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  1. Article ; Online: PD-L1 in the palm of your hand

    Andreas von Knethen / Bernhard Brüne

    Signal Transduction and Targeted Therapy, Vol 4, Iss 1, Pp 1-

    palmitoylation as a target for immuno-oncology

    2019  Volume 2

    Keywords Medicine ; R ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2019-06-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Antioxidants as Therapeutic Agents in Acute Respiratory Distress Syndrome (ARDS) Treatment—From Mice to Men

    Andreas von Knethen / Ulrike Heinicke / Volker Laux / Michael J. Parnham / Andrea U. Steinbicker / Kai Zacharowski

    Biomedicines, Vol 10, Iss 98, p

    2022  Volume 98

    Abstract: Acute respiratory distress syndrome (ARDS) is a major cause of patient mortality in intensive care units (ICUs) worldwide. Considering that no causative treatment but only symptomatic care is available, it is obvious that there is a high unmet medical ... ...

    Abstract Acute respiratory distress syndrome (ARDS) is a major cause of patient mortality in intensive care units (ICUs) worldwide. Considering that no causative treatment but only symptomatic care is available, it is obvious that there is a high unmet medical need for a new therapeutic concept. One reason for a missing etiologic therapy strategy is the multifactorial origin of ARDS, which leads to a large heterogeneity of patients. This review summarizes the various kinds of ARDS onset with a special focus on the role of reactive oxygen species (ROS), which are generally linked to ARDS development and progression. Taking a closer look at the data which already have been established in mouse models, this review finally proposes the translation of these results on successful antioxidant use in a personalized approach to the ICU patient as a potential adjuvant to standard ARDS treatment.
    Keywords ARDS ; antioxidant ; Nrf2 ; GSH ; NADPH oxidase ; SOD ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2022-01-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Angiotensin II treatment in COVID-19 patients

    Ulrike Heinicke / Elisabeth Adam / Michael Sonntagbauer / Andreas von Knethen / Kai Zacharowski / Holger Neb

    Critical Care, Vol 24, Iss 1, Pp 1-

    more risk than benefit? A single-center experience

    2020  Volume 4

    Keywords Medical emergencies. Critical care. Intensive care. First aid ; RC86-88.9 ; covid19
    Language English
    Publishing date 2020-07-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Redox Regulation of PPARγ in Polarized Macrophages

    Verena Trümper / Ilka Wittig / Juliana Heidler / Florian Richter / Bernhard Brüne / Andreas von Knethen

    PPAR Research, Vol

    2020  Volume 2020

    Abstract: The peroxisome proliferator-activated receptor (PPARγ) is a central mediator of cellular lipid metabolism and immune cell responses during inflammation. This is facilitated by its role as a transcription factor as well as a DNA-independent protein ... ...

    Abstract The peroxisome proliferator-activated receptor (PPARγ) is a central mediator of cellular lipid metabolism and immune cell responses during inflammation. This is facilitated by its role as a transcription factor as well as a DNA-independent protein interaction partner. We addressed how the cellular redox milieu in the cytosol and the nucleus of lipopolysaccharide (LPS)/interferon-γ- (IFNγ-) and interleukin-4- (IL4-) polarized macrophages (MΦ) initiates posttranslational modifications of PPARγ, that in turn alter its protein function. Using the redox-sensitive GFP2 (roGFP2), we validated oxidizing and reducing conditions following classical and alternative activation of MΦ, while the redox status of PPARγ was determined via mass spectrometry. Cysteine residues located in the zinc finger regions (amino acid fragments AA 90-115, AA 116-130, and AA 160-167) of PPARγ were highly oxidized, accompanied by phosphorylation of serine 82 in response to LPS/IFNγ, whereas IL4-stimulation provoked minor serine 82 phosphorylation and less cysteine oxidation, favoring a reductive milieu. Mutating these cysteines to alanine to mimic a redox modification decreased PPARγ-dependent reporter gene transactivation supporting a functional shift of PPARγ associated with the MΦ phenotype. These data suggest distinct mechanisms for regulating PPARγ function based on the redox state of MΦ.
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2020-01-01T00:00:00Z
    Publisher Hindawi Limited
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Histone Deacetylation Inhibitors as Modulators of Regulatory T Cells

    Andreas von Knethen / Ulrike Heinicke / Andreas Weigert / Kai Zacharowski / Bernhard Brüne

    International Journal of Molecular Sciences, Vol 21, Iss 7, p

    2020  Volume 2356

    Abstract: Regulatory T cells (T regs ) are important mediators of immunological self-tolerance and homeostasis. Being cluster of differentiation 4 + Forkhead box protein3 + (CD4 + FOXP3 + ), these cells are a subset of CD4 + T lymphocytes and can originate from ... ...

    Abstract Regulatory T cells (T regs ) are important mediators of immunological self-tolerance and homeostasis. Being cluster of differentiation 4 + Forkhead box protein3 + (CD4 + FOXP3 + ), these cells are a subset of CD4 + T lymphocytes and can originate from the thymus (tT regs ) or from the periphery (pT regs ). The malfunction of CD4 + T regs is associated with autoimmune responses such as rheumatoid arthritis (RA), multiple sclerosis (MS), type 1 diabetes (T1D), inflammatory bowel diseases (IBD), psoriasis, systemic lupus erythematosus (SLE), and transplant rejection. Recent evidence supports an opposed role in sepsis. Therefore, maintaining functional T regs is considered as a therapy regimen to prevent autoimmunity and allograft rejection, whereas blocking T reg differentiation might be favorable in sepsis patients. It has been shown that T regs can be generated from conventional naïve T cells, called iT regs , due to their induced differentiation. Moreover, T regs can be effectively expanded in vitro based on blood-derived tT regs . Taking into consideration that the suppressive role of T regs has been mainly attributed to the expression and function of the transcription factor Foxp3, modulating its expression and binding to the promoter regions of target genes by altering the chromatin histone acetylation state may turn out beneficial. Hence, we discuss the role of histone deacetylation inhibitors as epigenetic modulators of T regs in this review in detail.
    Keywords tolerance induction ; epigenetics ; Foxp3 expression ; histone deacetylase inhibitor ; sepsis ; transplantation ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 333
    Language English
    Publishing date 2020-03-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Macrophage S1PR1 Signaling Alters Angiogenesis and Lymphangiogenesis During Skin Inflammation

    Shahzad Nawaz Syed / Rebecca Raue / Andreas Weigert / Andreas von Knethen / Bernhard Brüne

    Cells, Vol 8, Iss 8, p

    2019  Volume 785

    Abstract: The bioactive lipid sphingosine-1-phosphate (S1P), along with its receptors, modulates lymphocyte trafficking and immune responses to regulate skin inflammation. Macrophages are important in the pathogenesis of psoriasiform skin inflammation and express ... ...

    Abstract The bioactive lipid sphingosine-1-phosphate (S1P), along with its receptors, modulates lymphocyte trafficking and immune responses to regulate skin inflammation. Macrophages are important in the pathogenesis of psoriasiform skin inflammation and express various S1P receptors. How they respond to S1P in skin inflammation remains unknown. We show that myeloid specific S1P receptor 1 (S1PR1) deletion enhances early inflammation in a mouse model of imiquimod-induced psoriasis, without altering the immune cell infiltrate. Mechanistically, myeloid S1PR1 deletion altered the formation of IL-1β, VEGF-A, and VEGF-C, and their receptors’ expression in psoriatic skin, which subsequently lead to reciprocal regulation of neoangiogenesis and neolymphangiogenesis. Experimental findings were corroborated in human clinical datasets and in knockout macrophages in vitro. Increased blood vessel but reduced lymph vessel density may explain the exacerbated inflammatory phenotype in conditional knockout mice. These findings assign a novel role to macrophage S1PR1 and provide a rationale for therapeutically targeting local S1P during skin inflammation.
    Keywords macrophage ; S1PR1 ; sphingosine-1-phosphate ; psoriasis ; inflammation ; lymphangiogenesis ; angiogenesis ; Biology (General) ; QH301-705.5
    Subject code 571
    Language English
    Publishing date 2019-07-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: RELSA—A multidimensional procedure for the comparative assessment of well-being and the quantitative determination of severity in experimental procedures

    Steven R. Talbot / Birgitta Struve / Laura Wassermann / Miriam Heider / Nora Weegh / Tilo Knape / Martine C. J. Hofmann / Andreas von Knethen / Paulin Jirkof / Christine Häger / André Bleich

    Frontiers in Veterinary Science, Vol

    2022  Volume 9

    Abstract: Good science in translational research requires good animal welfare according to the principles of 3Rs. In many countries, determining animal welfare is a mandatory legal requirement, implying a categorization of animal suffering, traditionally dominated ...

    Abstract Good science in translational research requires good animal welfare according to the principles of 3Rs. In many countries, determining animal welfare is a mandatory legal requirement, implying a categorization of animal suffering, traditionally dominated by subjective scorings. However, how such methods can be objectified and refined to compare impairments between animals, subgroups, and animal models remained unclear. Therefore, we developed the RELative Severity Assessment (RELSA) procedure to establish an evidence-based method based on quantitative outcome measures such as body weight, burrowing behavior, heart rate, heart rate variability, temperature, and activity to obtain a relative metric for severity comparisons. The RELSA procedure provided the necessary framework to get severity gradings in TM-implanted mice, yielding four distinct RELSA thresholds L1<0.27, L2<0.59, L3<0.79, and L4<3.45. We show further that severity patterns in the contributing variables are time and model-specific and use this information to obtain contextualized between animal-model and subgroup comparisons with the severity of sepsis > surgery > restraint stress > colitis. The bootstrapped 95% confidence intervals reliably show that RELSA estimates are conditionally invariant against missing information but precise in ranking the quantitative severity information to the moderate context of the transmitter-implantation model. In conclusion, we propose the RELSA as a validated tool for an objective, computational approach to comparative and quantitative severity assessment and grading. The RELSA procedure will fundamentally improve animal welfare, data quality, and reproducibility. It is also the first step toward translational risk assessment in biomedical research.
    Keywords severity assessment ; laboratory animal ; animal welfare ; data science ; animal experiments ; sepsis model ; Veterinary medicine ; SF600-1100
    Language English
    Publishing date 2022-11-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Macrophage-Derived Iron-Bound Lipocalin-2 Correlates with Renal Recovery Markers Following Sepsis-Induced Kidney Damage

    Christina Mertens / Laura Kuchler / Anna Sola / Roser Guiteras / Stephan Grein / Bernhard Brüne / Andreas von Knethen / Michaela Jung

    International Journal of Molecular Sciences, Vol 21, Iss 7527, p

    2020  Volume 7527

    Abstract: During the course of sepsis in critically ill patients, kidney dysfunction and damage are among the first events of a complex scenario toward multi-organ failure and patient death. Acute kidney injury triggers the release of lipocalin-2 (Lcn-2), which is ...

    Abstract During the course of sepsis in critically ill patients, kidney dysfunction and damage are among the first events of a complex scenario toward multi-organ failure and patient death. Acute kidney injury triggers the release of lipocalin-2 (Lcn-2), which is involved in both renal injury and recovery. Taking into account that Lcn-2 binds and transports iron with high affinity, we aimed at clarifying if Lcn-2 fulfills different biological functions according to its iron-loading status and its cellular source during sepsis-induced kidney failure. We assessed Lcn-2 levels both in serum and in the supernatant of short-term cultured renal macrophages (MΦ) as well as renal tubular epithelial cells (TEC) isolated from either Sham-operated or cecal ligation and puncture (CLP)-treated septic mice. Total kidney iron content was analyzed by Perls’ staining, while Lcn-2-bound iron in the supernatants of short-term cultured cells was determined by atomic absorption spectroscopy. Lcn-2 protein in serum was rapidly up-regulated at 6 h after sepsis induction and subsequently increased up to 48 h. Lcn-2-levels in the supernatant of TEC peaked at 24 h and were low at 48 h with no change in its iron-loading. In contrast, in renal MΦ Lcn-2 was low at 24 h, but increased at 48 h, where it mainly appeared in its iron-bound form. Whereas TEC-secreted, iron-free Lcn-2 was associated with renal injury, increased MΦ-released iron-bound Lcn-2 was linked to renal recovery. Therefore, we hypothesized that both the cellular source of Lcn-2 as well as its iron-load crucially adds to its biological function during sepsis-induced renal injury.
    Keywords lipocalin-2 ; macrophages ; renal tubular epithelial cells ; iron ; CLP ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 616
    Language English
    Publishing date 2020-10-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: The Nuclear Hormone Receptor PPARγ as a Therapeutic Target in Major Diseases

    Martina Victoria Schmidt / Bernhard Brüne / Andreas von Knethen

    The Scientific World Journal, Vol 10, Pp 2181-

    2010  Volume 2197

    Abstract: The peroxisome proliferator-activated receptor γ (PPARγ) belongs to the nuclear hormone receptor superfamily and regulates gene expression upon heterodimerization with the retinoid X receptor by ligating to peroxisome proliferator response elements ( ... ...

    Abstract The peroxisome proliferator-activated receptor γ (PPARγ) belongs to the nuclear hormone receptor superfamily and regulates gene expression upon heterodimerization with the retinoid X receptor by ligating to peroxisome proliferator response elements (PPREs) in the promoter region of target genes. Originally, PPARγ was identified as being essential for glucose metabolism. Thus, synthetic PPARγ agonists, the thiazolidinediones (TZDs), are used in type 2 diabetes therapy as insulin sensitizers. More recent evidence implied an important role for the nuclear hormone receptor PPARγ in controlling various diseases based on its anti-inflammatory, cell cycle arresting, and proapoptotic properties. In this regard, expression of PPARγ is not restricted to adipocytes, but is also found in immune cells, such as B and T lymphocytes, monocytes, macrophages, dendritic cells, and granulocytes. The expression of PPARγ in lymphoid organs and its modulation of macrophage inflammatory responses, lymphocyte proliferation, cytokine production, and apoptosis underscore its immune regulating functions. Moreover, PPARγ expression is found in tumor cells, where its activation facilitates antitumorigenic actions. This review provides an overview about the role of PPARγ as a possible therapeutic target approaching major, severe diseases, such as sepsis, cancer, and atherosclerosis.
    Keywords Technology ; T ; Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2010-01-01T00:00:00Z
    Publisher Hindawi Limited
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Correction

    Thea K. Wöbke / Andreas von Knethen / Dieter Steinhilber / Bernd L. Sorg

    PLoS ONE, Vol 9, Iss

    CD69 Is a TGF-β/1α,25-dihydroxyvitamin D3 Target Gene in Monocytes.

    2014  Volume 1

    Keywords Medicine ; R ; Science ; Q
    Language English
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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