TY - JOUR A1 - Higuchi, Takahiro A1 - Serfling, Sebastian E. A1 - Rowe, Steven P. A1 - Werner, Rudolf A. T1 - Therapeutic effects of lipid lowering medications on myocardial blood flow, inflammation, and sympathetic nerve activity using nuclear techniques JF - Current Cardiology Reports N2 - Purpose of Review Statins are routinely applied in patients with coronary artery disease, as they allow significantly to reduce blood cholesterol levels. Although those drugs are endorsed by current guidelines and prescribed routinely, a substantial portion of patients are still statin-intolerant and image-piloted strategies may then be helpful to identify patients that need further intensified treatment, e.g., to initiate treatment with proprotein convertase subtilisin / kexin type 9 inhibitors (PCSK9i). In addition, it has also been advocated that statins exhibit nonlipid, cardio-protective effects including improved cardiac nerve integrity, blood flow, and anti-inflammatory effects in congestive heart failure (HF) patients. Recent Findings In subjects after myocardial infarction treated with statins, \(^{123}\)I-metaiodobenzylguanidine (MIBG) scintigraphy has already revealed enhanced cardiac nerve function relative to patients without statins. In addition, all of those aforementioned statin-targeted pathways in HF can be visualized and monitored using dedicated cardiac radiotracers, e.g., \(^{123}\)I-MIBG or \(^{18}\)F-AF78 (for cardiac nerve function), \(^{18}\)F-flurpiridaz (to determine coronary flow) or \(^{68}\)Ga-PentixaFor (to detect inflammation). Summary Statins exhibit various cardio-beneficial effects, including improvement of cardiac nerve function, blood flow, and reduction of inflammation, which can all be imaged using dedicated nuclear cardiac radiotracers. This may allow for in vivo monitoring of statin-induced cardioprotection beyond lipid profiling in HF patients. KW - sympathetic nervous system KW - cardiac nerve KW - MIBG KW - inflammation KW - blood flow KW - statin Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324599 VL - 24 IS - 12 ER - TY - JOUR A1 - García-Fernández, Patricia A1 - Reinhold, Colette A1 - Üçeyler, Nurcan A1 - Sommer, Claudia T1 - Local inflammatory mediators involved in neuropathic pain JF - International Journal of Molecular Sciences N2 - Polyneuropathy (PNP) is a term to describe diseases of the peripheral nervous system, 50% of which present with neuropathic pain. In some types of PNP, pain is restricted to the skin distally in the leg, suggesting a local regulatory process leading to pain. In this study, we proposed a pro-inflammatory pathway mediated by NF-κB that might be involved in the development of pain in patients with painful PNP. To test this hypothesis, we have collected nerve and skin samples from patients with different etiologies and levels of pain. We performed RT-qPCR to analyze the gene expression of the proposed inflammatory pathway components in sural nerve and in distal and proximal skin samples. In sural nerve, we showed a correlation of TLR4 and TNFα to neuropathic pain, and an upregulation of TNFα in patients with severe pain. Patients with an inflammatory PNP also presented a lower expression of TRPV1 and SIRT1. In distal skin, we found a reduced expression of TLR4 and miR-146-5p, in comparison to proximal skin. Our findings thus support our hypothesis of local inflammatory processes involved in pain in PNP, and further show disturbed anti-inflammatory pathways involving TRPV1 and SIRT1 in inflammatory PNP. KW - polyneuropathy KW - pain KW - inflammation KW - NF-κB KW - TNFα Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313613 SN - 1422-0067 VL - 24 IS - 9 ER - TY - JOUR A1 - Schanbacher, Constanze A1 - Hermanns, Heike M. A1 - Lorenz, Kristina A1 - Wajant, Harald A1 - Lang, Isabell T1 - Complement 1q/tumor necrosis factor-related proteins (CTRPs): structure, receptors and signaling JF - Biomedicines N2 - Adiponectin and the other 15 members of the complement 1q (C1q)/tumor necrosis factor (TNF)-related protein (CTRP) family are secreted proteins composed of an N-terminal variable domain followed by a stalk region and a characteristic C-terminal trimerizing globular C1q (gC1q) domain originally identified in the subunits of the complement protein C1q. We performed a basic PubMed literature search for articles mentioning the various CTRPs or their receptors in the abstract or title. In this narrative review, we briefly summarize the biology of CTRPs and focus then on the structure, receptors and major signaling pathways of CTRPs. Analyses of CTRP knockout mice and CTRP transgenic mice gave overwhelming evidence for the relevance of the anti-inflammatory and insulin-sensitizing effects of CTRPs in autoimmune diseases, obesity, atherosclerosis and cardiac dysfunction. CTRPs form homo- and heterotypic trimers and oligomers which can have different activities. The receptors of some CTRPs are unknown and some receptors are redundantly targeted by several CTRPs. The way in which CTRPs activate their receptors to trigger downstream signaling pathways is largely unknown. CTRPs and their receptors are considered as promising therapeutic targets but their translational usage is still hampered by the limited knowledge of CTRP redundancy and CTRP signal transduction. KW - adiponectin KW - AMPK KW - C1q/TNF related protein (CTRP) KW - inflammation KW - metabolism Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304136 SN - 2227-9059 VL - 11 IS - 2 ER - TY - JOUR A1 - Kollmann, Catherine A1 - Buerkert, Hannah A1 - Meir, Michael A1 - Richter, Konstantin A1 - Kretzschmar, Kai A1 - Flemming, Sven A1 - Kelm, Matthias A1 - Germer, Christoph-Thomas A1 - Otto, Christoph A1 - Burkard, Natalie A1 - Schlegel, Nicolas T1 - Human organoids are superior to cell culture models for intestinal barrier research JF - Frontiers in Cell and Developmental Biology N2 - Loss of intestinal epithelial barrier function is a hallmark in digestive tract inflammation. The detailed mechanisms remain unclear due to the lack of suitable cell-based models in barrier research. Here we performed a detailed functional characterization of human intestinal organoid cultures under different conditions with the aim to suggest an optimized ex-vivo model to further analyse inflammation-induced intestinal epithelial barrier dysfunction. Differentiated Caco2 cells as a traditional model for intestinal epithelial barrier research displayed mature barrier functions which were reduced after challenge with cytomix (TNFα, IFN-γ, IL-1ß) to mimic inflammatory conditions. Human intestinal organoids grown in culture medium were highly proliferative, displayed high levels of LGR5 with overall low rates of intercellular adhesion and immature barrier function resembling conditions usually found in intestinal crypts. WNT-depletion resulted in the differentiation of intestinal organoids with reduced LGR5 levels and upregulation of markers representing the presence of all cell types present along the crypt-villus axis. This was paralleled by barrier maturation with junctional proteins regularly distributed at the cell borders. Application of cytomix in immature human intestinal organoid cultures resulted in reduced barrier function that was accompanied with cell fragmentation, cell death and overall loss of junctional proteins, demonstrating a high susceptibility of the organoid culture to inflammatory stimuli. In differentiated organoid cultures, cytomix induced a hierarchical sequence of changes beginning with loss of cell adhesion, redistribution of junctional proteins from the cell border, protein degradation which was accompanied by loss of epithelial barrier function. Cell viability was observed to decrease with time but was preserved when initial barrier changes were evident. In summary, differentiated intestinal organoid cultures represent an optimized human ex-vivo model which allows a comprehensive reflection to the situation observed in patients with intestinal inflammation. Our data suggest a hierarchical sequence of inflammation-induced intestinal barrier dysfunction starting with loss of intercellular adhesion, followed by redistribution and loss of junctional proteins resulting in reduced barrier function with consecutive epithelial death. KW - intestinal epithelial barrier KW - Caco2 cells KW - intestinal organoids KW - enteroids KW - gut barrier KW - inflammatory cell model KW - inflammation Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357317 SN - 2296-634X VL - 11 ER - TY - JOUR A1 - Rolfes, Leoni A1 - Ruck, Tobias A1 - David, Christina A1 - Mencl, Stine A1 - Bock, Stefanie A1 - Schmidt, Mariella A1 - Strecker, Jan-Kolja A1 - Pfeuffer, Steffen A1 - Mecklenbeck, Andreas-Schulte A1 - Gross, Catharina A1 - Gliem, Michael A1 - Minnerup, Jens A1 - Schuhmann, Michael K. A1 - Kleinschnitz, Christoph A1 - Meuth, Sven G. T1 - Natural Killer Cells Are Present in Rag1\(^{−/−}\) Mice and Promote Tissue Damage During the Acute Phase of Ischemic Stroke JF - Translational Stroke Research N2 - Rag1\(^{−/−}\) mice, lacking functional B and T cells, have been extensively used as an adoptive transfer model to evaluate neuroinflammation in stroke research. However, it remains unknown whether natural killer (NK) cell development and functions are altered in Rag1\(^{−/−}\) mice as well. This connection has been rarely discussed in previous studies but might have important implications for data interpretation. In contrast, the NOD-Rag1\(^{null}\)IL2rg\(^{null}\) (NRG) mouse model is devoid of NK cells and might therefore eliminate this potential shortcoming. Here, we compare immune-cell frequencies as well as phenotype and effector functions of NK cells in Rag1\(^{−/−}\) and wildtype (WT) mice using flow cytometry and functional in vitro assays. Further, we investigate the effect of Rag1\(^{−/−}\) NK cells in the transient middle cerebral artery occlusion (tMCAO) model using antibody-mediated depletion of NK cells and adoptive transfer to NRG mice in vivo. NK cells in Rag1\(^{−/−}\) were comparable in number and function to those in WT mice. Rag1\(^{−/−}\) mice treated with an anti-NK1.1 antibody developed significantly smaller infarctions and improved behavioral scores. Correspondingly, NRG mice supplemented with NK cells were more susceptible to tMCAO, developing infarctions and neurological deficits similar to Rag1−/− controls. Our results indicate that NK cells from Rag1−/− mice are fully functional and should therefore be considered in the interpretation of immune-cell transfer models in experimental stroke. Fortunately, we identified the NRG mice, as a potentially better-suited transfer model to characterize individual cell subset-mediated neuroinflammation in stroke. KW - infarction KW - middle cerebral artery occlusion KW - animal model KW - inflammation KW - natural killer cells Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-308924 SN - 1868-4483 SN - 1868-601X VL - 13 IS - 1 ER -