查找使用阿拉丁产品的科研文献

The Biological-Behavioral Effect Of Neuritin On Non-Small Cell Lung Cancer Vascular Endothelial Cells Via VEGFR And Notch1

Qiao Zhang,Juan Zhang,Jian Zhang,Patiguli Aerxiding,Amina Quhai,Cuncun Chen,Li Shan

Purpose This study aims to elucidate the biological behavior of Neuritin abnormal expression in pulmonary vascular endothelial cells (VECs) of non-small cell lung cancer (NSCLC), and explore its possible underlying mechanisms. Patients and methods Primary NSCLC-VECs were isolated from 10 cancer tissues from NSCLC patients, purified and identified by CD34 and Factor VIII staining. Real-time PCR and Western-blot were adopted for detecting the expression levels of Neuritin, Notch1, and VEGFR in NSCLC-VECs and HPMECs. Neuritin-overexpression, Neuritin-knockdown NSCLC-VECs and HPMECs were constructed by transfection of pcDNA3, 1-Neuritin vector, and pBS/U6-Neuritin siRNA. Changes in cell proliferation, migration, cell cycle, and apoptosis were determined by using the MTT assay, scratch assay, transwell migration assay, and flow cytometry, respectively. Post-transfection changes in cell morphology were examined by scanning electron microscopy. Results The expression of Neuritin in NSCLC-VECs was significantly higher compared to that in HPMECs (p<0.01). Overexpression of Neuritin increased the expression of VEGFR while it reduced the expression of Notch1 (p<0.01); it also promoted cell proliferation, scratch healing, and in vitro migration (p<0.05) in HPMECs and NSCLC-VECs cells. Additionally, overexpression of Neuritin stimulated cell cycle progression and inhibited apoptosis in HPMECs and NSCLC-VECs (p<0.001). Under electron microscope, the pseudopodium of cell surface was obvious, indicating that the intercellular adhesion was upregulated. However, knockdown of Neuritin in HPMECs and NSCLC-VECs played exactly the opposite roles. Conclusion Neuritin was key in the progression of NSCLC through its biological activities, including anti-apoptosis, promoting VEC proliferation, migration, and cell cycle progression. Neuritin may affect its biological activity by positively regulating VEGFR expression and negatively regulating Notch1 signaling. Neuritin may serve as a potential biomarker for NSCLC.

Targeted Alpha Therapy of Glioma Using 211At-Labeled Heterodimeric Peptide Targeting Both VEGFR and Integrins

Weihao Liu,Huan Ma,Ranxi Liang,Xijian Chen,Hongyan Li,Tu Lan,Jijun Yang,Jiali Liao,Zhi Qin,Yuanyou Yang,Ning Liu,Feize Li

Targeted radionuclide therapy based on α-emitters plays an increasingly important role in cancer treatment. In this study, we proposed to apply a heterodimeric peptide (iRGD-C6-lys-C6-DA7R) targeting both VEGFR and integrins as a new vector for 211At radiolabeling to obtain high-performance radiopharmaceuticals with potential in targeted alpha therapy (TAT). An astatinated peptide, iRGD-C6-lys(211At-ATE)-C6-DA7R, was prepared with a radiochemical yield of ∼45% and high radiochemical purity of >95% via an electrophilic radioastatodestannylation reaction. iRGD-C6-lys(211At-ATE)-C6-DA7R showed good stability in vitro and high binding ability to U87MG (glioma) cells. Systematic in vitro antitumor investigations involving cytotoxicity, apoptosis, distribution of the cell cycle, and reactive oxygen species (ROS) clearly demonstrated that 211At-labeled heterodimeric peptides could significantly inhibit cell viability, induce cell apoptosis, arrest the cell cycle in G2/M phase, and increase intracellular ROS levels in a dose-dependent manner. Biodistribution revealed that iRGD-C6-lys(211At-ATE)-C6-DA7R had rapid tumor accumulation and fast normal tissue/organ clearance, which was mainly excreted through the kidneys. Moreover, in vivo therapeutic evaluation indicated that iRGD-C6-lys(211At-ATE)-C6-DA7R was able to obviously inhibit tumor growth and prolong the survival of mice bearing glioma xenografts without notable toxicity to normal organs. All these results suggest that TAT mediated by iRGD-C6-lys(211At-ATE)-C6-DA7R can provide an effective and promising strategy for the treatment of glioma and some other tumors.

Fenofibrate inhibits the expression of VEGFC and VEGFR-3 in retinal pigmental epithelial cells exposed to hypoxia

Jianfeng Zhao,Yu Geng,Hairong Hua,Biyun Cun,Qianbo Chen,Xiaoting Xi,Liushu Yang,Yan Li

The aim of the present study was to examine the mechanisms through which fenofibrate inhibits the ability of human retinal pigment epithelial cells (RPE cells) exposed to hypoxia to stimulate the proliferation and migration of human umbilical vein endothelial cells (HUVECs). For this purpose, RPE cells and HUVECs were divided into the following groups: RPE-normoxia, RPE + fenofibrate, RPE-hypoxia, RPE hypoxia + fenofibrate; HUVECs normal culture and HUVECs + RPE-hypoxia culture supernatant. RPE cell hypoxia was induced by cobalt(II) chloride (CoCl2). A superoxide anion probe was used to measure the production of superoxide anion, which is indicative of hypoxic conditions. Cell proliferation was assessed by MTT assay, and the expression of vascular endothelial growth factor C (VEGFC) and vascular endothelial growth factor receptor-3 (VEGFR-3) in the RPE cell culture supernatant was measured by enzyme-linked immunosorbent assay (ELISA). The migration ability of the HUVECs was determined by scratch-wound assay, and the angiogenic ability of the HUVECs was examined by measuring cell lumen formation. The mRNA and protein expression levels of VEGFC and VEGFR-3 in the RPE cells were measured by RT-qPCR and western blot analysis, respectively. Our results revealed that fenofibrate inhibited the increase in the expression and release of VEGFC and VEGFR-3 into the RPE cell culture supernatant induced by exposure to hypoxia. The culture of HUVECs in medium supernatant of RPE cells epxosed to hypoxia enhanced the viability and migration ability of the HUVECs and promoted lumen formation; these effects were inhibited by fenofibrate. In conclusion, our data demonstrated that the exposure of RPE cells to hypoxia induced the expression and release of VEGFC and VEGFR-3 into the cell culture supernatant. The culture of HUVECs in conditioned medium from RPE cells exposed to hypoxia increased VEGFC and VEGFR-3 expression, and promoted the proliferation and migration of the HUVECs, as well as capillary tube formation, suggesting that RPE cells play an important role in the formation of choroidal neovascularization resulting from hypoxia. Fenofibrate inhibited the upregulation of VEGFC and VEGFR-3 in the RPE cells exposed to hypoxia, and thus reduced the ability of HUVECs to form new blood vessels.

AT-533, a novel Hsp90 inhibitor, inhibits breast cancer growth and HIF-1α/VEGF/VEGFR-2-mediated angiogenesis in vitro and in vivo

Peng-Chao Zhang,Xiao Liu,Man-Mei Li,Yan-Yan Ma,Hong-Tao Sun,Xu-Yan Tian,Yan Wang,Min Liu,Liang-Shun Fu,Yi-Fei Wang,Hong-Yuan Chen,Zhong Liu

The inhibition of angiogenesis is suggested to be an attractive strategy for cancer therapeutics. Heat shock protein 90 (Hsp90) is closely related to tumorigenesis as it regulates the stabilization and activated states of many client proteins that are essential for cell survival and tumor growth. Here, we investigated the mechanism whereby AT-533, a novel Hsp90 inhibitor, inhibits breast cancer growth and tumor angiogenesis. Based on our results, AT-533 suppressed the tube formation, cell migration, and invasion of human umbilical vein endothelial cells (HUVECs), and was more effective than the Hsp90 inhibitor, 17-AAG. Furthermore, AT-533 inhibited angiogenesis in the aortic ring, Matrigel plug, and chorioallantoic membrane (CAM) models. Mechanically, AT-533 inhibited the activation of VEGFR-2 and the downstream pathways, including Akt/mTOR/p70S6K, Erk1/2 and FAK, in HUVECs, and the viability of breast cancer cells and the HIF-1α/VEGF signaling pathway under hypoxia. In vivo, AT-533 also inhibited tumor growth and angiogenesis by inducing apoptosis and the HIF-1α/VEGF signaling pathway in breast cancer cells. Taken together, our findings indicate that the Hsp90 inhibitor, AT-533, suppresses breast cancer growth and angiogenesis by blocking the HIF-1α/VEGF/VEGFR-2 signaling pathway. AT-533 may thus be a potentially useful drug candidate for breast cancer therapy.

Tumor Specific Delivery and Therapy by Double-Targeted Nanostructured Lipid Carriers with Anti-VEGFR-2 Antibody

Donghua Liu,Fengxi Liu,Zhihong Liu,Lili Wang,Na Zhang

Vascular endothelial growth factor receptors (VEGFRs) are overexpressed on the surface of a variety of tumor cells and on tumor neovasculature in situ, which are potential targets for “double targeting” (tumor- and vascular-targeting) tumor therapy. This study aimed to develop a VEGFR-mediated drug delivery system to target chemotherapeutic agents to VEGFR-overexpressed tumor cells and tumor neovasculature endothelial cells in vitro and in vivo. An antibody modified docetaxel (DTX)-loaded targeted nanostructured lipid carrier (tNLC) was designed and prepared with DSPE-PEG-NH2 as linker. The cellular cytotoxicity, cellular uptake, in vivo therapeutic effect and biodistribution of tNLC were investigated. The tNLC showed a particle size about 168 nm with encapsulation efficiency >95%, drug loading 5.55 ± 0.06% (w/w) and an average ligand coupling efficiency of 3.34 ± 2.63%. Cytotoxicity of tNLC against three human cell lines and one murine malignant melanoma was superior to that of Duopafei and nontargeted NLC (nNLC). The tNLC also showed better tolerance and antitumor efficacy in a murine model bearing B16 compared with Duopafei or nNLC. The studies on cellular uptake and biodistribution indicated that the better antitumor efficacy of tNLC was attributed to the increased accumulation of drug in both tumor and tumor vasculature. These findings suggested that tNLC designed to bind specifically to VEGFR-2 can be used to deliver DTX to the tumor vasculature and tumor and may inhibit tumor growth.

Discovery of novel VEGFR-2-PROTAC degraders based on the localization of lysine residues via recruiting VHL for the treatment of gastric cancer

Xing-Rong Wang,Shuai Wang,Hong-Xia Mu,Kai-Yan Xu,Xue-Ting Wang,Jian-Tao Shi,Qi-Hang Cui,Li-Wen Zhang,Shi-Wu Chen

VEGFR-2 is an attractive therapeutic target for antitumor drug research by blocking tumor angiogenesis and PROTAC provides a new technology for targeted protein knockout. Herein, a library of novel VEGFR-2-PROTAC degraders were rationally designed and synthesized based on the Lys residue region on the surface of VEGFR-2 protein using protein structure-based drug design strategy. Among them, P7 exhibited preferable antitumor activity against HGC-27 cells and less toxic to human normal HUVEC, HEK293T and GES-1 cells in vitro , as well as the potent degradation activity of VEGFR-2 protein in HGC-27 cells (DC 50 : 0.084 ± 0.04 μM, D max : 73.7%) and HUVEC cells (DC 50 : 0.51 ± 0.10 μM, Dmax: 76.6%). Additionally, P7 degraded VEGFR-2 protein by the formation of ternary complex and the ubiquitin proteasome pathway in HGC-27 cells. Furthermore, P7 shortened the half-life of VEGFR-2 protein synthesis and had no inhibitory effect on the expression of VEGFR-2 mRNA in HGC-27 cells. Moreover, P7 inhibited the colony formation, migration and invasion of HGC-27 cells in a time- and dose-dependent manner, and meanwhile induced G 2 /M phase cycle arrest and apoptosis . All the results demonstrated that P7 could be as a promising VEGFR-2-PROTAC degrader for gastric cancer therapy.

Design, Synthesis, Molecular Docking, and Anticancer Activity of Chalcone Derivatives as VEGFR-2 Inhibitors

Mingjun Yu,Xin Zhang,Hui Zhu,Xiaoqian Zhang

A series of 4-phenylurea chalcones (2a–2s) as VEGFR-2 inhibitors has been designed, synthesized, and evaluated for in vitro cytotoxic activity against K562, SiHa, and B16 cancer cells. Compared to sorafenib, the compounds exhibited strong cytotoxicity against K562, SiHa and B16 cells. Compounds2r,2o, and2lexhibited remarkable cytotoxicity against K562, SiHa, and B16 cells, with IC50values of 0.97 μM, 1.22 μM, and 1.39 μM, respectively. Moreover, compound2lexhibited potent cytotoxicity against K562, SiHa, and B16, with IC50values ranging from 1.25 μM to 1.39 μM. Compounds2land2oalso exhibited excellent inhibitory activity on VEGFR-2 kinase, with IC50values of 0.42 ± 0.03 and 0.31 ± 0.02 μM, respectively. Molecular docking proved that the target compounds had strong binding interactions with VEGFR-2 proteins. Flow cytometry analysis showed that compound2linduced apoptosis and arrested the cell cycle at the G1 and S phases.

Design, synthesis, and evaluation of VEGFR-targeted macromolecular MRI contrast agent based on biotin–avidin-specific binding

Yongjun Liu,Xiaoyun Wu,Xiaohe Sun,Dan Wang,Ying Zhong,Dandan Jiang,Tianqi Wang,Dexin Yu,Na Zhang

Establishment of a Mouse Model of Mycoplasma pneumoniae-Induced Plastic Bronchitis

Peng Jin,Lin-Sheng Zhao,Tong-Qiang Zhang,Han Di,Wei Guo

Plastic bronchitis (PB) constitutes a life-threatening pulmonary disorder, predominantly attributed toMycoplasma pneumoniae(MP) infection. The pathogenic mechanisms involved remain largely unexplored, leading to the absence of reliable approaches for early diagnosis and clear treatment. Thus, the present investigation aimed to develop an MP-induced mouse model of PB, thereby enhancing our understanding of this complex condition. In the first stage, healthy BALB/c mice were utilized to investigate the optimal methods for establishing PB. This involved the application of nebulization (15–20 min) and intratracheal administration (6–50 μL) with 2-chloroethyl ethyl sulfide (CEES) concentrations ranging from 4.5% to 7.5%. Subsequently, the MP model was induced by administering an MP solution (2 mL/kg/day, 108CFU/50 μL) via the intranasal route for a duration of five consecutive days. Ultimately, suitable techniques were employed to induce plastic bronchitis in the MP model. Pathological changes in lung tissue were analyzed, and immunohistochemistry was employed to ascertain the expression levels of vascular endothelial growth factor receptor 3 (VEGFR-3) and the PI3K/AKT/mTOR signaling pathway. The administration of 4.5% CEES via a 6 µL trachea was the optimal approach to establishing a PB model. This method primarily induced neutrophilic inflammation and fibrinous exudate. The MP-infected group manifested symptoms indicative of respiratory infection, including erect hair, oral and nasal secretions, and a decrease in body weight. Furthermore, the pathological score of the MP+CEES group surpassed that of the groups treated with MP or CEES independently. Notably, the MP+CEES group demonstrated significant activation of the VEGFR-3 and PI3K/AKT/mTOR signaling pathways, implying a substantial involvement of lymphatic vessel impairment in this pathology. This study successfully established a mouse model of PB induced by MP using a two-step method. Lymphatic vessel impairment is a pivotal element in the pathogenetic mechanisms underlying this disease entity. This accomplishment will aid in further research into treatment methods for patients with PB caused by MP.

Transmembrane modification of tumor vascular targeting peptide A7R as molecular cargo delivery tool

Qingqing Zhang,Zeyu Yang,Jie Zhang,Yanchen Li,Xintao Dang,Jingkun Qu,Xiaoyan Pan,Jie Zhang

In recent years, targeting tumor angiogenesis has emerged as a prominent research focus in the treatment and prevention of tumor expansion. A7R (ATWLPPR) exhibits high affinity and specificity for VEGFR-2, which is overexpressed in various tumors. To enhance the tumor tissue and cell penetration capabilities of A7R, we substituted its non-critical amino acid with Arginine (R) and Glutamic acid (E), cyclized the mutant peptide, and linked it to the membrane permeation sequence using coordination principles. We designed and synthesized fifteen novel penetrating peptides that target tumor blood vessels and cells, followed by conducting various biological evaluations and cell imaging experiments. The results demonstrated that Cyclo-A7R-RRR and A7R-RLLRLLR exhibited excellent permeability towards tumor cells, with Cyclo-A7R-RRR showing superior serum stability compared to A7R. Furthermore, the modified peptides showed no toxicity towards HeLa cells, U251 cells, HuH-7 cells, and HEK293 cells under 10 μmol/L. Utilizing Cyclo-A7R-RRR or A7R-RLLRLLR for transmembrane delivery of drug molecules could significantly improve their efficacy. Our findings broaden the potential application scenarios of A7R in targeted tumor angiogenesis.

Pinocembrin alleviates tubular inflammatory fibrosis and glomerular mesangial lesions in diabetic nephropathy through HSP90AB1/TGF-β1/Smad3 and VEGFR/ERK signaling

Wang Yujie,Wang Jiajie,Cai Maoxuan,Ren Jie,Jia Fang,Jiang Wenjie,Su Dan,Yang Hao,Chen Guilin

Diabetic nephropathy (DN) ranks as the primary contributor to end-stage renal disease across the globe, characterized by progressive glomerular mesangial proliferation and tubular interstitial fibrosis, which poses a severe threat to public health. Pinocembrin is a major flavonoid compound that has been reported to exhibit a variety of prominent biological effects. However, its dual regulatory effects on glomerular and tubular injuries in DN remain unclear. The present study aims to investigate the potential role of pinocembrin in alleviating the progression of DN, providing a combination therapeutic strategy. In vivo experiments were performed to verify its efficacy in improving renal injury and fibrosis of pinocembrin in Lep db /Lep db ( db/db) mice. Pinocembrin-related targets were retrieved from Traditional Chinese Medicine Systems Pharmacology (TCMSP), Comparative Toxigenomics Database (CTD), Swiss Target Prediction, and Symmap databases. Differentially expressed genes in DN tubules and glomeruli were obtained from Gene Expression Omnibus (GEO) dataset GSE30122. Overlapping targets between pinocembrin and DN tissues were identified, followed by Protein-Protein Interaction (PPI) network construction, Gene Ontology (GO) annotation, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Molecular docking predicted potential binding interactions between pinocembrin and key targets. In vitro experiments demonstrated that in HG-induced HK-2 cells, pinocembrin might target HSP90AB1 to suppress inflammatory response and epithelial-mesenchymal transition, thereby alleviating tubular fibrosis injury. In HG-treated SV40 cells, pinocembrin downregulated expression of VEGFR, thereby inhibiting cell proliferation and extracellular matrix deposition to improve glomerular pathological damage. This study clarifies the dual protective mechanism of pinocembrin on DN via regulatory pathways. These findings provide experimental foundation and theoretical insight for the application of pinocembrin as a functional food ingredient for the prevention and treatment of DN.

Design and Synthesis of Novel Thiazolo[5,4-d]pyrimidine Derivatives as Potential Angiogenesis Inhibitors

Wen-Jun Xue,Jian-Yao Du,Ya-Hui Deng,Zhong-Hui Yan,Ji-Ping Liu,Yu Liu,Li-Ping Sun

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays an important role in both vasculogenesis and angiogenesis. Inhibition of VEGFR-2 has been demonstrated as a key method against tumor-associated angiogenesis. Thiazolopyrimidine is an important analog of the purine ring, and we choose the thiazolopyrimidine scaffold as the mother nucleus. Two series of thiazolo[5,4- d ]pyrimidine derivatives were synthesized and evaluated for their antiproliferative activity. In HUVEC inhibition assay, compounds 3l (=1-(5-{[2-(4-chlorophenyl)-5-methyl[1,3]thiazolo[5,4- d ]pyrimidin-7-yl]amino}pyridin-2-yl)-3-(3,4-dimethylphenyl)urea) and 3m (=1-(5-{[2-(4-chlorophenyl)-5-methyl[1,3]thiazolo[5,4- d ]pyrimidin-7-yl]amino}pyridin-2-yl)-3-(4-methoxyphenyl)urea) exhibited the most potent inhibitory effect (IC 50 =1.65 and 3.52 μ m , respectively). Compound 3l also showed the best potency against VEGFR-2 at 50 μ m (98.5 %). These results suggest that further investigation of compound 3l might provide potential angiogenesis inhibitors. Graphical