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The role of angiotensin-(1-7) and its receptors Mas and MrgD in the proliferation/regeneration of pancreatic β-cells
Full text linkDiabetes mellitus (DM) remains a burden affecting hundreds of millions of people worldwide with increasing prevalence. Achieving a genuine cure for type I diabetes mellitus (T1DM) relies on regenerating functional β-cell mass. The renin-angiotensin system (RAS), traditionally known for regulating blood pressure, also plays a crucial role in metabolic regulation and diabetic complications. The classical pathway contributes to metabolic issues, such as insulin resistance, while the alternative pathway provides protective effects. Angiotensin (Ang)-(1-7), a key peptide of the alternative pathway of the RAS, exhibits regenerative properties and is linked to beneficial effects on glucose homeostasis and β-cell function, making it a promising therapeutic strategy for DM. This study investigates the impact of Ang-(1-7) and its receptors, Mas and MrgD, on restoring glucose homeostasis by stimulating β-cell proliferation and differentiation. Wild-type normoglycemic mice received varying doses of Ang-(1-7) via an osmotic pump for 14 days to examine its effects on pancreatic islets and β-cell mass. Ang-(1-7) was also applied to wild-type and Mas and/or MrgD KO mice by osmotic pumps for 14 days to characterize its impact on insulin and glucose tolerance and identify the receptor mediating this action. Due to their role in glucose metabolism, the effect of Ang-(1-7) on insulin-induced phosphorylation of insulin receptor (IR), IR substrate-1 (IRS-1), and Akt was examined in WT and KO skeletal muscle cells. Isolated islets from WT and KO mice were stimulated with Ang-(1-7) to determine its effect on the transcription of key genes for β-cell identity, function, and maturation. Ang-(1-7) was administered to Streptozotocin (STZ)-induced diabetic mice to evaluate its therapeutic potential under pathophysiological conditions. The results showed that exogenous administration of Ang-(1-7) at 400 µg/kg/day significantly increased β-cell mass and insulin content in normoglycemic mice compared to lower or higher doses. Administering Ang-(1-7) had only marginal effects on glucose tolerance in wild-type mice but still led to improved insulin secretion in response to glucose in vivo. Ang-(1-7) improved insulin-induced phosphorylation of IRS-1 and Akt in primary skeletal muscle cells through the Mas receptor, highlighting the role of the Ang-(1-7)/Mas axis in glycemic control. Furthermore, Ang-(1-7)/MrgD axis was shown to upregulate essential genes for pancreatic β-cell function (Ins2), β-cell identity (PDX1, Nkx6.1), and β-cell maturation (TCIRG1, Fltp, Ucn3, and MafA). Ang-(1-7) also upregulates progenitor stem cell genes (Ngn3 and CD133) through the MrgD receptor, while it downregulates CD133 via the Mas receptor in the islets. Ultimately, administering Ang-(1-7) failed to repair STZ-induced damage to pancreatic β-cells or to restore insulin production ability within a 14-day treatment time. Despite this, Ang-(1-7) administration delayed the rise of blood glucose levels in STZ-induced diabetic mice. In conclusion, this thesis presents new evidence underlining the therapeutic potential of Ang-(1-7) and its mechanistic pathways, through Mas and MrgD receptors, emphasizing its importance as a promoter of β-cell proliferation and differentiation, thereby potentially
addressing the deficit of β-cell mass in T1DM
Zusammenhänge von Stressempfinden und Selbstwirksamkeitserwartung mit Emotionsregulation bei Lehramtsstudierenden
Full text linkLehramtsstudierende weisen ein erhöhtes Risiko auf, im Verlauf ihres Studiums und ihrer
beruflichen Laufbahn psychische Belastungsstörungen zu entwickeln. Ursächlich hierfür sind
insbesondere ein hohes Stressempfinden sowie unzureichend ausgeprägte
Bewältigungsstrategien. Die COVID-19-Pandemie hat diese Belastungen weiter intensiviert.
Diese Arbeit untersucht die Zusammenhänge zwischen Stressempfinden,
Selbstwirksamkeitserwartungen, Emotionsregulation, kognitiver und emotionaler Irritation und
COVID-19-bedingtem Stressempfinden bei Lehramtsstudierenden. Ziel ist es, diese
Erkenntnisse für die Entwicklung gezielter Präventions- und Interventionsmaßnahmen zu
nutzen, um die Gesundheit und das Wohlbefinden der angehenden Lehrkräfte zu fördern. Die
Untersuchung basiert auf einer querschnittlich angelegten quantitativen Studie mit 262
Lehramtsstudierenden an der Universität Greifswald. Die Erhebung der einzelnen Variablen
erfolgte jeweils zu Beginn und Ende des Wintersemesters 2020/21 und des Sommersemesters
2021 durch den Einsatz etablierter Fragebögen. Anschließend wurden die Zusammenhänge
zwischen den Variablen durch Korrelationsanalysen sowie lineare, hierarchische und
moderierte Regressionsanalysen untersucht. Die Ergebnisse zeigen, dass Stressempfinden mit
höherer emotionaler und kognitiver Irritation verbunden ist und dass die pandemiebedingten
Belastungen das Stressempfinden weiter verstärken. Eine höhere Selbstwirksamkeitserwartung
ist hingegen mit geringerer Irritation und einer besseren Emotionsregulation assoziiert. Zudem
hat Selbstwirksamkeitserwartung einen moderierenden Einfluss auf den Zusammenhang
zwischen Stressempfinden und emotionaler Irritation. Die vorliegende Arbeit hebt die
Wirksamkeit gezielter Interventionen zur Förderung von Selbstwirksamkeitserwartung und
Emotionsregulation hervor, um Stressempfinden und psychische Fehlbelastungen zu
verringern, insbesondere in Zeiten zusätzlicher Beanspruchungen, wie sie während einer
Pandemie auftreten. Dabei ist es wichtig, geschlechtsspezifische sowie schulformspezifische
Unterschiede zu berücksichtigen
Einfluss von kaltem atmosphärischem Plasma auf in vitro synchronisierte Osteosarkom-Zellen während verschiedener Zellzyklusphasen
Full text linkKaltes atmosphärisches Plasma (CAP) hat sich in den vergangenen Jahren in vitro als wirksames Mittel zur Hemmung des Zellwachstums ossärer Sarkome erwiesen. RONS-abhängige Mechanismen gelten bisher als Hauptdeterminanten der CAP-Wirksamkeit, wobei diese noch nicht vollends verstanden werden. Ein tiefergehendes Verständnis über die komplexen Wirkmechanismen von CAP ist daher dringend erforderlich. Die Wirksamkeit von CAP bei einer Behandlung während bestimmter Zellzyklusphasen wurde bisher nicht untersucht. Ob ossäre Sarkomzellen während einer bestimmten Zellzyklusphase besonders vulnerabel für eine CAP-Behandlung sind, war bis zum gegenwärtigen Zeitpunkt ebenfalls unbekannt.
Anhand eines präklinischen in vitro Osteosarkom-Modellsystems mit U2OS- und MNNG-HOS-Zellen wurde bestätigt, dass CAP die Proliferation von Osteosarkomzellen effektiv hemmt. Dies gilt für Behandlungen während des G1/S-Übergangs, der S-Phase sowie der G2-/M-Phase. Die Hemmung der Zellproliferation resultiert sowohl aus einer Induktion der Apoptose als auch aus einer Reduktion der Zellteilungsrate. Darüber hinaus wurde nach einer CAP-Behandlung während des G1/S-Übergangs sowie der S-Phase ein Verlust der Plasmamembranintegrität beobachtet. Besonders hervorzuheben ist die gesteigerte Induktion der caspaseabhängigen Apoptose bei CAP-Behandlungen während der S-Phase. Ferner bietet diese Arbeit eine valide Grundlage für zukünftige Experimente mit synchronisierten Osteosarkom-Zelllinien.
Diese Arbeit unterstreicht die Notwendigkeit weiterführender Grundlagenforschung, um das therapeutische Leistungsvermögen von CAP bei Osteosarkomen zu eruieren und zukünftig auszuschöpfen. Angesichts des ausgesprochen großen Bedarfs an innovativen Therapien für Patienten mit Osteosarkomen ist es essenziell, diese Forschung zu forcieren.In recent years, cold atmospheric plasma (CAP) has proven to be an effective in vitro method for inhibiting the cell growth of osseous sarcomas. RONS-dependent mechanisms are currently considered to be the main determinants of CAP efficacy, but these are not yet fully understood. Therefore a deeper understanding of the complex mechanisms of action of CAP is urgently needed. The efficacy of CAP treatments during specific cell cycle phases has not yet been investigated. Whether osteosarcoma cells are particularly vulnerable to CAP treatment during a specific cell cycle phase was also unknown until now.
Using the human osteosarcoma cell lines U2OS and MNNG-HOS in a preclinical in vitro model, we confirmed that CAP effectively inhibits osteosarcoma cell proliferation. This was observed for treatments administered during the G1/S transition, S phase, and G2-/M phase. The Inhibition of cell proliferation results both from the induction of apoptosis and from a reduction in the cell division rate. In addition, a loss of plasma membrane integrity was observed after CAP treatment during the G1/S transition and the S phase. Notably, the induction of caspase-dependent apoptosis is enhanced when CAP is applied during the S phase. Furthermore, this work provides a robust basis for future experiments employing synchronized osteosarcoma cell lines.
This study underscores the need for further fundamental research to elucidate and ultimately exploit the therapeutic potential of CAP in osteosarcoma. Given the exceedingly high demand for innovative therapies for patients with osteosarcoma, it is essential to intensify research in this field
Transcriptional activation domains interact with ATPase subunits of yeast chromatin remodelling complexes SWI/SNF, RSC and INO80
Full text linkChromatin remodelling complexes (CRC) are ATP-dependent molecular machines important for the dynamic organization of nucleosomes along eukaryotic DNA. CRCs SWI/SNF, RSC and INO80 can move positioned nucleosomes in promoter DNA, leading to nucleosome-depleted regions which facilitate access of general transcription factors. This function is strongly supported by transcriptional activators being able to interact with subunits of various CRCs. In this work we show that SWI/SNF subunits Swi1, Swi2, Snf5 and Snf6 can bind to activation domains of Ino2 required for expression of phospholipid biosynthetic genes in yeast. We identify an activator binding domain (ABD) of ATPase Swi2 and show that this ABD is functionally dispensable, presumably because ABDs of other SWI/SNF subunits can compensate for the loss. In contrast, mutational characterization of the ABD of the Swi2-related ATPase Sth1 revealed that some conserved basic and hydrophobic amino acids within this domain are essential for the function of Sth1. While ABDs of Swi2 and Sth1 define separate functional protein domains, mapping of an ABD within ATPase Ino80 showed co-localization with its HSA domain also required for binding actin-related proteins. Comparative interaction studies finally demonstrated that several unrelated activators each exhibit a specific binding pattern with ABDs of Swi2, Sth1 and Ino80
Drug administration via feeding tubes—a procedure that carries risks: systematic identification of critical factors based on commonly administered drugs in a cohort of stroke patients
Full text linkPurpose
Drug administration via feeding tubes is considered a process with many uncertainties. This review aimed to give a comprehensive overview of data available on feeding tube application and to carry out risk assessments for drug substances commonly administered to stroke patients.
Methods
Drugs frequently administered via feeding tubes were identified through a retrospective analysis of discharge letters from a stroke unit. Physicochemical, pharmacokinetic, and stability properties of these drugs and data on drug-enteral nutrition interactions were systematically searched for in the European Pharmacopoeia, Hagers Handbook of Pharmaceutical Practice, Birchers clinical-pharmacological data compilation, and the Martindale Complete Drug Reference, as well as from databases including DrugBank, DrugDex, PubChem, Google Scholar, and PubMed.
Results
Of the drugs most commonly administered via feeding tubes in the present stroke patient cohort, bisoprolol, candesartan, and ramipril could be considered the least critical due to their overall favourable properties. Acetylsalicylic acid, amlodipine, hydrochlorothiazide, omeprazole and esomeprazole, simvastatin, and torasemide pose risks based on pH or light-dependent instability or proposed food effects. The most critical drugs to be administered via feeding tubes are considered to be furosemide, levodopa, and levothyroxine as they show relevant instabilities under administration conditions and substantial food effects; the latter two even possess a narrow therapeutic index. However, little information is available on drug-tube and drug-formula interactions.
Conclusion
Feeding tube administration of medications turned out to be a highly complex process with several unmet risks. Therefore, investigations that systematically assess these risk factors using clinically relevant model systems are urgently needed
The role of MRI biomarkers in evaluation of symptomatic pineal cysts – a retrospective analysis
Full text linkBackground
Our aim was to determine whether the Apparent Diffusion Coefficient is able to predict the presence of a symptomatic pineal cyst by detecting cerebral edema.
Methods
We retrospectively analyzed MRIs of 45 patients with pineal cysts before and after resection and 51 patients without pineal cysts, comparing ADC values of thalamus, central, periventricular and subcortical white matter. Furthermore we evaluated cyst size and morphology and analyzed its correlation to ADC values in corresponding patients.
Results
Differences between patients with symptomatic pineal cyst and control group were not significant ( p = 0.200 – 0.968). ADC ratios did not change significantly after resection of the cyst ( p = 0.575 – 0.862). Cyst size showed no significant correlation to ADC ratios ( p = 0.071 – 0.918). Raw data analyses revealed more significance, especially periventricularly and in central white matter, which resulted in significant interhemispheric differences in ADC ratios in both subgroups ( p < 0.001 and p = 0.031). MRI of 1.5T showed consistently higher values than 3T but mostly insignificant.
Conclusion
Our analysis revealed no evidence that pineal cysts lead to intracerebral edema caused by venous compression. Since variability was higher than the differences seen, ADC sequences do not appear to be an appropriate diagnostic tool for symptomatic pineal cysts
FRUITS: feature extraction using iterated sums for time series classification
Full text linkWe introduce a pipeline for time series classification that extracts features based on the iterated-sums signature (ISS) and then applies a linear classifier. These features are intrinsically nonlinear, capture chronological information, and, under certain settings, are invariant to a form of time-warping. We achieve competitive results, both in accuracy and speed, on the UCR archive. We make our code available at https://github.com/irkri/fruits
Fecal glycoprotein 2 is a marker of gut microbiota dysbiosis and systemic inflammation
Full text linkBackground
Antimicrobial autoantigenic glycoprotein 2 (GP2) is an important component of the innate immune system which originates from the exocrine pancreas as well as from the small intestines. The relationship of GP2 with the intestinal microbiome as well as the systemic implications of increased fecal GP2 levels are, however, still unclear. Therefore, fecal samples from 2,812 individuals of the Study of Health in Pomerania (SHIP) were collected to determine GP2 levels (enzyme-linked immunosorbent assay) and gut microbiota profiles (16 S rRNA gene sequencing). These data were correlated and associated with highly standardised and comprehensive phenotypic data of the study participants.
Results
Fecal GP2 levels were increased in individuals with higher body mass index and smokers, whereas lower levels were found in case of preserved exocrine pancreatic function, female sex or a healthier diet. Moreover, higher GP2 levels were associated with increased serum levels of high-sensitivity C-reactive protein, loss of gut microbial diversity and an increase of potentially detrimental bacteria ( Streptococcus , Haemophilus , Clostridium XIVa , or Collinsella ). At the same time, predicted microbial pathways for the biosynthesis of beneficial short-chain fatty acids or lactic acid were depleted in individuals with high fecal GP2. Of note, GP2 exhibited a stronger association to overall microbiome variation than calprotectin.
Conclusion
Fecal GP2 is a biomarker of gut microbiota dysbiosis and associated with increased systemic inflammation. The intestines may be more important as origin for GP2 than pancreatic acinar cells. Future studies need to investigate the potential clinical value in disease specific patient cohorts
A “Self-Milieux” perspective on help-seeking: examining the impact of a person’s sociocultural background on help-seeking in people with untreated depressive symptoms
Full text linkBackground
Mental illness is a global concern and the leading cause of years lived with disability. Research on help-seeking behaviour has focused on individual factors, but there is still much unexplained variance. Suggesting complex interactions between determinants of human behaviour a new framework called Self-Milieux is proposed to represent a person’s sociocultural background. The article introduces a statistical approach to determine Self-Milieux and exemplarily examines its predictive validity for health-related research.
Methods
Self-Milieux are determined through a two-stage clustering method based on the determinants socioeconomic status and self-construal profile. Descriptive analyses are used to compare Self-Milieux characteristics. Hierarchical binary logistic regression models test the association between Self-Milieux and help-seeking behaviour, while controlling for socioeconomic status as an established predictor.
Results
The sample size was N = 1535 (Mage = 43.17 and 64.89% female participants). Average depression severity was M = 12.22, indicating mild to moderate symptoms. Six Self-Milieux were determined and named. Participants from privileged (aOR = 0.38) and self-sufficient (aOR = 0.37) milieux were less likely to seek help from a general practitioner than those from the entitled milieu. Participants from privileged (aOR = 0.30), collaborators (aOR = 0.50), disadvantaged (aOR = 0.33), and self-sufficient (aOR = 0.21) milieux were less likely to seek help from family members than those from the entitled and family-bound milieux.
Discussion
The study’s strengths and limitations, as well as the cluster methodology, are discussed. The comparative results for the six Self-Milieux are interpreted based on current research. For example, participants from some milieux follow a help-seeking process proposed in previous research, while participants from other milieux seem to show a different process, one that ends in informal help-seeking
Profitieren Palliativpatienten von einer genuin zahnmedizinischen Betreuung? Eine Interventionsstudie auf der Palliativstation des Helios Klinikums Bad Saarow
Full text linkDespite the significant impact of oral problems on the quality of life of palliative care patients, comprehensive studies are lacking. This study is the first of its kind to address this gap by including both a dental examination and an intervention and assessing quality of life using the EORTC QLQ OH 15 questionnaire.Palliativpatienten leiden in der letzten Lebensphase oft an quälenden oralen Symptomen wie Mundtrockenheit, Candidiasis, Aphthen, Druckstellen und Ent-zündungen der Mundhöhle. Bisher gibt es zu dieser Thematik weder eine gute Datenlage noch ausreichend publizierte Literatur. Aufgrund der Literaturrecherchen im Rahmen der Studie und der in diesem Kontext geführten Gespräche mit anderen Palliativeinheiten ist davon auszugehen, dass bisher oft Strukturen und Konzepte für die zahnärztliche Behandlung von Palliativpatienten fehlen.
Die vorliegende Studie untersuchte die Fragestellung, ob eine zahnmedizinische Begleitung und Behandlung von Palliativpatienten zu einer Verbesserung der mund-gesundheitsbezogenen Lebensqualität und Linderung der Symptomlast führen und ob somit eine zahnmedizinische Betreuung Teil der palliativen Komplexbehandlung sein sollte.
Die insgesamt 103 Patienten einer authentischen Stichprobe neu aufgenommener Patienten einer Palliativstation zeigte ein deutliches Versorgungsdefizit; so wiesen nur ein knappes Drittel der Patienten eine gute Mundhygiene auf, die überwiegende Mehrheit zeigte dagegen erhebliche Beeinträchtigungen, die detailliert dokumentiert wurden. Der Prä-Post-Vergleich nach einer genuin zahnmedizinischen Betreuung dieser Patienten lieferte empirische Belege für den Nutzen einer solchen palliativen Komplexbehandlung mit integrierter zahnärztlicher Betreuung. Durch regelmäßige zahnärztliche Konsultationen konnte insbesondere eine signifikante Verbesserung der Symptome klebriger Speichel, Probleme mit Sensitivitäten beim Essen und Trinken, Mundtrockenheit und schlechtsitzender Zahnersatz erzielt werden. Zudem verbesser-ten sich die Symptome Mukositis und Candidiasis.
Hervorzuheben ist, dass diese Interventionen, ohne einen großen medizinischen Aufwand oder Equipment, direkt am Patientenbett durchgeführt werden können.
Die positive Resonanz sowohl der Patienten als auch des Pflegepersonals unterstreicht die Notwendigkeit, die zahnärztliche Betreuung als integralen Bestandteil der palliativen Versorgung zu etablieren