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  1. Article ; Online: Midgut Volvulus Adds a Murine, Neutrophil-Driven Model of Septic Condition to the Experimental Toolbox

    Julia Elrod / Antonia Kiwit / Moritz Lenz / Holger Rohde / Daniela Börnigen / Malik Alawi / Christoph Mohr / Laia Pagerols Raluy / Magdalena Trochimiuk / Jasmin Knopf / Konrad Reinshagen / Martin Herrmann / Michael Boettcher

    Cells, Vol 12, Iss 366, p

    2023  Volume 366

    Abstract: Background: Severe infections that culminate in sepsis are associated with high morbidity and mortality. Despite continuous efforts in basis science and clinical research, evidence based-therapy is mostly limited to basic causal and supportive measures. ... ...

    Abstract Background: Severe infections that culminate in sepsis are associated with high morbidity and mortality. Despite continuous efforts in basis science and clinical research, evidence based-therapy is mostly limited to basic causal and supportive measures. Adjuvant therapies often remain without clear evidence. The objective of this study was to evaluate the septic volvulus ischemia-reperfusion model in comparison to two already established models and the role of neutrophil extacellular traps (NETs) in this model. Methods: The technique of the murine model of midgut volvulus was optimized and was compared to two established models of murine sepsis, namely cecal ligation and puncture (CLP) and intra-peritoneal (i.p.) injection of lipopolysaccharide (LPS). Results: Midgut volvulus for 15 min caused a comparable mortality (38%) as CLP (55%) and peritoneal LPS injection (25%) at 48 h. While oxidative stress was comparable, levels of circulating free DNA (cfDNA), and splenic/hepatic and pulmonary translocation of bacteria were decreased and increased, respectively at 48 h. DNases were increased compared to the established models. Proteomic analysis revealed an upregulation of systemic Epo, IL-1b, Prdx5, Parp1, Ccl2 and IL-6 at 48 h in comparison to the healthy controls. Discussion and Conclusion: Midgut volvulus is a stable and physiological model for sepsis. Depending on the duration and subsequent tissue damage, it represents a combination of ischemia-reperfusion injury and hyperinflammation.
    Keywords sepsis ; extracellular DNA ; sepsis model ; volvulus ; CLP ; LPS ; Biology (General) ; QH301-705.5
    Subject code 630
    Language English
    Publishing date 2023-01-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Biliatresone induces cholangiopathy in C57BL/6J neonates

    Hans Christian Schmidt / Johanna Hagens / Pauline Schuppert / Birgit Appl / Laia Pagerols Raluy / Magdalena Trochimiuk / Clara Philippi / Zhongwen Li / Konrad Reinshagen / Christian Tomuschat

    Scientific Reports, Vol 13, Iss 1, Pp 1-

    2023  Volume 10

    Abstract: Abstract Exposure to plant toxins or microbiota that are able to digest common food ingredients to toxic structures might be responsible for biliary atresia (BA). An isoflavonoid, biliatresone is known to effectively alter the extrahepatic bile duct ( ... ...

    Abstract Abstract Exposure to plant toxins or microbiota that are able to digest common food ingredients to toxic structures might be responsible for biliary atresia (BA). An isoflavonoid, biliatresone is known to effectively alter the extrahepatic bile duct (EHBD) development in BALB/c mice. Biliatresone causes a reduction of Glutathione (GSH) levels, SOX17 downregulation and is effectively countered with N-Acetyl-L-cysteine treatment in vitro. Therefore, reversing GSH-loss appears to be a promising treatment target for a translational approach. Since BALB/c mice have been described as sensitive in various models, we evaluated the toxic effect of biliatresone in robust C57BL/6J mice and confirmed its toxicity. Comparison between BALB/c and C57BL/6J mice revealed similarity in the toxic model. Affected neonates exhibited clinical symptoms of BA, such as jaundice, ascites, clay-colored stools, yellow urine and impaired weight gain. The gallbladders of jaundiced neonates were hydropic and EHBD were twisted and enlarged. Serum and histological analysis proved cholestasis. No anomalies were seen in the liver and EHBD of control animals. With our study we join a chain of evidence confirming that biliatresone is an effective agent for cross-lineage targeted alteration of the EHBD system.
    Keywords Medicine ; R ; Science ; Q
    Subject code 630
    Language English
    Publishing date 2023-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Time- and dose-dependent inhibition of neutrophil extracellular trap formation by blocking of the interleukin-1 receptor

    Hannah Wadehn / Laia Pagerols Raluy / Jan Kolman / Charlotte Duecker / Magdalena Trochimiuk / Birgit Appl / Michael Boettcher / Konrad Reinshagen / Julian Trah

    Central European Journal of Immunology, Vol 46, Iss 4, Pp 419-

    2021  Volume 426

    Abstract: Besides performing phagocytosis and degranulation, neutrophils are capable of eliminating microorganisms by releasing neutrophil extracellular traps (NETs). NET formation was found to be associated with increased mortality in sepsis. During sepsis levels ...

    Abstract Besides performing phagocytosis and degranulation, neutrophils are capable of eliminating microorganisms by releasing neutrophil extracellular traps (NETs). NET formation was found to be associated with increased mortality in sepsis. During sepsis levels of interleukin 1 (IL-1), a cytokine, increases significantly and also was associated with increased mortality. Blocking of the interleukin 1 (IL-1) receptor by anakinra leads to less NET formation in gout patients. However, NET formation is crucial during infection by trapping pathogens and thereby slowing the process. Total or early blocking of cascades leading to NETs may lead to aggravation of infection in otherwise mild cases. The dose- and time-dependent effect of the IL-1 receptor antagonist anakinra was tested on spontaneous, lipopolysaccharide (LPS)-induced and phorbol-12-myristate 13-acetate (PMA)-induced formation of NETs in vitro . Quantitative detection of NETs was performed for NETspecific proteins and cell-free DNA. Immunostained microscopy imaging was used for visualization. Our study shows a dose- and time-dependent inhibitory effect of anakinra that involves the change of intracellular calcium mobilization on the formation of NETs in vitro for PMA-stimulated neutrophils but not for LPS-stimulated neutrophils. It may be useful for treatment of sepsis as part of a multimodal treatment concept, but it seems that timing and dose need to be carefully chosen.
    Keywords neutrophil granulocytes ; neutrophil extracellular traps ; interleukin-1 receptor antagonist ; anakinra ; sepsis ; Medicine ; R
    Subject code 616 ; 610
    Language English
    Publishing date 2021-12-01T00:00:00Z
    Publisher Termedia Publishing House
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Development of an improved murine model of necrotizing enterocolitis shows the importance of neutrophils in NEC pathogenesis

    Michaela Klinke / Deirdre Vincent / Magdalena Trochimiuk / Birgit Appl / Bastian Tiemann / Konrad Reinshagen / Laia Pagerols Raluy / Michael Boettcher

    Scientific Reports, Vol 10, Iss 1, Pp 1-

    2020  Volume 9

    Abstract: Abstract Various research models to induce necrotizing enterocolitis (NEC) in animals exist, yet significant differences in NEC severity between murine animal models and human patients persist. One possible explanation for the difference in severity may ... ...

    Abstract Abstract Various research models to induce necrotizing enterocolitis (NEC) in animals exist, yet significant differences in NEC severity between murine animal models and human patients persist. One possible explanation for the difference in severity may be the variance in neutrophil concentration among newborn humans (50–70%) in comparison to neonatal mice (10–25%). However, neutrophil activity has yet to be evaluated in NEC pathogenesis. Thus, the aim of the study was to evaluate the effects of altered neutrophil concentrations in neonatal mice while simultaneously undergoing a NEC induction. A total of 44 neonatal mice were included in this study and 40 were subjected to an established NEC induction paradigm and 4 were assigned a sham group. Of the 40 mice, 30 received granulocyte-colony stimulating factor (G-CSF) on a daily basis, while 10 were used as controls (receiving inactivated G-CSF). Mice undergoing G-CSF treatment were further divided into two subgroups: (1) wildtype and (2) ELANE-knockout (KO). ELANE - KO mice are incapable of producing neutrophil elastase (NE) and were used to evaluate the role of neutrophils in NEC. For each of the groups, the following metrics were evaluated: survival, NEC severity, tissue damage, neutrophil count and activation, and NETs formation. An improved murine model of NEC was developed using (1) Lipopolysaccharides and Neocate gavage feeding, (2) hypoxia, and (3) G-CSF administration. The results suggest that the addition of G-CSF resulted in significantly elevated NEC manifestation rates with consequent tissue damage and intestinal inflammation, without affecting overall mortality. Animals without functioning NE (ELANE-KO) appeared to have been protected from NEC development. This study supports the importance of neutrophils in NEC pathogenesis. The optimized NEC induction paradigm, using G-CSF administration, resulted in elevated neutrophil counts, resembling those of neonatal humans. Elevation of neutrophil levels significantly improved NEC disease manifestation by modeling human physiology more accurately than current NEC models. Thus, in the future, murine NEC experiments should include the elevation of neutrophil levels to improve the transition of research findings from mice to humans.
    Keywords Medicine ; R ; Science ; Q
    Subject code 690
    Language English
    Publishing date 2020-05-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Neutrophil extracellular traps and DNases orchestrate formation of peritoneal adhesions

    Julia Elrod / Annika Heuer / Jasmin Knopf / Janina Schoen / Lavinia Schönfeld / Magdalena Trochimiuk / Carolin Stiel / Birgit Appl / Laia Pagerols Raluy / Ceren Saygi / Leticija Zlatar / Sami Hosari / Dmytro Royzman / Thomas H. Winkler / Günter Lochnit / Moritz Leppkes / Robert Grützmann / Georg Schett / Christian Tomuschat /
    Konrad Reinshagen / Martin Herrmann / Tobias A. Fuchs / Michael Boettcher

    iScience, Vol 26, Iss 12, Pp 108289- (2023)

    2023  

    Abstract: Summary: Peritoneal adhesions are poorly understood but highly prevalent conditions that can cause intestinal obstruction and pelvic pain requiring surgery. While there is consensus that stress-induced inflammation triggers peritoneal adhesions, the ... ...

    Abstract Summary: Peritoneal adhesions are poorly understood but highly prevalent conditions that can cause intestinal obstruction and pelvic pain requiring surgery. While there is consensus that stress-induced inflammation triggers peritoneal adhesions, the molecular processes of their formation still remain elusive. We performed murine models and analyzed human samples to monitor the formation of adhesions and the treatment with DNases. Various molecular analyses were used to evaluate the adhesions. The experimental peritoneal adhesions of the murine models and biopsy material from humans are largely based on neutrophil extracellular traps (NETs). Treatment with DNASE1 (Dornase alfa) and the human DNASE1L3 analog (NTR-10), significantly reduced peritoneal adhesions in experimental models.We conclude that NETs serve as essential scaffold for the formation of adhesions; DNases interfere with this process. Herein, we show that therapeutic application of DNases can be employed to prevent the formation of murine peritoneal adhesions. If this can be translated into the human situation requires clinical studies.
    Keywords Health sciences ; Biological sciences ; Immunology ; Cell biology ; Science ; Q
    Language English
    Publishing date 2023-12-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Markers of neutrophil activation and extracellular traps formation are predictive of appendicitis in mice and humans

    Michael Boettcher / Melina Esser / Julian Trah / Stefan Klohs / Nariman Mokhaberi / Julia Wenskus / Madgalena Trochimiuk / Birgit Appl / Konrad Reinshagen / Laia Pagerols Raluy / Michaela Klinke

    Scientific Reports, Vol 10, Iss 1, Pp 1-

    a pilot study

    2020  Volume 7

    Abstract: Abstract Appendicitis is one of the most frequent emergencies in pediatric surgery, yet current biomarkers for diagnosis are unspecific and have low predictive values. As neutrophils and extracellular traps (ETs) are an essential component of the immune ... ...

    Abstract Abstract Appendicitis is one of the most frequent emergencies in pediatric surgery, yet current biomarkers for diagnosis are unspecific and have low predictive values. As neutrophils and extracellular traps (ETs) are an essential component of the immune defense against bacterial infections, and appendicitis is considered an inflammation reaction of the appendix, we hypothesized that neutrophil activation and NET formation play an essential role in appendicitis development and maintenance. Therefore, this pilot study aimed to establish a murine model of appendicitis and to evaluate ETs markers to diagnose appendicitis in mice and humans. The study used 20 (12 appendicitis- and 8 controls) 6-week old mice which underwent advanced appendicitis induction using a modified caecal ligation puncture procedure. During the study, cell-free DNA, neutrophil elastase (NE), myeloperoxidase (MPO), and citrullinated Histone H3 (H3cit) were assessed. Additionally, samples of 5 children with histologically confirmed appendicitis and 5 matched controls with catarrhal appendicitis, were examined for the same biomarkers. Moreover, NE, MPO, and H3cit were assessed histologically via immunofluorescence in mice and humans. All mice in the appendicitis group developed an advanced form of appendicitis with focal peritonitis. In mice and humans with appendicitis, markers of neutrophil activation and ETs formation (especially cfDNA, NE and H3cit) were significantly elevated in blood and tissue compared to controls. Ultimately, biomarkers correlated extremely well with tissue expression and thus disease severity. It appears that neutrophil activation and possibly NETs contribute to appendicitis development and biomarkers of neutrophil activation and ET formation reflect disease severity and thus could be used as biomarkers for appendicitis. However, large prospective clinical studies are needed to confirm our findings.
    Keywords Medicine ; R ; Science ; Q
    Subject code 572
    Language English
    Publishing date 2020-10-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Lithocholic bile acid induces apoptosis in human nephroblastoma cells

    Julian Trah / Jonas Arand / Jun Oh / Laia Pagerols-Raluy / Magdalena Trochimiuk / Birgit Appl / Hannah Heidelbach / Deirdre Vincent / Moin A. Saleem / Konrad Reinshagen / Anne K. Mühlig / Michael Boettcher

    Scientific Reports, Vol 10, Iss 1, Pp 1-

    a non-selective treatment option

    2020  Volume 8

    Abstract: Abstract Lithocholic bile acid (LCA) has been reported to selectively kill cancer cells within many tumor cell lines including neuroblastoma or glioblastoma. Wilms’ tumor shares similarities with neuro- and glioblastoma. Hence, the aim of the study was ... ...

    Abstract Abstract Lithocholic bile acid (LCA) has been reported to selectively kill cancer cells within many tumor cell lines including neuroblastoma or glioblastoma. Wilms’ tumor shares similarities with neuro- and glioblastoma. Hence, the aim of the study was to evaluate the effects of LCA on nephroblastoma. To test the effects of LCA, nephroblastoma cell line WT CLS1 was used. SK NEP1 was tested as well. It was originally classified as a nephroblastoma cell line but was meanwhile reclassified as an ewing sarcoma cell line. As control cell lines HEK 293 from embryonic kidney and RC 124 from adult kidney tissue as well as podocytes were used. The effects were evaluated using proliferation assay, caspase activity assay, FACS and Western blot. LCA showed a dose and time-dependent selective effect inducing apoptosis in nephroblastoma cells. However, these effects were not limited to the nephroblastoma cell line but also affected control kidney cell lines and the sarcoma cells; only podocytes are significantly less affected by LCA (at dosages < 200 µm). There were no significant differences regarding the TGR5 receptor expression. The study showed that LCA has a strong, yet unselective effect on all used in vitro cell-lines, sparing the highly differentiated podocytes in lower concentrations. Further studies are needed to verify our results before dismissing LCA as an anti-cancer drug.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2020-11-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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