In vitro epithelial-to-mesenchymal transformation in human adult epicardial cells is regulated by TGFβ-signaling and WT1

Adult epicardial cells are required for endogenous cardiac repair. After myocardial injury, they are reactivated, undergo epithelial-to-mesenchymal transformation (EMT) and migrate into the injured myocardium where they generate various cell types, including coronary smooth muscle cells and cardiac interstitial fibroblasts, which contribute to cardiac repair. To understand what drives epicardial EMT, we used an in vitro model for human adult epicardial cells. These cells have an epithelium-like morphology and markedly express the cell surface marker vascular cell adhesion marker (VCAM-1). In culture, epicardial cells spontaneously undergo EMT after which the spindle-shaped cells now express endoglin. Both epicardial cells before and after EMT express the epicardial marker, Wilms tumor 1 (WT1). Adding transforming growth factor beta (TGFβ) induces loss of epithelial character and initiates the onset of mesenchymal differentiation in human adult epicardial cells. In this study, we show that TGFβ-induced EMT is dependent on type-1 TGFβ receptor activity and can be inhibited by soluble VCAM-1. We also show that epicardial-specific knockdown of Wilms tumor-1 (WT1) induces the process of EMT in human adult epicardial cells, through transcriptional regulation of platelet-derived growth factor receptor alpha (Pdgfrα), Snai1 and VCAM-1. These data provide new insights into the process of EMT in human adult epicardial cells, which might provide opportunities to develop new strategies for endogenous cell-based cardiac repair

Regulation of endothelial cell plasticity by TGF-β

Recent evidence has demonstrated that endothelial cells can have a remarkable plasticity. By a process called Endothelial-to-Mesenchymal Transition (EndMT) endothelial cells convert to a more mesenchymal cell type that can give rise to cells such as fibroblasts, but also bone cells. EndMT is essential during embryonic development and tissue regeneration. Interestingly, it also plays a role in pathological conditions like fibrosis of organs such as the heart and kidney. In addition, EndMT contributes to the generation of cancer associated fibroblasts that are known to influence the tumor-microenvironment favorable for the tumor cells. EndMT is a form of the more widely known and studied Epithelial-to-Mesenchymal Transition (EMT). Like EMT, EndMT can be induced by transforming growth factor (TGF)-β. Indeed many studies have pointed to the important role of TGF-β receptor/Smad signaling and downstream targets, such as Snail transcriptional repressor in EndMT. By selective targeting of TGF-β receptor signaling pathological EndMT may be inhibited for the therapeutic benefit of patients with cancer and fibrosis

Temperature-dependent polymorphism of N-(4-fluorophenyl)-1,5-dimethyl-1H-imidazole-4-carboxamide 3-oxide: experimental and theoretical studies on intermolecular interactions in the crystal state

X-ray analysis of N-(4-fluorophenyl)-1,5-dimethyl-1H-imidazole-4-carboxamide 3-oxide reveals the temperature-dependent polymorphism associated with the crystallographic symmetry conversion. The observed crystal structure transformation corresponds to a symmetry reduction from I41 /a (I) to P43 (II) space groups. The phase transition mainly concerns the subtle but clearly noticeable reorganization of molecules in the crystal space, with the structure of individual molecules left almost unchanged. The Hirshfeld surface analysis shows that various intermolecular contacts play an important role in the crystal packing, revealing graphically the differences in spatial arrangements of the molecules in both polymorphs. The N-oxide oxygen atom acts as a formally negatively charged hydrogen bonding acceptor in intramolecular hydrogen bond of N–H…O− type. The combined crystallographic and theoretical DFT methods demonstrate that the observed intramolecular N-oxide N–H…O hydrogen bond should be classified as a very strong charge-assisted and closed-shell non-covalent interaction

In vitro models for the study of osteoarthritis

AbstractOsteoarthritis (OA) is a prevalent disease of most mammalian species and is a significant cause of welfare and economic morbidity in affected individuals and populations. In vitro models of osteoarthritis are vital to advance research into the causes of the disease, and the subsequent design and testing of potential therapeutics. However, a plethora of in vitro models have been used by researchers but with no consensus on the most appropriate model. Models attempt to mimic factors and conditions which initiate OA, or dissect the pathways active in the disease. Underlying uncertainty as to the cause of OA and the different attributes of isolated cells and tissues used mean that similar models may produce differing results and can differ from the naturally occurring disease.This review article assesses a selection of the in vitro models currently used in OA research, and considers the merits of each. Particular focus is placed on the more prevalent cytokine stimulation and load-based models. A brief review of the mechanism of these models is given, with their relevance to the naturally occurring disease. Most in vitro models have used supraphysiological loads or cytokine concentrations (compared with the natural disease) in order to impart a timely response from the cells or tissue assessed. Whilst models inducing OA-like pathology with a single stimulus can answer important biological questions about the behaviour of cells and tissues, the development of combinatorial models encompassing different physiological and molecular aspects of the disease should more accurately reflect the pathogenesis of the naturally occurring disease

High mass photon pairs in lepton+ lepton-gamma gamma events at LEP

High mass photon pairs in lepton+ lepton-gamma gamma events at LEP Adriani, O.; Aguilar-Benitez, M.; Ahlen, S.P.; Alcaraz, J.; Aloisio, A.; Alverson, G.; Alviggi, M.G.; Ambrosi, G.; Linde, F.L. Published in: Physics Letters B DOI: 10.1016/0370-2693(92)91576-U Link to publication Citation for published version (APA): Adriani, O., Aguilar-Benitez, M., Ahlen, S. P., Alcaraz, J., Aloisio, A., Alverson, G., ... Linde, F. L. (1992). High mass photon pairs in lepton+ lepton-gamma gamma events at LEP. Physics Letters B, 295,[337][338][339][340][341][342][343][344][345][346] https://doi.org/10.1016/0370-2693(92)91576-U General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Download date: 28 Jun 2019 Physics Letters B 295 (1992) From the analysis of the reactions e + e-~ g + g-(n?) (g = e, #, ~) we observe four events, one e+e -~'7 and three #+ ~-??, with the invariant mass of the photon pairs close to 60 GeV. These events were selected from a data sample collected in the L3 detector corresponding to 950000 produced Z°'s. More data are necessary to ascertain the origin of these events

Pilot Study of Use of Nitric Oxide in Monitoring Multiple Dental Foci in Oral Cavity—A Case Report

Background: The most common cause of implant loss and deteriorating restoration aesthetics is infection and chronic inflammation of the tissues around the implants. Inflammation in the oral cavity, confirmed by clinical and histopathological examination and determination of exhaled nitric oxide, is a situation which may cause the complications on the whole human body. Elimination of the patology in the oral cavity in some cases is the only resonable treatment. The aims and objectives of our work is to present a gradual treatment of advanced infalmmation and present huge reduction stamp of inflammation measured with marker nitric oxide (NO) in exhaled air. Materials and Methods: Simple treatment containing elimantion of pathology in the oral cavity was conducted. Patient that came to the dental practice suffered from the inflammation caused by lack of proper hygiene. First aid in this situation was to eliminate the inflammation which may affect negatively for general health. At first visit full hygienization was performed, at the second visit roots of abutment teeth and implants were removed under local anesthesia along with cystic changes. Results: The hygiene precedures and extraction of the unsteady inflammationprosthetic restorations significantly decreased the level of NO in exhaled air. Conclusions: During the examination of the patient coming to the dental practice great attention should be paid to the coexistence of pathologies related to the oral cavity. Omission of a dental examination and possible elimination of odontogenic foci may affect the implication of the results of general diagnostics and subsequent treatment. Measuring the level of NO on exhaled air seems to be useful diagnostic method

Exercise-stimulated interleukin-15 is controlled by AMPK and regulates skin metabolism and aging

Aging is commonly associated with a structural deterioration of skin that compromises its barrier function, healing, and susceptibility to disease. Several lines of evidence show that these changes are driven largely by impaired tissue mitochondrial metabolism. While exercise is associated with numerous health benefits, there is no evidence that it affects skin tissue or that endocrine muscle-to-skin signaling occurs. We demonstrate that endurance exercise attenuates age-associated changes to skin in humans and mice and identify exercise-induced IL-15 as a novel regulator of mitochondrial function in aging skin. We show that exercise controls IL-15 expression in part through skeletal muscle AMP-activated protein kinase (AMPK), a central regulator of metabolism, and that the elimination of muscle AMPK causes a deterioration of skin structure. Finally, we establish that daily IL-15 therapy mimics some of the anti-aging effects of exercise on muscle and skin in mice. Thus, we elucidate a mechanism by which exercise confers health benefits to skin and suggest that low-dose IL-15 therapy may prove to be a beneficial strategy to attenuate skin aging

The AMPK activator R419 improves exercise capacity and skeletal muscle insulin sensitivity in obese mice

OBJECTIVE: Skeletal muscle AMP-activated protein kinase (AMPK) is important for regulating glucose homeostasis, mitochondrial content and exercise capacity. R419 is a mitochondrial complex-I inhibitor that has recently been shown to acutely activate AMPK in myotubes. Our main objective was to examine whether R419 treatment improves insulin sensitivity and exercise capacity in obese insulin resistant mice and whether skeletal muscle AMPK was important for mediating potential effects. METHODS: Glucose homeostasis, insulin sensitivity, exercise capacity, and electron transport chain content/activity were examined in wildtype (WT) and AMPK β1β2 muscle-specific null (AMPK-MKO) mice fed a high-fat diet (HFD) with or without R419 supplementation. RESULTS: There was no change in weight gain, adiposity, glucose tolerance or insulin sensitivity between HFD-fed WT and AMPK-MKO mice. In both HFD-fed WT and AMPK-MKO mice, R419 enhanced insulin tolerance, insulin-stimulated glucose disposal, skeletal muscle 2-deoxyglucose uptake, Akt phosphorylation and glucose transporter 4 (GLUT4) content independently of alterations in body mass. In WT, but not AMPK-MKO mice, R419 improved treadmill running capacity. Treatment with R419 increased muscle electron transport chain content and activity in WT mice; effects which were blunted in AMPK-MKO mice. CONCLUSIONS: Treatment of obese mice with R419 improved skeletal muscle insulin sensitivity through a mechanism that is independent of skeletal muscle AMPK. R419 also increases exercise capacity and improves mitochondrial function in obese WT mice; effects that are diminished in the absence of skeletal muscle AMPK. These findings suggest that R419 may be a promising therapy for improving whole-body glucose homeostasis and exercise capacity