomies from 1995 to 2005 without adjuvant or neoadjuvant therapy and for whom adequate tumor content was available.Total RNA was extracted from formalin-fixed paraffin-embedded tumor samples,preserving the small RNA fraction.Initial profiling using miR microarrays was performed to identify potential biomarkers o...     

Epidermal growth factor receptor as a therapeutic target in lung cancer

Almost two decades of research to determine how cancer cells differ from noncancerous cells at the molecular level have been richly rewarding. Several molecular growth factors and receptors have been discovered that play a role in tumor development and are differentially expressed in tumor cells. In this regard, the structure and function of the epidermal growth factor receptor (EGFR) have been characterized. Efforts to develop effective anticancer therapy have targeted this receptor because it is critical to tumor cell proliferation, survival, and invasiveness. Overexpression of EGFR occurs in several epithelial cell tumors, including non-small cell lung cancer (NSCLC). Small-molecular-weight EGFR tyrosine kinase inhibitors and EGFR monoclonal antibodies are among the agents that have demonstrated activity against NSCLC. These compounds, which are designed to selectively target tumor cells, represent a new and novel treatment approach that is being evaluated in NSCLC clinical trials.     

Leptin serves as an upstream activator of an obligatory signaling cascade in the embryo-implantation process

Leptin is essential for mouse reproduction, but the exact roles it serves are yet to be determined. Treatment of cultured endometrial cells with leptin increases the level of beta3-integrin, IL-1, leukemia inhibitory factor, and their corresponding receptors. These leptin-induced effects are eliminated by inhibitors of leptin receptor (OB-R) signaling. Herein the impact of blocking leptin/OB-R signaling in the mouse endometrium was assessed. Intrauterine injection of either leptin peptide antagonists (LPA-1 or -2) or OB-R antibody on d 3 of pregnancy impaired mouse implantation in comparison to intrauterine injection of scrambled peptides (LPA-Sc) or species-matched IgGs. Significant reduction in the number of implantation sites and uterine horns with implanted embryos was found after intrauterine injection of LPA-1 (1 of 22) vs. LPA-1Sc (11 of 15) and LPA-2 (3 of 17) vs. LPA-2Sc (14 of 16). The impact of disruption of leptin signaling on the endometrial expression of several molecules in pregnant mice was assessed by Western blot, immunohistochemistry, and confocal microscopy. Disruption of leptin signaling resulted in a significant reduction of IL-1 receptor type I, leukemia inhibitory factor, vascular endothelial growth factor receptor 2, and beta3-integrin levels. The levels of colony stimulating factor-1 receptor and OB-R were unaltered after treatment with LPAs compared with controls. Expression of OB-R protein was pregnancy dependent and found only in glandular epithelium after implantation occurred. Our findings support previous observations that leptin signaling is critical to the implantation process and suggest that molecules downstream of leptin-activated receptor may serve obligatory roles in endometrial receptivity and successful implantation.     

Focal adhesion kinase serves as a marker of cervical lymph node metastasis and is a potential therapeutic target in tongue cancer

Purpose  

The aims of the present study were to examine whether focal adhesion kinase (FAK) expression is correlated with cervical lymph node metastasis of tongue cancer and to investigate the roles of FAK in the process of cancer cell migration, invasion and anoikis resistance using the human tongue cancer cell line, Tca8113.     

Epidermal growth factor receptor-related protein: a potential therapeutic agent for colorectal cancer

BACKGROUND & AIMS: Epidermal growth factor receptor is frequently implicated in epithelial cancers and is, therefore, being considered as a potential target for therapy. Recently, we reported the isolation and characterization of epidermal growth factor receptor-related protein, a negative regulator of epidermal growth factor receptor. To discern whether epidermal growth factor receptor-related protein could be an effective therapeutic agent for colorectal cancer, we generated epidermal growth factor receptor-related protein fusion protein and studied its effect on the growth of colon cancer cells in vivo and in vitro. We also studied whether epidermal growth factor receptor-related protein expression is altered in colorectal cancer. METHODS: A 55-kilodalton epidermal growth factor receptor-related protein fusion protein with V5 and His tags was generated in a drosophila expression system and subsequently purified by a His antibody affinity column. Rabbit polyclonal antibodies against epidermal growth factor receptor-related protein were used to examine the expression of epidermal growth factor receptor-related protein. RESULTS: Epidermal growth factor receptor-related protein expression was found to be high in benign human colonic epithelium but low in adenocarcinoma. Exposure of the colon cancer cell lines HCT-116 and Caco-2 to purified recombinant epidermal growth factor receptor-related protein caused a marked inhibition of proliferation, as well as attenuation of basal and ligand-induced stimulation of epidermal growth factor receptor phosphorylation. Epidermal growth factor receptor-related protein-induced inhibition of proliferation of colon cancer cells was prevented by epidermal growth factor receptor-related protein antibodies. Reduced epidermal growth factor receptor phosphorylation was partly due to sequestration of epidermal growth factor receptor ligands by epidermal growth factor receptor-related protein, resulting in the formation of inactive heterodimers with epidermal growth factor receptor. Intratumoral or subcutaneous (away from the tumor site) injections of purified epidermal growth factor receptor-related protein caused regression of palpable colon cancer xenograft tumors in some severely compromised immunodeficient mice and arrested tumor growth in others. CONCLUSIONS: We propose that epidermal growth factor receptor-related protein inhibits cellular growth by attenuating epidermal growth factor receptor signaling processes and is an effective therapeutic agent for colorectal cancer.     

The epidermal growth factor receptor as a target for cancer therapy

Epidermal growth factor (EGF) receptors are expressed at high levels in about one third of epithelial cancers, and autocrine activation of EGF receptors appears to be critical for the growth of many tumors. We hypothesized that blockade of the binding sites for EGF and transforming growth factor-alpha on EGF receptors with an antireceptor monoclonal antibody (mAb) might be an effective anti-cancer therapy. We produced murine mAb 225 against EGF receptors and demonstrated blockade of receptor function, as well as inhibition of cell growth in cultures and in nude mouse xenografts. mAb C225 is the human:murine chimeric version of mAb 225. Cell cycle inhibition occurred in G(1) phase, and was due to upregulation of p27(Kip1), resulting in inhibition of cyclin E/cyclin dependent kinase-2 activity and hypophosphorylation of Rb. In addition, the amount and/or activities of a number of proapoptotic molecules were enhanced. The antitumor activity in vivo against xenografts was at least partly attributable to reduced vascularization, resulting from decreased vascular endothelial growth factor and basic fibroblast growth factor production by the tumor cells. Metastasis of xenografts was curtailed with mAB C225 treatment, accompanied by a decrease in tumor production of MMP-9. Further studies showed that mAbs 225 and C225 enhanced the cytotoxicity of chemotherapy against xenografts of a variety of human cancer cell lines. Well established xenografts resistant to either mAb or drug treatment alone were eradicated by the combination therapy. Drugs for which this has been demonstrated include doxorubicin, paclitaxel, cisplatin, and topotecan. Antibody treatment also potentiated the responsiveness of human tumor xenografts to radiation therapy. These findings led to clinical trials of human:murine chimeric mAb C225 in combination with chemotherapy or radiotherapy. Results from phase I and II trials involving more than 500 patients are quite promising, in particular in advanced head and neck cancer treated with C225 plus cisplatin or radiation, in advanced colon cancer treated with C225 plus CPT-11, and in advanced pancreatic cancer treated with C225 plus gemcitabine. Phase III trials are now underway.