Mouse Model Of Contact Dermatitis Research Articles

Development of PSL-Loaded PLGA Nanoparticles for the Treatment of Allergic Contact Dermatitis

Allergic contact dermatitis (ACD) can easily develop once sensitization is established by exposure to small amounts of antigen, and steroids are used for treatment. In this study, we evaluated the therapeutic efficacy of prednisolone (PSL)-loaded poly(DL-lactide-co-glycolide) (PLGA) nanoparticles (NPs) on a mouse model of contact dermatitis (CHS). Nanoparticles were prepared using a poor solvent diffusion method, and particle size distribution and mean particle size were measured using dynamic light scattering. Treatment experiments with PSL-loaded PLGA NPs were performed before and after sensitization with 1-fluoro-2,4-dinitrobenzene (DNFB), and evaluation was performed by quantifying intracutaneous IL-4 and TNF-α levels in a mouse model of CHS using ELISA. When PSL-loaded PLGA NPs were administered before sensitization, IL-4 expression was significantly decreased, and TNF-α tended to decrease in the group treated with PSL-loaded PLGA NPs compared to the non-treated group. When PSL-loaded PLGA NPs were administered after sensitization, IL-4 expression was significantly decreased in the group treated with PSL-loaded PLGA NPs compared to the non-treated group. In both cases, there were no significant differences between the PSL-loaded PLGA NP treatment group and the PSL-containing ointment group. These results suggest that, in the treatment of CHS, PSL-loaded PLGA NPs show a certain therapeutic effect when preadministration.

Therapeutic Effects of Pinus koraiensis on 1-Fluoro-2,4-Dinitrofluorobenzene-induced Contact Dermatitis in Mice

Background Korean pine nuts (Semen Pinus koraiensis ( P. koraiensis)) have been a valuable ingredient in Korean cuisine since ancient times, and the classical literature on traditional medicine states that pine nuts can moisturize skin. Aims To confirm the therapeutic efficacy of the ethanol extract of these pine nuts in an animal contact dermatitis (CD) model. Materials and Methods Korean pine nuts were extracted using 70% ethanol, and the crude extract obtained was condensed and lyophilized to produce EEPK (the 70% ethanol extract of P. koraiensis). A DNFB (1-fluoro-2,4-dinitrofluorobenzene)-induced BALB/c mouse model of CD was used to investigate the effects of EEPK on skin symptoms, histopathological abnormalities, and cytokine secretion in inflamed tissues. Results EEPK reduced skin color changes, lesion severities, and dorsal skin thickening and inhibited epidermis hyperplasia and immune cell infiltration into inflamed tissues. In addition, EEPK suppressed the productions of tumor necrosis factor-α, interferon-γ, interleukin-6, and monocyte chemoattractant protein-1 but did not affect body weights or spleen/body weight ratios. Conclusion P. koraiensis has potential as a therapeutic agent for CD and as a treatment for inflammatory skin disease management products. Furthermore, the mechanism underlying its therapeutic effects differs from that of corticosteroids.

Hydrophobic Fractions of Triticum aestivum L. Extracts Contain Polyphenols and Alleviate Inflammation by Regulating Nuclear Factor-kappa B

As a nutritional supplement, wheatgrass (Triticum aestivum L.) is well-known for its anti-inflammatory effects that are exerted through signal transduction pathways. Wheatgrass was extracted in 80% ethanol (WGE), and the ethanol extracts were further fractionated using ethyl acetate, n-butanol, and water. To determine the antioxidant activity, WGE was tested using various radical-scavenging assays. To explain the anti-inflammatory mechanisms, western blotting, reverse-transcription polymerase chain reaction, luciferase assay, immunofluorescence staining, and the inhibition of mitogen-activated protein kinase (MAPK) phosphorylation were performed using mouse macrophage cells (RAW 264.7). Inhibition of proinflammatory and Th2 cytokines was analyzed using a 2,4-dinitrochlorobenzene-induced contact dermatitis mouse model. WGE exhibited a strong antioxidant activity in radical scavenging-assays conducted using artificial and natural substrates. The ethyl acetate and n-butanol fractions (hydrophobic fractions) obtained from the 80% ethanolic extract, inhibited the expression of inducible nitric oxide synthase gene, whereas the aqueous layer (the hydrophilic fraction) showed no inhibitory effects. In addition, the hydrophobic fractions inhibited nuclear factor-kappa B (NF-κB) and reduced phosphorylation of MAPK, indicating that inflammation was alleviated possibly by the regulation of NF-κB signaling. This mechanism was further elucidated using the RAW 264.7 cell line and mouse model. Using high-performance liquid chromatography, the hydrophobic fractions were separated into over 10 phenolic compounds, among which benzoic acid, quercetin, and luteolin were abundant. The study demonstrated that wheatgrass is a potential nutraceutical candidate with antioxidant and anti-inflammatory properties for future use in health foods and cosmetics.

Ethanol extract of Thuja orientalis L. seeds ameliorated skin lesions in a dinitrofluorobenzene-induced mouse model of contact dermatitis

Background: Seed oils like sesame and camellia oils are used in herbal medicine to treat skin diseases and it has been reported that the seeds of Thuja orientalis have antioxidant, antibacterial, anti-inflammatory, and anti-allergic effects. Objectives: We investigate the anti-inflammatory effects of an ethanol extract of the seeds of T. orientalis (EETO) on a dinitrofluorobenzene-induced mouse model of contact dermatitis (CD). Materials and Methods: We investigated the effects of EETO on CD lesions and skin thickness, skin color, histopathologic findings, and cytokine production in mouse skins. Results: EETO ameliorated skin roughness, excoriation, scabs, and erythema. EETO also reduced erythema, melanin index, and inhibited skin thickness increases in CD mice. In addition, histopathologic examinations showed that EETO decreased epidermal hyperplasia, keratinization, and the productions of inflammatory cytokines (i.e., interleukin [IL]-6, tumor necrosis factor [TNF]-α, and monocyte chemotactic protein [MCP]-1). Conclusion: These results suggest that ethanolic extracts of the seeds of T. orientalis might provide relatively safe treatments for CD and that its therapeutic effect is exerted through inhibitions of IL-6, TNF-α, and MCP-1.

Nalbuphine, a kappa opioid receptor agonist and mu opioid receptor antagonist attenuates pruritus, decreases IL-31, and increases IL-10 in mice with contact dermatitis

Chronic itch is one of the disturbing symptoms of inflammatory skin diseases. Kappa opioid receptor agonists are effective in suppressing scratching in mice against different pruritogens. Nalbuphine, a nonscheduled kappa opioid receptor agonist and mu opioid receptor antagonist, has been in clinical use for post-operative pain management since the 1980s and recently has been in clinical trials for chronic itch of prurigo nodularis (https://www.trevitherapeutics.com/nalbuphine). We studied whether nalbuphine is effective against chronic scratching induced by rostral neck application of 1-fluoro-2,4-dinitrobenzene (DNFB), an accepted mouse model of contact dermatitis to study pruritoceptive itch. Mice were treated once a week with either saline or nalbuphine 20 min before the third, fifth, seventh, and ninth sensitizations with DNFB and the number of scratching bouts was counted for 30 min. Skin samples from the neck of mice at week 4 were used to measure protein levels and mRNA expressions of chemokines and cytokines. Different sets of mice were used to study sedation and anhedonic-like behavior of nalbuphine. We found that: nalbuphine (a) antagonized scratching in a dose- and time-dependent manner without affecting locomotion, b) decreased IL-31, and increased anti-inflammatory IL-10, and c) induced more elevations in the levels of CCL2, CCL3, CCL12, CXCL1, CXCL2, CXCL9, CXCL10, IL-1β, IL-16, TIMP-1, M-CSF, TREM-1 and M1-type macrophages compared to saline. Increases in chemokines and cytokines and M1 macrophages by nalbuphine suggest an inflammatory phase of healing in damaged skin due to scratching. Our data indicate that nalbuphine is an effective antipruritic in murine model of pruritoceptive itch.

Spinal dorsal horn astrogliosis facilitates itch transmission in a mouse model of contact dermatitis.

Spinal dorsal horn astrogliosis facilitates itch transmission in a mouse model of contact dermatitis.

Topical anti-inflammatory and anti-oxidative effects of porcine placenta extracts on 2,4-dinitrochlorobenzene-induced contact dermatitis

BackgroundThe placenta is a reservoir enriched with growth factors, hormones, cytokines and minerals. While several beneficial effects of placenta extracts on wound healing, anti-aging and anti-inflammatory responses have been reported, relatively limited mechanistic exploration has been conducted to date. Here, we provide compelling evidence of anti-inflammatory and anti-oxidative activities of porcine placenta extracts (PPE) against contact dermatitis in vivo.MethodsA contact dermatitis mouse model was established by sensitizing the dorsal skin of BALB/c mice using the contact allergen, 2,4-dinitrochlorobenzene (DNCB), and molecular consequences of topical application of PPE were investigated. PPEs were pre-sterilized via γ-irradiation, which is a milder but more effective way of sterilizing biomolecules relative to the conventional autoclaving method.ResultsDNCB-induced skin lesions displayed clear contact dermatitis-like symptoms and topical application of PPE dramatically alleviated both local and systemic inflammatory responses. Inflammatory epidermal thickening was completely abrogated and allergen-specific serum IgE levels significantly reduced in the presence of PPE. Moreover, anti-oxidative activities of PPE were observed both in vitro and in vivo, which may lead to attenuation of inflammatory responses. Prolonged treatment with PPE strongly inhibited production of DNCB-induced reactive oxygen species (ROS) and subsequently prevented oxidative degradation of hyaluronic acid (HA), which triggers innate inflammatory responses.ConclusionOur findings supply valuable insights into the mechanisms underlying the anti-inflammatory effects of PPE and provide a functional basis for the clinical application of PPE in inflammatory diseases.

Itching in a trichophytin contact dermatitis mouse model and the antipruritic effect of antifungal agents.

Tinea is an infectious disease by dermatophytes, of which Trichophyton species accounts for the overwhelming majority of case. Tinea often causes itching with inflammation. In terms of pruritus by fungal infection, however, tinea has not been investigated sufficiently to date. To evaluate itch caused by Trichophyton infection and the effect of antifungal agents on the infection, by measuring scratch behaviour and profiles of inflammatory cytokines and chemokines. We used a previously established mouse model of contact hypersensitivity induced by trichophytin, a crude extract from Trichophyton mentagrophytes. Scratching behaviour was recorded using a counting device that measured an electric current induced in a coil by movement of magnets that had been inserted into the hind paws of each animal. We investigated expression of various genes in lesional skin of mice and in normal human epidermal keratinocytes. We also investigated the antipruritic effects of the corticosteroid dexamethasone (DEX) and three antifungal agents: ketoconazole (KCZ), terbinafine (TBF) and liranaftate (LNF). Biphasic peaks of scratching were observed at 1 h and at 6-7 h during an observation period of 14 h after trichophytin induction. For lesional skin, RNA was extracted 24 h after trichophytin challenge, and increased expression was seen in the genes for interleukin (IL)-17A, interferon-γ, tumour necrosis factor (TNF)-α, macrophage inflammatory protein (MIP)-2 and Dectin-1, whereas there was no obvious change in the genes for IL-31 and prostaglandin (PG)E2. Furthermore, KCZ inhibited histidine decarboxylase (HDC) expression in vitro and in vivo, and inhibited scratching in the very early phase. LNF inhibited expression of thymic stromal lymphopoietin (TSLP) and IL-8 in vitro, and TSLP, TNF-α, IL-1α and MIP2 in vivo, and also scratching in the early phase. TBF did not induce any significant alterations in either gene expression or scratching. DEX suppressed expression of all the chemical mediators except HDC in vitro and in vivo, and inhibited scratching. Antifungals can inhibit itching induced by fungal infection through different mechanisms.

Formononetin attenuated allergic diseases through inhibition of epithelial-derived cytokines by regulating E-cadherin

Radix Astragali, has long been used to alleviate allergic diseases (ADs). Formononetin is one of the major active components in Radix Astragali, but its mechanism on ADs is not definitively known. The fluorescein isothiocyanate isomer-induced atopic contact dermatitis mouse model and poly I:C or lipopolysaccharide-treated HaCaT cells were used to examine thymic stromal lymphopoietin (TSLP)/interleukin (IL)-33 production and expression of E-cadherin. After administration of formononetin, TSLP/IL-33 levels decreased both in vitro and in vivo, while E-cadherin was increased in vivo and restored in vitro. Furthermore, small interference RNA silencing of E-cadherin resulted in elevated levels of TSLP, whereas the inhibitory effect of formononetin on TSLP was no longer observed. In addition, TSLP resulted in no detectable changes in delocalization or protein expression of E-cadherin in HaCaT cells. These results indicated that formononetin showed a protective effect in ADs, which was correlated with decreasing TSLP/IL-33 production via regulation of E-cadherin.

Inhibitory Effects of CD99-derived Peptide CD99CRIII3 on the Extravasation of Monocytes and Inflammatory Reactions in Contact Dermatitis Mouse Model

Inhibitory Effects of CD99-derived Peptide CD99CRIII3 on the Extravasation of Monocytes and Inflammatory Reactions in Contact Dermatitis Mouse Model

Irritant contact dermatitis is regulated by antioxidative enzyme NAD(P)H:quinone oxidoreductase (Nqo1).

Abstract Irritant contact dermatitis (ICD) is the most common occupational skin inflammatory disorder caused by the exposure of chemical or physical irritants. Local release of inflammatory mediators such as cytokines, lipid mediators, and reactive oxygen species (ROS) are known to be important in the establishment of ICD. Antioxidative enzymes such as Nqo1 are known to be responsible for the degradation of ROS. Therefore, in the current study, we focused on the involvement of Nqo1 in ICD. In the mouse ICD model using croton oil, we found that Nqo1-deficient mice exhibited increased ear swelling and augmented expression of proinflammatory cytokines such as IL-6 and IL-17A in the skin. As we expected, it is indicated that Nqo1 has protective role against ICD. However, it is not applicable for general inflammatory responses, because the knockout mice showed unaltered response in the allergic contact dermatitis mouse model. Interestingly, we found that severe reduction of Vγ5Vδ1+ dendritic epidermal T cells (DETCs) in the skin of Nqo1 deficient mice, which are reported to inhibit ICD. Transfer of DETCs into RAG−/− mice revealed impaired survival of Nqo1-deficient DETCs. In addition, Nqo1-deficient DETCs were sensitive to oxidative stress-induced cell death, and anti-oxidant NAC treatment rescued decreased DETCs in Nqo1-deficient mice. These results suggest that Nqo1 regulates ICD through DETC development and/or homeostasis, possibly by antioxidative function.

Protective effect of small molecule analogues of the Acanthocheilonema viteae secreted product ES-62 on oxazolone-induced ear inflammation

ES-62 is the major secreted protein of the rodent filarial nematode Acanthocheilonema viteae. The molecule contains covalently attached phosphorylcholine (PC) residues, which confer anti-inflammatory properties on ES-62, underpinning the idea that drugs based on this active moiety may have therapeutic potential in human diseases associated with aberrant inflammation. Here we demonstrate that two synthetic small molecule analogues (SMAs) of ES-62 termed SMA 11a and SMA 12b are protective in the oxazolone-induced acute allergic contact dermatitis mouse model of skin inflammation, as measured by a significant reduction in ear inflammation following their administration before oxazolone sensitisation and before oxazolone challenge. Furthermore, it was found that when tested, 12b was effective at reducing ear swelling even when first administered before challenge. Histological analysis of the ears showed elevated cellular infiltration and collagen deposition in oxazolone-treated mice both of which were reduced by treatment with the two SMAs. Likewise, the oxazolone-induced increase in IFNγ mRNA in the ears was reduced but no effect on other cytokines investigated was observed. Finally, no influence on the mast cell populations in the ear was observed.

Ethanol Extract of Peanut Sprout Exhibits a Potent Anti-Inflammatory Activity in Both an Oxazolone-Induced Contact Dermatitis Mouse Model and Compound 48/80-Treated HaCaT Cells.

BackgroundWe developed an ethanol extract of peanut sprouts (EPS), a peanut sprout-derived natural product, which contains a high level of trans-resveratrol (176.75 µg/ml) and was shown to have potent antioxidant activity.ObjectiveWe evaluated the potential anti-inflammatory activity of EPS by measuring its antioxidant potential in skin.MethodsThe anti-inflammatory activity of EPS was tested using two models of skin inflammation: oxazolone (OX)-induced contact dermatitis in mice and compound 48/80-treated HaCaT cells. As biomarkers of skin inflammation, cyclooxygenase-2 (COX-2) and nerve growth factor (NGF) levels were measured.ResultsOX-induced contact dermatitis was suppressed markedly in mice that were treated with an ointment containing 5% EPS as evidenced by a decrease in the extent of scaling and thickening (p<0.05) and supported by a histological study. COX-2 (messenger RNA [mRNA] and protein) and NGF (mRNA) levels, which were upregulated in the skin of OX-treated mice, were suppressed markedly in the skin of OX+EPS-treated mice. Consistent with this, compound 48/80-induced expression of COX-2 (mRNA and protein) and NGF (mRNA) in HaCaT cells were suppressed by EPS treatment in a dose-dependent manner. As an inhibitor of NF-κB, IκB protein levels were dose-dependently upregulated by EPS. Fluorescence-activated cell sorting (FACS) analysis revealed that EPS scavenged compound 48/80-induced reactive oxygen species (ROS) in HaCaT cells.ConclusionEPS exerts a potent anti-inflammatory activity via its anti-oxidant activity in both mouse skin and compound 48/80-treated HaCaT cells in vitro. Compound 48/80-treated HaCaT cells are a useful new in vitro model of skin inflammation.

Topical application of Kochia scoparia inhibits the development of contact dermatitis in mice

Ethnopharmacological relevanceKochia scoparia (Chenopodiaceae) has been reported to have anti-nociceptive, anti-inflammatory, anti-allergic, and anti-pruritic actions. This study investigated the anti-inflammatory effects of externally applied Kochia scoparia water extract (KSW) in 2,4-dinitrochlorobenzene (DNCB)-induced contact dermatitis mouse model. Materials and methodsTo develop atopic dermatitis-like skin lesions, 100μL of 1% DNCB in acetone/olive oil (4:1) had been applied for three days on shaved dorsal skin. 1% KSW was topically applied to DNCB-induced mice. After KSW treatment, histological analysis was measured by hematoxylin eosin staining. The cytokine and pro-inflammatory expressions were examined using reverse transcription polymerase chain reaction and western blotting analysis. ResultsHistological studies showed that hyperplasia of the epidermis and dermis in the KSW treated group was markedly decreased as compared with the DNCB group. The expression levels of pro-inflammatory cytokine such as IL-1β, and TNF-α mRNA were significantly reduced by topical application of KSW, whereas these cytokines were increased in DNCB-induced dorsal skin. In addition, NF-κB expression was inhibited by KSW treatment in DNCB-induced mice. Similarly, KSW treatment significantly suppressed the expression of several MAP kinases, including ERK1/2, p38, and JNK compared to their expression in DNCB-induced mice. ConclusionsThese findings indicated that KSW ameliorates contact dermatitis via inhibition of the production of several inflammatory mediators. Therefore, external application of KSW may be used for the treatment of contact dermatitis as an alternative therapy.

Topical Anti‐inflammatory Potential of Standardized Pomegranate Rind Extract and Ellagic Acid in Contact Dermatitis

The present study evaluated the topical anti-inflammatory potential of a standardized pomegranate rind extracts (SPRE) in parallel with its marker compound ellagic acid (EA, 13% w/w) against a mouse model of contact dermatitis. In the phenol-induced mouse ear edema, topical application of SPRE (5, 2.5, and 1 mg/ear) and EA (0.65, 0.325, and 0.13 mg/ear, equivalent to its content in SPRE) dose-dependently reduced the ear edema with the maximal inhibition of 79.12% and 73.63%, respectively. Triamcinolone (0.1 mg/ear) and diclofenac (1 mg/ear) as reference drugs inhibited the edema by 73.63% and 37.91%. Myeloperoxidase (MPO) activity in the mouse ear was also decreased by SPRE and EA up to 69.68% and 68.79%, respectively. Triamcinolone and diclofenac decreased the MPO activity by 76.66% and 80.14% similarly. The results indicated that topical application of SPRE and EA is promising for use in the treatment of inflammatory skin disorders.

A Novel Transdermal Fomulation of 18β-Glycyrrhetic Acid with Lysine for Improving Bioavailability and Efficacy

The aim of this study was to develop a novel topical liposomal system entrapping 18β-glycyrrhetic acid (GA) for the treatment of chronic allergic dermatitis. A novel liposomal system with molar ratios of GA to lysine from 1:1 to 1:3 was prepared by high-pressure homogenization. The liposomes at the optimized molar ratio of GA to lysine of 1:2 significantly improved GA loading (1.2%) and penetration in vitro. Liposomal gels containing GA 0.3, 0.6 and 0.9% were prepared to investigate the dosage effect on transdermal delivery and anti-inflammatory activity. In vivo pharmacokinetic studies were carried out by nonocclusive application of GA liposomal gels to ICR mouse ears. GA concentrations in skin and plasma increased proportionally with dose over the dose range of 0.3–0.9%. A 2,4-dinitrofluorobenzene-induced contact dermatitis mouse model was made up to evaluate the pharmacodynamics of GA liposomal gels. The liposomal gel with GA 0.9% showed a stronger anti-inflammatory activity than triamcinolone acetonide and econazole nitrate cream, while few side effects were observed in the present model. The topical administration of gel containing novel elastic liposomes of GA was safe and effective in the treatment of chronic allergic dermatitis.

Effect of Sophora flavescens Aiton extract on degranulation of mast cells and contact dermatitis induced by dinitrofluorobenzene in mice

Ethnopharmacological relevanceThe dried root of Sophora flavescens Aiton (Sophorae radix, SR) has long been used in traditional medicine for the treatment of fever and swelling in eastern countries. Materials and methodsThe present study investigated the anti-allergic and anti-inflammatory effects of SR using 1-fluoro-2,4-dinitrofluorobenzene (DNFB)-induced contact dermatitis mouse model and in vitro using RBL-2H3 cells. ResultsIn mice, the topical application of 10mg/mL of SR effectively inhibited enlargement of ear thickness and weight induced by repeated painting with DNFB. Topical application of SR also inhibited hyperplasia, edema, spongiosis and infiltration of mononuclear cells in ear tissue. In addition, production levels of interferon-gamma and tumor necrosis factor-alpha were decreased by SR in vivo. Finally, the release of histamine and β-hexosaminidase, and migration were inhibited by treatment with SR. ConclusionsThese data indicate the potential of SR in treating patients with allergic skin diseases and also suggest that related mechanisms are involved in anti-inflammatory action on the Th 1 skewing reaction and inhibition against recruitment and degranulation of mast cells.

Acetaminophen enhances pruritus in a mouse model of contact dermatitis induced by suboptimal concentration of hapten

Acetaminophen (APAP) is one of the most commonly used drugs worldwide to reduce fever, particularly in children. It is generally considered to be a safe drug. However, a number of studies have shown that regular use of APAP increases the risk of developing allergic diseases. Nonetheless, no animal models have been used to investigate these findings. Therefore, we aimed to create an animal model of APAP-induced pruritus in mice. APAP (0.25% and 0.5%) was administered via drinking water daily from infancy, and a suboptimal concentration of 2,4,6-trinitrochlorobenzene (TNCB) was applied repeatedly to each ear three times a week for 7 weeks to evoke chronic allergic contact dermatitis. Neither 0.25% nor 0.5% APAP was overtly hepatotoxic after 73 days of daily administration. Repeated challenge with TNCB evoked increase in the number of scratching bouts compared to day 1. This increase in the number of scratching bouts was significant in 0.25% and 0.5% APAP groups but not in the group treated with TNCB alone. Daily administration of 0.5% APAP significantly increased in the number of scratching bouts compared to TNCB alone on day 29. This animal model will be useful for investigating the mechanism underlying the increased risk of development of eczema caused by regular APAP use and for examining safer and more effective therapy with APAP.

Dendritic polyglycerol sulfates as multivalent inhibitors of inflammation

Adhesive interactions of leukocytes and endothelial cells initiate leukocyte migration to inflamed tissue and are important for immune surveillance. Acute and chronic inflammatory diseases show a dysregulated immune response and result in a massive efflux of leukocytes that contributes to further tissue damage. Therefore, targeting leukocyte trafficking may provide a potent form of anti-inflammatory therapy. Leukocyte migration is initiated by interactions of the cell adhesion molecules E-, L-, and P-selectin and their corresponding carbohydrate ligands. Compounds that efficiently address these interactions are therefore of high therapeutic interest. Based on this rationale we investigated synthetic dendritic polyglycerol sulfates (dPGS) as macromolecular inhibitors that operate via a multivalent binding mechanism mimicking naturally occurring ligands. dPGS inhibited both leukocytic L-selectin and endothelial P-selectin with high efficacy. Size and degree of sulfation of the polymer core determined selectin binding affinity. Administration of dPGS in a contact dermatitis mouse model dampened leukocyte extravasation as effectively as glucocorticoids did and edema formation was significantly reduced. In addition, dPGS interacted with the complement factors C3 and C5 as was shown in vitro and reduced C5a levels in a mouse model of complement activation. Thus, dPGS represent an innovative class of a fully synthetic polymer therapeutics that may be used for the treatment of inflammatory diseases.

LXRα Enhances Lipid Synthesis in SZ95 Sebocytes

Differentiation of sebocytes is strongly associated with enhanced lipid synthesis and accumulation in the cells. Liver X receptors (LXRs) are members of the nuclear receptor superfamily, which play a critical role in cholesterol homeostasis and lipid metabolism. We examined whether LXRalpha regulated lipid synthesis in the immortalized human sebaceous gland cell line SZ95. When the SZ95 sebocytes were treated with the ligand of LXR such as TO901317 or 22(R)-hydroxycholesterol, lipid droplets were accumulated in the majority of cells when examined by Oil Red O staining. The expression of the known LXR targets, such as fatty acid synthase and sterol regulatory-binding protein-1, was induced by TO901317. TO901317 treatment increased expression of LXRalpha but not that of LXRbeta. Transfection of antisense LXRalpha significantly decreased TO901317-induced target gene expression and lipid droplet accumulation, suggesting a major role of LXRalpha in differentiation of sebocytes. Further, TO901317 decreased the expression of cyclooxygenase-2 and inducible nitric oxide synthase that was induced by lipopolysaccharide treatment. Together, these results indicate that important roles of LXRalpha in differentiation and inflammatory signaling in sebaceous glands. Thus, we suggest that LXR ligands could provide a new class of therapeutic agents for sebaceous gland-associated disorders such as seborrhea and acne.