Modulation Of Angiogenesis Research Articles

Abstract 2627: Inhibition of TGFβ in colorectal cancer cells is associated with a compensatory activation of AXL and p38 MAPK signaling pathways

Abstract According to the consensus molecular subtypes (CMS), almost 23% of human colorectal cancer (CRC) are classified in the CMS4 group, characterized by a mesenchymal signature and the activation of transforming growth factor β (TGF-β) signaling. AXL is a tyrosine kinase receptor involved in epithelial to mesenchymal transition, angiogenesis and immune modulation in CRC. We have previously demonstrated that AXL gene is amplified in approximately 5% of human CRC, and that AXL inhibition causes a significant blockade of CRC cell proliferation and migration. Here we have evaluated the role of TGF-β signaling and the potential interaction between TGF-β and AXL in human CRC cell lines. We assessed the expression and activation of TGF-β and AXL in a panel of six human CRC cell lines by western blot (WB) and real time PCR. We tested the sensitivity of HCT116 and LOVO cells to treatment with galunisertib ( LY21209761), a selective TGF-β R1 inhibitor, by MTT, cell invasion, wound healing and soft-agar colony forming assays. Further, intracellular CRC cell signaling was evaluated following galunisertib treatment by WB. TGF-β receptors 1 and 2 were expressed in all human CRC cell lines (HCT116, SW480, LOVO, LIM 1215, SW48 and CaCo2), whereas AXL expression was restricted to HCT116, SW480, LOVO cells. Treatment with galunisertib had little or no effect on cancer cell growth, whereas it partially reduced TGF-β induced cell migration, invasion and colony formation in HCT116 and LOVO cells (that co-expressed both TGF-β receptors and AXL). Interestingly, TGF-β inhibition resulted in a concomitant significant activation of AXL and p38 MAPK in both cell lines, that could represent a cancer cell adaptive mechanism of resistance to galunisertib treatment. These results suggest a potential functional cross talk between TGF-β, AXL and p38 MAPK signals in human CRC cells. In this respect, further experiments are ongoing to better understand this interaction with the aim of identifying potential novel anti-AXL and anti-TGF-β therapeutic strategies. Citation Format: Davide Ciardiello, Pietro Paolo Vitiello, Nunzia Matrone, Valentina Belli, Claudia Cardone, Luca Poliero, Carola Borrelli, Gianluca Arrichiello, Giulia Martini, Vincenza Ciaramella, Giusi Barra, Floriana Morgillo, Teresa Troiani, Davide Melisi, Fortunato Ciardiello, Erika Martinelli. Inhibition of TGFβ in colorectal cancer cells is associated with a compensatory activation of AXL and p38 MAPK signaling pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2627.

Downregulation of microRNA‑451 improves cell migration, invasion and tube formation in hypoxia‑treated HUVECs by targeting MIF.

Angiogenesis is a critical process of recovery from cerebrovascular disease. A growing body of evidence has confirmed that microRNAs (miRNAs/miRs) have an important role in the modulation of angiogenesis under physiological and pathological conditions including cerebral ischemia injury (CII). Therefore, the aim of the present study was to explore the function and mechanism of microRNAs in regulating angiogenesis using a cell model of CII. Firstly, a miRNA microarray was performed to analyze miRNA expression in serum samples from patients with cerebral ischemia and the results revealed that miR-451 was one of the miRNAs that was the most significantly downregulated. Subsequently, human umbilical vein endothelial cells (HUVECs) were used as an in vitro model to further explore the mechanisms governing angiogenesis during hypoxia. The results demonstrated that overexpression of miR-451 had a significantly anti-angiogenic effect by suppressing tube formation, migration and wound healing in vitro. By contrast, reducing the expression of miR-451 promoted HUVEC migration and tubulogenesis under normoxic conditions. The present study further identified that macrophage migration inhibitory factor (MIF), an important angiogenic regulator, was a novel target of miR-451 that could reverse the effects of miR-451 on the regulation of angiogenesis in HUVECs under hypoxic or normoxic conditions. These results revealed that downregulation of miR-451 promotes angiogenesis by targeting MIF in hypoxic HUVECs and indicated that miR-451 is a potential candidate for CII therapeutics.

Curcumin as an Alternative Epigenetic Modulator: Mechanism of Action and Potential Effects.

Curcumin (a polyphenolic compound in turmeric) is famous for its potent anti-inflammatory, anti-oxidant, and anti-cancer properties, and has a great potential to act as an epigenetic modulator. The epigenetic regulatory roles of curcumin include the inhibition of DNA methyltransferases (DNMTs), regulation of histone modifications via the regulation of histone acetyltransferases (HATs) and histone deacetylases (HDACs), regulation of microRNAs (miRNA), action as a DNA binding agent and interaction with transcription factors. These mechanisms are interconnected and play a vital role in tumor progression. The recent research has demonstrated the role of epigenetic inactivation of pivotal genes that regulate human pathologies such as cancers. Epigenetics helps to understand the mechanism of chemoprevention of cancer through different therapeutic agents. In this regard, dietary phytochemicals, such as curcumin, have emerged as a potential source to reverse epigenetic modifications and efficiently regulate the expression of genes and molecular targets that are involved in the promotion of tumorigenesis. The curcumin may also act as an epigenetic regulator in neurological disorders, inflammation, and diabetes. Moreover, curcumin can induce the modifications of histones (acetylation/deacetylation), which are among the most important epigenetic changes responsible for altered expression of genes leading to modulating the risks of cancers. Curcumin is an effective medicinal agent, as it regulates several important molecular signaling pathways that modulate survival, govern anti-oxidative properties like nuclear factor E2-related factor 2 (Nrf2) and inflammation pathways, e.g., nuclear factor kappa B (NF-κB). Curcumin is a potent proteasome inhibitor that increases p-53 level and induces apoptosis through caspase activation. Moreover, the disruption of 26S proteasome activity induced by curcumin through inhibiting DYRK2 in different cancerous cells resulting in the inhibition of cell proliferation opens up a new horizon for using curcumin as a potential preventive and treatment approach in proteasome-linked cancers. This review presents a brief summary of knowledge about the mechanism of epigenetic changes induced by curcumin and the potential effects of curcumin such as anti-oxidant activity, enhancement of wound healing, modulation of angiogenesis and its interaction with inflammatory cytokines. The development of curcumin as a clinical molecule for successful chemo-prevention and alternate therapeutic approach needs further mechanistic insights.

Circulating Exosomal miR-141-3p and miR-375 in Metastatic Progression of Rectal Cancer

As many as 30% to 40% of locally advanced rectal cancer (LARC) patients experience metastatic progression of the disease. Recognizing the potential of the genetic cargo in tumor-derived exosomes, we hypothesized that plasma exosomal microRNA (miRNA) may reflect biological aggressiveness in LARC and provide new markers for rectal cancer aggressiveness and risk stratification. In a prospective LARC cohort (NCT01816607), plasma samples were collected from 29 patients at the time of diagnosis, before neoadjuvant therapy and surgery. Exosomes, precipitated from plasma using a commercial kit, were verified by cryo-electron microscopy, nanoparticle tracking analysis, and western blotting. Expression of exosomal miRNAs was profiled using a miRCURY LNA miRNA microarray and validation of six miRNAs associated with pathological and clinical end-points was undertaken in plasma collected at the time of diagnosis from 64 patients in an independent prospective LARC cohort (NCT00278694). In both cohorts, exosomal miR-141-3p and miR-375 were higher in patients with synchronous liver metastasis than in those without (P = .010 and P = .017 respectively in the investigative cohort, and P < .001 for both in the validation cohort). Further, high exosomal miR-141-3p was associated with post-operative metastatic liver progression in the investigative cohort (P = .034). Because both miRNAs are associated with tumor angiogenesis and immune modulation, we propose that these miRNAs in circulating exosomes may reflect rectal cancer aggressiveness and accordingly be candidate biomarkers for further investigations.

High mitogenic stimulation arrests angiogenesis

Appropriate therapeutic modulation of endothelial proliferation and sprouting is essential for the effective inhibition of angiogenesis in cancer or its induction in cardiovascular disease. The current view is that an increase in growth factor concentration, and the resulting mitogenic activity, increases both endothelial proliferation and sprouting. Here, we modulate mitogenic stimuli in different vascular contexts by interfering with the function of the VEGF and Notch signalling pathways at high spatiotemporal resolution in vivo. Contrary to the prevailing view, our results indicate that high mitogenic stimulation induced by VEGF, or Notch inhibition, arrests the proliferation of angiogenic vessels. This is due to the existence of a bell-shaped dose-response to VEGF and MAPK activity that is counteracted by Notch and p21, determining whether endothelial cells sprout, proliferate, or become quiescent. The identified mechanism should be considered to achieve optimal therapeutic modulation of angiogenesis.

Is There A Role for Abscisic Acid, A Proven Anti-Inflammatory Agent, in the Treatment of Ischemic Retinopathies?

Ischemic retinopathies (IRs) are the main cause of severe visual impairment and sight loss, and are characterized by loss of blood vessels, accompanied by hypoxia, and neovascularization. Actual therapies, based on anti-vascular endothelial growth factor (VEGF) strategies, antioxidants or anti-inflammatory therapies are only partially effective or show some adverse side effects. Abscisic acid (ABA) is a phytohormone present in vegetables and fruits that can be naturally supplied by the dietary intake and has been previously studied for its benefits to human health. It has been demonstrated that ABA plays a key role in glucose metabolism, inflammation, memory and tumor growth. This review focuses on a novel and promising role of ABA as a potential modulator of angiogenesis, oxidative status and inflammatory processes in the retina, which are the most predominant characteristics of the IRs. Thus, this nutraceutical compound might shed some light in new therapeutic strategies focused in the prevention or amelioration of IRs-derived pathologies.

Angiopoietin-like 4 production upon treatment with hypoxia and L-mimosine in periodontal fibroblasts.

Background and objectiveA key factor in the modulation of angiogenesis as well as in bone resorption is angiopoietin‐like 4. However, the role of angiopoietin‐like 4 in periodontal tissue is unknown. Here, we hypothesized that hypoxia and the hypoxia mimetic agent L‐mimosine can induce the production of angiopoietin‐like 4 in periodontal fibroblasts.MethodsHuman periodontal ligament fibroblasts (PDLF) were cultured in monolayer and spheroid cultures. The cultures were incubated in the presence of hypoxia or L‐mimosine. Angiopoietin‐like 4 mRNA and protein levels were measured by qPCR and ELISA, respectively. Also, the impact of Lipopolysaccharides of E. coli and P. gingivalis, interleukin (IL)‐1β and tumor necrosis factor (TNF)α was evaluated. Furthermore, we tested dependency on hypoxia‐inducible factor (HIF)‐1 activity by Western blotting for HIF‐1 and inhibitor studies with echinomycin. Potential autocrine effects were assessed by exposure of PDLF to recombinant angiopoietin‐like 4 in full length, C‐terminal and N‐terminal fragments. The impact on viability, DNA synthesis, alkaline phosphatase, and matrix mineralization was evaluated.ResultsBoth hypoxia and L‐mimosine elevated angiopoietin‐like 4 mRNA and protein levels in monolayer cultures of PDLF. HIF‐1 was elevated after both hypoxia and L‐mimosine treatment. LPS, IL‐1β, and TNFα did not modulate angiopoietin‐like 4 levels significantly. Addition of echinomycin in the cultures inhibited the production of angiopoietin‐like 4. In spheroid cultures of PDLF, the increase did not reach the level of significance at mRNA and protein levels. Angiopoietin‐like 4 in full length, C‐terminal, and N‐terminal fragments did not modulate viability, DNA synthesis, alkaline phosphatase, and matrix mineralization.ConclusionOverall, we found that hypoxia and the hypoxia mimetic agent L‐mimosine can stimulate angiopoietin‐like 4 production in monolayer cultures of PDLF. This increase depends on HIF‐1 activity. Future studies will reveal how the modulation of angiopoietin‐like 4 in the periodontium contributes to periodontal disease and regeneration.

Allicin-induced modulation of angiogenesis in lung cancer cells (A549)

Purpose: To investigate the effectiveness of allicin as a candidate for lung cancer therapy.Methods: Allicin solution at different concentrations was tested on A549 lung cancer cell line. Viability and proliferation of A549 cells were determined. The cytotoxic effects of allicin solution on A549 lung cancer cells were quantitatively determined using Alamar blue assay. Cell proliferation and cell cycle were measured by DAPI-flow cytometry analysis in order to investigate the possible cell signalling pathway targeted by allicin. The level of expression of VEGF-A protein was determined with confocal laser scanning microscopy.Results: Allicin inhibited lung cancer proliferation and down-regulated the protein expression of VEGF, but had no significant cytotoxic effects on A549 cells. Flow cytometric results showed that allicin induced cell cycle arrest of A549 cells at the G1 phase.Conclusion: These results indicate that allicin exerts anti-proliferative effects on A549 lung cancer cells. Thus allicin, an active component of garlic, might be a promising therapy against lung cancer metastasis.Keywords: A549 cells, Allicin, qPCR Taqman assay, VEGF-A protein expression, Garlic, Lung cancer

Prostaglandin-mediated effects in early canine corpus luteum: In vivo effects on vascular and immune factors

Prostaglandins (PGs) are important regulators of the early corpus luteum (CL) in the dog. Whereas, initially, CL is gonadotropin independent, in the second half of its lifespan, hypophyseal support is required. The transition period is marked by decreased availability of PGs, in particular of PGE2. We previously reported that inhibition of COX2/PTGS2 in vivo suppressed luteal production of PGE2, lowered circulating progesterone and negatively affected luteal development. Therefore, bitches were treated with a COX2-specific blocker, firocoxib, for 5, 10, 20 and 30 days after ovulation, leading to suppression of the steroidogenic machinery. Control groups received a placebo for the same periods. Considering the wide range of possible modulatory roles of PGs shown in different organ systems, this follow-up project aimed to understand further possible PG-mediated effects in early canine CL. Thirty-four (34) factors related predominantly to vascularization and immune response were screened (mRNAs and proteins) on samples from the above described in vivo study. Most of the effects were observed during the transitional period (days 20 and 30). The inhibition of COX2 diminished the expression of angiopoietin family members ANGPT1, -2, Tie1 and -2 receptors. The expression of endothelin (ET)-1 was increased. Concerning the immune system, increased expression of the pro-inflammatory cytokines, IL1β, IL6 and IL12a, and elevated expression levels of CD4, was observed. Cumulatively, besides its involvement in regulating steroidogenesis, our results indicate a broader role of PGs in the canine CL, including modulation of angiogenesis, vascular stabilization and local immunomodulation. Possible cross-species translational effects are strongly implied.

AA genotype of deSNP rs6726639 of MERTK gene is associated with development of Hepatocellular Carcinoma after eradication of Hepatitis C Virus infection

Background and aims: In patients with cirrhosis, the risk for hepatocellular carcinoma (HCC) development after hepatitis C virus (HCV) clearance is not canceled altogether. MERTK (MER-Tyrosine Kinase) gene, located in chromosome 2, is a regulator of tumor-associated macrophages (TMA) involved in the modulation of inflammatory responses and angiogenesis. We evaluated the role of the Single Nucleotide Polymorphism (deSNP) rs6726639 of MERTK gene in the development of HCC in patients with a sustained virologic response (SVR) after treatment with Direct Antiviral Agents (DAAs).

Mucoadhesive formulation containing Curcuma longa L. reduces oral mucositis induced by 5-fluorouracil in hamsters.

We explored the effects of a mucoadhesive formulation containing curcuminoid (MFC) from Curcuma longa L. extract on oral mucositis (OM) induced by 5-fluorouracil (5-FU) in hamsters. Seventy-two golden Syrian hamsters were randomly allocated into four groups: control, placebo, chamomilla, and MFC. Animals received an intraperitoneal injection of 5-FU at Days 0 and 2. On Days 3 and 4, the buccal mucosa was scratched. Therapy was initiated on Day 5. Animals received two applications of the substances per day according to the experimental group. Six animals were euthanized on Days 8, 10, and 14. Clinical analysis were performed using photography and histopathological sections of 3μm were stained by hematoxylin-eosin for semiquantitative analysis of re-epithelization and inflammation. Immunohistochemistry was used for angiogenesis (CD31) and transforming growth factor beta 1 (TGF-β1) analysis. On Day 5, all groups exhibited OM. Clinical and histopathological findings revealed that on Day 8, both MFC and chamomilla groups exhibited better wound healing. In addition, the MFC group demonstrated lower angiogenesis and TGF-β1 levels on Day 8 compared with placebo and control groups. Collectively, these findings suggest that MFC has a therapeutic effect on OM, accelerating wound healing through re-epithelization and anti-inflammatory action as modulation of angiogenesis and TGF-β1 expression.

An update on angiogenesis modulators with a potential therapeutic role

Angiogenesis or formation of new blood vessels as a consequence of sprouting in a pre-existent vascular network represents a phenomenon of paramount importance in physiology and pathology. Although the molecular pathways and factors which modulate angiogenesis are similar regardless the clinical context, there are numerous aspects related to this process which are incompletely understood. At the present time, significant research focuses in finding the best method to control the pro-angiogenic factors as well as anti-angiogenesis since therapy of various medical conditions requires either stimulation or inhibition of formation of new blood vessels. However, angiogenesis is different in various vascular systems and organs. In this review, we will present the most promising factors that interfere with angiogenesis suggesting new or improved therapeutic methods in various pathological settings.

The Platelet Response to Tissue Injury.

In recent years, various studies have increasingly explained platelet functions not only in their central role as a regulator in cellular hemostasis and coagulation. In fact, there is growing evidence that under specific conditions, platelets act as a mediator between the vascular system, hemostasis, and the immune system. Therefore, they are essential in many processes involved in tissue remodeling and tissue reorganization after injury or inflammatory responses. These processes include the promotion of inflammatory processes, the contribution to innate and adaptive immune responses during bacterial and viral infections, the modulation of angiogenesis, and the regulation of cell apoptosis in steady-state tissue homeostasis or after tissue breakdown. All in all platelets may contribute to the control of tissue homeostasis much more than generally assumed. This review summarizes the current knowledge of platelets as part of the tissue remodeling network and seeks to provide possible translational implications for clinical therapy.

SATB family chromatin organizers as master regulators of tumor progression.

SATB (Special AT-rich binding protein) family proteins have emerged as key regulators that integrate higher-order chromatin organization with the regulation of gene expression. Studies over the past decade have elucidated the specific roles of SATB1 and SATB2, two closely related members of this family, in cancer progression. SATB family chromatin organizers play diverse and important roles in regulating the dynamic equilibrium of apoptosis, cell invasion, metastasis, proliferation, angiogenesis, and immune modulation. This review highlights cellular and molecular events governed by SATB1 influencing the structural organization of chromatin and interacting with several co-activators and co-repressors of transcription towards tumor progression. SATB1 expression across tumor cell types generates cellular and molecular heterogeneity culminating in tumor relapse and metastasis. SATB1 exhibits dynamic expression within intratumoral cell types regulated by the tumor microenvironment, which culminates towards tumor progression. Recent studies suggested that cell-specific expression of SATB1 across tumor recruited dendritic cells (DC), cytotoxic T lymphocytes (CTL), T regulatory cells (Tregs) and tumor epithelial cells along with tumor microenvironment act as primary determinants of tumor progression and tumor inflammation. In contrast, SATB2 is differentially expressed in an array of cancer types and is involved in tumorigenesis. Survival analysis for patients across an array of cancer types correlated with expression of SATB family chromatin organizers suggested tissue-specific expression of SATB1 and SATB2 contributing to disease prognosis. In this context, it is pertinent to understand molecular players, cellular pathways, genetic and epigenetic mechanisms governed by cell types within tumors regulated by SATB proteins. We propose that patient survival analysis based on the expression profile of SATB chromatin organizers would facilitate their unequivocal establishment as prognostic markers and therapeutic targets for cancer therapy.

The Mechanism of Exosomes Function in Neurological Diseases: A Progressive Review.

Exosomes are extracellular microparticles (≈30-100 nm in diameter) secreted from nearly all types of cells, containing a whole set of biological information including proteins, ribonucleic acid (RNA) and lipids. Latest studies show that exosomes contribute to cell-cell communication and are considered closely related with the modulation of angiogenesis and neurogenesis in many neurological diseases. In the past decade, numerous researchers were devoted to exosomes study, but the mechanism of exosomes function and delivery is uncertain. In this review, we summarized several potential mechanisms of exosomes function in angiogenesis, neurogenesis and Blood Brain Barrier (BBB) delivery, and differentiate various sources of exosomes in stroke, tumor, Traumatic Brain Injury (TBI) and Alzheimer's Disease (AD) aimed to report the most advanced mechanical theories in related past three years to provide a new sight for this research area.

NADPH oxidase 1/4 inhibition attenuates the portal hypertensive syndrome via modulation of mesenteric angiogenesis and arterial hyporeactivity in rats

NADPH oxidase (NOX)-derived reactive oxygen species (ROS) plays key roles in the development of portal hypertension (PHT) and represents a potential therapeutic method. The objective of this study was to investigate whether pharmacological inhibition of NADPH oxidase activity could ameliorate PHT in rats. PHT model was established by partial portal vein ligation (PPVL). Rats were treated with 30 mg/kg GKT137831 (the most specific Nox1/4 inhibitor) or vehicle daily by gavage for 14 days beginning at the day of PPVL or sham operation (SO). Hemodynamics, severity of portal-systemic shunting, vascular contractility, vascular endothelial growth factor (VEGF), VEGFR-2, CD31, AKT, phospho-AKT (p-AKT, at Ser473), endothelial nitric oxide synthase (eNOS), and phospho-eNOS (p-eNOS, at Ser1177) expressions were evaluated. Nitric oxide (NO) production and oxidative stress in mesenteric arteries, and hydrogen peroxide (H2O2) in both mesenteric tissues and arteries were measured. Inhibition of NOX1/4 with GKT137831 significantly decreased cardiac index, increased portal flow resistance, reduced portal pressure (PP), portal blood flow, mesenteric angiogenesis and portal-systemic shunting (PSS) in PPVL rats. GKT137831 reduced the production of H2O2, down regulated mesenteric angiogenesis markers (CD31, vascular endothelial growth factor (VEGF) and VEGFR-2 expression. Compared with controls), the mesenteric artery contraction to norepinephrine (NE) was impaired in PPVL rats, which was reversed by exposure to GKT137831. In addition, GKT137831 markedly decrease NADPH oxidase activity and ROS production in mesenteric arteries, and reduced NO production by decreasing the level of phosphor-AKT and eNOS. Inhibition of NOX1/4 decreased PP, ameliorated hyperdynamic circulation, mesenteric angiogenesis and arterial hyporesonse in portal hypertensive rats. Pharmacological inhibition of NOX1/4 activity may be a potential treatment for PHT-related complications.

Biomolecular basis related to inflammation in the pathogenesis of endometrial cancer.

Endometrial cancer (EC) is a complex gynecological neoplasm with several clinical, histopathological and genetic features. Different hormonal, metabolic and biochemical axes are involved in pathogenesis. Obesity is a well-known risk factor for this disease and the role of local and systemic effects of adipose tissue, especially in the promotion of subclinical chronic inflammation, is an important issue. Indeed, inflammation is related to the pathogenesis of different tumors, including EC. This review aims to remark the role of obesity and inflammation in the pathogenesis of EC cancer through an exploration of the current literature. We performed a comprehensive review of the literature through a PubMed search using key words and including English language papers looking at this topic. Only few authors analyzed the role of inflammatory cytokines released by adipose tissue in visceral abdominal fat depots. Tumor Necrosis Factor-α, Interleukin-6, Interleukin-1 Receptor Antagonist, Nuclear Factor-kB, Leptin, Adiponectin and C Reactive Protein were studied for cancer risk prediction models, risk stratification or targeted therapies. Furthermore, genetic studies evaluated the effect of inflammatory cytokines secreted by visceral adipocytes in the modulation of angiogenesis and signaling pathways such as PI3K/AKT/mTOR, that result altered in the pathogenesis of EC. The identification of inflammatory biomarkers released by adipose tissue, in the pathogenesis of EC, could be useful in improving diagnostic accuracy, identifying targets of therapy, suggesting useful lifestyle behaviors. A deeper knowledge of the genetic background of alterations in inflammatory pathway genes could better define the population exposed to a higher susceptibility to EC due to genetic polymorphisms. Future studies are needed to better understand this field.

Lysimachia Capillipes Inhibit Adipogenesis via Angiogenesis Inhibition.

Obesity is a common and increasingly prevalent human condition due to unhealthy diet and less-exercise lifestyle. Development of obesity is associated with substantial modulation of adipose tissue structure. The expansion of adipose tissue is linked to the development of its vasculature, and modulation of angiogenesis may have the potential to impair adipose tissue development. In this study, we used obesity model of zebrafish fed by egg yolk to investigate the effect of Lysimachia capillipes on the obesity. The results showed that Lysimachia capillipes inhibited angiogenesis of adipose tissue in transgenic zebrafish Tg (Fli 1: EGFP), which was similar to surppressing effect of TNP-470, which was accompanied by decreased Oil Red O staining of the zebrafish. The treatment of Lysimachia capillipes reduced expression of MTP significantly, but modestly reduced expression of Ppar g, FABP10a, and CD36 level through ISH, which was accordant with the results by PCR analysis. The study proved that Lysimachia capillipes might possess novel therapeutic properties for prevention and treatment of obesity.

Metformin suppresses tumor angiogenesis and enhances the chemosensitivity of gemcitabine in a genetically engineered mouse model of pancreatic cancer

AimsPancreatic ductal adenocarcinoma (PDAC) is one of the most malignant diseases and has few effective and reliable therapeutic strategies. The anti-tumor effect of metformin is widely known, however, there is only limited evidence regarding the anti-angiogenesis effect and chemosensitization of metformin and its underlying mechanisms in PDAC. Main methodsIn the present study, we adopted a spontaneous PDAC mouse model named LSL‑KrasG12D/+; Trp53fl/+; Pdx1‑Cre (KPC) mice to explore the mechanism of the modulation of tumor angiogenesis and chemosensitization of metformin by treating KPC mice with metformin, gemcitabine or a combination of the two. H&E staining, Masson staining and immunohistochemical staining were adopted to describe the histopathology and biomarkers of the KPC in different groups. Key findingsMetformin plus gemcitabine reduced tumorigenic potential of PDAC. Specifically, metformin showed an anti-pancreatic stellate cells (PSCs) effect via decreasing the expression of sonic hedgehog (SHH) and then sparked some downstream effects, for example, inhibiting the production of vascular endothelial growth factor (VEGF) in the tumor microenvironment, reducing the formation of tumor neovascularization, attenuating the desmoplastic reaction and enhancing the antitumor effect of gemcitabine. SignificanceWe concluded that metformin suppressed tumor angiogenesis and enhanced the chemosensitivity of gemcitabine via inactivating PSCs in PDAC of KPC mice.

Associations of anticoagulant use with outcome in newly diagnosed glioblastoma

BackgroundTo test the hypothesis that despite bleeding risk, anticoagulants improve the outcome in glioblastoma because of reduced incidence of venous thromboembolic events and modulation of angiogenesis, infiltration and invasion. MethodsWe assessed survival associations of anticoagulant use from baseline up to the start of temozolomide chemoradiotherapy (TMZ/RT) (period I) and from there to the start of maintenance TMZ chemotherapy (period II) by pooling data of three randomised clinical trials in newly diagnosed glioblastoma including 1273 patients. Progression-free survival (PFS) and overall survival (OS) were compared between patients with anticoagulant use versus no use; therapeutic versus prophylactic versus no use; different durations of anticoagulant use versus no use; anticoagulant use versus use of anti-platelet agents versus neither anticoagulant nor anti-platelet agent use. Cox regression models were stratified by trial and adjusted for baseline prognostic factors. ResultsAnticoagulant use was documented in 75 patients (5.9%) in period I and in 104 patients (10.2%) in period II. Anticoagulant use during period II, but not period I, was associated with inferior OS than no use on multivariate analysis (p = 0.001, hazard ratio [HR] = 1.52, 95% confidence interval [CI]: 1.18–1.95). No decrease in OS became apparent when only patients with prophylactic anticoagulant use were considered. No survival association was established for anti-platelet agent use. ConclusionsAnticoagulant use was not associated with improved OS. Anticoagulants may not exert relevant anti-tumour properties in glioblastoma.