Vascular endothelial growth factor/platelet-derived growth factor receptor pathway is involved in bone marrow mesenchymal stem cell differentiation and directional migration toward gliomas

BACKGROUND： Vascular endothelial growth factor （VEGF） induces bone marrow-derived mesenchymal stem cell （BMSC） differentiation into vascular endothelial-like cells and promotes BMSC migration toward gliomas. However, the molecular mechanisms by which VEGF induces BMSC differentiation and migration remain poorly understood. OBJECTIVE; To investigate the role of platelet-derived growth factor （PDGF） receptor （PDGFR） in BMSC differentiation and migration induced by VEGE DESIGN, TIME AND SETTING： A parallel, controlled, in vitro experiment was performed at the Molecular Neurobiology ＆ Neural Regeneration and Repairing Laboratory, Anhui Provincial Hospital of Anhui Medical University, China from June 2008 to March 2009. MATERIALS： U87 glioma cells were purchased from Shanghai Institutes for Biological Sciences; mouse anti-human PDGFR and VEGF receptor （VEGFR） monoclonal antibodies were purchased from Peprotech, USA. METHODS： Isolated BMSCs were precultured with neutralizing antibody for VEGFR-1, VEGFR-2, PDGFR-α, and PDGFR-β to block biological activity of related receptors, followed by induced differentiation with 50μg/L VEGF. BMSCs induced with 50μg/L VEGF alone served as the VEGF-induced group. The control group remained untreated. MAIN OUTCOME MEASURES： Cell surface markers were identified by flow cytometry; BMSC surface cytokine receptor expression was detected by reverse transcription-polymerase chain reaction; the Transwell model was used to observe cell migration. RESULTS： After blocking the PDGFR, VEGF did not induce BMSC cell surface marker CD-31 or von Willebrand factor （vWF） expression. However, inhibition with VEGF receptor blocking agents, VEGF induced BMSCs to express CD-31 and vWE Following inhibition of the PDGFR, the number of cells migrating through the polycarbonate membrane Transwell chamber was decreased, as well as the number of BMSCs migrating to glioma cells. However, through the use of VEGF receptor blocking agents, the number of migrating cells remained unchanged. VEGF preculture increased the number of BMSCs migrating to gliomas. CONCLUSION： VEGF interacts with PDGFRs on the BMSC surface to attract BMSC directional migration and induce BMSC differentiation. The VEGF/PDGFR pathway participates in BMSC directional migration to glioma. VEGF pretreatment increased efficiency of BMSC migration to glioma.

Implication of platelet-derived growth factor receptor alpha in prostate cancer skeletal metastasis

Metastasis represents by far the most feared complication of prostate carcinoma and is the main cause of death for patients.The skeleton is frequently targeted by disseminated cancer cells and represents the sole site of spread in more than 80% of prostate cancer cases.Compatibility between select malignant phenotypes and the microenvironment of colonized tissues is broadly recognized as the culprit for the organ-tropism of cancer cells.Here,we review our recent studies showing that the expression of platelet-derived growth factor receptor alpha(PDGFR a) supports the survival and growth of prostate cancer cells in the skeleton and that the soluble fraction of bone marrow activates PDGFR a in a ligand-independent fashion.Finally,we offer pre-clinical evidence that this receptor is a viable target for therapy.

Deficiency of platelet-derived growth factor receptor-α-positive cells in Hirschsprung's disease colon

AIM: To investigate whether the expression of platelet-derived growth factor receptor-α-positive (PDGFRα+)-cells is altered in Hirschsprung’s disease (HD).METHODS: HD tissue specimens (n = 10) were collected at the time of pull-through surgery, while colonic control samples were obtained at the time of colostomy closure in patients with imperforate anus (n = 10). Immunolabelling of PDGFRα+-cells was visualized using confocal microscopy to assess the distribution of these cells, while Western blot analysis was undertaken to quantify PDGFRα protein expression.RESULTS: Confocal microscopy revealed PDGFRα+-cells within the mucosa, myenteric plexus and smooth muscle in normal controls, with a marked reduction in PDGFRα+-cells in the HD specimens. Western blotting revealed high levels of PDGFRα protein expression in normal controls, while there was a striking decrease in PDGFRα protein expression in the HD colon.CONCLUSION: These findings suggest that the altered distribution of PDGFRα+-cells in both the aganglionic and ganglionic HD bowel may contribute to the motility dysfunction in HD.

KIT and platelet-derived growth factor receptor α wild-type gastrointestinal stromal tumor associated with neurofibromatosis type 1: Two case reports

BACKGROUND Gastrointestinal stromal tumors(GISTs) associated with neurofibromatosis are uncommon compared to their gastrointestinal counterparts. Patients with neurofibromatosis type 1(NF-1) have an increased risk of developing gastrointestinal tumors, including rare types such as GIST.CASE SUMMARY A 60-year-old male Chinese patient was diagnosed with NF-1 10 years ago and presented with upper abdominal discomfort and black stools. Endoscopic ultrasonography and an enhanced abdominal computed tomography scan revealed a mass located 4 cm from the muscular layer of the descending duodenum. A 59-year-old Chinese woman who was diagnosed with NF-1 25 years ago presented with sudden unconsciousness and black stools. Multiple masses in the duodenum were noted by echogastroscopy and an enhanced abdominal computed tomography scan. Both patients presented with cutaneous neurofibromas. The histologic examination of tumors from both patients revealed spindle cells and low mitotic activity. Immunohistochemically, the tumor cells showed strong positivity for KIT(CD117), DOG-1, CD34, and Dehydrogenase Complex Subunit B, and negativity for SMA, desmin, S-100, and β-catenin. None of the six tumors from two patients had KIT exon 9, 11, 13, or 17 or platelet-derived growth factor receptor α exon 12 or 18 mutation, which is a typical finding for sporadic GISTs. None of the six tumors from the two patients had a BRAFV600 E mutation. The patients were alive and well during the follow-up period(range:0.6-5 yr).CONCLUSION There have been only a few previous reports of GISTs associated with NF-1.Although GISTs associated with NF-1 have morphologic and immunohistochemical similarities with GISTs, the pathogenesis, incidence,genetic background, and prognosis are not completely known. A medical history of NF-1 in a patient who has gastrointestinal bleeding or anemia and an intraabdominal mass with nonspecific computed tomography features may help in diagnosing GIST by virtue of the well-known association of these two entities.Molecular genetic studies of cases indicated that GISTs in NF-1 patients have a different pathogenesis than sporadic GISTs.

Distribution of platelet-derived growth factor-alpha receptor expressing oligodendrocyte precursor cells in the adult rat brain

BACKGROUND： Studies have demonstrated that NG2-positive glial cells in the adult rats are predominantly located in the gray and white matter of the cerebral cortex and hippocampus. Platelet-derived growth factor-a receptor （PDGF-αR） cells are a subset of oligodendrocytes, which are not as mature as NG2-positive cells. Distribution and migration of PDGF-αR-positive cells in the rat brain remain poorly understood. OBJECTIVE： Using immunohistochemical methods, the distribution of oligodendrocyte precursor cells （PDGF-αR-positive） was analyzed in the adult rat brain. DESIGN, TIME AND SETTING： Immunohistochemical study was performed at the Department of Histology and Embryology of the Third Military Medical University from September 2007 to September 2008. MATERIALS： Rabbit anti-PDGF-αR polyclonal antibody was purchased from Santa Cruz Biotechnology, USA. Streptomycin-avidin-biotin complex immunohistochemistry kit was purchased from Zhongshan Goldenbridge Biotechnology, China. METHODS： Whole brains from 5 healthy, adult, Wistar rats were collected for immunohistochemistry, and the mean value of PDGF-αR-expressing cells was quantified. The absolute values were translated to ranked data of high, moderate, and low grades （high grade： 10 positive cells; moderate grade： 5-9 cells; low grade： 〈 5 cells in a 400 × visual field）. Based on the number of cell processes and branches, as well as the number of PDGF-αR-positive cells, in different regions, the cells were classified into three categories, i.e., type Ⅰ-Ⅲ. From type I to type Ill, the number of processes gradually increased. MAIN OUTCOME MEARSURES： The number and distribution of PDGF-αR-positive cells in different brain regions of adult rats. RESULTS： PDGF-αR-positive cells were located in the forebrain and midbrain, but not in the cerebellum or brainstem. In the olfactory bulb and hippocampus, a total of 60% PDGF-αR-positive cells were type Ⅰ and these cells were not mature as others. In the cerebral cortex, olfactory system, hippocampus, and optic chiasma, where neuronal bodies aggregated, approximately 40% of the PDGF-αR-positive cells were type Ⅱ, with few type Ⅲ cells. In the white matter, corpus callosum, basal nucleus, and thalamus, PDGF-αR-positive cell density was moderate. In the olfactory bulb and hippocampus, PDGF-αR-positive cell density was high. PDGF-αR-positive cells were not observed in the cerebellum or brainstem CONCLUSION： PDGF-αR-positive cells were aggregated in the olfactory bulb and hippocampus in the adult, rat brain, but few cells were detected in the cerebellum and brainstem.

Effects of (-)-Epigallocatechin gallate on some protein factors involved in the epidermal growth factor receptor signaling pathway

（-）-Epigallocatechin gallate （EGCG）, a major polyphenolic constituent of green tea, can inhibit activity of specific receptor tyrosine kinases （RTKs） and related downstream signal transduction pathways, resulting in the control of unwanted cell proliferation. The epidermal growth factor receptor （EGFR） signaling pathway is one of the most important pathways that regulates growth, survival,proliferation and differentiation in mammalian cells. This review addresses the effects of EGCG on some protein factors involved in the EGFR signaling pathway in a direct or indirect manner. Based on our understanding of the interaction between EGCG and these factors, and based on their structures, EGCG could be used as a lead compound for designing and synthesizing novel drugs with significant biological activity.

Expression of NG2 and platelet-derived growth factor receptor alpha in the developing neonatal rat brain

Platelet-derived growth factor receptor alpha （PDGFRct） is a marker of oligodendrocyte precursor cells in the central nervous system. NG2 is also considered a marker of oligodendrocyte precursor cells. However, whether there are differences in the distribution and morphol- ogy of oligodendrocyte precursor cells labeled by NG2 or PDGFRa in the developing neonatal rat brain remains unclear. In this study, by immunohistochemical staining, NG2 positive （NG2＋） cells were ubiquitous in the molecular layer, external pyramidal layer, internal pyramidal layer, and polymorphic layer of the cerebral cortex, and corpus callosum, external capsule, piriform cortex, and medial septal nucleus. NG2~ cells were stellate or fusiform in shape with long processes that were progressively decreased and shortened over the course of brain development. The distribution and morphology of PDGFRct positive （PDGFRa＋） cells were coincident with NG2＋ cells. The co- localization of NG2 and PDGFRu in the cell bodies and processes of some cells was confirmed by double immunofluorescence labeling. Moreover, cells double-labeled for NG2 and PDGFRa were predominantly in the early postnatal stage of development. The numbers of NG2＋/PDGFRa＋ cells and PDGFRa＋ cells decreased, but the number of NG2＋ cells increased from postnatal days 3 to 14 in the developing brain. In addition, amoeboid microglial cells of the corpus callosum, newborn brain macrophages in the normal developing brain, did not express NG2 or PDGFRu, but NG2 expression was detected in amoeboid microglia after hypoxia. The present results suggest that NG2 and PDGFRct are specific markers of oligodendrocyte precursor cells at different stages during early development. Additionally, the NG2 protein is involved in inflammatory and pathological processes of amoeboid microglial cells.

Dihydroergotamine ameliorates liver fibrosis by targeting transforming growth factor β type Ⅱ receptor

BACKGROUND The transforming growth factor β(TGFβ) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFβ type Ⅱ receptor(TGFβR2), followed by the recruitment of TGFβR1 finally triggering downstream signaling pathway.AIM To find drugs targeting TGFβR2 that inhibit TGFβR1/TGFβR2 complex formation, theoretically inhibit TGFβ signaling pathway, and thereby ameliorate liver fibrosis.METHODS Food and Drug Administration-approved drugs were screened for binding affinity with TGFβR2 by virtual molecular docking. We identified 6 candidates and further explored their potential by Cell Counting Kit-8(CCK-8) cell cytotoxic experiment to validate toxicity and titrated the best cellular working concentrations. Next, we further demonstrated the detailed molecular working mechanisms using mutagenesis analysis. Finally, we used a mouse model to investigate its potential anti-liver fibrosis effect.RESULTS We identified 6 drug candidates. Among these 6 drugs, dihydroergotamine(DHE) shows great ability in reducing fibrotic gene expressions such as collagen, p-SMAD3, and α-SMA in TGFβ induced cellular model of liver fibrosis in LX-2 cells. Furthermore, we demonstrated that DHE binds to TGFβR2. Moreover, mutation of Leu27, Phe30, Thr51, Ser52, Ile53, and Glu55 of TGFβR2 disrupted the binding of TGFβR2 with DHE. In addition, DHE significantly improved liver fibrosis, as evidenced by Masson’s trichrome staining of liver sections. This is further supported by the width and the velocity of the portal vein, and serum markers of liver function. In line with those observations, DHE also decreased macrophages infiltration and extracellular matrix deposition in the liver.CONCLUSION DHE alleviates liver fibrosis by binding to TGFβR2 thereby suppressing TGFβ signaling pathway. We show here that as far as drug repurposing, DHE has great potential to treat liver fibrosis.

Fibroblast growth factor receptor signaling as therapeutic targets in gastric cancer

Fibroblast growth factor receptors(FGFRs) regulate a variety of cellular functions, from embryogenesis to adult tissue homeostasis. FGFR signaling also plays significant roles in the proliferation, invasion, and survival of several types of tumor cells. FGFR-induced alterations, including gene amplification, chromosomal translocation, and mutations, have been shown to be associated with the tumor initiation and progression of gastric cancer, especially in diffuse-type cancers. Therefore, the FGFR signaling pathway might be one of the therapeutic targets in gastric cancer. This review aims to provide an overview of the role of FGFR signaling in tumorigenesis, tumor progression, proliferation, and chemoresistance. We also discuss the accumulating evidence that demonstrates the effectiveness of using clinical therapeutic agents to inhibit FGFR signaling for the treatment of gastric cancer.

Impaired pericyte-Müller glia interaction via PDGFRβsuppression aggravates photoreceptor loss in a rodent model of light-induced retinal injury

AIM:To investigate the involvement of pericyte-Müller glia interaction in retinal damage repair and assess the influence of suppressing the platelet-derived growth factor receptorβ(PDGFRβ)signaling pathway in retinal pericytes on photoreceptor loss and Müller glial response.METHODS:Sprague-Dawley rats were exposed to intense light to induce retinal injury.Neutralizing antibody against PDGFRβwere deployed to block the signaling pathway in retinal pericytes through intravitreal injection.Retinal histology and Müller glial reaction were assessed following light injury.In vitro,normal and PDGFRβ-blocked retinal pericytes were cocultured with Müller cell line(rMC-1)to examine morphological and protein expression changes upon supplementation with light-injured supernatants of homogenized retinas(SHRs).RESULTS:PDGFRβblockage 24h prior to intense light exposure resulted in a significant exacerbation of photoreceptor loss.The upregulation of GFAP and p-STAT3,observed after intense light exposure,was significantly inhibited in the PDGFRβblockage group.Fur ther upregulation of cytokines monocyte chemoattractant protein 1(MCP-1)and interleukin-1β(IL-1β)was also observed following PDGFRβinhibition.In the in vitro coculture system,the addition of light-injured SHRs induced pericyte deformation and upregulation of proliferating cell nuclear antigen(PCNA)expression,while Müller cells exhibited neuron-like morphology and expressed Nestin.However,PDGFRβblockage in retinal pericytes abolished these cellular responses to light-induced damage,consistent with the in vivo PDGFRβblockage findings.CONCLUSION:Pericyte-Müller glia interaction plays a potential role in the endogenous repair process of retinal injury.Impairment of this interaction exacerbates photoreceptor degeneration in light-induced retinal injury.

Effects of ribozyme targeting platelet-derived growth factor receptor β subunit gene on the proliferation and apoptosis of hepatic stellate cells in vitro

Background Activation and proliferation of hepatic stellate cells (HSC) is essentially involved in the development and progression of hepatic fibrosis. The most potent growth factor for HSC is platelet-derived growth factor receptor (PDGF) and PDGF receptor β subunit (PDGFR-β) is the predominant signal transduction pathyway of PDGF which is overexpressed in activated HSC. This study investigated the cleavage activity of hammerhead ribozyme targeting PDGFR-β mRNA in HSC and the effect on biological characteristics of HSC.Methods Expression vector of anti-PDGFR-β ribozyme was constructed and transfected into rat activated HSC with lipofectamin. The positive cell clones were gained by G418 selection. The expression of PDGFR-β, α-smooth muscle actin, and typeⅠand type Ⅲ collagen were detected by using Northern blot, Western blot and immunocytochemical staining, respectively. The cell proliferation was determined with MTT colorimetric assay. The cell apoptosis was analyzed by using flow cytometry, acridine orange fluorescence vital staining and transmission electron microscopy.Results The expression of PDGFR-β at mRNA and protein level was markedly reduced in ribozyme-transfected HSC by 49%-57% ( P <0.05-0.01). The proliferation and α-smooth muscle actin expression of ribozyme-transfected HSC were significantly decreased ( P <0.05-0.01), and the type Ⅰ and type Ⅲ collagen synthesis were also reduced ( P <0.01). In addition, the proliferative response of ribozyme-transfected HSC to PDGF BB was significantly inhibited. Otherwise, the apoptotic cells were significantly increased in ribozyme-transfected HSC ( P <0.01), and typical apoptotic cells could be found under transmission electron microscopy.Conclusions The anti-PDGFR-β ribozyme effectively cleaved the target RNA and significantly inhibited its expression, which blocked the signal transduction of PDGF at receptor level, inhibited HSC proliferation and collagen synthesis, and induced HSC apoptosis. These results suggest that inhibiting PDGFR-β expression of HSC may be a new target for the therapy of liver fibrogenesis, and ribozyme may be a useful tool for inhibiting PDGFR-β expression.

PDGFR-β/TGF-β/Smad2/3信号通路调控阿尔茨海默病血脑屏障完整性和学习记忆能力的分子机制研究

目的:分析PDGFR-β/TGF-β/Smad2/3信号通路调控阿尔茨海默病(AD)血脑屏障(BBB)完整性和学习记忆能力的分子机制。方法:利用APP/PS1转基因AD小鼠模型,通过水迷路及觅食试验分析学习记忆能力;荧光免疫组织化学法检测海马区血管周细胞增殖率(ki67/desmin)、周细胞覆盖率(desmin/lectin);Western blot检测海马区血管周细胞TGF-βR1及其下游信号通路分子、紧密连接(TJs)蛋白的表达水平。经过外源性PDGF-BB脑室内注射和/或TGF-βR1激酶抑制剂SB431542腹腔内注射预处理后,分别进行上述分析。构建AD体外BBB模型,经过PDGF-BB和/或SB431542作用后,进行异硫氰酸荧光素-牛血清白蛋白(FITC-BSA)渗透性和跨细胞电阻检测。结果:与对照组相比,APP/PS1小鼠经过虚拟平台次数明显减少,达到终点所需时间明显延长(水迷路训练试验),投食区正确选择率明显下降(觅食训练试验);海马区desmin/lectin阳性细胞比例明显下降;TGF-βR1、p-Smad2、p-Smad3蛋白表达水平明显升高;TJs蛋白表达水平明显下降。外源性PDGF-BB可使APP/PS1小鼠经过虚拟平台次数明显增加、达到终点所需时间明显缩短(水迷路正式试验第28天)、投食区正确选择率明显提高(觅食正式试验第28天);海马区desmin/lectin阳性细胞比例明显增加;使TGF-βR1、p-Smad2、p-Smad3蛋白表达水平明显升高;使TJs蛋白表达水平明显升高。SB431542则可部分抑制上述作用。体外试验证明:外源性PDGF-BB可明显降低AD模型组的最终渗透系数,提高24 h时相对TEER值;SB431542则可部分抑制上述作用。结论:PDGFR-β/TGF-β/Smad2/3信号通路可通过诱导周细胞分化、覆盖,提高内皮细胞TJs的表达,调控AD血脑屏障完整性,以促进学习记忆能力恢复。

延胡索乙素改善PDGF-BB诱导的VSMCs氧化应激损伤的机制

目的研究延胡索乙素(Thp)对血小板衍生生长因子-BB(PDGF-BB)诱导的大鼠主动脉血管平滑肌细胞(VSMCs)氧化应激损伤的保护作用,并基于核因子红系2相关因子2(Nrf2)/血红素加氧酶1(HO-1)信号通路探究其可能机制。方法在Thp抑制PDGF-BB诱导的VSMCs氧化应激损伤效应研究中,将VSMCs分为对照组、PDGF-BB组(25 ng/mL)及Thp低、中、高浓度组(5、10、20 mg/mL)。在Thp作用机制研究(沉默Nrf2)中,将VSMCs分为PDGF-BB+阴性对照siRNA(NC-siNrf2)组(25 ng/mL PDGFBB+NC-siNrf2),PDGF-BB+Thp+NC-siNrf2组(25 ng/mL PDGF-BB+10 mg/mL Thp+NC-siNrf2),PDGF-BB+Nrf2小干扰RNA(siNrf2)组(25 ng/mL PDGF-BB+siNrf2),PDGF-BB+Thp+siNrf2组(25 ng/mL PDGF-BB+10.0 mg/mL Thp+siNrf2)。2个实验均检测VSMCs的增殖、迁移能力,活性氧(ROS)水平,超氧化物歧化酶(SOD)和过氧化氢酶(CAT)活性以及Nrf2和HO-1蛋白表达。结果与对照组比较,PDGF-BB组VSMCs的增殖、迁移能力显著增强(P<0.01),ROS水平显著升高(P<0.01),SOD、CAT活性及Nrf2、HO-1蛋白的相对表达量均显著降低(P<0.01);与PDGF-BB组比较,Thp不同浓度组VSMCs的增殖、迁移能力均显著下降(P<0.01),ROS水平均显著降低(P<0.01),SOD、CAT活性及Nrf2、HO-1蛋白的相对表达量均显著升高(P<0.01)。沉默Nrf2可显著逆转Thp对PDGF-BB诱导VSMCs氧化应激损伤的改善作用(P<0.01)。结论Thp可以通过激活Nrf2介导的抗氧化防御途径来降低VSMCs的氧化应激水平,从而抑制VSMCs的增殖、迁移。

电针通过PLC/IP3通路改善功能性消化不良大鼠胃肠动力障碍

目的确定电针是否调节了血小板衍生生长因子受体α阳性(PDGFRα+)细胞中磷脂酶C(PLC)/肌醇-1,4,5-三磷酸酯(PLC/IP3)通路,从而改善功能性消化不良(FD)胃肠动力障碍。方法将40只SD大鼠随机分为5组:空白组、模型组、电针组、U73122(PLC抑制剂)组、U73122+电针组,每组8只。除空白组外所有大鼠采用多因素应激干预法建立FD大鼠模型。造模成功后,U73122组予以腹腔注射抑制剂,电针组取足三里和太冲穴,U73122+电针组在针刺前2 h注射抑制剂。10 d后行胃肠动力学检测;采用免疫印迹法检测PDGFRα、PLC、P-PLC、IP3的蛋白表达水平;用免疫荧光检测PDGFRα和PLC、IP3的平均荧光密度和共定位表达情况;电子显微镜观察胃窦区域缝隙连接(GJ)情况。结果造模后大鼠胃肠动力减弱,PDGFRα、PLC和IP3的蛋白表达水平显著降低,GJ增宽,细胞形态改变;与模型组比较,电针组、U73122组和U73122+电针组大鼠胃肠动力显著改善,胃窦PDGFRα、PLC、P-PLC、IP3表达水平上升,GJ稍紧密,细胞形态恢复;U73122组和U73122+电针组胃窦PDGFRα、PLC、P-PLC、IP3表达水平无明显差异;PDGFRα与PLC和IP3存在荧光共定位。结论电针通过激活PDGFRα+细胞中的PLC/IP3通路改善FD大鼠的胃肠动力障碍。

Inducing effects of hepatocyte growth factor on the expression of vascular endothelial growth factor in human colorectal carcinoma cells through MEK and PI3K signaling pathways

Background Vascular endothelial growth factor plays a key role in human colorectal carcinoma invasion and metastasis. However, the regulation mechanism remains unknown. Recent studies have shown that several cytokines can regulate the expression of vascular endothelial growth factor in tumor cells. In this study, we investigated whether hepatocyte growth factor can regulate the expression of vascular endothelial growth factor in colorectal carcinoma cells. Methods Hepatocyte growth factor and vascular endothelial growth factor in human serum were measured by ELISA. The mRNA level of vascular endothelial growth factor was analyzed by reverse transcription-PCR. Western blot assay was performed to evaluate levels of c-Met and several other proteins involved in the MAPK and PI3K signaling pathways in colorectal carcinoma cells. Results Serum hepatocyte growth factor and vascular endothelial growth factor were significantly increased in colorectal carcinoma subjects. In vitro extraneous hepatocyte growth factor markedly increased protein and mRNA levels of vascular endothelial growth factor in colorectal carcinoma cells. Hepatocyte growth factor induced phosphorylation of c-Met, ERK1/2 and AKT in a dose-dependent manner. Specific inhibitors on MEK and PI3K inhibited the hepatocyte growth factor-induced expression of vascular endothelial growth factor in colorectal carcinoma cells.Conclusion This present study indicates that hepatocyte growth factor upregulates the expression of vascular endothelial arowth factor in colorectal carcinoma cells via the MEK/ERK and PI3K/AKT sianalina Pathways.

Targeting key signalling pathways in oesophageal adenocarcinoma:A reality for personalised medicine?

Cancer treatments are rapidly changing.Curative treatment for oesophageal adenocarcinoma currently involves surgery and cytotoxic chemotherapy or chemoradiotherapy.Outcomes for both regimes are generally poor as a result of tumor recurrence.We have reviewed the key signalling pathways associated with oesophageal adenocarcinomas and discussed the recent trials of novel agents that attempt to target these pathways.There are many trials underway with the aim of improving survival in oesophageal cancer.Currently,phase 2 and 3 trials are focused on MAP kinase inhibition,either through inhibition of growth factor receptors or signal transducer proteins.In order to avoid tumor resistance,it appears to be clear that targeted therapy will be needed to combat the multiple signalling pathways that are in operation in oesophageal adenocarcinomas.This may be achievable in the future with the advent of gene signatures and a combinatorial approach.

Regulation of the EGFR pathway by visfatin and its effect on cardiac hypertrophy

Objective:To investigate the regulation of the epidermal growth factor receptor(EGFR)pathway by visfatin and its effect on cardiac hypertrophy.Methods:60 Wistar male rats were randomly divided into control group,visfatin group and visfatin+AG1478 group,with 20 rats in each group.The cardiac mass index,left ventricular mass index and cardiomyocyte volume of rats in each group were calculated.The total protein content of each group of cardiomyocytes was detected by coomassie bright blue staining,and the protein expression was detected by Western blotting.Results:Compared with the control group,the cardiac mass index,left ventricular mass index,cardiomyocyte volume,protein content,and relative expressions of ANP and BNP were significantly increased in the visfatin group(P<0.05).The relative expression levels of EGFR,p-AKT,p-ERK1/2,p-STAT3,ANP and BNP in cardiac myocytes in the visfatin group were significantly higher than those in the control group and the visfatin+AG1478 group(P<0.05).Conclusion:Visfatin induces hypertrophy in cardiomyocytes by activating the EGFR signaling pathway.

脑脊液可溶性血小板衍生生长因子受体β浓度与动脉瘤性蛛网膜下腔出血病人认知功能损害的关系

目的探讨脑脊液可溶性血小板衍生生长因子受体β(sPDGFRβ)浓度与动脉瘤性蛛网膜下腔出血(aSAH)病人认知功能损害的关系。方法前瞻性收集55例aSAH病人发病72小时内的脑脊液标本和20例因其他神经疾病需行脑脊液检查的对照组脑脊液标本,采用ELISA检测脑脊液中sPDGFRβ的浓度。出院6个月后对aSAH病人进行随访,使用简易智能精神状态检查量表(MMSE)或修订版认知功能电话问卷(TICS-m)评估认知功能。结果aSAH组脑脊液中sPDGFRβ浓度为(1.076±0.353)ng/ml,对照组为(0.574±0.057)ng/ml,两组比较,差异有统计学意义(P<0.05);55例aSAH病人中,19例发生了认知功能损害,有认知障碍的病人早期脑脊液中的sPDGFRβ浓度[(1.387±0.280)ng/ml]高于无认知障碍者[(0.911±0.268)ng/ml],两组比较差异有统计学意义(P<0.05);多因素Logistic回归分析显示,Hunt-Hess分级Ⅳ~Ⅴ级、sPDGFRβ≥1.347 ng/ml是aSAH病人出院6个月后发生认知障碍的独立危险因素(P<0.01)。结论aSAH发生后,脑脊液sPDGFRβ浓度升高,且与病人发生认知功能损害有关。

切除修复交叉互补基因1血管内皮生长因子受体-3血小板衍生生长因子受体B在胃癌中的表达及意义

目的分析切除修复交叉互补基因1(ERCC1)、血管内皮生长因子受体-3(VEGFR3)、血小板衍生生长因子受体B(PDGFRB)在胃癌中的表达及意义。方法选取2019年6月至2021年6月河南科技大学第一附属医院病理科归档资料齐全完整的52例胃癌组织石蜡标本和距离癌组织边缘5cm的癌旁组织石蜡标本,采用免疫组织化学、实时荧光定量法检测ERCC1、VEGFR3、PDGFRB表达,分析ERCC1、VEGFR3、PDGFRB在胃癌中的表达变化及三者相关性。结果与癌旁组织相比,癌组织中ERCC1、VEGFR3、PDGFRB表达量升高,差异具有统计学意义(P<0.05)。ERCC1、VEGFR3、PDGFRB表达与胃癌患者的性别、年龄、肿瘤长径无关,与TNM分期、分化程度、淋巴结转移、浸润深度、病理类型相关,Ⅲ期、Ⅳ期、中低分化、有淋巴结转移、≥1/2肌层浸润、肠型胃癌患者ERCC1、VEGFR3、PDGFRB表达升高,差异具有统计学意义(P<0.05)。ERCC1、VEGFR3、PDGFRB之间Pearson相关性分析显示,ERCC1与VEGFR3之间正相关(r=0.572,P=0.001);ERCC1与PDGFRB之间正相关(r=0.617,P=0.001);VEGFR3与PDGFRB之间正相关(r=0.569,P=0.001)。ROC曲线显示,与ERCC1、VEGFR3、PDGFRB单项诊断相比,三项联合对胃癌的诊断价值较高(P<0.05)。结论ERCC1、VEGFR3、PDGFRB在胃癌组织中表达升高,并随着淋巴结的转移,ERCC1、VEGFR3、PDGFRB表达升高,参与疾病的发展。

新生血管性年龄相关性黄斑变性治疗的研究进展

年龄相关性黄斑变性(AMD)是一种中心性视力不可逆性丧失的疾病。血管内皮生长因子(VEGF)是新生血管性AMD(nAMD)发病的重要因素,目前抗VEGF治疗仍是临床一线治疗方案。尽管抗VEGF治疗在一定程度上能够减缓疾病进展和视力丧失,但患者仍需要频繁玻璃体腔注射,长期治疗效果并不理想。因此,为改善疗效,针对传统抗VEGF治疗的替代方案相继出现,如新型抗VEGF药物、基因治疗、血小板衍生生长因子抑制剂、血管生成素/Tie信号通路药物、新型药物缓释系统等。随着研究的深入,相信会有更多的延长型及多靶点药物可供nAMD患者选择。