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  • 1
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    Online Resource
    Placental Transcriptome Profiling in Subtypes of Diabetic Pregnancies Is Strongly Confounded by Fetal Sex
    MDPI AG ; 2022
    In:  International Journal of Molecular Sciences Vol. 23, No. 23 ( 2022-12-06), p. 15388-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 23, No. 23 ( 2022-12-06), p. 15388-
    Abstract: The placenta is a temporary organ with a unique structure and function to ensure healthy fetal development. Placental dysfunction is involved in pre-eclampsia (PE), fetal growth restriction, preterm birth, and gestational diabetes mellitus (GDM). A diabetic state affects maternal and fetal health and may lead to functional alterations of placental metabolism, inflammation, hypoxia, and weight, amplifying the fetal stress. The placental molecular adaptations to the diabetic environment and the adaptive spatio–temporal consequences to elevated glucose or insulin are largely unknown (2). We aimed to identify gene expression signatures related to the diabetic placental pathology of placentas from women with diabetes mellitus. Human placenta samples (n = 77) consisting of healthy controls, women with either gestational diabetes mellitus (GDM), type 1 or type 2 diabetes, and women with GDM, type 1 or type 2 diabetes and superimposed PE were collected. Interestingly, gene expression differences quantified by total RNA sequencing were mainly driven by fetal sex rather than clinical diagnosis. Association of the principal components with a full set of clinical patient data identified fetal sex as the single main explanatory variable. Accordingly, placentas complicated by type 1 and type 2 diabetes showed only few differentially expressed genes, while possible effects of GDM and diabetic pregnancy complicated by PE were not identifiable in this cohort. We conclude that fetal sex has a prominent effect on the placental transcriptome, dominating and confounding gene expression signatures resulting from diabetes mellitus in settings of well-controlled diabetic disease. Our results support the notion of placenta as a sexual dimorphic organ.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms232315388
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2019364-6
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  • 2
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    Abstract P226: Transcriptome Signature Of Placentas From Diabetic Pregnancies Is Confounded By Fetal Sex.
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Hypertension Vol. 78, No. Suppl_1 ( 2021-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 78, No. Suppl_1 ( 2021-09)
    Abstract: Hypertension-associated obstetric diseases like diabetes mellitus (DM) or preeclampsia occur in 25-35% of pregnancies and are related to placental dysfunction. The placenta has a unique structure and function to guarantee healthy pregnancy, fetal development, and outcome. Thus, the diabetic environment featuring inflammation, metabolic alterations, and hypoxia, is challenging with increased stress for mother and foetus. Delivery-related complications and adverse post-pregnancy outcomes, for example the increased risk for preeclampsia, are related to placental pathology in the different types of DM. Therefore, understanding disturbed placental development during pathologic pregnancy is important. We hypothesize a placental transcriptome signature present in pathologic pregnancy. We aimed to broaden our understanding of placental adaptations to various forms of diabetic pregnancy. Human placenta samples from healthy controls (n = 29), women with gestational DM (GDM, n = 12), DM type 1 (DM1, n = 17), DM type 2 (DM2, n = 3) and GDM, DM1 or DM2 superimposed by preeclampsia (n = 16) were included. We quantified gene expression by Illumina TruSeq stranded total RNA Sequencing and analyzed data by means of principal component analysis (PCA), differential expression and gene set enrichment. The samples were mainly split by fetal sex in the PCA rather than diabetic subgroups. Genes associated with the principal components were primary located on the male sex chromosome ( Xist, Uty, Usp9y, Ddx3y ) and only weakly enriched in functionally relevant gene sets. The fetal sex was identified as single main explanatory variable when the principal components were associated with clinical patient data. Placentas complicated by DM2 identified 93 and 27 significant differential expressed genes (DEG; adj. p-value 〈 0.05) in comparison to healthy controls and GDM, respectively. Comparison of DM1 to DM2 or GDM showed four and two significant genes. In this cohort possible effects of GDM and preeclampsia were not observed.We conclude that fetal sex is dominating placental gene expression and confounding transcriptome signatures resulting from diabetes, in settings of well controlled diabetic disease.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.78.suppl_1.P226
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 2094210-2
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  • 3
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    Diabetic pregnancy as a novel risk factor for cardiac dysfunction in the offspring—the heart as a target for fetal programming in rats
    Springer Science and Business Media LLC ; 2021
    In:  Diabetologia Vol. 64, No. 12 ( 2021-12), p. 2829-2842
    Details
    In: Diabetologia, Springer Science and Business Media LLC, Vol. 64, No. 12 ( 2021-12), p. 2829-2842
    Abstract: The impact of diabetic pregnancy has been investigated extensively regarding offspring metabolism; however, little is known about the influence on the heart. We aimed to characterise the effects of a diabetic pregnancy on male adult offspring cardiac health after feeding a high-fat diet in an established transgenic rat model. Methods We applied our rat model for maternal type 2 diabetes characterised by maternal insulin resistance with hyperglycaemia and hyperinsulinaemia. Diabetes was induced preconceptionally via doxycycline-induced knock down of the insulin receptor in transgenic rats. Male wild-type offspring of diabetic and normoglycaemic pregnancies were raised by foster mothers, followed up into adulthood and subgroups were challenged by a high-fat diet. Cardiac phenotype was assessed by innovative speckle tracking echocardiography, circulating factors, immunohistochemistry and gene expression in the heart. Results When feeding normal chow, we did not observe differences in cardiac function, gene expression and plasma brain natriuretic peptide between adult diabetic or normoglycaemic offspring. Interestingly, when being fed a high-fat diet, adult offspring of diabetic pregnancy demonstrated decreased global longitudinal (−14.82 ± 0.59 vs −16.60 ± 0.48%) and circumferential strain (−23.40 ± 0.57 vs −26.74 ± 0.34%), increased relative wall thickness (0.53 ± 0.06 vs 0.37 ± 0.02), altered cardiac gene expression, enlarged cardiomyocytes (106.60 ± 4.14 vs 87.94 ± 1.67 μm), an accumulation of immune cells in the heart (10.27 ± 0.30 vs 6.48 ± 0.48 per fov) and higher plasma brain natriuretic peptide levels (0.50 ± 0.12 vs 0.12 ± 0.03 ng/ml) compared with normoglycaemic offspring on a high-fat diet. Blood pressure, urinary albumin, blood glucose and body weight were unaltered between groups on a high-fat diet. Conclusions/interpretation Diabetic pregnancy in rats induces cardiac dysfunction, left ventricular hypertrophy and altered proinflammatory status in adult offspring only after a high-fat diet. A diabetic pregnancy itself was not sufficient to impair myocardial function and gene expression in male offspring later in life. This suggests that a postnatal high-fat diet is important for the development of cardiac dysfunction in rat offspring after diabetic pregnancy. Our data provide evidence that a diabetic pregnancy is a novel cardiac risk factor that becomes relevant when other challenges, such as a high-fat diet, are present. Graphical abstract
    Type of Medium: Online Resource
    ISSN: 0012-186X , 1432-0428
    URL: Article
    DOI: 10.1007/s00125-021-05566-5
    RVK:
    XA 40615
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 1458993-X
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  • 4
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    Abstract P212: Kidney Injury Caused By Preeclamptic Pregnancy Improves Postpartum In A Transgenic Rat Model
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Hypertension Vol. 76, No. Suppl_1 ( 2020-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 76, No. Suppl_1 ( 2020-09)
    Abstract: Preeclamptic pregnancies involve mild renal injuries. However, there has been evidence that women with a history of preeclampsia (PE) have an increased risk to develop kidney disease in association to high blood pressure later in life. This study aims to characterize renal injury during pregnancy and postpartum in an established transgenic rat model for PE. Female Sprague-Dawley rats transgenic for the human angiotensinogen gene develop a PE phenotype in pregnancy, including cardiac remodeling, when mated with male rats harboring the human renin gene. Postpartum, blood pressure restores but cardiac remodeling persists. We hypothesize that PE during pregnancy mediates kidney injuries but does not fully restore after ending of the high blood pressure (postpartum). The renal alterations were analyzed by histological staining, gene expression and urine analysis. PE rats have elevated mean arterial blood pressure during pregnancy (PE d19 148.4 ± 20.7 mmHg) compared to normotensive values in control animals (WT d19 105.3 ± 4.6 mmHg). During PE increased expression of kidney injury marker 1 ( Kim-1/18S : PE d21 4.14 ± 3.26; WT d21 0.08 ± 0.02), neutrophil gelatinase associated lipocalin 2 ( Ngal/18S : PE d21 1.64 ± 0.83; WT d21 0.59 ± 0.28) and connective-tissue growth factor ( Ctgf/18S: PE d21 1.51 ± 0.46; WT d21 0.92 ± 0.32) were detected. Kidneys of PE rats showed mild glomerular (PAS-positive glomerular area PE d21 86.2 ± 4.4%; WT d21 79.1 ± 3.2%) and tubular changes during PE pregnancy resulting in albuminuria (albumin/creatinine ratio PE d19 2193.8 ± 1878.2; WT d19 290.4 ± 252.0). However, 4 weeks after pregnancy (approx. 2 years in humans) most of the PE related renal damages were absent including albuminuria and elevated expression of biomarkers ( Kim-1/18S : PE d50 0.09 ± 0.05; WT d50 0.23 ± 0.13; Ctgf/18S : PE d50 0.78 ± 0.25; WT d50 0.8 ± 0.25; Ngal/18S : PE d50 0.37 ± 0.17; WT 50 0.47 ± 0.11). Only mild enlargement of glomerular tuft area (PE d50 7523.8 ± 418.7 μm 2 ; WT d50 7058.4 ± 198.8 μm 2 ) was detected. Overall, the glomerular and tubular injuries are present during pregnancy in this transgenic PE rat. Most restore postpartum, speculating long-term kidney failure observed in humans is associated to hypertension and additional cardiovascular events.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.76.suppl_1.P212
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 2094210-2
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  • 5
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    Intrauterine Exposure to Diabetic Milieu Does Not Induce Diabetes and Obesity in Male Adulthood in a Novel Rat Model
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Hypertension Vol. 77, No. 1 ( 2021-01), p. 202-215
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 77, No. 1 ( 2021-01), p. 202-215
    Abstract: Several studies show an association of maternal diabetes during pregnancy with adverse offspring metabolic health. Other studies, however, suggest that this effect might be biased by obesity, which is independently associated with offspring metabolic disease and often coexistent to maternal diabetes. We performed a prospective study in a rat model to test the hypothesis that the burden of a diabetic pregnancy without obesity deteriorates metabolic health in male offspring. We generated maternal type 2 diabetes before conception that persisted during pregnancy by knockdown of the insulin receptor in small hairpin RNA–expressing transgenic rats. Male WT (wild type) offspring were followed up until adulthood and metabolically challenged by high-fat diet. Blood glucose was measured continuously via a telemetry device. Glucose and insulin tolerance tests were performed, and body composition was analyzed. Weight gain and glucose levels during adolescence and adulthood were similar in male offspring of diabetic and control pregnancies. Body weight and fat mass after high-fat diet, as well as glucose and insulin tolerance tests, were unaltered between male adult offspring of both groups. Glycemic control consisting of up to 49 000 individual glucose measures was comparable between both groups. Intrauterine exposure to maternal hyperglycemia and hyperinsulinemia without obesity had no impact on male offspring metabolic health in our model. We conclude that the intrauterine exposure itself does not represent a mechanism for fetal programming of diabetes and obesity in our model. Other maternal metabolic parameters during pregnancy, such as obesity, might impact long-term offspring metabolic health.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/HYPERTENSIONAHA.120.16360
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 2094210-2
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  • 6
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    Kidney Injury Caused by Preeclamptic Pregnancy Recovers Postpartum in a Transgenic Rat Model
    MDPI AG ; 2021
    In:  International Journal of Molecular Sciences Vol. 22, No. 7 ( 2021-04-05), p. 3762-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 22, No. 7 ( 2021-04-05), p. 3762-
    Abstract: Preeclampsia (PE) is characterized by the onset of hypertension (≥140/90 mmHg) and presence of proteinuria ( 〉 300 mg/L/24 h urine) or other maternal organ dysfunctions. During human PE, renal injuries have been observed. Some studies suggest that women with PE diagnosis have an increased risk to develop renal diseases later in life. However, in human studies PE as a single cause of this development cannot be investigated. Here, we aimed to investigate the effect of PE on postpartum renal damage in an established transgenic PE rat model. Female rats harboring the human-angiotensinogen gene develop a preeclamptic phenotype after mating with male rats harboring the human-renin gene, but are normotensive before and after pregnancy. During pregnancy PE rats developed mild tubular and glomerular changes assessed by histologic analysis, increased gene expression of renal damage markers such as kidney injury marker 1 and connective-tissue growth factor, and albuminuria compared to female wild-type rats (WT). However, four weeks postpartum, most PE-related renal pathologies were absent, including albuminuria and elevated biomarker expression. Only mild enlargement of the glomerular tuft could be detected. Overall, the glomerular and tubular function were affected during pregnancy in the transgenic PE rat. However, almost all these pathologies observed during PE recovered postpartum.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms22073762
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2019364-6
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  • 7
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    Soluble guanylate cyclase (sGC) stimulation with vericiguat : From the pharmacological idea to the treatment of chronic heart failure
    Springer Science and Business Media LLC ; 2022
    In:  Die Kardiologie Vol. 16, No. 6 ( 2022-12), p. 466-478
    Details
    In: Die Kardiologie, Springer Science and Business Media LLC, Vol. 16, No. 6 ( 2022-12), p. 466-478
    Abstract: According to the new European Society of Cardiology (ESC) guidelines on the diagnostics and treatment of acute and chronic heart failure, vericiguat (Verquvo®) can be included in the treatment of adult patients with symptomatic chronic heart failure and reduced ejection fraction who, despite standard treatment after a recently occurring decompensation event, were stabilized with the necessary intravenous (i.v.) therapy. Objective This review article summarizes the development of vericiguat, a soluble guanylate cyclase stimulator (sGC stimulator), which is a good example for the stringent implementation of a novel pharmacological therapy approach into treatment of heart failure. It provides valuable approaches for the practical use via the characterization of this patient collective that was investigated for the first time. Results The two relevant trials in the clinical development program for vericiguat, SOCRATES-Reduced and VICTORIA, have clearly demonstrated the efficacy and safety of vericiguat. The primary efficacy endpoint in the VICTORIA study “cardiovascular death or hospitalization due to heart failure” was significantly reduced in the vericiguat arm compared to placebo. Relevant subgroup analyses as well as safety data confirm this result and support the safe use in this high-risk population. Conclusion The presented data allow the conclusion that vericiguat can be efficaciously and safely added to an existing treatment with a recommended standard medication for heart failure. It can be expected that in the routine practice the target dose of 10 mg can be reliably reached and maintained. Vericiguat should be regarded as a novel, easy and safe treatment option in a vulnerable patient population, for which there was previously hardly any medicinal treatment option.
    Type of Medium: Online Resource
    ISSN: 2731-7129 , 2731-7137
    URL: Article
    DOI: 10.1007/s12181-022-00576-y
    Language: German
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 3120903-8
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  • 8
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    Antibiotic-induced accumulation of lipid II synergizes with antimicrobial fatty acids to eradicate bacterial populations
    eLife Sciences Publications, Ltd ; 2023
    In:  eLife Vol. 12 ( 2023-03-06)
    Details
    In: eLife, eLife Sciences Publications, Ltd, Vol. 12 ( 2023-03-06)
    Abstract: Antibiotic tolerance and antibiotic resistance are the two major obstacles to the efficient and reliable treatment of bacterial infections. Identifying antibiotic adjuvants that sensitize resistant and tolerant bacteria to antibiotic killing may lead to the development of superior treatments with improved outcomes. Vancomycin, a lipid II inhibitor, is a frontline antibiotic for treating methicillin-resistant Staphylococcus aureus and other Gram-positive bacterial infections. However, vancomycin use has led to the increasing prevalence of bacterial strains with reduced susceptibility to vancomycin. Here, we show that unsaturated fatty acids act as potent vancomycin adjuvants to rapidly kill a range of Gram-positive bacteria, including vancomycin-tolerant and resistant populations. The synergistic bactericidal activity relies on the accumulation of membrane-bound cell wall intermediates that generate large fluid patches in the membrane leading to protein delocalization, aberrant septal formation, and loss of membrane integrity. Our findings provide a natural therapeutic option that enhances vancomycin activity against difficult-to-treat pathogens, and the underlying mechanism may be further exploited to develop antimicrobials that target recalcitrant infection.
    Type of Medium: Online Resource
    ISSN: 2050-084X
    URL: Article
    DOI: 10.7554/eLife.80246
    Language: English
    Publisher: eLife Sciences Publications, Ltd
    Publication Date: 2023
    detail.hit.zdb_id: 2687154-3
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  • 9
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    The Cascade Analysis Tool: software to analyze and optimize care cascades
    F1000 Research Ltd ; 2019
    In:  Gates Open Research Vol. 3 ( 2019-6-7), p. 1488-
    Details
    In: Gates Open Research, F1000 Research Ltd, Vol. 3 ( 2019-6-7), p. 1488-
    Type of Medium: Online Resource
    ISSN: 2572-4754
    URL: Journal
    URL: Article
    DOI: 10.12688/gatesopenres
    DOI: 10.12688/gatesopenres.13031.1
    Language: English
    Publisher: F1000 Research Ltd
    Publication Date: 2019
    detail.hit.zdb_id: 3016436-9
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  • 10
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    Harnessing ultrasound-stimulated phase change contrast agents to improve antibiotic efficacy against methicillin-resistant Staphylococcus aureus biofilms
    Elsevier BV ; 2021
    In:  Biofilm Vol. 3 ( 2021-12), p. 100049-
    Details
    In: Biofilm, Elsevier BV, Vol. 3 ( 2021-12), p. 100049-
    Type of Medium: Online Resource
    ISSN: 2590-2075
    URL: Article
    DOI: 10.1016/j.bioflm.2021.100049
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 3071218-X
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