Max Planck Institute For Experimentelle Medizin

Göttingen, Germany

Max Planck Institute For Experimentelle Medizin

Göttingen, Germany

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Sussulini A.,University of Campinas | Sussulini A.,Max Planck Institute For Experimentelle Medizin | Sussulini A.,University of Sao Paulo
Advances in Biological Psychiatry | Year: 2014

Bipolar disorder (BD) is a chronic psychiatric illness characterised by transitions between manic and depressive episodes. Diagnosis of BD is based on subjective clinical evaluation and, consequently, quite difficult, due to the oscillating character of the disease. Increasing accuracy regarding BD diagnosis can improve the mental health and treatment of patients. A path that can lead to a more reliable medical diagnostic of BD and also possibly to an optimisation of treatment for each patient is the identification of specific biological markers. Recently, proteomics and metabolomics have become the most applied advanced analytical tools allowing the discovery of protein and metabolite biomarkers for diseases and/or treatments. The present chapter reviews studies described in the literature that employ proteomic and metabolomic strategies to investigate potential biomarkers for BD and also for lithium therapy, which is the most widely used drug treatment of this illness. The main results from investigations using human samples are presented, as well as hypotheses concerning the biological processes and molecular mechanisms involved in BD pathophysiology and treatment, as demonstrated by proteomic and metabolomic analyses. © 2014 S. Karger AG, Basel.


Liu Y.,Saarland University | Schirra C.,Saarland University | Edelmann L.,Saarland University | Matti U.,Saarland University | And 7 more authors.
Journal of Cell Biology | Year: 2010

Priming of large dense-core vesicles (LDCVs) is a Ca2+-dependent step by which LDCVs enter a release-ready pool, involving the formation of the soluble N-ethyl-maleimide sensitive fusion protein attachment protein (SNAP) receptor complex consisting of syntaxin, SNAP-25, and synaptobrevin. Using mice lacking both isoforms of the calcium-dependent activator protein for secretion (CAPS), we show that LDCV priming in adrenal chromaffin cells entails two distinct steps. CAPS is required for priming of the readily releasable LDCV pool and sustained secretion in the continued presence of high Ca2+ concentrations. Either CAPS1 or CAPS2 can rescue secretion in cells lacking both CAPS isoforms. Furthermore, the deficit in the readily releasable LDCV pool resulting from CAPS deletion is reversed by a constitutively open form of syntaxin but not by Munc13-1, a priming protein that facilitates the conversion of syntaxin to the open conformation. Our data indicate that CAPS functions downstream of Munc13s but also interacts functionally with Munc13s in the LDCV-priming process. © 2010 Liu et al.


Kolodziejczyk K.,University College London | Saab A.S.,Max Planck Institute For Experimentelle Medizin | Nave K.-A.,Max Planck Institute For Experimentelle Medizin | Attwell D.,University College London
F1000 Biology Reports | Year: 2010

The function of glutamate receptors on oligodendrocytes and their precursor cells is poorly understood, with their only clear action being to damage these cells in pathological conditions. Here we review recent studies of glutamate signalling to oligodendrocyte lineage cells, and explore what its physiological function may be. © 2010 Faculty of 1000 Ltd.


Ortiz C.S.,National Polytechnic Institute of Mexico | Ortiz C.S.,Instituto Nacional Of Ciencias Medicas Y Nutricion Salvador Zubiran | Montante-Montes D.,Instituto Nacional Of Ciencias Medicas Y Nutricion Salvador Zubiran | Saqui-Salces M.,Instituto Nacional Of Ciencias Medicas Y Nutricion Salvador Zubiran | And 12 more authors.
Oncology Reports | Year: 2011

Human ether à-go-go 1 (Eag1) potassium channels are potential tumor markers and therapeutic targets for several types of malignancies, including cervical cancer. Estrogens and human papilloma virus oncogenes regulate Eag1 gene expression, suggesting that Eag1 may already be present in pre-malignant lesions. Therefore, Eag1 could be used as an early marker and/or a potential risk indicator for cervical cancer. Consequently, we studied Eag1 protein expression by immunochemistry in cervical cancer cell lines, normal keratinocytes, cervical cytologies from intraepithelial lesions, biopsies from cervical intraepithelial neoplasias (CIN 1, 2 and 3) and in normal smears from patients taking or not taking estrogens. Two hundred and eighty-six samples obtained by liquid-based cytology and fifteen CIN biopsies were studied. We observed Eag1 protein expression in the cervical cancer cell lines, as opposed to normal keratinocytes. Eag1 was found in 67% of the cervical cytologies from low-grade intra epithelial lesions and in 92% of the samples from high-grade intraepithelial lesions, but only in 27% of the normal samples. Noteworthy, morphologically normal cells obtained from dysplastic samples also exhibited Eag1 expression. In CIN biopsies we found that the higher the grade of the lesion, the broader the Eag1 protein distribution. Almost 50% of the normal patients taking estrogens displayed Eag1 expression. We suggest Eag1 as a potential marker of cervical dysplasia and a risk indicator for developing cervical lesions in patients taking estrogens. Eag1 detection in cervical cancer screening programs should help to improve early diagnosis and decrease mortality rates from this disease.


Mutations in the enzyme superoxide dismutase-1 (SOD1) cause hereditary variants of the fatal motor neuron disease amyotrophic lateral sclerosis (ALS). The pathophysiology of the disease is non-cell-autonomous: neurotoxicity is derived not only from mutant motor neurons but also from mutant neighbouring non-neuronal cells. In particular, microglia contribute to disease progression. By investigating acute lesions of spinal cord white matter in anaesthetised mice with fluorescently labelled microglia and axons using in vivo 2-photon laser-scanning microscopy (2P-LSM), we identified the messenger nitric oxide (NO) as a modulator of activated microglia. Subsequently, we investigated the role of microglia-related neuroinflammation in the affected lateral spinal cord of the ALS-linked transgenic SOD1 G93A mice. Different phases of microglia-mediated inflammation were observed: highly reactive microglial cells in preclinical stages and morphologically transformed ameboid microglia that have lost their function of tissue surveillance and injury-directed response in clinical stages. In another study, we observed rapid morphological reactions of mutant astroglial cells towards laser-induced axonal transection. Finally, we began to investigate the effect of methylene blue as an inhibitor of the NO pathway on microglia-mediated inflammation in affected motor parts of the spinal cord. An understanding of the pathomechanisms of degenerative processes in the spinal cord will be a prerequisite to develop efficient therapies for ALS. © Georg Thieme Verlag KG Stuttgart · New York.


Hartung F.,Max Planck Institute For Experimentelle Medizin | Stuhmer W.,Max Planck Institute For Experimentelle Medizin | Pardo L.A.,Max Planck Institute For Experimentelle Medizin
Molecular Cancer | Year: 2011

Background: The search for strategies to target ion channels for therapeutic applications has become of increasing interest. Especially, the potassium channel KV10.1 (Ether-á-go-go) is attractive as target since this surface protein is virtually not detected in normal tissue outside the central nervous system, but is expressed in approximately 70% of tumors from different origins.Methods: We designed a single-chain antibody against an extracellular region of KV10.1 (scFv62) and fused it to the human soluble TRAIL. The KV10.1-specific scFv62 antibody -TRAIL fusion protein was expressed in CHO-K1 cells, purified by chromatography and tested for biological activity.Results: Prostate cancer cells, either positive or negative for KV10.1 were treated with the purified construct. After sensitization with cytotoxic drugs, scFv62-TRAIL induced apoptosis only in KV10.1-positive cancer cells, but not in non-tumor cells, nor in tumor cells lacking KV10.1 expression. In co-cultures with KV10.1-positive cancer cells the fusion protein also induced apoptosis in bystander KV10.1-negative cancer cells, while normal prostate epithelial cells were not affected when present as bystander.Conclusions: KV10.1 represents a novel therapeutic target for cancer. We could design a strategy that selectively kills tumor cells based on a KV10.1-specific antibody. © 2011 Hartung et al; licensee BioMed Central Ltd.


De Queiroz F.M.,Max Planck Institute For Experimentelle Medizin | Sanchez A.,Max Planck Institute For Experimentelle Medizin | Agarwal J.R.,Max Planck Institute For Experimentelle Medizin | Stuhmer W.,Max Planck Institute For Experimentelle Medizin | Pardo L.A.,Max Planck Institute For Experimentelle Medizin
Molecular Biology Reports | Year: 2012

Transfection has become an everyday technique widely used for functional studies in living cells. The choice of the particular transfection method is usually determined by its efficiency and toxicity, and possible functional consequences specific to the method used are normally overlooked. We describe here that nucleofection, a method increasingly used because of its convenience and high efficiency, increases the metabolic rate of some cancer cells, which can be misleading when used as a measure of proliferation. Moreover, nucleofection can alter the subcellular expression pattern of the transfected protein. These undesired effects are independent of the transfected nucleic acid, but depend on the particular cell line used. Therefore, the interpretation of functional data using this technology requires further controls and caution. © Springer Science+Business Media B.V. 2011.


Eckstein F.,Max Planck Institute For Experimentelle Medizin
Nucleic Acid Therapeutics | Year: 2014

Phosphorothioates have found their usefulness in the general area of oligonucleotide therapeutic applications. Initially this modification was introduced into the antisense methodology because of the nuclease resistance of the phosphorothioate linkage in comparison with that of the phosphate linkage. However, as experimental data accumulated, it was detected that this chemical modification also facilitates cellular uptake and bioavailibity in vivo. Thus, today the majority of therapeutic oligonucleotides contain this modification. This review will discuss the historical development of this modification and present some of its chemical properties where they differ from those of the phosphate group. The antisense application will be discussed in the original context with cleavage of the target mRNA, but other target RNAs such as microRNAs and long noncoding RNAs will also be covered. It continues with applications where the target RNA should not be cleaved. A brief presentation of decoy oligonucleotides will be included, as well as some miscellaneous applications. Cellular uptake is a crucial step for oligonucleotides to reach their target and will be briefly reviewed. Lastly, a most surprising recent observation is the presence of phosphorothioate groups in bacterial DNA where functions still remain to be fully determined. © Copyright 2014, Mary Ann Liebert, Inc. 2014.


Schizophrenias are diagnosed purely clinically. The biological basis for this clinical entity is still fully unknown. Genetic studies have revealed some interesting hints but have not led to the identification of actual disease genotypes. On the contrary, it has become more and more probable that widely differing genotype constellations together with manifold environmental factors can trigger schizophrenia according to the motto "many roads lead to Rome..o". Thus, new strategies that allow a better insight into complex genotype-phenotype relationships, e. g. PGAS (phenotype-based genetic associations studies) are urgently needed. PGAS became possible on the basis of the GRAS data collection, the as yet largest worldwide phenotypical databank of schizophrenic patients. First PGAS proof-of-concept results on cognition or development-relevant genes are already available. © Georg Thieme Verlag KG Stuttgart, New York.


PubMed | Max Planck Institute For Experimentelle Medizin
Type: Historical Article | Journal: Nucleic acid therapeutics | Year: 2014

Phosphorothioates have found their usefulness in the general area of oligonucleotide therapeutic applications. Initially this modification was introduced into the antisense methodology because of the nuclease resistance of the phosphorothioate linkage in comparison with that of the phosphate linkage. However, as experimental data accumulated, it was detected that this chemical modification also facilitates cellular uptake and bioavailibity in vivo. Thus, today the majority of therapeutic oligonucleotides contain this modification. This review will discuss the historical development of this modification and present some of its chemical properties where they differ from those of the phosphate group. The antisense application will be discussed in the original context with cleavage of the target mRNA, but other target RNAs such as microRNAs and long noncoding RNAs will also be covered. It continues with applications where the target RNA should not be cleaved. A brief presentation of decoy oligonucleotides will be included, as well as some miscellaneous applications. Cellular uptake is a crucial step for oligonucleotides to reach their target and will be briefly reviewed. Lastly, a most surprising recent observation is the presence of phosphorothioate groups in bacterial DNA where functions still remain to be fully determined.

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