Prostaglandin D2 plays an essential role in chronic allergic inflammation of the skin via CRTH2 receptor

PGD(2) plays roles in allergic inflammation via specific receptors, the PGD receptor designated DP and CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cells). We generated mutant mice carrying a targeted disruption of the CRTH2 gene to investigate the functional roles of CRTH2 in cutaneous inflammatory responses. CRTH2-deficent mice were fertile and grew normally. Ear-swelling responses induced by hapten-specific IgE were less pronounced in mutant mice, giving 35-55% of the responses of normal mice. Similar results were seen in mice treated with a hemopoietic PGD synthase inhibitor, HQL-79, or a CRTH2 antagonist, ramatroban. The reduction in cutaneous responses was associated with decreased infiltration of lymphocytes, eosinophils, and basophils and decreased production of macrophage-derived chemokine and RANTES at inflammatory sites. In models of chronic contact hypersensitivity induced by repeated hapten application, CRTH2 deficiency resulted in a reduction by approximately half of skin responses and low levels (63% of control) of serum IgE production, although in vivo migration of Langerhans cells and dendritic cells to regional lymph nodes was not impaired in CRTH2-deficient mice. In contrast, delayed-type hypersensitivity to SRBC and irritation dermatitis in mutant mice were the same as in wild-type mice. These findings indicate that the PGD(2)-CRTH2 system plays a significant role in chronic allergic skin inflammation. CRTH2 may represent a novel therapeutic target for treatment of human allergic disorders, including atopic dermatitis.     

Diet among people in the Terai region of Nepal, an area of micronutrient deficiency

In the Terai region, despite its ecological richness, the people have long suffered from a deficiency of micronutrients such as vitamin A, iron and zinc. The aim of this study was to investigate dietary and nutritional intakes among people in the Terai region of Nepal. The results were compared by sex and ethnicity. Food consumption surveys (one-day weighed records) were conducted among 114 people (55 Mushar and 59 Tharu). Nutritional intakes were calculated using Nepali food composition and other tables. The diet in the Terai region was characterized by a large amount of rice consumed with a tiny amount of curry or dal as a side dish. Intakes of vitamin A, iron, riboflavin and selenium were less than 50% of the recommended daily allowance irrespective of ethnicity or sex (with the exception of iron intake among Tharu males). Intakes of thiamine, riboflavin, niacin, phosphorus and zinc were higher among the Tharu than the Mushar, while intakes of selenium and iodine were higher among the Mushar than the Tharu. The nutritional significance of these differences was slight. Protein intake (per kg body weight) was lower in females than in males, while the energy-adjusted micronutrient intakes did not differ by sex. Intakes of vitamin A, iron, riboflavin and selenium were deficient among the participants. Intervention projects such as the introduction of kitchen gardens or fish farming may be effective, but will increase the degree of inequality between the two ethnic groups.     

Electric and magnetic fields in cryopreservation: A response

Our recent studies showed that a programmed freezer with a magnetic field (CAS freezer) is helpful in the survival of periodontal ligament (PDL) cells after cryopreservation. The theory is that a magnetic field can prevent the cluster from growing by causing it to vibrate. In this letter, we commented in detail on the influence of a magnetic field during cryopreservation.     

Cord Blood Levels of Toxic and Essential Trace Elements and Their Determinants in the Terai Region of Nepal: A Birth Cohort Study

The purpose of this study is to evaluate the cord blood level of toxic and trace elements and to identify their determinants in Terai, Nepal. One hundred pregnant women were recruited from one hospital in Chitwan, Nepal in 2008. The cord blood levels of toxic [lead (Pb), arsenic (As), and cadmium (Cd)], essential trace elements [zinc (Zn), selenium (Se), and copper (Cu)], demographic, socioeconomic, and behavioral variables were measured. The mean values of Pb, As, Cd, Zn, Se, and Cu in cord blood level were found as 31.7, 1.46, 0.39, 2,286, 175, and 667 μg/L, respectively. In the multivariate regression model, cord blood As levels from less educated mothers were higher than those from educated mothers (coefficient = -0.01, 95% confidence interval [CI] = -0.02-0.00). The maternal age was positively associated with the cord blood Cd level (coefficient = 0.02, 95% CI = 0.01-0.03), while it was negatively associated with the cord blood As level (coefficient = -0.01, 95% CI = -0.03--0.01). Cord blood levels of Pb, Zn, Se, and Cu were not associated with maternal age, socioeconomic status, living environment, and smoking status. As and Cd levels were relatively lower than those reported in previous studies in Asia, while the levels of Pb and the trace elements were similar. Less educated mothers are more likely to become a higher in utero As source to their fetus, and fetuses of older mothers were more likely to have higher in utero Cd exposure in Terai, Nepal.     

Defining early lineage specification of human embryonic stem cells by the orchestrated balance of canonical Wnt/beta-catenin, Activin/Nodal and BMP signaling

The canonical Wnt/beta-catenin signaling has remarkably diverse roles in embryonic development, stem cell self-renewal and cancer progression. Here, we show that stabilized expression of beta-catenin perturbed human embryonic stem (hES)-cell self-renewal, such that up to 80% of the hES cells developed into the primitive streak (PS)/mesoderm progenitors, reminiscent of early mammalian embryogenesis. The formation of the PS/mesoderm progenitors essentially depended on the cooperative action of beta-catenin together with Activin/Nodal and BMP signaling pathways. Intriguingly, blockade of BMP signaling completely abolished mesoderm generation, and induced a cell fate change towards the anterior PS progenitors. The PI3-kinase/Akt, but not MAPK, signaling pathway had a crucial role in the anterior PS specification, at least in part, by enhancing beta-catenin stability. In addition, Activin/Nodal and Wnt/beta-catenin signaling synergistically induced the generation and specification of the anterior PS/endoderm. Taken together, our findings clearly demonstrate that the orchestrated balance of Activin/Nodal and BMP signaling defines the cell fate of the nascent PS induced by canonical Wnt/beta-catenin signaling in hES cells.     

Effect of dietary sodium on vasoconstriction and eNOS-mediated vascular relaxation in caveolin-1-deficient mice

Changes in dietary sodium intake are associated with changes in vascular volume and reactivity that may be mediated, in part, by alterations in endothelial nitric oxide synthase (eNOS) activity. Caveolin-1 (Cav-1), a transmembrane anchoring protein in the plasma membrane caveolae, binds eNOS and limits its translocation and activation. To test the hypothesis that endothelial Cav-1 participates in the dietary sodium-mediated effects on vascular function, we assessed vascular responses and nitric oxide (NO)-mediated mechanisms of vascular relaxation in Cav-1 knockout mice (Cav-1-/-) and wild-type control mice (WT; Cav-1+/+) placed on a high-salt (HS; 4% NaCl) or low-salt (LS; 0.08% NaCl) diet for 16 days. After the systolic blood pressure was measured, the thoracic aorta was isolated for measurement of vascular reactivity and NO production, and the heart was used for measurement of eNOS expression and/or activity. The blood pressure was elevated in HS mice treated with NG-nitro-l-arginine methyl ester and more so in Cav-1-/- than WT mice and was significantly reduced during the LS diet. Phenylephrine caused vascular contraction that was significantly reduced in Cav-1-/- (maximum 0.25 +/- 0.06 g/mg) compared with WT (0.75 +/- 0.22 g/mg) on the HS diet, and the differences were eliminated with the LS diet. Also, vascular contraction in response to membrane depolarization by high KCl (96 mM) was reduced in Cav-1-/- (0.27 +/- 0.05 g/mg) compared with WT mice (0.53 +/- 0.12 g/mg) on the HS diet, suggesting that the reduced vascular contraction is not limited to a particular receptor. Acetylcholine (10(-5) M) caused aortic relaxation in WT mice on HS (23.6 +/- 3.5%) and LS (23.7 +/- 5.5%) that was enhanced in Cav-1-/- HS (72.6 +/- 6.1%) and more so in Cav-1-/- LS mice (93.6 +/- 3.5%). RT-PCR analysis indicated increased eNOS mRNA expression in the aorta and heart, and Western blots indicated increased total eNOS and phosphorylated eNOS in the heart of Cav-1-/- compared with WT mice on the HS diet, and the genotypic differences were less apparent during the LS diet. Thus Cav-1 deficiency during the HS diet is associated with decreased vasoconstriction, increased vascular relaxation, and increased eNOS expression and activity, and these effects are altered during the LS diet. The data support the hypothesis that endothelial Cav-1, likely through an effect on eNOS activity, plays a prominent role in the regulation of vascular function during substantial changes in dietary sodium intake.