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Abstract Mast cells (MCs) are immune cells of the myeloid lineage distributed in tissues throughout the body. Phenotypically, they are a heterogeneous group characterized by different protease repertoires stored in secretory granules and differential presence of receptors. To adequately address aspects of MC biology either primary MCs isolated from human or mouse tissue or different human MC lines, like HMC-1.1 and -1.2, or rodent MC lines like L138.8A or RBL-2H3 are frequently used. Nevertheless, cellular systems to study MC functions are very limited. We have generated a murine connective tissue-like MC line, termed PMC-306, derived from primary peritoneal MCs (PMCs), which spontaneously transformed. We analyzed PMC-306 cells regarding MC surface receptor expression, effector functions and respective signaling pathways, and found that the cells reacted very similar to primary wildtype (WT) PMCs. In this regard, stimulation with MAS-related G-protein-coupled receptor member B2 (MRGPRB2) ligands induced respective signaling and effector functions. Furthermore, PMC-306 cells revealed significantly accelerated cell cycle progression, which however was still dependent on IL-3 and stem cell factor (SCF). Phenotypically, PMC-306 cells adopted an immature connective tissue-like MCs appearance. The reason for immortalization most likely is the loss of the two critical cell cycle regulators Cdkn2a /INK4A and Arf /p19, respectively. The loss of Cdkn2a and Arf expression could be mimicked in primary bone marrow-derived mast cells (BMMCs) by SCF supplementation strongly arguing for an involvement of KIT activation in the transformation process. Hence, this new cell line might be a useful tool to study further aspects of PMC function and to address tumorigenic processes associated with MC leukemia.
Background: Lipocalin-2 (LCN2) or neutrophil gelatinase-associated lipocalin (NGAL) is a small secreted adipokine belonging to the lipocalin family [1]. It binds and transports small hydrophobic molecules and limits bacterial growth by sequestering iron-containing siderophores. In the liver, LCN2 plays a protective role in inflammation, infection, and cellular stress. Recently, we demonstrated that LCN2 regulates lipid droplet protein Perilipin 5 (PLIN5) expression in primary hepatocytes and showed that LCN2 animals are more prone to hepatic inflammation and steatosis [2 – 4]. Methods: We here comparatively analyzed the proteome (label-free proteomics or 2D-DIGE protein expression profiling) of wild type and Lcn2-deficient mice fed either a standard-chow and a methionine- and choline-deficient (MCD) diet. The differential expression was confirmed by Western blot analysis and quantitative real-time PCR. We further employed comparative MALDI-TOF Imaging Mass Spectrometry to monitor the spatial distribution of a broad range of lipids in liver tissue sections of respective groups. Results: We identified a multitude of genes that are either upregulated during hepatic steatosis or differentially induced or repressed in mice lacking LCN2. Differentially expressed proteins were BRIT1/MCPH1, FABP5, HMGB1, HBB2, and L-FABP. In addition, we identified significantly altered m/z signal intensities for several sphingomyelins, triglycerides, and phospholipid species. Most notably, phosphatidylinositol phosphates were substantially elevated in MCD-fed mice, indicating chronic activation of phosphatidylinositol phosphate-dependent signaling pathways, and this alteration was unaffected by LCN2 deletion. Moreover, the abundance of some 20:4 lipids were elevated in the livers of Lcn2-deficient mice suggesting that this gene disruption might interfere with arachidonic acid and eicosanoid metabolism. Conclusion: In summary, our data indicate that LCN2 is a key switch influencing triglyceride balance, reactive oxidative stress formation, inflammatory response, and cellular apoptosis.
<p>miR-371~373 cluster expression in extracted xenografts and its effect on metastatic outgrowth capacity in SW620 SCs</p>
Read moreAcute and chronic liver diseases are frequently associated with proliferation of Hepatocytes and Hepatic stellate cells (HSC). The proliferation of immune cells in this context is poorly investigated. Sustained activation of these processes can lead to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). E-cyclins (E1, E2) control transition into S-phase of the cell cycle and play a crucial role during carcinogenesis. Our own preliminary work demonstrated an essential role of Cyclin E1 for liver fibrogenesis and HCC development in mice. Thus Cyclin E1 could be a suitable diagnostic marker for indication of liver fibrosis and HCC. The aim of the present study was to develop novel strategies for early diagnosis of aberrant Cyclin E1 expression and identification of novel Cyclin E1 expressing cell populations in liver fibrosis and HCC.
Read moreNon-alcoholic fatty liver disease (NAFLD) is a common and prevalent disorder affecting 25 percent of the adults in the United States and 32 percent of adults globally. It is one of the common causes of chronic liver disease characterized by steatosis, which can lead to inflammation, fibrosis, and cirrhosis. NAFLD is strongly associated with obesity and insulin resistance. Multiple genetic variants have been consistently found to be associated with NAFLD; one of them is found in the TMC4-MBOAT7 loci. One variant (rs641738 C>T) within MBOAT7 encoding lysophosphatidyl inositol acyltransferase increases the risk for NAFLD development and triggers hepatic inflammation by regulating arachidonic acid levels. This review provides an overview of the MBOAT7 gene, pathogenesis of NAFLD, understanding the regulation of MBOAT7 and mechanistic link between MBOAT7 and NAFLD. It further summarizes pathophysiologically relevant in vivo and in vitro studies on MBOAT7 and challenges in treating complex NAFLD with recent progress made in the treatment of NAFLD. As such, this review provides useful information on MBOAT7 and NAFLD interrelation, which has the potential of deciphering novel therapeutic targets rather than well-known genetic variants such as PNPLA3 and TM6SF2.
Read moreSpinal cord injury (SCI) results in the production of proinflammatory cytokines due to inflammasome activation. Lipocalin 2 (LCN2) is a small secretory glycoprotein upregulated by toll-like receptor (TLR) signaling in various cells and tissues. LCN2 secretion is induced by infection, injury, and metabolic disorders. In contrast, LCN2 has been implicated as an anti-inflammatory regulator. However, the role of LCN2 in inflammasome activation during SCI remains unknown. This study examined the role of Lcn2 deficiency in the NLRP3 inflammasome-dependent neuroinflammation in SCI. Lcn2−/− and wild-type (WT) mice were subjected to SCI, and locomotor function, formation of the inflammasome complex, and neuroinflammation were assessed. Our findings demonstrated that significant activation of the HMGB1/PYCARD/caspase-1 inflammatory axis was accompanied by the overexpression of LCN2 7 days after SCI in WT mice. This signal transduction results in the cleaving of the pyroptosis-inducing protein gasdermin D (GSDMD) and the maturation of the proinflammatory cytokine IL-1β. Furthermore, Lcn2−/− mice showed considerable downregulation in the HMGB1/NLRP3/PYCARD/caspase-1 axis, IL-1β production, pore formation, and improved locomotor function compared with WT. Our data suggest that LCN2 may play a role as a putative molecule for the induction of inflammasome-related neuroinflammation in SCI.
Read more<p>The miR-371~373 cluster represses colony formation potential of SW620 SCs without affecting cellular proliferation</p>
Read moreWilson disease (WD) is a rare, inherited metabolic disorder manifested with varying clinical presentations including hepatic, neurological, psychiatric, and ophthalmological features, often in combination. Causative mutations in the ATP7B gene result in copper accumulation in hepatocytes and/or neurons, but clinical diagnosis remains challenging. Diagnosis is complicated by mild, non-specific presentations, mutations exerting no clear effect on protein function, and inconclusive laboratory tests, particularly regarding serum ceruloplasmin levels. As early diagnosis and effective treatment are crucial to prevent progressive damage, we report here on the establishment of a global collaboration of researchers, clinicians, and patient advocacy groups to identify and address the outstanding challenges posed by WD.
Read more<div>Abstract<p>The vast majority of colorectal cancer–related deaths can be attributed to metastatic spreading of the disease. Therefore, deciphering molecular mechanisms of metastatic dissemination is a key prerequisite to improve future treatment options. With this aim, we took advantage of different colorectal cancer cell lines and recently established primary cultures enriched in colon cancer stem cells, also known as tumor-initiating cells (TIC), to identify genes and miRNAs with regulatory functions in colorectal cancer progression. We show here that metastasis-derived TICs display increased capacity for self-renewal, TGFβ signaling activity, and reduced expression of the miR-371∼373 cluster compared with nonmetastatic cultures. TGFβ receptor 2 (<i>TGFBR2</i>) and aldehyde dehydrogenase A1 (<i>ALDH1A1</i>) were identified as important target genes of the miR-371∼373 cluster. In addition, TGFBR2 repression, either by direct knockdown or indirectly via overexpression of the entire miR-371∼373 cluster, decreased tumor-initiating potential of TICs. We observed significantly reduced <i>in vitro</i> self-renewal activity as well as lowered tumor initiation and metastatic outgrowth capacity <i>in vivo</i> following stable overexpression of the miR-371∼373 cluster in different colon TIC cultures. Inhibitor of DNA binding 1 (ID1) was affected by both TGFBR2 and miR-371∼373 cluster alterations. Functional sphere and tumor formation as well as metastatic dissemination assays validated the link between miR-371∼373 and ID1. Altogether, our results establish the miR-371∼373/TGFBR2/ID1 signaling axis as a novel regulatory mechanism of TIC self-renewal and metastatic colonization.</p><p><b>Significance:</b> These findings establish the miR-371∼373/TGFBR2/ID1 signaling axis as a novel mechanism regulating self-renewal of tumor-initiating cell and metastatic colonization, potentially opening new concepts for therapeutic targeting of cancer metastasis.</p><p><b>Graphical Abstract:</b> <a href="http://cancerres.aacrjournals.org/content/canres/78/14/3793/F1.large.jpg" target="_blank">http://cancerres.aacrjournals.org/content/canres/78/14/3793/F1.large.jpg</a>. <i>Cancer Res; 78(14); 3793–808. ©2018 AACR</i>.</p></div>
Read moreBackground: In the setting of mastocytosis, mast cells have been shown to promote renal and lung fibrosis, whereas their effect in the liver is under debate [1 – 4]. Mast cell effects are based on the secretion of mitogenic and profibrotic, e.g. TGF-β1, cytokines – leading to activation and proliferation of fibroblasts [5] – and proteases – causing a direct or indirect modulation of extracellular matrix homeostasis [6]. Besides these paracrine effects, mast cells are able to process TGF-β1 signals on their own but the exact mechanisms and responses are less well characterized.
Read more<p>Short hairpin (sh) RNA knockdown control of TGFBR2</p>
Read moreBackground: Platelet-derived growth factor-D (PDGF-D) is a more recent recognized growth factor of the PDGF family [1]. It regulates several cellular processes including cell proliferation, transformation, invasion, and angiogenesis through specifically binding to and activating its cognate receptor PDGFR-β. In experimental liver fibrotic models (BDL and carbon tetrachloride), we have shown that PDGF-D is upregulated comparable to that of PDGF-B [2, 3]. Moreover, adenoviral expression of PDGF-D induces hepatic stellate cell (HSC) proliferation and liver fibrosis [4]. We now seek to investigate the molecular mechanism of PDGF-D involvement in liver fibrogenesis.
Read moreJournal Article Anthocyanidin Floral Pigmentation in Red Clover Get access N. L. TAYLOR, N. L. TAYLOR Search for other works by this author on: Oxford Academic PubMed Google Scholar C. J. KELLER, C. J. KELLER Search for other works by this author on: Oxford Academic PubMed Google Scholar M. K. ANDERSON, M. K. ANDERSON Search for other works by this author on: Oxford Academic PubMed Google Scholar W. A. KENDALL W. A. KENDALL The authors are professor and assistant professors of agronomy, University of Kentucky and plant physiologist, Crops Research Division, ARS, USDA, Lexington, 40506, respectively. Cooperative research by the Kentucky Agricultural Experiment Station and Crops Research Division, Agricultural Research Service, U. S. Department of Agriculture. The investigation reported in this paper (No. 70-3H51) was in connection with a project of the Kentucky Agricultural Experiment Station and is published with approval of the Director. The authors gratefully acknowledge the technical assistance of Mr. Moss Long, Mrs. Doris Watkins, and Mrs. Carol Wyatt. Search for other works by this author on: Oxford Academic PubMed Google Scholar Journal of Heredity, Volume 62, Issue 1, January 1971, Pages 13–16, https://doi.org/10.1093/oxfordjournals.jhered.a108109 Published: 01 January 1971
Read more<p>Antibodies, primers, and lentiviral particles (S1); in vivo tumorigenicity for SW480 vs. SW620 (S2); top 20 differentially expressed miRNAs (S3); peritoneal cancer index scores (S4)</p>
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