IL-17 is the defining cytokine of the Th17, Tc17, and γδ T cell populations that plays a critical role in mediating inflammation and autoimmunity. Psoriasis vulgaris is an inflammatory skin disease ...mediated by Th1 and Th17 cytokines with relevant contributions of IFN-γ, TNF-α, and IL-17. Despite the pivotal role IL-17 plays in psoriasis, and in contrast to the other key mediators involved in the psoriasis cytokine cascade that are capable of inducing broad effects on keratinocytes, IL-17 was demonstrated to regulate the expression of a limited number of genes in monolayer keratinocytes cultured in vitro.
Given the clinical efficacy of anti-IL-17 agents is associated with an impressive reduction in a large set of inflammatory genes, we sought a full-thickness skin model that more closely resemble in vivo epidermal architecture. Using a reconstructed human epidermis (RHE), IL-17 was able to upregulate 419 gene probes and downregulate 216 gene probes. As possible explanation for the increased gene induction in the RHE model is that C/CAAT-enhancer-binding proteins (C/EBP) -β, the transcription factor regulating IL-17-responsive genes, is expressed preferentially in differentiated keratinocytes.
The genes identified in IL-17-treated RHE are likely relevant to the IL-17 effects in psoriasis, since ixekizumab (anti-IL-17A agent) strongly suppressed the "RHE" genes in psoriasis patients treated in vivo with this IL-17 antagonist.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Streets are public spaces where people pass through in going from one place to another. As such, streets are not supposed to be dwelling places. However, rapid urbanization has ushered in problems on ...housing, livelihood, and basic social facilities and services, giving rise to informal settlements and street living in cities. In Cebu City (a highly urbanized city in Central Philippines), displacement from urban slums as well as, lack of livelihood options have pushed some people to dwell on the streets and sidewalks in sites most visited by foreign and local tourists. Through street ethnography, this research uncovers how street dwellers in a heritage site in downtown Cebu City came to live and make a living here. The findings point to the fact that street dwellers have socially constructed and purposely transformed heritage spaces into places where they do their daily domestic routines as well as livelihood activities, in order to survive. This article posits that placemaking by these street dwellers in this heritage site is a process from entering and integrating into the place, appropriating specific spaces into places with meanings for them, building and maintaining social networks, contesting notions of the place, and developing a street culture over time.
•Red thyme oil vapours showed a MIC of 50 µL/L against Penicillium spp.•RTO vapours controlled fungal decay on oranges during cold storage.•Polypropylene was the appropriate packaging film for RTO ...application.•p-Cymene was the main compound in vapour phase.•Main quality and sensory parameters were not affected by RTO treatment.
This work has been aimed at studying the effect of red thyme oil (RTO, Thymus vulgaris L.) on the shelf-life and Penicillium decay of oranges during cold storage. RTO vapours significantly reduced (P ≤ 0.05) the percentage of infected wounds, the external growth area and the production of spores in inoculated orange fruit stored for 12 days at 7 °C in a polypropylene film selected for its appropriate permeability. Among the RTO compounds, p-cymene and thymol were the most abundant in packed boxes at the end of cold storage. The RTO vapours did not affect the main quality parameters of the oranges, or the taste and odour of the juice. The results have shown that an active packaging, using RTO vapours, could be employed, by the citrus industry, to extend the shelf-life of oranges for fresh market use and juice processing.
Polysaccharide-based hydrogels are achieving remarkable performances in chronic wounds treatment. In this work, a carboxymethyl cellulose-based hydrogel film was developed to support skin repair. The ...hydrogel was loaded with berberine, a polyphenolic molecule endowing antioxidant and cytoprotective features. The film was physico-chemically characterized and in vitro tested on keratinocytes and fibroblasts subjected to oxidative stress. The biocomposite showed high thermal stability (onset decomposition temperature 245 °C) and significant fluid uptake performances, both in free conditions (up to 6510%) and under external pressure (up to 3400%). Moreover, it was able to control oxidative stress and inflammation markers involved in wound chronicity. Keratinocytes hyperproliferation, features that normally hamper injury restoration, was reduced of 25%. Our results showed that the combination of berberine and hydrogel provides a synergic improvement of the material properties. The biocomposite represents a promising candidate for dermatological applications against oxidative stress at the chronic wound site, promoting the healing process.
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Background and Purpose
Catechol‐O‐methyltransferase (COMT) is an important target in the levodopa treatment of Parkinson's disease; however, the inhibitors available have problems, and not all ...patients benefit from their efficacy. Opicapone was developed to overcome those limitations. In this study, opicapone's pharmacological properties were evaluated as well as its potential cytotoxic effects.
Experimental Approach
The pharmacodynamic effects of opicapone were explored by evaluating rat COMT activity and levodopa pharmacokinetics, in the periphery through microdialysis and in whole brain. The potential cytotoxicity risk of opicapone was explored in human hepatocytes by assessing cellular ATP content and mitochondrial membrane potential.
Key Results
Opicapone inhibited rat peripheral COMT with ED50 values below 1.4 mg⋅kg−1 up to 6 h post‐administration. The effect was sustained over the first 8 h and by 24 h COMT had not returned to control values. A single administration of opicapone resulted in increased and sustained plasma levodopa levels with a concomitant reduction in 3‐O‐methyldopa from 2 h up to 24 h post‐administration, while tolcapone produced significant effects only at 2 h post‐administration. The effects of opicapone on brain catecholamines after levodopa administration were sustained up to 24 h post‐administration. Opicapone was also the least potent compound in decreasing both the mitochondrial membrane potential and the ATP content in human primary hepatocytes after a 24 h incubation period.
Conclusions and Implications
Opicapone has a prolonged inhibitory effect on peripheral COMT, which extends the bioavailability of levodopa, without inducing toxicity. Thus, it exhibits some improved properties compared to the currently available COMT inhibitors.
There is a controversy surrounding the existence of palmoplantar pustulosis (PPP) and palmoplantar pustular psoriasis (PPPP) as separate clinical entities or as variants of the same clinical entity. ...We used gene expression microarray to compare gene expression in PPP and PPPP.
Skin biopsies from subjects with PPP (3), PPPP (6), psoriasis vulgaris (10) and acral skin from normal subjects (7) were analyzed using gene expression microarray. Principal component analysis showed that PPP and PPPP were different from psoriasis vulgaris and normal acral skin. However gene expression of PPP and PPPP clustered together and could not be used to differentiate PPP from PPPP. Gene-wise comparison between PPP and PPPP found no gene to be differentially expressed at a false discovery rate lower than 0.05. Surprisingly we found a higher expression of several genes involved in neural pathways (e.g. GPRIN and ADAM23) in PPP/PPPP as compared to psoriasis vulgaris and normal acral skin. Immunohistochemistry confirmed those findings and showed a keratinocyte localization for those proteins.
PPP and PPPP could not be differentiated using gene expression microarray suggesting that they are not distinct clinical entities. Increased expression of GPRIN1, and ADAM23 in keratinocytes suggests that these proteins could be new therapeutic targets for PPP/PPPP.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Alopecia areata (AA) is a common inflammatory disease targeting the anagen‐stage hair follicle. Different cytokines have been implicated in the disease profile, but their pathogenic role is not yet ...fully determined. We studied biopsies of pretreatment lesional and non‐lesional (NL) scalp and post‐treatment (intra‐lesional steroid injection) lesional scalp of 6 patchy patients with AA using immunohistochemistry and gene expression analysis. Immunohistochemistry showed increases in CD3+, CD8+ T cells, CD11c+ dendritic cells and CD1a+ Langerhans cells within and around hair follicles of pretreatment lesional scalp, which decreased upon treatment. qRT‐PCR showed in pretreatment lesional scalp (compared to NL) significant increases (P < 0.05) in expression of inflammatory markers (IL‐2, IL‐2RA, JAK3, IL‐15), Th1 (CXCL10 and CXCL9), Th2 (IL‐13, CCL17 and CCL18), IL‐12/IL‐23p40 and IL‐32. Among these, we observed significant downregulation with treatment in IL‐12/IL‐23p40, CCL18 and IL‐32. We also observed significant downregulation of several hair keratins in lesional scalp, with significant upregulation of KRT35, KRT75 and KRT86 in post‐treatment lesional scalp. This study shows concurrent activation of Th1 and Th2 immune axes as well as IL‐23 and IL‐32 cytokine pathways in lesional AA scalp and defined a series of response biomarkers to corticosteroid injection. Clinical trials with selective antagonists coupled with cytokine‐pathway biomarkers will be necessary to further dissect pathogenic immunity.
Background Topical glucocorticosteroids are considered an efficient treatment option for atopic dermatitis (AD), but a global assessment of glucocorticosteroid responses on key disease circuits upon ...weeks to months of treatment is currently lacking. Objective We sought to assess short (4 weeks) and long-term (16 weeks) application of topical glucocorticosteroids on AD skin and define response biomarkers. Methods The effects of triamcinolone acetonide cream 0.025% were assessed based on gene expression and immunohistochemistry studies at baseline, 4 weeks, and 16 weeks in biopsy specimens from 15 patients with moderate-to-severe AD. Results At 16 weeks, only 3 patients were clinical responders (by using SCORAD50 criteria), but 6 patients qualified as responders based on histologic criteria. Baseline characteristics indicated more severe disease in nonresponders. While 3 of 15 patients experienced only transient benefit after 4 weeks, others showed progressive improvements toward 16 weeks. Topical glucocorticosteroid use in patients with AD resulted in improvements of the AD genomic signature of 25.6% at 4 weeks and 71.8% at 16 weeks, respectively, and even 123.9% in the histologic responder group. Cytokines (IL-12p40, IL-13, IL-22, CCL17, CCL18, peptidase inhibitor 3 PI3/elafin, and S100As) showed consistent decreases from baseline toward 16 weeks with corresponding improvements in epidermal disease hallmarks (keratin 16 and loricrin) in lesional skin from responders ( P < .05). Nonresponders largely showed lesser/nonsignificant reductions in key inflammatory and barrier markers (keratin 16, IL-13, IL-22, CCL17, CCL18, PI3/elafin, S100As, and loricrin). The combination of IL-21 and IFN-γ baseline expression closely predicted individual clinical glucocorticosteroid responses at 16 weeks of treatment. Conclusion Our study indicates that even low-potency glucocorticosteroids can broadly affect immune and barrier responses in patients with moderate-to-severe AD, associating higher baseline severity with increased steroid resistance in patients with AD.
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