VEGF、RANTES、sflt-1及MCP-1在子宫内膜异位症合并代谢综合征的表达及意义

目的 探究血管内皮生长因子（VEGF）、T细胞表达和分泌的调节性激活因子（RANTES）、血管内皮生长因子可溶性受体（sflt-1）及单核细胞趋化蛋白-1（MCP-1）在子宫内膜异位症合并代谢综合征的表达及意义。方法 选取2012年1月至2015年4月期间内在江汉大学附属医院妇产科接受治疗的子宫内膜异位症合并代谢综合征240例患者作为研究组,同时选择输卵管系膜囊肿、卵巢良性肿瘤或是宫颈病变患者210例作为对照组。研究组患者根据病变部位、大小以及病灶粘连程度,分为Ⅰ~Ⅳ期,Ⅰ~Ⅱ期患者130例,Ⅲ~Ⅳ期患者110例。采用ELISA对患者血清及腹腔液中sflt-1、VEGF、MCP-1、RANTES表达表达水平进行检测,对比不同组别患者各项指标。结果 研究组患者血清及腹腔液内VEGF、sflt-1、MCP-1和RANTES表达水平均高于对照组,组间数据差异有统计学意义（血清：t值分别为119.385、32.115、13.521、104.776,腹腔液内：t值分别为94.576、42.023、14.762、35.738,均P=0.000〈0.05）;在Ⅰ-Ⅱ期组与Ⅲ-Ⅳ期组指标对比中,前者VEGF、sflt-1和R A NTES指标在血清和腹腔液中表达水平均低于后者,数据有显著统计学差异（血清：t值分别为78.152、6.151、49.337,腹腔液内：t值分别为73.424、8.424、23.385,均P=0.000〈0.05）;但MCP-1数据比较无统计学意义（P〉0.05）。结论 在子宫内膜异位症合并代谢综合征与检测指标包括sflt-1、VEGF、MCP-1、RANTES的表达水平存在密切关系,表明上述因子与疾病发生发展机制存在关联,因此可以在临床上将上述指标作为子宫内膜异位症合并代谢综合征的辅助检测生化指标。     

Dietary carbohydrate restriction improves insulin sensitivity,blood pressure,microvascular function,and cellular adhesion markers in individuals taking statins

Statins positively impact plasma low-density lipoprotein cholesterol, inflammation and vascular endothelial function (VEF). Carbohydrate restricted diets (CRD) improve atherogenic dyslipidemia, and similar to statins, have been shown to favorably affect markers of inflammation and VEF. No studies have examined whether a CRD provides additional benefit beyond that achieved by habitual statin use. We hypothesized that a CRD (<50 g carbohydrate/d) for 6 weeks would improve lipid profiles and insulin sensitivity, reduce blood pressure, decrease cellular adhesion and inflammatory biomarkers, and augment VEF (flow-mediated dilation and forearm blood flow) in statin users. Participants (n = 21; 59.3 ± 9.3 y, 29.5 ± 3.0 kg/m²) decreased total caloric intake by approximately 415 kcal at 6 weeks (P < .001). Daily nutrient intakes at baseline (46/36/17% carb/fat/pro) and averaged across the intervention (11/58/28% carb/fat/pro) demonstrated dietary compliance, with carbohydrate intake at baseline nearly 5-fold greater than during the intervention (P < .001). Compared to baseline, both systolic and diastolic blood pressure decreased after 3 and 6 weeks (P < .01). Peak forearm blood flow, but not flow-mediated dilation, increased at week 6 compared to baseline and week 3 (P ≤ .03). Serum triglyceride, insulin, soluble E-Selectin and intracellular adhesion molecule-1 decreased (P < .01) from baseline at week 3, and this effect was maintained at week 6. In conclusion, these findings demonstrate that individuals undergoing statin therapy experience additional improvements in metabolic and vascular health from a 6 weeks CRD as evidenced by increased insulin sensitivity and resistance vessel endothelial function, and decreased blood pressure, triglycerides, and adhesion molecules.     

Grape seed proanthocyanidins inhibit angiogenesis via the downregulation of both vascular endothelial growth factor and angiopoietin signaling

Vascular endothelial growth factor (VEGF)/VEGF receptor 2 and angiopoietin 1/tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 signaling pathways regulate different, but complementary, aspects of blood vessel growth in tumors. Simultaneous inhibition of both pathways not only exhibits additive antiangiogenic effects but also overcomes the resistance to anti-VEGF therapy. Grape seed proanthocyanidins (GSPs) are widely consumed dietary supplements with antiangiogenic activity. However, the molecular mechanisms underlying their antiangiogenic action have not been fully understood. We hypothesized that GSPs modulate multiple signaling pathways to exhibit antiangiogenic effects. In the present study, we aimed to test this hypothesis by examining the effects of GSPs on human microvascular endothelial cell–1 and chick chorioallantoic membrane. Our results showed that GSPs inhibited the migration, matrix metalloproteinase–2 and –9 secretion, and tube formation of human microvascular endothelial cell–1 in vitro in a dose-dependent manner. In addition, chick chorioallantoic membrane angiogenesis assay showed that GSPs inhibited neovascularization in a dose-dependent manner. Furthermore, we demonstrated that GSPs inhibited the phosphorylation of VEGF receptor 2 and tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 as well as downstream signaling component extracellular signal–regulated kinase 1/2. In summary, these data suggest that GSPs inhibit both VEGF and angiopoietin 1 signaling to execute the antiangiogenic effects and indicate that GSPs could be developed as a pharmacologically safe chemopreventive agent against cancer.     

2-OHOA supplementation reduced adiposity and improved cardiometabolic risk to a greater extent than n-3 PUFA in obese mice

ObjectiveWe aimed to assess whether 2-hydroxyoleic acid (2-OHOA) and n-3 polyunsaturated fatty acids (PUFA) could counteract changes on adipokine secretion and cardiometabolic risk biomarkers associated with high-fat diet-induced obesity in mice.MethodsFemale ICR/CD1 mice (8 weeks old) were divided into four groups receiving different diets (n = 8/group): (1) standard chow (control) for 18 weeks; (2) 22% fat for 4 weeks + 60% fat for 14 weeks (obesogenic diet, OD); 3) OD + 2-OHOA (1500 mg kg^?1 diet) for the last 6 weeks (ODHO); and 4) OD + n-3 PUFA (eicosapentaenoic + docosahexaenoic acids, 1500 + 1500 mg kg^?1 diet) for the last 6 weeks (OD-N3). After 18 weeks, body weight, periovarian visceral fat, heart and liver weights were measured, as well as cardiometabolic parameters (systolic and diastolic blood pressure, blood glucose, insulin, HOMA index, triglycerides, total cholesterol, apolipoproteins A1 and E), plasma adipokines and inflammatory proteins (leptin, adiponectin, plasminogen activator inhibitor 1 [PAI1], soluble E-selectin [sE-selectin], matrix metalloproteinase-9 [MMP-9], fibrinogen, soluble intercellular adhesion molecule [sICAM] and soluble vascular adhesion molecule [sVCAM]), and secretion of pro-inflamatory cytokines and inflammatory biomarkers from periovarian adipocytes.ResultsOD mice had greater body and heart weights, and plasma leptin, and lower adiponectin and resistin secretion from adipocytes. Supplementation with 2-OHOA reduced body and heart weights, blood pressure, triglycerides and leptin, and restored adiponectin and resistin secretion, while n-3 PUFA only reduced triglyceride levels (all P < 0.05).Conclusion2-OHOA supplementation was more effective in reducing adiposity, modulating adipokine secretion and ameliorating cardiometabolic risk than n-3 PUFA.     

Phosphatidylserine inhibits inflammatory responses in interleukin-1β–stimulated fibroblast-like synoviocytes and alleviates carrageenan-induced arthritis in rat

Recently, phosphatidylserine (PS) has received attention for its anti-inflammatory effect; however, the molecular mechanisms of its action have not been fully understood. Thus, we hypothesized that PS might have antiarthritic and anti-inflammatory effects. To test this hypothesis, the in vitro anti-inflammatory effect of soybean-derived PS was tested on interleukin (IL)-1β–stimulated fibroblast-like synoviocytes from rheumatoid arthritis patients (RA-FLS) by measuring the levels of IL-6, IL-8, prostaglandin E₂, and vascular endothelial growth factor by enzyme-linked immunosorbent assay. The analgesic and antiarthritic activities of PS were investigated in rat models of carrageenan-induced acute paw pain and arthritis. The former was evaluated with a paw pressure test; the latter, by measuring paw volume and weight distribution ratio. In addition, the participation of mitogen-activated protein kinase signaling in the anti-inflammatory and antiarthritic effects of PS was investigated in RA-FLS. Phosphatidylserine inhibited the production of inflammatory mediators IL-6; IL-8; vascular endothelial growth factor; and, in particular, prostaglandin E₂ in IL-1β–stimulated RA-FLS. These effects were associated with abrogation of inhibitor of nuclear factor–κBα phosphorylation and suppression of p38 and c-jun amino terminal kinase but not extracellular signal–regulated kinase 1/2 phosphorylation. In rats, PS also showed a significant inhibitory effect on arthritic and nociceptive symptoms induced by carrageenan. These findings suggest that PS has anti-inflammatory and antiarthritic effects in vitro and in in vivo animal models; thus, PS should be further studied to determine its potential use as either a pharmaceutical or dietary supplement for alleviating arthritic symptoms.     

Acute exposure to high-fat diets increases hepatic expression of genes related to cell repair and remodeling in female rats

High-fat diets (HFD) promote the development of both obesity and fatty liver disease through the up-regulation of hepatic lipogenesis. Insulin resistance, a hallmark of both conditions, causes dysfunctional fuel partitioning and increases in lipogenesis. Recent work has demonstrated that systemic insulin resistance occurs in as little as the first 72 hours of an HFD, suggesting the potential for hepatic disruption with HFD at this time point. The current study sought to determine differences in expression of lipogenic genes between sexes in 3-month-old male and female Long-Evans rats after 72 hours of a 40% HFD or a 17% fat (chow) diet. Owing to the response of estrogen on hepatic signaling, we hypothesized that a sexual dimorphic response would occur in the expression of lipogenic enzymes, inflammatory cytokines, apoptotic, and cell repair and remodeling genes. Both sexes consumed more energy when fed an HFD compared with their low fat–fed controls. However, only the males fed the HFD had a significant increase in body fat. Regardless of sex, HFD caused down-regulation of lipogenic and inflammatory genes. Interestingly, females fed an HFD had up-regulated expression of apoptotic and cell repair–related genes compared with the males. This may suggest that females are more responsive to the acute hepatic injury effects caused by HFDs. In summary, neither male nor female rats displayed disrupted hepatic metabolic pathways after 72 hours of the HFD treatment. In addition, female rats appear to have protection from increases in fat deposition, possibly due to increased caloric expenditure; male rats fed an HFD were less active, as demonstrated by distance traveled in their home cage.     

Dietary intervention with vitamin D,calcium, and whey protein reduced fat mass and increased lean mass in rats

The aim of the current study was to determine the effects and the mechanisms of inclusion of dietary whey protein, high calcium, and high vitamin D intake with either a high-sucrose or high-fat base diets on body composition of rodents. Male Wistar rats were assigned to either no whey protein, suboptimal calcium (0.25%), and vitamin D (400 IU/kg) diet (LD), or a diet containing whey protein, high calcium (1.5%), and vitamin D (10 000 IU/kg) diet (HD), and either high-fat (40% of energy) or high-sucrose (60%) base diets for 13 weeks. Liver tissue homogenates were used to determine [¹⁴C]glucose and [¹⁴C]palmitate oxidation. mRNA expression of enzymes related to energy metabolism in liver, adipose, and muscle, as well as regulators of muscle mass and insulin receptor was assessed. The results demonstrated that there was reduced accumulation of body fat mass (P = .01) and greater lean mass (P = .03) for the HD- compared to LD-fed group regardless of the background diet. There were no consistent differences between the LD and HD groups across background diets in substrate oxidation and mRNA expression for enzymes measured that regulate energy metabolism, myostatin, or muscle vascular endothelial growth factor. However, there was an increase in insulin receptor mRNA expression in muscle in the HD compared to the LD groups. In conclusion, elevated whey protein, calcium, and vitamin D intake resulted in reduced accumulation of body fat mass and increased lean mass, with a commensurate increase in insulin receptor expression, regardless of the level of calories from fat or sucrose.     

A DNA vaccine expressing an optimized secreted FAPα induces enhanced anti-tumor activity by altering the tumor microenvironment in a murine model of breast cancer

Cancer-associated fibroblasts (CAFs), major components of the tumor microenvironment (TME), promote tumor growth and metastasis and inhibit the anti-tumor immune response. We previously constructed a DNA vaccine expressing human FAPα, which is highly expressed by CAFs, to target these cells in the TME, and observed limited anti-tumor effects in the 4T1 breast cancer model. When the treatment time was delayed until tumor nodes formed, the anti-tumor effect of the vaccine completely disappeared. In this study, to improve the safety and efficacy, we constructed a new FAPα-targeted vaccine containing only the extracellular domain of human FAPα with a tissue plasminogen activator signal sequence for enhanced antigen secretion and immunogenicity. The number of CAFs was more effectively reduced by CD8⁺ T cells induced by the new vaccine. This resulted in decreases in CCL2 and CXCL12 expression, leading to a significant decrease in the ratio of myeloid-derived suppressor cells in the TME. Moreover, when mice were treated after the establishment of tumors, the vaccine could still delay tumor growth. To facilitate the future application of the vaccine in clinical trials, we further optimized the gene codons and reduced the homology between the vaccine and the original sequence, which may be convenient for evaluating the vaccine distribution in the human body. These results indicated that the new FAPα-targeted vaccine expressing an optimized secreted human FAPα induced enhanced anti-tumor activity by reducing the number of FAPα⁺ CAFs and enhancing the recruitment of effector T cells in the 4T1 tumor model mice.