Showing papers by "Martina Schmidt published in 2021"

Elevated cAMP protects against diclofenac-induced toxicity in primary rat hepatocytes: a protective effect mediated by EPACs

Abstract: Chronic consumption of the nonsteroidal anti-inflammatory drug diclofenac may induce drug-induced liver injury (DILI) The mechanism of diclofenac-induced liver injury is partially elucidated and involves mitochondrial damage Elevated cAMP protects hepatocytes against bile acid-induced injury However, it is unknown whether cAMP protects against DILI and, if so, which downstream targets of cAMP are implicated in the protective mechanism, including the classic protein kinase A (PKA) pathway or alternative pathways like the exchange protein directly activated by cAMP (EPAC) The aim of this study was to investigate whether cAMP and/or its downstream targets protect against diclofenac-induced injury in hepatocytes Rat hepatocytes were exposed to 400 µmol/l diclofenac Apoptosis and necrosis were measured by caspase-3 activity assay and Sytox green staining, respectively Mitochondrial membrane potential (MMP) was measured by JC-10 staining mRNA and protein expression were assessed by quantitative polymerase chain reaction (qPCR) and Western blot, respectively The cAMP-elevating agent 7β-acetoxy-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one (forskolin), the pan-phosphodiesterase inhibitor IBMX, and EPAC inhibitors 5,7-dibromo-6-fluoro-3,4-dihydro-2-methyl-1(2H)-quinoline carboxaldehyde (CE3F4) and ESI-O5 were used to assess the role of cAMP and its effectors, PKA or EPAC Diclofenac exposure induced apoptotic cell death and loss of MMP in hepatocytes Both forskolin and IBMX prevented diclofenac-induced apoptosis EPAC inhibition but not PKA inhibition abolished the protective effect of forskolin and IBMX Forskolin and IBMX preserved the MMP, whereas both EPAC inhibitors diminished this effect Both EPAC1 and EPAC2 were expressed in hepatocytes and localized in mitochondria cAMP elevation protects hepatocytes against diclofenac-induced cell death, a process primarily involving EPACs The cAMP/EPAC pathway may be a novel target for treatment of DILI SIGNIFICANCE STATEMENT: This study shows two main highlights First, elevated cAMP levels protect against diclofenac-induced apoptosis in primary hepatocytes via maintenance of mitochondrial integrity In addition, this study proposes the existence of mitochondrial cAMP-EPAC microdomains in rat hepatocytes, opening new avenues for targeted therapy in drug-induced liver injury (DILI) Both EPAC1 and EPAC2, but not protein kinase A, are responsible for this protective effect Our findings present cAMP-EPAC as a potential target for the treatment of DILI and liver injury involving mitochondrial dysfunction

Mental health and health-related quality of life in preschool-aged childhood cancer survivors. Results of the prospective cohort study ikidS-OEVA.

Abstract: Objectives Long-term survivors of childhood cancer are at increased risk for sequelae such as poor mental health (MH) or impaired health-related quality of life (HrQoL). We aimed to evaluate early adverse effects on MH and HrQoL in young childhood cancer survivors (YCCS) before school entry. Methods In a nationwide prospective cohort study, children with cancer other than brain tumors diagnosed at preschool age and completed cancer treatments were identified from the German Childhood Cancer Registry. The comparison group was children of the same age without a cancer diagnosis who participated in the prospective population-based health survey ikidS. MH problems and HrQoL were assessed by parental versions of the Strengths and Difficulties Questionnaire (SDQ) and the questionnaire for health-related quality of life in children (KINDL), respectively. Associations between cancer and MH as well as HrQoL were analyzed by multivariable linear regression. Results Of 382 YCCS contacted, 145 were enrolled (mean age 6.6 years) and 124 analyzed. Compared to children without a cancer diagnosis (3683 contacted, 2003 enrolled, 1422 analyzed), YCCS had more MH problems (13% vs. 3%) and slightly worse HrQoL (median 78.7 vs. 80.2 points). In the adjusted analysis, YCCS had higher SDQ scores (2.2 points, 95% confidence interval [CI] 1.3, 3.0) and lower KINDL scores (-2.4 points, 95% CI -3.7, -1.1) compared to children without cancer diagnosis. Conclusion Already at preschool age, YCCS may be at increased risk of MH problems and impaired HrQoL. This could have impacts on subsequent school performance and educational attainment. Follow-up health care for YCCS may include early screening for MH problems and reasons for HrQoL deficits.

Glucosamine protects against neuronal but not vascular damage in experimental diabetic retinopathy

Abstract: Objective Glucosamine, an intermetabolite of the hexosamine biosynthesis pathway (HBP), is a widely used nutritional supplement in osteoarthritis patients, a subset of whom also suffer from diabetes. HBP is activated in diabetic retinopathy (DR). The aim of this study is to investigate the yet unclear effects of glucosamine on DR. Methods In this study, we tested the effect of glucosamine on vascular and neuronal pathology in a mouse model of streptozotocin-induced DR in vivo and on cultured endothelial and Muller cells to elucidate the underlying mechanisms of action in vitro. Results Glucosamine did not alter the blood glucose or HbA1c levels in the animals, but induced body weight gain in the non-diabetic animals. Interestingly, the impaired neuronal function in diabetic animals could be prevented by glucosamine treatment. Correspondingly, the activation of Muller cells was prevented in the retina as well as in cell culture. Conversely, glucosamine administration in the normal retina damaged the retinal vasculature by increasing pericyte loss and acellular capillary formation, likely by interfering with endothelial survival signals as seen in vitro in cultured endothelial cells. Nevertheless, under diabetic conditions, no further increase in the detrimental effects were observed. Conclusions In conclusion, the effects of glucosamine supplementation in the retina appear to be a double-edged sword: neuronal protection in the diabetic retina and vascular damage in the normal retina. Thus, glucosamine supplementation in osteoarthritis patients with or without diabetes should be taken with care.

Age at school entry and reported symptoms of attention-deficit/hyperactivity in first graders: results of the prospective cohort study ikidS.

Abstract: Young age at school entry (ASE) is related to attention-deficit/hyperactivity disorder in higher grades. The reason for this association is unclear, but medical oversupply and stress-related factors are discussed. We aimed to investigate whether ASE is associated with reported symptoms of attention-deficit/hyperactivity (ADH) already in first grade. Data of a population-based prospective cohort study (N = 2003; Mainz-Bingen region; Rhineland-Palatinate; Germany) with baseline assessments prior to school entry and two follow-ups during first grade were analysed. ADH symptoms were assessed by parent and teacher versions of the Strengths and Difficulties Questionnaire. Associations between ASE and scores of the hyperactivity/inattention subscale (range 0–10) were investigated by regression analysis and adjusted for potential confounders and baseline symptoms prior to school entry. In total, 1633 children (52% boys, mean ASE 6.5 years) were included. There were no relationships between ASE and parent-reported scores of the hyperactivity/inattention subscale prior to school entry and 3 months thereafter. However, at the end of first grade, ASE was negatively associated with the hyperactivity/inattention subscale in parent (− 0.7 subscale points per year ASE, standard error = 0.16, p < 0.0001) and teacher reports (− 1.2 subscale points per year ASE, standard error = 0.25, p < 0.0001). This ASE effect appeared more pronounced in girls than in boys. Young ASE is related to more reported symptoms of ADH at the end of first grade, but not before. The evolvement of this effect during first grade may be a clue to ASE-related stress factors.

Effects of (a Combination of) the Beta2-Adrenoceptor Agonist Indacaterol and the Muscarinic Receptor Antagonist Glycopyrrolate on Intrapulmonary Airway Constriction.

Abstract: Expression of bronchodilatory β2-adrenoceptors and bronchoconstrictive muscarinic M3-receptors alter with airway size. In COPD, (a combination of) β2-agonists and muscarinic M3-antagonists (anticholinergics) are used as bronchodilators. We studied whether differential receptor expression in large and small airways affects the response to β2-agonists and anticholinergics in COPD. Bronchoprotection by indacaterol (β2-agonist) and glycopyrrolate (anticholinergic) against methacholine- and EFS-induced constrictions of large and small airways was measured in guinea pig and human lung slices using video-assisted microscopy. In guinea pig lung slices, glycopyrrolate (1, 3 and 10 nM) concentration-dependently protected against methacholine- and EFS-induced constrictions, with no differences between large and small intrapulmonary airways. Indacaterol (0.01, 0.1, 1 and 10 μM) also provided concentration-dependent protection, which was greater in large airways against methacholine and in small airways against EFS. Indacaterol (10 μM) and glycopyrrolate (10 nM) normalized small airway hyperresponsiveness in COPD lung slices. Synergy of low indacaterol (10 nM) and glycopyrrolate (1 nM) concentrations was greater in LPS-challenged guinea pigs (COPD model) compared to saline-challenged controls. In conclusion, glycopyrrolate similarly protects large and small airways, whereas the protective effect of indacaterol in the small, but not the large, airways depends on the contractile stimulus used. Moreover, findings in a guinea pig model indicate that the synergistic bronchoprotective effect of indacaterol and glycopyrrolate is enhanced in COPD.

Isotopic characterization of coal mine methane in the Upper Silesian Coal Basin, Poland

Abstract:

Emissions from fossil fuels are one of the primary sources of atmospheric methane (CH₄) growth. However, estimates of anthropogenic CH₄ emissions still show large uncertainties on global and regional scales. Differences in CH₄ isotopic source signatures δ¹³C and δD can help to constrain different source contributions (e.g. fossil, thermogenic, or biogenic).

The Upper Silesian Coal Basin (USCB) represents one of the largest European CH₄ emission source regions, with more than 500 Gg CH₄ yr^-1 released by more than 50 coal mine ventilation shafts. During the CoMet (Carbon Dioxide and Methane Mission) campaign in June 2018 methane observations were conducted from a variety of platforms including aircraft and cars. Beside the continuous sampling of atmospheric methane concentration, numerous air samples were taken from inside the ventilation shafts, around the ventilation shafts (1‑2 km distance) and aboard the DLR Cessna Caravan aircraft and analyzed in the laboratory for the isotopic composition of CH₄.

The ground-based samples allowed determining the source signatures of individual ventilation shafts. These signatures displayed a considerable range between different shafts and also varied from day to day. The airborne samples contained a mixture of methane emissions from several mines and thus enabled accurately determining the signature of the entire region. The mean isotopic signature of methane emissions over the USCB derived from the aircraft samples was -51.9 ± 0.5 ‰ for δ¹³C and -233 ± 6 ‰ for δD. This is in between the range of other microbial and thermogenic coal reservoirs, but more depleted in δD than previous USCB studies reported based on samples taken within the mines. Signatures of methane enhancements sampled upwind of the mines and in the free troposphere clearly showed the presence of methane of biogenic origin (e.g. wetlands, waste, ruminants).

Furthermore, we simulated the methane isotopologues using the on-line three-times nested global regional chemistry climate model MECO(n). We implemented a submodel extension, which includes the kinetic fractionation and uses the isotopic source signatures determined by the ground-based observations. We compare the regional simulations to flask samples taken during CoMet.

A transcriptomics-guided drug target discovery strategy identifies novel receptor ligands for lung regeneration

Abstract: Currently, there is no pharmacological treatment targeting defective tissue repair in chronic disease. Here we utilized a transcriptomics-guided drug target discovery strategy using gene signatures of smoking-associated chronic obstructive pulmonary disease (COPD) and from mice chronically exposed to cigarette smoke, identifying druggable targets expressed in alveolar epithelial progenitors of which we screened the function in lung organoids. We found several drug targets with regenerative potential of which EP and IP prostanoid receptor ligands had the most significant therapeutic potential in restoring cigarette smoke-induced defects in alveolar epithelial progenitors in vitro and in vivo. Mechanistically, we discovered by using scRNA-sequencing analysis that circadian clock and cell cycle/apoptosis signaling pathways were enriched in alveolar epithelial progenitor cells in COPD patients and in a relevant model of COPD, which was prevented by PGE2 or PGI2 mimetics. Conclusively, specific targeting of EP and IP receptors offers therapeutic potential for injury to repair in COPD.

Evaluation der Sprachaufgaben des sozialpädiatrischenEntwicklungsscreenings für Schuleingangsuntersuchungen (SOPESS):Ergebnisse der prospektiven Kindergesundheitsstudie ikidS

Abstract: Hintergrund Eine fruhe Diagnostik und Behandlung von Entwicklungsstorungen vor der Einschulung ist fur den weiteren Bildungserfolg masgeblich. Deshalb wurde das Sozialpadiatrische Entwicklungsscreening fur Schuleingangsuntersuchungen (SOPESS) konzipiert und in mehreren Bundeslandern flachendeckend eingefuhrt. Fragestellung Wir untersuchten die Zusammenhange zwischen den Screening-Ergebnissen der SOPESS-Sprachaufgaben vor der Einschulung und den schulischen Sprachkompetenzen am Ende der ersten Klasse als Teil einer umfassenden Evaluation des SOPESS. Methoden Daten der rheinland-pfalzischen Schuleingangsuntersuchung und der prospektiven Kindergesundheitsstudie ikidS wurden zusammengefuhrt und ausgewertet. Zusammenhange zwischen dem Gesamtrisikowert Sprache des SOPESS vor Einschulung (ordinal-skaliertes Merkmal, 6 Risikostufen) und dem Gesamtfahigkeitswert Sprache am Ende der ersten Klasse (subjektive Lehrkrafteinschatzung, intervall-skaliertes Merkmal, Range −4 bis+4) wurden mittels linearer Regressionsmodelle ohne und mit Berucksichtigung von weiteren sozio-demografischen und medizinischen Sprachpradiktoren untersucht (z. B. Alter bei Einschulung, Geschlecht, Schulbildung der Eltern, Migrationshintergrund, Horstorung). Der zusatzliche Nutzen des Gesamtrisikowertes Sprache des SOPESS wurde durch Varianzanalysen gepruft. Ergebnisse In die Auswertung konnten 1357 Kinder einbezogen werden (48% Madchen, Alter bei Schuleingangsuntersuchung 4,9–7,2 Jahre). Es zeigte sich ein klarer negativer Zusammenhang zwischen den Stufen des Gesamtrisikowertes Sprache des SOPESS und den schulischen Sprachkompetenzen. In der Risikostufe 0 (kein Risiko) lag der Mittelwert der Sprachkompetenzen bei 0,8 (SD=1,7); in der Stufe 6 (hohes Risiko fur Entwicklungsstorung) sank der Wert auf −3,2 Punkte ab (SD=0,9). Varianzanalysen zeigten zudem, dass der Gesamtrisikowert Sprache des SOPESS einen signifikanten Zusatznutzen gegenuber weiteren Sprachpradiktoren hat. Schlussfolgerungen Es zeigte sich ein klarer Zusammenhang zwischen den vorschulischen SOPESS-Sprachaufgaben und den schulischen Sprachkompetenzen am Ende der ersten Klasse. Dieses Sprachscreening konnte daher – unter Einbezug von weiteren soziodemografischen und medizinischen Pradiktoren – die Basis fur eine passgenaue Auswahl von weiteren Versorgungs- und/oder Fordermasnahmen sein.

Lebensqualität nach Brustkrebs: Erfassung, Relevanz und effektive Interventionen

Abstract: Gesundheitsbezogene Lebensqualitat ist fur Brustkrebsbetroffene in allen Stadien, sowohl wahrend als auch mittel- und langfristig nach Abschluss der Therapie, von groser Relevanz. Bei Zulassungsstudien fur neue Behandlungen sowie wissenschaftlichen Studien zum Vergleich verschiedener Therapien gewinnt Lebensqualitat als Endpunkt zunehmend an Bedeutung. Neben einer kurzen globalen Einschatzung der Lebensqualitat sollten weitere wichtige Patient-Reported Outcomes erhoben werden. Patientinnen mit Brustkrebs berichten haufig uber Einschrankungen durch Fatigue, Schlafprobleme, sexuelle bzw. klimakterische Probleme, kognitive Probleme, psychische Probleme und Verlust an korperlicher Leistungsfahigkeit. Die Lebensqualitat nach Brustkrebs konnte vermutlich weiter gesteigert werden, wenn Aufklarung, Screening und Behandlung dieser Symptome systematischer Bestandteil der onkologischen Versorgung wurden.