Polyunsaturated Fatty Acid Diet and Upregulation of Lipoxin A4 Reduce the Inflammatory Response of Preeclampsia.

The aim of this study was to investigate the effects and mechanisms of polyunsaturated fatty acids (PUFAs) and lipoxin A4 (LXA4) on preeclampsia (PE). The LXA4 level was significantly reduced in PE rats. The PUFA diet upregulated the expressions of lipoxygenase 12 (LOX12) and lipoxygenase 15 (LOX15) and downregulated those of cyclooxygenase-2, tumor necrosis factor-α (TNF-α), and endoglin. Lipopolysaccharides could inhibit cell growth and cause inflammatory response, while the presence of PUFAs inhibited the inflammatory response and promoted the expressions of LOX12, LOX15, and LXA4. Nordihydroguaiaretic acid (NDGA) regulated LXA4 expression and inflammation levels by affecting LOX. Inhibition of lipoxygenase 5 activity by NDGA upregulated the expressions of LOX12 and LOX15, while LXA4 reversed LXA4, nitric oxide downregulation, and TNF-α upregulation by NDGA. A decrease in LXA4 levels played an important role in the development and progression of PE.

Long noncoding RNA MALAT1 contributes to pregnancy-induced hypertension development by enhancing oxidative stress and inflammation through the regulation of the miR-150-5p/ET-1 axis.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been identified previously in the pathogenesis of hypertension and some gestational diseases. However, the biological functions of MALAT1 in pregnancy-induced hypertension (PIH) are still poorly understood. Herein, we aim to explore the functional relevance of MALAT1 in PIH and to explain the potential underlying mechanisms. We found that the levels of ET-1 and MALAT1 were upregulated and that of miR-150-5p were downregulated in the serum of pregnant women with PIH and the aortic endothelial cells (ECs) of reduced uterine perfusion pressure (RUPP)-induced rat models. In aortic ECs, MALAT1 could competitively bind to miR-150-5p to upregulate the expression of ET-1. The MALAT1/miR-150-5p/ET-1 axis regulated the expression of endothelin B receptor (ETBR) in aortic ECs leading to oxidative stress imbalance and increased the release of proinflammatory cytokines (IL-18 and IL-1ß), which concurrently activated the NF-κB pathway to regulate the ETBR expression and to stimulate smooth muscle cell (SMC) contraction. Furthermore, silencing MALAT1 could alleviate the hypertensive symptoms of RUPP-induced rat models. Taken conjointly, the upregulation of MALAT1 can reduce the expression of ET-1 by competitively binding to miR-150-5p, which enhances the expression of ETBR via the activation of the NF-κB pathway in SMCs, thus exacerbating the hypertensive symptoms in the RUPP-induced rat models.

IL-6 promoter polymorphism increased risks of recurrent stroke in the young patients with moderate internal carotid artery stenosis.

Interleukin-6 (IL-6) is a pleiotropic cytokine with both pro-inflammatory and anti-inflammatory properties. Increased serum IL-6 is associated with higher risk of cerebral vascular diseases, however, the circulating levels of IL-6 vary greatly between individuals for bioenvironmental or genetic interferes by IL-6 transcription, therefore, this study was to investigate if IL-6 promoter polymorphisms predict the recurrence of young stroke. A total of 94 patients with moderate internal carotid artery stenosis and 94 healthy subjects were selected. Color Doppler was used to screen internal carotid artery stenosis, PCR restriction enzyme fragment length polymorphism for genotypes. Stroke recurrence rates in patients with different genotypes of IL-6 promoter were evaluated by 1-year follow-up. The frequencies of 634C/G genotype of IL-6 promoter were CC 38.29%, CG 46.81%, and GG 14.90%, while CC 59.51%, CG 35.11%, GG 6.38% in the control group (P < 0.01). The frequency of G allele was significantly higher than that in the control group (38.30% vs 21.28%, P < 0.01). The relative risk was 2.2838, and 95% confidence interval was 1.0026 to 5.2026, adjusted age, sex, blood pressure, BMI, blood lipid levels and IL-6 (P < 0.05). The recurrent rate was 25.53% at 1-year follow-up; the recurrent rate among carriers with wild-type G allele (CG + GG genotype) was 32.76%, but CC 13.89% (P < 0.01). IL-6 G allele promoter increased stroke recurrent risk, therefore, it would be a predictor for recurrence of stroke in the young with moderate internal carotid artery stenosis.

Reduction of Uterine Perfusion Pressure Induced Redistribution of Endothelin Receptor Type-B Between the Intima and Media Contributes to the Pathogenesis of Pregnancy-Induced Hypertension.

BACKGROUND/AIMS: Studies have shown that a change in endothelin receptor expression in the artery is related to pregnancy-induced hypertension (PIH). However, the mechanism underlying this change remains unclear. METHODS: To test whether the distribution of endothelin receptor type-A (ETAR) and type-B (ETBR) plays an important role in PIH, a reduction of uterine perfusion pressure (RUPP) rat model was used to mimic some of the features of PIH; the resulting variable endothelin receptor expression was investigated in the media and intima of the aorta. Single vascular smooth muscle cells (VSMCs) were isolated from RUPP and normal pregnant (NP) rats to study the effect of ETAR and ETBR in smooth muscle cells. RESULTS: Compared with NP rats, RUPP rats had a significant redistribution of ETBR expression in the intima and media, while there was no significant difference in ETAR expression between the two groups. ETBR upregulation in VSMCs enhanced cellular contraction and contributed to PIH. The TNF-α plasma levels in RUPP rats were two-fold higher than those of NP rats, which upregulated the expression of ETBR in VSMCS through the NF-κB pathways in RUPP rats. CONCLUSION: Redistribution of ETBR between the media and intima played an important role in the pathogenesis of PIH.

Adaptive regulation of endothelin receptor type-A and type-B in vascular smooth muscle cells during pregnancy in rats.

Normal pregnancy is associated with systemic vasodilation and decreased vascular contraction, partly due to increased release of endothelium-derived vasodilator substances. Endothelin-1 (ET-1) is an endothelium-derived vasoconstrictor acting via endothelin receptor type A (ETA R) and possibly type B (ETB R) in vascular smooth muscle cells (VSMCs), with additional vasodilator effects via endothelial ETB R. However, the role of ET-1 receptor subtypes in the regulation of vascular function during pregnancy is unclear. We investigated whether the decreased vascular contraction during pregnancy reflects changes in the expression/activity of ETAR and ETBR. Contraction was measured in single aortic VSMCs isolated from virgin, mid-pregnant (mid-Preg, day 12), and late-Preg (day 19) Sprague-Dawley rats, and the mRNA expression, protein amount, tissue and cellular distribution of ETAR and ETBR were examined using RT-PCR, Western blots, immunohistochemistry, and immunofluorescence. Phenylephrine (Phe, 10(-5) M), KCl (51 mM), and ET-1 (10(-6) M) caused VSMC contraction that was in late-Preg < mid-Preg and virgin rats. In VSMCs treated with ETB R antagonist BQ788, ET-1 caused significant contraction that was still in late-Preg < mid-Preg and virgin rats. In VSMCs treated with the ETAR antagonist BQ123, ET-1 caused a small contraction; and the ETBR agonists IRL-1620 and sarafotoxin 6c (S6c) caused similar contraction that was in late-Preg < mid-Preg and virgin rats. RT-PCR revealed similar ETAR, but greater ETBR mRNA expression in pregnant versus virgin rats. Western blots revealed similar ETAR, and greater protein amount of ETBR in endothelium-intact vessels, but reduced ETBR in endothelium-denuded vessels of pregnant versus virgin rats. Immunohistochemistry revealed prominent ETBR staining in the intima, but reduced ETAR and ETBR in the aortic media of pregnant rats. Immunofluorescence signal for ETAR and ETBR was less in VSMCs of pregnant versus virgin rats. The pregnancy-associated decrease in ETAR- and ETBR-mediated VSMC contraction appears to involve downregulation of ETAR and ETBR expression/activity in VSM, and may play a role in the adaptive vasodilation during pregnancy.

The limiting zero dynamics of discrete-time system based on forward triangle sample-and-hold.

Zero dynamics have crucial effect on system analysis and controller design. In the control analysis process, system performance is influenced by the unstable zero dynamics, greatly. This study concerns with the properties of limiting zero dynamics when the signal of controlled continuous-time systems was reconstructed by forward triangle sample-and-hold (FTSH). FTSH is a newly sample and hold method in the signal reconstruction area. However, more theoretical details about the limiting zero dynamics of the resulting discrete-time systems need to be revealed. Firstly, the framework for the limiting zero dynamics in the situation of sufficiently small or large sample period is introduced. Furthermore, this study provides the stable conditions of limiting zeros in the two different sampling situations. The results indicate that one can select a suitable variable parameter value of FTSH to replace the sampling zeros of discrete-time system locate inside the stable region. This paper also reveals the truth that FTSH has the outstanding advantage compared with the BTSH using theoretical analysis method. Finally, example simulations verify the effectiveness of the results in this study.

Oral nifedipine may be a preferential option for treating acute severe hypertension during pregnancy: a meta-analysis.

AIM: To compare oral nifedipine and intravenous labetalol in the treatment of acute severe hypertension in pregnancy (SHP). METHODS: The primary outcomes were the required time to achieve target blood pressure (RTATBP), systolic blood pressure (SBP) and diastolic BP (DBP) after treatment, secondary outcomes were the number of doses (NoD) and adverse events (AEs). RESULTS: There was no difference between oral nifedipine and intravenous labetalol in SBP, DBP, and AE. However, oral nifedipine provided less RTATBP and NoD. CONCLUSION: Oral nifedipine was associated with less RTATBP and NoD and otherwise did not differ from intravenous labetalol.

Expression level and clinical significance of LncRNA PVT1 in the serum of patients with LEASO.

Objective: Our study aims to investigate the long non-coding RNA plasmacytoma variant translocation 1 (lncRNA PVT1) in lower extremity arteriosclerosis obliterans (LEASO) patient serum and its clinical significance in LEASO. Patients and Methods: From July 2021 to April 2022, 133 LEASO patients diagnosed at the Qingdao Municipal Hospital were included. Among them, 44 complicated with coronary artery disease (CAD) were classified as the LEASO with CAD group. The remaining 89 were marked as the LEASO group, which was classified into single (n = 48) and double (n = 41) lower limb groups, with the former being subclassified into the left (n = 28) and right (n = 20) lower limb groups based on the affected sites. Fifty healthy individuals who came to our hospital for physical examination during the same period were randomly included and defined as the Healthy Control group. PVT1 expression was detected in serum samples from each group using a quantitative reverse transcriptase-polymerase chain reaction , and differences in expression levels were calculated. The ankle-brachial index (ABI) of patients in the LEASO group was measured using a sphygmomanometer, and its correlation with PVT1 was analyzed. Clinical data and laboratory test results (including blood routine, liver and renal function, and blood lipids) were collected for all patients upon admission. Logistic regression analyses were performed to determine the influence of PVT1 and laboratory test results on LEASO. The diagnosis and prediction of LEASO were obtained by combing PVT1 with laboratory test indicators. Results: It was found that lncRNA PVT1 expression was the highest in the serum of the LEASO with CAD group, followed by the LEASO and control groups (P < 0.05). Within the LEASO group, no significant difference in PVT1 expression was seen between the left and right limbs (P > 0.05), nor between the single and double lower limb groups. Furthermore, the PVT1 expression increased with the Rutherford grades, indicating a negative correlation between PVT1 and ABI. Logistic regression analysis revealed that triglycerides (OR = 2.972, 95% CI [1.159-7.618]), cholesterol (OR = 6.655, 95% CI [1.490-29.723]), C-reactive protein (OR = 1.686, 95% CI [1.218-2.335]), and PVT1 (OR = 2.885, 95% CI [1.350-6.167]) were independent risk factors for LEASO. Finally, strong sensitivity was observed in the receiver operating characteristic curve when combining PVT1 with meaningful laboratory indicators to diagnose and predict LEASO. Conclusion: lncRNA PVT1 promotes LEASO occurrence and progression and is related to atherosclerosis severity. The expression of PVT1 was negatively correlated with ABI. Logistic regression analysis suggested that blood lipid levels and inflammatory reactions might be related to LEASO occurrence. PVT1 was incorporated into laboratory indicators to predict LEASO. The subject's working curve area was large, and the prediction results were highly sensitive.

HOXA cluster antisense RNA 2 elevates KIAA1522 expression through microRNA-520d-3p and insulin like growth factor 2 mRNA binding protein 3 to promote the growth of vascular smooth muscle cells in thoracic aortic aneurysm.

AIMS: Recently, long non-coding RNAs (lncRNAs) have been revealed to mediate smooth muscle dysfunction in thoracic aortic aneurysm (TAA). LncRNA HOXA-AS2 has been proposed to engage in the regulation of diverse diseases. However, its function in TAA remains unknown. This study aimed to reveal the role and mechanism of HOXA-AS2 in VSMCs which were implicated in TAA formation. METHODS AND RESULTS: RT-qPCR or western blot was performed to detect RNA or protein expression levels. The role of HOXA-AS2 in VSMCs was explored by functional assays. The relationship among HOXA-AS2/miR-520d-3p/KIAA1522/IGF2BP3 was analysed via mechanism assays. HOXA-AS2 was detected to have significantly high expression in TAA tissues and function as an oncogene to promote proliferation of VSMCs, while inhibiting cell apoptosis (Figure 1, **P < 0.01). HOXA-AS2 was unveiled to bind with miR-520d-3p (Figure 2, *P < 0.05, **P < 0.01) and further up-regulate KIAA1522 to facilitate the growth of VSMCs (Figure 3-4, *P < 0.05, **P < 0.01). HOXA-AS2 was also found to recruit IGF2BP3 to stabilize KIAA1522 mRNA (Figure 5, **P < 0.01). All data were displayed as mean ± standard deviation. CONCLUSIONS: HOXA-AS2 up-regulates KIAA1522 through targeting miR-520d-3p/IGF2BP3 to drive VSMC growth in TAA.

Retraction Notice to: Overexpression of MicroRNA-340-5p Inhibits Pulmonary Arterial Hypertension Induced by APE by Downregulating IL-1ß and IL-6.

[This retracts the article DOI: 10.1016/j.omtn.2020.05.022.].

Mussel-Inspired and In Situ Polymerization-Modified Commercial Sponge for Efficient Crude Oil and Organic Solvent Adsorption.

Oil spills and pollution of oily wastewater from the industrial field have not only caused serious economic losses but also imposed a huge threat to human beings. To solve these issues, the development of advanced materials and technologies for the purification of oily wastewater has garnered great concern and become a central topic. Hence, a superhydrophobic polyurethane (PU) sponge adsorbent is designed via mussel-inspired coatings by double bonds to PU sponge, followed by in situ polymerization with 1-hexadecene. The prepared PU sponge adsorbent (PU@DB@16ene sponge) showed outstanding mechanical properties including low density, high porosity, and compression recovery ability. Moreover, the prepared PU@DB@16ene sponge showed excellent adsorption of oils and organic solvents (up to 187 g g-1) and exhibited superior recyclability. Particularly, when the PU@DB@16ene sponge was applied in the continuous and rapid separation of oils and organic solvents, it still showed desired properties at a rapid velocity of 8.3 L m-3 s-1. Additionally, the PU@DB@16ene sponge could not only adsorb organic solvents in laboratories but also adsorb crude oil and industrial waxy oil in practice. Therefore, we proposed a simple and convenient method to construct PU sponge absorbents with great application prospects, which would be highly valuable for crude oil and organic solvents cleanup.

Emerging roles of let­7d in attenuating pulmonary arterial hypertension via suppression of pulmonary artery endothelial cell autophagy and endothelin synthesis through ATG16L1 downregulation.

Pulmonary arterial hypertension (PAH) is a severe disease characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance, resulting in right ventricular failure and death. Compelling evidence has suggested the roles of microRNAs (miRNAs/miRs) in PAH. The present study investigated the possible effects of miR­let­7d on PAH through autophagy­related 16­like 1 (ATG16L1). Initially, the serum levels of let­7d in PAH patients were detected. Rats were then treated with monocrotaline to induce a rat model of PAH, after which the right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI) were determined. Next, the putative binding sites between let­7d and ATG16L1 were detected. The expression of let­7d and ATG16L1 in PAH rat models and cells was upregulated or downregulated to assess the effects of these molecules on autophagy in pulmonary artery vascular endothelial cells (PAECs) and on endothelin synthesis. In addition, the levels of p62, LC3­I, LC3­II, LC3B and endothelin­1 (ET­1) were assessed. The results obtained revealed that let­7d was downregulated in the serum of PAH patients and rats with PAH. Importantly, ATG16L1 was found to be a target gene of let­7d and let­7d could suppress the expression of ATG16L1. Overexpression of let­7d was found to reduce RVSP and RVHI values. Additionally, upregulation of let­7d or depletion of ATG16L1 led to suppression of PAEC autophagy and endothelin synthesis, corresponding to decreased ratios of LC3­II to LC3­I and reduced levels of LC3B but elevated levels of p62 in PAECs and ET­1 in plasma and lung tissues. In summary, let­7d upregulation alleviates PAH by inhibiting autophagy in PAECs and suppressing endothelin synthesis through negative regulation of ATG16L1.

Long non-coding RNA CDKN2B-AS1 contributes to atherosclerotic plaque formation by forming RNA-DNA triplex in the CDKN2B promoter.

BACKGROUND: Atherosclerosis involves a slow process of plaque formation on the walls of arteries, and comprises a leading cause of cardiovascular disease. Long non-coding RNAs (lncRNAs) have been implicated in the pathogenesis of atherosclerosis. In this study, we aim to explore the possible involvement of lncRNA 'cyclin-dependent kinase inhibitor 2B antisense noncoding RNA' (CDKN2B-AS1) and CDKN2B in the progression of atherosclerosis. METHODS: Initially, we quantified the expression of CDKN2B-AS1 in atherosclerotic plaque tissues and, in THP-1 macrophage-derived, and human primary macrophage (HPM)-derived foam cells. Next, we established a mouse model of atherosclerosis using apolipoprotein E knockout (ApoE-/-) mice, where lipid uptake, lipid accumulation, and macrophage reverse cholesterol transport (mRCT) were assessed, in order to explore the contributory role of CDKN2B-AS1 to the progression of atherosclerosis. RIP and ChIP assays were used to identify interactions between CDKN2B-AS1, CCCTC-binding factor (CTCF), enhancer of zeste homologue 2 (EZH2), and CDKN2B. Triplex formation was determined by RNA-DNA pull-down and capture assay as well as EMSA experiment. FINDINGS: CDKN2B-AS1 showed high expression levels in atherosclerosis, whereas CDKN2B showed low expression levels. CDKN2B-AS1 accelerated lipid uptake and intracellular lipid accumulation whilst attenuating mRCT in THP-1 macrophage-derived foam cells, HPM-derived foam cells, and in the mouse model. EZH2 and CTCF were found to bind to the CDKN2B promoter region. An RNA-DNA triplex formed by CDKN2B-AS1 and CDKN2B promoter was found to recruit EZH2 and CTCF in the CDKN2B promoter region and consequently inhibit CDKN2B transcription by accelerating histone methylation. INTERPRETATION: The results demonstrated that CDKN2B-AS1 promotes atherosclerotic plaque formation and inhibits mRCT in atherosclerosis by regulating CDKN2B promoter, and thereby could be a potential therapeutic target for atherosclerosis.

Downregulation of interleukin-6 and C-reactive protein underlies a novel inhibitory role of microRNA-136-5p in acute lower extremity deep vein thrombosis.

Deep vein thrombosis (DVT) comprises a critical and common health condition with high incidence, mortality, and long-term adverse sequelae. Several differentially expressed microRNAs (miRNAs) have emerged as promising prognostic markers in DVT. The present study intended to explore the functional relevance of miR-136-5p in acute lower extremity DVT (LEDVT). Rat models of acute LEDVT were established and miR-136-5p expression was altered by agomir or antagomir to assess its effects. In addition, in vitro gain- and loss-experiments, prior to exposure to CoCl2, were performed to investigate effects of miR-136-5p on human umbilical vein endothelial cell (HUVEC) apoptosis and levels of interleukin-6 (IL-6) and C-reactive protein (CRP). miR-136-5p was downregulated, whereas IL-6 and CRP were elevated in acute LEDVT patients. Notably, miR-136-5p was confirmed to target both IL-6 and CRP. Overexpression of miR-136-5p led to reduced length, weight, and ratio of weight to length of the venous thrombus. Furthermore, overexpressed miR-136-5p downregulated the expression of IL-6 and CRP, consequently inhibiting HUVEC apoptosis. Conjointly, our data indicate that the overexpression of miR-136-5p has the potential to bind to the 3'-UTR in the mRNAs for IL-6 and CRP and mitigate acute LEDVT, which provides a basis for new therapeutic targets in acute LEDVT treatment.

Overexpression of MicroRNA-340-5p Inhibits Pulmonary Arterial Hypertension Induced by APE by Downregulating IL-1ß and IL-6.

Pulmonary arterial hypertension (PAH) is a fatal cardiovascular disease that could eventually result in right ventricular failure. Recently, the roles of microRNAs (miRNAs) in PAH have been highlighted. The present study aims to investigate the effects of miRNA (miR)-340-5p on PAH induced by acute pulmonary embolism (APE) and the underlying mechanisms. miR-340-5p was lowly expressed, whereas interleukin 1ß (IL-1ß) and IL-6 were highly expressed in plasma of APE-PAH patients as compared to normal human plasma. Subsequently, IL-1ß and IL-6 were confirmed to be two target genes of miR-340-5p using a dual-luciferase reporter gene assay. By conducting overexpression and rescue experiments, overexpression of miR-340-5p was evidenced to inhibit proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) and inflammation via reducing IL-1ß and IL-6 levels. Meanwhile, miR-340-5p led to the blocked nuclear factor κB (NF-κB) pathway with reduced NF-κB p65, matrix metalloproteinase 2 (MMP2), and MMP9 expression in PASMCs. Finally, the ameliorative effect of miR-340-5p on pathological lesions was further verified in rat models of APE-PAH. Altogether, overexpressed miR-340-5p inhibited the inflammatory response, proliferation, and migration of PASMCs by downregulating IL-1ß and IL-6, thereby suppressing the progression of APE-PAH. miR-340-5p therefore holds promise as an anti-inflammatory therapeutic target.

Upregulated MiR-9-5p Protects Against Inflammatory Response in Rats with Deep Vein Thrombosis via Inhibition of NF-κB p50.

Recently, microRNAs (miRNAs) have been demonstrated to play important roles in the cardiovascular system, including heart, blood vessels, plasma, and vascular diseases. Deep vein thrombosis (DVT) refers to the formation of blood clot in the deep veins of the human body and is a common peripheral vascular disease. Herein, we explored the mechanism of miR-9-5p in DVT through nuclear factor-κB (NF-κB). The expression of miR-9-5p in DVT rats was measured through the establishment of DVT rat models, followed by the alteration of miR-9-5p and NF-κB p50 in rats through the injection of constructed lentiviral vectors so as to explore the role of miR-9-5p and NF-κB p50 expression in rats. Next, the expression of NF-κB p50 and levels of inflammation-related factors plasminogen activator inhibitor-1 (PAI-1), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and interleukin-8 (IL-8) were measured after the injection with lentiviral vectors, followed by the assessment of platelet aggregation and TXB2 content. MiR-9-5p was found to be downregulated in DVT rats. Through dual luciferase reporter gene assay, NF-κB p50 was verified as the target gene of miR-9-5p and miR-9-5p could negatively regulate NF-κB p50. MiR-9-5p over-expression decreased the levels of PAI-1, TNF-α, IL-6, and IL-8 and platelet aggregation as well as TXB2 content, thus inhibiting thrombosis. Meanwhile, over-expressed NF-κB p50 could reverse the anti-inflammatory or anti-thrombotic effect of miR-9-5p. In summary, miR-9-5p over-expression can suppress the NF-κB signaling pathway through p50 downregulation, thus alleviating inflammation and thrombosis in DVT rats. MiR-9-5p could serve as a potential therapeutic target for DVT.

A polysaccharide from Sargassum thunbergii inhibits angiogenesis via downregulating MMP-2 activity and VEGF/HIF-1α signaling.

A water-soluble polysaccharide (STPC2) was isolated from the boiling-water extract of Sargassum thunbergii, purified by CaCl2 precipitation and chromatography on DEAE-cellulose and Sephacryl S-300 column. It was found that STPC2, with a molecular weight of 57kD, was composed of fucose, xylose, galactose and glucuronic acid, in a ratio of 8.1: 3.8: 2.1: 1.0. Additionally, we found that STPC2 significantly inhibited endothelial cell migration and tube formation without toxicity. Moreover, STPC2 significantly inhibited lung cancer cell A549 migration and proliferation. It was found that STPC2 treatment suppressed MMP-2 gene expression at transcriptional level and enzymatic activity. Furthermore, STPC2 reduced the mRNA and protein expression of vascular endothelial growth factor-A (VEGF-A) and hypoxia-inducible factor (HIF)-1 alpha in the endothelial cells. Taken together, our findings indicated that STPC2 was a potent bioactive polysaccharide with distinct anti-angiogenesis activity against tumor migration via down-regulation of MMP-2 activity and VEGF/HIF-1α signaling pathway.

Epidermal growth factor (EGF) triggers the malignancy of hemangioma cells via activation of NF-κB signals.

Hemangioma (HA) is tumor formed by hyper-proliferation of vascular endothelial cells. However, the role and mechanisms of epidermal growth factor (EGF) on the progression of HA are not well illustrated. Our present study revealed that EGF can significantly promote the in vitro proliferation and motility of HA cells, which was confirmed by the up regulation of Bcl-2, proliferating cell nuclear antigen (PCNA), and metalloproteinase-2 (MMP-2) and MMP-9. The pharmacological inhibition of NF-κB, while not ERK1/2 or PI3K/Akt, attenuated EGF induced cell proliferation and expression of MMP-2 and MMP-9. EGF treatment also increased the phosphorylation, nuclear translocation and transcriptional activities of NF-κB in HA cells. These data suggested that NF-κB plays an essential role in EGF induced malignancy of HA cells. Furthermore, EGF treatment also increased the phosphorylation of IκB and IKKα, while not IKKß or IKKγ. The knockdown of IKKα reversed EGF induced activation of NF-κB. EGF treatment also decreased the phosphorylation of GSK-3ß and increased its activities in both HDEC and CRL-2586 EOMA cells. LiCl, a potent GSK-3ß inhibitor, can obviously reverse EGF induced up regulation of p65 phosphorylation. Collectively, our study revealed that EGF can trigger the malignancy of HA cells via induction of proliferation and invasion. The activation of NF-κB through IKKα/IκBα and GSK-3ß signal is essential for this process. It suggested that EGF/NF-κB signal may represent a novel therapeutic target for the treatment of human HA.