Bioactive oxylipins in type 2 diabetes mellitus patients with and without hypertriglyceridemia

ObjectiveDyslipidemia, in particular elevated triglycerides (TGs) contribute to increased cardiovascular risk in type 2 diabetes mellitus (T2DM). In this pilot study we aimed to assess how increased TGs affect hepatic fat as well as polyunsaturated fatty acid (PUFA) metabolism and oxylipin formation in T2DM patients.Methods40 patients with T2DM were characterized analyzing routine lipid blood parameters, as well as medical history and clinical characteristics. Patients were divided into a hypertriglyceridemia (HTG) group (TG ≥ 1.7mmol/l) and a normal TG group with TGs within the reference range (TG < 1.7mmol/l). Profiles of PUFAs and their oxylipins in plasma were measured by gas chromatography and liquid chromatography/tandem mass spectrometry. Transient elastography (TE) was used to assess hepatic fat content measured as controlled attenuation parameter (CAP) (in dB/m) and the degree of liver fibrosis measured as stiffness (in kPa).ResultsMean value of hepatic fat content measured as CAP as well as body mass index (BMI) were significantly higher in patients with high TGs as compared to those with normal TGs, and correlation analysis showed higher concentrations of TGs with increasing CAP and BMI scores in patients with T2DM. There were profound differences in plasma oxylipin levels between these two groups. Cytochrome P450 (CYP) and lipoxygenase (LOX) metabolites were generally more abundant in the HTG group, especially those derived from arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), γ-linolenic acid (γ-LA), and α-linolenic acid (α-LA), and a strong correlation between TG levels and plasma metabolites from different pathways was observed.ConclusionsIn adult patients with T2DM, elevated TGs were associated with increased liver fat and BMI. Furthermore, these patients also had significantly higher plasma levels of CYP- and LOX- oxylipins, which could be a novel indicator of increased inflammatory pathway activity, as well as a novel target to dampen this activity

Strukturierte Peer-Support-Programme: Wie Hühneraugen und überlanges Warten die sprachliche und interkulturelle Kompetenz fördern

An australischen Universitäten werden jedes Jahr Tausende internationale Studierende empfangen, die teilweise Sprachen sprechen, die an australischen Universitäten gelehrt werden. Unsere Langzeitstudie, die seit 2004 an der University of Western Australia durchgeführt wird, untersucht die Art und Weise des Erwerbs der interkulturellen Kompetenz anhand von Peer-Support-Programmen, in denen deutschsprachige, internationale Studierende mit DaF-Studierenden zusammentreffen. In diesem Beitrag zeigen wir, wie Anreize zur interkulturellen Begegnung und Reflektion geschaffen werden können und der beiderseitige Lernprozess durch optimale Ausnutzung des Parameters von freiwilliger bis hin zu verpflichtender Teilnahme gefördert werden kann. Die qualitative und quantitative Auswertung von studentischen Aufsätzen und Interviews zum Thema kulturelle Unterschiede dokumentiert einen allseitigen Erkenntnisgewinn und zeigt, wie die geleitete Interaktion zur Verbesserung sprachlicher und interkultureller Kompetenzen beiträgt. Australian universities welcome thousands of international students every year. Many of them speak languages being studied at university level by local students. Our long-term study, conducted at The University of Western Australia since 2004, analyses the way in which intercultural competencies are gained in German Studies with the help of a peer-support program that utilises international students who are native-speakers of German. In this paper we show how incentives can be provided for intercultural encounters (along with reflection on those encounters), and how this mutual learning process can be supported by the optimal use of voluntary and obligatory participation. Our qualitative and quantitative analysis of student essays and interviews on the topic of intercultural differences documents a comprehensive increase in knowledge, with the guided interaction able to contribute to the improvement of linguistic and cultural competencies

Bioactive oxylipins in type 2 diabetes mellitus patients with and without hypertriglyceridemia

Objective: Dyslipidemia, in particular elevated triglycerides (TGs) contribute to increased cardiovascular risk in type 2 diabetes mellitus (T2DM). In this pilot study we aimed to assess how increased TGs affect hepatic fat as well as polyunsaturated fatty acid (PUFA) metabolism and oxylipin formation in T2DM patients. Methods: 40 patients with T2DM were characterized analyzing routine lipid blood parameters, as well as medical history and clinical characteristics. Patients were divided into a hypertriglyceridemia (HTG) group (TG ≥ 1.7mmol/l) and a normal TG group with TGs within the reference range (TG < 1.7mmol/l). Profiles of PUFAs and their oxylipins in plasma were measured by gas chromatography and liquid chromatography/tandem mass spectrometry. Transient elastography (TE) was used to assess hepatic fat content measured as controlled attenuation parameter (CAP) (in dB/m) and the degree of liver fibrosis measured as stiffness (in kPa). Results: Mean value of hepatic fat content measured as CAP as well as body mass index (BMI) were significantly higher in patients with high TGs as compared to those with normal TGs, and correlation analysis showed higher concentrations of TGs with increasing CAP and BMI scores in patients with T2DM. There were profound differences in plasma oxylipin levels between these two groups. Cytochrome P450 (CYP) and lipoxygenase (LOX) metabolites were generally more abundant in the HTG group, especially those derived from arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), γ-linolenic acid (γ-LA), and α-linolenic acid (α-LA), and a strong correlation between TG levels and plasma metabolites from different pathways was observed. Conclusions: In adult patients with T2DM, elevated TGs were associated with increased liver fat and BMI. Furthermore, these patients also had significantly higher plasma levels of CYP- and LOX- oxylipins, which could be a novel indicator of increased inflammatory pathway activity, as well as a novel target to dampen this activity

Omega‐3 fatty acids protect from colitis via an Alox15‐derived eicosanoid

An increased omega-3 polyunsaturated fatty acid (n-3 PUFA) tissue status can lead to a significant formation of anti-inflammatory lipid mediators and effective reduction in inflammation and tissue injury in murine colitis. Arachidonic acid lipoxygenases (ALOX) have been implicated in the pathogenesis of inflammatory bowel disease as well as in the formation of pro- and anti-inflammatory lipid mediators. To explore the role of Alox15 in the protective response found in fat1 transgenic mice with endogenously increased n-3 PUFA tissue status fat1 transgenic mice were crossed with Alox15-deficient animals and challenged in the dextran sulfate sodium (DSS)- and the 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis model. Transgenic fat1 mice rich in endogenous n-3 PUFAs were protected from colitis. However, additional systemic inactivation of the Alox15 gene counteracted this protective effect. To explore the molecular basis for this effect Alox15 lipid metabolites derived from n-3 PUFA were analyzed in the different mice. Alox15 deficiency suppressed the formation of n-3 PUFA-derived 15-hydroxy eicosapentaenoic acid (15-HEPE). In contrast, treating mice with intraperitoneal injections of 15S-HEPE protected wild-type mice from DSS- and TNBS-induced colitis. These data suggest that the anti-colitis effect of increased n-3 PUFA in the transgenic fat1 mouse model is mediated in part via Alox15-derived 15-HEPE formation

Ultrafast Photodynamics of the Indoline Dye D149 Adsorbed to Porous ZnO in Dye‐Sensitized Solar Cells

We investigate the ultrafast dynamics of the photoinduced electron transfer between surface-adsorbed indoline D149 dye and porous ZnO as used in the working electrodes of dye-sensitized solar cells. Transient absorption spectroscopy was conducted on the dye in solution, on solid state samples and for the latter in contact to a I−/I3− redox electrolyte typical for dye-sensitized solar cells to elucidate the effect of each component in the observed dynamics. D149 in a solution of 1:1 acetonitrile and tert-butyl alcohol shows excited-state lifetimes of 300±50 ps. This signature is severely quenched when D149 is adsorbed to ZnO, with the fastest component of the decay trace measured at 150±20 fs due to the charge-transfer mechanism. Absorption bands of the oxidized dye molecule were investigated to determine regeneration times which are in excess of 1 ns. The addition of the redox electrolyte to the system results in faster regeneration times, of the order of 1 ns

Knock-In Mice Expressing a 15-Lipoxygenating Alox5 Mutant Respond Differently to Experimental Inflammation Than Reported Alox5−/− Mice

Arachidonic acid 5-lipoxygenase (ALOX5) is the key enzyme in the biosynthesis of pro-inflammatory leukotrienes. We recently created knock-in mice (Alox5-KI) which express an arachidonic acid 15-lipoxygenating Alox5 mutant instead of the 5-lipoxygenating wildtype enzyme. These mice were leukotriene deficient but exhibited an elevated linoleic acid oxygenase activity. Here we characterized the polyenoic fatty acid metabolism of these mice in more detail and tested the animals in three different experimental inflammation models. In experimental autoimmune encephalomyelitis (EAE), Alox5-KI mice displayed an earlier disease onset and a significantly higher cumulative incidence rate than wildtype controls but the clinical score kinetics were not significantly different. In dextran sodium sulfate-induced colitis (DSS) and in the chronic constriction nerve injury model (CCI), Alox5-KI mice performed like wildtype controls with similar genetic background. These results were somewhat surprising since in previous loss-of-function studies targeting leukotriene biosynthesis (Alox5(-/-) mice, inhibitor studies), more severe inflammatory symptoms were observed in the EAE model but the degree of inflammation in DSS colitis was attenuated. Taken together, our data indicate that these mutant Alox5-KI mice respond differently in two models of experimental inflammation than Alox5(-/-) animals tested previously in similar experimental setups

Hypoxia-Inducible Factor 1α Determines Gastric Cancer Chemosensitivity via Modulation of p53 and NF-κB

BACKGROUND: Reduced chemosensitivity of solid cancer cells represents a pivotal obstacle in clinical oncology. Hence, the molecular characterization of pathways regulating chemosensitivity is a central prerequisite to improve cancer therapy. The hypoxia-inducible factor HIF-1alpha has been linked to chemosensitivity while the underlying molecular mechanisms remain largely elusive. Therefore, we comprehensively analysed HIF-1alpha's role in determining chemosensitivity focussing on responsible molecular pathways. METHODOLOGY AND PRINCIPAL FINDINGS: RNA interference was applied to inactivate HIF-1alpha or p53 in the human gastric cancer cell lines AGS and MKN28. The chemotherapeutic agents 5-fluorouracil and cisplatin were used and chemosensitivity was assessed by cell proliferation assays as well as determination of cell cycle distribution and apoptosis. Expression of p53 and p53 target proteins was analyzed by western blot. NF-kappaB activity was characterized by means of electrophoretic mobility shift assay. Inactivation of HIF-1alpha in gastric cancer cells resulted in robust elevation of chemosensitivity. Accordingly, HIF-1alpha-competent cells displayed a significant reduction of chemotherapy-induced senescence and apoptosis. Remarkably, this phenotype was completely absent in p53 mutant cells while inactivation of p53 per se did not affect chemosensitivity. HIF-1alpha markedly suppressed chemotherapy-induced activation of p53 and p21 as well as the retinoblastoma protein, eventually resulting in cell cycle arrest. Reduced formation of reactive oxygen species in HIF-1alpha-competent cells was identified as the molecular mechanism of HIF-1alpha-mediated inhibition of p53. Furthermore, loss of HIF-1alpha abrogated, in a p53-dependent manner, chemotherapy-induced DNA-binding of NF-kappaB and expression of anti-apoptotic NF-kappaB target genes. Accordingly, reconstitution of the NF-kappaB subunit p65 reversed the increased chemosensitivity of HIF-1alpha-deficient cells. CONCLUSION AND SIGNIFICANCE: In summary, we identified HIF-1alpha as a potent regulator of p53 and NF-kappaB activity under conditions of genotoxic stress. We conclude that p53 mutations in human tumors hold the potential to confound the efficacy of HIF-1-inhibitors in cancer therapy

Role of hypoxia-inducible transcription factor HIF-1 for malignant progression of human gastric cancer

Die Überexpression des Hypoxie-induzierbaren Transkriptionsfaktors 1 (HIF-1) ist ein zentrales Charakteristikum vieler Tumorentitäten. Eine Vielzahl von Studien lässt vermuten, dass HIF-1 eine funktionelle Bedeutung für das Wachstum und die Progression solider Tumoren zukommt. Der Transkriptionsfaktor HIF-1 scheint insbesondere auch an der Regulation der Metastasierung und der Vermittlung von Chemoresistenz beteiligt zu sein, wobei die zugrunde liegenden Mechanismen weitgehend unklar sind. Das humane Magenkarzinom ist durch eine sehr ungünstige Prognose gekennzeichnet. Der Verlauf der Erkrankung wird weitgehend durch das Ausmaß der Metastasierung und durch die Ausbildung von Therapieresistenzen bestimmt. Daher sollten in der vorliegenden Arbeit die Bedeutung des Transkriptionsfaktors HIF-1 für die Regulation der Metastasierung und die Vermittlung von Chemoresistenz im humanen Magenkarzinom untersucht und potentielle Wirkmechanismen identifiziert werden. Für diese Untersuchungen wurde eine funktionelle Inaktivierung der regulatorischen α-Untereinheit von HIF-1 (HIF-1α) in zwei humanen Magenkarzinomzelllinien mittels RNA-Interferenz erfolgreich etabliert. Erste Hinweise auf einen Einfluss von HIF-1 auf die Regulation der Metastasierung lieferte die Expressionsanalyse humaner Magenkarzinompräparate. Die immunhistochemische Untersuchung zeigte, dass HIF-1α vor allem in fortgeschrittenen Stadien der Magenkarzinogenese exprimiert wird, wobei invasiv wachsende Tumorbereiche eine verstärkte Expression aufwiesen. Die in vitro-Analyse verschiedener tumorrelevanter Parameter bestätigte die metastasierungsfördernde Wirkung von HIF-1: Die Inhibition von HIF-1α führte zu einer signifikanten Reduktion der Migration, der Invasion, der Anoikisresistenz und der Interaktion mit Endothelzellen. Als molekularer Mechanismus der HIF-1-bedingten Anoikisresistenz wurde eine Suppression des α5-Integrins identifiziert, das einen gut etablierten Vermittler der Anoikis darstellt. Durch diese umfangreiche Charakterisierung konnte HIF-1 erstmals als zentraler Regulator der Metastasierung beim humanen Magenkarzinom beschrieben werden. Des Weiteren führte die funktionelle Inaktivierung von HIF-1α zu einer Steigerung der antiproliferativen Wirkung des Chemotherapeutikums 5-Fluorouracil. Diese Daten legen nahe, dass HIF-1 eine zentrale Bedeutung bei der Resistenzvermittlung gegenüber der Chemotherapie im humanen Magenkarzinom zukommt. Die Analyse der verantwortlichen Mechanismen ergab, dass HIF-1 die Chemosensitivität der Magenkarzinomzellen einerseits durch Inhibition von p53 und andererseits durch Stimulation der NF-κB-Aktivität reguliert. Sowohl die Regulation der Anoikisresistenz durch Suppression des α5-Integrins als auch die Resistenzvermittlung durch Regulation von p53 beruhten zumindest teilweise auf einer HIF-1-abhängigen Hemmung reaktiver Sauerstoffspezies. Zusammengefasst zeigten sowohl deskriptive als auch funktionelle Untersuchungen der vorliegenden Arbeit, dass HIF-1 die systemische Metastasierung und die Therapiesensitivität des humanen Magenkarzinoms maßgeblich beeinflusst. In Anbetracht dieser Ergebnisse scheinen HIF-1-inhibierende Strategien eine innovative und sinnvolle Ergänzung der aktuellen Behandlungsverfahren für das humane Magenkarzinom darzustellen.Overexpression of the hypoxia-inducible transcription factor 1 (HIF-1) is a common feature in a wide variety of human tumors. In several studies HIF-1 has been identified as a positive factor for growth and progression of solid tumors. HIF-1 appears to play a central role in determining metastasis and in mediating chemoresistance; however, the underlying molecular mechanisms are only beginning to emerge. Human gastric cancer is characterized by an unfavourable prognosis. The course of this often fatal disease is mainly determined by the metastatic spread and the occurrence of therapy resistance. Therefore, the aim of the present study was to characterize HIF-1’s role in regulating metastasis and in mediating chemoresistance in human gastric cancer as well as the identification of potential underlying mechanisms. To achieve this, a functional inactivation of the regulatory α-subunit of HIF-1 (HIF-1α) in two human gastric cancer cell lines was established via lentiviral mediated RNA interference. The expression analysis of HIF-1α in human gastric cancer tissues initially indicated a functional relevance of HIF-1 for the regulation of metastasis. Immunhistochemistry showed specific HIF-1α staining in advanced gastric adenocarcinoma and especially high HIF-1α expression levels at the invading tumor edge. The assumed metastasis promoting impact of HIF-1 was further supported by the analysis of different tumor-relevant aspects in vitro: the inactivation of HIF-1α significantly reduced migration, invasion, anoikis resistance and adhesion to endothelial cells. Interestingly, the induction of anoikis resistance by HIF-1 was attributed to the suppression of the α5 integrin, a well established mediator of anoikis. In this comprehensive study, HIF-1 was characterized for the first time as a central regulator of metastasis in human gastric cancer. Furthermore, functional inactivation of HIF-1α significantly increased the antiproliferative effect of the chemotherapeutic agent 5-fluorouracil. These findings strongly suggest a pivotal role for HIF-1 in mediating chemoresistance in human gastric cancer. With respect to the underlying molecular mechanisms, the present study could show that HIF-1 regulates chemosensitivity of gastric cancer cells by inhibition of p53 protein as well as stimulation of NF-κB activity. Both, the α5 integrin-mediated anoikis resistance and the p53-regulated chemoresistance were at least partly caused by a HIF-1-dependent inhibition of reactive oxygen species. Taken together, both descriptive and functional investigations of the present study revealed that HIF-1 holds the potential to affect systemic metastasis and therapy sensitivity in human gastric cancer. In consideration of these results, HIF-1-inhibiting treatment strategies might be an innovative and useful supplement of the current treatment options for human gastric cancer

Strukturierte Peer-Support-Programme: Wie Hühneraugen und überlanges Warten die sprachliche und interkulturelle Kompetenz fördern

An australischen Universitäten werden jedes Jahr Tausende internationale Studierende empfangen, die teilweise Sprachen sprechen, die an australischen Universitäten gelehrt werden. Unsere Langzeitstudie, die seit 2004 an der University of Western Australia durchgeführt wird, untersucht die Art und Weise des Erwerbs der interkulturellen Kompetenz anhand von PeerSupport-Programmen, in denen deutschsprachige, internationale Studierende mit DaF-Studierenden zusammentreffen. In diesem Beitrag zeigen wir, wie Anreize zur interkulturellen Begegnung und Reflektion geschaffen werden können und der beiderseitige Lernprozess durch optimale Ausnutzung des Parameters von freiwilliger bis hin zu verpflichtender Teilnahme gefördert werden kann. Die qualitative und quantitative Auswertung von studentischen Aufsätzen und Interviews zum Thema kulturelle Unterschiede dokumentiert einen allseitigen Erkenntnisgewinn und zeigt, wie die geleitete Interaktion zur Verbesserung sprachlicher und interkultureller Kompetenzen beiträgt

Nah und fern

In dieser Sendung kapern Studierende der Hochschule für angewandte Wissenschaften in Hamburg das Studio. Heute geht es um das Thema „Nah und Fern“. Wir nehmen euch unter anderem mit in die Sesamstraße, schauen hinter die Kulissen einer Refugee-Kantine und beschäftigen uns mit Begriff Heimat. Die Leitung des Workshops hatte Ulrich Hägele