Distinct Characteristics of Circulating Vascular Endothelial Growth Factor-A and C Levels in Human Subjects

The mechanisms that lead from obesity to atherosclerotic disease are not fully understood. Obesity involves angiogenesis in which vascular endothelial growth factor-A (VEGF-A) plays a key role. On the other hand, vascular endothelial growth factor-C (VEGF-C) plays a pivotal role in lymphangiogenesis. Circulating levels of VEGF-A and VEGF-C are elevated in sera from obese subjects. However, relationships of VEGF-C with atherosclerotic risk factors and atherosclerosis are unknown. We determined circulating levels of VEGF-A and VEGF-C in 423 consecutive subjects not receiving any drugs at the Health Evaluation Center. After adjusting for age and gender, VEGF-A levels were significantly and more strongly correlated with the body mass index (BMI) and waist circumference than VEGF-C. Conversely, VEGF-C levels were significantly and more closely correlated with metabolic (e.g., fasting plasma glucose, hemoglobin A1c, immunoreactive insulin, and the homeostasis model assessment of insulin resistance) and lipid parameters (e.g., triglycerides, total cholesterol (TC), low-density-lipoprotein cholesterol (LDL-C), and non-high-density-lipoprotein cholesterol (non-HDL-C)) than VEGF-A. Stepwise regression analyses revealed that independent determinants of VEGF-A were the BMI and age, whereas strong independent determinants of VEGF-C were age, triglycerides, and non-HDL-C. In apolipoprotein E-deficient mice fed a high-fat-diet (HFD) or normal chow (NC) for 16 weeks, levels of VEGF-A were not significantly different between the two groups. However, levels of VEGF-C were significantly higher in HFD mice with advanced atherosclerosis and marked hypercholesterolemia than NC mice. Furthermore, immunohistochemistry revealed that the expression of VEGF-C in atheromatous plaque of the aortic sinus was significantly intensified by feeding HFD compared to NC, while that of VEGF-A was not. In conclusion, these findings demonstrate that VEGF-C, rather than VEGF-A, is closely related to dyslipidemia and atherosclerosis

Effect of CYP2C19 Polymorphism on Treatment Success in Lansoprazole-Based 7-Day Treatment Regimen for Cure of H. pylori Infection in Japan

Recently, Helicobacter pylori (H. pylori)-positive peptic ulcer patients were treated by a 1-week triple therapy [lansoprazole (LPZ) 30 mg, amoxicillin 750 mg and clarithromycin 200 or 400 mg, each twice daily] without the checking CYP2C19 genotype in Japan. This regimen was done to obtain sufficient cure rates for H. pylori infection using a high dose of LPZ (60 mg/day) without the great cost of having to determine the genotype. However, the failure rate for eradicating H. pylori was reported to be 12.5%. The reasons for this were studied in 33 Japanese patients with H. pylori-positive gastric or duodenal ulcer. Blood samples of the patients were collected to determine the genotype of CYP2C19 and plasma concentrations of LPZ and its metabolites at 3 h postdose on the morning of the 7th day of treatment. H. pylori infection was cured in 25 of the 33 patients (75.8%). The cure rate was highest in the group of poor metabolizers (PM), intermediate in the group of extensive metabolizers of the heterozygous type (htEM) and lowest in the group of extensive metabolizers of the homozygous type (hmEM). The relative ratio of mean plasma concentration for LPZ among the 3 groups was 1.00:1.43:2.93 (hmEM:htEM:PM groups). Our data suggest that success of the eradication is dependent on the CYP2C19-related genotypic status or the plasma concentrations of LPZ in a steady state condition after a multiple dosing regimen; that is to say, checking CYP2C19 is necessary even on occasions when treatment is done by H. pylori eradication methods as performed in Japan

The correlation of circulating vascular endothelial growth factor-A (VEGF-A) or C (VEGF-C) levels with their independent determinants.

<p>A. The correlation between circulating VEGF-A levels and the body mass index. B. The correlation between those of VEGF-C and those of triglycerides. C. The correlation between those of VEGF-C and those of non-high-density-lipoprotein cholesterol (nonHDL-C).</p

Independent determinants of VEGF-A and VEGF-C levels.

<p>Abbreviations used in this table are the same as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029351#pone-0029351-t001" target="_blank">Table 1</a>. These models include data on the age, a male gender, body mass index, waist circumference, systolic and diastolic blood pressures, fasting plasma glucose, hemoglobin A1c, immunoreactive insulin, HOMA-IR, triglycerides, HDL-C, total cholesterol, LDL-C, non-HDL-C, hsCRP, and adiponectin.</p

Correlations of Vascular Endothelial Growth Factor-A (VEGF-A) and Vascular Endothelial Growth Factor–C (VEGF-C) with Other Parameters.

<p>Abbreviations used in this table are the same as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029351#pone-0029351-t001" target="_blank">Table 1</a>.</p>a<p>Log-transformed to obtain normal distributions. Values were adjusted for age and gender.</p

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field