Uremic toxin indoxyl 3-sulfate regulates the differentiation of Th2 but not of Th1 cells to lessen allergic asthma.

Immune system dysfunctions including the increased Th1/Th2 ratio are common in chronic kidney disease (CKD) patients, and a wide variety of skin diseases including Th1-mediated uremic pruritis are associated with CKD. Although there are more than 90 uremic toxins reported, it is yet to be known which uremic solute is associated with the unbalanced Th1/Th2 ratio and how it works. Indoxyl 3-sulfate (I3S), one of uremic toxins and a potent aryl hydrocarbon receptor (AhR) ligand, accumulates in blood and tissues, increasing up to 81.04 µM in CKD patients, compared with 1.03 µM in healthy subjects. I3S activates NF-κB and AhR. Thus, we investigated roles of I3S in the differentiation of Th1 and Th2 cells. I3S inhibited Th2 differentiation but showed little or no effect on Th1 differentiation. I3S suppressed Th2-mediated ovalbumin-induced allergic asthma in mice and decreased the frequency of IL-4 producing CD4 T cells in the lungs. I3S inhibited phosphorylation of STAT5 and STAT6, transcription factors associated with Th2 differentiation. Effects of I3S on Th2 differentiation were suppressed by α-naphtoflavone, an AhR antagonist, indicating that I3S regulates Th2 differentiation AhR-dependently.

Indoxyl 3-sulfate stimulates Th17 differentiation enhancing phosphorylation of c-Src and STAT3 to worsen experimental autoimmune encephalomyelitis.

Although AhR activation regulates CD4T cell differentiation, how it works has yet to be elucidated. In the present study, using in vitro Th17 differentiation model, we examined effects of AhR activation by indoxyl 3-sulfate (I3S), a uremic toxin, on Th17 differentiation and investigated underlying mechanisms. I3S increased expression of RORγt, the master transcription factor for Th17 differentiation, and stimulated Th17 differentiation, in a comparative manner as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a prototypical AhR ligand. Activation of STAT3, which is phosphorylated by the IL-6 signaling pathways and thus is necessary for Th17 differentiation, was strongly stimulated by I3S and TCDD. Phosphorylation of c-Src, which was shown to be activated by AhR ligands, was also increased by I3S and TCDD, and blocking of c-Src activity by 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo[3,4-d]pyrimidine (PP2) inhibited phosphorylation of both c-Src and STAT3, raising a possibility that stimulatory activities of I3S and TCDD on Th17 differentiation could be exerted via increased phosphorylation of c-Src, which in turn stimulates STAT3 activation. Finally, we found that I3S worsened experimental autoimmune encephalomyelitis (EAE), which is primarily mediated by Th17 cells, enhancing the frequency of IL-17-producing cells in draining lymph nodes.

Safety assessment of chromium by exposure from cosmetic products.

Low level impurities often reside in cosmetic products. The aim of the present study was to estimate the human exposure to chromium from cosmetic products purchased at a local market in South Korea, and to assess the risk on public health. Hexavalent chromium is an impurity substance that contaminates cosmetic products during manufacture. The potential for chromium to induce and elicit allergic contact dermatitis, as well as the degree of chromium exposure from cosmetic products, were assessed. Chromium exposure was estimated using the chromium concentrations found in cosmetic samples taken from the local market along with the expected user pattern data that was taken from the literature. Of the cosmetics we tested and available for purchase on the Korean market, seven had chromium contents above the detection limit of 0.1 ppm (0.1 microg/mL), ranging from 0.2 to 3.15 ppm. In risk assessment, scientifically defensible dose-response relationships must be established for the end points of concern. In the case of chromium contaminated cosmetic products, this includes conducting dose-response assessments for allergic contact dermatitis following dermal exposure. This dose-response information can then be integrated with site-specific exposure assessments to regulate consumer safety by use of these products. We found that dermal exposure to chromium concentrations ranging from 0.0002 to 0.003 microg/cm(2) does not appear to cause concern for eliciting allergic contact dermatitis.

Skin permeation of retinol in Tween 20-based deformable liposomes: in-vitro evaluation in human skin and keratinocyte models.

To develop a more effective transdermal delivery method for lipophilic functional cosmetic compounds such as retinol, we formulated various deformable liposomes and compared their transdermal delivery efficiency with those of neutral or negatively-charged conventional liposomes. We tested the deformability of liposomes containing edge activators such as bile salts, polyoxyethylene esters and polyoxyethylene ethers. As indicators of deformability, we used the passed volume and phospholipid ratios during extrusion, as well as the deformability index. We found that the type of edge activator significantly affected the extent of deformability, and that Tween 20 provided the highest level of deformability. Accordingly, we used Tween 20 to formulate deformable liposomes containing retinol in the membrane bilayers, and conducted a skin permeation study in Franz diffusion cells, using dermatomed human skin and three-dimensional human keratinocyte layers. As compared with the use of conventional neutral or negatively-charged liposomes, the use of Tween 20-based deformable liposomes significantly increased the skin permeation of retinol. These results suggested that deformable liposomes might be of potential use for the formulation of retinol and other lipophilic functional cosmetic compounds.