TY  - JOUR
AB  - The pathophysiological foundations of various diseases are often subject to alteration through the utilization of small compounds, rendering them invaluable tools for the exploration and advancement of novel therapeutic strategies. Within the scope of this study, we meticulously curated a diverse library of novel small compounds meticulously designed to specifically target the c-Myc/Max complex. We conducted in vitro examinations of novel c-Myc inhibitors across a spectrum of cancer cell lines, including PANC1 (pancreatic adenocarcinoma), MCF7 (breast carcinoma), DU-145 (prostate carcinoma), and A549 (lung cancer). The initial analysis involved a 25 μM dose, which enabled the identification of potent anticancer compounds effective against a variety of tumour types. We identified c-Myc inhibitors with remarkable potency, featuring IC50 values as low as 1.6 μM and up to 40 times more effective than the reference molecule in diminishing cancer cell viability. Notably, c-Myc-i7 exhibited exceptional selectivity, displaying 37-fold and 59-fold preference for targeting prostate and breast cancers, respectively, over healthy cells. Additionally, we constructed drug-likeness models. This study underscores the potential for in vitro investigations of various tumour types using novel c-Myc inhibitors to yield ground-breaking and efficacious anticancer compounds.
AU  - Yıldırım, S.
AU  - Kocabaş, F.*
AU  - Mermer, A.*
C1  - 70440
C2  - 55971
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Development, synthesis and validation of improved c-Myc/Max inhibitors.
JO  - J. Cell. Mol. Med.
VL  - 28
IS  - 8
PB  - Wiley
PY  - 2024
SN  - 1582-1838
ER  - 

TY  - JOUR
AB  - ABCA3 is a phospholipid transporter implicated in pulmonary surfactant homoeostasis and localized at the limiting membrane of lamellar bodies, the storage compartment for surfactant in alveolar type II cells. Mutations in ABCA3 display a common genetic cause for diseases caused by surfactant deficiency like respiratory distress in neonates and interstitial lung disease in children and adults, for which currently no causal therapy exists. In this study, we investigated the effects of ivacaftor and genistein, two potentiators of the cystic fibrosis transmembrane conductance regulator (CFTR), on ABCA3-specific lipid transport function. Wild-type (WT) and functional ABCA3 mutations N568D, F629L, G667R, T1114M and L1580P were stably expressed in A549 cells. Three-dimensional modelling predicted functional impairment for all five mutants that was confirmed by in vitro experiments (all <14% of WT functional activity). Treatment with potentiators rescued the mutants N568D (up to 114% of WT), F629L (up to 47% of WT), and G667R (up to 60% of WT), the latter variation needing higher concentrations of genistein, showing reduced affinity of the potentiator to the mutant protein. Our results present a first proof that functional ABCA3 mutations are rescued by CFTR potentiators, making them a potential therapeutical option for patients suffering from surfactant deficiency due to ABCA3 mutations.
AU  - Kinting, S.*
AU  - Li, Y.*
AU  - Forstner, M.*
AU  - Delhommel, F.
AU  - Sattler, M.
AU  - Griese, M.*
C1  - 56342
C2  - 47015
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 5225-5234
TI  - Potentiation of ABCA3 lipid transport function by ivacaftor and genistein.
JO  - J. Cell. Mol. Med.
VL  - 23
IS  - 8
PB  - Wiley
PY  - 2019
SN  - 1582-1838
ER  - 

TY  - JOUR
AB  - Metabolomics studies now approach large sample sizes and the health characterization of the study population often include complete blood count (CBC) results. Upon careful interpretation the CBC aids diagnosis and provides insight into the health status of the patient within a clinical setting. Uncovering metabolic signatures associated with parameters of the CBC in apparently healthy individuals may facilitate interpretation of metabolomics studies in general and related to diseases. For this purpose 879 subjects from the population-based Study of Health in Pomerania (SHIP)-TREND were included. Using metabolomics data resulting from mass-spectrometry based measurements in plasma samples associations of specific CBC parameters with metabolites were determined by linear regression models. In total, 118 metabolites significantly associated with at least one of the CBC parameters. Strongest associations were observed with metabolites of heme degradation and energy production/consumption. Inverse association seen with mean corpuscular volume and mean corpuscular haemoglobin comprised metabolites potentially related to kidney function. The presently identified metabolic signatures are likely derived from the general function and formation/elimination of blood cells. The wealth of associated metabolites strongly argues to consider CBC in the interpretation of metabolomics studies, in particular if mutual effects on those parameters by the disease of interest are known.
AU  - Masuch, A.*
AU  - Budde, K.*
AU  - Kastenmüller, G.
AU  - Artati, A.
AU  - Adamski, J.
AU  - Völzke, H.*
AU  - Nauck, M.*
AU  - Pietzner, M.*
C1  - 56354
C2  - 47031
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 5144-5153
TI  - Metabolic signature associated with parameters of the complete blood count in apparently healthy individuals.
JO  - J. Cell. Mol. Med.
VL  - 23
IS  - 8
PB  - Wiley
PY  - 2019
SN  - 1582-1838
ER  - 

TY  - JOUR
AB  - Non-tuberculous mycobacteria (NTM), also known as an environmental and atypical mycobacteria, can cause the chronic pulmonary infectious diseases. Macrophages have been suggested as the main host cell to initiate the innate immune responses to NTM infection. However, the molecular mechanism to regulate the antimicrobial immune responses to NTM is still largely unknown. Current study showed that the NTM clinical groups, Mycobacterium abscessus and Mycobacterium smegmatis, significantly induced the M1 macrophage polarization with the characteristic production of nitric oxide (NO) and marker gene expression of iNOS, IFNγ, TNF-α, IL1-β and IL-6. Interestingly, a non-histone nuclear protein, HMGN2 (high-mobility group N2), was found to be spontaneously induced during NTM-activated M1 macrophage polarization. Functional studies revealed that HMGN2 deficiency in NTM-infected macrophage promotes the expression of M1 markers and the production of NO via the enhanced activation of NF-κB and MAPK signalling. Further studies exhibited that HMGN2 knock-down also enhanced IFNγ-induced M1 macrophage polarization. Finally, we observed that silencing HMGN2 affected the survival of NTM in macrophage, which might largely relevant to enhanced macrophage polarization into M1 phenotype under the NTM infection. Collectively, current studies thus suggested a novel function of HMGN2 in regulating the anti-non-tuberculous mycobacteria innate immunity of macrophage.
AU  - Wang, X.
AU  - Chen, S.*
AU  - Ren, H.*
AU  - Chen, J.*
AU  - Li, J.*
AU  - Wang, Y.*
AU  - Hua, Y.*
AU  - Wang, X.*
AU  - Huang, N.*
C1  - 57039
C2  - 47489
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 7985-7998
TI  - HMGN2 regulates non-tuberculous mycobacteria survival via modulation of M1 macrophage polarization.
JO  - J. Cell. Mol. Med.
VL  - 23
IS  - 12
PB  - Wiley
PY  - 2019
SN  - 1582-1838
ER  - 

TY  - JOUR
AB  - Human guanylate binding protein-1 (GBP-1) belongs to the family of large GTPases. The expression of GBP-1 is inducible by inflammatory cytokines, and the protein is involved in inflammatory processes and host defence against cellular pathogens. GBP-1 is the first GTPase which was described to be secreted by eukaryotic cells. Here, we report that precipitation of GBP-1 with GMP-agarose from cell culture supernatants co-purified a 47-kD fragment of GBP-1 (p47-GBP-1) in addition to the 67-kD full-length form. MALDI-TOF sequencing revealed that p47-GBP-1 corresponds to the C-terminal helical part of GBP-1 and lacks most of the globular GTPase domain. In silico analyses of protease target sites, together with cleavage experiments in vitro and in vivo, showed that p67-GBP-1 is cleaved by the inflammatory caspases 1 and 5, leading to the formation of p47-GBP-1. Furthermore, the secretion of p47-GBP-1 was found to occur via a non-classical secretion pathway and to be dependent on caspase-1 activity but independent of inflammasome activation. Finally, we showed that p47-GBP-1 represents the predominant form of secreted GBP-1, both in cell culture supernatants and, in vivo, in the cerebrospinal fluid of patients with bacterial meningitis, indicating that it may represent the biologically active form of extracellular GBP-1. These findings confirm the involvement of caspase-1 in non-classical secretion mechanisms and open novel perspectives for the extracellular function of secreted GBP-1.
AU  - Naschberger, E.*
AU  - Geißdörfer, W.*
AU  - Bogdan, C.*
AU  - Tripal, P.*
AU  - Kremmer, E.
AU  - Stürzl, M.*
AU  - Britzen-Laurent, N.*
C1  - 50676
C2  - 42834
CY  - Hoboken
SP  - 1954-1966
TI  - Processing and secretion of guanylate binding protein-1 depend on inflammatory caspase activity.
JO  - J. Cell. Mol. Med.
VL  - 21
IS  - 9
PB  - Wiley
PY  - 2017
SN  - 1582-1838
ER  - 

TY  - JOUR
AB  - Members of the transforming growth factor (TGF)- family govern a wide range of mechanisms in brain development and in the adult, in particular neuronal/glial differentiation and survival, but also cell cycle regulation and neural stem cell maintenance. This clearly created some discrepancies in the field with some studies favouring neuronal differentiation/survival of progenitors and others favouring cell cycle exit and neural stem cell quiescence/maintenance. Here, we provide a unifying hypothesis claiming that through its regulation of neural progenitor cell (NPC) proliferation, TGF- signalling might be responsible for (i) maintaining stem cells in a quiescent stage, and (ii) promoting survival of newly generated neurons and their functional differentiation. Therefore, we performed a detailed histological analysis of TGF-1 signalling in the hippocampal neural stem cell niche of a transgenic mouse that was previously generated to express TGF-1 under a tetracycline regulatable Ca-Calmodulin kinase promoter. We also analysed NPC proliferation, quiescence, neuronal survival and differentiation in relation to elevated levels of TGF-1 in vitro and in vivo conditions. Finally, we performed a gene expression profiling to identify the targets of TGF-1 signalling in adult NPCs. The results demonstrate that TGF-1 promotes stem cell quiescence on one side, but also neuronal survival on the other side. Thus, considering the elevated levels of TGF-1 in ageing and neurodegenerative diseases, TGF-1 signalling presents a molecular target for future interventions in such conditions.
AU  - Kandasamy, M.*
AU  - Lehner, B.*
AU  - Kraus, S.*
AU  - Sander, P.R.*
AU  - Marschallinger, J.*
AU  - Rivera, F.J.*
AU  - Trümbach, D.
AU  - Ueberham, U.*
AU  - Reitsamer, H.A.*
AU  - Strauss, O.*
AU  - Bogdahn, U.*
AU  - Couillard-Despres, S.*
AU  - Aigner, L.*
C1  - 32181
C2  - 35435
CY  - Hoboken
SP  - 1444-1459
TI  - TGF-beta signalling in the adult neurogenic niche promotes stem cell quiescence as well as generation of new neurons.
JO  - J. Cell. Mol. Med.
VL  - 18
IS  - 7
PB  - Wiley-Blackwell
PY  - 2014
SN  - 1582-1838
ER  - 

TY  - JOUR
AB  - Human heart failure is a complex syndrome and a primary cause of morbidity and mortality in the world. However, the molecular pathways involved in the remodelling process are poorly understood. In this study, we performed exhaustive global proteomic surve
AU  - Li, W.M.*
AU  - Rong, R.*
AU  - Zhao, S.*
AU  - Zhu, X.M.*
AU  - Zhang, K.
AU  - Xiong, X.*
AU  - Yu, X.Q.*
AU  - Cui, Q.H.*
AU  - Li, S.Q.*
AU  - Chen, L.*
AU  - Cai, J.*
AU  - Du, J.*
C1  - 8015
C2  - 29978
SP  - 59-71
TI  - Proteomic analysis of metabolic, cytoskeletal and stress response proteins in human heart failure.
JO  - J. Cell. Mol. Med.
VL  - 16
IS  - 1
PB  - Wiley-Blackwell
PY  - 2012
SN  - 1582-1838
ER  - 

TY  - JOUR
AB  - The major stress-inducible heat shock protein 70 (Hsp70) is frequently present on the cell surface of human tumors, but not on normal cells. Herein, the binding characteristics of the cmHsp70.1 mouse monoclonal antibody (mAb) were evaluated in vitro and in a syngeneic tumor mouse model. More than 50% of the CT26 mouse colon carcinoma cells express Hsp70 on their cell surface at 4 degrees C. After a temperature shift to 37 degrees C, the cmHsp70.1-FITC mAb translocates into early endosomes and lysosomes Intraoperative and near-infrared fluorescence (NIRF) imaging revealed an enrichment of Cy5.5-conjugated mAb cmHsp70.1, but not an identically labelled IgG1 isotype-matched control, in i.p. and s.c. located CT26 tumors, as soon as 30min after i.v. injection into the tail vein. Due to the rapid turnover rate of membrane-bound Hsp70, the fluorescence-labelled cmHsp70.1 mAb became endocytosed and accumulated in the tumor, reaching a maximum after 24h and remained detectable at least up to 96h after a single i.v. injection. The tumor-selective internalization of mAb cmHsp70.1 at the physiological temperature of 37 degrees C might enable a targeted uptake of toxins or radionuclides into Hsp70 membrane-positive tumors. The anti-tumoral activity of the cmHsp70.1 mAb is further supported by its capacity to mediate antibody dependent cytotoxicity (ADCC).
AU  - Stangl, S.
AU  - Gehrmann, M.
AU  - Dressel, R.
AU  - Alves, F.
AU  - Dullin, C.
AU  - Themelis, G.
AU  - Ntziachristos, V.
AU  - Staeblein, E.
AU  - Walch, A.K.
AU  - Winkelmann, I.
AU  - Multhoff, G.
C1  - 2001
C2  - 27225
SP  - 874-887
TI  - In vivo imaging of CT26 mouse tumours by using cmHsp70.1 monoclonal antibody.
JO  - J. Cell. Mol. Med.
VL  - 15
IS  - 4
PB  - Wiley-Blackwell
PY  - 2011
SN  - 1582-1838
ER  - 

TY  - JOUR
AB  - Cell motility is controlled by the dynamic cytoskeleton and its related proteins, such as members of the ezrin/radixin/moesin (ERM) family, which act as signaling molecules inducing cytoskeleton remodeling. Although ERM proteins have been identified as important factors in various malignancies, functional redundancy between these proteins has hindered the dissection of their individual contribution. The aim of the present study was to analyze the functional role of moesin in pancreatic malignancies. Cancer cells of different malignant lesions of human and transgenic mice pancreata were evaluated by immunohistochemistry. For functional analysis, cell growth, adhesion, and invasion assays were carried out after transient and stable knock-down of moesin expression in pancreatic cancer cells. In vivo tumorigenicity was determined using orthotopic and metastatic mouse tumor models. We now show that moesin knock-down increases migration, invasion, and metastasis and influences extracellular matrix organization of pancreatic cancer. Moesin-regulated migratory activities of pancreatic cancer cells were in part promoted through cellular translocation of beta-catenin, and re-distribution and organization of the cytoskeleton. Analysis of human and different transgenic mouse pancreatic cancers, demonstrated that moesin is a phenotypic marker for anaplastic carcinoma, suggesting that this ERM protein plays a specific role in pancreatic carcinogenesis.
AU  - Abiatari, I.*
AU  - Esposito, I.
AU  - de Oliveira, T.*
AU  - Felix., K.*
AU  - Xin, H.*
AU  - Penzel, R.*
AU  - Giese, T.*
AU  - Friess, H.*
AU  - Kleeff, J.*
C1  - 1259
C2  - 26916
SP  - 1166-1179
TI  - Moesin dependent cytoskeleton remodeling is associated with an anaplastic phenotype of pancreatic cancer.
JO  - J. Cell. Mol. Med.
VL  - 14
IS  - 5
PB  - Wiley-Blackwell
PY  - 2010
SN  - 1582-1838
ER  - 

TY  - JOUR
AB  - Although natural killer (NK) cells are often described as first line defense against infected or malignant cells which act without the need of prior activation, it is known now that the NK cell activity is tightly regulated by other cells and soluble factors. We show here that the stress-inducible heat shock protein (HSP) 70 activates human NK cells to kill target cells expressing MICA (major histocompatibility complex class I chain-related molecule A) in a NKG2D (natural killer group 2 member D) dependent manner. The HSP70-derived peptide TKD (TKDNNLLGRFELSG) was able to replace the full-length HSP70 and to exert the same function. Interestingly, the expression of the cytotoxic effector protease granzyme B in NK cells was increased after TKD-stimulation. When MICA and MICB expression was induced in human tumor cells by a histone deacetylase inhibitor and NK cells were activated by HSP70 or TKD, both treatments jointly improved the killing of the tumor cells. Thus, the synergistic activity of two stress-inducible immunological danger signals, HSP70 and MICA/B, leads to activation and enhanced cytotoxicity of human NK cells against tumor cells.
AU  - Elsner, L.*
AU  - Flügge, P.F.*
AU  - Lozano, J.*
AU  - Muppala, V.*
AU  - Eiz-Vesper, B.*
AU  - Demiroglu, S.Y.*
AU  - Malzahn, D.*
AU  - Herrmann, T.*
AU  - Brunner, E.*
AU  - Bickeböller, H.*
AU  - Multhoff, G.
AU  - Walter, L.*
AU  - Dressel, R.*
C1  - 417
C2  - 26313
SP  - 992-1002
TI  - The endogenous danger signals HSP70 and MICA cooperate in the activation of cytotoxic effector functions of NK cells.
JO  - J. Cell. Mol. Med.
VL  - 14
IS  - 4
PB  - Wiley-Blackwell
PY  - 2010
SN  - 1582-1838
ER  - 

TY  - JOUR
AB  - Reduced E-cadherin expression is associated with tumour progression of many carcinomas, including endometrial cancers. The transcription factor Snail is known as one of the most prominent transcriptional E-cadherin repressors; its regulation in cancer tissues, however, still remains unclear. Here, we report that activation of epidermal growth factor receptor (EGFR) resulted in over-expression of Snail and also identified critical downstream signalling molecules. Stimulation of two endometrial carcinoma cell lines with epidermal growth factor (EGF) lead to an increase of Snail protein expression. In primary human endometrioid endometrial carcinomas Snail protein expression correlated with the activated, phosphorylated form of EGFR (Tyr1086) as revealed by profiling 24 different signalling proteins using protein lysate microarrays. In addition, we observed an inverse correlation between Snail and E-cadherin protein levels in these tumours. Most likely, p38 MAPK, PAK1, AKT, ERK1/2 and GSK-3β are involved in the up-regulation of Snail downstream of EGFR. Snail mRNA expression did not show a correlation with activated EGFR in these tumours. Taken together, profiling of signalling proteins in primary human tissues provided strong evidence that EGFR signalling is involved in Snail protein over-expression.
AU  - Hipp, S.*
AU  - Walch, A.K.
AU  - Schuster, T.*
AU  - Losko, S.*
AU  - Laux, H.*
AU  - Bolton, T.*
AU  - Höfler, H.
AU  - Becker, K.F.*
C1  - 559
C2  - 26902
SP  - 3858-3867
TI  - Activation of epidermal growth factor receptor results in snail protein but not mRNA over-expression in endometrial cancer.
JO  - J. Cell. Mol. Med.
VL  - 13
IS  - 9B
PB  - Wiley-Blackwell
PY  - 2009
SN  - 1582-1838
ER  - 

TY  - JOUR
AB  - In spite of growing evidence linking vitamin D(3) levels to mental health disorders, little is known about its direct targets in the brain. This study set out to investigate targets of vitamin D(3) in a human brain stem cell line. We employed arrays with antibodies directed against more than 600 structural and signalling proteins, including phospho-variants. Over 180 proteins responded to vitamin D(3), such as cyclin-dependent protein-serine kinase 1/2, epidermal growth factor receptor-tyrosine kinase, protein kinase A, protein-serine kinase Bgamma and protein-serine kinase Calpha. PEA-15 (phosphoprotein enriched in astrocytes-15 kD, also known as PED), known to be involved in various anti-proliferative and anti-apoptotic effects, was strongly up-regulated. In silico promoter analysis revealed conserved binding sites for vitamin D(3) receptor, suggesting a strong vitamin D(3) dependency of the PEA-15 promoter. PEA-15 up-regulation by vitamin D(3) could be confirmed by Western blot in two different cell lines. Analysis of mRNA and protein phosphorylation status of PEA-15 suggests that increased PEA-15 promoter activity and increased protein stabilization contribute to the overall rise of PEA-15 protein. In a functional test of this novel pathway, we demonstrated that vitamin D(3) was able to rescue cells from TRAIL-induced apoptosis through regulation of the PEA-15 expression and function. Summarized, our study presents novel targets of vitamin D(3) relevant for apoptosis and cell proliferation, and thus strongly supports a function of vitamin D(3) in the brain that impacts on processes highly relevant for major neurological disorders.
AU  - Obradovic, D.*
AU  - Zanca, C.*
AU  - Vogl, A.*
AU  - Trümbach, D.
AU  - Deussing, J.M.*
AU  - Condorelli, G.*
AU  - Rein, T.*
C1  - 218
C2  - 27175
SP  - 3315-3328
TI  - Vitamin D₃ signalling in the brain enhances the function of phosphoprotein enriched in astrocytes - 15 kD (PEA-15).
JO  - J. Cell. Mol. Med.
VL  - 13
IS  - 9B
PB  - Wiley-Blackwell Publishing, Inc.
PY  - 2009
SN  - 1582-1838
ER  - 

TY  - JOUR
AB  - Diseases caused by gammaherpesviruses continue to be a challenge for human health and antiviral treatment. Most of the commonly used antiviral drugs are directed against viral gene products. However, the emergence of drug-resistant mutations ma limit the effectiveness of these drugs. Since viruses require a host cell to propagate, the search for host cell targets is an interestin alternative. Methods: In this study, we infected three different cell types (fibroblasts, endothelial precursor cells and macrophages with a murine gammaherpesvirus and analysed the host cell response for changes either common to all or unique to a particular cell type using oligonucleotide microarrays. Results: The analysis revealed a number of genes whose transcription was significantly up- or down-regulated in either one or two of the cell types tested. After infection, only two genes, Lman1 (also known as ERGIC53) an synaptobrevin-like 1 (sybl1) were significantly up-regulated in all three cell types, suggestive for a general role for the virus life cycl independent of the cell type. Both proteins have been implicated in cellular exocytosis and transport of glycoproteins through the secre tory pathway. To test the significance of the observed up-regulation, the functionality of these proteins was modulated, and the effect on virus replication was monitored. Inhibition of either Lman1 or sybl1 resulted in a significant reduction in virus production. Conclusions: This suggests that proteins of the secretory pathway which appear to be rate limiting for virus production may represent new targets for intervention.
AU  - Mages, J.*
AU  - Freimüller, K.
AU  - Lang, R.*
AU  - Hatzopoulos, A.K.
AU  - Guggemoos, S.
AU  - Koszinowski, U.H.*
AU  - Adler, H.
C1  - 140
C2  - 25715
SP  - 1974-1989
TI  - Proteins of the secretory pathway govern virus productivity during lytic gammaherpesvirus infection.
JO  - J. Cell. Mol. Med.
VL  - 12
IS  - 5B
PB  - Wiley-Blackwell
PY  - 2008
SN  - 1582-1838
ER  -