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The article discusses UR-60427, a novel H4 receptor-inverse agonist investigated at Palau Pharma and found to show good efficacy in the rat asthma model. It details that the effects of histamine as full agonist and thioperamide as inverse agonist were compared. The article concludes that the rat asthma model showed increased airway hyperactivity indicating pulmonary resistance in sensitised animals that was reduced by all doses of UR-60427.

The clinical relevance of avian metapneumovirus (aMPV) is growing in the poultry sector, especially in broiler farming, where no vaccination is administered in Italy. Given the naïve status of the birds, a serological survey was conducted in a densely populated area of Northern Italy, to evaluate aMPV circulation. Seven farms were selected and sampled in summer/fall, then sampling was repeated in the following season (winter/spring) to assess a possible seasonal effect. In each farm, fifteen birds were blood sampled towards the end of the cycle and sera were analyzed with an ELISA test. Clinical signs were reported in 5 out of 7 farms, although all farms were positive at both sampling points, except for one, which was negative at the first sampling. The seroprevalence within farm ranged from 26.6% to 100%, and antibody titres appear to increase with age. No seasonality effect was evidenced, whereas a farm effect was more distinct. aMPV circulation appears wide in Northern Italian farms, with different clinical outcomes that could be modulated by intrinsic characteristics of the farms. In absence of vaccination, serological monitoring can be a useful tool for viral entrance monitoring, although sampling timing should be evaluated in order to spot seroconversion after late infections., Competing Interests: DISCLOSURES The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aldosterone, the main mineralocorticoid hormone in humans, plays a pivotal role in the control of water and salt reabsorption via activation of the mineralocorticoid receptor (MR). Alterations in MR signaling pathway lead to renal dysfunction, including chronic kidney disease and renal fibrosis, that can be prevented or treated with mineralocorticoid receptor antagonists (MRAs). Here, we used RNA-Sequencing to analyze effects of two MRAs, spironolactone and finerenone, on the aldosterone-induced transcriptome of a human renal cell line stably expressing the MR. Bioinformatics analysis of the data set reveals the identity of hundreds of genes induced or repressed by aldosterone. Their regulation is modulated in a time-dependent manner and, for the induced genes, depends on the aldosterone-driven direct binding of the MR onto its genomic targets that we have previously characterized. Although both MRAs block aldosterone-induced as well as aldosterone-repressed genes qualitatively similarly, finerenone has a quantitatively more efficient antagonism on some aldosterone-induced genes. Our data provide the first complete transcriptome for aldosterone on a human renal cell line and identifies pro-inflammatory markers (IL6, IL11, CCL7, and CXCL8) as aldosterone-repressed genes., (© 2021 Federation of American Societies for Experimental Biology.)

Screening of cellular activity for inhibitors of histone lysine modifiers is most frequently performed indirectly by analyzing changes in the total levels of histone marks targeted by lysine methylases/demethylases. However, inhibition of histone lysine modifiers often leads to local rather than total changes in histone marks. Also, because histone modifications can be modulated by more than one cellular enzyme, it is not always clear whether changes in histone marks are a direct or indirect consequence of the inhibitor treatment applied. Direct assessment of target occupation can provide a useful tool to quantify the fraction of an epigenetic modifier that is bound to a pharmacological inhibitor (target engagement). Here, we developed and used a novel chemoprobe-based immunoassay to quantify target engagement in cells. Quantification of the fraction of free KDM1A was made possible, in an immune-based assay, by coupling a biotinylated chemoprobe to a warhead capable of selectively and irreversibly binding to the free active form of KDM1A. The results obtained confirmed that this approach is able to determine the degree of target engagement in a dose-dependent manner. Furthermore, the assay can be also used on tissue extracts to analyze the in vivo pharmacokinetics and pharmacodynamics relationship of KDM1A inhibitors, as has been exemplified with ORY-1001 (iadademstat), a potent and irreversible inhibitor of KDM1A. The principle of this assay may be applied to other targets, and the KDM1A probe may be employed in chemoproteomic analyses., (© 2019 Mascaró et al.)

Endogenous and synthetic glucocorticoids (GCs) regulate epidermal development and combat skin inflammatory diseases. GC actions can be mediated through the GC receptor (GR) and/or the mineralocorticoid receptor (MR), highly homologous ligand-activated transcription factors. While the role of GR as a potent anti-inflammatory mediator is well known, that of MR is not as clear, nor is whether these receptors cooperate or antagonize each other in the epidermis. To address this, we generated mice with epidermal-specific loss of both receptors (double knockout, DKO), and analyzed the phenotypical and functional consequences relative to single KOs or controls (CO). At birth, DKO epidermis displayed a phenotype of defective differentiation and inflammation, which was more severe than in either single KO, featuring neutrophil-containing infiltrates, and gene dysregulation characteristic of human psoriatic lesions. This phenotype resolved spontaneously. However, in adulthood, single or combined loss of GC receptors increased susceptibility to inflammation and hyperproliferation triggered by phorbol ester which, different to CO, was not effectively counteracted by GC treatment. Also, DKOs were more susceptible to imiquimod-induced psoriasis than CO showing severe defective epidermal differentiation and microabcesses while single KOs showed an intermediate response. Immortalized DKO keratinocytes featured increased proliferation kinetics and reduced cell size, a unique phenotype relative to single KO cells. The lack of GR and MR in keratinocytes, individual or combined, caused constitutive increases in p38 and ERK activities, which were partially reversed upon reinsertion of receptors into DKO cells. DKO keratinocytes also displayed significant increases in AP-1 and NF-κB transcriptional activities, which were partially rescued by ERK and p38 inhibition, respectively. Reinsertion of GR and MR in DKO keratinocytes resulted in physical and cooperative functional interactions that restored the transcriptional response to GCs. In conclusion, our data have revealed that epidermal GR and MR act cooperatively to regulate epidermal development and counteract skin inflammation.

Background: The measurement of weight loss after bariatric surgery is under constant review in order to obtain the ideal standard for reporting weight loss. Several formulas have been proposed for this purpose. Our goal is to analyse weight loss after sleeve gastrectomy, with or without antrum preservation through different measurement formulas., Methods: A prospective randomised study of 60 patients (30 patients with initial section at 3 cm from pylorus and 30 patients at 8 cm from the pylorus). We calculate the following variables at 3, 6 and 12 months from surgery: BMI, excess weight loss (%EWL), percentage of excess of BMI loss (%PEBMIL), expected BMI, % PEBMIL corrected by EBMI and percentage of total weight loss (%TWL)., Results: Weight evolution is similar in both groups, reaching a mean BMI of 33.62 ± 4.35 and 34.48 ± 4.23 kg/m 2 respectively 12 months after surgery, closer to expected BMI. TWL follows the same trend, with losses exceeding 30%, although 3 cm group is above the tables of percentiles made with our series. Regarding PEBMIL, the 3 cm group reaches 67.8% classified as excellent, while 8 cm group reaches 62.8% classified as a good result. EWL situates the best results for 3 cm group., Conclusions: Group 3 cm obtained a lower percentage of suboptimal results using EWL. %TWL places the 3 cm group in higher percentile than 8 cm group. Through EBMI, both groups are equally effective. It is necessary to have standardised dynamic tables for each surgical technique, becoming essential elements to measure weight loss after surgery.

Psoriasis vulgaris is a chronic inflammatory skin disease affecting millions of people. Its pathophysiology is complex and involves a skin compartment with epidermal and immune cells which produce cytokines, e.g. belonging to the IL-23-Th17-cell axis. Glucocorticoids (GCs) are the most common therapeutics used in cutaneous inflammatory disorders and GC-induced leucine zipper (GILZ) has emerged as a mediator of GCs due to its anti-inflammatory actions, theoretically lacking GC side-effects. We evaluated whether GILZ may provide a better therapeutic index in comparison to GCs during the onset and progression of psoriasis by generating and characterizing a mouse model with generalized overexpression of this protein (GILZ-Tg mice) and the imiquimod (IMQ) psoriasis model. Unexpectedly, in GILZ-Tg mice, the severity of IMQ-induced psoriasis-like skin lesions as well as induction of cytokines commonly up-regulated in human psoriasis (Il-17, Il-22, Il-23, Il-6, S100a8/a9, and Stat3) was significantly more pronounced relative to GILZ-Wt mice. The increased susceptibility to IMQ-induced psoriasis of GILZ-Tg mice was significantly associated with skin-specific over-activation of TGF-β1-mediated signaling via SMAD2/3. Our findings demonstrate that GILZ may behave as pro-inflammatory protein in certain tissues and that, similar to prolonged GC therapy, GILZ as an alternative treatment for psoriasis may also have adverse effects.

Glucocorticoids (GCs) regulate skin homeostasis and combat cutaneous inflammatory diseases; however, adverse effects of chronic GC treatments limit their therapeutic use. GCs bind and activate the GC receptor and the mineralocorticoid receptor (MR), transcription factors that recognize identical hormone responsive elements. Whether epidermal MR mediates beneficial or deleterious GC effects is of great interest for improving GC-based skin therapies. MR epidermal knockout mice exhibited increased keratinocyte proliferation and differentiation and showed resistance to GC-induced epidermal thinning. However, crucially, loss of epidermal MR rendered mice more sensitive to inflammatory stimuli and skin damage. MR epidermal knockout mice showed increased susceptibility to phorbol 12-myristate 13-acetate-induced inflammation with higher cytokine induction. Likewise, cultured MR epidermal knockout keratinocytes had increased phorbol 12-myristate 13-acetate-induced NF-κB activation, highlighting an anti-inflammatory function for MR. GC-induced transcription was reduced in MR epidermal knockout keratinocytes, at least partially due to decreased recruitment of GC receptor to hormone responsive element-containing sequences. Our results support a role for epidermal MR in adult skin homeostasis and demonstrate nonredundant roles for MR and GC receptor in mediating GC actions., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Determining the best indicator to report weight loss takes on special relevance following bariatric surgery. Our objective is to apply a method proposed by Baltasar et al. to express weight loss results following bariatric surgery., Materials and Methods: Anthropometric data were collected from 265 patients who had undergone Sleeve gastrectomy (SG, n = 172) and Roux-en-Y gastric bypass (RYGBP, n = 93) with a 2-year follow-up period. Initial BMI was calculated as well as BMI 2 years after, percentage of excess BMI loss (PEBMIL), expected BMI (EBMI), and corrected PEBMIL., Results: In SG group, average BMI 2 years after surgery fell within a 95 % CI of expected BMI, with an average BMI of 31.58 ± 4.05 kg/m 2 in 35-45 BMI group, an average BMI of 33.62 ± 4.96 kg/m 2 in 45-55 BMI group, and an average BMI of 37.40 ± 5.93 kg/m 2 in 55-65 BMI group. In RYGBP group, average BMI 2 years after the surgery was below than average expected BMI (28.76 ± 3.20 kg/m 2 in 35-45 BMI group and 29.71 ± 3.30 kg/m 2 in 45-55 BMI group). Results are considered excellent for the group with an initial BMI of above 45 kg/m 2 ., Conclusions: EBMI is a good weight loss indicator, mainly when 95 % CI is taken into account. EBMI is consistent with the results obtained 2 years after surgery in our patients who underwent SG and RYGBP. Corrected PEBMIL is a good indicator for expressing the percentage of BMI loss and offers more realistic values than conventional formula with a cut-off point of 25 points.