Article

Corrigendum to “Indigo naturalis upregulates claudin-1 expression in human keratinocytes and psoriatic lesions”

Authors:
  • Chang Gung Memorial Hospital, Keelung, Taiwan
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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. Results: 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. Conclusions: 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.

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... 3 compounds: synergistic effect on upregulating tight junction function. (Lin et al., 2013) In vitro: Human skin Extract and its three major ingredients (Indirubin, Indigo, Tryptanthrin) ...
... Apart from anti-inflammatory activities, antiproliferative including activities on cell apoptosis and cell differentiation activities were reported for Artemisia anomala (Gao et al., 2019), Celastrus orbiculatus (Zhou et al., 2011), Prunus and soybean , Gloriosa superba and Catharanthus roseus (Pattarachotanant et al., 2014), Leguminous plants Sophora flavescens, S. alopecuroides, S. subprostrata , Radix rubiae (Tse et al., 2007), Rubia cordifolia (Mok et al., 2013), Salvia miltiorrhiza Bunge (Jia et al., 2020;Tang et al., 2018), Salvia miltiorrhiza Radix (Li et al., 2012), Scutellaria baicalensis , Zanthoxylum nitidum , as well as Dang-Gui-Liu-Huang Tang , PSORI-CM01 (Han et al., 2017;Wei et al., 2016), PSORI-CM02 (Chen et al., 2017a), and Wannachawee (Na formulas. Anti-oxidative activities were demonstrated for Artemisia anomala S. (Gao et al., 2019), Cruciferous vegetables (Weng et al., 2019), Indigo Naturalis (Lin et al., 2013), Melissa officinalis (lemon balm) (Dimitris et al., 2020), Lagenaria siceraria (Zhang et al., 2016), quercetin compound and Sinapis alba . Studies on antiangiogenesis activities were limited to only a few herbs, that is, Indigo Naturalis Chang et al., 2019) and Panax ginseng Radix . ...
... The most well-studied plants were Indigo Naturalis Chang et al., 2019;Chang et al., 2010;Cheng et al., 2017a;Lee et al., 2019;Lin et al., 2007;Lin et al., 2008;Lin et al., 2009;Lin et al., 2011;Lin et al., 2013;Lin et al., 2014;Lin et al., 2015, Ruanunculaceae (Pang et al., 2018, Aloe vera (Arora et al., 2016;Leng et al., 2018;Syed et al., 1996), and C. longa (Arora et al., 2016;Kang et al., 2016;Zhang et al., 2019), Indigo Naturalis or Qing Dai is obtained from the aerial part/stem/leaf mainly of Strobilanthes formosanus Moore or, in some cases, Baphicacanthus cusia, Polygonum tincyorium, and Isatis indigotoca. It is widely used in TCM for psoriasis, inflammatory diseases, and leukemia. ...
... In vivo [113][114][115][116][117][118][119][120] Memecylon malabaricum Melastomataceae Leaves ...
... [ [113][114][115][116] p-Coumaric acid (14) Picea mariana Inhibition of NO production through the inhibition of the expression of iNOS mRNA [125][126][127] Pinoresinol (15) Picea mariana Inhibition of NO production through the inhibition of the expression of iNOS mRNA [125][126][127] Resveratrol (16) Picea mariana Inhibition of NO production through the inhibition of the expression of iNOS mRNA [125][126][127] skin diseases, such as psoriasis [61]. Phytochemical screening reported cassane furanoditerpenes from different parts of the plant [62][63][64]. ...
... The ability of I. naturalis extract to increase the expression of claudin-1 and tight junction (TJ) function was investigated in human keratinocytes and psoriatic lesions [115]. I. naturalis was able to up-regulate both mRNA and protein expression of claudin-1 and function of TJ in a concentration-dependent manner. ...
Article
Psoriasis is a chronic inflammatory immune-mediated skin disease. It affects most races, does not have any sexual predilections and can manifest at any age of life. Psoriasis is more frequent in certain racial groups and geographical areas. For these reasons, both genetic and environmental factors could be considered. In this review, we discuss promising natural compounds, their molecular targets and mechanisms, which may help the further design of new anti-psoriasis agents. Literature documents the widespread use of herbal remedies worldwide, and the presence of some phytochemicals supports the efficacy of some botanical treatments. The research on natural products has greatly contributed to the progress in the treatment of skin diseases such as psoriasis and many of these compounds are now being used. Understanding the mechanism of these molecules will contribute to the development of more specific preventive strategies for the treatment of psoriasis.
... Our previous clinical studies have shown that topical use of ointment-based indigo naturalis improved the epidermal thickness, leukocyte infiltration, and angiogenesis of the psoriatic skin lesion safely and effectively (Lin et al., 2007). Indigo naturalis has been proved to modulate differentiation and proliferation of keratinocytes, downregulate inflammatory reactions by suppressing human neutrophils and vascular cell adhesion molecule-1 expression in human umbilical vein endothelial cells (HUVECs), inhibit epidermal growth factor (EGFR) activation and EGF-induced CDC25B gene expression, and upregulate claudin-1 expression in human keratinocytes (Chang et al., 2010;Hsieh et al., 2012;Lin et al., 2013;Lin et al., 2009a;Lin et al., 2009b). However, the mechanism of how indigo naturalis regulates angiogenesis remains unclear. ...
... The pathophysiology of psoriasis is mostly believed to be associated to immune dysfunction which results in keratinocytes proliferation, leukocytes infiltration, and angiogenesis. In our previous study, indigo naturalis has been proved to modulate the differentiation and proliferation of human keratinocytes (Lin et al., 2009b), improve barrier function of keratinocytes (Lin et al., 2013), and inhibit tumor necrosis factor-α-induced vascular cell adhesion molecule-1 expression in human vascular endothelial cells in vitro (Chang et al., 2010). From the histological analysis of the skin samples before and after the treatment with indigo naturalis, the area of rete ridges and vascular formation was decreased significantly after the treatment. ...
Article
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Indigo naturalis has been used to treat inflammatory diseases and dermatosis, including psoriasis, since thousands of years in China. It has been proven effective in our previous clinical studies on treating psoriasis, but the active component and the mechanism of how indigo naturalis working still needs to be clarified. Since the dysregulated angiogenesis is known to play an important role in the pathogenesis of psoriasis, the anti-angiogenic effect of indigo naturalis and tryptanthrin, a pure component of indigo naturalis, was investigated.
... Additionally, since indigoids herbal remedies have been commonly used in traditional chinese medicine for treating dermatosis and skin lesions such as eczema, aphtha, or eruptions, a few clinical trials suggested that topical treatment with Indigo naturalis ointment is effective in treating PS [191,192] and AD [193]. Studies on cultured primary human keratinocytes indicated that the anti-psoriatic effects of I. naturalis extract rely on blocking keratinocyte proliferation, inducing keratinocyte differentiation, upregulating claudin-1 expression, and enhancing the function of tight junctions [194,195]. ...
... Effective in the treatment of PS and AD patients [191][192][193]. Induce keratinocyte differentiation [194,195] Indirubin Inhibits inflammatory reactions in DTH mouse model [187] 3,3 -diindolylmethane (DIM) ...
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Aryl hydrocarbon receptor (AHR) is an important regulator of skin barrier function. It also controls immune-mediated skin responses. The AHR modulates various physiological functions by acting as a sensor that mediates environment–cell interactions, particularly during immune and inflammatory responses. Diverse experimental systems have been used to assess the AHR’s role in skin inflammation, including in vitro assays of keratinocyte stimulation and murine models of psoriasis and atopic dermatitis. Similar approaches have addressed the role of AHR ligands, e.g., TCDD, FICZ, and microbiota-derived metabolites, in skin homeostasis and pathology. Tapinarof is a novel AHR-modulating agent that inhibits skin inflammation and enhances skin barrier function. The topical application of tapinarof is being evaluated in clinical trials to treat psoriasis and atopic dermatitis. In the present review, we summarize the effects of natural and synthetic AHR ligands in keratinocytes and inflammatory cells, and their relevance in normal skin homeostasis and cutaneous inflammatory diseases.
... [4][5][6] Our previous studies showed that indigo naturalis repairs the abnormal epidermal barrier by promoting differentiation, upregulating claudin-1 expression, restoring tight junction proteins and inhibiting keratinocyte proliferation. [7][8][9] In addition, there is evidence that indigo naturalis and indirubin (the active component of indigo naturalis) inhibit activation of epidermal growth factor receptor, which is known to contribute to psoriasis pathogenesis. [10][11][12] Indirubin may also suppress skin inflammation through inhibition of cytokines production, nuclear factor kappa B activity and mitogen activated protein kinase activation. ...
... [18][19][20] Lindioil is primarily composed of indirubin, but also contains small amounts of indigo and tryptanthrine. 7,8 The botanical drugs used in traditional Chinese medicine, including indigo naturalis, often have varying concentrations of active ingredients depending on the source. The objective of this study was to determine and compare the efficacy and safety of different concentrations of indirubin in the Lindioil ointment formulation (in a previous trial, we examined only one indirubin concentration in Lindioil ointment, 105 lg g À1 ). ...
Article
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Background: Indigo naturalis and its refined formulation, Lindioil, are effective in treating psoriatic symptoms topically. Indirubin is the active ingredient in indigo naturalis. Objectives: To determine the efficacy and safety of different concentrations of indirubin in Lindioil ointment for treating psoriasis. Methods: In this randomized, double-blind trial, adult patients presenting with chronic plaque psoriasis for >1 year and with <20% of the body surface area (BSA) affected were randomized to apply Lindioil ointment containing 200 μg/g, 100 μg/g, 50 μg/g, or 10 μg/g of indirubin twice daily for 8 weeks followed by an additional 12-week safety/extension period. The primary endpoint was the mean percentage change in Psoriasis Area and Severity Index (PASI) score along with the proportion of subjects achieving 75% and 90% reductions in PASI scores (PASI75 and PASI90, respectively) from baseline to week 8. Results: The results from week 8 revealed that the 200 μg/g group had the greatest reduction in PASI score (69·2%, 95% confidence interval [CI] 82·8-55·5), followed by the 100 μg/g group (63·1%, 95% CI 73·5-52·8), the 10 μg/g group (53·4%, 95% CI 64·0-42·8), and the 50 μg/g group (50·3%, 95% CI 63·2-37·4), with between-group comparison of P = 0·0445). The highest proportion of the subjects in the 200 μg/g group achieved PASI75 (56·5%, P = 0·0474) and PASI90 (30·4%, P = 0·0098). No severe treatment-related adverse events were reported during the 20-week evaluation. Conclusions: 200 μg/g of indirubin in Lindioil ointment is the most effective concentration studied so far for treating psoriasis topically, and is safe ClinicalTrials . gov Identifier: NCT01735864 This article is protected by copyright. All rights reserved.
... Indirubin additionally inhibits the activation of epidermal growth factor receptor (EGFR) as well as CDC25B gene expression induced by epidermal growth factor (EGF) [109]. In cultured human keratinocytes and in psoriatic lesions, indirubin also causes upregulation of claudin-1, which functions as major constituent of tight junction complexes that regulate the permeability of epithelia [110]. Application of 5nitro-indirubinoxime (incorrectly [111] designated as modified at the five-prime position) to mouse skin epidermal cells results in the inhibition of neoplastic cell transformation induced by EGF or 12-O-tetradecanoylphorbol-13-acetate (TPA). ...
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Indirubin is the active component of Danggui Longhui Wan, a traditional Chinese medicine formulation. The encouraging clinical results from the 1980s obtained in chronic myelocytic leukemia patients treated with indirubin stimulated numerous studies on this compound. These investigations explored the use of indirubin in different types of cancer and reported the synthesis of novel derivatives with improved chemical and pharmacokinetic properties. In this paper, we review the impressive progress that has been made in elucidating the mechanistic understanding of how indirubin and its derivatives affect physiological and pathophysiological processes, mainly by inhibition of cell proliferation and induction of cell death. Furthermore, we survey the therapeutic use of these compounds in combating proliferative diseases such as cancer, restenosis, and psoriasis.
... In recent years, more and more reports have shown that indigo naturalis and indirubin can be effectively and safely used for the treatment of psoriasis 80 , especially nail psoriasis and plaque-type psoriasis [81][82][83] . Indigo naturalis upregulates claudin-1 expression and tight-junctions in human keratinocytes and also has a strong inhibitory effect on the inflammatory response of human neutrophils 84,85 . Therefore, an exploration of the relationship between natural products and activity will be of great value to the development of anti-inflammatory and barrier repair skin treatments. ...
Article
Full-text available
Psoriasis is a common inflammatory disease. It affects 1-3% of the population worldwide and is associated with increasing medical costs every year. Typical psoriatic skin lesions are reddish, thick, scaly plaques that can occur on multiple skin sites all over the body. Topical application of imiquimod (IMQ), a toll-like receptor (TLR)7 agonist and potent immune system activator, can induce and exacerbate psoriasis. Previous studies have demonstrated that isoflavone extract has an antioxidant effect which may help decrease inflammation and inflammatory pain. Through in vivo studies in mice, we found that the topical application to the shaved back and right ear of mice of isoflavone extract prior to IMQ treatment significantly decreased trans-epidermal water loss (TEWL), erythema, blood flow speed, and ear thickness, while it increased surface skin hydration, and attenuated epidermal hyperplasia and inflammatory cell infiltration. Through in vitro experiments, we found that isoflavone extract can reduce IL-22, IL-17A, and TNF-α-induced MAPK, NF-κB, and JAK-STAT activation in normal human epidermal keratinocytes. At the mRNA level, we determined that isoflavone extract attenuated the increased response of the TNF-α-, IL-17A-, and IL-22- related pathways. These results indicate that isoflavone extract has great potential as an anti-psoriatic agent and in the treatment of other inflammatory skin diseases.
... It has been isolated from the cannonball tree Couroupita guianensis (Chavda 2015), from other so-called indigoid plants, and recently from marine alphaproteobacteria (Wagner-Dober et al. 2004). Tryptanthrin shows anti-microbial and anti-protozoan activities (Mitscher and Baker 1998;Hwang et al. 2013;Lin et al. 2013). It also demonstrates cytotoxic, antitumor, and anti-inflammatory properties (Ishihara et al. 2000;Koya-Miyata et al. 2001;Jao et al. 2008;Pergola et al. 2012;Chiang et al. 2013;Moskovkina et al. 2013;Han et al. 2014;Srivastava 2014;Deryabin et al. 2017). ...
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Nine tryptanthrin derivatives, including tryptanthrin itself, were synthesized using different methods, including oxidation of the corresponding isatins to obtain 1–4, the reaction of tryptanthrin 1 with hydrazine and its derivatives to obtain 5–7, and aldol condensation of 1 with acetone and methylethylketone to obtain 8 and 9. The action of 1–9 in doses corresponding to the IC50 against developing embryos of the sea urchin Strongylocentrotus intermedius and in the sperm test allowed us to estimate to potency of all the compounds and to determine which were cytotoxic. In addition, these studies showed that compounds 3, 4, 8, and 9 had a stimulatory effect at lower doses. In particular, the tryptanthrin derivatives stimulated the larval stages of development in surviving embryos at concentrations lower than the IC50.
... Previously we had shown that treatment with DiC8 triggered the appearance of ZO-1 at cell borders in cells cultured in LC (Balda et al., 1993) and that nPKCε induces the exit of ZO-2 from the nucleus (Chamorro et al., 2009). Moreover, treatment with the traditional Chinese medicine, indigo naturalis (Lin et al., 2013), or the anti-inflammatory molecule, oxyresveratrol (Jo et al., 2017), increased TJ function and protein expression through a process mediated by PKC activation. In a similar manner, treatment of intestinal cells with probiotic secretory proteins (Seth et al., 2008), or bile duct epithelia with EGF (Guntaka et al., 2011), protected TJ barrier function from hydrogen peroxideinduced insult through a mechanism mediated by cPKC and nPKCε. ...
Article
ZO-2 is a tight junction (TJ) cytoplasmic protein, whose localization varies according to cell density and Ca ²⁺ in the media. In cells cultured in low calcium (LC), ZO-2 displays a diffuse cytoplasmic distribution, but activation of the Ca ²⁺ sensing receptor (CaSR) with Gd ³⁺ triggers the appearance of ZO-2 at the cell borders. CaSR downstream signaling involves activation of PKC, which phosphorylates and activates with no lysine kinase-4 that phosphorylates ZO-2 inducing its concentration at TJs. In LC, ZO-2 is protected from degradation by association to 14-3-3 proteins. When monolayers are transferred to normal calcium, the complexes ZO-2/14-3-3ζ and ZO-2/14-3-3σ move to the cell borders and dissociate. 14-3-3 proteins are then degraded in proteosomes, whereas ZO-2 integrates to TJs. From the plasma membrane residual ZO-2 is endocyted and degradaded in lysosomes. U2 region of ZO-2, and S261 located within a nuclear localization signal, are critical for the interaction with 14-3-3 ζ and σ and for the efficient nuclear importation of ZO-2. These results explain the molecular mechanism through which extracellular Ca ²⁺ triggers the appearance of ZO-2 at TJs in epithelial cells and reveal the novel interaction between ZO-2 and 14-3-3 proteins, which is critical for ZO-2 protection and intracellular traffic.
... 16,17 In addition, indirubin suppresses skin inflammation by inhibiting cytokine production, nuclear factor kappa B (NF-κB) activity, and mitogen-activated protein kinase signaling. 18,19 Tryptanthrin also possesses antiinflammatory properties that attenuate the T-helper 17 (Th17) signature 12 and downregulate the IL-17 pathway. 20 Another component, indigo, is less active than the other two, 10 but both indigo and indirubin activate the aryl hydrocarbon receptor signaling pathway to modulate the immune response. ...
Article
Full-text available
Purpose: Lindioil, a medicine refined from indigo naturalis (a herb used in Chinese medicine), is effective in treating severe psoriasis; however, responses vary across individual patients. We aim to investigate genetic predispositions associated with treatment response to topical Lindioil among patients with psoriasis and correlations with plasma cytokine patterns. Patients and methods: We enrolled 72 psoriasis patients treated with Lindioil ointment and analyzed the human leukocyte antigen class C (HLA-Cw) genotypes and plasma cytokine expression patterns. We developed regression models of treatment response, defined as Psoriasis Area and Severity Index (PASI) 75, to examine correlations among HLA-Cw alleles, cytokine levels, and treatment response to Lindioil. Results: Patients harboring HLA-Cw*06:02 were significantly more likely to respond to Lindioil (P = 0.02, odds ratio [OR]: 6.88), whereas Lindoil was ineffective in those harboring HLA-Cw*01:02 (P = 0.01, OR: 0.28). Patients who were HLA-Cw*06:02-positive or HLA-Cw*01:02-negative had better PASI scores and body surface area (BSA) improvement (73.3% vs 44.4%, P<0.001) following an 8-week treatment period. Psoriasis patients achieving PASI 75 after 8 weeks presented with lower baseline plasma interleukin-17 (IL-17) levels than those who did not achieve PASI 75 (PASI 75: 11.28 pg/mL vs PASI <75: 15.82 pg/mL, P = 0.05). Conclusion: Our findings suggest that the presence of the HLA-Cw*06:02 or HLA-Cw*01:02 alleles and plasma IL-17 levels are predictive markers of treatment response to Lindioil ointment in patients with psoriasis.
... Indigo naturalis (in China, also known as Qing Dai, or QD), a dark-blue powder, is sourced from the leaves and branches of various indigo-producing plants, such as Baphicacanthus cusia (Nees) Bremek, Indigofera tinctoria L., Isatis indigotica Fort, Polygonum tinctoria Ait, and Strobilanthes cusia (Nees) Kuntze [14]. In traditional Chinese medicine (TCM), QD has been widely used for treating various infectious and inflammatory diseases, such as enteritis, carbuncles, eczema, and psoriasis [14,15]. A recent multicenter randomized controlled trial and retrospective observational studies have demonstrated that QD could be effective in inducing mucosal healing in patients with UC and intractable UC [16][17][18]. ...
Article
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Indigo naturalis (also known as Qing-dai, or QD), a traditional Chinese medicine, has been widely used as an anticolitis regimen in the clinical practice of Chinese medicine. However, the precise mechanisms behind its efficacy remain unknown. We investigated the protective effects and associated molecular mechanisms of QD in DSS-induced colitis in mice. We found that QD administration attenuated DSS-induced colon shortening, tissue damage, and the disease activity index during the onset of colitis. Moreover, QD administration significantly suppressed colonic MPO activity and increased the activities of colonic T-SOD, CAT, and GSH-Px, as well the expression of p-AMPK and Nrf-2 in colon tissues of colitic mice. In addition, QD was capable of reducing the colonic Th1 and Th17 cell cytokines, the frequencies of Th1 and Th17 cells, and the phosphorylation of p-STAT1 and p-STAT3 in the mesenteric lymph nodes of colitic mice. An in vitro assay showed that QD significantly suppressed the differentiation of Th1 and Th17 cells. These findings suggest that QD has the potential to alleviate experimental colitis by suppressing colonic oxidative stress and restraining colonic Th1/Th17 responses, which are associated with activating AMPK/Nrf-2 signals and inhibiting STAT1/STAT3 signals, respectively. These findings also support QD as an effective regimen in the treatment of IBD.
... In one of our previous studies, we demonstrated that indigo naturalis can inhibit proliferation and promote differentiation in epidermal keratinocytes [20]. In addition, we also found that indigo naturalis upregulates claudin-1 expression and restores tight junction proteins in keratinocytes that help restore the impaired epidermal barrier [21]. ...
Article
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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.
... [72] Indirubin from Indigo naturalis has been reported for the treatment of nail psoriasis and plaque psoriasis. [73,74,75] It was found that the indirubin act by upregulation of claudin-1 expression in human keratinocytes. [76] Isoliquiritigenin, a flavanoid component of liquorice also provides a promising effect in the treament of psoriasis by exhibiting NF-κB suppression activity thereby downregulating IL-6 and IL-8 cytokine. ...
Article
Psoriasis is characterized by hyperproliferation of cells with itchy and painful skin patches due to the failure of replacement of dead skin cells every three to four weeks that occur in a normal skin. Therapeutic strategies for psoriasis depend upon the severity and location of lesions. Conventional treatments include phototherapy, photochemotherapy and systemic therapy involving biologicals and immunomodulators. The synthetic drugs in use for treating psoriasis are associated with severe adverse effects. Patient affordability, intolerance, drug resistance, serious adverse events play a crucial role in the choice of systemic therapy. Eventhough biologicals might be life saving in cases of severe psoriasis, risks of infection in particular reactivation of latent tuberculosis and possibilities of cancer on prolonged treatment demands safe and efficient alternative treatments. Easy availability, better patient tolerance, affordability, multiple modes of biochemical action and acceptability strengthens the use of natural products for psoriasis. This comparative review documents the existing natural treasure with various plant extracts and secondary metabolites reported as antipsoriatic agents over conventional drugs and their associated adverse effects in the management of psoriasis.
... It has been shown that PKCδ altered the expression of tight junction proteins, including CLDN1, in pancreas, liver, skin and melanoma cell lines [19][20][21][22]. Furthermore, previous studies have shown that TNF-α increases PKC activity in A549 cells [23][24][25]. ...
Article
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Claudin 1 (CLDN1) is a critical component of tight junction adhesion complexes that maintains the structural integrity of epithelial cell layers. Dysregulation of CLDN1 is associated with the growth and metastasis of human lung adenocarcinoma. TNF-α treatment was previously shown to increase expression of CLDN1 that mediated lung cancer cell morphology changes and migration. This study aimed to elucidate the molecular mechanisms involved in TNF-α induced CLDN1 expression in human lung carcinoma A549 cells. Chemical inhibition or siRNA downregulation of Src, PI3K, Akt, MAPKs, NFκB, caspase and PKC demonstrated that PKC, specifically PKCδ, is required for TNF-α induced CLDN1 expression. Further investigation of the PKC pathway revealed that CLDN1 expression is enhanced by the downstream molecules iPLA2, PGE2, 15-keto PGE2 and PPARγ. Conversely, inhibition of these molecules decreased CLDN1 expression. Additionally, a wound-healing assay demonstrated that TNF-α stimulation, PKC activation, prostaglandin treatment or PPARγ activation enhanced cell migration. In conclusion, TNF-α induced CLDN1 expression is regulated by the PKCδ-iPLA2-PGE2-PPARγ signaling cascade in human lung carcinoma A549 cells. Copyright © 2014. Published by Elsevier Inc.
... In psoriatic lesions indigo naturalis has been shown to upregulate claudin-1 expression and restore tight junction function; synergistic effect was reported for indirubin, inigo and tryptanthrin (Lin et al., 2013). Clinical studies by Lin and his group (2007Lin and his group ( , 2008Lin and his group ( , 2011 on topical formulations of indigo naturalis, including oils and ointments, report efficacy in plaque psoriasis, nail psoriasis, also recalcitrant forms, in both adult and pediatric patients. ...
Article
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Psoriasis is a chronic inflammatory skin disease, with an important impact on the patient's quality of life. Its incidence and prevalence are continuously increasing. The complex ethiopathology of this disorder is only partially known; there is a clear genetic predisposition, which associates a number of environmental triggering factors such as an unbalanced diet and lifestyle. The conventional therapeutic options are not always satisfactory in terms of efficiency and safety, therefore, complementary and alternative medicine approaches are frequently chosen by patients, mostly as self-medication. This review, based on recent literature flow data, outlines the pharmacological benefits of herbal formulations with antipsoriatic activity. It also reveals the molecules responsible for their effects, as well as their interference with the metabolic and immunopathogenic mechanisms of this disease. An important number of plants have been proved to act as antipsoriatic agents, many botanical-based preparations containing keyphytochemical molecules (belonging mainly to phenolics, triterpenoids and phytosterols or unsaturated fatty acids, as mentioned in pecific phyto-pharmaceutical databases). Specific mechanisms of action, which can explain their activity (such as lipoxygenase inhibition, antioxidant, anti-inflammatory, anti prostaglandin), were recently described. Only some of these formulations have been actively tested in vitro or in vivo. Most publications in the field agree on the need for more in vitro and in vivo studies, especially clinical assessment on patients with Psoriasis vulgaris. These would provide more accurate data on the efficacy and safety of such herbal formulations for this disease.
... As is well known, psoriasis has long been associated with skin barrier dysregulation [6], in which tight junction (TJ), as an important component in epidermal barrier function, is also seen to be clearly altered in psoriasis [7,8]. Claudin-1, a composition of TJ proteins that are extremely important to skin barrier, is reported to be downregulated in the uppermost and lowermost layers in early stages of skin lesion [9][10][11], while in the late stages of skin lesion, it is often completely absent [10]. Until now, there is little consensus on Claudin-1 patterns in psoriatic skin. ...
Article
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Objective: This study aimed to estimate serum IL-17A and Claudin-1 levels, investigate their correlation, and evaluate their diagnostic significance as potential blood-based biomarkers in psoriasis. Methods: Serum IL-17A and Claudin-1 concentrations were determined using enzyme-linked immunosorbent assay (ELISA). Statistical analyses were performed to determine differences in serum levels of IL-17A and Claudin-1, their bivariable correlation with psoriasis severity, as Psoriasis Area Severity Index (PASI), and their predictive abilities using receiver operating characteristic (ROC) curves. Results: Significantly higher IL-17A and lower Claudin-1 levels were found in psoriasis (p < 0.05). PASI did not correlate significantly with either IL-17A or Claudin-1 in psoriasis and their subtypes. The only significant correlation between serum IL-17A and Claudin-1 was shown in late-onset psoriasis (r = 0.630, p = 0.028). ROC curve analysis indicated the serum IL-17A, serum Claudin-1, and combination of IL-17A and serum Claudin-1 for predicting psoriasis with the areas under the curve (AUC) of 0.951 (p < 0.0001), 0.709 (p = 0.0119), and 0.949 (p < 0.0001), respectively. Moreover, the potential role in distinguishing between early-onset and late-onset psoriasis: we obtained serum IL-17A, serum Claudin-1, and their combination AUC of 0.590 (p = 0.3126), 0.741 (p = 0.0045), and 0.741 (p = 0.0067), respectively. However, none of the serum IL-17A, serum Claudin-1, and their combination was well-performed discriminating mild psoriasis from moderate-to-severe psoriasis with AUC of 0.553 (p = 0.5596), 0.518 (p = 0.8539), and 0.559 (p = 0.5225), respectively. Conclusion: These preliminary results suggest that the serum Claudin-1 as a potential biomarker and the relationship and possible regulatory interactions between IL-17A and Claudin-1 in psoriasis are distinguishable by age of onset.
... Male mice at 6-8 weeks of age received applications of 5% imiquimod (IMQ) daily for 13 days (62.5 mg, imiquimod cream; Sichuan Med-Shine Pharmaceutical Co., Ltd., Chengdu, China). Indigo Naturalis (QD) is another TCM commonly used to treat inflammatory skin diseases, which has been shown to significantly improve psoriasis [28,29]. Fu-Fang Qing-Dai Jiao-Nang (approved by Z20010157; Shanxi Pharmaceutical Holdings Tianning Pharmaceutical Co., Ltd., Yulin, China) was use as the positive control drug (QD). ...
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Background: Psoriasis is a common chronic inflammatory skin disease with multifactor etiology, characterized by abnormal proliferation and differentiation of keratinocytes. Huang-Lian Jie-Du decoction (HLJDD) is a traditional Chinese medicine prescription with good clinical curative effect on psoriasis. However, its therapeutic mechanisms are still unclear. Methods: The psoriasis model of SKH-1 nude mice was established by imiquimod-induced and HLJDD gavage was given. Hematoxylin and eosin staining were used to evaluate pathological morphologies, and immunohistochemistry was used to detect the expressions of Wnt1, β-catenin, and c-Myc in psoriasis mice. Western blot was used to examine the expressions of Frizzled-2, LRP5/6, GSK-3β, APC, Axin2, TCF4, LEF1, cyclin D1, TBX3, EPHB2, and NOTUM enzyme. Results: In this study, HLJDD reduced skin erythema and lesions, decreased the thickness of epidermal and downregulated the expressions of Wnt1, β-catenin, and c-Myc. Western blot results showed that HLJDD reduced the expressions of Wnt receptors Frizzled-2 and LRP5/6, and Wnt downstream target genes TCF4, LEF1, cyclin D1, TBX3, and EPHB2, while upregulated destruction complex proteins GSK-3β, APC, and Axin2. Conclusions: HLJDD can effectively treat psoriasis and inhibit the Wnt/β-catenin signaling pathway at multiple stages.
Article
Indigo naturalis, a Chinese herb, has been used for decades.¹ Olive oil was used to remove the blue component within indigo naturalis to yield a purple-red product to treat skin and nail psoriasis without obvious staining.²,3 This trial compared indigo naturalis extract in oil (Lindioil) with topical calcipotriol in treating psoriatic nails.
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In Europe it is allowed to officially claim benefits of cosmetic products based on evidence that can objectively prove their efficacy. On the other hand, beneficial claims of cosmetic products are legally restricted in Japan, because according to pharmaceutical laws cosmetics are defined as products showing weak potency on the skin. However, Japanese consumers strongly demand beneficial effects in cosmetic products and quasi-drugs like pharmaceutical products. Thus, cosmetic scientists always make efforts to develop products that meet these consumer demands. There are substantial differences in benefits between cosmetic products and pharmaceutical products. Although some side effects are allowed in pharmaceutical products, no effects that disrupt skin conditions are allowed in cosmetic products. In other words, cosmetic products should provide benefits and be safe to use on the skin.
Article
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.
Article
Background: Indigo naturalis (IND) is an herbal medicine that has been used as an anti-inflammatory agent to treat diseases including dermatitis and inflammatory bowel disease in China. However, the mechanism by which IND exerts its immunomodulatory effect is not well understood. Methods: A murine model of dermatitis and inflammatory bowel disease, both induced by oxazolone (OXA), was treated with IND. The severity of dermatitis was evaluated based on ear thickness measurements and histological scoring. The severity of colitis was evaluated by measuring body weight, histological scoring, and endoscopic scoring. The expression of inflammatory cytokines in ear and colon tissue was evaluated using real-time PCR. 16S rRNA DNA sequencing of feces from OXA-induced colitis mice was performed before and after IND treatment. The effects of IND on OXA-induced colitis were also evaluated after depleting the gut flora with antibiotics to test whether alteration of the gut flora by IND influenced the course of intestinal inflammation in this model. Results: IND treatment ameliorated OXA dermatitis with a reduction in IL-4 and eosinophil recruitment. However, OXA colitis was significantly aggravated in spite of a reduction in intestinal IL-13, a pivotal cytokine in the induction of the colitis. It was found that IND dramatically altered the gut flora and IND no longer exacerbated colitis when colitis was induced after gut flora depletion. Conclusions: Our data suggest that IND could modify the inflammatory immune response in multiple ways, either directly (i.e., modification of the allergic immune cell activity) or indirectly (i.e., alteration of commensal compositions).
Article
Ethnopharmacological relevance In recent years, there are increasing that the number of patients with psoriasis day by day, and it has become a common disease endangering public health. However, there is no specific cure for psoriasis or control of recurrence. Therefore, it's necessity to seek alternative and efficient therapy, such as Traditional Chinese Medicine (TCM). As a traditional Chinese medicine and effective medicine for the treatment of psoriasis, Indigo Naturalis (Baphicacanthus Cusia (Nees) Bremek.) has the effect of clearing heat, detoxifying blood, eliminating spots, reducing fire and calming panic, and it is used in many classical prescriptions for the treatment of psoriasis. Aim of review To review the latest progress and strategies of Indigo Naturalis in the treatment of psoriasis. This manuscript mainly clarifies the traditional medicinal applications, the mechanism of action and application strategies of Indigo Naturalis, and its preparations in the treatment of psoriasis. Materials and methods Detailed information on Indigo Naturalis was collected from various online databases (PubMed, GeenMedical, Web of Science, Google Scholar, China National Knowledge Infrastructure Database, and National Intellectual Property Administration). Results This manuscript reviews a great deal of information about how Indigo Naturalis can treat psoriasis through immune cells, signal pathways and disease-related mediators. The mechanism of cymbididae is expounded from the aspects of regulating keratinocyte proliferation and differentiation, regulating inflammatory infiltration of cellular immune system and improving microvascular dilation and hyperplasia in skin lesions. Conclusion The action mechanisms of Indigo Naturalis on psoriasis reflect the characteristics of multiple components, multiple targets, and multiple pathways of Traditional Chinese medicine. However, some pharmacological and clinical research methods are improper, so that the results are difficult to explain at present. Therefore, further in-depth research is needed to provide knowledge in a wider range of areas to confirm the great therapeutic potential of IN.
Article
Tryptanthrin (6,12-dihydro-6,12-dioxoindolo-(2,1-b)-quinazoline) has been reported to have a variety of pharmacological activities. Present study investigated the cytoprotective effects of tryptanthrin on arachidonic acid (AA) + iron-mediated oxidative stress and the molecular mechanisms responsible. In HepG2 cells, pretreatment with tryptanthrin inhibited the cytotoxic effect of AA + iron in a concentration-dependent manner. In addition, tryptanthrin prevented the changes in the levels of apoptosis-related proteins, and attenuated reactive oxygen species production, glutathione depletion, and mitochondrial membrane impairment induced by AA + iron. Mechanistic investigations showed that tryptanthrin increased the phosphorylations of AMP-activated protein kinase (AMPK) and of p38 mitogen-activated protein kinase (p38). Furthermore, inhibition of AMPK or p38 reduced the ability of tryptanthrin to prevent AA + iron-induced cell death and mitochondrial dysfunction. Transfection experiments using AMPK mutants indicated that p38 phosphorylation by tryptanthrin was dependent on AMPK activation. In a phenylhydrazine-induced acute liver injury model, tryptanthrin decreased serum levels of alanine aminotransferase, aspartate aminotransferase, and bilirubin in mice. Additionally, tryptanthrin reduced numbers of degenerating hepatocytes, infiltrating inflammatory cells, 4-hydroxynonenal-, and nitrotyrosine-positive cells in hepatic tissues. Thus, these results suggest tryptanthrin has therapeutic potential to protect cells from oxidative injury via AMPK-dependent p38 activation.
Article
Ethnopharmacological relevance: Indigo naturalis, a herbal medicine with a history of use dating back to ancient times, may be a good alternative topical treatment for atopic dermatitis (AD). Aim of the study: To provide empirical evidence of the efficacy and safety of Indigo naturalis ointment in treating AD. Materials and methods: In this randomized double-blind clinical trial, participants aged 6 to 65 years with AD affecting less than 40% of their body surface area (BSA) and an Investigator's Global Assessment (IGA) score of 2 to 4 were randomized (2:1) to receive either Lindioil ointment or a vehicle ointment twice daily for 6 weeks. The primary endpoint was the percentage change in the Eczema Area Severity Index (EASI) from baseline to week 6. Secondary endpoints were as follows: EASI improvement ≥50%, 75%, and 90%; IGA score; BSA affected by AD; pruritus severity; and Dermatology Life Quality Index. The safety assessment included adverse events (AEs), laboratory tests, and physical examinations. Results: The Lindioil group (32 participants) and vehicle group (16 participants) achieved mean percentage EASI reductions of 49.9% ± 36.5% (95% CI 36.8%-63.1%) and 19.6% ± 52.2% (95% CI -8.2%-47.4%), respectively (P = 0.0235). The Lindioil group also showed greater improvement in every secondary assessment category. No significant AEs occurred. Conclusion: Indigo naturalis ointment is effective for treating mild to severe AD topically, and appears to be safe. This is the first clinical trial to provide evidence supporting topical indigo-based AD treatment. ClinicalTrials.gov identifier: NCT02669888.
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Psoriasis is a common non-contagious chronic inflammatory skin lesion, with frequent recurrence. It mainly occurs due to aberrant regulation of the immune system leading to abnormal proliferation of skin cells. However, the pathogenic mechanisms of psoriasis are not fully understood. Although most of the current therapies are mostly efficient, the side effects can result in therapy stop, which makes the effectiveness of treatment strategies limited. Therefore, it is urgent and necessary to develop novel therapeutics. Here, we investigated the efficacy of chrysin, a plant flavonoid, which we previously reported to possess strong antioxidant and anti-inflammatory effects, against psoriasis-like inflammation. Our results revealed that chrysin significantly attenuated imiquimod-induced psoriasis-like skin lesions in mice, and improved imiquimod-induced disruption of skin barrier. Moreover, the TNF-α, IL-17A, and IL-22-induced phosphorylation of MAPK and JAK-STAT pathways, and activation of the NF-κB pathway were also attenuated by chrysin pretreatment of epidermal keratinocytes. Most importantly, chrysin reduced TNF-α-, IL-17A-, and IL-22-induced CCL20 and antimicrobial peptide release from epidermal keratinocytes. Thus, our findings indicate that chrysin may have therapeutic potential against inflammatory skin diseases. Our study provides a basis for further investigating chrysin as a novel pharmacologic agent and contributes to the academic advancement in the field of Chinese herbal medicine.
Article
Ethnopharmacological relevance Strobilanthes cusia (Nees) Kuntze (SCK, Malan), a traditional Chinese medicinal plant, has long applied to detoxification, defervescence, detumescence and antiphlogosis. “Southern Banlangen” (Rhizoma et Radix Baphicacanthis Cusiae, RRBC), root and rhizome of SCK, is widely used for treatment of many epidemic diseases. Malanye (Sourthern Daqingye), stem and leaf of SCK, is an antipyretic-alexipharmic drug frequently-used in southern China. Qingdai (Indigo Naturalis, IN), a processed product of SCK, is always applied to dermatoses in the folk. Aim of the review In order to elucidate the historical uses, recent advances and pharmaceutical prospects of SCK, we summarized roundly in aspects of history, processing method, chemical constitution, quality control, pharmacological activity and toxicity. Some deficiencies in current studies and research directions in the future are also discussed. This is the first comprehensive review of SCK and its herbal medicines, which may be of some help for further research. Methodology Comprehensive analysis was conducted on the basis of academic papers, pharmaceutical monographs, ancient medicinal works, and drug standards of China. All available information on SCK and its herbal medicines was collected by using the keywords such as “Strobilanthes cusia”, “Southern Banlangen”, “indirubin”, “tryptanthrin” through different electronic databases including NCBI Pubmed, Google Scholar, Chinese National Knowledge Infrastructure and so on. Pharmacopoeia of China and some ancient works were obtained from National Digital Library of China. Result Medicinal uses of SCK were already described by famous ancient researchers. Because of vague description, plant species in some works cannot be confirmed. Literature demonstrated that multiple components including total 36 alkaloids and 35 glycosides, the main bioactive components of SCK, were found in SCK and its herbal medicines. Modern studies indicated that SCK and some of its components had multiple pharmacological effects including resistance to cancer, remission of inflammation, suppression of microorganisms, relief of dermatoses, and so on. However, studies on pharmacology, pharmacokinetics, and quality control are still not enough. Conclusion A number of reports suggested that SCK and its processed medicines could be promising drug candidates for multiple diseases especially promyelocytic leukemia, ulcerative colitis (UC) and psoriasis. However, bioactive activities of most components, especially glycosides should still be explored further. It is crucial to elucidate the in-depth molecular mechanisms, and pharmacokinetic characteristics of main components in those herbal medicines. Moreover, to ensure the effectiveness of clinical medication, future studies should undoubtedly give the priority to clarifying the effective compositions of SCK, and then a measurement standard of those indicators should be protocolled to establish a comprehensive quality evaluation mode.
Article
Introduction : Psoriasis is an inflammatory and proliferative disease. Indigo naturalis is a blue herbal pigment extracted from Indigofera tinctoria and other plants. The purpose of this study was to compare Iranian ointment made of Indigofera tinctoria with Chinese ointment made of indigo naturalis from China, and topical betamethasone on the severity of chronic plaque-type psoriasis. Methods : In this preliminary randomized double-blind pilot study, patients with localized chronic plaque-type psoriasis divided into three groups to receive either topical Iranian herbal ointment, Chinese herbal ointment, or betamethasone ointment twice a day for 8 weeks. Results : At the end of the 8th week of treatment, the mean PASI score in the three groups was 5.8 ± 3.13, 6.32 ± 2.85, 3.04 ± 2.23 in Chinese, Iranian and betamethasone ointment respectively; and the mean PASI score changes from baseline was statistically significant only in the topical betamethasone group (p=0.0082). Conclusion : The Iranian herbal ointment used for psoriasis for 8 weeks caused lower clinical response in comparison with topical betamethasone or Chinese herbal ointment in the studied patients.
Article
Psoriatic skin inflammation is mainly driven by complex interactions of infiltrating immune cells and activated keratinocytes. Keratinocytes play an active role in initiating and maintenance of psoriatic skin inflammation by secreting chemokines and cytokines. IL-17A produced by T cells potently upregulates the production of chemokine CCL20 in the keratinocytes, which further chemoattracts IL-17A-producing CCR6+ immune cells to the site of inflammation. Indirubin, an active constituent of indigo naturalis, has been reported to possess anti-inflammatory activities, but whether it can suppress the production of chemokines in keratinocytes is largely unknown. To address this question, IL-17A stimulated HaCaT cells were used as cell model to explore the effects of indirubin on the expression and secretion of chemokines. Also, RNA-seq analysis was performed to extensively understand the entire gene expression changes after indirubin treatment and identify the differentially expressed genes further. Indirubin treatment strongly inhibited CCL20 expression and secretion in IL-17A stimulated HaCaT cells. The inhibitory action of indirubin on CCL20 expression was mainly mediated by TAK1 signaling pathway in a mouse psoriasis-like model and cultured HaCaT cells in vitro. Combining with our previous report, indirubin ameliorated psoriasiform dermatitis by breaking CCL20/CCR6 axis-mediated inflammatory loops. Our results provide novel insights into the mechanisms of indirubin in the treatment of psoriasis.
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Inflammatory bowel disease (IBD) is a chronic inflammatory intestinal disease caused by an abnormal response of the intestinal mucosal immune system, including ulcerative colitis and Crohn's disease. IBD is also accompanied by extraintestinal complications, such as joint, skin, and eye diseases. In recent years, phytomedicine has played an important role in the treatment of IBD because of its strong anti-inflammatory activities and minor side effects. Due to the lack of a review of the literature examining the extent to which phytomedicine can be used to treat IBD, this paper summarizes the experimental research on IBD from the perspective of phytomedicine according to the structural classification of phytomedicine and provides a reference for the further development of new IBD therapies.
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The nail is a specialized keratinous skin appendage that is often overlooked, even though nail disorders comprise approximately 10% of all dermatologic conditions. We provide an overview on the basic anatomy of the nail and function of each structure. We examine the chemical profile, including the keratin and mineral composition, of the nail plate. Subsequently, nail manifestations are reviewed, as virtually every nutritional deficiency can affect nail growth in some manner. We focus on how each nutritional deficiency can affect the different anatomic structures of the nail unit. The terminology and the differential diagnoses of the many different nail plate and nail bed abnormalities are reviewed. Finally, we focus on the evidence behind nutrition-based treatments in the setting of several nail disorders
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Indigo naturalis (IN), which is derived from indigo plants such as Strobilanthes cusia (Nees) Kuntze, Persicaria tinctoria (Aiton) Spach, and Isatis tinctoria L., has been traditionally used in the treatment of hemoptysis, epistaxis, chest pain, aphtha, and infantile convulsion in China for thousands of years. Clinical trials have shown that the curative effect of IN for psoriasis and ulcerative colitis (UC) is remarkable. A total of sixty-three compounds, including indole alkaloids, terpenoids, organic acids, steroids, and nucleosides, have been isolated from IN, of which indole alkaloids are the most important. Indirubin, isolated from IN, was used as a new agent to treat leukemia in China in the 1970s. Indirubin is also an active ingredient in the treatment of psoriasis. Pharmacological studies have confirmed that IN has inhibitory effects on inflammation, tumors, bacteria, and psoriasis. Indigo, indirubin, tryptanthrin, isorhamnetin, indigodole A, and indigodole C are responsible for these activities. This review provides up-to-date and comprehensive information on IN with regard to its chemistry, pharmacokinetics, pharmacology, clinical applications, adverse events, and quality control. This review may also serve a reference for further research on IN.
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This review summarizes the mechanisms, applications, and adverse effects of colorful dyes, such as Castellani’s paint, gentian violet, and potassium permanganate, as well as two other vibrant topical creams—vitamin B12 and indigo naturalis. Certain dyes such as Castellani’s paint, gentian violet, and potassium permanganate were once commonplace topical therapies for cutaneous infections; these dyes are brightly colored on application and have been suggested to be efficacious and well tolerated through case studies as well as controlled studies. Moreover, topical vitamin B12 and topical indigo naturalis creams for atopic dermatitis and psoriasis have been extensively studied through multiple controlled trials and may also be effective, with minimal adverse effects. Understanding the composition and mechanism of action has helped guide the development of these therapies.
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Keratinocyte terminal differentiation is the process that ultimately forms the epidermal barrier that is essential for mammalian survival. This process is controlled, in part, by signal transduction and gene expression mechanisms, and the epidermal growth factor receptor (EGFR) is known to be an important regulator of multiple epidermal functions. Using microarray analysis of a confluent cell density-induced model of keratinocyte differentiation, we identified 2,676 genes that are regulated by epidermal growth factor (EGF), a ligand of the EGFR. We further discovered, and separately confirmed by functional assays, that EGFR activation abrogates all of the known essential processes of keratinocyte differentiation by 1) decreasing the expression of lipid matrix biosynthetic enzymes, 2) regulating numerous genes forming the cornified envelope, and 3) suppressing the expression of tight junction proteins. In organotypic cultures of skin, EGF acted to impair epidermal barrier integrity, as shown by increased transepidermal water loss. As defective epidermal differentiation and disruption of barrier function are primary features of many human skin diseases, we used bioinformatic analyses to identify genes that are known to be associated with skin diseases. Compared with non-EGF-regulated genes, EGF-regulated genes were significantly enriched for skin disease genes. These results provide a systems-level understanding of the actions of EGFR signaling to inhibit keratinocyte differentiation, providing new insight into the role of EGFR imbalance in skin pathogenesis.
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Atopic dermatitis (AD) is characterized by dry skin and a hyperactive immune response to allergens, 2 cardinal features that are caused in part by epidermal barrier defects. Tight junctions (TJs) reside immediately below the stratum corneum and regulate the selective permeability of the paracellular pathway. We evaluated the expression/function of the TJ protein claudin-1 in epithelium from AD and nonatopic subjects and screened 2 American populations for single nucleotide polymorphisms in the claudin-1 gene (CLDN1). Expression profiles of nonlesional epithelium from patients with extrinsic AD, nonatopic subjects, and patients with psoriasis were generated using Illumina's BeadChips. Dysregulated intercellular proteins were validated by means of tissue staining and quantitative PCR. Bioelectric properties of epithelium were measured in Ussing chambers. Functional relevance of claudin-1 was assessed by using a knockdown approach in primary human keratinocytes. Twenty-seven haplotype-tagging SNPs in CLDN1 were screened in 2 independent populations with AD. We observed strikingly reduced expression of the TJ proteins claudin-1 and claudin-23 only in patients with AD, which were validated at the mRNA and protein levels. Claudin-1 expression inversely correlated with T(H)2 biomarkers. We observed a remarkable impairment of the bioelectric barrier function in AD epidermis. In vitro we confirmed that silencing claudin-1 expression in human keratinocytes diminishes TJ function while enhancing keratinocyte proliferation. Finally, CLDN1 haplotype-tagging SNPs revealed associations with AD in 2 North American populations. Collectively, these data suggest that an impairment in tight junctions contributes to the barrier dysfunction and immune dysregulation observed in AD subjects and that this may be mediated in part by reductions in claudin-1.
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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.
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The tight junction (TJ) and its adhesion molecules, claudins, are responsible for the barrier function of simple epithelia, but TJs have not been thought to play an important role in the barrier function of mammalian stratified epithelia, including the epidermis. Here we generated claudin-1-deficient mice and found that the animals died within 1 d of birth with wrinkled skin. Dehydration assay and transepidermal water loss measurements revealed that in these mice the epidermal barrier was severely affected, although the layered organization of keratinocytes appeared to be normal. These unexpected findings prompted us to reexamine TJs in the epidermis of wild-type mice. Close inspection by immunofluorescence microscopy with an antioccludin monoclonal antibody, a TJ-specific marker, identified continuous TJs in the stratum granulosum, where claudin-1 and -4 were concentrated. The occurrence of TJs was also confirmed by ultrathin section EM. In claudin-1-deficient mice, claudin-1 appeared to have simply been removed from these TJs, leaving occludin-positive (and also claudin-4-positive) TJs. Interestingly, in the wild-type epidermis these occludin-positive TJs efficiently prevented the diffusion of subcutaneously injected tracer (approximately 600 D) toward the skin surface, whereas in the claudin-1-deficient epidermis the tracer appeared to pass through these TJs. These findings provide the first evidence that continuous claudin-based TJs occur in the epidermis and that these TJs are crucial for the barrier function of the mammalian skin.
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Psoriasis is one of the most common human skin diseases and is considered to have key genetic underpinnings. It is characterized by excessive growth and aberrant differentiation of keratinocytes, but is fully reversible with appropriate therapy. The trigger of the keratinocyte response is thought to be activation of the cellular immune system, with T cells, dendritic cells and various immune-related cytokines and chemokines implicated in pathogenesis. The newest therapies for psoriasis target its immune components and may predict potential treatments for other inflammatory human diseases.
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Tight Junction (TJ) proteins have been shown to exert a barrier function within the skin. Here, we study the fate of TJ proteins during the challenge of the skin by bacterial colonization and infection. We investigated the influence of various exfoliative toxin-negative Staphylococcus strains on TJ, adherens junction (AJ), desmosomal proteins, and actin in a human keratinocyte infection culture and in a porcine skin infection model. We found that the pathogen Staphylococcus aureus downregulates TJ and subsequently AJ and desmosomal proteins, including atypical protein kinase C, an essential player in TJ formation, at the cell-cell borders of keratinocytes in a time and concentration dependent manner. Little changes in protein and RNA levels were seen, indicating redistribution of proteins. In cultured keratinocytes, a reduction of transepithelial resistance was observed. Staphylococcus epidermidis shows only minor effects. All strains induced enhanced expression of occludin and ZO-1 at the beginning of colonization/infection. Thus, we demonstrate that TJ are likely to be involved in skin infection of exfoliative toxin-negative S. aureus. As we did not find a change in actin, and as changes of TJ preceded alterations of AJs and desmosomes, we suggest that S. aureus targets TJ.
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The epithelium of upper respiratory tissues such as human nasal mucosa forms a continuous barrier via tight junctions, which is thought to be regulated in part through a protein kinase C (PKC) signaling pathway. To investigate the mechanisms of the regulation of PKC-mediated tight junction barrier function of human nasal epithelium in detail, primary human nasal epithelial cells were treated with the PKC activator 12-O-tetradecanoylophorbol-13-acetate (TPA). In primary human nasal epithelial cells, treatment with TPA led not only to activation of phosphorylation of PKC, myristoylated alanine-rich C kinase substrate, and mitogen-activated protein kinase but also expression of novel PKC-delta, PKC-theta, and PKC-epsilon. Treatment with TPA increased transepithelial electrical resistance, with tight junction barrier function more than 4-fold that of the control, together with up-regulation of tight junction proteins, occludin, zona occludens (ZO)-1, ZO-2 and claudin-1 at the transcriptional level. Furthermore, it affected the subcellular localization of the tight junction proteins and the numbers of tight junction strands. The up-regulation of barrier function and tight junction proteins was prevented by a pan-PKC inhibitor, and the inhibitors of PKC-delta and PKC-theta but not PKC-epsilon. In primary human nasal epithelial cells, transcriptional factors GATA-3 and -6 were detected by reverse transcription-polymerase chain reaction. The knockdown of GATA-3 using RNA interference resulted in inhibition of up-regulation of ZO-1 and ZO-2 by treatment with TPA. These results suggest that TPA-induced PKC signaling enhances the barrier function of human nasal epithelial cells via transcriptional up-regulation of tight junction proteins, and the mechanisms may contribute to a drug delivery system.
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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.
Article
Although the existence of tight junction (TJ) structures (or a secondary epidermal barrier) was postulated for a long time, the first description of TJ proteins in the epidermis (occludin, ZO-1, and ZO-2) was only fairly recent. Since then, a wealth of new insights concerning TJs and TJ proteins, including their functional role in the skin, have been gathered. Of special interest is that the epidermis as a multilayered epithelium exhibits a very complex localization pattern of TJ proteins, which results in different compositions of TJ protein complexes in different layers. In this review, we summarize our current knowledge about the role of TJ proteins in the epidermis in barrier function, cell polarity, vesicle trafficking, differentiation, and proliferation. We hypothesize that TJ proteins fulfill TJ structure-dependent and structure-independent functions and that the specific function of a TJ protein may depend on the epidermal layer where it is expressed.
Article
Tight junctions (TJ) are barrier forming cell–cell junctions that are found in a variety of cell types and tissues but their existence in mammalian epidermis has been shown only in the last years. A variety of TJ proteins were identified in mammalian epidermis, comprising several members of the claudin family, occludin, and JAM-A as well as ZO-1 and MUPP-1. TJ proteins exhibit complex expression and localization patterns in the epidermis. Nonetheless, even though several TJ proteins are found in various layers, typical TJ structures are only found in the stratum granulosum. TJ are important for barrier function of the skin, especially for inside–out barrier. In addition, TJ proteins might also be involved in additional functions in epidermal cells. Localization and expression of TJ proteins are altered in several skin diseases, e.g. psoriasis. Meanwhile several TJ modulators are known from simple epithelia. We discuss their putative usability for drug delivery into and through the skin.
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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.
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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.
Article
Tight junctions (TJ) are cell-cell junctions that have proved to form a paracellular barrier for solutes and water between cells of epithelia, including the stratum granulosum of the stratified epithelium of the epidermis of newborn mice. In mice lacking claudin-1, a major barrier-forming TJ component, this barrier was abolished. However, the role of TJ in human skin is controversially discussed as unambiguous data were missing so far. Here, we investigated TJ barrier function in healthy human skin as well as in skin samples from psoriatic lesions which are characterized by an altered localization of TJ proteins. We demonstrate for human skin that occludin- and claudin-1-positive sites in the stratum granulosum form a barrier for extracellular biotin-SH (557Da) and that in psoriatic skin the localization of the barrier and the TJ proteins are altered in parallel.
Article
In human pancreatic cancer, integral membrane proteins of tight junction claudins are abnormally regulated, making these proteins promising molecular diagnostic and therapeutic targets. However, the regulation of claudin-based tight junctions remains unknown not only in the pancreatic cancer cells but also in normal human pancreatic duct epithelial (HPDE) cells. To investigate the regulation of tight junction molecules including claudins in normal HPDE cells, we introduced the human telomerase reverse transcriptase (hTERT) gene into HPDE cells in primary culture. The hTERT-transfected HPDE (hTERT-HPDE) cells were positive for the pancreatic duct epithelial markers such as CK7, CK19, and carbonic anhydrase isozyme 2 and expressed epithelial tight junction molecules claudin-1, -4, -7 and, -18, occludin, JAM-A, ZO-1, ZO-2, and tricellulin. By treatment with fetal bovine serum or 12-O-tetradecanoylphorbol 13-acetate (TPA), the tight junction molecules were up-regulated at the transcriptional level via a protein kinase C (PKC) signal pathway. A PKC-alpha inhibitor, Gö6976, prevented up-regulation of claudin-4 by TPA. Furthermore, a PKC-delta inhibitor, rottlerin, prevented up-regulation of claudin-7, occludin, ZO-1, and ZO-2 by TPA. By GeneChip analysis, up-regulation of the transcription factor ELF3 was observed in both fetal bovine serum- and TPA-treated cells. Treatment with small interfering RNAs of ELF3 prevented up-regulation of claudin-7 by TPA. These data suggest that tight junctions of normal HPDE cells were at least in part regulated via a PKC signal pathway by transcriptional control.
Article
Psoriasis is an inflammatory skin disease characterized by hyperproliferation of keratinocytes, impaired barrier function, and pronounced infiltration of inflammatory cells. Tight junctions (TJs) are cell-cell junctions that form paracellular barriers for solutes and inflammatory cells. Altered localization of TJ proteins in the epidermis was described in plaque-type psoriasis. Here we show that localization of TJ proteins is already altered in early-stage psoriasis. Occludin, ZO-1, and claudin-4 are found in more layers than in normal epidermis, and claudin-1 and -7 are down-regulated in the basal and in the uppermost layers. In plaque-type psoriasis, the staining patterns of occludin and ZO-1 do not change, whereas the claudins are further down-regulated. Near transmigrating granulocytes, all TJ proteins except for junctional adhesion molecule-A are down-regulated. Treatment of cultured keratinocytes with interleukin-1beta and tumor necrosis factor-alpha, which are present at elevated levels in psoriatic skin, results in an increase of transepithelial resistance at early time points and a decrease at later time points. Injection of interleukin-1beta into an ex vivo skin model leads to an up-regulation of occludin and ZO-1, resembling TJ protein alteration in early psoriasis. Our results show for the first time that alteration of TJ proteins is an early event in psoriasis and is not the consequence of the more profound changes found in plaque-type psoriasis. Our data indicate that cytokines are involved in alterations of TJ proteins observed in psoriasis.
Article
Indigo naturalis is used by traditional Chinese medicine to treat various inflammatory diseases. Topical indigo naturalis ointment showed efficacy in treating psoriasis in our previous clinical studies. In this study, we investigated the anti-inflammatory effects of the extract of indigo naturalis (QD) and its main components indirubin, indigo, and tryptanthrin in human neutrophils. Superoxide anion (O2(.-)) generation and elastase release were measured by spectrophotometry. Some important signals including mitogen-activated protein kinase (MAPK), cAMP, and calcium were studied by Western blot analysis, an enzyme immunoassay, and spectrofluorometry. QD significantly inhibited O2(.-) generation and elastase release in formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP)-activated human neutrophils in a concentration-dependent fashion, while neither indirubin, indigo, nor tryptanthrin produced a comparable result. QD attenuated the FMLP-induced phosphorylation of extracellular regulated kinase, p38 MAPK, and c-Jun N-terminal kinase. Furthermore, QD inhibited calcium mobilization caused by FMLP. However, QD did not affect cellular cAMP levels. On the other hand, neither indirubin, indigo, nor tryptanthrin produced similar changes in human neutrophils. Taken collectively, these findings indicate that QD, but not indirubin, indigo, or tryptanthrin, inhibited O2(.-) generation and elastase release in FMLP-induced human neutrophils, which was at least partially mediated by the inhibition of MAPK activation and regulation of calcium mobilization.
Article
Indigo naturalis has shown efficacy in treating psoriasis in our previous clinical studies. To investigate the potential effect of indigo naturalis on regulating keratinocyte proliferation and differentiation. Skin samples from six patients were analyzed for proliferating cell nuclear antigen (PCNA) and involucrin expression by immunohistochemical staining. In addition, indigo naturalis extracts from 10 to 500 microg/ml were added to cultured keratinocytes and cell viability determined. Real-time RT-PCR, Western blotting analysis and indirect immunofluorescent labeling were used to investigate the messenger (m)RNA and protein expressions of PCNA and involucrin. Finally, high-performance liquid chromatography (HPLC) was used to identify major components of indigo naturalis and their in vitro effects compared. Immunohistochemical results demonstrated decreased PCNA and increased involucrin in psoriatic lesions after indigo naturalis treatment. Cultured keratinocytes decreased after indigo naturalis treatment, while G(0)/G(1) arrest was observed to dose-dependently increase. Staining revealed decreased PCNA-stained nuclei and increased cytosolic involucrin in treated keratinocytes. Decreased PCNA and increased involucrin at both the mRNA and protein levels were confirmed. Both major components, indirubin and indigo, could cause G(0)/G(1) phase arrest; however, only indirubin modulated the expressions of PCNA and involucrin similar to indigo naturalis. Together, these findings indicate that the anti-psoriatic effects of indigo naturalis are mediated, at least in part, by modulating the proliferation and differentiation of keratinocytes, with indirubin as the major active component.
Article
To evaluate the efficacy and safety of treatment with indigo naturalis in patients with recalcitrant plaque-type psoriasis. Randomized, observer-blind, vehicle-controlled, intrapatient comparison study. Ambulatory department of a hospital. Forty-two outpatients with chronic plaque psoriasis were enrolled in the study from May 1, 2004, to April 30, 2005. The patients applied either indigo naturalis ointment or vehicle ointment topically to each of 2 bilaterally symmetrical psoriatic plaque lesions for 12 weeks (depending on the date of enrollment in the study). The outcomes were assessed using the following criteria: the sum of erythema, scaling, and induration scores and the clearing percentage of the target plaque lesion assessed by 2 blinded observers. Significant reductions in the sum of scaling, erythema, and induration scores (P < .001) (mean score, 6.3 after indigo naturalis treatment vs 12.8 in control subjects) and plaque area percentage (P < .001) (mean percentage, 38.5% after indigo naturalis treatment vs 90% in controls) were achieved with topical application of indigo naturalis ointment. Approximately 31 of 42 patients (74%) experienced clearance or near clearance of their psoriasis in the indigo ointment-treated lesion. Topical indigo naturalis ointment was a novel, safe, and effective therapy for plaque-type psoriasis.
Article
The mechanism by which epithelial and endothelial cells interact to form polarized tissue is of fundamental importance to multicellular organisms. Dysregulation of these barriers occurs in a variety of diseases, destroying the normal cellular environments and leading to organ failure. Increased levels of growth factors are a common characteristic of diseases exhibiting tissue permeability, suggesting that growth factors play a direct role in elevating permeability. Of particular concern for this laboratory, increased expression of vascular endothelial growth factor may enhance vascular permeability in diabetic retinopathy, leading to vision impairment and blindness. However, the mechanism by which growth factors increase permeability is unclear. Polarized cells form strong barriers through the development of tight junctions, which are specialized regions of the junctional complex. Tight junctions are composed of three types of transmembrane proteins, a number of peripheral membrane structural proteins, and are associated with a variety of regulatory proteins. Recent data suggest that growth factor-stimulated alterations in tight junctions contribute to permeability in a variety of disease states. The goal of this review was to elucidate potential mechanisms by which elevated growth factors elicit deregulated paracellular permeability via altered regulation of tight junctions, with particular emphasis on the tight junction proteins occludin and ZO-1, protein kinase C signaling, and endocytosis of junctional proteins. Understanding the molecular mechanisms underlying growth factor-mediated regulation of tight junctions will facilitate the development of novel treatments for diseases such as brain tumors, diabetic retinopathy and other diseases with compromised tight junction barriers.
Article
Overexpression of amphiregulin (AR) has been linked to psoriasis in mouse and man. Since psoriasis is marked by hyperproliferation of keratinocytes and loss of epidermal barrier function with infiltration of inflammatory cells into the epidermis and dermis, we hypothesized that AR might contribute to the pathogenesis of psoriasis by affecting the integrity of cell-cell junctions. We find that there is a marked reduction of functional E-cadherin in psoriatic lesions from both INV-AR mice and individuals with psoriasis. Total E-cadherin levels are dramatically reduced in psoriatic lesions from INV-AR mice. Compared with normal skin, psoriatic lesions from individuals with psoriasis exhibit downregulation of the cytoskeletal-associated triton-insoluble pool of E-cadherin and the appearance of an 80 kDa ectodomain fragment in the cytoplasmic triton-soluble pool. There is reduced immunohistochemical staining for E-cadherin in the basal epidermis of human psoriatic lesions. Moreover, there is enhanced transmigration of human neutrophils through polarized epithelial cell monolayers of MDCK cells after administration of AR, but not transforming growth factor-alpha, further supporting a specific role for AR in the pathogenesis of psoriasis.
Article
To identify differentially expressed genes which play causal roles in pathogenesis and maintenance for psoriasis, we used BodyMapping and introduced amplified fragment length polymorphism approaches. From the BodyMap database, we selected 2007 genes which specifically expressed in epithelial tissues. Among 2007 genes, we surveyed genes which differentially expressed in involved or uninvolved psoriatic lesional skin samples compared with atopic dermatitis, mycosis fungoides, and normal skin samples. As a result of surveying 2007 genes, 241 genes were differentially expressed only in involved psoriatic skin but not in the other samples. Hierarchical cluster analysis of gene expression profiles showed that 13 independent psoriatic-involved skin samples clustered tightly together, reflecting highly similar expression profiles. Using the same 2007 gene set, we examined gene expression levels in five serial lesions from distal uninvolved psoriatic skin to involved psoriatic plaque. We identified seven genes such as alpha-1-microglobulin/bikunin precursor, calnexin, claudin 1, leucine zipper down-regulated in cancer 1, tyrosinase-related protein 1, Yes-associated protein 1, and unc-13-like protein (Coleonyx elegans) which show high-expression levels only in uninvolved psoriatic lesions. These seven genes, which were reported to be related to apoptosis or antiproliferation, might have causal roles in pathophysiology in psoriasis.
Article
Skin is at the interface between the complex physiology of the body and the external, often hostile, environment, and the semipermeable epidermal barrier prevents both the escape of moisture and the entry of infectious or toxic substances. Newborns with rare congenital barrier defects underscore the skin's essential role in a terrestrial environment and demonstrate the compensatory responses evoked ex utero to reestablish a barrier. Common inflammatory skin disorders such as atopic dermatitis and psoriasis exhibit decreased barrier function, and recent studies suggest that the complex response of epidermal cells to barrier disruption may aggravate, maintain, or even initiate such conditions. Either aiding barrier reestablishment or dampening the epidermal stress response may improve the treatment of these disorders. This Review discusses the molecular regulation of the epidermal barrier as well as causes and potential treatments for defects of barrier formation and proposes that medical management of barrier disruption may positively affect the course of common skin disorders.
Article
It has long been accepted that tight junctions (TJ) are crucial for the formation and maintenance of the paracellular barrier and for cell polarity in simple epithelia and endothelia. Moreover, it is long known that they play a role in barrier function of amphibian skin. However, only in recent years were TJ and TJ proteins identified in the epidermis of men and mice. Their involvement in the barrier function of mammalian skin has been shown. This review summarizes our current knowledge about TJ and TJ proteins in mammalian skin.
Article
Cells of the granular layer are interconnected by tight junctions (TJs) in normal epidermis. The structural proteins of epidermal TJs include occludin, ZO-1, and claudin-1 and -4. Our aim was to correlate the expression of TJ components with keratinocyte differentiation using psoriasis as a model of premature keratinization. The distribution of TJ proteins was evaluated in the skin of nine patients with psoriasis. Punch biopsies were taken from perilesional skin, from active psoriasis plaques, and from healed, previously lesional locations. The punch biopsies were analysed using indirect immunolabelling for ZO-1, occludin and claudin-1, -4 and -5. In addition, epidermal samples were analysed by reverse transcription-polymerase chain reaction for claudin-1, -4 and -5 mRNAs. Claudin-5 was localized to the granular cell layers of normal control skin as well as perilesional and lesional psoriatic epidermis. This was unexpected, as previous studies have not detected claudin-5 in the epidermis. Occludin and ZO-1 were expressed in the granular cell layer in psoriatic perilesional epidermis. In the psoriasis plaques, ZO-1 and occludin were detected in a wider zone extending from the granular layer to the middle spinous cell layers. In healed psoriasis plaques, the expression of occludin and ZO-1 resumed a normal-looking profile, being restricted to the upper epidermis only. Claudin-1 and -4 did not show marked changes in psoriasis compared with normal skin. The results demonstrate claudin-5 in normal epidermis and psoriatic skin, and abnormal distribution of occludin and ZO-1 in psoriasis plaques. Clinical healing of aberrant keratinization is associated with restoration of the normal distribution of occludin, ZO-1 and also involucrin.
Article
It has been reported in the Chinese literature that indigo naturalis exhibits potential antipsoriatic effects in systemic therapy. To evaluate the efficacy and safety of topically applied indigo naturalis on treating plaque-type psoriasis and to analyze the histological change in skin tissues. Fourteen patients with chronic plaque psoriasis were enrolled. The patients were topically applied with either indigo naturalis ointment or vehicle ointment on contralateral skin lesions daily for 8 weeks. Efficacy was evaluated on the basis of the clinical scores, including induration, scaling, erythema and clearing percentage. At the end of treatment, skin punch biopsies were taken and prepared for the immunohistochemical analysis. A significant reduction in clinical scores was achieved with topically applied indigo naturalis ointment. Analysis of biopsies showed a marked improvement of skin histology. The expressions of proliferating marker Ki-67 and inflammatory marker CD3 were decreased, but the differentiation marker such as filaggrin was increased in the epidermis after indigo naturalis ointment treatment. The results suggest that topical application of indigo naturalis ointment may be a novel, safe and effective therapy for psoriasis that is mediated, at least in part, by modulating the proliferation and differentiation of keratinocytes in epidermis, as well as by inhibiting the infiltration of T lymphocytes and therefore the subsequent inflammatory reactions in psoriatic lesions.
Article
Epithelial tight junctions play a central role in cell-cell adhesion and are necessary for the selective paracellular movement of ions. Claudins are key components of tight junctions and their expression is altered in gut epithelia in a variety of inflammatory enteropathies, including ulcerative colitis and Crohn's disease. Psoriasis is a chronic inflammatory skin disease affecting approximately 2% of the western population, with significantly increased occurrence in individuals with Crohn's disease. Initial studies investigated the expression of claudins in skin of healthy volunteers and patients with chronic plaque psoriasis. We report here that claudins-1 and -3 are the major protein species present in the epidermis of healthy skin; they are expressed on the surface of epidermal keratinocytes, consistent with their localization to tight junctions. In plaques of psoriasis, claudin-1 was not identifiable in the epidermis, although typical staining patterns were observed in clinically normal, uninvolved skin of patients with psoriasis. Claudin-3 was present in the epidermal granular cell layer in normal skin, but was only identified within the cytosol of epidermal keratinocytes in both involved and uninvolved skin of psoriasis patients. We examined further whether exposure of keratinocytes in vitro to pro-inflammatory cytokines mimicked the observed changes in claudin expression seen in chronic plaque psoriasis; lipopolysaccharide, interferon-gamma and tumour necrosis factor-alpha had no effect on claudin protein expression or distribution. Addition of interleukin-1beta, however, resulted in down-regulation of claudins-1 and -3. Tumour necrosis factor-alpha and interleukin-1beta were further used in an in vivo model of skin inflammation; interleukin-1beta alone modulated claudin protein expression in this system. These data demonstrate that epidermal claudin expression is altered in chronic plaque psoriasis and that expression is in part modulated by interleukin-1beta.
Article
The choice of drug target and the ability to deliver drug to those targets are pivotal in drug development. Most druggable targets are membrane proteins, such as G-protein-coupled receptors, channels and transporters. However, little attention has been paid to potential druggable targets in the membrane proteins of tight junctions (TJs), through which adjacent cell membranes contact one another. Recent progress in the cell biology of TJs provides new insights into the barrier and fence functions of TJs, suggesting that TJ components are promising candidates for drug discovery. In this review, we summarize the cell biology of TJs and discuss the TJ-based drug discovery.