Publications by authors named "Brigitte Vollmar"

291 Publications

Pharmaceutical immunoglobulin G impairs anti-carcinoma activity of oxaliplatin in colon cancer cells.

Br J Cancer 2021 Feb 9. Epub 2021 Feb 9.

Department of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, Schillingallee 69, 18057, Rostock, Germany.

Background: Recent evidence proves that intravenous human immunoglobulin G (IgG) can impair cancer cell viability. However, no study evaluated whether IgG application benefits cancer patients receiving chemotherapeutics.

Methods: Influence of pharmaceutical-grade human IgG on the viability of a series of patient-derived colon cancer cell lines with and without chemotherapeutic intervention was determined. Cell death was analysed flow cytometrically. In addition, the influence of oxaliplatin and IgG on the ERK1/2-signalling pathway was evaluated by western blots.

Results: We evaluated the effects of pharmaceutical IgG, such as PRIVIGEN IgG and Tonglu IgG, in combination with chemotherapeutics. We did not observe any significant effects of IgG on tumour cell viability directly; however, human IgG significantly impaired the anti-tumoral effects of oxaliplatin. Primary cancer cell lines express IgG receptors and accumulate human IgG intracellularly. Moreover, while oxaliplatin induced the activation of ERK1/2, the pharmaceutical IgG inhibited ERK1/2 activity.

Conclusions: The present study demonstrates that pharmaceutical IgG, such as PRIVIGEN IgG and Tonglu IgG, can impair the anti-carcinoma activity of oxaliplatin. These data strongly suggest that therapeutic IgG as co-medication might have harmful side effects in cancer patients. The clinical significance of these preclinical observations absolutely advises further preclinical, as well as epidemiological and clinical research.
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http://dx.doi.org/10.1038/s41416-021-01272-6DOI Listing
February 2021

Neuroprotective Effects of the FGF21 Analogue LY2405319.

J Alzheimers Dis 2021 Jan 30. Epub 2021 Jan 30.

Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany.

Background: To date, there are no effective treatments for Alzheimer's disease (AD). Thus, a significant need for research of therapies remains.

Objective: One promising pharmacological target is the hormone fibroblast growth factor 21 (FGF21), which is thought to be neuroprotective. A clinical candidate for medical use could be the FGF21 analogue LY2405319 (LY), which has a specificity and potency comparable to FGF21.

Methods: The present study investigated the potential neuroprotective effect of LY via PPARγ/apoE/abca1 pathway which is known to degrade amyloid-β (Aβ) plaques by using primary glial cells and hippocampal organotypic brain slice cultures (OBSCs) from 30- and 50-week-old transgenic APPswe/PS1dE9 (tg) mice. By LY treatment of 52-week-old tg mice with advanced Aβ deposition, we further aimed to elaborate the effect of LY on AD pathology in vivo.

Results: LY application to primary glial cells caused an upregulation of pparγ, apoE, and abca1 mRNA expression and significantly decreased number and area of Aβ plaques in OBSCs. LY treatment in tg mice increased cerebral [18F] FDG uptake and N-acetylaspartate/creatine ratio indicating enhanced neuronal activity and integrity. Although LY did not reduce the number of Aβ plaques in tg mice, the number of iba1-positive cells was significantly decreased indicating reduced microgliosis.

Conclusion: These data identified LY in vitro as an activator of Aβ degrading genes leading to cerebral Aβ load amelioration in early and late AD pathology. Although Aβ plaque reduction by LY failed in vivo, LY may be used as therapeutic agent to treat AD-related neuroinflammation and impaired neuronal integrity.
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http://dx.doi.org/10.3233/JAD-200837DOI Listing
January 2021

Dietary-Induced Low-Grade Inflammation in the Liver.

Biomedicines 2020 Dec 9;8(12). Epub 2020 Dec 9.

Rudolf-Zenker-Institute for Experimental Surgery, Medical University Rostock, 18057 Rostock, Germany.

The literature describes a close correlation between metabolic disorders and abnormal immune responses, like low-grade inflammation (LGI), which may be one mechanistic link between obesity and various comorbidities, including non-alcoholic fatty liver disease (NAFLD). In our study, we investigated the influence of dietary composition on obesity-derived LGI in the liver. We used a dietary induced obesity mouse model of C57BL/6J mice fed with high fat diet (HFD, 60% fat, 20% protein, 20% carbohydrates) and two different controls. One was rich in carbohydrates (10% fat, 20% protein, 70% carbohydrates), further referred to as the control diet (CD), and the other one is referred to as the standard diet (SD), with a more balanced macronutrient content (9% fat, 33% protein, 58% carbohydrates). Our results showed a significant increased NAFLD activity score in HFD compared to both controls, but livers of the CD group also differed in their macroscopic appearance from healthy livers. Hepatic fat content showed significantly elevated cholesterol concentrations in the CD group. Histologic analysis of the cellular immune response in the liver showed no difference between HFD and CD and expression analysis of immunologic mediators like interleukin (IL)-1β, IL-6, IL-10 and tumor necrosis factor alpha also point towards a pro-inflammatory response to CD, comparable to LGI in HFD. Therefore, when studying diet-induced obesity with a focus on inflammatory processes, we encourage researchers to carefully select controls and not use a control diet disproportionally rich in carbohydrates.
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http://dx.doi.org/10.3390/biomedicines8120587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763065PMC
December 2020

Analysis of Animal Well-Being When Supplementing Drinking Water with Tramadol or Metamizole during Chronic Pancreatitis.

Animals (Basel) 2020 Dec 5;10(12). Epub 2020 Dec 5.

Rudolf-Zenker-Institute of Experimental Surgery, Rostock University Medical Center, 18057 Rostock, Germany.

Pain management during in vivo experiments is an animal welfare concern and is in many countries also legally required. In this study, we evaluated C57Bl/6J mice when 3 g/L metamizole or 1 g/L tramadol was provided via drinking water, before and during cerulein-induced chronic pancreatitis. Supplementation of drinking water with metamizole or tramadol did not significantly reduce the amount of consumed water. In order to evaluate the wellbeing of mice, a distress score, burrowing activity, nesting behavior, and body weight was assessed. Before induction of pancreatitis, neither tramadol nor metamizole influenced these readout parameters. Chronic pancreatitis caused a significantly increased distress score, decreased burrowing activity and a reduction in body weight. Mice drinking tramadol-supplemented water experienced less loss in body weight and consumed more water than mice drinking metamizole, at a few time-points during chronic pancreatitis. Pancreatic atrophy, a characteristic feature of chronic pancreatitis was not differentially influenced by either analgesic. In conclusion, both analgesics can be used during 33 days of chronic pancreatitis, but tramadol seems to be moderately advantageous when compared to metamizole.
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http://dx.doi.org/10.3390/ani10122306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762076PMC
December 2020

Comparing distress of mouse models for liver damage.

Sci Rep 2020 11 13;10(1):19814. Epub 2020 Nov 13.

Rudolf-Zenker, Institute of Experimental Surgery, Rostock University Medical Center, Rostock, Germany.

In order to foster animal welfare as well as high quality of research, many countries regulate by law that the severity of animal experiments must be evaluated and considered when performing biomedical research. It is well accepted that multiple parameters rather than a single readout parameter should be applied to describe animal distress or suffering. However, since the performance of readout parameters for animal distress is rarely defined and methods for multivariate analysis have only in rare cases been used, it is not known which methodology is most appropriate to define animal distress. This study used receiver operating characteristic curve analysis to quantify the performance of burrowing activity, body weight change and a distress score of mice after induction of liver damage by bile duct ligation or carbon tetrachloride. In addition, Support Vector Machine classification was used to compare the distress of these mouse models. This approach demonstrated that bile duct ligation causes much more distress than carbon tetrachloride-induced liver damage. This study, therefore, provides a prototype how to compare two animal models by considering several readout parameters. In the future these or similar methods for multivariate analysis will be necessary, when assessing and comparing the severity of animal models.
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http://dx.doi.org/10.1038/s41598-020-76391-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666197PMC
November 2020

Limited potential of resolvin D1 in treatment of cholestatic liver fibrosis.

Hepatobiliary Surg Nutr 2020 Oct;9(5):587-596

Institute for Experimental Surgery, University Medicine Rostock, Rostock, Germany.

Background: Several studies suggest a role for EPA- and DHA-derived pro-resolving mediators like resolvins in reversing metabolic and inflammatory disturbances seen in various chronic diseases. Here, we investigated the effects of resolvin D1 (RvD1) on bile duct ligation (BDL)-induced cholestatic liver injury.

Methods: Mice were treated daily with RvD1 or 0.1% ethanol (control) from the day of BDL until the final observation time points. Blood and liver tissue were collected 2, 5 and 14 days after BDL for different analyses.

Results: RvD1 treatment of mice had no impact on the extent of cholestatic liver injury upon BDL, neither in the acute phase nor in the progressive state of liver fibrosis. Although RvD1 treatment resulted in a significantly reduced activity of hepatic stellate cells as well as reduced deposition of extracellular matrix 2 days after BDL, mice were not protected from inflammation and further fibrosis progression.

Conclusions: These data indicate that RvD1 has a limited therapeutic potential to treat cholestatic liver diseases, as it has no significant impact on regression of hepatic necroinflammation and fibrotic changes in bile duct-ligated mice.
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http://dx.doi.org/10.21037/hbsn.2019.08.07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603936PMC
October 2020

Anatomical MRI and [F]FDG PET/CT imaging of Schistosoma mansoni in a NMRI mouse model.

Sci Rep 2020 10 15;10(1):17343. Epub 2020 Oct 15.

Division of Tropical Medicine and Infectious Diseases, Center of Internal Medicine II, University Medical Center Rostock, Rostock, Germany.

Schistosomiasis represents one of the most devastating worm parasitosis in the world. Current diagnostic methods are insufficient to determine the infection grade and the disease related organ damage. We herein investigated whether discrimination of infection grade and its correlation to liver damage could be accurately performed by multimodal imaging in a mouse model of Schistosoma mansoni infection. Therefore, groups of uninfected and infected mice underwent MRI and [F]FDG PET/CT imaging. Anatomical MRI images were used for liver volumetry and for quantification of hepatic granulomas. For PET/CT images a volume of interest based analyses were employed to calculate the [F]FDG uptake in liver, portal vein, spleen and abdomen. Herein, we demonstrate that the combined use of [F]FDG-PET/CT and MRI represents an appropriate diagnostic tool for Schistosoma mansoni infection, but fails to discriminate the infection grade and the linked organ damage. Only the splenic [F]FDG uptake in the 25 cercariae group (5.68 ± 0.90%ID/cc) and 50 cercariae group (4.98 ± 1.43%ID/cc) was significantly higher compared to the control group (2.13 ± 0.69%ID/cc). Nevertheless, future multimodal imaging studies with new radiopharmaceuticals could build a highly sensitive and specific basis for the diagnosis and evaluation of organ damage of schistosomiasis.
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http://dx.doi.org/10.1038/s41598-020-74226-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566647PMC
October 2020

MicroRNAs as systemic biomarkers to assess distress in animal models for gastrointestinal diseases.

Sci Rep 2020 10 9;10(1):16931. Epub 2020 Oct 9.

Rudolf-Zenker-Institute of Experimental Surgery, University Medical Center Rostock, Schillingallee 69a, 18057, Rostock, Germany.

Severity assessment of animal experiments is mainly conducted by using subjective parameters. A widely applicable biomarker to assess animal distress could contribute to an objective severity assessment in different animal models. Here, the distress of three murine animal models for gastrointestinal diseases was assessed by multiple behavioral and physiological parameters. To identify possible new biomarkers for distress 750 highly conserved microRNAs were measured in the blood plasma of mice before and after the induction of pancreatitis. Deregulated miRNA candidates were identified and further quantified in additional animal models for pancreatic cancer and cholestasis. MiR-375 and miR-203 were upregulated during pancreatitis and down regulated during cholestasis, whereas miR-132 was upregulated in all models. Correlation between miR-132 and plasma corticosterone concentrations resulted in the highest correlation coefficient, when compared to the analysis of miR-375, miR-203 and miR-30b. These results indicate that miR-132 might function as a general biomarker for distress, whereas the other miRNAs were altered in a disease specific manner. In conclusion, plasma miRNA profiling may help to better characterize the level of distress in mouse models for gastrointestinal diseases.
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http://dx.doi.org/10.1038/s41598-020-73972-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547723PMC
October 2020

Longitudinal [F]FDG-PET/CT analysis of the glucose metabolism in ApoE-deficient mice.

EJNMMI Res 2020 Oct 7;10(1):119. Epub 2020 Oct 7.

Institute for Experimental Surgery, Rostock University Medical Center, Schillingallee 69a, 18057, Rostock, Germany.

Background: Strong line of evidence suggests that the increased risk to develop AD may at least be partly mediated by cholesterol metabolism. A key regulator of cholesterol transport is the Apolipoprotein E4 (ApoE4), which plays a fundamental role in neuronal maintenance and repair. Impaired function of ApoE4 may contribute to altered cerebral metabolism leading to higher susceptibility to neurodegeneration.

Methods: To determine a possible link between ApoE function and alterations in AD in the brain of Apolipoprotein E-deficient mice (ApoE-/-) in a longitudinal manner metabolic and neurochemical parameters were analyzed. Cortical metabolism was measured by 2-deoxy-2-[F]fluoroglucose ([F]FDG)-PET/CT and proton magnetic resonance spectroscopy (H-MRS) served to record neurochemical status.

Results: By using [F]FDG-PET/CT, we showed that brain metabolism declined significantly stronger with age in ApoE-/- versus wild type (wt) mice. This difference was particularly evident at the age of 41 weeks in almost each analyzed brain region. In contrast, the H-MRS-measured N-acetylaspartate to creatine ratio, a marker of neuronal viability, did not decline with age and did not differ between ApoE-/- and wt mice.

Conclusion: In summary, this longitudinal in vivo study shows for the first time that ApoE-/- mice depict cerebral hypometabolism without neurochemical alterations.
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http://dx.doi.org/10.1186/s13550-020-00711-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541807PMC
October 2020

Hydrogen sulfide reduces the activity of human endothelial cells.

Clin Hemorheol Microcirc 2020 ;76(4):513-523

Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany.

Introduction: The volatile endogenous mediator hydrogen sulfide (H2S) is known to impair thrombus formation by affecting the activity of human platelets. Beside platelets and coagulation factors the endothelium is crucial during thrombogenesis.

Objective: This study evaluates the effect of the H2S donor GYY4137 (GYY) on human umbilical vein endothelial cells (HUVECs) in vitro.

Methods: Flow cytometry of resting, stimulated or GYY-treated and subsequently stimulated HUVECs was performed to analyse the expression of E-selectin, ICAM-1 and VCAM-1. To study a potential reversibility of the GYY action, E-selectin expression was further assessed on HUVECs that were stimulated 24 h after GYY exposure. A WST-1 assay was performed to study toxic effects of the H2S donor. By using the biotin switch assay, protein S-sulfhydration of GYY-exposed HUVECs was assessed. Further on, the effects of GYY on HUVEC migration and von Willebrand factor (vWF) secretion were assessed.

Results: GYY treatment significantly reduced the expression of E-selectin and ICAM-1 but not of VCAM-1. When HUVECs were stimulated 24 h after GYY treatment, E-selectin expression was no longer affected. The WST-1 assay revealed no effects of GYY on endothelial cell viability. Furthermore, GYY impaired endothelial migration, reduced vWF secretion and increased protein S-sulfhydration.

Conclusions: Summarizing, GYY dose dependently and reversibly reduces the activity of endothelial cells.
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http://dx.doi.org/10.3233/CH-200868DOI Listing
February 2021

Cardiomyocyte Transplantation after Myocardial Infarction Alters the Immune Response in the Heart.

Cells 2020 08 3;9(8). Epub 2020 Aug 3.

Department of Cardiac Surgery, Rostock University Medical Centre, 18057 Rostock, Germany.

We investigated the influence of syngeneic cardiomyocyte transplantation after myocardial infarction (MI) on the immune response and cardiac function. Methods and Results: We show for the first time that the immune response is altered as a result of syngeneic neonatal cardiomyocyte transplantation after MI leading to improved cardiac pump function as observed by magnetic resonance imaging in C57BL/6J mice. Interestingly, there was no improvement in the capillary density as well as infarct area as observed by CD31 and Sirius Red staining, respectively. Flow cytometric analysis revealed a significantly different response of monocyte-derived macrophages and regulatory T cells after cell transplantation. Interestingly, the inhibition of monocyte infiltration accompanied by cardiomyocyte transplantation diminished the positive effect of cell transplantation alone. The number of CD68+ macrophages in the remote area of the heart observed after four weeks was also different between the groups. Transcriptome analysis showed several changes in the gene expression involving circadian regulation, mitochondrial metabolism and immune responses after cardiomyocyte transplantation. Conclusion: Our work shows that cardiomyocyte transplantation alters the immune response after myocardial infarction with the recruited monocytes playing a role in the beneficial effect of cell transplantation. It also paves the way for further optimization of the efficacy of cardiomyocyte transplantation and their successful translation in the clinic.
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http://dx.doi.org/10.3390/cells9081825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465503PMC
August 2020

[Ga]-NODAGA-RGD Positron Emission Tomography (PET) for Assessment of Post Myocardial Infarction Angiogenesis as a Predictor for Left Ventricular Remodeling in Mice after Cardiac Stem Cell Therapy.

Cells 2020 05 30;9(6). Epub 2020 May 30.

Department of Nuclear Medicine, Rostock University Medical Center, 18057 Rostock, Germany.

Angiogenesis plays a central role in the healing process following acute myocardial infarction. The PET tracer [Ga]-NODAGA-RGD, which is a ligand for the αβ integrin, has been investigated for imaging angiogenesis in the process of healing myocardium in both animal and clinical studies. It´s value as a prognostic marker of functional outcome remains unclear. Therefore, the aim of this work was to establish [Ga]-NODAGA-RGD for imaging angiogenesis in the murine infarct model and evaluate the tracer as a predictor for cardiac remodeling in the context of cardiac stem cell therapy. [Ga]-NODAGA-RGD PET performed seven days after left anterior descending coronary artery (LAD) occlusion in 129S6 mice showed intense tracer accumulation within the infarct region. The specificity was shown in a sub-group of animals by application of the competitive inhibitor cilengitide prior to tracer injection in a subgroup of animals. Myocardial infarction (MI) significantly reduced cardiac function and resulted in pronounced left ventricular remodeling after three weeks, as measured by cardiac MRI in a separate group. Cardiac induced cells (CiC) that were derived from mESC injected intramyocardially in the therapy group significantly improved left ventricular ejection fraction (LVEF). Surprisingly, CiC transplantation resulted in significantly lower tracer accumulation seven days after MI induction. Accordingly, we successfully established the PET tracer [Ga]-NODAGA-RGD for the assessment of αβ integrin expression in the healing process after MI in the mouse model. Yet, our results indicate that the mere extent of angiogenesis following MI does not serve as a sufficient prognostic marker for functional outcome.
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http://dx.doi.org/10.3390/cells9061358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349714PMC
May 2020

F-FDG PET-Based Imaging of Myocardial Inflammation Following Acute Myocardial Infarction in a Mouse Model.

Int J Mol Sci 2020 May 8;21(9). Epub 2020 May 8.

Department of Cardiology, Rostock University Medical Center, 18057 Rostock, Germany.

Cellular inflammation is an integral part of the healing process following acute myocardial infarction and has been under intense investigation for both therapeutic and prognostic approaches. Monocytes and macrophages are metabolically highly active and show increased uptake rates of glucose and its analog, F-FDG. Yet, the specific allocation of the radioactivity to the inflammatory cells via positron emission tomography (PET) imaging requires the suppression of glucose metabolism in viable myocardium. In mice, the most important model organism in basic research, this can be achieved by the application of ketamine/xylazine (KX) for anesthesia instead of isoflurane. Yet, while the consensus exists that glucose metabolism is effectively suppressed, a strategy for reproducible image analysis is grossly lacking and causes uncertainty concerning data interpretation. We introduce a simple strategy for systematic image analysis, which is a prerequisite to evaluate therapies targeting myocardial inflammation. Mice underwent permanent occlusion of the left anterior descending artery (LAD), inducing an acute myocardial infarction (MI). Five days after MI induction, 10MBq F-FDG was injected intravenously and a static PET/CT scan under ketamine/xylazine anesthesia was performed. For image reconstruction, we used an algorithm based on three-dimensional ordered subsets expectation maximization (3D-OSEM) followed by three-dimensional ordinary Poisson maximum a priori (MAP) reconstruction. Using this approach, high focal tracer uptake was typically located in the border zone of the infarct by visual inspection. To precisely demarcate the border zone for reproducible volume of interest (VOI) positioning, our protocol relies on positioning VOIs around the whole left ventricle, the inferobasal wall and the anterolateral wall guided by anatomical landmarks. This strategy enables comparable data in mouse studies, which is an important prerequisite for using a PET-based assessment of myocardial inflammation as a prognostic tool in therapeutic applications.
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http://dx.doi.org/10.3390/ijms21093340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246846PMC
May 2020

Collagen membranes of dermal and pericardial origin-In vivo evolvement of vascularization over time.

J Biomed Mater Res A 2020 Dec 3;108(12):2368-2378. Epub 2020 Jun 3.

Department of Oral, Maxillofacial Plastic Surgery, University Medical Center Rostock, Rostock, Germany.

Aim of the study was to compare the evolvement of vascularization over time of collagen membranes (CMs) of dermal and pericardial origin in an in vivo animal study. Twenty-eight mice underwent implantation of three commercially available CM derived from porcine dermis (homogenous structure: CM1 (Control 1) and bilayer structure: CM2 [Control 2]), from porcine pericardium (CM3; Test 1) as well as CM3 sprayed with silica-enhanced nanostructured hydroxyapatite (CM4, Test 2). After 3, 6, 9, and 12 days, intravital fluorescence microscopy was conducted for determination of capillary diameter, density, flow, and length. At Day 12, samples were examined immunohistologically for expression of fibroblast growth factor receptor 4 (FGFR4), CD11b, CD68, αSMA, and CD34. In all CM, intravital fluorescence microscopy over time showed increasing values for all parameters with the highest levels in CM4 and the lowest values in CM1. Significant lower amounts of FGFR4, CD11b, and CD68 were detected in CM4 when compared to CM2 (p < .05). In contrast to CM3, lower values of αSMA and higher numbers of CD34 positive-marked vessels were observed in CM4 (p < .05). In conclusion, dermal bilayer as well as pericardial CM seem to have a higher vascularization rate than dermal homogenous CM. Additional coating of pericardial CM with a silica-enhanced hydroxyapatite increases the speed of vascularization as well as biological remodeling processes.
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http://dx.doi.org/10.1002/jbm.a.36989DOI Listing
December 2020

Grading animal distress and side effects of therapies.

Ann N Y Acad Sci 2020 08 24;1473(1):20-34. Epub 2020 Mar 24.

Rudolf-Zenker Institute of Experimental Surgery, University Medical Center, Rostock, Germany.

In order to combine high-quality research with minimal harm to animals, a prospective severity assessment for animal experiments is legally required in many countries. In addition, an assessment of the evidence-based severity level might allow realistic harm-benefit analysis and the appraisal of refinement methods. However, only a few examples describe the distress of animals by simple, cost-efficient, and noninvasive methods. We, therefore, evaluated the severity of an orthotopic mouse model for pancreatic cancer using C57BL/6J mice when pursuing two different chemotherapies. We assessed fecal corticosterone metabolites, body weight, distress score, and burrowing, as well as nesting activity. Moreover, we established a multifactorial model using multivariate logistic regression to describe animal distress. This multifactorial analysis revealed that metformin + galloflavin treatment caused higher distress than metformin + α-cyano-4-hydroxycinnamate therapy. Similar results were obtained by using the best cutoff calculated by Youden's J index when using only single parameters, such as burrowing activity or fecal corticosterone metabolite concentration. Thus, the present study revealed that single readout parameters, as well as multivariate analysis, can help to assess the severity of animal experiments and detect side effects of therapies.
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http://dx.doi.org/10.1111/nyas.14338DOI Listing
August 2020

Effects of excessive or restricted phosphorus and calcium intake during early life on markers of bone architecture and composition in pigs.

J Anim Physiol Anim Nutr (Berl) 2020 Mar 17. Epub 2020 Mar 17.

Chair of Nutrition Physiology and Animal Nutrition, University of Rostock, Rostock, Germany.

Sufficient supply of pigs with calcium (Ca) and phosphorus (P) is essential for animal health and welfare during the growth period. However, the P content in animal manure is considered as a cause of massive environmental problems in soil and aquatic ecosystems. To complement previous findings, the objective of this study is the investigation of effects of a reduced and increased Ca and P supplementation on bone mineralization and bone structure compared with the current dietary recommendation. Another aim is to find possible serum markers that would allow the assessment of adequacy of P supply for bone health during growth. The result validated that the recommended Ca and P supply is sufficient, without the addition of microbial phytases. However, addition of P has no further beneficial effects on bone stability, while P supplementation below the recommended level affects bone development and growth performance. Reduced P levels have consequences for cancellous bone density and trabecular architecture. Further fine-tuning of the P supply in conjunction with an appropriate Ca supply will contribute to a reduction in P waste and associated environmental impact while maintaining animal health and welfare.
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http://dx.doi.org/10.1111/jpn.13286DOI Listing
March 2020

Teduglutide Promotes Epithelial Tight Junction Pore Function in Murine Short Bowel Syndrome to Alleviate Intestinal Insufficiency.

Dig Dis Sci 2020 12 19;65(12):3521-3537. Epub 2020 Feb 19.

Department of General, Thoracic, Vascular and Transplantation Surgery, Rostock University Medical Center, Schillingallee 35, 18057, Rostock, Germany.

Background: In short bowel syndrome, epithelial surface loss results in impaired nutrient absorption and may lead to intestinal insufficiency or intestinal failure. Nucleotide oligomerization domain 2 (Nod2) dysfunction predisposes to the development of intestinal failure after intestinal resection and is associated with intestinal barrier defects. Epithelial barrier function is crucial for intestinal absorption and for intestinal adaptation in the short bowel situation.

Aims: The aim of the study was to characterize the effects of the GLP-2 analogue Teduglutide in the small intestine in the presence and absence of Nod2 in a mouse model of short bowel syndrome.

Methods: Mice underwent 40% ICR and were thereafter treated with Teduglutide versus vehicle injections. Survival, body weight, stool water, and sodium content and plasma aldosterone concentrations were determined. Intestinal and kidney tissue was examined with light and fluorescence microscopy, Ussing chamber studies and quantitative PCR in wild type and transgenic mice.

Results: Teduglutide reduced intestinal failure incidence in Nod2 k.o. mice. In wt mice, Teduglutide attenuated intestinal insufficiency as indicated by reduced body weight loss and lower plasma aldosterone concentrations, lower stool water content, and lower stool sodium losses. Teduglutide treatment was associated with enhanced epithelial paracellular pore function and enhanced claudin-10 expression in tight junctions in the villus tips, where it colocalized with sodium-glucose cotransporter 1 (SGLT-1), which mediates Na-coupled glucose transport.

Conclusions: In the SBS situation, Teduglutide not only maximizes small intestinal mucosal hypertrophy but also partially restores small intestinal epithelial function through an altered distribution of claudin-10, facilitating sodium recirculation for Na-coupled glucose transport and water absorption.
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http://dx.doi.org/10.1007/s10620-020-06140-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661426PMC
December 2020

Molecular Mechanisms of the Efficacy of Cold Atmospheric Pressure Plasma (CAP) in Cancer Treatment.

Cancers (Basel) 2020 Jan 22;12(2). Epub 2020 Jan 22.

Clinic and Polyclinic for Dermatology and Venereology, University Medical Center Rostock, 18057 Rostock, Germany.

Recently, the potential use of cold atmospheric pressure plasma (CAP) in cancer treatment has gained increasing interest. Especially the enhanced selective killing of tumor cells compared to normal cells has prompted researchers to elucidate the molecular mechanisms for the efficacy of CAP in cancer treatment. This review summarizes the current understanding of how CAP triggers intracellular pathways that induce growth inhibition or cell death. We discuss what factors may contribute to the potential selectivity of CAP towards cancer cells compared to their non-malignant counterparts. Furthermore, the potential of CAP to trigger an immune response is briefly discussed. Finally, this overview demonstrates how these concepts bear first fruits in clinical applications applying CAP treatment in head and neck squamous cell cancer as well as actinic keratosis. Although significant progress towards understanding the underlying mechanisms regarding the efficacy of CAP in cancer treatment has been made, much still needs to be done with respect to different treatment conditions and comparison of malignant and non-malignant cells of the same cell type and same donor. Furthermore, clinical pilot studies and the assessment of systemic effects will be of tremendous importance towards bringing this innovative technology into clinical practice.
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http://dx.doi.org/10.3390/cancers12020269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072164PMC
January 2020

The slow releasing hydrogen sulfide donor GYY4137 reduces neointima formation upon FeCl3 injury of the carotid artery in mice.

Clin Hemorheol Microcirc 2020 ;75(4):409-417

Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany.

Introduction: Neointima formation is closely linked to vascular stenosis and occurs after endothelial damage. Hydrogen sulfide is an endogenous pleiotropic mediator with numerous positive effects on the cardio vascular system.

Objective: This study evaluates the effect of the slow releasing hydrogen sulfide donor GYY4137 (GYY) on neointimal formation in vivo.

Methods: The effect of GYY on neointimal formation in the carotid artery was studied in the FeCl3 injury model in GYY- or vehicle-treated mice. The carotid arteries were studied at days 7 and 21 after treatment by means of histology and immunohistochemistry for proliferating cell nuclear antigen (PCNA) and alpha smooth muscle actin (α-SMA).

Results: GYY treatment significantly reduced the maximal diameter and the area of the newly formed neointima on both days 7 and 21 when compared to vehicle treatment. GYY additionally reduced the number of PCNA- and α-SMA-positive cells within the neointima on day 21 after FeCl3 injury of the carotid artery.

Conclusions: Summarizing, single treatment with the slow releasing hydrogen sulfide donor GYY reduced the extent of the newly formed neointima by affecting the cellular proliferation at the site of vascular injury.
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http://dx.doi.org/10.3233/CH-190747DOI Listing
November 2020

Metformin and LW6 impairs pancreatic cancer cells and reduces nuclear localization of YAP1.

J Cancer 2020 1;11(2):479-487. Epub 2020 Jan 1.

Institute for Experimental Surgery, Rostock University Medical Center, Schillingallee 69a, 18059, Rostock, Germany.

The poor survival rate of pancreatic cancer is still a major challenge for the clinicians and their patients. In this study, we evaluated the efficacy of metformin, an inhibitor of oxidative phosphorylation, in combination with LW6, which impairs malate dehydrogenase 2 activities, in treating pancreatic cancer cells. We observed that this combinational therapy significantly reduced cell proliferation, migration, and significantly induced cell death when compared to cells treated by each monotherapy or Sham. In addition, we found that the combination of metformin and LW6 increased the phosphorylation of yes-associated protein 1 at serine 127 and attenuated the nuclear localization of this transcription factor. This combinatorial treatment also decreased the level of cellular yes-associated protein 1. This suggests that metformin in combination with LW6 impairs pancreatic cancer cells and reduces nuclear localization of yes-associated protein 1.
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http://dx.doi.org/10.7150/jca.33029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930432PMC
January 2020

Galloflavin Plus Metformin Treatment Impairs Pancreatic Cancer Cells.

Anticancer Res 2020 Jan;40(1):153-160

Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany

Background/aim: In this study, we evaluated the effect of galloflavin, an inhibitor of lactate dehydrogenase, in combination with metformin, an anti-diabetic drug and inhibitor of oxidative phosphorylation, on pancreatic ductal adenocarcinoma cells.

Materials And Methods: We explored the effect of galloflavin and metformin on proliferation and cell death of murine 6606PDA and human MIA PaCa-2 cells.

Results: We observed that monotherapies of galloflavin and metformin both inhibit proliferation and induce cancer cell death. Moreover, the combination of both agents increased these effects on pancreatic ductal adenocarcinoma cells. The inhibition of proliferation by this combination therapy can be detected under hypoxic and normoxic conditions, leading to the assumption that this therapy might impair insufficiently supplied solid tumors as well as small clusters of cancer cells, e.g. after metastatic dissemination.

Conclusion: Galloflavin, especially in combination with metformin, has a strong anti-cancerous effect on pancreatic ductal adenocarcinoma cells.
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http://dx.doi.org/10.21873/anticanres.13936DOI Listing
January 2020

18F-FDG PET-Based Imaging of Myocardial Inflammation Predicts a Functional Outcome Following Transplantation of mESC-Derived Cardiac Induced Cells in a Mouse Model of Myocardial Infarction.

Cells 2019 12 11;8(12). Epub 2019 Dec 11.

Department of Cardiology, Rostock University Medical Center, 18057 Rostock, Germany.

Cellular inflammation following acute myocardial infarction has gained increasing importance as a target mechanism for therapeutic approaches. We sought to investigate the effect of syngeneic cardiac induced cells (CiC) on myocardial inflammation using 18F-FDG PET (Positron emission tomography)-based imaging and the resulting effect on cardiac pump function using cardiac magnetic resonance (CMR) imaging in a mouse model of myocardial infarction. Mice underwent permanent left anterior descending coronary artery (LAD) ligation inducing an acute inflammatory response. The therapy group received an intramyocardial injection of 10 CiC into the border zone of the infarction. Five days after myocardial infarction, 18F-FDG PET was performed under anaesthesia with ketamine and xylazine (KX) to image the inflammatory response in the heart. Flow cytometry of the mononuclear cells in the heart was performed to analyze the inflammatory response. The effect of CiC therapy on cardiac function was determined after three weeks by CMR. The 18F-FDG PET imaging of the heart five days after myocardial infarction (MI) revealed high focal tracer accumulation in the border zone of the infarcted myocardium, whereas no difference was observed in the tracer uptake between infarct and remote myocardium. The CiC transplantation induced a shift in 18F-FDG uptake pattern, leading to significantly higher 18F-FDG uptake in the whole heart, as well as the remote area of the heart. Correspondingly, high numbers of CD11 cells could be measured by flow cytometry in this region. The CiC transplantation significantly improved the left ventricular ejection function (LVEF) three weeks after myocardial infarction. The CiC transplantation after myocardial infarction leads to an improvement in pump function through modulation of the cellular inflammatory response five days after myocardial infarction. By combining CiC transplantation and the cardiac glucose uptake suppression protocol with KX in a mouse model, we show for the first time, that imaging of cellular inflammation after myocardial infarction using 18F-FDG PET can be used as an early prognostic tool for assessing the efficacy of cardiac stem cell therapies.
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http://dx.doi.org/10.3390/cells8121613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952872PMC
December 2019

A rational approach of early humane endpoint determination in a murine model for cholestasis.

ALTEX 2020 9;37(2):197-207. Epub 2019 Dec 9.

Rudolf-Zenker-Institute of Experimental Surgery, University Medical Center Rostock, Rostock, Germany.

Reduction of animal suffering during in vivo experiments is usually ensured by continuously monitoring the health status using a score sheet and by applying humane endpoints. However, most studies do not evaluate the plausibility of score sheets and do not attempt to reduce the suffering of animals by determining earlier and, therefore, more humane endpoints. The present study uses data from BALB/cANCrl mice after bile duct ligation to retrospectively analyze which score sheet criteria are informative to determine humane endpoints. The performance of each single as well as com­binations of multiple animal welfare parameters was analyzed by a Cox proportional-hazards model followed by Harrell’s concordance index. The addition of behavioral parameters, such as burrowing activity, helped to define a more humane early endpoint for euthanizing these animals. Using this approach, we determined that a body weight loss of 10-20% combined with a reduction of burrowing activity by more than 79.4% was able to predict that these animals would die within two days. Thus, this approach successfully determined an earlier humane endpoint and will reduce the suffering of animals in future experiments. Application of such an approach or similar methods can contribute to the refinement of various animal experiments.
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http://dx.doi.org/10.14573/altex.1909111DOI Listing
January 2021

Where are we heading? Challenges in evidence-based severity assessment.

Lab Anim 2020 Feb 13;54(1):50-62. Epub 2019 Nov 13.

Institute for Laboratory Animal Science, Hannover Medical School, Germany.

Evidence-based severity assessment in laboratory animals is, apart from the ethical responsibility, imperative to generate reproducible, standardized and valid data. However, the path towards a valid study design determining the degree of pain, distress and suffering experienced by the animal is lined with pitfalls and obstacles as we will elucidate in this review. Furthermore, we will ponder on the genesis of a holistic concept relying on multifactorial composite scales. These have to combine robust and reliable parameters to measure the multidimensional aspects that define the severity of animal experiments, generating a basis for the substantiation of the refinement principle.
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http://dx.doi.org/10.1177/0023677219877216DOI Listing
February 2020

A safe bet? Inter-laboratory variability in behaviour-based severity assessment.

Lab Anim 2020 Feb 7;54(1):73-82. Epub 2019 Nov 7.

Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Germany.

Evidence-based severity assessment is essential as a basis for ethical evaluation in animal experimentation to ensure animal welfare, legal compliance and scientific quality. To fulfil these tasks scientists, animal care and veterinary personnel need assessment tools that provide species-relevant measurements of the animals' physical and affective state. In a three-centre study inter-laboratory robustness of body weight monitoring, mouse grimace scale (MGS) and burrowing test were evaluated. The parameters were assessed in naïve and tramadol treated female C57BL/6J mice. During tramadol treatment a body weight loss followed by an increase, when treatment was terminated, was observed in all laboratories. Tramadol treatment did not affect the MGS or burrowing performance. Results were qualitatively comparable between the laboratories, but quantitatively significantly different (inter-laboratory analysis). Burrowing behaviour seems to be highly sensitive to inter-laboratory differences in testing protocol. All locations obtained comparable information regarding the qualitative effect of tramadol treatment in C57BL/6J mice, however, datasets differed as a result of differences in test and housing conditions. In conclusion, our study confirms that results of behavioural testing can be affected by many factors and may differ between laboratories. Nevertheless, the evaluated parameters appeared relatively robust even when conditions were not harmonized extensively and present useful tools for severity assessment. However, analgesia-related side effects on parameters have to be considered carefully.
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http://dx.doi.org/10.1177/0023677219881481DOI Listing
February 2020

Endogenously increased n-3 PUFA levels in fat-1 transgenic mice do not protect from non-alcoholic steatohepatitis.

Hepatobiliary Surg Nutr 2019 Oct;8(5):447-458

Rudolf-Zenker-Institute for Experimental Surgery, University Medicine Rostock, 18057 Rostock, Germany.

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) and fibrosis. Possible reasons for the NAFLD epidemic in industrialized countries are the high intake of pro-inflammatory n-6 polyunsaturated fatty acids (n-6 PUFAs) and low consumption of healthy n-3 PUFAs. Due to their anti-inflammatory properties, n-3 PUFAs may have the potential to alleviate chronic liver disease. Herein, we examined the therapeutic effect of increased n-3 PUFA tissue levels in fat-1 transgenic mice on progressive NASH.

Methods: Disease was induced in mice by streptozotocin and high fat diet (STZ/HFD) resulting in NASH. NAFLD in 6 and 8 weeks old wild type and fat-1 transgenic STZ/HFD treated mice was analyzed. Unlike all other mammals, fat-1 transgenic mice ubiquitously express an n-3 fatty acid desaturase, which converts n-6 to n-3 PUFAs, leading to increased n-3 and decreased n-6 PUFA tissue contents.

Results: Liver damage, NAFLD activity score (NAS), hepatic lipid accumulation and inflammation were significantly reduced in fat-1 transgenic STZ/HFD treated mice in the early (6 weeks) but not late (8 weeks) phase of NASH. Simultaneously, mRNA expression of genes involved in fatty acid uptake and storage ( and , respectively) was significantly down-regulated in 6 week old but not 8 week old fat-1 transgenic STZ/HFD treated mice.

Conclusions: Endogenously elevated n-3 PUFA levels in fat-1 transgenic mice transiently delay the onset of STZ/HFD induced NASH but failed to efficiently protect from NASH development.
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http://dx.doi.org/10.21037/hbsn.2019.04.03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791993PMC
October 2019

Defining body-weight reduction as a humane endpoint: a critical appraisal.

Lab Anim 2020 Feb 30;54(1):99-110. Epub 2019 Oct 30.

Rudolf-Zenker-Institute of Experimental Surgery, University Medical Center, Rostock, Germany.

In many animal experiments scientists and local authorities define a body-weight reduction of 20% or more as severe suffering and thereby as a potential parameter for humane endpoint decisions. In this study, we evaluated distinct animal experiments in multiple research facilities, and assessed whether 20% body-weight reduction is a valid humane endpoint criterion in rodents. In most experiments (restraint stress, distinct models for epilepsy, pancreatic resection, liver resection, caloric restrictive feeding and a mouse model for Dravet syndrome) the animals lost less than 20% of their original body weight. In a glioma model, a fast deterioration in body weight of less than 20% was observed as a reliable predictor for clinical deterioration. In contrast, after induction of chronic diabetes or acute colitis some animals lost more than 20% of their body weight without exhibiting major signs of distress. In these two animal models an exclusive application of the 20% weight loss criterion for euthanasia might therefore result in an unnecessary loss of animals. However, we also confirmed that this criterion can be a valid parameter for defining the humane endpoint in other animal models, especially when it is combined with additional criteria for evaluating distress. In conclusion, our findings strongly suggest that experiment and model specific considerations are necessary for the rational integration of the parameter 'weight loss' in severity assessment schemes and humane endpoint criteria. A flexible implementation tailored to the experiment or intervention by scientists and authorities is therefore highly recommended.
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http://dx.doi.org/10.1177/0023677219883319DOI Listing
February 2020

Benefits of non-invasive methods compared to telemetry for distress analysis in a murine model of pancreatic cancer.

J Adv Res 2020 Mar 14;21:35-47. Epub 2019 Sep 14.

Rudolf-Zenker-Institute of Experimental Surgery, University Medical Center, 18057 Rostock, Germany.

Prospective severity assessment is legally required in many countries to ensure high-quality research along with high welfare standards for laboratory animals. Mice and rats, the most common laboratory species, are prey animals that usually suppress signs of pain and suffering. Therefore, highly sensitive readout parameters are necessary to adequately quantify distress. The present study compared the performance of different non-invasive methods in determining animal distress, such as measuring body weight, distress score, faecal corticosterone metabolites, burrowing, and nesting behaviour, with continuous monitoring of heart rate, body temperature and activity by telemetry. The distress caused by two surgical interventions was compared and the burden caused by tumour growth was described. Transmitter implantation caused higher distress than laparotomy plus carcinoma cell injection into the pancreas. Surprisingly, no significant increase in distress was observed during tumour growth. The receiver operating characteristic curve analysis revealed that some non-invasive distress-parameters, i.e., distress-score and burrowing activity, exhibited slightly better performance to quantify distress than the most suitable parameters measured by telemetry. Due to the high burden caused by the implantation of the telemetric device, the use of non-invasive methods to assess distress in laboratory animals after surgical interventions should be favoured in future studies.
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http://dx.doi.org/10.1016/j.jare.2019.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796693PMC
March 2020

Liver-specific Bid silencing inhibits APAP-induced cell death in mice.

Apoptosis 2019 12;24(11-12):934-945

Institute for Experimental Surgery, Rostock University Medical Center, Schillingallee 69a, 18057, Rostock, Germany.

Acetaminophen (APAP)-induced acute liver failure (ALF) is a life-threatening disease with only a few treatment options available. Though extensive research has been conducted for more than 40 years, the underlying pathomechanisms are not completely understood. Here, we studied as to whether APAP-induced ALF can be prevented in mice by silencing the BH3-interacting domain death agonist (Bid) as a potential key player in APAP pathology. For silencing Bid expression in mice, siRNA was formulated with the liver-specific siRNA delivery system DBTC and administered 48 h prior to APAP exposure. Mice which were pre-treated with HEPES (vehicle) and siRNA served as siRNA controls. Hepatic pathology was assessed by in vivo fluorescence microscopy, molecular biology, histology and laboratory analysis 6 h after APAP or PBS exposure. Application of siRNA caused a significant decrease of mRNA and protein expression of Bid in APAP-exposed mice. Off-targets, such as cytochrome P450 2E1 and glutathione, which are known to be consumed under APAP intoxication, were comparably reduced in all APAP-exposed mice, underlining the specificity of Bid silencing. In APAP-exposed mice non-sterile inflammation with leukocyte infiltration and perfusion failure remained almost unaffected by Bid silencing. However, the Bid silencing reduced hepatocellular damage, evident by a remarkable decrease of DNA fragmented cells in APAP-exposed mice. In these mice, the expression of the pro-apoptotic protein Bax, which recently gained importance in the cell death pathway of regulated necrosis, was also significantly reduced, in line with a decrease in both, necrotic liver tissue and plasma transaminase activities. In addition, plasma levels of HMGB1, a marker of sterile inflammation, were significantly diminished. In conclusion, the liver-specific silencing of Bid expression did not protect APAP-exposed mice from microcirculatory dysfunction, but markedly protected the liver from necrotic cell death and in consequence from sterile inflammation. The study contributes to the understanding of the molecular mechanism of the APAP-induced pathogenic pathway by strengthening the importance of Bid and Bid silencing associated effects.
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http://dx.doi.org/10.1007/s10495-019-01571-7DOI Listing
December 2019

A novel multi-parametric analysis of non-invasive methods to assess animal distress during chronic pancreatitis.

Sci Rep 2019 Oct 1;9(1):14084. Epub 2019 Oct 1.

Rudolf-Zenker-Institute of Experimental Surgery, Rostock University Medical Center, Rostock, Germany.

Ethical responsibility, legal requirements and the need to improve the quality of research create a growing interest in the welfare of laboratory animals. Judging the welfare of animals requires readout parameters, which are valid and sensitive as well as specific to assess distress after different interventions. In the present study, we evaluated the sensitivity and specificity of different non-invasive parameters (body weight change, faecal corticosterone metabolites concentration, burrowing and nesting activity) by receiver operating characteristic curves and judged the merit of a multi-parametric analysis by logistic regression. Chronic pancreatitis as well as laparotomy caused significant changes in all parameters. However, the accuracy of these parameters was different between the two animal models. In both animal models, the multi-parametric analysis relying on all the readout parameters had the highest accuracy when predicting distress. This multi-parametric analysis revealed that C57BL/6 mice during the course of chronic pancreatitis often experienced less distress than mice after laparotomy. Interestingly these data also suggest that distress does not steadily increase during chronic pancreatitis. In conclusion, combining these non-invasive methods for severity assessment represents a reliable approach to evaluate animal distress in models such as chronic pancreatitis.
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http://dx.doi.org/10.1038/s41598-019-50682-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773730PMC
October 2019