An Aliphatic Ester Diisopropyl Sebacate Exhibited an Adjuvant Effect on Fluorescein Isothiocyanate-Induced Contact Hypersensitivity Mouse Models.

Alternative plasticizers have become more popular due to health concerns about phthalate esters. We demonstrated that phthalate esters enhanced skin sensitization to fluorescein isothiocyanate (FITC) in mouse contact hypersensitivity models. Alternative plasticizers have not been well studied as to their effect on the immune system. We previously found that diisopropyl adipate (DIPA), an aliphatic dicarboxylic acid ester, enhanced skin sensitization to FITC. Sebacate esters are also widely used as alternative plasticizers. Here we tested diisopropyl sebacate (DIPS), which has the same alcohol with an aliphatic dicarboxylic acid of longer chain, using BALB/c mice. The results showed that DIPS facilitated skin sensitization to FITC and increased FITC-presenting dendritic cell trafficking from the skin to draining lymph nodes. Furthermore, DIPS activated transient receptor potential ankyrin 1 (TRPA1). The latter feature has been commonly observed for phthalate esters and DIPA, which have adjuvant effects. In summary, the adjuvant effect of a sebacate ester was demonstrated in a mouse model.

Adjuvant Effect of an Alternative Plasticizer, Diisopropyl Adipate, on a Contact Hypersensitivity Mouse Model: Link with Sensory Ion Channel TRPA1 Activation.

Due to health concerns about phthalate esters, the use of alternative plasticizers is being considered. Phthalate esters enhance skin sensitization to fluorescein isothiocyanate (FITC) in mouse models. We have demonstrated that phthalate esters stimulate transient receptor potential ankyrin 1 (TRPA1) cation channels expressed on sensory neurons. We also found a correlation between TRPA1 activation and the enhancing effect on FITC-induced contact hypersensitivity (CHS) when testing various types of phthalate esters. Here we investigated the effects of an alternative plasticizer, diisopropyl adipate (DIA). Activation of TRPA1 by DIA was demonstrated by calcium mobilization using Chinese hamster ovary cells expressing TRPA1 in vitro. The effect of DIA was inhibited by a TRPA1-specific antagonist, HC-030031. The presence of DIA or dibutyl phthalate (DBP; positive control) during skin sensitization of BALB/c mice to FITC augmented the CHS response, as revealed by the level of ear-swelling. The enhancing effect of DIA was inhibited by in vivo pretreatment with HC-030031. FITC-presenting CD11c(+) dendritic cell (DC)-trafficking to draining lymph nodes was facilitated both by DIA and by DBP. DBP and DIA were similarly active in the enhancement of interferon-γ production by draining lymph nodes, but the effect on interleukin-4 production was weaker with DIA. Overall, DIA activated TRPA1 and enhanced FITC-induced CHS, as DBP did. The adjuvant effects of adipate esters may need to be considered because they are used as ingredients in cosmetics and drug formulations topically applied to the skin.

The promoting activity on human megakaryocytopoiesis and thrombopoiesis by liquid crystal-related compounds.

The liquid crystal compounds have a common structure with the cell membrane, having both a hydrophilic and hydrophobic residue, thus suggesting an affinity to the cell membrane. However, little information regarding a biological effect by liquid crystal compounds has been reported. In order to view the biological potential of liquid crystal compounds, the present study evaluated the in vitro human hematopoietic promoting effects by 18 liquid crystal-related compounds. In particular, these compounds are evaluated regarding their potential for platelet production from mature megakaryocytes by the culturing of CD34(+) cells derived from normal human peripheral blood. Often, in the case of severe thrombocytopenia there is no choice but to perform a transfusion of platelet concentrates. Three of the tested compounds promoted megakacyocyte generation in the culture stimulated with thrombopoietin alone. In addition, two compounds led to a significant increase in CD42a(+) particles which seemed to be platelets. At the same time, interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF), that were used as a positive control for in vitro megakaryocytopoiesis and thrombopoiesis, resulted in a dramatic increase in the total number of cells; however, their promoting activity on in vitro hematopoiesis was almost at a similar level with the compounds. These results suggest that some liquid crystal-related compounds have a promoting effect on human thrombopoiesis, and that these compounds act with a different mechanism from either IL-3 or GM-CSF since the compounds specifically stimulated thrombopoiesis. The liquid crystal compounds may therefore be useful to develop a new functional medicine or a medical application.

[Effects of liquid crystal-related compounds on human megakaryocytopoiesis and thrombopoiesis].

In the present study, the effects of liquid crystal-related compounds on the megakaryocytopoiesis and thrombopoiesis were evaluated in vitro using CD34+ cells prepared from human placental and umbilical cord blood (CB). About 20 kinds of compounds were tested for their effects on the clonal growth of CB CD34+ megakaryocytic progenitor cells (CFU-Meg) in plasma clot culture. The compounds, dissolved in DMSO, were added to the cultures within a concentration range of 10-100 nM. When used alone, none of the compounds supported the clonal growth of CFU-Meg. However, when thrombopoietin (TPO) was used as a growth factor, three compounds increased CFU-Meg clonal growth significantly, producing approximately 1.3-1.4 fold increases in the total number of megakaryocyte colonies in comparison with the control. These compounds promoted mainly mature CFU-Meg-derived small colonies, suggesting that their target is relatively mature CFU-Meg. These effective compounds were examined in liquid culture supplemented with TPO alone for 14 days. Although there was no evident promotion of the total number of cells harvested from the culture, two compounds suppressed cell growth significantly. Only one compound enhanced the generation of CFU-Meg in the harvested cells. Although these results do not indicate a strong correlation between the chemical structure of each compound and biological effectiveness, the incorporation of phenylpyridine and phenylpyrimidine and binding of a hydroxyl residue into the structure may play an important role in the activity. Thus, liquid crystal-related compounds whose biological action was previously unknown have been shown to act as regulators of hematopoiesis.