[Show abstract][Hide abstract] ABSTRACT: Objective:
Psoriasis is a chronic inflammatory skin disease and topical therapy remains a key role for treatment. The aim of this study is to evaluate the influence of psoriasis-like lesions on the cutaneous permeation of anti-psoriatic drugs.
We first set up imiquimod-induced dermatitis in mice that closely resembles human psoriasis lesions. The development of the lesions is based on the IL-23/IL17A axis for phenotypical and histological characteristics. Four drugs, 5-aminolevulinic acid (ALA), tacrolimus, calcipotriol, and retinoic acid, were used to evaluate percutaneous absorption.
The most hydrophilic molecule, ALA, revealed the greatest enhancement on skin absorption after imiquimod treatment. Imiquimod increased the skin deposition and flux of ALA by 5.6 to 14.4-fold, respectively, compared to normal skin. The follicular accumulation of ALA was also increased 3.8-fold. The extremely lipophilic drug retinoic acid showed a 1.7- and 3.8-fold increase in skin deposition and flux, respectively. Tacrolimus flux was enhanced from 2 to 21 μg/cm2/h by imiquimod intervention. However, imiquimod did not promote skin deposition of this macrolide. The lipophilicity, but not the molecular size, dominated drug permeation enhancement by psoriatic lesions. The in vivo percutaneous absorption of ALA and rhodamine B examined by confocal microscopy confirmed the deficient resistance of epidermal barrier for facilitating cutaneous delivery of drugs via psoriasis-like skin.
We established the topical delivery profiles of anti-psoriatic drugs via imiquimod-treated psoriasis-like skin.
PLoS ONE 09/2015; 10(9):e0137890. DOI:10.1371/journal.pone.0137890 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Topically applied natural antioxidants can be an effective treatment for inhibiting oxidative damage and photoaging of the skin. Due to the barrier function of the stratum corneum (SC), it is necessary to use an enhancement approach to promote the cutaneous absorption of natural antioxidants. Some factors that should be considered when developing delivery systems for natural antioxidants include increased solubility, enhanced storage stability, improved permeability and bioavailability, skin targeting, and minimal side effects. This review describes the skin delivery systems for natural antioxidant permeation that have been developed during the last decade. The antioxidants introduced include vitamins, polyphenols, and carotenoids. Various types of formulations are employed to improve the skin penetration of the antioxidants, such as hydrogels, cyclodextrin, microemulsions, nanoparticles, liposomes and niosomes. This review focuses on the introduction of natural antioxidants used in skin protection, the mechanisms of antioxidant activity on the skin, and formulation designs for enhancing absorption and efficacy.
Current pharmaceutical design 04/2015; 21(20). DOI:10.2174/1381612821666150428125428 · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ultraviolet (UV) exposure and menopause are known as the inducers of damage to the skin structure. The combination of these two factors accelerates the skin aging process. In this study, we aimed to evaluate the influence of UV and ovariectomy (OVX) on the permeation of drugs through the skin. The role of tight junctions (TJs) and adherens junctions (AJs) in the cutaneous absorption of extremely lipophilic permeants and macromolecules was explored. The OVX nude mouse underwent bilateral ovary removal. Both UVA and UVB were employed to irradiate the skin. The physiological and biochemical changes of the skin structure were examined with focus on transepidermal water loss (TEWL), skin color, immunohistochemistry, and mRNA levels of proteins. UVB and OVX increased TEWL, resulting in stratum corneum (SC) integrity disruption and dehydration. A hyperproliferative epidermis was produced by UVB. UVA caused a pale skin color tone due to keratinocyte apoptosis in the epidermis. E-cadherin and β-catenin showed a significant loss by both UVA and UVB. OVX downregulated the expression of filaggrin and involucrin. A further reduction was observed when UV and OVX were combined. The in vitro cutaneous absorption demonstrated that UV increased the skin permeation of tretinoin by about twofold. However, skin accumulation and flux of estradiol were not modified by photoaging. OVX basically revealed a negligible effect on altering the permeation of small permeants. OVX increased tretinoin uptake by the appendages from 1.36 to 3.52 μg/cm(2). A synergistic effect on tretinoin follicular uptake enhancement was observed for combined UV and OVX. However, the intervention of OVX to photoaged skin resulted in less macromolecule (dextran, molecular weight = 4 kDa) accumulation in the skin reservoir because of retarded partitioning into dry skin. The in vivo percutaneous absorption of lipophilic dye examined by confocal microscopy had indicated that the SC was still important to controlling topical delivery, although the role of epidermal junctions could not be simply ignored.
Journal of the American Aging Association 04/2015; 37(2):9757. DOI:10.1007/s11357-015-9757-1 · 3.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
In this study, we aimed to illustrate the utility of fractional radiofrequency (RF) that generated microchannels in the skin, allowing delivery of peptide and siRNA via the skin. The mechanisms involved in the correlation between macromolecule permeation and skin structure were also elucidated.
The morphology of the skin was examined by transmission electron microscopy (TEM), higher harmonic generation microscopy (HGM), and physiological factors. In vivo skin distribution of macromolecules was assessed by fluorescence and confocal microscopies.
RF thermolysis selectively created an array of micropores deep into the epidermis without significant removal of the stratum corneum (SC). With energy of 30 mJ, a pore depth of 35 μm was achieved. The bipolar RF resulted in a 3-fold increase of transepidermal water loss (TEWL) compared with intact skin. The respective skin accumulation and flux of the peptide with a molecular weight (MW) of 2335 Da was 3- and 23-fold greater for the RF-treated group than for the non-treatment group. RF enhanced skin accumulation of siRNAs with MW of 10 and 15 kDa by 6.2- and 2.6-fold, respectively. Cutaneous penetration of the macromolecules with an MW of at least 40 kDa could be accomplished by RF. Confocal microscopy imaging revealed that RF could effectively deliver the peptide up to at least a 74-μm depth. The penetration depth of siRNA by RF irradiation was about 50 μm.
The novel RF device efficiently delivered macromolecules into the skin while reserving SC layers to support some barrier functions. In this work, for the first time the assistance of fractional RF on peptide and siRNA transport was demonstrated.
Pharmaceutical Research 11/2014; 32(5). DOI:10.1007/s11095-014-1568-z · 3.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Treating nail psoriasis is notoriously difficult and lacks standardized therapeutic regimens. Indigo naturalis has been demonstrated to be safe and effective in treating skin psoriasis. This trial was conducted to evaluate the efficacy and safety of refined indigo naturalis extract in oil (Lindioil) in treating nail psoriasis. Thirty-one outpatients with symmetrically comparable psoriatic nails were enrolled. Lindioil (experimental group) or olive oil (control group) was applied topically to the same subjects’ two bilaterally symmetrical psoriatic nails twice daily for the first 12 weeks and then subjects applied Lindioil to both hands for 12 additional weeks. Outcomes were measured using Nail Psoriasis Severity Index (NAPSI) for five nails on one hand and for the single most severely affected nail from either hand. The results show a reduction of NAPSI scores for the 12-week treatment for the Lindioil group (49.8% for one hand and 59.3% for single nail) was superior to the reduction in the scores for the control group (22.9%, 16.3%, respectively). There were no adverse events during the 24 weeks of treatment. This trial demonstrates that Lindioil is a novel, safe and effective therapy for treating nail psoriasis.
Phytomedicine: international journal of phytotherapy and phytopharmacology 06/2014; 21(7). DOI:10.1016/j.phymed.2014.02.013 · 3.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Indigo naturalis is effective in treating nail psoriasis coexisting with microorganism infections. This study examines the antimicrobial effects of indigo naturalis prepared from Strobilanthes formosanus Moore. Eight bacterial and seven fungal strains were assayed using the agar diffusion method to examine the effects of indigo naturalis and its bioactive compounds. The bioactive compounds of indigo naturalis were purified sequentially using GFC, TLC, and HPLC. Their structures were identified using mass spectrometry and NMR spectroscopy. UPLC-MS/MS was applied to compare the metabolome profiles of indigo naturalis ethyl-acetate (EA) extract and its source plant, Strobilanthes formosanus Moore. The results of in vitro antimicrobial assays showed that indigo naturalis EA-extract significantly (≥1 mg/disc) inhibits Gram-positive bacteria (Staphylococcus aureus, S. epidermis and methicillin-resistant S. aureus (MRSA)) and mildly inhibits non-dermatophytic onychomycosis pathogens (Aspergillus fumigates and Candida albicans), but has little effect on dermatophyes. Isatin and tryptanthrin were identified as the bioactive compounds of indigo naturalis using S. aureus and S. epidermis as the bioassay model. Both bioactive ingredients had no effect on all tested fungi. In summary, indigo naturalis prepared from Strobilanthes formosanus Moore exhibits antimicrobial effects on Staphylococcus and non-dermatophytic onychomycosis pathogens. Tryptanthrin and isatin may be its major bioactive ingredients against Staphylococcus and the inhibitory effect on MRSA may be due to other unidentified ingredients.
[Show abstract][Hide abstract] ABSTRACT: Ethnopharmacological relevance:
Indigo naturalis is used in traditional Chinese medicine to treat various dermatoses. Our previous clinical studies showed that indigo naturalis is an effective treatment for psoriasis. Herein, the capabilities of indigo naturalis extract and its derivatives to increase claudin-1 expression and tight junction (TJ) function in human keratinocytes and psoriatic lesions were further studied.
Materials and methods:
Claudin-1 expression in psoriatic plaques with or without indigo naturalis treatment was analyzed by immunohistochemical methods. In primary human keratinocytes, the expression of claudin-1 was analyzed by fluorescent immunostaining, a real-time RT-PCR, and Western blot analysis. The effect of indigo naturalis on TJs was evaluated by measuring the transepithelial electrical resistance (TEER) and paracellular tracer flux.
The indigo naturalis extract upregulated mRNA and protein expressions of claudin-1 and function of TJs in primary human keratinocytes in concentration-dependent manners. Its main components, indirubin, indigo, and tryptanthrin, exerted synergistic effects on upregulating TJ functions in primary human keratinocytes. In addition, indigo naturalis increased the activity of protein kinase C (PKC), and a known potent PKC inhibitor, Ro318220, attenuated the indigo naturalis-induced claudin-1 expression. Significantly, restoration of claudin-1 was observed in healed psoriatic lesions after indigo naturalis treatment.
Indigo naturalis upregulates claudin-1 expression and restores TJ function in keratinocytes. Our data also suggest that indirubin, indigo, and tryptanthrin have a synergistic effect on TJ function.
Journal of ethnopharmacology 12/2012; 147(2). DOI:10.1016/j.jep.2012.11.044 · 3.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Diphencyprone (DPCP) is a therapeutic agent for treating alopecia areata. To improve skin absorption and follicular targeting nanostructured lipid carriers (NLCs) were developed.
Nanoparticles were characterized by size, zeta potential, molecular environment, differential scanning calorimetry (DSC), and nuclear magnetic resonance (NMR). In vitro and in vivo skin absorption experiments were performed. Fluorescence and confocal microscopes for imaging skin distribution were used.
NLCs with different designs were 208 ~ 265 nm with > 77% DPCP encapsulation. NLCs incorporating a cationic surfactant or more soybean phosphatidylcholine (SPC) showed higher lipophilicity compared to typical NLCs by Nile red emission. All NLCs tested revealed controlled DPCP release; burst release was observed for control. The formulation with more SPC provided 275 μg/g DPCP skin retention, which was greater than control and other NLCs. Intersubject deviation was reduced after DPCP loading into NLCs. Cyanoacrylate skin biopsy demonstrated greater follicular deposition for NLCs with more SPC compared to control. Cationic NLCs but not typical or SPC-containing carriers were largely internalized into keratinocytes. In vivo skin retention of NLCs with more SPC was higher than free control. Confocal imaging confirmed localization of NLCs in follicles and intercellular lipids of stratum corneum.
This work encourages further investigation of DPCP absorption using NLCs with a specific formulation design.
Pharmaceutical Research 10/2012; 30(2). DOI:10.1007/s11095-012-0888-0 · 3.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Topical indigo naturalis ointment is clinically proved to be an effective therapy for plaque-type psoriasis. Indirubin, as the active component of indigo naturalis, inhibits cell proliferation of epidermal keratinocytes. However, the detailed underlying mechanism is not fully understood.
To further investigate the anti-proliferating effects of indigo naturalis and indirubin on epidermal keratinocytes.
The decreased expression of CDC25B in indigo naturalis- or indirubin-treated epidermal keratinocytes, as revealed by cDNA microarray analysis, was studied. The CDC25B expression was examined under different serum concentrations and compared between primary and immortalized keratinocytes. The activation of EGFR and the effect of EGF on the cell proliferation and CDC25B expression were also investigated in epidermal keratinocytes. RT/real-time PCR and western blot method were used to analyze the CDC25B expression at the mRNA and protein levels, respectively.
Indigo naturalis and indirubin were confirmed to down-regulate CDC25B expression significantly at both the mRNA and protein levels. The growth-dependent expression of CDC25B was demonstrated by the increased expression in serum-stimulated and immortalized keratinocytes. The activation of EGF receptor, known to be highly expressed in psoriatic lesions, was inhibited by indigo naturalis or indirubin. The cell proliferation and CDC25B expression of epidermal keratinocytes were induced by EGF alone and confirmed to be inhibited by indigo naturalis or indirubin.
Except being a common therapeutic target in various cancers, CDC25B also plays an important role in the hyper-proliferation of epidermal keratinocytes which can be suppressed by anti-psoriatic drug indigo naturalis and its component, indirubin.
[Show abstract][Hide abstract] ABSTRACT: Psoriasis of the nail greatly affects quality of life because of the difficulty in achieving long-lasting remission. Pustular psoriasis of the nail apparatus is characterized by the formation of sterile pustules, starting on one or two fingers or less often on the toes, and spontaneous improvement has rarely been observed. This case presents a girl with refractory nail psoriasis accompanied by periodic pustular eruption that responded well to topical treatment with indigo naturalis oil extract drops, achieving a remission of longer than 1 year.
[Show abstract][Hide abstract] ABSTRACT: Indigo naturalis is used in traditional Chinese medicine to treat various skin disorders.
The aims were to explore the effect of indigo naturalis on suppressing oxidative stress and protein modifications by hydrogen peroxide (H(2)O(2)) and 4-hydroxy-2-nonenal (HNE), a lipid peroxidation product, in cultured primary human keratinocytes.
Indigo naturalis extract at a dose that did not cause cytotoxicity was added to cultured keratinocytes in the absence or the presence of H(2)O(2) or HNE. The degree of cytotoxicity, levels of reactive oxygen species (ROS), and amount of protein carbonyl groups were evaluated.
Indigo naturalis extract at the concentration of 10μg/ml had no protective effect against H(2)O(2) or HNE-induced cytotoxicity, but decreased intracellular levels of ROS after H(2)O(2) treatment and suppressed the increase of protein carbonyl groups induced by HNE.
Indigo naturalis possesses an inhibitory effect on formation of intracellular ROS induced by exogenous ROS and protein modification induced by HNE in human keratinocytes, which is relevant to the alleviation of inflammatory skin diseases.
Journal of ethnopharmacology 12/2011; 139(3):893-6. DOI:10.1016/j.jep.2011.12.037 · 3.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In the treatment of nail psoriasis, standardized therapeutic regimens are currently lacking.
To evaluate the therapeutic efficacy of indigo naturalis oil extract in patients with nail psoriasis.
Patients with nail psoriasis applied indigo naturalis oil extract on affected nails twice daily for 24 weeks. Efficacy was evaluated using the Nail Psoriasis Severity Index (NAPSI) and modified target NAPSI for the single most severely affected nail.
Twenty-eight out of 32 patients completed the study. The mean NAPSI was 36.1 ± 14.7 at baseline and decreased to 14.9 ± 11.1 at week 24 while the mean modified target NAPSI was 11.7 ± 3.9 at baseline and decreased to 3.6 ± 3.2 at week 24.
Indigo naturalis oil extract appeared to improve nail psoriasis. Although preliminary, these results indicate that it could provide a novel therapeutic option for nail psoriasis, a disease notoriously difficult to treat.
[Show abstract][Hide abstract] ABSTRACT: Psoriasis has a significant negative impact on quality of life. The aim of this study was to identify factors associated with the quality of life of patients with psoriasis in Taiwan.
A retrospective study analyzing data from psoriasis patients who visited the outpatient clinics in the Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital at Taipei, Taoyuan and Keelung from July 2009 to January 2010 was performed.
A total of 480 patients who had completed the assessment of disease severity and the dermatology life quality index (DLQI) questionnaire were analyzed. Of these patients, 67.5% were men. The mean score on the DLQI was 9.16 ± 6.3 and 67% of all patients reported a moderate to extremely large impact on their quality of life (DLQI > 6). A higher psoriasis area and severity index (PASI), younger age and initial lesions on the nails significantly negatively impacted patients' quality of life. Smoking, alcohol intake and gender were also weakly correlated.
The clinical severity, age and site of initial lesions are associated with negative impacts on the quality of life of patients with psoriasis. These findings provide significant new insights into factors that affect the life quality of patients with psoriasis in Taiwan.
[Show abstract][Hide abstract] ABSTRACT: Tryptanthrin is an ancient medicine which recently was also found to have a function of downregulating multidrug resistance (MDR). However, tryptanthrin is insoluble in water, which limits its availability for delivery into cancer cells. There is a need to improve delivery systems to increase the inhibition of MDR. The aim of this study was to employ nanoparticles encapsulating tryptanthrin to improve the delivery and promote the sustained release of this drug. The approach was to encapsulate tryptanthrin in various nanoparticles, including solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), and lipid emulsions (LEs). We compared the particle size and zeta potential of these nanoparticles, and evaluated the partitioning behavior of tryptanthrin in them. We also determined the release kinetics of tryptanthrin from these nanoparticles. Moreover, cellular cytotoxicity toward and uptake of tryptanthrin-loaded nanoparticles by human breast cancer cells were determined. We found that the mean particle size of NLCs was lower, and the partition coefficient was higher than those of SLNs, and an increased tryptanthrin release rate was found with the NLC delivery system. NLCs achieved the sustained release of tryptanthrin without an initial burst. In particular, the NLC-C formulation, composed of a mixture of Compritol and squalene as the core materials, showed the highest release rate and cytotoxic effect. Confocal laser scanning microscopic images confirmed drug internalization into cells which enhanced the endocytosis of the particles. These results suggested that NLCs can potentially be exploited as a drug carrier for topical or intravenous use in the future.
[Show abstract][Hide abstract] ABSTRACT: The use of indigo naturalis to treat psoriasis has proved effective in our previous clinical studies. The present study was designed to examine the anti-inflammatory effect of indigo naturalis in primary cultured human umbilical vein endothelial cells (HUVECs). Pretreatment of cells with indigo naturalis extract attenuated TNF-α-induced increase in Jurkat T cell adhesion to HUVECs as well as decreased the protein and messenger (m)RNA expression levels of vascular cell adhesion molecule-1 (VCAM-1) on HUVECs. Indigo naturalis extract also inhibited the protein expression of activator protein-1 (AP-1)/c-Jun, a critical transcription factor for the activation of VCAM-1 gene expression. Since the reduction of lymphocyte adhesion to vascular cells by indigo naturalis extract could subsequently reduce the inflammatory reactions caused by lymphocyte infiltration in the epidermal layer and help to improve psoriasis, this study provides a potential mechanism for the anti-inflammatory therapeutic effect of indigo naturalis extract in psoriasis.
[Show abstract][Hide abstract] ABSTRACT: The combination of calcipotriol with methotrexate can strengthen the topical therapy for psoriasis. The aim of the present study was to evaluate the potential of nanostructured lipid carriers (NLCs) loaded with lipophilic calcipotriol and hydrophilic methotrexate as topical therapy. NLCs composed of Precirol ATO 5 with various amounts of squalene as the liquid lipid were prepared. The particle size, surface charge, molecular environment, drug permeation, and skin irritation of the carriers were assessed. Hyperproliferative skin was also used as a permeation barrier in this study. It was found that variations in the Precirol/squalene ratio had profound effects on the physicochemical characteristics of the NLCs. The range of particle size of the NLC preparations was 270 to 320 nm, with vehicles containing a higher Precirol amount exhibiting a larger diameter. NLCs with a higher Precirol/squalene ratio also showed greater polarity in their molecular environment. Calcipotriol-loaded NLC systems provided drug fluxes of 0.62 to 1.08 microg/cm(2)/h, which were slightly higher or comparable to the 30% ethanol vehicle (control, 0.72 microg/cm(2)/h). The methotrexate amount permeating the skin was 2.4 to 4.4-times greater using NLCs compared to that with the control. Dual drug-loaded NLCs exhibited reduced skin permeation of calcipotriol but not methotrexate. The in vivo topical delivery examined by confocal laser scanning microscopy (CLSM) showed a good correlation with the in vitro results. These two drugs with extremely different polarities can successfully be combined in NLCs. Results suggest that NLCs may have the potential to serve as delivery carriers for antipsoriatic drugs because of enhanced drug permeation and limited skin irritation.
International Journal of Nanomedicine 03/2010; 5(1):117-28. · 4.38 Impact Factor