Atopic dermatitis (AD) is a multifactorial, heterogenous disease that arises as a result of the interaction between both environmental and genetic factors. Changes in at least three groups of genes encoding structural proteins, epidermal proteases, and protease inhibitors predispose to a defective epidermal barrier and increase the risk of developing AD. Loss-of-function mutations found within the FLG gene encoding the structural protein, filaggrin, represent the most significant genetic factor predisposing to AD identified to date. Enhanced protease activity and decreased synthesis of the lipid lamellae lead to exacerbated breakdown of the epidermal barrier. Environmental factors, including the use of soap and detergents, exacerbate epidermal barrier breakdown, attributed to the elevation of stratum corneum pH. A sustained increase in pH enhances the activity of degradatory proteases and decreases the activity of the lipid synthesis enzymes. The strong association between both genetic barrier defects and environmental insults to the barrier with AD suggests that epidermal barrier dysfunction is a primary event in the development of this disease. Our understanding of gene-environment interactions should lead to a better use of some topical products, avoidance of others, and the increased use and development of products that can repair the skin barrier.
Alpha-melanocyte stimulating hormone (alpha-MSH) has pigmentary, anti-inflammatory, antipyretic, and general immunomodulatory roles. It can oppose several cytokines including tumor necrosis factor-alpha in a number of tissues, including skin. We have previously shown that alpha-MSH can inhibit tumor necrosis factor-alpha stimulated intercellular adhesion molecule 1 upregulation and nuclear factor kappaB (NFkappaB) transcription factor activation in melanocyte and melanoma cells. It is thought, however, that this MSH biology may also extend to other cells of the skin and in this study we extend our work to keratinocytes. We have investigated in detail the ability of three alpha-MSH peptides to inhibit tumor necrosis factor alpha stimulated NFkappaB activation in nonpigmentary HaCaT keratinocytes (alpha-MSH, L-Lys-L-Pro-L-Val, and L-Lys-L-Pro-D-Val) and two adrenocorticotropic hormone (ACTH) peptides (1-17 and 1-39), reported to be present in skin tissue. NFkappaB/p65 activation was analyzed by electrophoretic mobility shift assay and immunofluorescent microscopy. alpha-MSH, L-Lys-L-Pro-L-Val, and L-Lys-L-Pro-D-Val all significantly inhibited tumor necrosis factor alpha stimulated NFkappaB activation, whereas ACTH 1-17 and 1-39 did not, in the HaCaT keratinocytes. MSH peptides and ACTH 1-39 were effective, however, at inhibiting NFkappaB activation in normal human keratinocytes. Immunolabeling of inhibitor kappaBalpha of NFkappaB (IkappaBalpha) revealed an abnormal localization to the nucleus of HaCaT cells, which was unaffected by MSH/ACTH peptides. In contrast, normal human keratinocytes showed a normal IkappaBalpha distribution that responded to MSH/ACTH with nuclear translocation. Our data support previous work on the role of MSH/ACTH peptides as immunomodulatory/anti-inflammatory regulators, and extend this work to keratinocytes identifying a novel IkappaBalpha mechanism and extends findings to ACTH peptides, identifying an abnormal IkappaBalpha mechanism in the immortal HaCaT versus normal keratinocyte.
TranCell delivery of autologous cells is a promising treatment for chronic diabetic foot ulcers with no side-effects and no recurrence in the healed ulcers.
Background:
Delayed‐release mesalazine is traditionally taken as three divided doses. However, it is well‐recognized that dosing frequency has a significant impact on compliance and that once daily dosing is preferable.
Methods:
We measured serum, urinary, faecal and rectal tissue concentrations of 5‐aminosalicylic acid and N‐acetyl 5‐aminosalicylic acid in 24 healthy volunteers following dosing with delayed‐release mesalazine, 1.2 g or 2.4 g daily, given as either a single daily dose at 08:00 hours or in three divided doses at 08:00, 13:00 and 18:00 hours.
Results:
Urinary and faecal excretion and rectal tissue concentrations of 5‐aminosalicylic acid and N‐acetyl 5‐aminosalicylic acid were similar following single or divided daily dosing, at both doses studied. Peak serum concentrations were found at 06:00–09:00 following divided dosing and at 17:00–20:00 following once daily dosing. However, peak and trough serum levels and serum area under curve values (AUC) were similar with both regimens and at both doses.
Conclusions:
Urinary, faecal and rectal tissue concentrations are similar following single or divided daily dosing. Minor differences in serum levels were apparent but maximum, minimum and AUC values were similar. Clinical trials should examine the efficacy and toxicity of once daily dosing in patients with ulcerative colitis.
Repeated regular applications of the patient's keratinocytes, delivered on the carrier dressing, initiated wound healing in ulcers resistant to conventional therapy, with 18 out of 21 ulcers responding. The healing observed did not appear attributable to patient recruitment or the cell-free carrier dressing but to the delivery of the cultured cells.
The REGULATE-PCI trial and this analysis were funded by Regado Biosciences Inc. The sponsor of the trial, Regado Biosciences, participated in the design of the trial and the analysis plan for biospecimens collected in the trial, in collaboration with the investigators of the trial. The sponsor selected the core laboratories for the analysis, but did not perform the analyses or analyze the data. The corresponding author drafted this manuscript and made all revisions on the basis of input from the coauthors, including those employed by the sponsor. The sponsor had no role in the decision to submit the manuscript for publication. Disclosure of potential conflict of interest: T. J. Povsic has received a grant from Regado Biosciences. M. G. Lawrence has received consulting and/or advisory board fees from Baxter Healthcare, has received fees for participation in review activities from Regado Biosciences/Faculty Connections, and has consultant arrangements with Merck/Faculty Connections. A. M. Lincoff has received a grant and travel support from Regado Biosciences; has received grants from Roche/Genentech,
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