610 Medizin und Gesundheit
Refine
Year of publication
Document Type
- Article (93)
Language
- English (93)
Has Fulltext
- yes (93)
Is part of the Bibliography
- no (93)
Keywords
- inflammation (16)
- macrophage (14)
- cancer (7)
- breast cancer (6)
- macrophages (6)
- apoptosis (5)
- macrophage polarization (5)
- sphingosine-1-phosphate (5)
- hypoxia (4)
- lipocalin-2 (4)
- microRNA (4)
- mitochondria (4)
- reactive oxygen species (4)
- tumor microenvironment (4)
- Hypoxia (3)
- Macrophages (3)
- RNA therapeutics (3)
- iron (3)
- lipoxygenase (3)
- psoriasis (3)
- tumor-associated macrophages (3)
- ATP-citrate lyase (2)
- Breast cancer (2)
- Breast tumors (2)
- Cancer (2)
- Chronic inflammation (2)
- HIF (2)
- IL-1β (2)
- Immunology (2)
- Inflammation (2)
- Iron (2)
- Messenger RNA (2)
- Mitochondria (2)
- Mitochondrial ROS (2)
- Nrf2 (2)
- ROS (2)
- acetyl-CoA (2)
- angiogenesis (2)
- atherosclerosis (2)
- chemotherapy (2)
- cholesterol (2)
- endoplasmic reticulum (2)
- gene expression (2)
- histone acetylation (2)
- immunity (2)
- interleukin-4 (2)
- metabolism (2)
- monocytes (2)
- pain (2)
- phagocytosis (2)
- proliferation (2)
- prostaglandins (2)
- renal cell carcinoma (2)
- resolution (2)
- sepsis (2)
- tumor progression (2)
- 5' UTR (1)
- AMP-activated kinase (AMPK) (1)
- ASCT (1)
- AU-rich element (1)
- Acute inflammation (1)
- BIAM-switch (1)
- CD36 (1)
- CD40 (1)
- CHIP (1)
- CYP1A1 (1)
- Cell binding (1)
- Cell death (1)
- Cell death and immune response (1)
- Cell signalling (1)
- Cell staining (1)
- Cellular stress responses (1)
- Complex II (1)
- Cytoskeleton (1)
- DNA damage (1)
- ER stress (1)
- Erythrophagocytosis (1)
- Extracellular vesicles (1)
- FTMT (1)
- Ferritinophagy (1)
- Ferroptosis (1)
- Flow cytometry (1)
- G2A (1)
- GEMs (1)
- GPCR (1)
- GRAND-SLAM (1)
- Gene expression (1)
- Gene prediction (1)
- Gene/Regulation (1)
- Genome annotation (1)
- Glycolysis (1)
- HAI‐1 (1)
- HCC marker (1)
- HDAC (1)
- HGF (1)
- HIF-1α (1)
- HIF-2 (1)
- HIF-2α (1)
- Hepatocellular carcinoma (1)
- Hypoxia inducible factor (1)
- IFN-β (1)
- IL-27 cytokine (1)
- ISR (1)
- Immune cells (1)
- JNK (1)
- Kinases (1)
- Kupffer cells (1)
- LDHB (1)
- LDL (1)
- Lipid peroxidation (1)
- Lipid signalling (1)
- MMP9 (1)
- Macrophage (1)
- Mild hypoxia (1)
- Monocytes and macrophages (1)
- Mouse models (1)
- Mφs (1)
- NADPH oxidase (1)
- NASH (1)
- NCOA4 (1)
- NLRP3 inflammasomes (1)
- Oxidative phosphorylation (1)
- PD-L1 (1)
- PDPK1 (1)
- PPTC7 (1)
- PTEN inducible kinase 1 (1)
- Parkinson's disease (1)
- Peritoneal macrophages (1)
- Physiology (1)
- Protein translation (1)
- RNA extraction (1)
- RNA isolation (1)
- RNA sequencing (1)
- RNA stability (1)
- RNA therapy (1)
- RNA-binding protein (1)
- RNA/MicroRNA (1)
- Receptors/Nuclear (1)
- Respiratory chain (1)
- Ribosomes (1)
- S1PR1 (1)
- S1PR4 (1)
- SDH (1)
- SLAM-seq (1)
- SLC7A11 (1)
- SPM (1)
- STAT1 (1)
- Sterols (1)
- T cells (1)
- TMEM126B (1)
- Transcription (1)
- Translation initiation (1)
- UPR (1)
- Zymosan-induced peritonitis (1)
- acute inflammation (1)
- adipose-derived stem cells (ASCs) (1)
- alcoholic hepatitis (1)
- alpha-synuclein (1)
- antioxidants (1)
- arachidonate 12/15-lipoxygenase (Alox12/15) (1)
- arachidonate 15-lipoxygenase (1)
- arachidonic acid (AA) (1)
- asparaginyl endopepdidase (AEP) (1)
- astrocytes (1)
- autologous stem cell transplantation (1)
- breast tumor (1)
- cancer cell metabolism (1)
- cancer metastases (1)
- cancer-associated fibroblasts (1)
- carcinoma (1)
- chelation therapy (1)
- chemokine (1)
- chronic hypoxia (1)
- chronic myeloid leukemia (1)
- clonal dominance (1)
- clonal hematopoiesis (1)
- complex I (1)
- costimulation (1)
- cytokine (1)
- cytokine, angiogenesis (1)
- cytotoxic T cells (1)
- cytotoxic lymphocytes (1)
- cytotoxicity (1)
- de novo transcription (1)
- diabetic nephropathy (1)
- differentiation (1)
- drug discovery (1)
- efferocytosis (1)
- electron transport chain (1)
- electrophiles (1)
- endothelial cell (1)
- epigenetic (1)
- erastin (1)
- exosome (1)
- exosomes (1)
- extracellular signal-regulated kinase (1)
- fatty acid (1)
- fatty acids (1)
- ferroportin (1)
- ferroptosis (1)
- fibrosarcoma (1)
- flow cytometry (1)
- gene signature (1)
- glucosylceramides (1)
- glutamine (1)
- glycolysis (1)
- hematopoietic stem cells (1)
- hematopoietic stress (1)
- hierarchical clustering (1)
- immune checkpoint (1)
- immunotherapy (1)
- infection (1)
- innate immunity (1)
- inflammation (1)
- iron chelator (1)
- iron chelators (1)
- iron homeostasis (1)
- iron metabolism (1)
- iron-trafficking (1)
- legumain (1)
- leukemia (1)
- lipid mediator (1)
- lipid metabolism (1)
- lipids (1)
- lipoproteins (1)
- lipoxin A4 (1)
- liver (1)
- liver X receptor (1)
- lung cancer (1)
- lung tumor heterogeneity (1)
- lymphangiogenesis (1)
- mRNA stability (1)
- mTOR (1)
- mammary cancer (1)
- mammary carcinoma (1)
- mast cells (1)
- metabolic reprogramming (1)
- miR (1)
- miR-375 (1)
- miR-6862-5p (1)
- miRNA let-7e (1)
- microenvironment (1)
- migration (1)
- mitochondrial dynamics (1)
- mitochondrial respiration (1)
- multiple myeloma (1)
- multispectral flow cytometry (1)
- natural killer T cells (1)
- nuclear factor 2 (erythroid-derived 2-like factor) (NFE2L2) (Nrf2) (1)
- oxidative stress (1)
- oxidized low density lipoprotein (1)
- p-eIF2α (1)
- p53 (1)
- peritoneal macrophages (1)
- peroxisome proliferator-activated receptor (1)
- polarization (1)
- polyunsaturated fatty acid (1)
- post-transcriptional regulation (1)
- prostacyclin (1)
- prostaglandin (1)
- protein-protein interaction (1)
- proteomics (1)
- resolution of inflammation (1)
- resolution of inflammation (1)
- resveratrol (1)
- sensory loss (1)
- signal transduction (1)
- somatic mutations (1)
- specialized pro-resolving lipid mediators (SPMs) (1)
- specialized pro-resolving mediator (1)
- sphingolipids (1)
- sterol regulatory element binding protein-2 (1)
- thromboxane (1)
- toll-like receptor (1)
- transcription (1)
- transcription factor (1)
- transcriptional profiling (1)
- transcriptome (1)
- tumor stroma (1)
- tumor-associated macrophages (TAM) (1)
- tumor‐associated macrophages (1)
- type B (1)
- tyrosine kinase inhibitors. (1)
- xenobiotics (1)
- zymosan (1)
Institute
- Medizin (92)
- Sonderforschungsbereiche / Forschungskollegs (33)
- Biochemie und Chemie (10)
- Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit (ZAFES) (6)
- Biochemie, Chemie und Pharmazie (3)
- Exzellenzcluster Makromolekulare Komplexe (2)
- Pharmazie (2)
- Biowissenschaften (1)
- Buchmann Institut für Molekulare Lebenswissenschaften (BMLS) (1)
- Institut für Ökologie, Evolution und Diversität (1)
While aberrant cells are routinely recognized and removed by immune cells, tumors eventually escape innate immune responses. Infiltrating immune cells are even corrupted by the tumor to acquire a tumor-supporting phenotype. In line, tumor-associated macrophages are well-characterized to promote tumor progression and high levels of tumor-infiltrating macrophages are a poor prognostic marker in breast cancer. Here, we aimed to further decipher the influence of macrophages on breast tumor cells and determined global gene expression changes in three-dimensional tumor spheroids upon infiltration of macrophages. While various tumor-associated mRNAs were upregulated, expression of the cytochrome P450 family member CYP1A1 was markedly attenuated. Repression of CYP1A1 in tumor cells was elicited by a macrophage-shaped tumor microenvironment rather than by direct tumor cell-macrophage contacts. In line with changes in RNA expression profiles, macrophages enhanced proliferation of the tumor cells. Enhanced proliferation and macrophage presence further correlated with reduced CYP1A1 expression in patient tumors when compared with normal tissue. These findings are of interest in the context of combinatory therapeutic approaches involving cytotoxic and immune-modulatory compounds.
Tyrosine kinase inhibitors (TKIs) are currently the standard chemotherapeutic agents for the treatment of chronic myeloid leukemia (CML). However, due to TKI resistance acquisition in CML patients, identification of new vulnerabilities is urgently required for a sustained response to therapy. In this study, we have investigated metabolic reprogramming induced by TKIs independent of BCR-ABL1 alterations. Proteomics and metabolomics profiling of imatinib-resistant CML cells (ImaR) was performed. KU812 ImaR cells enhanced pentose phosphate pathway, glycogen synthesis, serine-glycine-one-carbon metabolism, proline synthesis and mitochondrial respiration compared with their respective syngeneic parental counterparts. Moreover, the fact that only 36% of the main carbon sources were utilized for mitochondrial respiration pointed to glycerol-phosphate shuttle as mainly contributors to mitochondrial respiration. In conclusion, CML cells that acquire TKIs resistance present a severe metabolic reprogramming associated with an increase in metabolic plasticity needed to overcome TKI-induced cell death. Moreover, this study unveils that KU812 Parental and ImaR cells viability can be targeted with metabolic inhibitors paving the way to propose novel and promising therapeutic opportunities to overcome TKI resistance in CML.
MicroRNAs (miRs) significantly contribute to the regulation of gene expression, by virtue of their ability to interact with a broad, yet specific set of target genes. MiRs are produced and released by almost every cell type and play an important role in horizontal gene regulation in the tumor microenvironment (TME). In the TME, both tumor and stroma cells cross-communicate via diverse factors including miRs, which are taking central stage as a therapeutic target of anti-tumor therapy. One of the immune escape strategies adopted by tumor cells is to release miRs as a Trojan horse to hijack circulating or tumor-localized monocytes/macrophages to tune them for pro-tumoral functions. On the other hand, macrophage-derived miRs exert anti-tumor functions. The transfer of miRs from host to recipient cells depends on the supramolecular structure and composition of miR carriers, which determine the distinct uptake mechanism by recipient cells. In this review, we provide a recent update on the miR-mediated crosstalk between tumor cells and macrophages and their mode of uptake in the TME.
Macrophages constitute a major part of the tumor-infiltrating immune cells. Within the tumor microenvironment, they acquire an alternatively activated, tumor-supporting phenotype. Factors released by tumor cells are crucial for the recruitment of tumor-associated macrophages. In the present project, we aimed to understand the role of hsa-miR-200c-3p (miR-200c) in the interplay between tumor cells and macrophages. To this end, we employed a coculture system of MCF7 breast tumor cells and primary human macrophages and observed the transfer of miR-200c from apoptotic tumor cells to macrophages, which required intact CD36 receptor in macrophages. We further comprehensively determined miR-200c targets in macrophages by mRNA-sequencing and identified numerous migration-associated mRNAs to be downregulated by miR-200c. Consequently, miR-200c attenuated macrophage infiltration into 3-dimensional tumor spheroids. miR-200c-mediated reduction in infiltration further correlated with a miR-200c migration signature comprised of the four miR-200c-repressed, predicted targets PPM1F, RAB11FIB2, RDX, and MSN.
Peroxisome proliferator-activated receptor γ (PPARγ) gained considerable interest as a therapeutic target during chronic inflammatory diseases. Remarkably, the pathogenesis of diseases such as multiple sclerosis or Alzheimer is associated with impaired PPARγ expression. Considering that regulation of PPARγ expression during inflammation is largely unknown, we were interested in elucidating underlying mechanisms. To this end, we initiated an inflammatory response by exposing primary human macrophages to lipopolysaccharide (LPS) and observed a rapid decline of PPARγ1 expression. Because promoter activities were not affected by LPS, we focused on mRNA stability and noticed a decreased mRNA half-life. As RNA stability is often regulated via 3′-untranslated regions (UTRs), we analyzed the impact of the PPARγ-3′-UTR by reporter assays using specific constructs. LPS significantly reduced luciferase activity of the pGL3-PPARγ-3′-UTR, suggesting that PPARγ1 mRNA is destabilized. Deletion or mutation of a potential microRNA-27a/b (miR-27a/b) binding site within the 3′-UTR restored luciferase activity. Moreover, inhibition of miR-27b, which was induced upon LPS exposure, partially reversed PPARγ1 mRNA decay, whereas miR-27b overexpression decreased PPARγ1 mRNA content. In addition, LPS further reduced this decay. The functional relevance of miR-27b-dependent PPARγ1 decrease was proven by inhibition or overexpression of miR-27b, which affected LPS-induced expression of the pro-inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin (IL)-6. We provide evidence that LPS-induced miR-27b contributes to destabilization of PPARγ1 mRNA. Understanding molecular mechanisms decreasing PPARγ might help to better appreciate inflammatory diseases.
A myriad of signaling molecules in a heuristic network of the tumor microenvironment (TME) pose a challenge and an opportunity for novel therapeutic target identification in human cancers. MicroRNAs (miRs), due to their ability to affect signaling pathways at various levels, take a prominent space in the quest of novel cancer therapeutics. The role of miRs in cancer initiation, progression, as well as in chemoresistance, is being increasingly investigated. The canonical function of miRs is to target mRNAs for post-transcriptional gene silencing, which has a great implication in first-order regulation of signaling pathways. However, several reports suggest that miRs also perform non-canonical functions, partly due to their characteristic non-coding small RNA nature. Examples emerge when they act as ligands for toll-like receptors or perform second-order functions, e.g., to regulate protein translation and interactions. This review is a compendium of recent advancements in understanding the role of miRs in cancer signaling and focuses on the role of miRs as novel regulators of the signaling pathway in the TME.
Ischemia/reperfusion (I/R) is at the basis of renal transplantation and acute kidney injury. Molecular mechanisms underlying proximal tubule response to I/R will allow the identification of new therapeutic targets for both clinical settings. microRNAs have emerged as crucial and tight regulators of the cellular response to insults including hypoxia. Here, we have identified several miRNAs involved in the response of the proximal tubule cell to I/R. Microarrays and RT-PCR analysis of proximal tubule cells submitted to I/R mimicking conditions in vitro demonstrated that miR-127 is induced during ischemia and also during reperfusion. miR-127 is also modulated in a rat model of renal I/R. Interference approaches demonstrated that ischemic induction of miR-127 is mediated by Hypoxia Inducible Factor-1alpha (HIF-1α) stabilization. Moreover, miR-127 is involved in cell-matrix and cell-cell adhesion maintenance, since overexpression of miR-127 maintains focal adhesion complex assembly and the integrity of tight junctions. miR-127 also regulates intracellular trafficking since miR-127 interference promotes dextran-FITC uptake. In fact, we have identified the Kinesin Family Member 3B (KIF3B), involved in cell trafficking, as a target of miR-127 in rat proximal tubule cells. In summary, we have described a novel role of miR-127 in cell adhesion and its regulation by HIF-1α. We also identified for the first time KIF3B as a miR-127 target. Both, miR-127 and KIF3B appear as key mediators of proximal epithelial tubule cell response to I/R with potential al application in renal ischemic damage management.
Human macrophages infiltrating hypoxic regions alter their metabolism, because oxygen becomes limited. Increased glycolysis is one of the most common cellular adaptations to hypoxia and mostly is regulated via hypoxia-inducible factor (HIF) and RAC-alpha serine/threonine–protein kinase (Akt) signaling, which gets activated under reduced oxygen content. We noticed that micro RNA (miR)-193a-3p enhances Akt phosphorylation at threonine 308 under hypoxia. In detail, miR-193a-3p suppresses the protein abundance of phosphatase PTC7 homolog (PPTC7), which in turn increases Akt phosphorylation. Lowering PPTC7 expression by siRNA or overexpressing miR-193a-3p increases Akt phosphorylation. Vice versa, inhibition of miR-193a-3p attenuates Akt activation and prevents a subsequent increase of glycolysis under hypoxia. Excluding effects of miR-193a-3p and Akt on HIF expression, stabilization, and function, we noticed phosphorylation of 6 phosphofructo-2-kinase/fructose 2,6-bisphosphatase PFKFB3 in response to the PI3K/Akt/mTOR signaling cascade. Inhibition of PFKFB3 blocked an increased glycolytic flux under hypoxia. Apparently, miR-193a-3p balances Akt phosphorylation and dephosphorylation by affecting PPTC7 protein amount. Suppression of PPTC7 increases Akt activation and phosphorylation of PFKFB3, which culminates in higher rates of glycolysis under hypoxia.
This study indicates that embryonic stem cells [ESCs] cultured with retinoic acid and activin A significantly upregulate the miRNA let-7e. This specific miRNA modulates the Wnt pathway and the expression of early nephrogenic markers under these differentiation conditions. The differentiation markers WT1, Pax2 and Wnt4 were downregulated when miRNA let-7e was silenced, thus indicating the role of miRNA let-7e in the differentiation process. PKCβ, GSK3β phosphorylation (GSK3βP) and β-catenin expression was reduced in differentiated cells and reversed by miRNA let-7e silencing. Addition of a PKCβ inhibitor to the miRNA let-7e silenced cells abolished let-7e-derived effects in differentiation markers, and reversed the increase in GSK3βP and β-catenin, thus indicating that miRNA let-7e is involved in differentiation via the modulation of GSK3β phosphorylation and β-catenin production.
miRNA let-7e is involved in stem cell differentiation, and metalloproteinases are among its potential target genes. We hypothesized that the inhibitory action of let-7e on regulation of MMP9 expression could represent a crucial mechanism during differentiation of adipose-derived stem cells (ASCs). ASCs were differentiated with all-trans retinoic acid (ATRA) to promote differentiation, and the effect of let-7 silencing during differentiation was tested. Results indicate that ASCs cultured with ATRA differentiated into cells of the epithelial lineage. We found that ASCs cultured with ATRA or transfected with miRNA let-7e expressed epithelial markers such as cytokeratin-18 and early renal organogenesis markers such as Pax2, Wt1, Wnt4 and megalin. Conversely, the specific knockdown of miRNA let-7e in ASCs significantly decreased the expression of these genes, indicating its vital role during the differentiation process. Using luciferase reporter assays, we also showed that MMP9 is a direct target of miRNA let-7e. Thus, our results suggest that miRNA let-7e acts as a matrix metalloproteinase-9 (MMP9) inhibitor and differentiation inducer in ASCs.