6″-Debromohamacanthin A,a Bis (Indole) Alkaloid,Inhibits Angiogenesis by Targeting the VEGFR2-Mediated PI3K/AKT/mTOR Signaling Pathways

Hamacanthins, bis (indole) alkaloids, are found in a few marine sponges, including Spongosorites sp. Hamacanthins have been shown to possess cytotoxic, antibacterial and antifungal activities. However, the precise mechanism for the biological activities of hamacanthins has not yet been elucidated. In the present study, the anti-angiogenic effects of 6″-debromohamacanthin A (DBHA), an active component of isolated hamacanthins, were evaluated in cultured human umbilical vascular endothelial cells (HUVEC) and endothelial-like cells differentiated from mouse embryonic stem (mES) cells. DBHA significantly inhibited vascular endothelial growth factor (VEGF)-induced cell proliferation, migration and tube formation in the HUVEC. DBHA also suppressed the capillary-like structure formation and the expression of platelet endothelial cell adhesion molecule (PECAM), an endothelial biomarker, in mES cell-derived endothelial-like cells. To further understand the precise molecular mechanism of action, VEGF-mediated signaling pathways were analyzed in HUVEC cells and mES cell-derived endothelial-like cells. DBHA suppressed the VEGF-induced expression of MAPKs (p38, ERK and SAPK/JNK) and the PI3K/AKT/mTOR signaling pathway. In addition, DBHA inhibited microvessel sprouting in mES/EB-derived embryoid bodies. In an ex vivo model, DBHA also suppressed the microvessel sprouting of mouse aortic rings. The findings suggest for the first time that DBHA inhibits angiogenesis by targeting the vascular endothelial growth factor receptor 2 (VEGFR2)-mediated PI3K/AKT/mTOR signaling pathway in endothelial cells.     

Heparanase and Syndecan-4 Are Involved in Low Molecular Weight Fucoidan-Induced Angiogenesis

Induction of angiogenesis is a potential treatment for chronic ischemia. Low molecular weight fucoidan (LMWF), the sulfated polysaccharide from brown seaweeds, has been shown to promote revascularization in a rat limb ischemia, increasing angiogenesis in vivo. We investigated the potential role of two heparan sulfate (HS) metabolism enzymes, exostosin-2 (EXT2) and heparanase (HPSE), and of two HS-membrane proteoglycans, syndecan-1 and -4 (SDC-1 and SDC-4), in LMWF induced angiogenesis. Our results showed that LMWF increases human vascular endothelial cell (HUVEC) migration and angiogenesis in vitro. We report that the expression and activity of the HS-degrading HPSE was increased after LMWF treatment. The phenotypic tests of LMWF-treated and EXT2- or HPSE-siRNA-transfected cells indicated that EXT2 or HPSE expression significantly affect the proangiogenic potential of LMWF. In addition, LMWF increased SDC-1, but decreased SDC-4 expressions. The effect of LMWF depends on SDC-4 expression. Silencing EXT2 or HPSE leads to an increased expression of SDC-4, providing the evidence that EXT2 and HPSE regulate the SDC-4 expression. Altogether, these data indicate that EXT2, HPSE, and SDC-4 are involved in the proangiogenic effects of LMWF, suggesting that the HS metabolism changes linked to LMWF-induced angiogenesis offer the opportunity for new therapeutic strategies of ischemic diseases.     

Dihydroaustrasulfone Alcohol Inhibits PDGF-Induced Proliferation and Migration of Human Aortic Smooth Muscle Cells through Inhibition of the Cell Cycle

Dihydroaustrasulfone alcohol is the synthetic precursor of austrasulfone, which is a marine natural product, isolated from the Taiwanese soft coral Cladiella australis. Dihydroaustrasulfone alcohol has anti-inflammatory, neuroprotective, antitumor and anti-atherogenic properties. Although dihydroaustrasulfone alcohol has been shown to inhibit neointima formation, its effect on human vascular smooth muscle cells (VSMCs) has not been elucidated. We examined the effects and the mechanisms of action of dihydroaustrasulfone alcohol on proliferation, migration and phenotypic modulation of human aortic smooth muscle cells (HASMCs). Dihydroaustrasulfone alcohol significantly inhibited proliferation, DNA synthesis and migration of HASMCs, without inducing cell death. Dihydroaustrasulfone alcohol also inhibited platelet-derived growth factor (PDGF)-induced expression of cyclin-dependent kinases (CDK) 2, CDK4, cyclin D1 and cyclin E. In addition, dihydroaustrasulfone alcohol inhibited PDGF-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), whereas it had no effect on the phosphorylation of phosphatidylinositol 3-kinase (PI3K)/(Akt). Moreover, treatment with PD98059, a highly selective ERK inhibitor, blocked PDGF-induced upregulation of cyclin D1 and cyclin E and downregulation of p27^kip1. Furthermore, dihydroaustrasulfone alcohol also inhibits VSMC synthetic phenotype formation induced by PDGF. For in vivo studies, dihydroaustrasulfone alcohol decreased smooth muscle cell proliferation in a rat model of restenosis induced by balloon injury. Immunohistochemical staining showed that dihydroaustrasulfone alcohol noticeably decreased the expression of proliferating cell nuclear antigen (PCNA) and altered VSMC phenotype from a synthetic to contractile state. Our findings provide important insights into the mechanisms underlying the vasoprotective actions of dihydroaustrasulfone alcohol and suggest that it may be a useful therapeutic agent for the treatment of vascular occlusive disease.     

Xyloketal B Suppresses Glioblastoma Cell Proliferation and Migration in Vitro through Inhibiting TRPM7-Regulated PI3K/Akt and MEK/ERK Signaling Pathways

Glioblastoma, the most common and aggressive type of brain tumors, has devastatingly proliferative and invasive characteristics. The need for finding a novel and specific drug target is urgent as the current approaches have limited therapeutic effects in treating glioblastoma. Xyloketal B is a marine compound obtained from mangrove fungus Xylaria sp. (No. 2508) from the South China Sea, and has displayed antioxidant activity and protective effects on endothelial and neuronal oxidative injuries. In this study, we used a glioblastoma U251 cell line to (1) explore the effects of xyloketal B on cell viability, proliferation, and migration; and (2) investigate the underlying molecular mechanisms and signaling pathways. MTT assay, colony formation, wound healing, western blot, and patch clamp techniques were employed. We found that xyloketal B reduced cell viability, proliferation, and migration of U251 cells. In addition, xyloketal B decreased p-Akt and p-ERK1/2 protein expressions. Furthermore, xyloketal B blocked TRPM7 currents in HEK-293 cells overexpressing TRPM7. These effects were confirmed by using a TRPM7 inhibitor, carvacrol, in a parallel experiment. Our findings indicate that TRPM7-regulated PI3K/Akt and MEK/ERK signaling is involved in anti-proliferation and migration effects of xyloketal B on U251 cells, providing in vitro evidence for the marine compound xyloketal B to be a potential drug for treating glioblastoma.     

Identification of a Pro-Angiogenic Potential and Cellular Uptake Mechanism of a LMW Highly Sulfated Fraction of Fucoidan from Ascophyllum nodosum

Herein we investigate the structure/function relationships of fucoidans from Ascophyllum nodosum to analyze their pro-angiogenic effect and cellular uptake in native and glycosaminoglycan-free (GAG-free) human endothelial cells (HUVECs). Fucoidans are marine sulfated polysaccharides, which act as glycosaminoglycans mimetics. We hypothesized that the size and sulfation rate of fucoidans influence their ability to induce pro-angiogenic processes independently of GAGs. We collected two fractions of fucoidans, Low and Medium Molecular Weight Fucoidan (LMWF and MMWF, respectively) by size exclusion chromatography and characterized their composition (sulfate, fucose and uronic acid) by colorimetric measurement and Raman and FT-IR spectroscopy. The high affinities of fractionated fucoidans to heparin binding proteins were confirmed by Surface Plasmon Resonance. We evidenced that LMWF has a higher pro-angiogenic (2D-angiogenesis on Matrigel) and pro-migratory (Boyden chamber) potential on HUVECs, compared to MMWF. Interestingly, in a GAG-free HUVECs model, LMWF kept a pro-angiogenic potential. Finally, to evaluate the association of LMWF-induced biological effects and its cellular uptake, we analyzed by confocal microscopy the GAGs involvement in the internalization of a fluorescent LMWF. The fluorescent LMWF was mainly internalized through HUVEC clathrin-dependent endocytosis in which GAGs were partially involved. In conclusion, a better characterization of the relationships between the fucoidan structure and its pro-angiogenic potential in GAG-free endothelial cells was required to identify an adapted fucoidan to enhance vascular repair in ischemia.     

Antimetastatic Effect of Halichondramide,a Trisoxazole Macrolide from the Marine Sponge Chondrosia corticata,on Human Prostate Cancer Cells via Modulation of Epithelial-to-Mesenchymal Transition

Halichondramide (HCA), a trisoxazole-containing macrolide isolated from the marine sponge Chondrosia corticata has been shown to exhibit cytotoxicity and antifungal activities. In our previous study, HCA was also found to exhibit antiproliferative activity against a variety of cancer cells. However, the precise mechanism of action of HCA in the antitumor activity remains to be elucidated. In the present study, we identified the antimetastatic activity of HCA in the highly metastatic PC3 human prostate cancer cells. HCA showed potent growth inhibitory activity of the PC3 cells with an IC₅₀ value of 0.81 µM. Further analysis revealed that HCA suppressed the expression of a potential metastatic biomarker, phosphatase of regenerating liver-3 (PRL-3), in PC3 cells. The suppression of PRL-3 by HCA sequentially down-regulates the expression of phosphoinositide 3-kinase (PI3K) subunits p85 and p110. The antimetastatic effect of HCA was also correlated with the down-regulation of matrix metalloproteases (MMPs) and the modulation of cadherin switches N-cadherin and E-cadherin. In addition, HCA also effectively suppressed the migration and invasion of PC3 cells. These findings suggest that halichondramide might serve as a potential inhibitor of tumor cell metastasis with the modulation of PRL-3.     

Coral-Derived Compound WA-25 Inhibits Angiogenesis by Attenuating the VEGF/VEGFR2 Signaling Pathway

Background: WA-25 (dihydroaustrasulfone alcohol, a synthetic derivative of marine compound WE-2) suppresses atherosclerosis in rats by reducing neointima formation. Because angiogenesis plays a critical role in the pathogenesis of atherosclerosis, the present study investigated the angiogenic function and mechanism of WA-25. Methods: The angiogenic effect of WA-25 was evaluated using a rat aortic ring assay and transgenic zebrafish models were established using transgenic Tg(fli-1:EGFP)^y1 and Tg(kdrl:mCherry^ci5-fli1a:negfp^y7) zebrafish embryos. In addition, the effect of WA-25 on distinct angiogenic processes, including matrix metalloproteinase (MMP) expression, endothelial cell proliferation and migration, as well as tube formation, was studied using human umbilical vein endothelial cells (HUVECs). The effect of WA-25 on the endothelial vascular endothelial growth factor (VEGF) signaling pathway was elucidated using qRT-PCR, immunoblot analysis, immunofluorescence and flow cytometric analyses. Results: The application of WA-25 perturbed the development of intersegmental vessels in transgenic zebrafish. Moreover, WA-25 potently suppressed microvessel sprouting in organotypic rat aortic rings. Among cultured endothelial cells, WA-25 significantly and dose-dependently inhibited MMP-2/MMP-9 expression, proliferation, migration and tube formation in HUVECs. Mechanistic studies revealed that WA-25 significantly reduced the VEGF release by reducing VEGF expression at the mRNA and protein levels. In addition, WA-25 reduced surface VEGF receptor 2 (VEGFR2/Flk-1) expression by repressing the VEGFR2 mRNA level. Finally, an exogenous VEGF supply partially rescued the WA-25-induced angiogenesis blockage in vitro and in vivo. Conclusions: WA-25 is a potent angiogenesis inhibitor that acts through the down-regulation of VEGF and VEGFR2 in endothelial cells. General Significance: WA-25 may constitute a novel anti-angiogenic drug that acts by targeting endothelial VEGF/VEGFR2 signaling.     

鹿茸多肽对冈田酸诱导的小鼠海马神经元HT22细胞损伤模型中PI3K、AKT、Caspase-9表达的影响

目的观察鹿茸多肽对冈田酸(OA)诱导的小鼠海马神经元HT22细胞损伤模型中磷脂酰肌醇-3激酶(PI3K)、蛋白激酶B(AKT)、半胱氨酸蛋白酶-9(Caspase-9)表达的影响,探讨鹿茸多肽对HT22细胞损伤模型的保护作用机制。方法采用含10%胎牛血清(FBS)培养液(DMEM/F12)传代培养HT22细胞7d后,分为正常对照组、二甲基亚砜(DMSO)对照组、OA细胞损伤模型组、鹿茸多肽高、中、低剂量组。正常对照组给予含10%FBS的DMEM/F12,DMSO对照组给予DMSO终浓度<0.01%的DMEM/F12,OA细胞损伤模型组给予10nmol OA的DMEM/F12,鹿茸多肽高、中、低剂量组分别给予50、500、1000μg/ml的DMEM/F12,于37℃、5%CO2条件下孵育24h。利用噻唑蓝(MTT)比色法检测细胞存活率,酶联免疫法(ELISA)检测各组实验细胞内PI3K、AKT含量,蛋白质印迹法(Western Blot)检测各组实验细胞内PI3K、AKT、Caspase-9表达水平。结果MTT比色法检测结果表明,与OA细胞损伤模型组比较,鹿茸多肽能够明显提高细胞存活率(P<0.05);ELISA检测结果表明,与OA细胞损伤模型组比较,鹿茸多肽能够明显提高受损HT22细胞内PI3K、AKT含量(P<0.05或P<0.01);Western Blot检测结果表明,与OA细胞损伤模型组比较,鹿茸多肽能够明显提高受损HT22细胞内PI3K、AKT、Caspase-9表达水平(P<0.05或P<0.01)。结论鹿茸多肽对OA诱导的HT22细胞损伤模型具有保护作用,作用机制可能与调节受损HT22细胞内PI3K、AKT、Caspase-9表达水平相关。     

Inhibitory Effect of Dihydroaustrasulfone Alcohol on the Migration of Human Non-Small Cell Lung Carcinoma A549 Cells and the Antitumor Effect on a Lewis Lung Carcinoma-Bearing Tumor Model in C57BL/6J Mice

There are many major causes of cancer death, including metastasis of cancer. Dihydroaustrasulfone alcohol, which is isolated from marine coral, has shown antioxidant activity, but has not been reported to have an anti-cancer effect. We first discovered that dihydroaustrasulfone alcohol provided a concentration-dependent inhibitory effect on the migration and motility of human non-small cell lung carcinoma (NSCLC) A549 cells by trans-well and wound healing assays. The results of a zymography assay and Western blot showed that dihydroaustrasulfone alcohol suppressed the activities and protein expression of matrix metalloproteinase (MMP)-2 and MMP-9. Further investigation revealed that dihydroaustrasulfone alcohol suppressed the phosphorylation of ERK1/2, p38, and JNK1/2. Dihydroaustrasulfone alcohol also suppressed the expression of PI3K and the phosphorylation of Akt. Furthermore, dihydroaustrasulfone alcohol markedly inhibited tumor growth in Lewis lung cancer (LLC)-bearing mice. We concluded that dihydroaustrasulfone alcohol is a new pure compound with anti-migration and anti-tumor growth activity in lung cancer and might be applied to clinical treatment in the future.     

In Vitro Antitumor Activity of Stellettin B,a Triterpene from Marine Sponge Jaspis stellifera,on Human Glioblastoma Cancer SF295 Cells

Stellettin B was isolated from marine sponge Jaspis stellifera. In vitro antitumor activities were investigated on 39 human cancer cell lines. Stellettin B exhibited highly potent inhibition against the growth of a human glioblastoma cell line SF295, with a GI50 of 0.01 μM. In contrast, stellettin B showed very weak inhibitory activity on normal cell lines including HMEC, RPTEC, NHBE and PrEC, with GI50s higher than 10 μM, suggesting its relatively selective cytotoxicity against human cancer cells compared to normal human cell lines. We then focused on the antitumor activity of this compound on SF295 cells. Flow cytometric analysis indicated that stellettin B induced apoptosis in SF295 cells in a concentration-dependent manner. Further study indicated that stellettin B increased the production of ROS, the activity of caspase 3/7, as well as the cleavage of PARP, each of which is known to be involved in apoptosis. To investigate the molecular mechanism for cell proliferation inhibition and apoptosis induction, effect on the phosphorylation of several signal proteins of PI3K/Akt and RAS/MAPK pathways was examined. Stellettin B inhibited the phosphorylation of Akt potently, with no activity on p-ERK and p-p38, suggesting that inhibition of PI3K/Akt pathway might be involved in the antiproliferative and apoptosis-inducing effect. However, homogenous time-resolved fluorescence (HTRF) assay indicated that stellettin B did not inhibit PI3K activity, suggesting that the direct target might be signal protein upstream of Akt pathway other than PI3K.     

SD118-xanthocillin X (1), a novel marine agent extracted from Penicillium commune, induces autophagy through the inhibition of the MEK/ERK pathway

A compound named SD118-xanthocillin X (1) (C(18)H(12)N(2)O(2)), isolated from Penicillium commune in a deep-sea sediment sample, has been shown to inhibit the growth of several cancer cell lines in vitro. In the present study, we employed a growth inhibition assay and apoptotic analysis to identify the biological effect and detailed mechanism of SD118-xanthocillin X (1) in human hepatocellular carcinoma (HepG2) cells. SD118-xanthocillin X (1) demonstrated a concentration-dependent inhibitory effect on the growth of HepG2 cells and caused slight cellular apoptosis and significantly induced autophagy. Autophagy was detected as early as 12 h by the conversion of microtubule-associated protein 1 light chain 3 (LC3-I) to LC3-II, following cleavage and lipid addition to LC3-I. The pharmacological autophagy inhibitor 3-methyladenine largely attenuates the growth inhibition and autophagic effect of SD118-xanthocillin X (1) in HepG2 cells. Our data also indicated that the autophagic effect of SD118-xanthocillin X (1) occurs via the down-regulation of the MEK/ERK signaling pathway and the up-regulated class III PI3K/Beclin 1 signaling pathway.     

Effects of Oral Administration of Fucoidan Extracted from Cladosiphon okamuranus on Tumor Growth and Survival Time in a Tumor-Bearing Mouse Model

We evaluated the anti-tumor activities of the oral administration of fucoidan extracted from Cladosiphon okamuranus using a tumor (colon 26)-bearing mouse model. The materials used included low-molecular-weight fucoidan (LMWF: 6.5–40 kDa), intermediate-molecular-weight fucoidan (IMWF: 110–138 kDa) and high-molecular-weight fucoidan (HMWF: 300–330 kDa). The IMWF group showed significantly suppressed tumor growth. The LMWF and HMWF groups showed significantly increased survival times compared with that observed in the control group (mice fed a fucoidan-free diet). The median survival times in the control, LMWF, IMWF and HMWF groups were 23, 46, 40 and 43 days, respectively. It was also found that oral administration of fucoidan increased the population of natural killer cells in the spleen. Furthermore, from the results of the experiment using Myd-88 knockout mice, it was found that these effects are related to gut immunity. These results suggest that fucoidan is a candidate anti-tumor functional food.     

11-epi-Sinulariolide Acetate Reduces Cell Migration and Invasion of Human Hepatocellular Carcinoma by Reducing the Activation of ERK1/2, p38MAPK and FAK/PI3K/AKT/mTOR Signaling Pathways

Cancer metastasis is one of the major causes of death in cancer. An active compound, 11-epi-sinulariolide acetate (11-epi-SA), isolated from the cultured soft coral Sinularia flexibilis has been examined for potential anti-cell migration and invasion effects on hepatocellular carcinoma cells (HCC). However, the molecular mechanism of anti-migration and invasion by 11-epi-SA on HCC, along with their corresponding effects, remain poorly understood. In this study, we investigated anti-migration and invasion effects and the underlying mechanism of 11-epi-SA in HA22T cells, and discovered by trans-well migration and invasion assays that 11-epi-SA provided a concentration-dependent inhibitory effect on the migration of human HCC HA22T cells. After treatment with 11-epi-SA for 24 h, there were suppressed protein levels of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and urokinase-type plasminogen activator (uPA) in HA22T cells. Meanwhile, the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and metalloproteinase-2 (TIMP-2) were increased in a concentration-dependent manner. Further investigation revealed that 11-epi-SA suppressed the phosphorylation of ERK1/2 and p38MAPK. The 11-epi-SA also suppressed the expression of the phosphorylation of FAK/PI3K/AKT/mTOR pathways.     

Canolol induces apoptosis in human gastric carcinoma cell through PI3K/Akt signaling pathway

Canolol is a natural polyphenolic compound in rapeseed oil with multiple biological activities.Anti-cancer potential of canolol has been proposed in some studies.However,the effect and underlying mechanism of canolol on human gastric carcinoma(AGS)cells have not been well understood.This study showed that canolol had significant inhibition in proliferation and strongly apoptotic effects in AGS cells,which were verified by the decrease of cell viability,high level of reactive oxygen species(ROS),and damage in mitochondria membrane potential(MMP).Treatment with canolol arrested cells in S phase,and increased expressions of Bax,cleaved caspase-9,and cleaved caspase-3 proteins.Meanwhile,low expression of Bcl-2 and cytochrome C(Cyt C)release were found.The expressions of PI3K(phosphoinositide 3-kinase)and p-AKT(phosphorylated serine/threonine kinase)were also downregulated.Overall,these results suggested that canolol inhibited proliferation and induced apoptosis in AGS cells by regulating PI3K/Akt pathway,demonstrating a potential in gastric cancer treatment.     

In Vivo Induction of Apoptosis by Fucoxanthin, a Marine Carotenoid, Associated with Down-Regulating STAT3/EGFR Signaling in Sarcoma 180 (S180) Xenografts-Bearing Mice

Previous in vitro researches have showed that fucoxanthin, a natural carotenoid isolated from sargassum, can inhibit proliferation or induce apoptosis in human neuroblastoma, hepatoma, leukemia, colon carcinoma, prostate cancer or urinary bladder cancer cells. But the precise mechanism by which fucoxanthin exerts anticarcinogenic effects is not yet fully understood. In this study, we performed an in vivo study to investigate the anti-tumor effect and mechanisms of fucoxanthin on xenografted sarcoma 180 (S180) in mice. Results revealed that fucoxanthin significantly inhibited the growth of sarcoma at the dose of 50 or 100 mg/kg. TUNEL analysis showed that the number of positive cells in the fucoxanthin-treated group was higher than that in the control group. Western blotting analysis also revealed the suppressed expression of bcl-2 and enhanced expression of cleaved caspase-3 by fucoxanthin. In addition, immunohistochemistry analysis and Western blotting analysis showed that fucoxanthin significantly decreased the expressions of survivin and vascular endothelial growth factor (VEGF). Most importantly, fucoxanthin inhibited the expressions of the epidermal growth factor receptor (EGFR) and STAT3 and phosphorylated STAT3 proteins. These results indicated that in vivo induction of apoptosis by fucoxanthin is associated with down-regulating STAT3/EGFR signaling in S180 xenografts-bearing mice.     

(+)-儿茶素缓解大鼠低氧性肺动脉高压的作用和机制

研究了(+)-儿茶素对SD大鼠低氧性肺动脉高压(PAH)的影响及其机制。采用27只SD雄性大鼠按随机数字表法分为3组(对照组、缺氧模型组、(+)-儿茶素干预组)。通过检测大鼠平均肺动脉压(Mean pulmonary arterialpressure,mPAP)和肺血管阻力(Pulmonaryvascularresistance,PVR)反应体内肺血流动力学变化;处死大鼠后测算右心室肥厚指数(Rightventriclehypertrophyindex,RVHI)及肺动脉血管壁厚度和外周血管直径的比值(Vascular wall thickness of outer circumference ratio,WT%);WB检测肺动脉内皮细胞一氧化氮合酶(eNOS),用NO试剂盒检测NO表达量;用CCK-8法检测肺动脉平滑肌细胞增殖以确定细胞活力,利用WB检测分析肺动脉平滑肌细胞钙敏感受体(CaSR)、荧光探针法检测细胞内总Ca²⁺的浓度。研究结果表明,与缺氧模型组相比,(+)-儿茶素能够显著减缓肺缺氧诱导的肺动脉压力升高(n=9,P<0.05;);通过逆转缺氧引起的肺内皮细胞一氧化氮合酶(eNOS)显著减少(n=3,P<0.05)和NO合成显著减少(n=5,P<0.05),达到抑制肺动脉内皮血管收缩作用;通过下调缺氧诱导的平滑肌细胞内CaSR表达(n=3,P<0.05),逆转缺氧的升钙效应(n=27,P<0.05),达到抑制平滑肌细胞增殖的作用(n=30,P<0.05)。综上可见,(+)-儿茶素通过抑制肺血管收缩和血管平滑肌细胞增殖来缓解缺氧诱导的PAH,为PAH的治疗方法提供了新思路。     

Marine cyclotripeptide X-13 promotes angiogenesis in zebrafish and human endothelial cells via PI3K/Akt/eNOS signaling pathways

Cyclotripeptide X-13 is a core of novel marine compound xyloallenoide A isolated from mangrove fungus Xylaria sp. (no. 2508). We found that X-13 dose-dependently induced angiogenesis in zebrafish embryos and in human endothelial cells, which was accompanied by increased phosphorylation of eNOS and Akt and NO release. Inhibition of PI3K/Akt/eNOS by LY294002 or L-NAME suppressed X-13-induced angiogenesis. The present work demonstrates that X-13 promotes angiogenesis via PI3K/Akt/eNOS pathways.