Publications by authors named "Karoline Koch"

24 Publications

  • Page 1 of 1

The mycotoxin beauvericin impairs development, fertility and life span in the nematode Caenorhabditis elegans accompanied by increased germ cell apoptosis and lipofuscin accumulation.

Toxicol Lett 2020 Nov 28;334:102-109. Epub 2020 Sep 28.

Martin-Luther-University Halle-Wittenberg, Institute of Agricultural and Nutritional Sciences, Weinbergweg 22, 06120 Halle/Saale, Germany. Electronic address:

Beauvericin is an ubiquitous mycotoxin with relevant occurrence in food and feed. It causes a high toxicity in several cell lines, but its general mechanism of action is not fully understood and only limited in vivo studies have been performed. We used Caenorhabditis elegans as a model organism to investigate effects of beauvericin. The mycotoxin displays a moderate acute toxicity at 100 μM; at this concentration also reproductive toxicity occurred (reduction of total progeny to 32.1 %), developmental toxicity was detectable at 250 μM. However, even lower concentrations were capable to reduce stress resistance and life span of the nematode: A significant reduction was detected at 10 μM beauvericin (decrease in mean survival time of 4.3 % and reduction in life span of 12.9 %). An increase in lipofuscin fluorescence was demonstrated starting at 10 μM suggesting oxidative stress as a mechanism of beauvericin toxicity. Beauvericin (100 μM) increases the number of apoptotic germ cells comparable to the positive control UV-C (400 J/m). Conclusion: Low concentrations of beauvericin are capable to cause adverse effects in C. elegans, which may be relevant for hazard identification of this compound.
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http://dx.doi.org/10.1016/j.toxlet.2020.09.016DOI Listing
November 2020

Juvenile Blastic Plasmacytoid Dendritic Cell Neoplasm.

Acta Derm Venereol 2020 Aug 18;100(15):adv00245. Epub 2020 Aug 18.

Department of Dermatology and Allergy, University Hospital of Munich LMU, DE-80337 Munich, Germany. E-mail:

is missing (Short communication).
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http://dx.doi.org/10.2340/00015555-3603DOI Listing
August 2020

Localized- and advanced-stage follicular lymphomas differ in their gene expression profiles.

Blood 2020 01;135(3):181-190

Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Stuttgart, Germany.

The genetic background of follicular lymphomas (FLs) diagnosed in advanced clinical stages III/IV, and which are frequently characterized by t(14;18), has been substantially unraveled. Molecular features, as exemplified in the clinicogenetic risk model m7FLIPI, are important tools in risk stratification. In contrast, little information is available concerning localized-stage FL (clinical stages I/II), which accounts for ∼20% of newly diagnosed FL in which the detection rate of t(14;18) is only ∼50%. To investigate the genetic background of localized-stage FL, patient cohorts with advanced-stage FL or localized-stage FL, uniformly treated within phase 3 trials of the German Low-Grade Lymphoma Study Group, were comparatively analyzed. Targeted gene expression (GE) profiling of 184 genes using nCounter technology was performed in 110 localized-stage and 556 advanced-stage FL patients. By penalized Cox regression, a prognostic GE signature could not be identified in patients with advanced-stage FL, consistent with results from global tests and univariate regression. In contrast, it was possible to define robust GE signatures discriminating localized-stage and advanced-stage FL (area under the curve, 0.98) by penalized logistic regression. Of note, 3% of samples harboring an "advanced-stage signature" in the localized-stage cohort exhibited inferior failure-free survival (hazard ratio [HR], 7.1; P = .0003). Likewise, in the advanced-stage cohort, 7% of samples with a "localized-stage signature" had prolonged failure-free survival (HR, 2.3; P = .017) and overall survival (HR, 3.4; P = .072). These data support the concept of a biological difference between localized-stage and advanced-stage FL that might contribute to the superior outcome of localized FL.
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http://dx.doi.org/10.1182/blood.2019000560DOI Listing
January 2020

Stereotactic body radiotherapy for ventricular tachycardia (cardiac radiosurgery) : First-in-patient treatment in Germany.

Strahlenther Onkol 2020 Jan 31;196(1):23-30. Epub 2019 Oct 31.

Klinik für Innere Medizin III, Kardiologie, Abteilung für Elektrophysiologie und Rhythmologie, Universitätsklinikum Schleswig-Holstein, Kiel, Germany.

Purpose: Single-session cardiac stereotactic body radiotherapy, called cardiac radiosurgery (CRS) or radioablation (RA), may offer a potential treatment option for patients with refractory ventricular tachycardia (VT) and electrical storm who are otherwise ineligible for catheter ablation. However, there is only limited clinical experience. We now present the first-in-patient treatment using (CRS/RA) for VT in Germany.

Methods: A 78-year-old male patient with dilated cardiomyopathy and significantly reduced ejection fraction (15%) presented with monomorphic VT refractory to poly-anti-arrhythmic medication and causing multiple implantable cardioverter-defibrillator (ICD) interventions over the course of several weeks, necessitating prolonged treatment on an intensive care unit. Ultra-high-resolution electroanatomical voltage mapping (EVM) revealed a re-entry circuit in the cardiac septum inaccessible for catheter ablation. Based on the EVM, CRS/RA with a single session dose of 25 Gy (83% isodose) was delivered to the VT substrate (8.1 cc) using a c-arm-based high-precision linear accelerator on November 30, 2018.

Results: CRS/RA was performed without incident and dysfunction of the ICD was not observed. Following the procedure, a significant reduction in monomorphic VT from 5.0 to 1.6 episodes per week and of ICD shock interventions by 81.2% was observed. Besides periprocedural nausea with a single episode of vomiting, no treatment-associated side effects were noted. Unfortunately, the patient died 57 days after CRS/RA due to sepsis-associated cardiac circulatory failure after Clostridium difficile-associated colitis developed during rehabilitation. Histopathologic examination of the heart as part of a clinical autopsy revealed diffuse fibrosis on most sections of the heart without apparent differences between the target area and the posterior cardiac wall serving as a control.

Conclusion: CRS/RA appears to be a possible treatment option for otherwise untreatable patients suffering from refractory VT and electrical storm. A relevant reduction in VT incidence and ICD interventions was observed, although long-term outcome and consequences of CRS/RA remain unclear. Clinical trials are strongly warranted and have been initiated.
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http://dx.doi.org/10.1007/s00066-019-01530-wDOI Listing
January 2020

Abyssinone V, a prenylated flavonoid isolated from the stem bark of Erythrina melanacantha increases oxidative stress and decreases stress resistance in Caenorhabditis elegans.

J Pharm Pharmacol 2019 Jun 21;71(6):1007-1016. Epub 2019 Feb 21.

Institute of Agricultural and Nutritional Sciences, Biofunctionality of Secondary Plant Compounds, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.

Objectives: Recent studies showed that distinct extracts of Erythrina species used in the traditional medicine of sub-Saharan Africa are protective against stress conditions. However, the underlying molecular mechanisms as well as relevant compounds remain unclear.

Methods: We used the model organism Caenorhabditis elegans to investigate compounds isolated from the stem bark of Erythrina melanacantha (abyssinone V (1), abyssinon-4'O-methylether (2), sigmoidin B-4'O-methylether (3), glabranin (4), 8-prenylnaringenin (5), citflavanone (6), exiguaflavanone (7) and homoeriodictyol (8)). Antioxidative capacity in vitro (trolox equivalent antioxidative capacity assay) and modulation of oxidative stress in vivo (2', 7'-dichlorofluorescein assay) were investigated; stress resistance was analysed using the nucleic acid stain SYTOX green.

Key Findings: None of the prenylated flavonoids caused protection against thermal stress; in contrast, most of the compounds (1, 4, 5, 8) decreased stress resistance. None of the compounds decreased the accumulation of reactive oxygen species, but abyssinone V (1) caused an increase in oxidative stress. In line with these results, none of these compounds showed radical-scavenging effects in vitro.

Conclusions: The stem bark of E. melanacantha contains various prenylated flavonoids, but no compound protected C. elegans against stress conditions. In contrast, abyssinone V increases oxidative stress and reduces stress resistance in this model organism.
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http://dx.doi.org/10.1111/jphp.13074DOI Listing
June 2019

Hibiscus sabdariffa L. extract prolongs lifespan and protects against amyloid-β toxicity in Caenorhabditis elegans: involvement of the FoxO and Nrf2 orthologues DAF-16 and SKN-1.

Eur J Nutr 2020 Feb 1;59(1):137-150. Epub 2019 Feb 1.

Institute of Agricultural and Nutritional Sciences, Biofunctionality of Secondary Plant Compounds, Martin-Luther-University Halle-Wittenberg, Weinbergweg 22, 06120, Halle/Saale, Germany.

Purpose: Hibiscus sabdariffa L. is commonly used as an ingredient for herbal teas and food supplements. Several studies demonstrated the beneficial effects of Hibiscus sabdariffa L. extracts (HSE); however, the bioactive components and their mode of action still remain unclear. Caenorhabditis elegans (C. elegans) was used to study health-related effects and the underlying molecular mechanisms of HSE in this model organism as well as effects of hydroxycitric acid (HCA), a main compound of HSE, and its structural analogue isocitric acid (ICA).

Methods: Survival and locomotion were detected by touch-provoked movement. Thermotolerance was analysed using the nucleic acid stain SYTOX green, and intracellular ROS accumulation was measured via oxidation of HDCF. Localisation of the transcription factors DAF-16 and SKN-1 was analysed in transgenic strains (DAF-16::GFP, SKN-1::GFP). The involvement of DAF-16 and SKN-1 was further investigated using loss-of-function strains as well as gene silencing by feeding RNAi-inducing bacteria. Protection against amyloid-β toxicity was analysed using a transgenic strain with an inducible expression of human amyloid-β peptides in body wall muscle cells (paralysis assay).

Results: HSE treatment resulted in a prominent extension of lifespan (up to 24%) and a reduction of the age-dependent decline in locomotion. HCA, a main compound of HSE increased lifespan too, but to a lesser extent (6%) while ICA was not effective. HSE and HCA did not modulate resistance against thermal stress conditions and did not exert antioxidative effects: HSE rather increased intracellular ROS levels, suggesting a pro-oxidative effect of the extract in vivo. HSE and HCA increased the nuclear localisation of the pivotal transcription factors DAF-16 and SKN-1 indicating an activation of these factors. Consistent with this result, lifespan prolongation by HSE was dependent on both transcription factors. In addition to the positive effect on lifespan, HSE treatment also elicited a (strong) protection against amyloid-ß induced toxicity in C. elegans in a DAF-16- and SKN-1-dependent manner.

Conclusion: Our results demonstrate that HSE increases lifespan and protects against amyloid-β toxicity in the model organism C. elegans. These effects were mediated, at least in parts via modulation of pathways leading to activation/nuclear localisation of DAF-16 and SKN-1. Since HCA, a main component of HSE causes only minor effects, additional bioactive compounds like flavonoids or anthocyanins as well as synergistic effects of these compounds should be investigated.
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http://dx.doi.org/10.1007/s00394-019-01894-wDOI Listing
February 2020

Wallr. Extract Increases Stress Resistance and Prolongs Life Span in via Transcription Factor DAF-16 (FoxO Orthologue).

Antioxidants (Basel) 2018 Dec 14;7(12). Epub 2018 Dec 14.

Biofunctionality of Secondary Plant Compounds, Institute of Agricultural and Nutritional Sciences, Martin-Luther-University Halle-Wittenberg, Weinbergweg 22, 06120 Halle (Saale), Germany.

is a pharmacologically interesting plant which is proposed to protect against various diseases due to its high amount of phytochemicals, e.g., polyphenols. However, in spite of the amount of postulated health benefits, studies concerning the mechanistic effects of are limited. Using the nematode , we were able to show that an ethanol extract of herba (eAE) mediates strong antioxidative effects in the nematode: Beside a strong radical-scavenging activity, eAE reduces accumulation of reactive oxygen species (ROS) accumulation and protects against paraquat-induced oxidative stress. The extract does not protect against amyloid-β-mediated toxicity, but efficiently increases the life span (up to 12.7%), as well as the resistance to thermal stress (prolongation of survival up to 22%), of this model organism. Using nematodes deficient in the forkhead box O (FoxO)-orthologue DAF-16, we were able to demonstrate that beneficial effects of eAE on stress resistance and life span were mediated via this transcription factor. We showed antioxidative, stress-reducing, and life-prolonging effects of eAE and were able to demonstrate a molecular mechanism of this extract. These results may be important for identifying further molecular targets of eAE in humans.
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http://dx.doi.org/10.3390/antiox7120192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315603PMC
December 2018

T-Cell Clustering in Neoplastic Follicles of Follicular Lymphoma.

Cancer Microenviron 2018 Dec 11;11(2-3):135-140. Epub 2018 Sep 11.

Department of Pathology, Hematopathology Section and Lymph Node Registry, University of Kiel/University Hospital Schleswig-Holstein, Arnold-Heller-Strasse 3, Haus 14, 24105, Kiel, Germany.

The nonneoplastic microenvironment is abundant in follicular lymphoma. Its composition has been reported to be associated with the course of the disease. Lack of animal models hampers studies of interaction between lymphoma and bystander cells. We aimed to identify indicators of cellular interaction exemplified by nonrandom distribution of cell types within neoplastic follicles. Physiological germinal centers and follicles in follicular lymphoma were stained to identify macrophages, all T, follicular T-helper, dendritic and B cells. Density of cell types and cell distribution (spatial point pattern) were analyzed by digital image analysis. The density of all T, follicular T-helper and dendritic cells was higher in the dark zone than in the light zone of physiological germinal centers. Densities of cell types in follicular lymphoma were intermediate between the light and the dark zone. All cell types analyzed showed a completely random spatial distribution pattern within the dark and the light zone, respectively. In follicular lymphoma B cells and macrophages displayed complete spatial randomness. In contrast, all T cells, follicular T-helper cells and dendritic cells showed clustering of each individual cell type within a radius of 6-10 μm in the lymphoma. We conclude that the distribution of nonneoplastic cells within follicles of follicular lymphoma is not random. T cells and dendritic cells form clusters within the follicles, suggestive of sites of interaction between microenvironment and lymphoma cells. These clusters might help to understand the interaction of lymphoma cells with the microenvironment and might provide a structure for therapeutic intervention.
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http://dx.doi.org/10.1007/s12307-018-0217-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6250612PMC
December 2018

Extract Exerts Antioxidative Effects and Increases Life Span and Stress Resistance in the Model Organism via DAF-16 and SIR-2.1.

Plants (Basel) 2018 Jul 20;7(3). Epub 2018 Jul 20.

Institute of Agricultural and Nutritional Sciences, Martin-Luther-University Halle-Wittenberg, Weinbergweg 22, 06120 Halle (Saale), Germany.

Extracts of the Chinese plant (PME) are used for medicinal purposes as well as food supplement due to anti-aging effects. Despite of the common use of these food supplements, experimental data on physiological effects of PME and its underlying molecular mechanisms in vivo are limited. We used the model organism to analyze anti-aging-effects of PME in vivo (life span, lipofuscin accumulation, oxidative stress resistance, thermal stress resistance) as well as the molecular signaling pathways involved. The effects of PME were examined in wildtype animals and mutants defective in the sirtuin-homologue SIR-2.1 (VC199) and the FOXO-homologue DAF-16 (CF1038). PME possesses antioxidative effects in vivo and increases oxidative stress resistance of the nematodes. While the accumulation of lipofuscin is only slightly decreased, PME causes a significant elongation (18.6%) of mean life span. DAF-16 is essential for the reduction of thermally induced ROS accumulation, while the resistance against paraquat-induced oxidative stress is dependent on SIR-2.1. For the extension of the life span, both DAF-16 and SIR-2.1 are needed. We demonstrate that PME exerts protective effects in via modulation of distinct intracellular pathways.
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http://dx.doi.org/10.3390/plants7030060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160924PMC
July 2018

Spindle-Cell Variants of Primary Cutaneous Follicle Center B-Cell Lymphomas Are Germinal Center B-Cell Lymphomas by Gene Expression Profiling Using a Formalin-Fixed Paraffin-Embedded Specimen.

J Invest Dermatol 2017 11 3;137(11):2450-2453. Epub 2017 Jul 3.

Department of Pathology, Hematopathology Section and Lymph Node Registry, Christian-Albrechts-University of Kiel, University-Hospital Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Germany.

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http://dx.doi.org/10.1016/j.jid.2017.06.016DOI Listing
November 2017

The resveratrol derivatives trans-3,5-dimethoxy-4-fluoro-4'-hydroxystilbene and trans-2,4',5-trihydroxystilbene decrease oxidative stress and prolong lifespan in Caenorhabditis elegans.

J Pharm Pharmacol 2017 Jan 23;69(1):73-81. Epub 2016 Nov 23.

Institute of Agricultural and Nutritional Sciences, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany.

Objectives: Resveratrol (trans-3,4',5-trihydroxystilbene (1)) was previously shown to extend the lifespan of different model organisms. However, its pharmacological efficiency is controversially discussed. Therefore, the bioactivity of four newly synthesized stilbenes (trans-3,5-dimethoxy-4-fluoro-4'-hydroxystilbene (3), trans-4'-hydroxy-3,4,5-trifluorostilbene (4), trans-2,5-dimethoxy-4'-hydroxystilbene (5), trans-2,4',5-trihydroxystilbene (6)) was compared to (1) and pterostilbene (trans-3,5-dimethoxy-4'-hydroxystilbene (2)) in the established model organism Caenorhabditis elegans.

Methods: Trolox equivalent antioxidant capacity (TEAC), 2',7'-dichlorofluorescein (DCF), thermotolerance assays, C. elegans lifespan analyses.

Key Findings: All compounds exert a strong in-vitro radical scavenging activity (6 > 1 > 5 > 2 = 3 = 4), but in vivo, only (3) and (6) reduce reactive oxygen species (ROS) accumulation. Furthermore, (3) and (6) increased the mobility of aged nematodes and prolonged their mean lifespans, while these compounds decreased the thermal stress resistance. Using daf-16 (FoxO), skn-1 (Nrf2) and sir-2.1 (sirtuin) loss-of-function mutant strains, the in vivo antioxidant effects of compounds (3) and (6) were abolished, showing the necessity of these evolutionary highly conserved factors. However, short-time treatment with stilbenes (3) and (6) did not modulate the cellular localization of the transcription factors DAF-16 and SKN-1.

Conclusion: In contrast to resveratrol, the synthetic stilbene derivatives (3) and (6) increase the lifespan of C. elegans, rendering them promising candidates for pharmacological anti-ageing purposes.
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http://dx.doi.org/10.1111/jphp.12657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938959PMC
January 2017

Scintigraphy Leading to the Misdiagnosis of Chronic Thromboembolic Disease in a Patient With Pulmonary Veno-Occlusive Disease.

Circulation 2016 Apr;133(16):1627-8

From Departments of Internal Medicine (L.B., T.S., B.B.), Radiology (M.B.), Nuclear Medicine (C.W.), and Pathology (C.R., K.K.), University Hospital of Schleswig-Holstein, Kiel, Germany.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.116.019171DOI Listing
April 2016

Skin Involvement of Mantle Cell Lymphoma May Mimic Primary Cutaneous Diffuse Large B-cell Lymphoma, Leg Type.

Am J Surg Pathol 2015 Aug;39(8):1093-101

*Department of Dermatology †Medical Department II §Department of Pathology, Hematopathology Section, Christian-Albrechts-University Kiel, Kiel ‡Department of Internal Medicine III, University Hospital of Munich, Munich, Germany.

Mantle cell lymphoma (MCL) is a B-cell neoplasm with a variable and generally aggressive clinical course. So far our knowledge of skin involvement of MCL is limited. To understand the clinical and histopathologic features of MCL with skin involvement, the files of the Lymph Node Registry Kiel were screened for MCL diagnosed in the skin. Over a period of 13 years, 1321 biopsy specimens were diagnosed as MCL; among them, 14 patients (1%) showed skin involvement. Of these, skin was the initial site of manifestation in 6/11 (55%) cases. One patient presented with a skin-limited lymphoma. Furthermore, 7/12 (58%) patients presented with lesions on the leg. The lymphomas were highly proliferative with blastoid cytology in 12/14 (86%) cases. Moreover, the immunophenotype with expression of BCL2 (100%), MUM-1/IRF4 (83%), and IgM (82%) and lack of CD10 (25%) and BCL6 (0%) closely resembled the features of primary cutaneous diffuse large B-cell lymphoma, leg type. Solely the expression of cyclin D1 (100%) and the presence of t(11;14) (100%) allowed a distinction from cases of primary cutaneous diffuse large B-cell lymphoma, leg type. Only 2 MCL cases with skin involvement presented with classical cytology. Interestingly, in these 2 cases skin involvement occurred simultaneously in a lesion of coexisting primary cutaneous marginal zone lymphoma. Our data suggest that clinical presentation on the leg and blastoid cytology along with high proliferation and expression of Bcl2, Mum-1/IRF4, and IgM are typical for MCL involving the skin. Lymphomas with these features might be erroneously diagnosed as diffuse large B-cell lymphoma, leg type, if cyclin D1 staining is not performed.
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http://dx.doi.org/10.1097/PAS.0000000000000445DOI Listing
August 2015

The Lignan Pinoresinol Induces Nuclear Translocation of DAF-16 in Caenorhabditis elegans but has No Effect on Life Span.

Phytother Res 2015 Jun 31;29(6):894-901. Epub 2015 Mar 31.

Martin Luther University Halle-Wittenberg, Institute of Agricultural and Nutritional Sciences, Biofunctionality of Secondary Plant Compounds, Weinbergweg 22 (Biozentrum), 06120, Halle/Saale, Germany.

The lignan pinoresinol is a constituent of flaxseed, sesame seeds and olive oil. Because of different molecular effects reported for this compound, e.g. antioxidative activity, pinoresinol is suggested to cause positive effects on humans. Because experimental data are limited, we have analysed the effects of the lignan on the nematode Caenorhabditis elegans: in spite of a strong antioxidative capacity detected in an in vitro assay, no antioxidative effects were detectable in vivo. In analogy to this result, no modulation of the sensitivity against thermal stress was detectable. However, incubation with pinoresinol caused an enhanced nuclear accumulation of the transcription factor DAF-16 (insulin/IGF-like signalling pathway). Using a strain with an enhanced oxidative stress level (mev-1 mutant), we clearly see an increase in stress resistance caused by this lignan, but no change in reactive oxygen species. Furthermore, we investigated the effects of pinoresinol on the life span of the nematode, but no modulation was found, neither in wild-type nor in mev-1 mutant nematodes. These results suggest that pinoresinol may exert pharmacologically interesting effects via modulation of the insulin-like signalling pathway in C. elegans as well as in other species like mammals due to the evolutionary conservation of this signalling pathway.
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http://dx.doi.org/10.1002/ptr.5330DOI Listing
June 2015

Isoxanthohumol, a constituent of hop (Humulus lupulus L.), increases stress resistance in Caenorhabditis elegans dependent on the transcription factor DAF-16.

Eur J Nutr 2016 Feb 3;55(1):257-65. Epub 2015 Feb 3.

Biofunctionality of Secondary Plant Compounds, Institute of Agricultural and Nutritional Sciences, Martin-Luther-Universität Halle-Wittenberg, Weinbergweg 22 (Biozentrum), 06120, Halle/Saale, Germany.

Purpose: The flavanone isoxanthohumol (IX) has gained attention as antioxidative and chemopreventive agent, but the molecular mechanism of action remains unclear. We investigated effects of this secondary plant compound in vivo using the model organism Caenorhabditis elegans.

Methods: Adult C. elegans nematodes were incubated with IX, and then, the stress resistance was analysed in the SYTOX assay; lifespan was monitored by touch-provoked movement method, the amount of reactive oxygen species (ROS) was measured in the DCF assay, and the nuclear localisation of the transcription factor DAF-16 was analysed by using a transgenic strain. By the use of a DAF-16 loss-of-function strain, we analysed whether the effects are dependent on DAF-16.

Results: IX increases the resistance of the nematode against thermal stress. Additionally, a reduction in ROS in vivo was caused by IX. Since the flavanone only has a marginal radical-scavenging capacity (TEAC assay), we suggest that IX mediates its antioxidative effects indirectly via activation of DAF-16 (homologue to mammalian FOXO proteins). The nuclear translocation of this transcription factor is increased by IX. In the DAF-16-mutated strain, the IX-mediated increase in stress resistance was completely abolished; furthermore, an increased formation of ROS and a reduced lifespan was mediated by IX.

Conclusion: IX or a bacterial metabolite of IX causes antioxidative effects as well as an increased stress resistance in C. elegans via activation of DAF-16. The homologous pathway may have implications in the molecular mechanism of IX in mammals.
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http://dx.doi.org/10.1007/s00394-015-0843-zDOI Listing
February 2016

No evidence of cell cycle dysregulation in mantle cell lymphoma in vivo.

Leuk Lymphoma 2015 Jul 14;56(7):2134-40. Epub 2014 Nov 14.

Department of Pathology, Hematopathology Section and Lymph Node Registry, University Hospital Schleswig-Holstein , Campus Kiel, Kiel , Germany.

Mantle cell lymphoma (MCL) is characterized by the translocation t(11;14)(q13;q32) leading to an overexpression of cyclin D1, a mediator of G1-S phase transition. Thus MCL is regarded as a paradigm of lymphoma with a dysregulated cell cycle. The proliferation rate of MCL is in fact a strong predictor of outcome. We analyzed proteins that are expressed at defined cell cycle phases, such as Ki67, survivin and phosphorylated histone H3 as well as cyclin D1, p53 and p27, on the cellular level by immunofluorescence double stainings in MCL biopsy specimens. Unexpectedly, we did not detect a shortening of early phases in MCL in vivo. Despite the control of the immunoglobulin enhancer, cyclin D1 was expressed in a cell cycle-dependent manner. However, the proliferating Ki67-positive tumor cells expressed low amounts of cyclin D1. Therefore, the expression of cyclin D1 appears not to be the driving factor behind the total proliferation rate of MCL.
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http://dx.doi.org/10.3109/10428194.2014.975700DOI Listing
July 2015

Histopathological features and their prognostic impact in nodular lymphocyte-predominant Hodgkin lymphoma--a matched pair analysis from the German Hodgkin Study Group (GHSG).

Br J Haematol 2014 Oct 26;167(2):238-42. Epub 2014 Jun 26.

Dr. Senckenberg Institute of Pathology, Goethe University, Frankfurt am Main, Germany.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma entity. We performed a matched-pair analysis to evaluate the prognostic impact of several histopathological features in this distinct Hodgkin lymphoma subtype. Lymph node samples of NLPHL patients were tested for CD15, IgD, phosphorylated STAT6, ICOS and Epstein-Barr virus status of the malignant lymphocyte-predominant cells as well as epithelioid cell clusters and activated T cells in the microenvironment. None of these features was associated with a particular clinical outcome. However, patients presenting with epithelioid cell clusters showed a non-significant trend towards a lower relapse rate, justifying further evaluation of this marker.
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http://dx.doi.org/10.1111/bjh.12997DOI Listing
October 2014

Caenorhabditis elegans as model system in pharmacology and toxicology: effects of flavonoids on redox-sensitive signalling pathways and ageing.

ScientificWorldJournal 2014 30;2014:920398. Epub 2014 Apr 30.

Institute of Agricultural and Nutritional Sciences, Martin-Luther-Universität Halle-Wittenberg, Weinbergweg 22 (Biozentrum), 06120 Halle, Germany.

Flavonoids are secondary plant compounds that mediate diverse biological activities, for example, by scavenging free radicals and modulating intracellular signalling pathways. It has been shown in various studies that distinct flavonoid compounds enhance stress resistance and even prolong the life span of organisms. In the last years the model organism C. elegans has gained increasing importance in pharmacological and toxicological sciences due to the availability of various genetically modified nematode strains, the simplicity of modulating genes by RNAi, and the relatively short life span. Several studies have been performed demonstrating that secondary plant compounds influence ageing, stress resistance, and distinct signalling pathways in the nematode. Here we present an overview of the modulating effects of different flavonoids on oxidative stress, redox-sensitive signalling pathways, and life span in C. elegans introducing the usability of this model system for pharmacological and toxicological research.
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http://dx.doi.org/10.1155/2014/920398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032668PMC
January 2015

The prognostic impact of variant histology in nodular lymphocyte-predominant Hodgkin lymphoma: a report from the German Hodgkin Study Group (GHSG).

Blood 2013 Dec 7;122(26):4246-52; quiz 4292. Epub 2013 Oct 7.

Dr. Senckenberg Institute of Pathology, Goethe University, Frankfurt am Main, Germany;

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) accounts for approximately 5% of all Hodgkin lymphoma cases. The aim of this study was to evaluate the prognostic implication of histopathologic NLPHL variants. Biopsies of 423 NLPHL patients treated within 9 prospective clinical trials performed by the German Hodgkin Study Group were classified as tumor cell-rich cases (n = 10), typical NLPHL (n = 308), or histopathologic variants (n = 105). Histopathologic variants were characterized by the presence of lymphoma cells outside the B-cell nodules or B-cell depletion of the microenvironment. Compared with typical NLPHL, histopathologic variants were associated with advanced disease (29.5% vs 14.6%, P = .0012) and a higher relapse rate (18.1% vs 6.5% at 5 years, P = .0009). Variant histology represented an independent prognostic factor (odds ratio = 2.955) in a multivariate model of progression/relapse. A prognostic score, including the risk factors variant histopathologic growth pattern, low serum albumin, and male gender, was derived from this model and allowed the definition of 3 distinct risk groups. NLPHL patients presenting with histopathologic variants have a poorer outcome compared with those showing typical histology. The newly developed prognostic score combining histologic and clinical features allows allocating NLPHL patients to defined risk groups.
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http://dx.doi.org/10.1182/blood-2013-07-515825DOI Listing
December 2013

The polygenetically inherited metabolic syndrome of male WOKW rats is associated with enhanced autophagy in adipose tissue.

Diabetol Metab Syndr 2013 13;5:23. Epub 2013 May 13.

IFB AdiposityDiseases, Junior Research Group 2 "Animal models of obesity", University Leipzig, Leipzig, Germany.

Background: Recent studies revealed that autophagy is up-regulated in obese individuals, as evidenced by increased expression of autophagy related genes. As argued elsewhere, it is possible that initially insulin resistance functions as an adaptive mechanism to increase autophagy in order to protect cells against death. We have shown that Wistar Ottawa Karlsburg W (RT1(u)) rats (WOKW) develop a metabolic syndrome with insulin resistance in adipose tissue, closely resembling the human disease. Therefore, the aim of this study was to characterize the autophagy phenotype in WOKW rats to clarify the interrelation between insulin resistance and autophagy in adipose tissue.

Methods: Subcutaneous and epidydimal adipose tissue samples of 5-months-old WOKW and healthy LEW.1 W male rats were investigated and protein levels (Western blot and immunhistochemistry) of key autophagy genes, including Atg5, Atg7, LC3-II/LC3-I and apoptosis marker cleaved caspase-3 were analyzed.

Results: WOKW rats displayed a significant increase of autophagy related proteins (Atg5, Atg7) in adipose tissue compared with LEW.1 W. This increase was predominantly found in epididymal adipose tissue. Furthermore, the LC3-II/LC3-I ratio as a marker of autophagosomes was significantly up-regulated in subcutaneous adipose tissue of WOKW rats. Cleaved caspase-3 was just slightly detectable in visceral adipose tissue and not detected in subcutaneous fat.

Conclusion: Insulin resistance in adipose tissue of obese WOKW rats is associated with up-regulation of differing autophagy markers in visceral and subcutaneous fat depots. This fact not only qualifies the WOKW rat for further detailed analysis of genetic determinants of metabolic syndrome but also highlights its suitability for autophagy research.
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http://dx.doi.org/10.1186/1758-5996-5-23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3685536PMC
May 2014

The composition of the microenvironment in follicular lymphoma is associated with the stage of the disease.

Hum Pathol 2012 Dec 15;43(12):2274-81. Epub 2012 Jul 15.

Department of Pathology, Hematopathology Section and Lymph Node Registry, University Hospital Schleswig-Holstein, Campus Kiel, Germany.

The role of regulatory and follicular helper T-cells as prognostic markers in follicular lymphoma was evaluated within the setting of prospective, randomized trials because the previously published results were contradictory. Two hundred sixty-four diagnostic tissue specimens from patients suffering from follicular lymphoma who received therapy within prospective randomized trials of the German Low Grade Lymphoma Study Group were analyzed immunohistochemically for FoxP3 and PD-1 expression to detect regulatory and follicular helper T-cells, respectively. We did not find any correlation between the content of regulatory and follicular helper T-cells and the time to treatment failure or overall survival in patients with advanced stages of follicular lymphoma in need of treatment. However, a perifollicular pattern of regulatory T-cells was associated with a poorer prognosis. The content of regulatory T-cells was positively and the content of follicular helper T-cells inversely correlated with a higher stage of the disease at diagnosis, implying that the microenvironment changes during tumor dissemination. This finding is independent of any therapy administered and needs to be considered when possible biomarkers related to the microenvironment of follicular lymphoma are studied.
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http://dx.doi.org/10.1016/j.humpath.2012.03.025DOI Listing
December 2012

Revising the historical collection of epithelioid cell-rich lymphomas of the Kiel Lymph Node Registry: what is Lennert's lymphoma nowadays?

Histopathology 2011 Dec;59(6):1173-82

Senckenberg Institute of Pathology, Goethe University, Frankfurt am Main, Germany.

Aims: Lennert's lymphoma is a rare variant of peripheral T-cell lymphoma (PTCL) not otherwise specified (NOS). The aim of this study was to further characterize this tumour.

Methods And Results: Historical material of 97 lymphomas with a high content of epithelioid cells, collected at the Kiel Lymph Node Registry were reviewed, by applying immunohistochemistry and current diagnostic criteria. Among all cases revised, various B-cell lymphoma entities (25 cases), Hodgkin lymphomas (21 cases) and PTCL subtypes (48 cases) could be identified. A distinctive subgroup of eight PTCLs was found that were regarded as genuine Lennert's lymphomas. These cases were characterized by mild atypia, a non-activated cytotoxic phenotype [TIA1 cytotoxic granule-associated RNA binding protein (TIA1)-positive(+) and granzyme B-negative], and a substantial lack of follicular T-helper (T(FH) ) cell markers. Among the other PTCLs, including angioimmunoblastic T-cell lymphoma and PTCL NOS, many cases with positivity for more than three T(FH) cell-associated molecules were recorded.

Conclusions: Our study shows that, according to current criteria, Lennert's lymphoma is a rare but distinctive entity among epithelioid cell-rich lymphomas, differing on grounds of morphology and immunophenotype from other PTCL subtypes. An additional finding is the broad morphological spectrum of epithelioid-cell rich PTCLs showing a T(FH) cell phenotype.
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http://dx.doi.org/10.1111/j.1365-2559.2011.04069.xDOI Listing
December 2011

Endogenous interferon α therapy in follicular lymphoma?

Leuk Lymphoma 2011 Jul;52(7):1168-9

Hematopathology Section and Lymph Node Registry, Department of Pathology, University Hospital Schleswig-Holstein, Kiel, Germany.

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http://dx.doi.org/10.3109/10428194.2011.563887DOI Listing
July 2011

Clinical, pathological and genetic features of primary mediastinal large B-cell lymphomas and mediastinal gray zone lymphomas in children.

Haematologica 2011 Feb 22;96(2):262-8. Epub 2010 Oct 22.

Department of Pathology, Hematopathology Section and Lymph Node Registry, Christian-Albrechts-University Kiel, University Hospital Schleswig-Holstein, Kiel, Germany.

Unlabelled: Background Primary mediastinal large B-cell lymphoma is a rare lymphoma accounting for no more than 3% of all B-cell lymphomas in children and adolescents. However, patients in this young age group with this lymphoma have the shortest event-free survival of patients with any B-cell lymphoma under current standard chemotherapy protocols. Lymphomas with features intermediate between primary mediastinal large B-cell lymphoma and classical Hodgkin's lymphoma (mediastinal gray zone lymphomas) have been acknowledged in the latest World Health Organization classification. Recent studies suggest that mediastinal gray zone lymphomas have an aggressive clinical course whereas patients, at least adult ones, with primary mediastinal large B-cell lymphoma might respond very well to chemotherapy in combination with anti-CD20 antibody.

Design And Methods: We aimed to evaluate whether biological differences or so far unrecognized admixed mediastinal gray zone lymphomas might explain the relatively poor outcome of pediatric patients with apparent primary mediastinal large B-cell lymphoma. We, therefore, performed a retrospective histopathological, immunohistochemical and interphase cytogenetic analysis of 52 pediatric lymphomas.

Results: The childhood primary mediastinal large B-cell lymphomas (n=44) showed a similar pattern of histology, immunophenotype and gains at 9p (59%) and 2p (41%) as adult cases, as determined from published data. We identified only four so far unrecognized cases of mediastinal gray zone lymphoma among 52 lymphomas registered in previous trials. Conclusions Mediastinal gray zone lymphoma is very rare in children and adolescents. It does, therefore, seem unlikely that these lymphomas account for the unsatisfactory clinical results with current therapy protocols in pediatric patients. These data have major implications for the design of future treatment protocols for mediastinal lymphomas in children and adolescents.
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http://dx.doi.org/10.3324/haematol.2010.030809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3031694PMC
February 2011
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