JAK3 as an emerging target for topical treatment of inflammatory skin diseases

The recent interest and elucidation of the JAK/STAT signaling pathway created new targets for the treatment of inflammatory skin diseases (ISDs). JAK inhibitors in oral and topical formulations have shown beneficial results in psoriasis and alopecia areata. Patients suffering from other ISDs might also benefit from JAK inhibition. Given the development of specific JAK inhibitors, the expression patterns of JAKs in different ISDs needs to be clarified. We aimed to analyze the expression of JAK/STAT family members in a set of prevalent ISDs: psoriasis, lichen planus (LP), cutaneous lupus erythematosus (CLE), atopic dermatitis (AD), pyoderma gangrenosum (PG) and alopecia areata (AA) versus healthy controls for (p) JAK1, (p) JAK2, (p) JAK3, (p) TYK2, pSTAT1, pSTAT2 and pSTAT3. The epidermis carried in all ISDs, except for CLE, a strong JAK3 signature. The dermal infiltrate showed a more diverse expression pattern. JAK1, JAK2 and JAK3 were significantly overexpressed in PG and AD suggesting the need for pan-JAK inhibitors. In contrast, psoriasis and LP showed only JAK1 and JAK3 upregulation, while AA and CLE were characterized by a single dermal JAK signal (pJAK3 and pJAK1, respectively). This indicates that the latter diseases may benefit from more targeted JAK inhibitors. Our in vitro keratinocyte psoriasis model displayed reversal of the psoriatic JAK profile following tofacitinib treatment. This direct interaction with keratinocytes may decrease the need for deep skin penetration of topical JAK inhibitors in order to exert its effects on dermal immune cells. In conclusion, these results point to the important contribution of the JAK/STAT pathway in several ISDs. Considering the epidermal JAK3 expression levels, great interest should go to the investigation of topical JAK3 inhibitors as therapeutic option of ISDs

Effectiveness of interventions using self-monitoring to reduce sedentary behavior in adults : a systematic review and meta-analysis

Background: Sedentary behavior occurs largely subconsciously, and thus specific behavior change techniques are needed to increase conscious awareness of sedentary behavior. Chief amongst these behavior change techniques is self-monitoring of sedentary behavior. The aim of this systematic review and meta-analysis was to evaluate the short-term effectiveness of existing interventions using self-monitoring to reduce sedentary behavior in adults. Methods: Four electronic databases (PubMed, Embase, Web of Science, and The Cochrane Library) and grey literature (Google Scholar and the International Clinical Trials Registry Platform) were searched to identify appropriate intervention studies. Only (cluster-)randomized controlled trials that 1) assessed the short-term effectiveness of an intervention aimed at the reduction of sedentary behavior, 2) used self-monitoring as a behavior change technique, and 3) were conducted in a sample of adults with an average age >= 18 years, were eligible for inclusion. Relevant data were extracted, and Hedge's g was used as the measure of effect sizes. Random effects models were performed to conduct the meta-analysis. Results: Nineteen intervention studies with a total of 2800 participants met the inclusion criteria. Results of the meta-analyses showed that interventions using self-monitoring significantly reduced total sedentary time (Hedges g = 0,32; 95% CI = 0,14 - 0,50; p = 0,001) and occupational sedentary time (Hedge's g = 0,56; 95% CI = 0,07 - 0,90; p = 0,02) on the short term. Subgroup analyses showed that significant intervention effects were only found if objective self-monitoring tools were used (g = 0,40; 95% CI = 0,19 - 0,60; p < 0,001), and if the intervention only targeted sedentary behavior (g = 0,45; 95% CI = 0,15-0,75; p = 0,004). No significant intervention effects were found on the number of breaks in sedentary behavior. Conclusions: Despite the small sample sizes, and the large heterogeneity, results of the current meta-analysis suggested that interventions using self-monitoring as a behavior change technique have the potential to reduce sedentary behavior in adults. If future - preferably large-scale studies - can prove that the reductions in sedentary behavior are attributable to self-monitoring and can confirm the sustainability of this behavior change, multi-level interventions including self-monitoring may impact public health by reducing sedentary behavior

The association of healthy lifestyle behaviors with mental health indicators among adolescents of different family affluence in Belgium

Background Healthy lifestyles may contribute to better mental health, which is particularly important in adolescence, an age at which half of all mental health problems first occur. This association may be even more relevant in adolescents of low family affluence, who show more mental health problems, as well as more unhealthy lifestyles. This study investigated healthy lifestyle behaviors, namely sufficient sleep and physical activity, daily breakfast intake, low levels of alcohol use or smoking, in relation to mental health and symptoms of mental health problems (feelings of depression, anxiety, stress and self-esteem) among adolescents from different family affluence. Furthermore, the moderating role of family affluence was examined in those relations. Methods Adolescents aged 12-18y were recruited via a random sample of schools in Flanders, Belgium. A total of 1037 adolescents participated (mean age = 15.2, 49.8% female). Independent samples t-tests, Mann Whitney U-tests and chi(2)-tests determined the differences in healthy lifestyle behaviors and mental health indicators between adolescents of low-medium and high family affluence. Regression analyses assessed the association between healthy lifestyles and mental health outcomes and the moderating role of family affluence. Results All healthy lifestyle behaviors were associated with at least one mental health outcome, with the exception of alcohol consumption. Adolescents from low-medium family affluence had lower levels of physical activity, less often took breakfast, had lower levels of alcohol consumption and reported lower self-esteem than adolescents from high family affluence. The results showed no moderating effect of family affluence for the association between healthy lifestyle and mental health. Conclusion These findings support the value of integrating healthy lifestyle behaviors in interventions for mental health promotion, for both youth of low-medium and high family affluence

The increasing complexity of glucocorticoid receptor signaling and regulation

Glucocorticoids, although being one of the eldest drugs in the clinic and despite their widespread usage for the treatment of inflammatory and immune disorders and cancer, have not yet come of age when it comes to a full understanding of how they work. The majority of the biological actions of glucocorticoid hormones are explained by a wide diversity in the cellular action mechanism of the hormone-activated Glucocorticoid Receptor (GR). All molecular mechanisms described in the current overview are not only complex, exhibiting an astonishing degree of gene- and tissue-specificity, but on top of this they are also non-exclusive. This layering of mechanisms makes it extremely difficult for researchers to extract the crucial pieces of information that would assist in a rational design of drugs with an improved therapeutic profile, i.e. a satisfying and maintained therapeutic response in the absence of the many incapacitating glucocorticoid-associated side effects, such as diabetes, osteoporosis, muscle wasting, depression etc. In direct correlation with increased glucocorticoid usage as observed in the clinic, the impetus and desire to reveal all of these mechanisms -and most importantly, to try to integrate them in a sensible manner for the sake of finding better alternatives- has never been stronger

Glucocorticoid receptor-mediated transactivation is hampered by Striatin-3, a novel interaction partner of the receptor

The transcriptional activity of the glucocorticoid receptor (GR) is co-determined by its ability to recruit a vast and varying number of cofactors. We here identify Striatin-3 ( STRN3) as a novel interaction partner of GR that interferes with GR's ligand-dependent transactivation capacity. Remarkably, STRN3 selectively affects only GR-dependent transactivation and leaves GR-dependent transrepression mechanisms unhampered. We found that STRN3 down-regulates GR transactivation by an additional recruitment of the catalytic subunit of protein phosphatase 2A (PPP2CA) to GR. We hypothesize the existence of a functional trimeric complex in the nucleus, able to dephosphorylate GR at serine 211, a known marker for GR transactivation in a target gene-dependent manner. The presence of STRN3 appears an absolute prerequisite for PPP2CA to engage in a complex with GR. Herein, the C-terminal domain of GR is essential, reflecting ligand-dependency, yet other receptor parts are also needed to create additional contacts with STRN3

Compound A influences gene regulation of the dexamethasone-activated glucocorticoid receptor by alternative cofactor recruitment

The glucocorticoid receptor (GR) is a transcription factor of which the underlying gene regulatory mechanisms are complex and incompletely understood. The non-steroidal anti-inflammatory Compound A (CpdA), a selective GR modulating compound in various cell models, has been shown to favour GR-mediated gene repression but not GR-mediated gene activation. Shifting balances towards only a particular subset of GR gene regulatory events may be of benefit in the treatment of inflammatory diseases. We present evidence to support that the combination of CpdA with Dexamethasone (DEX), a classic steroidal GR ligand, can shape GR function towards a unique gene regulatory profile in a cell type-dependent manner. The molecular basis hereof is a changed GR phosphorylation status concomitant with a change in the GR cofactor recruitment profile. We subsequently identified and confirmed the orphan nuclear receptor SHP as a coregulator that is specifically enriched at GR when CpdA and DEX are combined. Combining CpdA with DEX not only leads to stronger suppression of pro-inflammatory gene expression, but also enhanced anti-inflammatory GR target gene expression in epithelial cells, making ligand combination strategies in future a potentially attractive alternative manner of skewing and fine-tuning GR effects towards an improved therapeutic benefit

Het kerkhofareaal van de Onze-Lieve-Vrouwekerk te Nieuwpoort (West-Vlaanderen). Eindverslag van een opgraving vanuit wetenschappelijke vraagstelling volgend uit een toevalsvondst

Het archeologisch onderzoek aan de Onze-Lieve-Vrouwekerk in Nieuwpoort is een archeologisch onderzoek met het oog op wetenschappelijke vraagstellingen (cf. het Onroerenderfgoeddecreet van 12 juli 2013, Hoofdstuk 5. Archeologie Afdeling 5). Hiertoe werd overgegaan aangezien de geplande bodemingrepen het te verwachten omvangrijke bodemarchief volledig zouden vernietigen. Bij aanvang van de werken zou al meteen gevolg moeten gegeven worden aan de meldingsplichthet kerkhof was aan deze zijde van de kerk immers tot minstens tijdens de Eerste Wereldoorlog in gebruik. De termijn voorzien voor het onderzoek van toevalsvondsten zou echter veel te ontoereikend zijn om dergelijk onderzoek uit te voeren. Bovendien zou dit nefast zijn voor de planning van de werken. In samenspraak met de bouwheer, de stad Nieuwpoort, en de zakelijkrechthouder, de Kerkfabriek O.L.V.-kerk, werd daarom afgesproken het agentschap Onroerend Erfgoed de mogelijkheid te geven een archeologisch onderzoek met het oog op wetenschappelijke vraagstellingen uit te voeren. Op die manier werd de werkput voor de bouwheer vrijgemaakt van archeologische sporen en resten en zouden de geplande werken niet gehinderd worden door de meldingsplicht voor toevalsvondsten. Gezien de lange geschiedenis van deze parochiekerk met een oorsprong in de 12de eeuw mocht een omvangrijk bodemarchief verwacht worden, opgebouwd door een lange opeenvolging van menselijke begravingen. Het kerkhofpakket was aanwezig vanaf ca. 0,5 m onder het maaiveld en was ca. 1,9 m dik. Onder de kerkhoflagen was de moederbodem aanwezig in de vorm van zandige lagen, afgezet door water. Tijdens de opgraving zijn in totaal 297 begravingen onderzocht en opgegraven

Compound A, a selective glucocorticoid receptor modulator, enhances heat shock protein Hsp70 gene promoter activation

Compound A possesses glucocorticoid receptor (GR)-dependent anti-inflammatory properties. Just like classical GR ligands, Compound A can repress NF-kappa B-mediated gene expression. However, the monomeric Compound A-activated GR is unable to trigger glucocorticoid response element-regulated gene expression. The heat shock response potently activates heat shock factor 1 (HSF1), upregulates Hsp70, a known GR chaperone, and also modulates various aspects of inflammation. We found that the selective GR modulator Compound A and heat shock trigger similar cellular effects in A549 lung epithelial cells. With regard to their anti-inflammatory mechanism, heat shock and Compound A are both able to reduce TNF-stimulated I kappa B alpha degradation and NF-kappa B p65 nuclear translocation. We established an interaction between Compound A-activated GR and Hsp70, but remarkably, although the presence of the Hsp70 chaperone as such appears pivotal for the Compound A-mediated inflammatory gene repression, subsequent novel Hsp70 protein synthesis is uncoupled from an observed CpdA-induced Hsp70 mRNA upregulation and hence obsolete in mediating CpdA's anti-inflammatory effect. The lack of a Compound A-induced increase in Hsp70 protein levels in A549 cells is not mediated by a rapid proteasomal degradation of Hsp70 or by a Compound A-induced general block on translation. Similar to heat shock, Compound A can upregulate transcription of Hsp70 genes in various cell lines and BALB/c mice. Interestingly, whereas Compound A-dependent Hsp70 promoter activation is GR-dependent but HSF1-independent, heat shock-induced Hsp70 expression alternatively occurs in a GR-independent and HSF1-dependent manner in A549 lung epithelial cells