Apelin is a bioactive peptide with diverse physiological actions on many tissues mediated by its interaction with its specific receptor APJ. Since the identification of apelin and APJ in 1998, ...pleiotropic roles of the apelin/APJ system have been elucidated in different tissues and organs, including modulation of the cardiovascular system, fluid homeostasis, metabolic pathway and vascular formation. In blood vessels, apelin and APJ expression are spatiotemporally regulated in endothelial cells (ECs) during angiogenesis. In vitro analysis revealed that the apelin/APJ system regulates angiogenesis by the induction of proliferation, migration and cord formation of cultured ECs. Moreover, apelin seems to stabilize cell-cell junctions of ECs. In addition, genetically engineered mouse models suggest that apelin/APJ regulates vascular stabilization and maturation in physiological and pathological angiogenesis. In this review, we summarize the current understanding of the apelin/APJ system for vascular formation and maturation.
Angiogenesis is controlled positively or negatively by extrinsic and intrinsic molecular cues in endothelial cells (ECs); in the tumor microenvironment, the action of positive regulators exceeds that ...of negative regulators. Thus, overinduction of negative regulators may inhibit tumor angiogenesis. MicroRNAs (miRNAs or miRs) are endogenous short noncoding RNAs regulating gene expression either through translational inhibition or destabilization of target mRNA. Here, we show that miR-125b expression is transiently induced in ECs on stimulation with vascular endothelial growth factor or by ischemia. miR-125b inhibits translation of vascular endothelial (VE)-cadherin mRNA and in vitro tube formation by ECs. Injection of miR-125b into the tumor inhibited VE-cadherin expression by ECs and induced nonfunctional blood vessel formation, resulting in inhibition of tumor growth. It has been suggested that pro-angiogenic signals in ECs also upregulate anti-angiogenic molecules simultaneously via negative feedback. Because miR-125b induction in ECs is transient after pro-angiogenic stimulation, prolonged overexpression of miR-125b could result in blood vessel regression. Thus, miR-125b may be useful in cancer therapy by causing the collapse of the lumen of ECs.
While blood vessels clearly have a fundamental role in supplying oxygen and nutrients, and transporting inflammatory cells throughout the body, they are also involved in organogenesis and ...maintenance. Blood vessels provide a niche that supports self‐renewal of stem cell populations in normal organs. This role unfortunately also extends to the field of cancer biology; it has been suggested that cancer stem cells are located in perivascular regions supporting their proliferation. Through cell‐to‐cell interactions, arteries also have the important function of guiding appropriate migration of neurites. Therefore, analysis of the molecular mechanisms responsible for blood vessel formation and maintenance is important for developing strategies to regulate tissue regeneration. According to the usual concept of angiogenesis, it is widely accepted that homogeneous endothelial cells from preexisting vessels sprout and proliferate during angiogenesis. Recently, however, at least three different endothelial cell types designated tip, stalk and phalanx cells have been suggested to be involved in new blood vessel formation in sprouting angiogenesis. Given this endothelial cell heterogeneity, the involvement of a stem cell system in preexisting blood vessels is proposed. In addition, endothelial cells possess the capacity to differentiate into mesenchymal stem cells upon stimulation with growth factors, and pericytes show stem cell behaviour in their ability to differentiate into a variety of different histotypes. Moreover, under normal physiological conditions, haematopoietic stem cells differentiate into mural cells to provide blood vessel stability. These findings make it necessary to reconsider issues concerning the regulation of blood vessels by accessory cells situated around those vessels.
Immature and unstable tumor vasculature provides an aberrant tumor microenvironment and leads to resistance of tumors to conventional therapy. Hence, normalization of tumor vessels has been reported ...to improve the effect of immuno-, chemo- and radiation therapy. However, the humoral factors, which can effectively induce maturation of tumor vasculature, have not been elucidated. In this study, we found that the novel peptide apelin and its receptor APJ can induce the morphological and functional maturation of blood vessels in tumors. This apelin-induced tumor vascular maturation enhances the efficacy of cancer dendritic cell-based immunotherapy and significantly suppresses tumor growth by promoting the infiltration of invariant natural killer T cells into the central region of the tumor and thereby robustly inducing apoptosis of tumor cells. Additionally, we showed APJ expression to be enhanced in the tumor endothelium in comparison with normal-state endothelial cells. These findings provide a new target for tumor vascular-specific maturation, which is expected to improve the efficacy of conventional cancer therapies.
Abstract Due to the broad spectrum of pesticide usages, consumers are exposed to mixtures of residues, which may have combined effects on human health. The PERICLES research program aims to test the ...potential combined effects of pesticide mixtures, which are likely to occur through dietary exposure. The co-exposure of the French general population to 79 pesticide residues present in the diet was first assessed. A Bayesian nonparametric model was then applied to define the main mixtures to which the French general population is simultaneously and most heavily exposed. Seven mixtures made of two to six pesticides were identified from the exposure assessment. An in vitro approach was used for investigating the toxicological effects of these mixtures and their corresponding individual compounds, using a panel of cellular models, i.e. primary rat and human hepatocytes, liver, intestine, kidney, colon and brain human cell lines. A set of cell functions and corresponding end-points were monitored such as cytotoxicity, real-time cell impedance, genotoxicity, oxidative stress, apoptosis and PXR nuclear receptor transactivation. The mixtures were tested in equimolar concentrations. Among the seven mixtures, two appeared highly cytotoxic, five activated PXR and depending on the assay one or two were genotoxic. In some experiments, the mixture effect was quantitatively different from the effect expected from the addition concept. The PERICLES program shows that, for the most pesticides mixtures to which the French general population is exposed, the toxic effects observed on human cells cannot be easily predicted based on the toxic potential of each compound. Consequently, additional studies should be carried on in order to more accurately define the mixtures of chemicals to which the consumers are exposed, as well as to improve the investigation, prediction and monitoring of their potential human health effects.
The purpose of this study was to investigate the effects of acupuncture and heating (application of hot pack) treatments on blood circulation in the contralateral Achilles tendon. During the ...treatments (10 min for acupuncture, 20 min for heating) and recovery period (40 min), the blood volume (THb) and oxygen saturation (StO2) of the treated and the non-treated tendons were measured using red laser lights. During both treatments, THb and StO2 of the treated tendon increased significantly from the resting level. The increased THb and StO2 of the treated tendon were maintained until the end of the recovery period after removal of the acupuncture needle, although these values decreased after removal of the hot pack. Although THb of the non-treated sides did not change during both acupuncture and heating treatments, it increased gradually after removal of the acupuncture needle or the hot pack. For both treatments, the amount of increase in THb of the non-treated tendon was significantly correlated to that of the treated tendon during the last phase of recovery period. These results obtained from the healthy subjects imply that blood circulation in the injured tendon in a plaster cast may be improved by applying acupuncture or heating treatments to the contralateral healthy limb.
Partner of SLD5 1 (PSF1) is an evolutionarily conserved DNA replication factor. Previous studies have suggested that transcriptional activity of the PSF1 gene correlated with malignancy of cancer ...cells. The objective of the current study was to evaluate the relationship between PSF1 expression and the clinical features of prostate cancer.
We determined the expression of PSF1 in 120 needle biopsy samples of prostate cancer by immunohistochemistry. We divided patients into PSF1-positive or -negative groups and analyzed the relationships between the expression of PSF1, the Gleason score, PSA level, TNM classification and prognosis.
Our results showed that the PSF1 expression correlated significantly with PSA values at diagnosis (P=0.0028), with tumor grade (P<0.0001), and with clinical stage (P=0.0005). Moreover, the PSF1 expression correlated significantly with overall survival (hazard ratio (HR) 5.5; 95% confidence interval (CI) 2.17-15.8; P=0.003) and progression-free survival in 99 consecutive patients with prostate cancer. Noteworthy, the prognosis of PSF1-positive cases was also worse in patients with a Gleason score of 8-10 (HR 3.7; 95% CI 1.28-13.43; P=0.0143). Limitations include that this study had a retrospective design, that patients in the study were heterogeneous and included those with early and advanced cancer, and that small tumor fragments may not be representative of the entire carcinoma.
PSF1 is expressed in high-grade prostate cancer and may be a useful biomarker to identify patients with a poor prognosis at the time of diagnosis.
Numerical simulation of the blanking process of a sheet metal, i.e. the formation of roll-over and a burnished surface, and crack initiation and propagation, is done using a rigid–plastic finite ...element code developed by the authors. The modified Cockcroft and Latham expression is used as a ductile fracture criterion and is linked with the simulation. It is assumed that when the ductile fracture threshold is satisfied at an element, a crack occurs and propagates through the element. The node separate method is proposed as a method for simulating the crack propagation. To confirm the results of finite element simulation, blanking experiments are also carried out using a steel sheet of 3
mm thickness under various clearances between the punch and the die, and the crack propagation with punch penetration and the shape of the sheared edge are observed. These experimental results show good agreement with those of the finite element simulation.
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