glioma-associated microglia/macrophages

Top PDF glioma-associated microglia/macrophages:

Dissecting the role of Toll-like receptors in microglia-glioma crosstalk

Dissecting the role of Toll-like receptors in microglia-glioma crosstalk

Like other solid cancers, gliomas are heterogeneous and keep interacting with other “healthy” resident cells in the brain. Gliomas may not only derive from the healthy cells but after the initiation they start to influence these cells and convert them to a tumor supporting phenotype. Among different types of tumor associated parenchymal cell populations in the brain, glioma associated microglia/macrophages would be the most interesting subtype. Firstly, they shared a large proportion of gliomas with a contribution of up to 30% of tumor mass. Secondly, as the guardians in the brain, microglial cells constantly screen brain tissue using their motile processes, once an insult is found, they become activated and move to the lesions very rapidly. However, this property raises a few interesting questions: How do microglial cells behave when brain resident cells just start to transform to tumor cells? Do they sense these events? Do they accumulate around it? Do they phagocytose these transformed cells? These questions are still obscure. Last but not least, microglial cells are the immune cells of the brain, they express a wide range of receptors like neurotransmitter receptors, pattern-recognition receptors and cytokine and chemokine receptors (Kettenmann et al. 2011), by which they may easily get activated by tumor released factors or physical contact. And they could also release different types of cytokines and chemokines, which may shape the characteristics of gliomas. Glioma research has been extensively developed in the past decades; however, the majority mainly focus on the biology of the tumor itself without much concern about tumor microenvironment. These tumor-associated resident brain cells also contribute immensely to gliomagenesis, and more importantly, these cells may also play part in drug resistance in conventional chemotherapy.
Mehr anzeigen

103 Mehr lesen

Neurotransmitter and neurohormone receptors on microglia

Neurotransmitter and neurohormone receptors on microglia

cytotoxicity and production of tumor necrosis factor alpha (Frei et al., 1987). This demonstrates the potential for the development of therapies which can alter microglial function to steer them to a more neuroprotective phenotype. However, in the case of glioma, the majority of research indicates that glioma release substances which suppress protective functions of microglia, for example suppressing the release of proinflammatory cytokines such as TNF-α, IL-1 or IL-6 (Hussain et al., 2006), while upregulating the production of enzymes beneficial to tumor expansion and growth (Konnecke and Bechmann, 2013). Membrane bound and secreted proteases such as membrane type-1 matrix metalloprotease (MT1- MMP) and MMP9 have been extensively studied in recent years. Their role in degrading the extracellular matrix to support tumor growth has been linked to microglia. MT1-MMP was shown to be upregulated in tumor associated microglia, which was triggered by factors released by the glioma via microglial toll-like receptors and the p38 MAPK pathway. MT1-MMP was not upregulated in glioma cells. The resulting upregulation in microglia leads to activation of glioma-derived pro-MMP-2 which in turn promotes glioma expansion (Markovic et al., 2009). Microglia have also been shown to modulate MMP-9 activity through the release of the co-chaperone stress inducible protein 1 (STI1) (Fonseca et al., 2012). Higher densities of microglia/brian macrophages in glioma tissue also positively correlates towards increased grade and invasiveness of the tumor (Markovic et al., 2005). In order to study glioma and glioma-associated microglia, there are a number of animal models of this disease which can effectively mimic the human condition when human samples are unavailable or limited. Mouse models of glioma can include genetic models (Chen et al., 2012), where genes such as those for cell- cycle control or tumor suppression are knocked out. For this study, we have used a stab wound model of glioma. This model involves the induction of a stab-wound injury, followed by the injection of a glioma cell line and is discussed in more detail in the methods section.
Mehr anzeigen

112 Mehr lesen

Comprehensive gene expression meta-analysis identifies signature genes that distinguish microglia from peripheral monocytes/macrophages in health and glioma

Comprehensive gene expression meta-analysis identifies signature genes that distinguish microglia from peripheral monocytes/macrophages in health and glioma

Monocytes/macrophages have begun to emerge as key cellular modulators of brain homeostasis and central nervous system (CNS) disease. In the healthy brain, resident microglia are the predominant macrophage cell population; however, under conditions of blood-brain barrier leakage, peripheral monocytes/macrophages can infiltrate the brain and participate in CNS disease pathogenesis. Distinguishing these two populations is often challenging, owing to a paucity of universally accepted and reliable markers. To identify discriminatory marker sets for microglia and peripheral monocytes/macrophages, we employed a large meta-analytic approach using five published murine transcriptional datasets. Following hierarchical clustering, we filtered the top differentially expressed genes (DEGs) through a brain cell type-specific sequencing database, which led to the identification of eight microglia and eight peripheral monocyte/macrophage markers. We then validated their differential expression, leveraging a published single cell RNA sequencing dataset and quantitative RT-PCR using freshly isolated microglia and peripheral monocytes/macrophages from two different mouse strains. We further verified the translation of these DEGs at the protein level. As top microglia DEGs, we identified P2ry12, Tmem119, Slc2a5 and Fcrls, whereas Emilin2, Gda, Hp and Sell emerged as the best DEGs for identifying peripheral monocytes/ macrophages. Lastly, we evaluated their utility in discriminating monocyte/macrophage populations in the setting of brain pathology (glioma), and found that these DEG sets distinguished glioma-associated microglia from macrophages in both RCAS and GL261 mouse models of glioblastoma. Taken together, this unbiased bioinformatic approach facilitated the discovery of a robust set of microglia and peripheral monocyte/macrophage expression markers to discriminate these monocyte populations in both health and disease.
Mehr anzeigen

43 Mehr lesen

Investigating the role of toll-like receptors in the glioma microenvironment

Investigating the role of toll-like receptors in the glioma microenvironment

Peripheral macrophages and resident microglia constitute the dominant glioma- infiltrating cells. The tumor induces an immunosuppressive and tumor supportive phenotype in these glioma associated microglia/brain macrophages (GAMs). A subpopulation of glioma cells has stem cell properties such as self-renewal, multipotency and act as glioma stem cells (GSCs). In the present study we explored the interaction between GSCs and GAMs. Using CD133 as a marker of stemness, we either enriched for or deprived the mouse glioma cell line GL261 of GSCs by FACS. Over the same period of time, 100 CD133 + GSCs had the capacity to form a tumor of
Mehr anzeigen

31 Mehr lesen

Glioma-associated mesenchymal stem cells have profound effects on brain tumors

Glioma-associated mesenchymal stem cells have profound effects on brain tumors

The resident macrophages of the brain are termed microglia. Those cells localize to brain during early development and form the ramified microglia thereafter [Hanisch and Kettenmann, 2007]. The activity of microglia depends on the type of pathology. In glioma microenvironment, microglia are thought to be inactive due to the immunosuppressive cytokines secreted by GBM, such as IL-10, IL-6, IL-4, TGF-β and Prostaglandin E2 [Wei et al, 2010]. Additionally, microglia express low levels of MHC Class II molecule along with some other costimulatory molecules [Badie et al, 2002]. When stimulated with lipopolysaccharides (LPS) and IFN-γ microglia assume M1 phenotype to secrete pro-inflammatory cytokines such as TNF-α, IL-1β and IL-12, present antigen and express high levels of inducible NO (iNOS) for NO production. This phenomenon takes place to kill pathogens and induce T cells for adaptive immune response [Gordon and Taylor, 2005]. In addition to M1 phenotype, microglia (and macrophages) display an M2 phenotype where they express anti-inflammatory cytokines such as IL-4, IL-10, IL3 and TGF-β, as well as Arginase-1 (Arg1) and CD206 which then leads to allergy response, parasite clearance, inflammatory dampening, tissue remodeling, angiogenesis, immune regulation and tumor promotion [Villalta et al., 2009]. In this respect, microglial cells seem to acquire M2 phenotype with the increasing histological malignancy. M2 phenotype represents the homeostatic state while M1 phenotype is a sign of inflammation. Given these facts, in GBM microenvironment, microglia assume an activated morphology but rather a different phenotype from that of a regular inflammation [Komohara et al, 2008; Charles et al, 2011]. Yet, microglia mediate tumor cell migration and tumor growth via MT1-MMP secretion in response to cues released from glioma cells, a phenomenon observed only when microglia are in the glioma-induced state [Markovic et al, 2005; Sliwa et al, 2007]. However, there are two contradictory studies where depletion of microglia, by Markovic et al, resulted in 80% decrease in tumor volume, while macrophage depletion, by Gallernau et al, induced 33% increase in the tumor volume, showing that myeloid depletion is both pro- and anti- tumorigenic due to potential unaccounted targeting of additional factors [Markovic et al, 2009; Galarneau et al, 2007].
Mehr anzeigen

110 Mehr lesen

The role of microglia in glioma expansion and progression

The role of microglia in glioma expansion and progression

Cancer is a disease linked to the inherent loss of normal tissue homeostasis and perpetual tissue stress and damage (Chang 2004; Dvorak 1986). Among the signals that perpetuate tissue damage are endogenously released TLR ligands. Several scientific studies point out to the classical protective functions of the Toll- like Receptor signaling against the devastating effects of various pathogens and damage-associated molecular patterns. However, recent research studies in different murine models of carcinoma revealed that the TLR signaling can also lead to tumor progression and metastasis (Harmey et al. 2002; Luo et al. 2004), and that the signaling was dependent on tumor-supportive cell types, namely the tumor-associated macrophages or TAMs. Although the exact role of these tumor- associated macrophages is yet to be clearly characterized, their presence within the tumor is linked to a worse clinical prognosis in a majority of tumor types (REF). Unfortunately, very few tumor-derived TLR ligands that activate TAMS to promote tumor progression and metastasis have been identified and characterized till date. Since macrophages are normally linked to the restoration of tissue integrity and homeostasis after tissue damage, many tumors exploit them for the soluble factors that promote tumor growth, angiogenesis and metastasis.
Mehr anzeigen

139 Mehr lesen

Arterial spin labeling in glioma imaging / submitted by Julia Furtner

Arterial spin labeling in glioma imaging / submitted by Julia Furtner

The period of event-free survival (EFS) within the same histopathological glioma grades may have high variability, mainly without a known cause. The purpose of this study was to reveal the prognostic value of quantified tumor blood flow (TBF) values obtained by arterial spin labeling (ASL) for EFS in patients with histopathologically proven astrocytomas independent of WHO (World Health Organization) grade. Twenty-four patients with untreated gliomas underwent tumor perfusion quantification by means of pulsed ASL in 3T. The clinical history of the patients was retrospectively extracted from the local database. Six patients had to be excluded due to insufficent follow-up data for further evaluation or histopathologically verified oligodendroglioma tumor components. Receiver operating characteristic (ROC) curves were used to define an optimal cut-off value of maximum TBF (mTBF) values for subgrouping in low-perfused and high-perfused gliomas. Kaplan- Meier curves and Cox proportional hazard regression model were used to determine the prognostic value of mTBF for EFS. An optimal mTBF cut-off value of 182 ml/100 g/min (sensitivity = 83%, specificity = 100%) was determined. Patients with low-perfused gliomas had significantly longer EFS compared to patients with high-perfused gliomas (p = 0.0012) independent of the WHO glioma grade. Quantified mTBF values obtained by ASL offer a new and totally non-invasive marker to prognosticate the EFS, independently on histopathological tumor grading, in patients with gliomas.
Mehr anzeigen

101 Mehr lesen

Target-specific glioma therapy in an immunocompetent mouse model : meeting abstract

Target-specific glioma therapy in an immunocompetent mouse model : meeting abstract

evaluate the role of STAT3 in tumour progression, we stably expressed siRNA against STAT3 in several murine glioma cell lines. The effect of STAT3 depletion on proliferation, invasion and survival will be first assessed in vitro and subsequently after transplantation in vivo. Upstream and

4 Mehr lesen

The role of microglia in glioma invasiveness

The role of microglia in glioma invasiveness

Microglia significantly contribute to the glioma tumor mass by infiltrating primary tumor mass (Fig 5.1. A). The net effect of microglial abundance in gliomas is tumor promoting by inducing the glioma invasiveness (Fig 5.1. B). The result of microglia- glioma cross-talk is escalation of MMP-2 activation and that leads to increased brakedown of ECM proteins which can explain increase of glioma invasiveness (Fig 5.1. C-D). Glioma release a factor which stimulates the production of a major MMP-2 activator- MT1-MMP in microglia. Moreover, the expression of MT1-MMP is mediated by p38 MAPK, which makes this kinase a possible target for therapy of invasive gliomas (Fig 5.1. D).
Mehr anzeigen

13 Mehr lesen

Proinflammatory activation of microglia in the brain of patients with sepsis

Proinflammatory activation of microglia in the brain of patients with sepsis

microglia and recruited macrophages in the human CNS. We selected autopsy material from patients with sepsis, confirmed by clinical microbiology, and com- pared them to patients, in whom a systemic inflamma- tory condition at the time of death could be excluded (Table 1). Since in two septic patients, microbiological confirmation of sepsis was not available, we addition- ally analysed the sections for bacteria containing intravascular macrophages using Gram staining and found them in variable numbers in all septic patients (Table 1; Figure 1F –K). The mean age of the inflamma- tory cohort was 52.5 years (range 21 to 89), which was slightly lower than in the control cohort (58 years, range 27 to 88). Gender distribution was nearly equal between septic and nonseptic patients (female 6:5; male 5:5). Since microglia are activated in the course of brain inflammation or neurodegeneration, we selected tissue blocks which were carefully screened for the absence of pathological changes, visible in sections stained with haematoxylin & eosin, luxol fast blue mye- lin staining and Bielschowsky silver impregnation (Fig- ure 1A –C). Specifically, no inflammatory infiltrates were seen in the sections in haematoxylin & eosin stained sections. As described previously [21] very few perivascular or parenchymal CD3 + T-cells were present and their number in the perivascular space and the parenchyma was not significantly different in septic vs. noninflammatory patients, both in the cortex and white matter (Figure 2A). Granulocyte infiltration was absent in both control and septic patients. The only global dif- ference between septic and control tissue was a more pronounced microglia activation phenotype, the cells being enlarged with partly increased and partly retracted processes in the former (Figure 1D,E).
Mehr anzeigen

13 Mehr lesen

How I treat anaplastic glioma without 1p/19q codeletion

How I treat anaplastic glioma without 1p/19q codeletion

18. van den Bent MJ, Klein M, Smits M, et al. Bevacizumab and temozolomide in patients with first recurrence of who grade II and III glioma, without 1p/19q co-deletion (TAVAREC): a randomised controlled phase 2 EORTC trial. Lancet Oncol 2018;19:1170–9. 19. Habets EJJ, Taphoorn MJB, Nederend S, et al. Health-Related quality of life and cognitive functioning in long-term anaplastic oligodendroglioma and oligoastrocytoma survivors. J Neurooncol 2014;116:161–8.

4 Mehr lesen

Analysis of the epigenetic landscape in murine macrophages

Analysis of the epigenetic landscape in murine macrophages

skin homogenate. While the specific identities and concentrations of the DAMPs, MAMPs, and other bioactive molecules in this homogenate are unknown, we provide evidence that the transcriptomic response of the macrophage to this mixture overlaps significantly with the transcriptional response observed in a skin wound, thereby validating its use. Through ChIP-Seq experiments, we demon- strate that this complex signal coordinately induces binding of NF-kB, AP-1, and Smad transcription factors. Furthermore, de novo motif analysis of activated enhancers led to the unexpected discovery that the tissue damage signal also acutely activates Nrf2. This finding illustrates the utility of enhancer analysis to identify transcriptional mediators of unknown environmental factors, providing a basis for subsequent directed analysis of corresponding upstream signaling pathways. Accordingly, the use of glutathione to neutralize reactive oxygen species, thus blocking the downstream disrup- tion of the Kelch-like ECH-associated protein 1 (Keap1)-Cuilin 3 (Cul3) complex required for activa- tion of Nrf2 ( Gorrini et al., 2013 ; Shibata et al., 2013 ) provides evidence for its functional importance in the transcriptional response to the tissue damage signal. Similarly, the use of inhibitors of NF-kB and TGFb provided corresponding support for functionally important roles of these tran- scription factors. Of course, there are likely to be many other signaling pathways and downstream transcription factors involved in the tissue damage response. Furthermore, Rev-erb deficiency likely modifies both basal and signal dependent transcriptional programs. To distinguish between ’prior’ versus ’post-activation’ roles of Rev-erbs in macrophages during wound healing may require the use of inducible Cre-expression strategies, as well as measurements of target gene expression in situ in macrophage infiltrated wounds.
Mehr anzeigen

264 Mehr lesen

Canine macrophages can like human macrophages be in vitro activated toward the M2a subtype relevant in allergy

Canine macrophages can like human macrophages be in vitro activated toward the M2a subtype relevant in allergy

The guidelines on macrophage activation propose using terms M (LPS þ IFN- g ) and M (IL4 þIL13) instead of M1 and M2a respec- tively ( Murray et al., 2014 ), but for the purpose of easier reading, we refer here to M1 and M2a for (LPS þ IFN- g ) and (IL4 þIL13), respectively. On day 7 e9 MDMs were detached using 2.5 mM EDTA (VWR, Radnor, PA) in ice-cold Dulbecco modi fied PBS w/o Mg 2þ and Ca 2 þ (ThermoScienti fic, Waltham, MA) and their activation was performed. The activation scheme is illustrated in Fig. 1 A and concentration and source of reagents are summarized and listed in Table 1 . In need of priming the monocytes towards a pre-state of anti- or pro-in flammatory macrophages, GM-CSF or M-SCF was used ( Vogel et al., 2014 ). In canine and human MDMs, we intro- duced four conditions, two negative controls GM-CSF and M-CSF and two activated M1 (LPS þ IFN- g ) and M2a (IL4 þIL13) cell types. Human cytokines were chosen to stimulate canine cells based on their high sequence similarity but a higher dose was required to activate canine cells in comparison to human MDMs based on their morphology appearance (data not shown). Canine M2a cells required 40 ng/ml compared to 20 ng/ml of M-CSF, IL4 and IL13 in human MDMs ( Table 1 ).
Mehr anzeigen

10 Mehr lesen

Kv1.3 inhibitors in the treatment of glioma and melanoma

Kv1.3 inhibitors in the treatment of glioma and melanoma

if not enhanced, when the derivatives were used without MDRi (see Patent in Materials and Methods). The higher effectiveness of the new compounds, with respect to the standard psoralens PAP-1 and Psora-4, has to be ascribed to their chemical properties, which improve the problems of low water solubility and consequently need of high dosages, and target them to the direct site, the mitochondria, by a positive charge attached. Indeed, the engineered groups of the new inhibitors confer them, respectively, a better water solubility and a lower partition coefficient (by the polyethylene glycol, PEG group, to PEGME), and the capability to be targeted to mitochondria (by the tetraphenylphosphonium, TPP group, to PCARBMTP and PAPTP), thus allowing a more efficient crossing of biological membranes and targeting of the mitochondrial channel. Furthermore, the increased ability of PAPTP and PCARBMTP to reach mitochondria also represents an advantage, since it avoids side effects that could arise from drug accumulation in the plasma membrane or in other subcellular compartments where the channel is present. Moreover, PCARBMTP has been developed as pro-drug: indeed, it has a big TPP ion bound to PAP-1 by a carbamate linker, which can be hydrolyzed inside the cells by esterase, thus releasing the free PAP-1 directly in the right site of action. Importantly, this large modification leads to a lower affinity in Kv1.3 inhibition, hence decreasing its capability to block the plasma membrane Kv1.3, thereby reducing its possible effects on immune system cells. Nevertheless, PCARBMTP is more labile and less efficient compared to the more stable PAPTP. Clofazimine needs to be discussed separately. Indeed, since clofazimine is also working as MDR inhibitor (MDRi), it can reduce cell survival at lower concentrations than the standard inhibitors PAP-1 and Psora-4. This drug can induce apoptosis also in other manners than specific targeting the mtKv1.3, e.g. via direct caspase-3 activation or in a phospholipase-dependent manner (Fukutomi Y. et al 2011, Van Rensburg C.E. et al 1994). However, the apoptotic effect I saw after glioma cells treatment specifically depends on Kv1.3 inhibition, since the siRNA downregulation of Kv1.3 prevents cell death upon treatment with the compounds. Specificity for Kv1.3 was shown in the same experiment also for all other newly synthesized inhibitors.
Mehr anzeigen

119 Mehr lesen

A Fatal Alliance between Microglia, Inflammasomes, and Central Pain

A Fatal Alliance between Microglia, Inflammasomes, and Central Pain

Of importance, psychiatric disorders, such as major depressive disorders (MDD) and chronic stress, are often associated with neuroinflammation and typically seen as comorbidities for the development of central pain syndromes [ 89 ]. Both pathophysiological scenarios imply the activation of microglia and mutually drive each other to remodel brain circuits and synaptic plasticity, leading to chronic pain manifestation and pain sensitization [ 89 , 90 ]. In the past few years, several review articles have highlighted the importance of microglia during the development and manifestation of psychiatric disorders, in particular for MDD [ 91 – 93 ]. This has led to the current working hypothesis that depression might be a microglia disease with microglia representing an interface in the pathology of neurocognitive disorders [ 93 , 94 ]. This is supported by clinical studies, which show that microglial markers in the cerebral cortex are related to cognitive dysfunction in MDD (as an example, the translocator protein total distribution volume, TSPO V T , analyzed by PET) [ 95 ]. In a mouse model for depression, microglia hyper-ramification occurred in the hippocampal dentate gyrus [ 96 ]. This effect, as well as depressive-like behavior, were ameliorated after treatment with the anti-depressive drug venlafaxine. Moreover, CX3CR1-deficient mice were resistant to stress-induced depression and changes in microglia morphology [ 87 ]. The future will evidence to what extent and in which subgroups of depressive patients, anti-inflammatory treatment will be a therapeutic option [ 97 ]. At least, a clinical pilot study supports the idea of treatment of MDD with anti-inflammatory and microglia-targeting compound minocycline [ 54 , 98 ]. Since microglia-driven neuroinflammation appears to be critically involved in the development and linked to the escalation of psychiatric disorders and pain symptoms, the question, therefore, is inflammasomes play what role during these processes. Wohleb and colleagues created the “inflammasome hypothesis of depression”, which favors the idea that inflammasomes are key actors in the etiopathophysiology of MDD and pain [ 90 , 91 ]. Indeed, the hippocampal NLRP1 pathway is important for the development of the depression-dependent chronic neuropathic brain in a rodent model [ 98 ]. In support, P2X7 receptor signaling and Casp1 activation both represent critical steps for inflammasome activation and for central pain manifestation, as well as for the development of depression [ 99 ]. Similarly, pain is modulated through NLRP3 activation via kinase-dependent phosphorylation [ 100 ], and antidepressants confer positive effects on chronic stress and related pain
Mehr anzeigen

13 Mehr lesen

Herstellung und Charakterisierung von Tetracyclin-induzierbaren, MIF-antisense-exprimierenden Glioma-Transfektanten

Herstellung und Charakterisierung von Tetracyclin-induzierbaren, MIF-antisense-exprimierenden Glioma-Transfektanten

Die RNA-Präparation erfolgte über eine Säule (s. 2.4.4.2) wurden pro Spur 2,5 µg RNA auf zwei parallelen Gelen elektrophoretisch aufgetrennt und auf Northern-Membranen geblo[r]

138 Mehr lesen

MicroRNA-dependent regulation of phagocytosis in human macrophages

MicroRNA-dependent regulation of phagocytosis in human macrophages

Macrophages play a key role in tissue homeostasis and as first line defense against invading microorganisms. In vitro experimental studies of primary human monocytes/macrophages are very challenging due to limited availability, the complexity of their activation and their phenotype heterogeneity. Furthermore, the metabolic and phenotypic discrepancies between macrophages from different species, make it difficult to extrapolate data obtained in in vivo studies in mice to the human system (98, 166). For this reason, it is necessary that pathway-specific, biologically relevant approaches are defined for each study. Here, the human monocytic cell line THP-1 (188) was selected for a functional cell-based miRNA high- content screen on macrophage phagocytosis. This cell line has been widely used to study phagocytosis of pathogens like Staphylococcus aureus (88), Escherichia coli (165), parasite infected erythrocytes (182) and cancer cells (13). Furthermore, recent studies have used this cell line to perform high-throughput phagocytosis assays of antigen-specific clinically relevant antibodies against the human immunodeficiency virus (HIV), dengue and influenza virus (2) as well as the
Mehr anzeigen

145 Mehr lesen

The role of PPARβ/δ in human macrophages

The role of PPARβ/δ in human macrophages

PPARγ is found mainly in adipose tissue. Through alternative transcription start sites and splicing PPARγ has two distinct isoforms in man: PPARγ2 and the predominantly expressed PPARγ1. PPARγ1 is found in a variety of tissues including immune cells while the PPARγ2 isoform is restricted to adipose tissue (Fajas et al. 1997). PPARγ is eminently important for adipogenesis, shown by the fact that forced expression of PPARγ in fibroblasts leads to terminal adipocyte differentiation (Rosen et al. 1999; Rosen et al. 2000; Tontonoz et al. 1994). On the other hand, mice deficient in PPARγ expression fail to generate adipose tissue, even if fed a high fat diet (Jones et al. 2005). Thiazolidinedione (TZD) was revealed to be a highly specific agonistic ligand for PPARγ causing increased lipid storage into adipocytes (Lehmann et al. 1995). The reduction of free fatty acids in circulation in combination with altered adipose-derived endocrine factors results in reduced systemic insulin resistance, which is favorable for the treatment of diabetes mellitus type 2 (Evans 2004; Rangwala & Lazar 2004). In fact Troglitazone was found to improve insulin resistance and used to treat type 2 diabetes prior to the discovery of its mode of action through PPARγ in 1995 (Fujiwara et al. 1988; Suter et al. 1992; Nolan et al. 1994). Today, however, TZDs prescription to treat insulin resistance is no longer advised due to various side effects. As of 2011, Pioglitazone remains the only approved TZD on the European market, although being associated with increased risk for bladder cancer (Ferwana et al. 2013).
Mehr anzeigen

36 Mehr lesen

Analysis of Ebola Virus Entry Into Macrophages

Analysis of Ebola Virus Entry Into Macrophages

DISCUSSION The present study confirms that TIM-1 and Axl can promote EBOV-GP –driven entry into certain cell lines and shows that these proteins do not augment entry into macrophages. In con- trast, NPC1 was required for entry into macrophages and all cell lines tested. Finally, evidence was obtained that also Mer, integrin αV, and possibly SR-A promote EBOV infection of macrophages. The comparative analysis of EBOV entry factors revealed that lectins are most ef ficient at increasing GP-driven entry into al- ready-susceptible 293T cells. However, mannose-speci fic lectins did not promote GP-dependent transduction of MDMs and have little impact on EBOV infection of monocyte-derived den- dritic cells [ 12 ]. These in vitro results argue against a major con- tribution of mannose-specific lectins to EBOV entry into macrophages and dendritic cells in vivo. Nevertheless, one should keep in mind that lectins such as human macrophage C-type lectin speci fic for galactose and N-acetylgalactosamine, LSECtin, and ASGPR-1, which recognize carbohydrates other than mannose and augment EBOV-GP –driven infection in cell culture [ 24 , 26 , 43 ], might affect viral cell tropism in vivo.
Mehr anzeigen

11 Mehr lesen

Caffeic acid phenethyl ester reduces inflammation in macrophages

Caffeic acid phenethyl ester reduces inflammation in macrophages

To be closer linked to the field of dentistry primary macrophages were exposed to crude fraction of Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia. As expected this preparation caused the increase of the inflammatory response by the expression of IL1. Consistent with the overall observation of the project presented here CAPE significantly decreased the inflammatory response again to the level at least 50 % below the maximum gene expression. These findings together with the observations observed with saliva point towards the general anti-inflammatory mechanism of CAPE that is independent of the cause of inflammation. These findings go along with the expression of HO1 on the mRNA as well as on the protein level as detected by RT-PCR and western blot respectively. Even though, the in vitro observations are obvious and supportive inflammatory role of CAPE the clinical relevance of the findings need to be discussed with caution. Theoretically, CAPE and other compounds that controlled the HO1 and Nrf2 pathway have a potential pharmacological role as a support for the wound healing and tissue regeneration in general. Nrf2 is released from its suppressor Kelch-like ECH-associated protein 1 (Keap1) upon stimulation with CAPE (Balogun et al., 2003) (Zhang et al., 2013). Nrf2 translocates into the nucleus and initiates the transcription of HO1. This compound could also serve to prevent catabolic events in the context of chronic inflammatory disease. CAPE is the main component of propolis that is widely used as a mouth rinse solution and for other applications to counteract at least of ease of the inflammatory symptoms (El-Sharkawy et al., 2016) (Ercan et al., 2015) (AkhavanKarbassi et al., 2016). CAPE could be among the key responsible molecules for this anti-inflammatory activity of propolis and other beneficial effects for the patients.
Mehr anzeigen

52 Mehr lesen

Show all 1125 documents...