CD147 (basigin, EMMPRIN) is a multifunctional, highly conserved glycoprotein enriched in pancreatic ductal adenocarcinomas (PDACs) which is associated with poor prognosis in many malignancies. The ...role of CD147 in pancreatic cancer, however, remains elusive.
Silencing of CD147 by RNA interference (RNAi) reduced the proliferation rate of MiaPaCa2 and Panc1 cells. CD147 is required for the function and expression of the monocarboxylate transporters MCT1 and MCT4 that are expressed in human PDAC cells as demonstrated by real-time reverse transcription-PCR (RT-PCR) as well as immunohistology. MCT1 and MCT4 are the natural transporters of lactate, and MiaPaCa2 cells exhibited a high rate of lactate production, which is characteristic for the Warburg effect, an early hallmark of cancer that confers a significant growth advantage. Further induction of lactate production by sodium azide in MiaPaCa2 cells increased MCT1 as well as MCT4 expression. CD147 silencing inhibited the expression and function of MCT1 and MCT4 and resulted in an increased intracellular lactate concentration. Addition of exogenous lactate inhibited cancer cell growth in a dose-dependent fashion. In vivo, knock-down of CD147 in MiaPaCa2 cells by inducible short hairpin RNA (shRNA)-mediated CD147 silencing reduced invasiveness through the chorioallantoic membrane of chick embryos (CAM assay) and inhibited tumourigenicity in a xenograft model in nude mice.
The function of CD147 as an ancillary protein that is required to sustain the expression and function of MCT1 and MCT4 is involved in the association of CD147 expression with the malignant potential of pancreatic cancer cells exhibiting the Warburg effect.
Recently, the novel myokine irisin was described to drive adipose tissue 'browning', to increase energy expenditure, and to improve obesity and insulin resistance in high fat-fed mice. Here, we ...assessed whether common single nucleotide polymorphisms (SNPs) in the FNDC5 locus, encoding the irisin precursor, contribute to human prediabetic phenotypes (overweight, glucose intolerance, insulin resistance, impaired insulin release).
A population of 1,976 individuals was characterized by oral glucose tolerance tests and genotyped for FNDC5 tagging SNPs. Subgroups underwent hyperinsulinaemic-euglycaemic clamps, magnetic resonance imaging/spectroscopy, and intravenous glucose tolerance tests. From 37 young and 14 elderly participants recruited in two different centres, muscle biopsies were obtained for the preparation of human myotube cultures.
After appropriate adjustment and Bonferroni correction for the number of tested variants, SNPs rs16835198 and rs726344 were associated with in vivo measures of insulin sensitivity. Via interrogation of publicly available data from the Meta-Analyses of Glucose and Insulin-related traits Consortium, rs726344's effect on insulin sensitivity was replicated. Moreover, novel data from human myotubes revealed a negative association between FNDC5 expression and appropriately adjusted in vivo measures of insulin sensitivity in young donors. This finding was replicated in myotubes from elderly men.
This study provides evidence that the FNDC5 gene, encoding the novel myokine irisin, determines insulin sensitivity in humans. Our gene expression data point to an unexpected insulin-desensitizing effect of irisin.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: Allergy has at least two components – a genetic predisposition referred to as atopy and the progress from an atopic state to clinically apparent disease. Peripheral blood monocytes are ...circulating myeloid precursors of antigen‐presenting cells. The expression of cell surface proteins on monocytes may therefore witness the disease status and affect the development of allergic disease.
Methods: Monocytes were isolated from atopic individuals with seasonal allergic rhinitis (n = 10), from atopic individuals sensitized to aeroallergens but without any signs of acute disease (n = 11), and from healthy nonatopic donors (n = 21). Detailed comparative phenotypic analysis of CD14+ and FcɛRI+CD14+ monocytes was performed by flow cytometry.
Results: CD14+ monocytes from symptomatic atopic donors showed a significant increase in the cell surface intensity of the integrin adhesion molecule CD11c over monocytes from asymptomatic atopic and nonatopic donors. Asymptomatic atopic individuals showed significantly enhanced expression of FcɛRI on the CD14highCD16dim monocyte subset compared with this subset from symptomatic atopic and nonatopic donors.
Conclusion: The increase in monocyte surface intensity of the adhesion molecule CD11c may be involved in the manifestation of allergic disease. FcɛRI on CD14highCD16dim monocytes of asymptomatic atopic donors may be of functional importance for the maintenance of clinical unresponsiveness toward allergens.
Recent studies have provided evidence that a type I interferon (IFN)-driven immune response might play an important role in the pathogenesis of lichen planus (LP), an inflammatory disorder of the ...skin of unclear etiology. Plasmacytoid dendritic cells in affected skin from LP have been proposed to produce IFN-alpha/beta locally, which leads to the expression of IFN-inducible chemokines such as IP10/CXCL10 in the epidermis. This chemokine recruits chemokine receptor CXCR3-expressing T-lymphocytes into the skin via CXCR3/IP10 interactions. Indoleamine 2,3-dioxygenase (IDO), which degrades tryptophan and suppresses T-cell proliferation, is induced by IFNs and other inflammatory cytokines. We show that type I IFN-mediated skin disorders, such as LP, strongly express IDO in lesional skin. This expression closely correlates to the expression of the highly specific type I IFN marker MxA. We further demonstrate that the IDO+ cells in LP are large myeloid CD11c+S100+CD68(-) dendritic cells. Accordingly, CD11c+ antigen-presenting cells significantly up-regulate IDO gene expression and intracellular IDO protein expression after stimulation with IFN-alpha in vitro. These findings reveal that both proinflammatory and counterregulatory mechanisms are operative in cutaneous lesions of LP. We propose that the balance of these mechanisms may be involved in the pathogenesis of this disorder.
Sildenafil (Viagra) has been proved effective in the therapy for erectile dysfunction. Cardiovascular adverse effects are a matter of continuous debate. The aim of the study was to investigate ...effects of sildenafil on isolated human cardiovascular tissue directly. Isometric force of contraction was determined in isolated, electrically stimulated (1 Hz, 37°C) human right atrial and left ventricular muscle strips. Vascular tension was determined in rings of human internal mammaria arteries and saphenous veins. Sildenafil (0.0001–10 μM) neither in human atrium (n = 12) nor in failing (n = 8) or nonfailing (n = 5) ventricle exerted a significant inotropic response. Furthermore, no effect on isoprenaline-elicited arrhythmias was observed. Neither addition of isoprenaline (0.1 μM) nor addition of the nitric oxide donor S-nitroso-N-acetylpenicillamine (SNAP) (100 μM) affected myocardial contractility in the presence of sildenafil (10 μM). In precontracted arteries and veins, addition of sildenafil (0.1–10 μM) led to pronounced vasorelaxation (maximal 35.5 ± 2.2% and 45.6 ± 6.3%, respectively, in the presence of 10 μM sildenafil). In the presence of SNAP (0.03 μM), this effect was markedly increased in arteries (72.4 ± 10.1%, n = 4, P < 0.02) as well as in veins (73.5 ± 6.3%, n = 6, P < 0.02). Sildenafil exerts potent vasodilatory actions but has no direct influence on human myocardial contractility or proarrhythmic effects in vitro.
Neue Studien zeigen, dass die Behandlung von Mäusen und Affen mit FGF21 in pharmakologischen Konzentrationen zu gesteigertem Energieverbrauch und verbesserter Insulinsensitivität führt. Des Weiteren ...wurde gezeigt, dass FGF21 die Differenzierung und das „browning“ von Maus-Präadipozyten in Kultur verbessert. Dieser Effekt wird durch Expressionsregulation spezifischer Gene hervorgerufen. In der vorliegenden Studie haben wir die Expression von Markergenen humaner subkutaner Präadipozyten (hSUB) untersucht, die während der Differenzierung mit humanem rekombinanten FGF21 (hrFGF21, 50 ng/ml) behandelt wurden. In den konditionierten Kulturüberständen wurden die Konzentrationen von Adiponectin und Leptin gemessen. Zusätzlich haben wir nach FGF21-abhängigen Unterschieden zwischen Zellen von 10 insulinsensitiven (IS) versus 10 insulinresistenten (IR) Spendern gesucht. Die hSUB wurden aus Biopsien von Teilnehmern der Tübinger Familien Studie für Typ 2 Diabetes gewonnen. Die IS- und IR-Subgruppen waren nach Geschlecht, Alter und Körperfettmasse abgeglichen. Die hSUB wurden über 18 Tage mit oder ohne Zugabe von hrFGF21 zu Adipozyten differenziert. Die Expression von FGFR1 und KLB, die für den Oberflächenrezeptor für FGF21 kodieren, war hoch und blieb unverändert während der gesamten Differenzierung. Gene, die bekannterweise während der Adipogenese induziert werden, wie CEBPA/B, PPARG, ADIPOQ und LEP wurden unbeeinflusst von hrFGF21 hochreguliert. Es wurden keine signifikanten Unterschiede in der Genexpression zwischen IS- und IR-Zellen beobachtet mit Ausnahme von UCP1, welches nach hrFGF21 in IR-Zellen signifikant stärker hochreguliert wurde als in IS-Zellen (p < 0,05). Unerwartet und im Gegensatz zu früheren Studien an Maus-Adipozyten zeigen hSUB keine Expression von FGF21 oder PPARGC1A. Auch die hrFGF21-Behandlung änderte nichts an diesen Negativbefunden. Interessanterweise reduzierte hrFGF21 die Adiponektinfreisetzung der Adipozyten von IS- und IR-Spendern (4-fach, p < 0,001 und 2-fach, p < 0,05). Die Leptinkonzentration stieg dagegen nur im konditionierten Medium der IR-Zellen signifikant während der Differenzierung an (p = 0,01). Zusammenfassend können wir zeigen, dass die Behandlung von hSUB mit hrFGF21 zu Ergebnissen führt, die den publizierten Mausdaten weitgehend widersprechen. Des Weiteren könnte die FGF21-induzierte Hemmung der Adiponektinfreisetzung in hSUB eine Insulin-desensibilisierende Wirkung haben.
To correlate findings of hip ultrasound on day 4-10 of life with sex, intrauterine position and a positive family history for congenital hip anomalies.
The SNiP-study ( Survey of Neonates In ...Pommerania) registered 2256 neonates (2030 term, 226 preterm) between May 2002 and March 2004. Hip ultrasound results of 1043 term and since October 2003 33 preterm neonates were analysed. Time of ultrasound was day 4-10 after birth. Preterm neonates were examined when reaching their corrected term gestational age. Ultrasound was applied with a 7.5 MHz linear scanner and results were classified according to Graf. Chi-square and Fishers exact test were used for statistical analysis.
4.9 % of the screened hips were classified as IIc or higher, 3.1 % were unilateral and 1.7 % bilateral. Incidence was significantly higher (p < 0.023) in females (6.6 %) than in males (3.2 %). There was no significant difference in intrauterine position or positive family history for hip anomalies with 3.7 % for mothers, 1.2 % of fathers and 2.4 % of siblings positive. There was a higher incidence for congenital hip dysplasia in preterms with 6.1 %, which is not significant due to the limited number.
Current screening methods miss up to 18 % of newborns with severe hip dysplasia. We were able to demonstrate that screening for congenital hip dysplasia with ultrasound is a diagnostic tool even during the first days of life. There is a significantly higher incidence of congenital hip dysplasia in females, but in contrast to other studies we found no significant difference in intrauterine position or familial history. Earlier diagnosis and therapy on the base of relevant risk factors might correspond with an improved prognosis and outcome. Further studies are warranted to evaluate the significance in preterm neonates.
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