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Abstract
Yin chai hu (Radix Stellariae) is a root medicine that is frequently used in Chinese traditional medicine to treat fever and malnutrition. In modern medicine, it has been discovered to have anti-inflammatory, anti-allergic, and anticancer properties. In a previous study, we were able to extract lipids from Stellariae Radix using supercritical CO2 extraction (SRE), and these sterol lipids accounted for up to 88.29% of the extract. However, the impact of SRE on the development of atopic dermatitis (AD) has not yet been investigated. This study investigates the inhibitory effects of SRE on AD development using a 2,4-dinitrochlorobenzene (DNCB)-induced AD mouse model. Treatment with SRE significantly reduced the dermatitis score and histopathological changes compared with the DNCB group. The study found that treatment with SRE resulted in a decrease of pro-inflammatory cytokines TNF-α, CXC-10, IL-12, and IL-1β in skin lesions. Additionally, immunohistochemical analysis revealed that SRE effectively suppressed M1 macrophage infiltration into the AD lesion. Furthermore, the anti-inflammatory effect of SRE was evaluated in LPS + INF-γ induced bone marrow-derived macrophages (BMDMs) M1 polarization, SRE inhibited the production of TNF-α, CXC-10, IL-12, and IL-1β and decreased the expression of NLRP3. Additionally, SRE was found to increase p-AMPKT172 , but had no effect on total AMPK expression, after administration of the AMPK inhibitor Compound C, the inhibitory effect of SRE on M1 macrophages was partially reversed. The results indicate that SRE has an inhibitory effect on AD, making it a potential therapeutic agent for this atopic disorder.
... Stellariae Radix (SR) is the dried root of Stellaria dichotoma L.var. lanceolata Bge, family Caryophyllaceae (Wu et al., 2024). It is efficient in clearing deficiency heat and removing chancre heat and is commonly used clinically for yin deficiency fever, bone vapor, and labor heat (Wu et al., 2024;Li et al., 2017). ...
... lanceolata Bge, family Caryophyllaceae (Wu et al., 2024). It is efficient in clearing deficiency heat and removing chancre heat and is commonly used clinically for yin deficiency fever, bone vapor, and labor heat (Wu et al., 2024;Li et al., 2017). Although the two herbs belong to different plant families and their effects and clinical pharmacological actions are different from each other, the medicinal parts of CR and SR are all dried roots and have similar traits and microscopic features such as cylindrical shape, yellowish brown surface with longitudinal wrinkles, more than 10 rows of cork cells, and sieve tube clusters (National Pharmacopoeia Commission, 2020). ...
Introduction
Under the background of digitalization of traditional Chinese medicine (TCM), this study aimed to realize the digital identification and adulteration analysis of Codonopsis Radix (CR) and Stellariae Radix (SR) based on chemical analysis.
Methods
This study combined digitalization concepts and chemical analysis and conducted a chemical analysis of CR and SR from different batches based on UHPLC-QTOF-MSE. Furthermore, the shared ions were extracted from different batches of CR and SR as their “ion characterization” after digital quantization. Then, the data matrices of unique ions of CR relative to SR and SR relative to CR were screened out, and the top-N ions were outputted as the “digital identities” of CR and SR, sorted by ionic strength. Finally, the above “digital identities” of CR and SR were used as benchmarks for matching positive samples and market samples to provide feedback on the matching credibility (MC) for identification and adulteration analysis.
Results
The results showed that based on the “digital identities” of CR and SR, the digital identification of CR, SR, and positive samples can be realized at the individual level of TCM efficiently and accurately, even if 3% of SR in the mixed samples can still be identified efficiently and accurately. Moreover, 1 of the 12 batches of market samples was identified as an adulterated sample.
Conclusion
It proved that the identification and adulteration analysis of two herbs can be realized efficiently and quickly through the “digital identities” of chemical compositions. It has important reference significance for developing the digital identification of CR and SR at the individual level of Chinese medicine based on the “digital identity” of chemical compositions, which was beneficial to the construction of digital quality control of CR and SR.
Macrophages, as specialized, long-lasting phagocytic cells of the innate immune system, have garnered increasing attention due to their wide distribution and various functions. The skin, being the largest immune organ in the human body, presents an intriguing landscape for macrophage research, particularly regarding their roles in inflammatory skin diseases and skin tumors. In this review, we compile the latest research on macrophages in conditions such as atopic dermatitis, psoriasis, systemic sclerosis, systemic lupus erythematosus, rosacea, bullous pemphigoid, melanoma and cutaneous T-cell lymphoma. We aim to contribute to illustrating the pathogenesis and potential new therapies for inflammatory skin diseases and skin tumors from the perspective of macrophages.
Stellaria Radix, called Yinchaihu in Chinese, is a traditional Chinese medicine, which is obtained from the dried roots of Stellaria dichotoma L. var. lanceolata Bge. Cultivated yinchaihu (YCH) has become a main source of production to alleviate the shortage of wild plant resources, but it is not clear whether the metabolites of YCH change with the mode of production. In this study, the contents of methanol extracts, total sterols and total flavonoids in wild and cultivated YCH are compared. The metabolites were analyzed by ultra-high performance liquid chromatography–tandem time-of-flight mass spectrometry. The content of methanol extracts of the wild and cultivated YCH all exceeded the standard content of the Chinese Pharmacopoeia. However, the contents of total sterols and total flavonoids in the wild YCH were significantly higher than those in the cultivated YCH. In total, 1586 metabolites were identified by mass spectrometry, and 97 were significantly different between the wild and cultivated sources, including β-sitosterol, quercetin derivatives as well as many newly discovered potential active components, such as trigonelline, arctiin and loganic acid. The results confirm that there is a rich diversity of metabolites in the wild and cultivated YCH, and provide a useful theoretical guidance for the evaluation of quality in the production of YCH.
Glyphosate (N-phosphonomethyl glycine) is a non-selective, broad-spectrum organophosphate herbicide. Its omnipresent application with large quantity has made glyphosate as a problematic contaminant in water. Therefore, an effective technology is urgently required to remove glyphosate and its metabolites from water. In this study, calcium peroxide nanoparticles (nCPs) were functioned as an oxidant to produce sufficient hydroxyl free radicals (·OH) with the presence of Fe2+ as a catalyst using a Fenton-based system. The nCPs with small particle size (40.88 nm) and high surface area (28.09 m2/g) were successfully synthesized via a co-precipitation method. The synthesized nCPs were characterized using transform infrared spectroscopy (FTIR), X-ray diffractometry (XRD), Brunauer–Emmett–Teller analysis (BET), dynamic light scattering (DLS), and field emission scanning electron microscopy (FESEM) techniques. Under the given conditions (pH = 3.0, initial nCPs dosage = 0.2 g, Ca2+/Fe2+ molar ratio = 6, the initial glyphosate concentration = 50 mg/L, RT), 99.60% total phosphorus (TP) removal and 75.10% chemical oxygen demand (COD) removal were achieved within 75 min. The degradation process fitted with the Behnajady–Modirshahla–Ghanbery (BMG) kinetics model. The H2O2 release performance and proposed degradation pathways were also reported. The results demonstrated that calcium peroxide nanoparticles are an efficient oxidant for glyphosate removal from aqueous systems.
Macrophages are key cells after tissue damage since they mediate both acute inflammatory phase and regenerative inflammation by shifting from pro-inflammatory to restorative cells. Glucocorticoids (GCs) are the most potent anti-inflammatory hormone in clinical use, still their actions on macrophages are not fully understood. We show that the metabolic sensor AMP-activated protein kinase (AMPK) is required for GCs to induce restorative macrophages. GC Dexamethasone activates AMPK in macrophages and GC receptor (GR) phosphorylation is decreased in AMPK-deficient macrophages. Loss of AMPK in macrophages abrogates the GC-induced acquisition of their repair phenotype and impairs GC-induced resolution of inflammation in vivo during post-injury muscle regeneration and acute lung injury. Mechanistically, two categories of genes are impacted by GC treatment in macrophages. Firstly, canonical cytokine regulation by GCs is not affected by AMPK loss. Secondly, AMPK-dependent GC-induced genes required for the phenotypic transition of macrophages are co-regulated by the transcription factor FOXO3, an AMPK substrate. Thus, beyond cytokine regulation, GR requires AMPK-FOXO3 for immunomodulatory actions in macrophages, linking their metabolic status to transcriptional control in regenerative inflammation.
Stellaria dichotoma L. var. lanceolata Bge. (SDL) is the original plant of the traditional Chinese medicine Yinchaihu (Stellaria Radix). It is mainly distributed in the arid desert areas of northwest China, which is the genuine medicinal material and characteristic cultivated crop in Ningxia. This study aims to analyze the effects of different origins on SDL metabolites and quality, as well as to screen the dominant habitat factors affecting SDL in different origins. In this study, metabolites of SDL from nine different production areas were analyzed by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF MS) based metabolomics. And field investigations were conducted to record thirteen habitat-related indicators. Results showed that 1586 metabolites were identified in different origins, which were classified as thirteen categories including lipids, organic acids and organic heterocyclic compounds derivatives. Multivariate statistical analysis showed that the metabonomic spectra of SDL from different origins had various characteristics. What’s more, co-expression network correlation analysis revealed that three metabolites modules (MEturquoise, MEbrown and MEblue) were more closely with the habitat factors and 104 hub metabolites were further screened out as the habitat-induced metabolite indicators. Besides, soil texture, soil pH value and soil total salt content were found as the dominant habitat factors which affect SDL metabolites. In conclusion, the study showed different habitat factors had various effects on SDL’s quality and established relationship between them, which provide reference for revealing SDL’s genuineness formation mechanism and guiding industrial crops practical production by habitat factors selection.
Primary atopic disorders (PADs) are monogenic diseases characterized by allergy or atopy‐related symptoms as fundamental features. In patients with PADs, primary immune deficiency and immune dysregulation symptoms are usually coexist. Chronic skin disease, manifesting with erythroderma, severe atopic dermatitis or eczema, and urticaria, is one of the main features observed in PADs, such as hyper‐IgE syndromes, Omenn syndrome, Wiskott‐Aldrich syndrome, IPEX‐linked syndrome, skin barrier disorders, as well as some autoinflammatory diseases. The recognition of PADs in the context of an allergic phenotype is crucial to ensure prompt diagnosis and appropriate treatment. This article provides an overview of the main PADs with skin involvement.
Background
Circular RNA (circRNA) was reported to involve in various diseases; however, its role in atopic dermatitis (AD) or psoriasis remains unclear.background
Objective: We sought to determine the differential expression profiles of circRNAs in peripheral blood mononuclear cells (PBMCs) between healthy controls and AD patients, and explore the mechanisms underlying the effects of circRNAs on the pathogenesis of AD.
Methods
The differential expression profiles of circRNAs were analyzed by circRNA microarray. In vitro function and mechanisms by which circRNAs regulate macrophage-mediated inflammation were detected by RT-qPCR, western blotting, RNA stability assay, immunoprecipitation, enzyme-linked immunosorbent assay (ELISA), and methylated RNA immunoprecipitation (MeRIP) assay. In vivo roles of circRNAs were determined in 2,4-dinitrochlorobenzene (DNCB)-induced dermatitis and imiquimod (IMQ)-induced psoriasis mouse model.
Results
We identified a functional unknown circRNA hsa_circ_0004287 from 88750 circRNAs, which was upregulated in PBMCs of both AD and psoriasis patients, and mainly expressed by macrophages under inflammatory conditions. hsa_circ_0004287 inhibited M1 macrophage activation in vitro, and macrophage-specific overexpression of hsa_circ_0004287 alleviated skin inflammation in both AD- and psoriasis-like mice. Mechanistically, hsa_circ_0004287 reduced the stability of its host gene metastasis associated lung adenocarcinoma transcript 1 (MALAT1) by competitively binding to IGF2BP3 with MALAT1 in an N6-methyladenosine (m6A)-dependent manner. Lower levels of MALAT1 promoted the ubiquitination degradation of S100A8/S100A9, thereby impeding p38/MAPK phosphorylation and macrophage-mediated inflammation.results
Conclusion
Hsa_circ_0004287 inhibits M1 macrophage activation in an m6A-dependent manner in AD and psoriasis, and may serve as a general therapeutic candidate for AD and psoriasis.conclusion
The mechanism of atopic dermatitis (AD) is modulated by the release of cytokines and chemokines through the mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B (NF-κB) signaling pathway. Topical steroids are used to treat AD, but some people need safer anti-inflammatory drugs to avoid side effects. Mentha arvensis has been used as a herbal plant with medicinal properties, but its anti-inflammatory effects have not been elucidated in an AD model. In this study, we investigated the anti-inflammatory effects of M. arvensis essential oil (MAEO) and its underlying molecular mechanism in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and HaCaT cells (human epidermal keratinocyte). Additionally, we examined the ameliorating effects of the MAEO in a dinitrochlorobenzene (DNCB)-induced murine model of AD. We found, in both RAW 264.7 cells and HaCaT cells, MAEO inhibited LPS-stimulated inflammatory mediators such as nitric oxide (NO) and prostaglandin E2 and proinflammatory cytokines, including IL-1β and IL-6, due to the suppression of COX-2 and iNOS expression. In LPS-stimulated macrophages, we also observed that MAEO inhibited the phosphorylation of ERK and P65. Furthermore, MAEO treatment attenuated AD symptoms, including the dermatitis score, ear thickness, epidermal thickness and infiltration of mast cells, in a DNCB-induced animal model of AD. Overall, our findings suggest that MAEO exerts anti-inflammatory and anti-atopic dermatitis effects via inhibition of the ERK/NF-κB signaling pathway.
Atopic dermatitis (AD) is a common chronic pruritic inflammatory skin disorder characterized by recurrent eczematous lesions. Interleukin (IL)-33, a cytokine of the IL-1 family, was found to play an important role in the pathogenesis of AD. As a key component of the inflammasome, NLRP3 has been mostly described in myeloid cells that to mediate inflammasome activation conducted proinflammatory cytokine production of the IL-1 family. However, the role of NLRP3 inflammasome in the pathogenesis of AD, as well as IL-33 processing are highly controversial. Whether NLRP3 can mediate IL-33 expression and secretion independently of the inflammasome in the epithelium of AD has remained unclear. In this article, we found the mRNA expression of Il33 and Nlrp3 were notably increased in the lesional skin of AD patients compared to healthy controls. We then found a significant positive correlation between the expression of Nlrp3 and Il33 in the epithelium of MC903-mediated AD mice model, but no changes were observed for Il36α, Il36γ, Il1β, or Il18 mRNA expression, as well as IL-1β or IL-18 production. Overexpression of NLRP3 in human immortalized epithelial cells increased IL-33 expression, whereas siRNA targeting NLRP3 abolished IL-33 expression. In addition, inhibition of NLRP3 inflammasome activation or caspase-1 activity with MCC950 or VX-765 showed no effect on the expression and secretion of IL-33 in AD mice. Unlike myeloid cells, NLRP3 predominantly located in the nucleus of epithelial cells, which could directly bind to Il33 specific-promoters and transactivate it through an interaction with transcription factor IRF4. Furthermore, NLRP3 deficient mice exhibited a significant alleviated epidermis inflammation and decreased mRNA expression and secretion of IL-33 in MC903-mediated AD mice without interfering with TSLP and IL-1β production. Our results demonstrate a novel ability of NLRP3 to function as a crucial transcription factor of IL-33 in epithelium independently of inflammasome that to mediate the pathological process of AD.
The intestinal microbiome is considered one of the key regulators of health. Accordingly, the severity of atopic dermatitis (AD) is mediated by the skin and intestinal microbiome environment. In this study, while evaluating the aggravation in AD symptoms by the antibiotics cocktail (ABX)-induced depletion of the intestinal microbiome, we sought to verify the effect of Gardenia jasminoides (GJ), a medicinal herb used for inflammatory diseases, on AD regarding its role on the intestinal microbiome. To verify the aggravation in AD symptoms induced by the depletion of the intestinal microbiome, we established a novel mouse model by administrating an ABX to create a microbiome-free environment in the intestine, and then applied 2,4-dinitrochlorobenzene (DNCB) to induce an AD-like skin inflammatory response. While ABX treatment aggravated AD-like symptoms, the 2-week administration of GJ improved these pathological changes. DNCB application upregulated immune cell count and serum cytokine expression, which were alleviated by GJ. Moreover, pathological alterations by antibiotics and DNCB, including histological damage of the intestine and the intestinal expression of IL-17, were recovered in GJ-treated mice. The beneficial effect of GJ was due to the restoration of the intestinal microbiome composition. Overall, we suggest GJ as a potential therapeutic agent for AD due to its regulation of the intestinal microbiome.
Plants of the genus Wikstroemia are used in Chinese traditional medicine to treat inflammatory diseases, such as arthritis, bronchitis, and pneumonia. The present study was designed to determine whether Wikstroemia ganpi (Siebold and Zucc.) Maxim. offers a potential means of treating 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis (AD) in mice. Symptoms such as redness, edema, and keratinization in AD mice induced by DNCB were alleviated by the co-application of an ethanolic extract of W. ganpi for 2 weeks. The severity of skin barrier function damage was evaluated by measuring TEWL (transepidermal water loss). TEWLs of DNCB sensitized mouse dorsal skin were reduced by the application of a W. ganpi ethanolic extract, and skin hydration was increased. In addition, the infiltration of inflammatory cells into the dermis was significantly reduced, as were blood levels of IgE and IL-4, which play an important role in the expression of AD. The results of this experiment suggest that W. ganpi is a potential therapeutic agent for AD.
Atopic dermatitis (AD) is a relapsing, acute, and chronic skin disease featured by intractable itching, eczematous skin. Conventional therapies based on immunosuppression such as corticosteroids are associated with multiple adverse reactions. Periploca forrestii Schltr saponin (PFS) was shown to potently inhibit murine arthritis by protecting bone and cartilage injury and suppressing NF-κB activation. However, its therapeutic effect on oxazolone-induced atopic dermatitis (AD) and the underlying mechanisms on macrophage are still unclear. The AD-like dermatitis was induced by repeated oxazolone challenge to the skin of BALB/c mice in vivo. Blood and ears were biochemically or histologically processed. RT-PCR, western blotting, and ELISA were conducted to evaluate the expression of macrophage factors. Mouse bone marrow-derived macrophages (BMDMs) stimulated with lipopolysaccharide (LPS) were used as a model in vitro. PFS treatment inhibited AD-like dermatitis development. PFS downregulated epidermis thickness and cell infiltration, with histological analysis of the skin lesion. PFS alleviated plasma immunoglobulin (Ig) E, IgG2a, and IgG1 levels. PFS downregulated the expression of M1 macrophage factors, tumor necrosis factor- (TNF-) α, interleukin- (IL-) 6, monocyte chemotactic protein-1 (MCP-1), and nitric oxide synthase2 (NOS2), and M2 macrophage factors, IL-4, arginase1 (Arg1) and CD163 in AD-like skin, which were confirmed by western blot and ELISA analysis. In addition, PFS inhibited LPS-induced macrophage polarization via the inhibition of the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and nuclear translocation of NF-κB p65. These results suggest that PFS exerted an antidermatitis effect against oxazolone by modulating macrophage activation. PFS administration might be useful in the treatment of AD and inflammatory skin diseases.
This study was conducted to monitor the macrophage infiltration of atopic dermatitis (AD)-like skin lesions and to evaluate the effects of anti-AD therapeutic agents in immunocompetent mice via optical reporter-gene-based molecular imaging. The enhanced firefly luciferase (effluc)-expressing macrophage cell line (Raw264.7/effluc) was intravenously introduced into mice with 2,4-dinitrochlorobenzene (DNCB)-induced AD, followed by bioluminescent imaging (BLI). After in vivo imaging, AD-like skin lesions were excised, and ex vivo imaging and Western blotting were conducted to determine the presence of infused macrophages. Finally, the therapeutic effect of dexamethasone (DEX), an AD-modulating agent, was evaluated via macrophage tracking. In vivo imaging with BLI revealed the migration of the reporter macrophages to DNCB-induced AD-like skin lesions on day 1 post-transfer. The greatest recruitment was observed on day 3, and a decline in BLI signal was observed on day 14. Notably, in vivo BLI clearly showed the inhibition of the reporter macrophage infiltration of DNCB-induced AD-like skin lesions by DEX, which was consistent with the reduced AD symptoms observed in DEX-treated mice. We successfully visualized the macrophage migration to DNCB-induced AD-like skin lesions, proving the feasibility of macrophage imaging for evaluating AD-regulating drugs in living organisms.
Background:
Atopic dermatitis (AD) is a worldwide chronic skin disease which burden public health. Sea buckthorn (SBT) (Hippophae rhamnoides L., Elaeagnaceae) oil, as a traditional herbal medicine, has been used for disease treatment for many years. The effects of SBT oil on AD mouse model induced by repeated administration of 2,4-dinitrochlorobenzene (DNCB) in BALB/c mice was evaluated in this study.
Methods:
Mice were divided into four groups including the normal control group, AD model group, AD model group treated with SBT oil (5 ml/kg) and AD model group treated with SBT oil (10 ml/kg). Same volume at different concentrations of SBT oil was applied daily on the latter two groups by gavage for 15 days following AD model induction. The function of skin barrier and the production of IL-4, IFN-γ, TNF-α and TSLP were examined after animal sacrifice. The migration and mature of langerhans cell (LCs) in lymph node was further assessed by flow cytometry.
Results:
SBT oil alleviated dermatitis scores, decreased ear thickness, prevented infiltration of mast cell, reduced lymph node weight and depressed activity of Th2 cells. SBT oil also reduced the expression of IL-4, IFN-γ, TNF-α and TSLP in ear tissue, IgE level in serum and mRNA relative expression of IL-4, IFN-γ, TNF-α in lymph node. Moreover, SBT oil inhibited the migration of LCs cells from local lesions to lymph node and it's mature in lymph node.
Conclusions:
These results suggest SBT oil had a beneficial effect either systemic or regional on DNCB-induced AD mice via maintain the balance of Th1/Th2 and may be a potential complementary candidate for AD treatment.
Macrophage, as an integral component of the immune system and the first responder to local damage, is on the front line of defense against infection. Over the past century, the prevailing view of macrophage origin states that all macrophage populations resided in tissues are terminally differentiated and replenished by monocytes from bone-marrow (BM) progenitors. Nonetheless, this theory has been reformed by ground-breaking discoveries from the past decades. It is now believed that tissue-resident macrophages (TRMs) are originated from the embryonic precursors and seeded in tissue prenatally. They can replenish via self-renewal throughout the lifespan. Indeed, recent studies have demonstrated that tissue-resident macrophages should not be classified by the over-simplified macrophage polarization (M1/M2) dogma during inflammation. Moreover, multiple lines of evidence have indicated that tissue-resident macrophages play critical roles in maintaining tissue homeostasis and facilitating tissue repair through controlling infection and resolving inflammation. In this review, we summarize the properties of resident macrophages in the lung, spleen and heart, and further highlight the impact of TRM populations on inflammation control and tissue repair. We also discuss the potential role of local proliferation in maintaining a physiologically stable TRM pool in response to acute inflammation.
Pyropia yezoensis, a red alga, is popular and harvested a lot in East Asia and is famous for its medicinal properties attributable to its bioactive compounds including amino acids (porphyra-334 and shinorine, etc.), polysaccharides, phytosterols, and pigments, but its anti-inflammatory effect and mechanism of anti-atopic dermatitis (AD) have not been elucidated. In this study, we investigate the anti-AD effect of P. yezoensis extract (PYE) on mRNA and protein levels of the pro-inflammatory chemokines, thymus, and activation-regulated chemokine (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22), in human HaCaT keratinocyte cells treated to interferon (IFN)-γ or tumor necrosis factor (TNF)-α (10 ng/mL each). The effect of the PYE on extracellular signal-regulated kinase (ERK) and other mitogen-activated protein kinases (MAPKs) was related to its suppression of TARC and MDC production by blocking NF-κB activation in HaCaT cells. Furthermore, astaxanthin and xanthophyll from P. yezoensis were identified as anti-AD candidate compounds. These results suggest that the PYE may improve AD and contained two carotenoids by regulating pro-inflammatory chemokines.
Wikstroemia indica (L.) C.A. Mey. is used in traditional Chinese medicine to treat inflammatory diseases such as arthritis and bronchitis. In this study, we aimed to investigate the effects of an ethanolic extract of W. indica on cutaneous inflammation in mice with 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis (AD). Dermal administration of W. indica ethanolic extract to DNCB-sensitized hairless mice with dermatitis, for two weeks, reduced erythema, scaling, and edema. Skin hydration was improved and transepidermal water loss was reduced at a W. indica concentration of 1%. Furthermore, W. indica also significantly reduced serum IgE and IL-4 concentrations in our mouse model. These results suggest that W. indica has potential as a topical treatment for AD and as an adjunctive agent to control AD.
Objective
IgG4‐related disease (IgG4‐RD) is a unique inflammatory disorder in which Th2 cytokines promote IgG4 production. In addition, recent studies have implicated the Toll‐like receptor (TLR) pathway. This study was undertaken to examine the expression of TLRs in salivary glands (SGs) from patients with IgG4‐RD.
Methods
SGs from 15 patients with IgG4‐RD, 15 patients with Sjögren's syndrome (SS), 10 patients with chronic sialadenitis, and 10 healthy controls were examined histologically. TLR family gene expression (TLR‐1 through TLR‐10) was analyzed by DNA microarray in the submandibular glands (SMGs). Up‐regulation of TLRs was confirmed in SGs from patients with IgG4‐RD. Finally, the phenotype of human TLR‐7 (huTLR‐7)–transgenic C57BL/6 mice was assessed before and after stimulation with TLR agonist.
Results
In patients with IgG4‐RD, TLR‐4, TLR‐7, TLR‐8, and TLR‐9 were overexpressed. Polymerase chain reaction validated the up‐regulation of TLR‐7 in IgG4‐RD compared with the other groups. Immunohistochemical analysis confirmed strong infiltration of TLR‐7–positive cells in the SGs of patients with IgG4‐RD. Double immunohistochemical staining showed that TLR‐7 expression colocalized with CD163+ M2 macrophages. After in vitro stimulation with a TLR‐7 agonist, CD163+ M2 macrophages produced higher levels of interleukin‐33 (IL‐33), which is a Th2‐activating cytokine. In huTLR‐7–transgenic mice, the focus and fibrosis scores in SMGs, pancreas, and lungs were significantly higher than those in wild‐type mice (P < 0.05). Moreover, the concentration of serum IgG, IgG1, and IL‐33 in huTLR‐7–transgenic mice was distinctly increased upon stimulation with a TLR‐7 agonist (P < 0.05).
Conclusion
TLR‐7–expressing M2 macrophages may promote the activation of Th2 immune responses via IL‐33 secretion in IgG4‐RD.
Macrophages are found in tissues, body cavities, and mucosal surfaces. Most tissue macrophages are seeded in the early embryo before definitive hematopoiesis is established. Others are derived from blood monocytes. The macrophage lineage diversification and plasticity are key aspects of their functionality. Macrophages can also be generated from monocytes in vitro and undergo classical (LPS+IFN-γ) or alternative (IL-4) activation. In vivo, macrophages with different polarization and different activation markers coexist in tissues. Certain mouse strains preferentially promote T-helper-1 (Th1) responses and others Th2 responses. Their macrophages preferentially induce iNOS or arginase and have been called M1 and M2, respectively. In many publications, M1 and classically activated and M2 and alternatively activated are used interchangeably. We tested whether this is justified by comparing the gene lists positively [M1(=LPS+)] or negatively [M2(=LPS–)] correlated with the ratio of IL-12 and arginase 1 in transcriptomes of LPS-treated peritoneal macrophages with in vitro classically (LPS, IFN-γ) vs. alternatively activated (IL-4) bone marrow derived macrophages, both from published datasets. Although there is some overlap between in vivo M1(=LPS+) and in vitro classically activated (LPS+IFN-γ) and in vivo M2(=LPS–) and in vitro alternatively activated macrophages, many more genes are regulated in opposite or unrelated ways. Thus, M1(=LPS+) macrophages are not equivalent to classically activated, and M2(=LPS–) macrophages are not equivalent to alternatively activated macrophages. This fundamental discrepancy explains why most surface markers identified on in vitro generated macrophages do not translate to the in vivo situation. Valid in vivo M1/M2 surface markers remain to be discovered.
Background
The impact of atopic dermatitis (AD) on health-related quality of life and health utility in the US adult population is not well established.
Objective
To determine the health utilities and quality-adjusted life-years (QALYs) lost in adults with AD versus without AD in the US population.
Methods
A cross-sectional, population-based study of 3495 adults was performed. AD was determined using modified UK diagnostic criteria for AD. AD severity was assessed using self-reported global AD severity, the Patient-Oriented Eczema Measure, the Patient-Oriented Scoring AD, and the Patient-Oriented Scoring AD itch and sleep. Six-dimensional health state short form (SF-6D) health utility scores and total QALY loss were assessed.
Results
The mean SF-6D score was lower in adults with AD compared with healthy adults (0.69 [95% CI, 0.68-0.70] versus 0.79 [95% CI, 0.77-0.79]). In particular, those with moderate-to-severe AD (mean, 0.53-0.66) had similar or lower SF-6D scores compared with those with all other self-reported disorders examined, except autoimmune disorders. Adults with AD and atopic comorbidities had significantly lower SF-6D scores compared with those without atopic comorbidities. Among the 7 disorders examined, AD was associated with higher total QALY loss than autoimmune disorders, diabetes, food allergy, and heart disease in both males and females. The largest QALY loss was for moderate AD in females and mild AD in males.
Conclusions
Moderate-to-severe AD is associated with significant decrements of health utility in the US population. These data illustrate the heavy societal burden of moderate and severe AD and provide important insight for prioritization of resource allocation and cost-effectiveness research.
Drug development involves pharmacometric experiments in animals. Such experiments should limit animal pain and stress. Conventional murine models of atopic dermatitis (AD) used in drug development are generated by weekly painting of hapten on dorsal skin for 5 weeks. The present study aimed to develop a protocol that involves less animal distress. The experiments focused on serum total IgE levels, which are a marker of AD. The conventional protocol induced ever rising IgE levels. Experiments with extended intervals between sensitizations showed that IgE peaked ~5 days after the second sensitization, after which it returned to the control level within 12-19 days. An additional third sensitization on day 28 further increased the serum IgE level. In the 4-5 days after the second sensitization, the dorsal skin exhibited typical AD-like lesions with edema, scabs, epithelial-cell hypertrophy, marked mast-cell and lymphocyte infiltration of dermis, and increased IL-4, IL-6, IL-10, IL-1β, IL-17A, IFN-γ and TNF-α expression. Thus, two 2,4-dinitrofluorobenzene sensitizations yield a murine AD model in less than 20 days. This study shows that animal model protocols used in drug development can be fine-tuned so that they remain effective yet cause animals less stress and pain.
Background:
There are sparse and conflicting data regarding the long-term clinical course of atopic dermatitis (AD). Although often described as a childhood disease, newer population-based estimates suggest the prevalence of pediatric and adult disease may be similar.
Methods:
Our objective was to determine whether there is a decline in the prevalence of AD in population-based cohorts of patients followed longitudinally beyond childhood. We conducted a systematic review and meta-analysis including studies assessing AD prevalence across 3 or more points in time. The primary outcome was weighted overall risk difference (percentage decrease in AD prevalence).
Results:
Of 2080 references reviewed, 7 studies with 13 515 participants were included. Participants were assessed at 3-6 time points, ranging from age 3 months to 26 years. The percentage decrease in prevalence after age 12 was 1%, which was not significantly different from zero (95% confidence interval -2%-5%). Similar results were found with other age cut-offs.
Conclusion:
The prevalence of AD in longitudinal birth cohort studies is similar in childhood and adolescence/early adulthood.
or moisturisers are widely recommended, but are these effective and safe? We searched for randomised controlled trials (RCTs) in the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library, Medline, Embase, LILACS, GREAT database and five trial registers to December 2015. We included 77 RCTs with 6603 participants. Seven studies (9.1%) were at low risk of bias, 34 (44.2%) at unclear and 36 (46.8%) at high risk. The quality of the evidence was mainly low or moderate for the prespecified outcomes. The most important comparison ‘moisturiser versus no moisturiser’ showed an improved SCORAD in the moisturiser group compared to no moisturiser (mean difference (MD) -2.42, 95% confidence interval (CI) -4.55 to -0.28), but did not meet the minimal important difference (MID) of 8.7. Fewer flares were seen (risk ratio (RR) 0.40, 95% CI 0.23 to 0.70) and rate of flare was reduced (hazard ratio (HR) 3.74, 95% CI 1.86 to 7.50). The groups applying moisturiser used less topical corticosteroids over six to eight weeks (MD -9.30 g, 95% CI 15.3 to -3.27). Glycyrrhetinic acid-containing cream, urea-containing and glycerol-containing creams worked better than their control (vehicle, placebo or no moisturiser) according to both participants and physicians. More flares were reported with moisturiser alone than when combined with twice weekly fluticasone propionate (RR 2.17, 95% CI 1.55 to 3.11). Adding moisturisers to topical anti-inflammatory treatment was more effective than anti-inflammatory treatment alone and with fewer flares
Background
Quince (Cydonia oblonga Miller) is a deciduous shrub belonging to the Rosaceae family. Quince seed extract has long been used as a cosmetic ingredient for its moisturizing effect. However, little is known about whether quince seed extract has therapeutic effects on keratinocyte-associated skin inflammation. Methods
In the present study, we investigated the effect of the topical application of ethanol extract of quince seeds (QSEtE) on atopic dermatitis (AD) symptoms in NC/Nga mice. The direct effect of QSEtE on keratinocytes was evaluated using the human keratinocyte cell line HaCaT. ResultsThe preliminary application of QSEtE markedly reduced house dust mite allergen-induced skin lesions. The expression of thymus- and activation-regulated chemokine (TARC) in dorsal skin was downregulated. QSEtE directly suppressed the expression and production of TARC in HaCaT cells. Conclusions
The results suggest that the topical application of QSEtE is effective in preventing the onset of and ameliorating the atopic symptoms of keratinocyte-associated skin inflammation by suppressing TARC production in keratinocytes.
Objective:
AMP-activated protein kinase (AMPK) is metabolic biosensor with anti-inflammatory activities. Gout is commonly associated with excesses in soluble urate and in nutrition, both of which suppress tissue AMPK activity. Gout is driven by macrophage-mediated inflammation transduced partly by NLRP3 inflammasome activation and interleukin (IL)-1β release. Hence, we tested the hypothesis that AMPK activation limits monosodium urate (MSU) crystal-induced inflammation.
Methods:
We studied bone marrow-derived macrophages (BMDMs) from AMPKα1 knockout and wild-type mice, and assessed the selective AMPK pharmacological activator A-769662 and a low concentration (10 nM) of colchicine. We examined phosphorylation (activation) of AMPKα Thr172, NLRP3 mRNA expression, and caspase-1 cleavage and IL-1β maturation using western blot and quantitative RT-PCR approaches. We also assessed subcutaneous murine air pouch inflammatory responses to MSU crystals in vivo.
Results:
MSU crystals suppressed phosphorylation of AMPKα in BMDMs. Knockout of AMPKα1 enhanced, and, conversely, A-769662-inhibited MSU crystal-induced inflammatory responses including IL-1β and CXCL1 release in vitro and in vivo. A-769662 promoted AMPK-dependent macrophage anti-inflammatory M2 polarisation and inhibited NLRP3 gene expression, activation of caspase-1 and IL-1β. Colchicine, at low concentration (10 nM) achieved in gout flare prophylaxis dosing, promoted phosphorylation of AMPKα and macrophage M2 polarisation, and reduced activation of caspase-1 and release of IL-1β and CXCL1 by MSU crystals in BMDMs in vitro.
Conclusions:
AMPK activity limits MSU crystal inflammation in vitro and in vivo, and transduces multiple anti-inflammatory effects of colchicine in macrophages. Targeting increased and sustained AMPK activation in inflammatory cells merits further investigation for enhancing efficacy of prophylaxis and treatment of gouty inflammation.
Herein, we demonstrate a role of AMP-activated protein kinase (AMPK) as a potent counterregulator of inflammatory signaling pathways in macrophages. Stimulation of macrophages with anti-inflammatory cytokines (i.e., IL-10 and TGFbeta) resulted in the rapid phosphorylation/activation of AMPK, whereas stimulation of macrophages with a proinflammatory stimulus (LPS) resulted in AMPK dephosphorylation/inactivation. Inhibition of AMPKalpha expression by RNA interference dramatically increased the mRNA levels of LPS-induced TNF-alpha, IL-6, and cyclooxygenase-2. Likewise, expression of a dominant negative AMPKalpha1 in macrophages enhanced TNF-alpha and IL-6 protein synthesis in response to LPS stimulation, while diminishing the production of IL-10. In contrast, transfection of macrophages with a constitutively active form of AMPKalpha1 resulted in decreased LPS-induced TNF-alpha and IL-6 production, and heightened production of IL-10. In addition, we found that AMPK negatively regulated LPS-induced IkappaB-alpha degradation and positively regulated Akt activation, accompanied by inhibition of glycogen synthase kinase beta and activation of CREB. Thus, AMPK directs signaling pathways in macrophages in a manner that suppresses proinflammatory responses and promotes macrophage polarization to an anti-inflammatory functional phenotype.
Huang Qi (黄芪 Astragalus membranaceus ) is a well-known and widely used herb in traditional Chinese medicine (TCM) tonic preparations. It has been used for many ailments over the last 2000 years. Flavonoids, saponins, and polysaccharides have been shown to be the main compounds responsible for the biological and pharmacological activities, especially the immunomodulatory properties, of such tonic preparations. This review summarizes the published data on Astragalus extracts and fractions and the natural compounds responsible for the immunomodulatory activity with special reference to the modulation of nuclear factor-kappa B and related pathways (e.g., Nrf2). In addition, this review highlights the importance of Astragalus membranaceus in TCM for treating patients with diseases related to immunocompromised conditions, such as cancer and diabetes.
Citrulline can be converted into argininosuccinate by argininosuccinate synthetase (ASS1) in the urea cycle and the citrulline-nitric oxide cycle. However, the regulation and biological function of citrulline metabolism remain obscure in the immune system. Unexpectedly, we found that macrophage citrulline declines rapidly after interferon gamma (IFN-γ) and/or lipopolysaccharide (LPS) stimulation, which is required for efficient proinflammatory signaling activation. Mechanistically, IFN-γ and/or LPS stimulation promotes signal transducers and activators of transcription 1 (STAT1)-mediated ASS1 transcription and Janus kinase2 (JAK2)-mediated phosphorylation of ASS1 at tyrosine 87, thereby leading to citrulline depletion. Reciprocally, increased citrulline directly binds to JAK2 and inhibits JAK2-STAT1 signaling. Blockage of ASS1-mediated citrulline depletion suppresses the host defense against bacterial infection in vivo. We therefore define a central role for ASS1 in controlling inflammatory macrophage activation and antibacterial defense through depletion of cellular citrulline and, further, identify citrulline as an innate immune-signaling metabolite that engages a metabolic checkpoint for proinflammatory responses.
The number of patients with atopic dermatitis is on the rise worldwide, and Japan is no exception. According to recent estimates of the percentage of patients with atopic dermatitis in Japan by age, the majority of patients are between 20 and 44 years old. Because the peak age of onset of atopic dermatitis is during infancy, many patients may experience prolonged symptoms from infancy to adulthood. A prolonged clinical course also increases the burden of atopic dermatitis on affected patients. Decreased productivity due to work disruptions, reduced daily activity, higher direct medical costs, fatigue, and daytime sleepiness due to sleep disturbances are typical burdens on patients with atopic dermatitis. In order to reduce these burdens, it is necessary to shorten its clinical course and achieve long-term control without relying on medications, possibly by using avoidance or coping measures of aggravating factors. Typical aggravating factors of atopic dermatitis include irritant dermatitis, food allergy in children, sweating, and psychological stress in adults. Food allergy places a heavy burden on the quality of life of affected patients and their families. The effectiveness of educational interventions for sweating and psychological stress is unclear. We must also evaluate the economic burden and cost-effectiveness of interventions on the patient as aggravating factors to be addressed.
Atopic dermatitis (AD) is a heterogenous disorder and can be classified into different types. Stratification of subtypes may enable personalized medicine approaches. AD can be categorized into the IgE-high, extrinsic subtype and the IgE-normal, intrinsic subtype. While extrinsic AD is the major subtype possessing skin barrier impairment (high incidence of filaggrin mutations), intrinsic AD occupies about 20% of AD with female dominance and preserved barrier. Extrinsic AD exhibits protein allergy and food allergy, but intrinsic AD shows metal allergy possibly in association with suprabasin deficiency. In particular, accumulated knowledge of food allergy has more clearly characterized extrinsic AD. European American (EA) and Asian AD subtypes have been also proposed. Asian patients with AD are characterized by a unique blended immune dysregulation and barrier feature phenotype between EA patients with AD and those with psoriasis. In another ethnic study, filaggrin loss-of-function mutations are not prevalent in African American patients with AD, and Th1/Th17 attenuation and Th2/Th22 skewing were seen in these patients. Recent endotype classification provides new insights for AD and other allergic disorders. Endotype is defined as the molecular mechanisms underlying the visible features/phenotype. Endotype repertoire harbors activation of type 2 cytokines, type 1 cytokines, and IL-17/IL-22, impairment of epidermal barrier, and abnormalities of intercellular lipids. Classification of endotype has been attempted with serum markers. These lines of evidence indicate a need for personalized or precision medicine appropriate for each subtype of AD.
Atopic dermatitis is a chronic disorder that usually starts in childhood but often persists in adulthood. The appearance and extent of lesions vary with age and race or ethnic group. Topical and systemic treatments targeting the underlying immune condition have been introduced.
Aims
The aim of this study was to investigate the role of TRPA1 in the pathogenesis of AD.
Main methods
The experimental atopic dermatitis (AD)-like skin lesions were established using 2,4-dinitrochlorobenzene (DNCB). Mice were divided into three groups: TRPA1−/− and WT groups were treated with DNCB dissolved in a 3:1 mixture of acetone and olive oil; the negative control group was treated with 3:1 mixture of acetone and olive oil without DNCB. The treatment lasted for 21 days, after which the animals were sacrificed and their blood, ears and dorsal skin tissue samples were collected for analysis.
Key findings
Lower dermatitis score, ear thickness, pruritus score, and epidermal hyperplasia were observed in mice in TRPA1−/− mice compared to the WT group. Besides, lower dermal mast cell infiltration, proinflammatory cytokines, Th2 cytokines and the infiltration of macrophages were observed in the TRPA1−/− mice compared to the WT group. Furthermore, we demonstrated that TRPA1 antagonist HC-030031 could alleviate AD-like symptoms and reduce the degree of epidermal hyperplasia in mice.
Significance
TRPA1 has a crucial role during the AD pathogenesis in mice, thus may be used as a potential new target for treating patients with chronic skin inflammatory disease.
Allergic disorders, including atopic dermatitis (AD), are closely linked to the activation of type 2 helper T (Th2) cells. The aim of this study was to investigate the possibility of using Rosae multiflorae fructus extract (RMFE) for AD treatment in the AD-like mouse model induced by treatment with trimellitic anhydride (TMA). Oral treatment of RMFE reduced the increase in ear thickness and suppressed inflammatory cytokine expression (interleukin [IL]-1β and tumor necrosis factor [TNF]-α) and Th2-associated immune responses (immunoglobulin [Ig] E and IL-4) in mouse ears. Furthermore, messenger RNA (mRNA) expression levels such as IL-4, IL-5, and IL-13, in draining lymph nodes were decreased by RMFE. Furthermore, we found that RMFE increased the level of heme oxygenase-1 (HO-1) through ERK and p38 pathways, reducing IL-2 production and CD4+ T cell proliferation, and inhibited STAT6 phosphorylation. Therefore, this study suggested that RMFE could be an effective treatment of AD induced by Th2-mediated immune responses by suppressing proliferation of CD4+ T cells via increased HO-1.
Ethnopharmacological relevance:
Atopic dermatitis (AD) is a pruritic, chronic, relapsing inflammatory skin disease. Gardenia jasminoides extract (GJE) has been used as a traditional remedy for the treatment of various inflammatory diseases, including AD. The specific effects of the extract components, which include crocin, geniposidic acid, and gardenoside, on inflammatory responses in AD are not entirely clear.
Aim of the study:
We determined the effects of G. jasminoides extract with crocin removed (GJE-C) on AD-like skin lesions in Dermatophagoies farina crude extract (Dfe)-treated NC/Nga mice, a well-known AD mouse model.
Materials and methods:
To prepare the mice, 150 μl of 4% sodium dodecyl sulfate (SDS) was applied to the shaved dorsal skin or ear of NC/Nga mice 1 h before application of 100 mg Dfe. After 7 d, GJE-C was applied every day for 14 d. We performed behavior, histological, ELISA, assays to evaluate chemokines, cytokines, and skin barrier proteins in skin or serum samples from treated and untreated NC/Nga mice.
Results:
Topical application of GJE-C improved the severity scores of the AD-like skin lesions, frequency of scratching, and ear swelling in Dfe-treated NC/Nga mice similar to the complete GJE. In addition, GJE-C also reduced serum IgE and chemokine levels as well as the inflammatory response. Topical application of GJE-C also resulted in decreased infiltration of inflammatory cells, such as mast cells, via reduction of Th2 inflammatory mediators, including interleukin (IL)-4, IL-5, and IL-13, pro-inflammatory cytokines, and chemokines, and increased skin barrier protein expression in Dfe-treated NC/Nga mice. The GJE components geniposidic acid and gardenoside inhibited the production of atopic-related chemokines in HaCaT cells, but inclusion of crocin dampened this inhibition of chemokine production.
Conclusions:
Together, these findings indicate that GJE-C may improve AD-like lesions by inhibiting the Th2 inflammatory response and expression of chemokines while increasing the expression of skin barrier proteins. These data provide experimental evidence that GJE-C may harbor therapeutic potential for AD.
Background:
Previous studies found conflicting results about the commonality of different atopic dermatitis (AD) signs and symptoms.
Objective:
To determine the prevalences of AD characteristics and differences by region and age.
Methods:
A systematic review was performed of all published studies in MEDLINE, EMBASE, SCOPUS, LILACS, Cochrane, China National Knowledge Infrastructure, Taiwan electronic periodical services and CiNii that analyzed the proportion of AD characteristics. Two reviewers performed study title/abstract review and data abstraction.
Results:
One hundred and one studies reported proportion of AD features with sufficient data for meta-analysis. The most prevalent AD features were pruritus, lichenification and xerosis. There were differences of AD characteristics by study region. Flexural involvement was less commonly reported in India, America and Iran. East Asian studies reported more erythroderma, truncal, extensor, scalp and auricular involvement. Southeast Asian studies reported more exudative eczema, truncal involvement, lichenification and prurigo nodules. Studies from Iran reported more head, face and neck involvement, pityriasis alba, and xerosis. Studies from Africa reported more papular lichenoid lesions, palmar hyperlinearity, ichthyosis and orbital darkening.
Limitations:
Heterogeneity between studies and limited reporting of certain AD clinical characteristics.
Conclusions:
AD characteristics are heterogeneous and vary by region and age.
Atopic dermatitis is the commonest chronic inflammatory skin disorder, affecting up to 20% of children and 10% of adults in industrialised countries. This highly debilitating condition poses a considerable burden to both the individual and society at large.
The pathophysiology of atopic dermatitis is complex, encompassing both genetic and environmental risk factors. Dysregulation of innate and adaptive immunity plays a key role; however, recent epidemiological, genetic and molecular research has focused interest on skin barrier dysfunction as a common precursor and pathological feature. Current understanding of the aetiology of atopic dermatitis highlights disruption of the epidermal barrier leading to increased permeability of the epidermis, pathological inflammation in the skin, and percutaneous sensitisation to allergens. Thus, most novel treatment strategies seek to target specific aspects of the skin barrier or cutaneous inflammation. Several studies have also shown promise in preventing atopic dermatitis, such as the early use of emollients in high‐risk infants. This may have broader implications in terms of halting the progression to atopic comorbidities including food allergy, hay fever, and asthma.
This article is protected by copyright. All rights reserved.
Atopic dermatitis (AD) is the most common chronic inflammatory skin disease, with a lifetime prevalence of up to 20% and substantial effects on quality of life. AD is characterized by intense itch, recurrent eczematous lesions and a fluctuating course. AD has a strong heritability component and is closely related to and commonly co-occurs with other atopic diseases (such as asthma and allergic rhinitis). Several pathophysiological mechanisms contribute to AD aetiology and clinical manifestations. Impairment of epidermal barrier function, for example, owing to deficiency in the structural protein filaggrin, can promote inflammation and T cell infiltration. The immune response in AD is skewed towards T helper 2 cell-mediated pathways and can in turn favour epidermal barrier disruption. Other contributing factors to AD onset include dysbiosis of the skin microbiota (in particular overgrowth of Staphylococcus aureus), systemic immune responses (including immunoglobulin E (IgE)-mediated sensitization) and neuroinflammation, which is involved in itch. Current treatments for AD include topical moisturizers and anti-inflammatory agents (such as corticosteroids, calcineurin inhibitors and cAMP-specific 3',5'-cyclic phosphodiesterase 4 (PDE4) inhibitors), phototherapy and systemic immunosuppressants. Translational research has fostered the development of targeted small molecules and biologic therapies, especially for moderate-to-severe disease.
Background:
Previous studies found conflicting results about whether atopic dermatitis (AD) begins in adulthood.
Objective:
To determine rates, predictors and phenotypical differences of adult-onset AD.
Methods:
A systematic review was performed of all published observational studies in MEDLINE, EMBASE, GREAT, LILACS, Cochrane Library, and Scopus that analyzed the age of AD onset beyond 10 years of age. Two reviewers performed study title/abstract review and data abstraction. Pooled meta-analysis of the proportion of adult-onset AD was performed using random-effects weighting (I2=99.3%).
Results:
Overall, 25 studies met inclusion criteria. Seventeen studies reported age of AD-onset past 16 years and had sufficient data for meta-analysis. The pooled proportion (95% CI) of adult-onset AD was 26.1% (16.5-37.2%). Similar results were found in sensitivity analyses by diagnostic method for AD, study region, and gender. Phenotypical differences were observed across studies for adult vs. child onset AD, including higher rates of foot dermatitis and personal history of atopy, but lower rates of flexural lesions and other signs and symptoms.
Limitations:
Characteristics of adult- vs. child-onset AD were not commonly reported.
Conclusions:
AD is not only a disease of childhood. One in 4 adults with AD report adult-onset disease. Adult-onset AD was associated with distinct clinical characteristics.
Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease prevalent worldwide. This study investigated the effects of glycyrrhizin, an extract of licorice root, on the well-established model of 2,4-dinitrochlorobenzene-induced AD-like symptoms in mice. The severity of dermatitis, histopathological changes, serum IgE levels, changes in expression of high-mobility group box 1 (HMGB1), the receptor for advanced glycation end products (RAGE), nuclear factor (NF)-κB and inflammatory cytokines were evaluated. Treatment with glycyrrhizin inhibited the HMGB1 signaling cascade and ameliorated the symptoms of AD. Furthermore, in an in vitro study, the expression of RAGE was detected in a mouse mast cell line, P815 cells, and rmHMGB1 was found to be a potent inducer of mast cell activation by increasing Ca2+ influx, upregulating the CD117 and activating NF-κB signaling; these effects were also inhibited by glycyrrhizin. These findings implicate HMGB1 in the pathogenesis of AD and suggest that GL could be an effective therapeutic approach for cutaneous inflammation.
The pathophysiology of atopic dermatitis is complex and multifactorial, involving elements of barrier dysfunction, alterations in cell mediated immune responses, IgE mediated hypersensitivity, and environmental factors. Loss of function mutations in filaggrin have been implicated in severe atopic dermatitis due to a potential increase in trans-epidermal water loss, pH alterations, and dehydration. Other genetic changes have also been identified which may alter the skin’s barrier function, resulting in an atopic dermatitis phenotype. The imbalance of Th2 to Th1 cytokines observed in atopic dermatitis can create alterations in the cell mediated immune responses and can promote IgE mediated hypersensitivity, both of which appear to play a role in the development of atopic dermatitis. One must additionally take into consideration the role of the environment on the causation of atopic dermatitis and the impact of chemicals such as airborne formaldehyde, harsh detergents, fragrances, and preservatives. Use of harsh alkaline detergents in skin care products may also unfavorably alter the skin’s pH causing downstream changes in enzyme activity and triggering inflammation. Environmental pollutants can trigger responses from both the innate and adaptive immune pathways. This chapter will discuss the multifaceted etiology of atopic dermatitis which will help us to elucidate potential therapeutic targets. We will also review existing treatment options and their interaction with the complex inflammatory and molecular triggers of atopic dermatitis.
Atopic dermatitis (AD) is a chronic pruritic inflammatory disease that commonly presents in the pediatric population. Although definitions and diagnosis of AD have largely been agreed upon, allergists and dermatologists have similar and divergent approaches to the management of AD. This review facilitated integration of the American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma & Immunology Joint Task Force 2012 AD Practice Parameter and the 2014 American Academy of Dermatology guidelines to highlight the basic principles of AD management and discuss therapies and management of AD from the distinct perspectives of the allergist and dermatologist.
Neuroinflammation remains the primary cause of morbidity and mortality in stroke-induced secondary brain injury. The NOD-like receptor pyrin 3 (NLRP3) inflammasome is involved in diverse inflammatory diseases, including cerebral ischemia, and is thus considered an effective therapeutic target. In the present study, we investigated the neuroprotection of Sinomenine (SINO), a potent natural anti-apoptotic and anti-inflammatory molecule, against cerebral ischemia in a mouse model of middle cerebral artery occlusion (MCAO) in vivo and in an oxygen glucose deprivation (OGD)-treated astrocytes/microglia model in vitro. SINO administration intraperitoneally alleviated the cerebral infarction, brain edema, neuronal apoptosis, and neurological deficiency after MCAO induction. SINO also attenuated astrocytic and microglial activation in the ischemic hemisphere. NLRP3 inflammasome activation after MCAO and OGD induction, with the up-regulation of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), cleaved caspase-1 and pro-inflammatory cytokines, was significantly inhibited by SINO treatment both in vivo and in vitro. In addition, SINO reversed the OGD-induced inhibition of AMPK phosphorylation in vitro. Further, the suppressive effect of SINO on NLRP3 inflammasomes was blocked by an AMPK inhibitor, Compound C. Our findings demonstrate that SINO exerts a neuroprotective effect in ischemic stroke by inhibiting NLRP3 inflammasomes via the AMPK pathway, which also provides evidence of a novel treatment for clinical stroke therapy.
Patients with atopic dermatitis have skin barrier impairment in both lesional and non-lesional skin. They are typically exposed to emollients daily and topical anti-inflammatory medicaments intermittently, hereby increasing the risk of developing contact allergy and systemic exposed to chemicals ingredients found in these topical preparations. We systematically searched for studies that investigated skin absorption of various penetrants, including medicaments, in atopic dermatitis patients, but also animals with experimentally induced dermatitis. We identified 40 articles, i.e. 11 human studies examining model penetrants, 26 human studies examining atopic dermatitis drugs and 3 animal studies. We conclude that atopic dermatitis patients have nearly two-fold increased skin absorption when compared to healthy controls. There is a need for well-designed epidemiological and dermato-pharmacokinetic studies that examine to what extent atopic dermatitis patients are systemically exposed to chemicals compared to non-atopics. This article is protected by copyright. All rights reserved.
It is becoming increasingly accepted that macrophages play a crucial role in many diseases associated with chronic inflammation, including atherosclerosis, obesity, diabetes, cancer, skin diseases, and even neurodegenerative diseases. It is therefore not surprising that macrophages in human diseases have gained significant interest during the last years. Molecular analysis combined with more sophisticated murine disease models and the application of genome-wide technologies has resulted in a much better understanding of the role of macrophages in human disease. We highlight important gain of knowledge during the last years for tumor-associated macrophages, and for macrophages in atherosclerosis, obesity and wound healing. Albeit these exciting findings certainly pave the way to novel diagnostics and therapeutics, several hurdles still need to be overcome. We propose a general outline for future research and development in disease-related macrophage biology based on integrating (1) genome-wide technologies, (2) direct human sampling, and (3) a dedicated use of in vivo model systems.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Rapamycin (RPM) and mycophenolic acid (MPA) are immunosuppressive drugs approved for use in preventing transplant rejection. These drugs have also been used in the field of dermatology as glucocorticoid sparing agents for autoimmune and inflammatory disorders such as atopic dermatitis (AD). The aim of this study was to investigate the therapeutic effect of topically applied RPM and/or MPA on AD-like skin lesions in NC/Nga mice. RPM (0.04% - 4%), MPA (0.2% - 5%), and formulations of both agents at various ratios were administrated topically to NC/Nga mice with 2-chloro-1,3,5-trinitrobenzene (TNCB)-induced AD-like skin lesions. The therapeutic effects of topical RPM, MPA, and the mixed formulations in TNCB-treated NC/Nga mice were assessed by measuring skin severity scores, ear thickness, and histological changes in the lesioned skin including mast cell count and total serum IgE levels. Expression of interleukin (IL)-4, and interferon (IFN)-γ was also assessed. Topical 4% RPM and/or 1% MPA treatment significantly improved clinical signs of AD such as erythema, edema, excoriation, and dryness on day 29 (P<0.05). In addition, 4% RPM, 1% MPA, and the mixed formulations significantly decreased epidermal thickening, dermal edema, and cellular infiltration into the dermis compared with the vehicle. RPM (4%) and/or MPA (1%) significantly reduced the expression of IL-4 and IFN-γ mRNA and protein levels compared with the vehicle (P<0.05). No significant change in the levels of total serum IgE was induced by topical 4% RPM and/or 1% MPA. The present results demonstrated that topical 4% RPM and/or 1% MPA improved TNCB-induced AD-like lesions of NC/Nga mice by suppressing expression of Th2-related cytokines (IL-4) and Th1-related cytokines (IFN-γ). These findings suggest that RPM and/or MPA may be promising topical therapeutic candidates for the treatment of AD.
Copyright © 2015. Published by Elsevier B.V.
The compound β-sitosterol (BS) is one of the most common forms of phytosterols and has anti-cancer, anti-oxidant, anti-bacterial, and anti-inflammatory effects. However, the effect of BS on atopic dermatitis (AD) has not been elucidated. Therefore, we investigated whether BS would be an effective treatment against AD. We treated BS on 2,4-dinitrofluorobenzene (DNFB)-induced AD-like skin lesions in NC/Nga mice, anti-CD3/anti-CD28-stimulated splenocytes, and phorbol myristate acetate/calcium ionophore A23187-stimulated human mast cell line (HMC-1) cells. Histological analysis, ELISA, PCR, caspase-1 assay, and Western blot analysis were performed. BS reduced the total clinical severity in DNFB-treated NC/Nga mice. Infiltration of inflammatory cells and number of scratching were clearly reduced in the BS-treated group compared with the DNFB-treated group. BS significantly reduced the levels of inflammation-related mRNA and protein in the AD skin lesions. BS significantly reduced the levels of histamine, IgE, and interleukin-4 in the serum of DNFB-treated NC/Nga mice. The activation of mast cell-derived caspase-1 was decreased by treatment with BS in the AD skin lesions. BS also significantly decreased the production of tumor necrosis factor-α from the stimulated splenocytes. In the stimulated human mast cell line, HMC-1 cells, increased intracellular calcium levels were decreased by treatment with BS. Further, BS inhibited the production and mRNA expression of TSLP through blocking of caspase-1 and nuclear factor-κB signal pathways in the stimulated HMC-1 cells. These results provide additional evidence that BS may be considered an effective therapeutic drug for the treatment of AD.
Metabolic changes in cells that participate in inflammation, such as activated macrophages and T-helper 17 cells, include a shift towards enhanced glucose uptake, glycolysis and increased activity of the pentose phosphate pathway. Opposing roles in these changes for hypoxia-inducible factor 1α and AMP-activated protein kinase have been proposed. By contrast, anti-inflammatory cells, such as M2 macrophages, regulatory T cells and quiescent memory T cells, have lower glycolytic rates and higher levels of oxidative metabolism. Some anti-inflammatory agents might act by inducing, through activation of AMP-activated protein kinase, a state akin to pseudo-starvation. Altered metabolism may thus participate in the signal-directed programs that promote or inhibit inflammation.
Macrophages and dendritic cells may play a role in chronicity of atopic dermatitis (AD); however, so far only limited data are documented on the distribution of these cells in the skin during cutaneous inflammation.
To gain better insight into the presence and distribution of macrophage and dendritic cell (sub)populations in acutely and chronically inflamed skin of AD patients.
Chronic inflammatory reactions were studied in lesional AD skin biopsies; the atopy patch test was used as a model for the initiation of AD lesions, representing acute inflammation. To determine the number and phenotype of different dermal macrophage and dendritic cell populations immunohistochemistry and digital imaging were used.
There was an increase in macrophage numbers in acutely and chronically inflamed AD skin, whereas absolute dendritic cell numbers were unchanged, compared with non-lesional AD skin. Furthermore, phenotypically heterogeneous and overlapping macrophage and dendritic cell populations were present in inflamed AD skin. The classic macrophage marker CD68 and prototypic dendritic cell marker CD1a could bind to the same cell subpopulation in the dermis of inflamed AD skin. Mannose receptors were expressed mainly by macrophages in inflamed AD skin.
In this study we observed changes in macrophage number and phenotype during cutaneous inflammation in AD. Dendritic cell numbers did not change; however, phenotypically dendritic cell and macrophage subpopulations showed increasing overlap during inflammation in AD skin. We show for the first time that within tissue-specific macrophage populations further subpopulations are present, and that monocyte-derived cells may express markers for both dendritic cells and macrophages. Our results point to the existence of a heterogeneous pool of macrophage/dendritic cell-like cells, from which subpopulations of dermal macrophages and dendritic cells arise.
Optimization of supercritical CO2 extraction process and component analysis of extract from Stellariae Radix
- Le SONG