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Background Psoriasis is a chronic inflammatory skin disease of unknown aetiology, and an active form of vitamin D3 (1α,25-dihydroxyvitamin D3) and its analogues (VD3As) are widely used topical reagents for psoriasis treatment. Besides their well-known calcium homeostasis functions, VD3As have been shown to have various immune-modulating effects including the induction of thymic stromal lymphopoietin (TSLP), a master cytokine for inducing Th2 inflammation, in mouse models, but not yet in human psoriasis. VD3As also have been shown to induce cathelicidin, an antimicrobial peptide and strong inducer of innate immunity. Cathelicidin is overexpressed in psoriatic skin lesions; however, its role in this disease seems as yet inconclusive. Objectives To clarify whether topical VD3As induce TSLP and cathelicidin, and to examine the modulation of expression patterns of related cytokines in human psoriatic lesions. Methods Skin biopsy samples from psoriatic lesions with or without VD3A treatment were subjected to immunohistochemical staining and quantitative reverse transcription-polymerase chain reaction analyses to measure the expression levels of various cytokines. Results Significantly higher levels of TSLP, thymus and activation-related chemokine and CCR4 expression were observed in VD3A+ skin samples than in VD3A− samples. In contrast, significantly lower levels of interleukin (IL)-12/23 p40, IL-1α, IL-1β and tumour necrosis factor (TNF)-α expression were observed in the VD3A+ samples than in the VD3A− samples. Expression of cathelicidin was elevated in VD3A+ samples. Conclusions Topical VD3As induce TSLP and cathelicidin in psoriatic lesions, resulting in suppression of IL-12/23 p40, IL-1α, IL-1β and TNF-α, thereby ameliorating psoriatic plaques. [ABSTRACT FROM AUTHOR]

The aims of the present study were to investigate the efficacy of measuring bovine urinary zearalenone (ZEN) concentrations by using a commercially available ELISA method in cattle kept under different feeding conditions to monitor the natural contamination of feeds at the farm level, and to investigate the effects of supplementation of a mycotoxin adsorbent (MA) product in the feed based on urinary ZEN concentration. First, Japanese Black cattle herds kept for breeding (4 herds) and fattening (4 herds) purposes were provided with similar feeding conditions. Then, urinary samples from 5 cows in each herd were collected and analyzed. Second, dairy cows from 1 herd fed with total mixed rations (TMR) were selected. After thorough mixing of the MA (40 g/d) with TMR, the supplemented TMR was fed according to the following schedule: with MA for 2 wk, without MA for 3 wk; then with MA for 2 wk and without MA for 6 wk. Urine samples were collected from cows (n = 6 to 7) and examined before and after each interval. Zearalenone concentrations were measured by the ELISA and liquid chromatography-tandem mass spectrometry methods. The concentration of ZEN and its metabolites was expressed after creatinine (Crea) correction [ZEN or metabolites (pg/mL)/Crea (mg/dL); pg/mg of Crea]. In the first experiment, the urinary concentrations of ZEN and its metabolites were variable in all herds, and significant differences were observed between herds. In 1 fattening herd, in particular, urinary ZEN concentrations were greater (P < 0.001) than in the other 3 herds. This might reflect significant natural ZEN contamination of the feed at the farm level. In Exp. 2, urinary ZEN concentrations displayed peculiar trends after, supplementation with MA. After 2 wk of supplementation, a significant decrease of ZEN (P < 0.05) was observed. Zearalenone concentrations remained at a reduced amount during 3 wk without MA supplementation and 2 wk with MA supplementation. When MA was not added to the feed for the next 6 wk, the concentrations increased to the original quantity. These findings indicate the usefulness of measuring concentrations of urinary ZEN and its metabolites not only for monitoring the natural ZEN contamination of cattle feed at the farm level but also for in vivo evaluation of MA function after supplementing feeds with MA. [ABSTRACT FROM AUTHOR]

Canonical epidermal growth factor (EGF) receptor (EGFR) activation involves the binding of seven EGFR ligands (EGFRLs); however, their extracellular dynamics remain elusive. Here, employing fluorescent probes and a tool for triggering ectodomain shedding, we show that epiregulin (EREG), a low-affinity EGFRL, rapidly and efficiently activates EGFR in Madin-Darby canine kidney (MDCK) epithelial cells and mouse epidermis. During collective cell migration, EGFR and extracellular signal-regulated kinase (ERK) activation waves propagate in an a disintegrin and metalloprotease 17 (ADAM17) sheddase- and EGFRL-dependent manner. Upon induced EGFRL shedding, low-affinity ligands EREG and amphiregulin (AREG) mediate faster and broader ERK waves than high-affinity ligands. Tight/adherens junction integrity is essential for ERK activation propagation, suggesting that tight intercellular spaces prefer the low-affinity EGFRLs for efficient signal transmission. In EREG-deficient mice, ERK wave propagation and cell migration were impaired during skin wound repair. We additionally show that heparin-binding EGF-like growth factor (HBEGF) primarily promotes surrounding cell motility. Our findings underscore the pivotal role of low-affinity EGFRLs in rapid intercellular signal transmission., Competing Interests: Declaration of interests The authors declare no competing interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Epidermal growth factor receptor ligands (EGFRLs) consist of seven proteins. In stark contrast to the amassed knowledge concerning the epidermal growth factor receptors themselves, the extracellular dynamics of individual EGFRLs remain elusive. Here, employing fluorescent probes and a tool for triggering ectodomain shedding of EGFRLs, we show that EREG, a low-affinity EGFRL, exhibits the most rapid and efficient activation of EGFR in confluent epithelial cells and mouse epidermis. In Madin-Darby canine kidney (MDCK) renal epithelial cells, EGFR- and ERK-activation waves propagate during collective cell migration in an ADAM17 sheddase- and EGFRL-dependent manner. Upon induction of EGFRL shedding, radial ERK activation waves were observed in the surrounding receiver cells. Notably, the low-affinity ligands EREG and AREG mediated faster and broader ERK waves than the high-affinity ligands. The integrity of tight/adherens junctions was essential for the propagation of ERK activation, implying that the tight intercellular spaces prefer the low-affinity EGFRL to the high-affinity ligands for efficient signal transmission. To validate this observation in vivo , we generated EREG-deficient mice expressing the ERK biosensor and found that ERK wave propagation and cell migration were impaired during skin wound repair. In conclusion, we have quantitatively demonstrated the distinctions among EGFRLs in shedding, diffusion, and target cell activation in physiological contexts. Our findings underscore the pivotal role of low-affinity EGFRLs in rapid intercellular signal transmission.

Background: Peroxisome proliferator-activated receptor delta (PPARδ) promotes inflammation and carcinogenesis in many organs, but the underlying mechanisms remains elusive. In stomachs, PPARδ significantly increases chemokine Ccl20 expression in gastric epithelial cells while inducing gastric adenocarcinoma (GAC). CCR6 is the sole receptor of CCL20. Here, we examine the role of PPARδ-mediated Ccl20/Ccr6 signaling in GAC carcinogenesis and investigate the underlying mechanisms., Methods: The effects of PPARδ inhibition by its specific antagonist GSK3787 on GAC were examined in the mice with villin-promoter-driven PPARδ overexpression (Ppard TG ). RNAscope Duplex Assays were used to measure Ccl20 and Ccr6 levels in stomachs and spleens. Subsets of stomach-infiltrating immune cells were measured via flow cytometry or immunostaining in Ppard TG mice fed GSK3787 or control diet. A panel of 13 optimized proinflammatory chemokines in mouse sera were quantified by an enzyme-linked immunosorbent assay., Results: GSK3787 significantly suppressed GAC carcinogenesis in Ppard TG mice. PPARδ increased Ccl20 level to chemoattract Ccr6 + immunosuppressive cells, including tumor-associated macrophages, myeloid-derived suppressor cells and T regulatory cells, but decreased CD8 + T cells in gastric tissues. GSK3787 suppressed PPARδ-induced gastric immunosuppression by inhibiting Ccl20/Ccr6 axis. Furthermore, Ccl20 protein levels increased in sera of Ppard TG mice starting at the age preceding gastric tumor development and further increased with GAC progression as the mice aged. GSK3787 decreased the PPARδ-upregulated Ccl20 levels in sera of the mice., Conclusions: PPARδ dysregulation of Ccl20/Ccr6 axis promotes GAC carcinogenesis by remodeling gastric tumor microenvironment. CCL20 might be a potential biomarker for the early detection and progression of GAC., (© 2023. The Author(s).)

Pancreatic intraepithelial neoplasia (PanIN) is a precursor of pancreatic ductal adenocarcinoma (PDAC), which commonly occurs in the general populations with aging. Although most PanIN lesions (PanINs) harbor oncogenic KRAS mutations that initiate pancreatic tumorigenesis; PanINs rarely progress to PDAC. Critical factors that promote this progression, especially targetable ones, remain poorly defined. We show that peroxisome proliferator-activated receptor-delta (PPARδ), a lipid nuclear receptor, is upregulated in PanINs in humans and mice. Furthermore, PPARδ ligand activation by a high-fat diet or GW501516 (a highly selective, synthetic PPARδ ligand) in mutant KRAS G12D (KRAS mu ) pancreatic epithelial cells strongly accelerates PanIN progression to PDAC. This PPARδ activation induces KRAS mu pancreatic epithelial cells to secrete CCL2, which recruits immunosuppressive macrophages and myeloid-derived suppressor cells into pancreas via the CCL2/CCR2 axis to orchestrate an immunosuppressive tumor microenvironment and subsequently drive PanIN progression to PDAC. Our data identify PPARδ signaling as a potential molecular target to prevent PDAC development in subjects harboring PanINs., (© 2022. The Author(s).)

Epidermal growth factor receptor (EGFR) plays a pivotal role in collective cell migration by mediating cell-to-cell propagation of extracellular signal-regulated kinase (ERK) activation. Here, we aimed to determine which EGFR ligands mediate the ERK activation waves. We found that epidermal growth factor ( EGF )-deficient cells exhibited lower basal ERK activity than the cells deficient in heparin-binding EGF ( HBEGF ), transforming growth factor alpha ( TGFα ) or epiregulin ( EREG ), but all cell lines deficient in a single EGFR ligand retained the ERK activation waves. Surprisingly, ERK activation waves were markedly suppressed, albeit incompletely, only when all four EGFR ligands were knocked out. Re-expression of the EGFR ligands revealed that all but HBEGF could restore the ERK activation waves. Aiming at complete elimination of the ERK activation waves, we further attempted to knockout NRG1 , a ligand for ErbB3 and ErbB4, and found that NRG1 -deficiency induced growth arrest in the absence of all four EGFR ligand genes. Collectively, these results showed that EGFR ligands exhibit remarkable redundancy in the propagation of ERK activation waves during collective cell migration., (© 2021 Lin et al.)

Because broad genetic diversity has recently been detected in Torque teno sus viruses (TTSuV1 and TTSuVk2), the viral genome detection method needs to be improved to understand the prevalence of these viruses. Here, we established single PCR-based detection methods for the TTSuV1 and TTSuVk2a genomes with newly designed primer pairs and applied them to investigate the prevalence of TTSuV1 and TTSuVk2a in Japanese pig populations. The results revealed that 98.2% and 81.7% of the pig farms tested positive for the TTSuV1 and TTSuVk2a genomes, respectively, indicating that both TTSuV1 and TTSuVk2a are widespread in Japan., (© 2020 The Societies and John Wiley & Sons Australia, Ltd.)

Aims: The prognosis of patients with gastric cancer and stage IV factors is poor. However, several recent studies have identified that curative surgery followed by S-1 chemotherapy for cytology positive (CY1) only patients contributed to a better prognosis. This study was designed to compare the prognosis between curative and palliative gastrectomy followed by chemotherapy in CY1 only stage IV gastric cancer., Methods: Between 2001 and 2016, 1507 patients underwent gastrectomy for gastric cancer. Of these, 51 consecutive patients with only CY1 factor who underwent gastrectomy followed by chemotherapy were enrolled in this study., Results: (1) Twenty three (45%) patients underwent curative D2 or D2+ gastrectomy, and the remaining 28 (55%) patients underwent palliative gastrectomy, followed by S-1 based or another historical recommended chemotherapy postoperatively. (2) Compared with patients undergoing palliative gastrectomy, patients undergoing curative gastrectomy had a significantly better prognosis (P = 0.042; median survival time: curative vs. palliative, 22.6 months vs. 11.8 months) and a lower incidence of recurrences (P = 0.091). Two- and five-year overall survival rates of patients following curative gastrectomy were 48.2% and 18.2%, respectively. A multivariate analysis showed that venous invasion [P = 0.006; hazard ratio (HR), 3.70 (95% CI: 1.27-9.43)] and curative gastrectomy [P < 0.005; HR, 0.28 (95% CI: 0.12-0.87)] were independent prognostic factors., Conclusion: Curative gastrectomy followed by chemotherapy might be justified to improve the prognosis of patients with only CY1 Stage IV gastric cancer.

Background/aim: The self-expandable metallic stent (SEMS) is an excellent non-invasive tool for emergent bowel obstruction. This study was designed to evaluate the clinical usefulness of the SEMS for avoiding perioperative complications., Patients and Methods: We analyzed a total of 47 consecutive patients who had a bowel obstruction due to colorectal cancer at initial diagnosis between 2012 and 2017 from hospital records., Results: Perioperative complications occurred in 30% (14/47) of patients. Univariate and multivariate logistic regression analyses identified an age of more than 75 years [p=0.037, OR=6.84 (95% CI=1.11-41.6)] and the absence of an SEMS treatment [p=0.028, OR=18.5 (95% CI=1.36-250.0)] as independent risk factors for perioperative complications. Pneumonia (12.7% (6/47)) was the most common complication. There were no pneumonia patients (0% (0/15)) who were treated with the SEMS. In contrast to patients with the non-SEMS treatment, 18.7% (6/32) of all patients and 35.7% (5/14) of elderly patients had pneumonia., Conclusion: The SEMS is a safe and effective treatment for avoiding perioperative complications, particularly pneumonia, and may be a crucial strategy in elderly patients with acute obstruction due to colorectal cancer., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)