Henning Ulrich

University of São Paulo, San Paulo, São Paulo, Brazil

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Publications (140)361.28 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Cell proliferation is orchestrated through diverse proteins related to calcium (Ca(2+)) signaling inside the cell. Cellular Ca(2+) influx occurs first by various mechanisms at the plasma membrane, is then followed by absorption of Ca(2+) ions by mitochondria and endoplasmic reticulum, and, finally, there is a connection of calcium stores to the nucleus. Experimental evidence indicates that the fluctuation of Ca(2+) from the endoplasmic reticulum provides a pivotal and physiological role for cell proliferation. Ca(2+) depletion in the endoplasmatic reticulum triggers Ca(2+) influx across the plasma membrane in an phenomenon called store-operated calcium entries (SOCE). SOCE is activated through a complex interplay between a Ca(2+) sensor, denominated STIM, localized in the endoplasmic reticulum and a Ca(2+) channel at the cell membrane, denominated Orai. The interplay between STIM and Orai proteins with cell membrane receptors and their role in cell proliferation are discussed in this review. Copyright © 2015. Published by Elsevier Inc.
    Cellular Signalling 08/2015; In press. DOI:10.1016/j.cellsig.2015.08.006 · 4.47 Impact Factor
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    ABSTRACT: The kinins bradykinin and des-arg(9) -bradykinin cleaved from kininogen precursors by kallikreins exert their biological actions by stimulating kinin-B2 and B1 receptors, respectively. In vitro models of neural differentiation such as P19 embryonal carcinoma cells and neural progenitor cells have suggested the involvement of B2 receptors in neural differentiation and phenotype determination; however, the involvement of B1 receptors in these processes has not been established. Here, we show that B1 and B2 receptors are differentially expressed in mouse embryonic E14Tg2A stem cells undergoing neural differentiation. Proliferation and differentiation assays, performed in the presence of receptor subtype-selective agonists and antagonists, revealed that B1 receptor activity is required for the proliferation of embryonic and differentiating cells as well as for neuronal maturation at later stages of differentiation, while the B2 receptor acts on neural phenotype choice, promoting neurogenesis over gliogenesis. Besides the elucidation of bradykinin functions in an in vitro model reflecting early embryogenesis and neurogenesis, this study contributes to the understanding of B1 receptor functions in this process. © 2015 International Society for Advancement of Cytometry. © 2015 International Society for Advancement of Cytometry.
    Cytometry Part A 08/2015; DOI:10.1002/cyto.a.22726 · 3.07 Impact Factor
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    ABSTRACT: Purinergic receptors belong to the most ancient neurotransmitter system. While their relevance in neurotransmission is well characterized, it has become clear that they have many other cellular functions. During development, they participate in regulation of proliferation and differentiation of stem cells. Here, we used rat embryonic telencephalon neurosphere cultures to detect purinergic P2 receptor subtype expression and possible synergistic actions of these receptors with NGF. Neurospheres proliferate in the presence of EGF and FGF-2; however, upon depletion of these growth factors, they migrate and differentiate into neurons and glial phenotypes. Expression patterns of P2X and P2Y receptors changed along neural differentiation. Gene expression of P2X2-7 and P2Y1,2,4,6,12,14 receptors was confirmed in undifferentiated and neural-differentiated neurospheres, with an up-regulation of P2X2 and P2X6 subtypes, together with a down-regulation of P2X4, P2X7 and P2Y subtypes upon induction to differentiation. BrdU-labeling and subsequent flow cytometry analysis was used to measure cell proliferation, which was increased by chronic exposure to NGF and increasing concentrations of ATP, in line with the expression levels of PCNA. Furthermore, a synergistic effect on proliferation was observed in conditions of co-incubation with ATP and NGF. While ATP and NGF independently promoted neural migration, no inter-relation between these factors was detected for this cellular process. As conclusion, an unknown synergism of ATP and NGF in proliferation is described. Future efforts may elucidate the underlying mechanisms of the interrelationship of ATP and NGF during neurogenesis.
    Neurochemical Research 08/2015; DOI:10.1007/s11064-015-1674-2 · 2.55 Impact Factor
  • Cancer Research 08/2015; 75(15 Supplement):4144-4144. DOI:10.1158/1538-7445.AM2015-4144 · 9.28 Impact Factor
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    ABSTRACT: Hybrid scaffolds made of xanthan and magnetite nanoparticles (XCA/mag) were prepared by dipping xanthan membranes (XCA) into dispersions of magnetic nanoparticles for different periods of time. The resulting hybrid scaffolds presented magnetization values ranging from 0.25 emu g(-1) to 1.80 emu g(-1) at 70 kOe and corresponding iron contents ranging from 0.25% to 2.3%, respectively. They were applied as matrices for in vitro embryoid body adhesion and neuronal differentiation of embryonic stem cells; for comparison, neat XCA and commercial plastic plates were also used. Adhesion rates were more pronounced when cells were seeded on XCA/mag than on neat XCA or plastic dishes; however, proliferation levels were independent from those of the scaffold type. Embryonic stem cells showed similar differentiation rates on XCA/mag scaffolds with magnetization of 0.25 and 0.60 emu g(-1), but did not survive on scaffolds with 1.80 emu g(-1). Differentiation rates, expressed as the number of neurons obtained on the chosen scaffolds, were the largest on neat XCA, which has a high density of negative charge, and were smallest on the commercial plastic dishes. The local magnetic field inherent of magnetite particles present on the surface of XCA/mag facilitates synapse formation, because synaptophysin expression and electrical transmission were increased when compared to the other scaffolds used. We conclude that XCA/mag and XCA hydrogels are scaffolds with distinguishable performance for adhesion and differentiation of ESCs into neurons.
    Biomedical Materials 08/2015; 10(4):045002. DOI:10.1088/1748-6041/10/4/045002 · 2.92 Impact Factor
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  • Mateja Delač · Helena Motaln · Henning Ulrich · Tamara T Lah
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    ABSTRACT: Aptamers are short single-stranded nucleic acids (RNA or ssDNA), identified by an in vitro selection process, denominated SELEX, from a partially random oligonucleotide library. They bind to a molecular target, a protein or other complex macromolecular structures of interest with high affinity and specificity, comparable to those of antibodies. Recently, aptamer selection protocols were developed for targeting living cells, including tumors. Chemical modifications of the aptamers and modalities of their detection and delivery systems are already available with high selectivity and targeting ability for the desired cancer cell type, making them promising for diagnosis and therapy. Glioblastoma multiformae represents the most malignant and fatal stage of glioma, and is also the most frequent brain tumor. Glioblastoma-specific aptamers were developed by either targeting the whole cell surface or known glioma biomarkers. These aptamers may gain importance for imaging, tumor cell isolation from biopsies and drug delivery. In biomedical imaging techniques, aptamers coupled with radionuclide or fluorescent labels, bioconjugates and nanoparticles offer an advanced, noninvasive manner for defining the glioblastoma tissue border. Though single modality aptamer imaging probes have some limitations, these are overcome by the use of multimodal probes. Due to selectivity and chemical characteristics, aptamers can be coupled to functionalized nanoparticles and loaded with a drug, appeared promising for in vivo targeting of glioblastoma. Finally, aptamers are effective mediators for gene silencing when coupled to small interfering RNA and a viral vector, thus providing a novel tool with enhanced targeting capability in drug delivery, designed for tailored treatment of glioblastoma patients. © 2015 International Society for Advancement of Cytometry. © 2015 International Society for Advancement of Cytometry.
    Cytometry Part A 07/2015; DOI:10.1002/cyto.a.22715 · 3.07 Impact Factor
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    ABSTRACT: Neural stem cells proliferate and differentiate into neurons and glial cells, being responsible for embryonic and postnatal development of the central nervous system (CNS) as well as for regeneration in the adult brain. These cells also play a key role in maintaining the physiological integrity of the CNS in face of injury or disease. The previous study has demonstrated that bradykinin (BK) treatment simultaneously induces neuronal enrichment (indicating that BK contributes to neurogenesis) and reduced proliferation rates during in vitro differentiation of rat embryonic telencephalon neural precursor cells (NPCs). Here, we provide a mechanism for the unresolved question whether (i) the low rate of proliferation is owed to enhanced neurogenesis or, conversely, (ii) the alteration of the population ratio could result from low proliferation of NPCs and glial cells. In agreement with the previous study, BK promoted neuron-specific β3-tubulin and MAP2 expression in differentiating embryonic mouse neurospheres, whereas glial protein expression and global proliferation rates decreased. Furthermore, BK augmented the global frequency of cells in G0 -phase of cell cycle after differentiation. Heterogeneous cell populations were observed at this stage, including neurons that always remaining a quiescent state (G0 -phase). It is noteworthy that BK did not interfere with proliferation of any particular cell type, evidenced by coimmunostaining for nestin, β3-tubulin, glial fibrillary acidic protein (GFAP), and 5-ethynyl-2'-deoxyuridine (EdU). Thus, we conclude that neuronal enrichment is owing only to the fostering of neurogenesis, and that the low proliferation rate on the seventh day of differentiation is a consequence and not the cause of BK-induced neuronal enrichment. © 2015 International Society for Advancement of Cytometry. © 2015 International Society for Advancement of Cytometry.
    Cytometry Part A 07/2015; DOI:10.1002/cyto.a.22705 · 3.07 Impact Factor
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    ABSTRACT: Phototaxis in flagellated zoospores of the aquatic fungus Blastocladiella emersonii depends on a novel photosensor BeGC1 comprised by a type I (microbial) rhodopsin fused to a guanylyl cyclase catalytic domain that produces the conserved second messenger cGMP. The rapid and transient increase in cGMP levels during zoospore exposure to green light was shown to be necessary for phototaxis and dependent on both, rhodopsin function and guanylyl cyclase activity. Noteworthy, BeGC1 was localized to the zoospore eyespot apparatus, consistent with its role in the phototactic response. A putative cyclic nucleotide gated channel (BeCNG1) was also identified in the genome of the fungus and implicated in flagellar beating via the action of a specific inhibitor (L-cis-diltiazem) that compromised zoospore motility. Here we show that B.emersonii expresses a K(+) channel that is activated by cGMP. The use of specific channel inhibitors confirmed the activation of the channel by cGMP and its K(+) selectivity. These characteristics are consistent with the function of an ion channel encoded by the BeCNG1 gene. Other blastocladiomycete fungi, such as Allomyces macrogynus and Catenaria anguillulae, possess genes encoding a similar K(+) channel, as well as the rhodopsin-guanylyl cyclase fusion protein, while both of these genes are absent in non-flagellated fungi. The presence of these genes as a pair seems to be exclusive of blastocladiomycete fungi. Taken together, these data demonstrate that B. emersonii cGMP-activated K(+) channel is involved in the control of zoospore motility, most probably participating in the cGMP-signaling pathway for the phototactic response of the fungus. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Eukaryotic Cell 07/2015; DOI:10.1128/EC.00087-15 · 3.18 Impact Factor
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    ABSTRACT: The central and peripheral nervous system is built by a network of many different neuronal phenotypes together with glial and other supporting cells. The repertoire of expressed receptors and secreted neurotransmitters and neuromodulators are unique for each single neuron leading to intracellular signaling cascades, many of them involving intracellular calcium signaling. Here we suggest the use of calcium signaling analysis upon specific agonist application to reliably identify neuronal phenotypes, being important not only for basic science, but also providing a reliable tool for functional characterization of cells prior to transplantation. Calcium imaging provides various cellular information including signaling amplitudes, cell localization, duration, and frequency. Microfluorimetry reveals a signal summarizing the entire population, and its use is indicated for high-throughput screening purposes.
    Methods in molecular biology (Clifton, N.J.) 07/2015; DOI:10.1007/7651_2015_271 · 1.29 Impact Factor
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    Dataset: bi101789y
    Arquimedes Cheffer · Henning Ulrich
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    Dataset: bi101789y
    Arquimedes Cheffer · Henning Ulrich
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    Dataset: bi101789y
    Arquimedes Cheffer · Henning Ulrich
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    ABSTRACT: Extracellular vesicles (EVs), including exosomes, microvesicles and apoptotic bodies, participate in intercellular communication, and particularly, in paracrine and endocrine signalling. The EVs and their specific contents have been considered hallmarks of different diseases. It has been recently discovered that EVs can co-transport nucleic acids such as DNAs, ribosomal RNAs, circular RNAs (circRNAs), long noncoding RNAs (lnRNAs) and microRNAs (miRNAs). miRNAs are important regulators of gene expression at the post-transcriptional level, although they may also play other roles. Recent evidence supports the hypothesis that miRNAs can activate Toll-like receptors (TLRs) under certain circumstances. TLRs belong to a multigene family of immune system receptors and have been recently described in the nervous system. In the immune system, TLRs are important for the recognition of the invading microorganisms, whereas in the nervous system, they recognise endogenous ligands released by undifferentiated or necrotic/injured cells. In the neuronal disease field, TLRs activity has been associated with amyotrophic lateral sclerosis (ALS), stroke, Alzheimer's and Parkinson's disease. Herein, we reviewed the current knowledge of the relationship between miRNA release by EVs and the inflammation signalling triggered by TLRs in neighbouring cells or during long-distance cell-to-cell communication. We highlight novel aspects of this communication mechanism, offering a valuable insight into such pathways in health and disease.
    Molecular Neurobiology 04/2015; DOI:10.1007/s12035-015-9142-1 · 5.29 Impact Factor
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    ABSTRACT: The kallikrein‐kinin system (KKS) is an endogenous pathway involved in many biological processes. Although primarily related to blood pressure control and inflammation, its activation goes beyond these effects. Neurogenesis and neuroprotection might be stimulated by bradykinin being of great interest for clinical applications following brain injury. This peptide is also an important player in spinal cord injury pathophysiology and recovery, in which bradykinin receptor blockers represent substantial therapeutic potential. Here, we highlight the participation of kinin receptors and especially bradykinin in mediating ischemia pathophysiology in the central and peripheral nervous systems. Moreover, we explore the recent advances on mechanistic and therapeutic targets for biological, pathological, and neural repair processes involving kinins.
    Cell Transplantation 03/2015; 24(4). DOI:10.3727/096368915X687778 · 3.57 Impact Factor
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    ABSTRACT: Acetylcholinesterase (AChE) inhibition has been described as the main mechanism of organophosphate (OP)-evoked toxicity. OPs represent a human health threat, because chronic exposure to low doses can damage the developing brain, and acute exposure can produce long-lasting damage to adult brains, despite post-exposure medical countermeasures. Although the main mechanism of OP toxicity is AChE inhibition, several lines of evidence suggest that OPs also act by other mechanisms. We hypothesized that rat neural progenitor cells extracted on embryonic day 14.5 would be affected by constant inhibition of AChE from chronic exposure to OP or pyridostigmine (a reversible AChE blocker) during differentiation. In this work, the OP paraoxon decreased cell viability in concentrations >50 μM, as measured with the MTT assay; however, this effect was not dose-dependent. Reduced viability could not be attributed to blockade of AChE activity, since treatment with 200 µM pyridostigmine did not affect cell viability, even after 6 days. Although changes in protein expression patterns were noted in both treatments, the distribution of differentiated phenotypes, such as the percentages of neurons and glial cells, was not altered, as determined by flow cytometry. Since paraoxon and pyridostigmine each decreased neurite outgrowth (but did not prevent differentiation), we infer that developmental patterns may have been affected.
    Neurochemical Research 03/2015; DOI:10.1007/s11064-015-1548-7 · 2.55 Impact Factor
  • Henning Ulrich · Peter Illes
    Neural Regeneration Research 12/2014; 9(23):2040-1. DOI:10.4103/1673-5374.147925 · 0.23 Impact Factor
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    ABSTRACT: CONTENTS 1. Introduction 1 1.1. Brain tumor glioblastoma multiforme (GBM) 1 1.2. Cancer stem cell (CSC) paradigm 2 1.3. GBM stem-like cells (GSCs) 4 2. Isolation methodologies of GSCs 4 2.1. SP and ABC transporters 5 2.2. Isolation based on biomarkers 5 2.2.1. CD133 5 2.2.2. ALDH 5 2.2.3. Aptamers 5 3. Enrichment of GSC cultures 6 3.1. Effects of medium and substrates 6 3.2. Effects of hypoxia 7 3.3. Effects of endothelial cells 8 3.4. Effects of pericyte cells 9 3.5. Effects of immunosuppressed animals 9 4. Validation of the GSC phenotype 10 4.1. Sphere-formation assay 10 4.2. Tumor formation in vivo 10 4.3. Expression of biomarkers 11 4.4. Chemoresistance assay 11 4.5. Differentiation assay 12 5. Conclusions 12 Acknowledgments 13 References 13 Abstract: Glioblastoma (GBM) stem-like cells (GSCs) represent the most undifferentiated state of malignant cells with distinct biological characteristics. The fraction of these cells within a glial brain tumor, ranging from 2–30%, is correlating with the increasing WHO stage and poor prognosis of patients' survival. GSCs represent the least vulnerable, thus most preferential target cell population to be exposed to various therapeutic modalities, although the underlying mechanisms of this resistance are not yet fully understood. For the development of GSC-targeting therapies, further in depth studies are needed using enriched and stable GSC cell populations. Here, we discuss the current approaches of GSC isolation and validation based on expression of stemness and oncogenic markers as well as on functional assays. The enrichment of GSC phenotypes in established cell lines and/or primary tumor cultures, achieved by different strategies, is reviewed, providing a comprehensive comparison of selected studies and contemplating the characterization of the plethora of variants of reported GBM population exhibiting the GSC phenotype. ABBREVIATIONS: Aldehyde dehydrogenase (ALDH) Brain tumor initiating cells (BTIC) Cancer stem cell (CSC) Epidermal growth factor (EGF) Epithelial to mesenchymal transition (EMT) Fibroblast growth factor (FGF) Glioblastoma multiforme (GBM) Glioblastoma stem-like cell (GSC) Iso-dehydrogenase 1 (IDH1) Neural progenitor cell (NPC) Neural stem cell (NSC) O-6-methylguanine-DNA-methyltransferase (MGMT) Temozolomide (TMZ)
    11/2014; 1(1). DOI:10.14343/JCSCR.2014.2e1007
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    ABSTRACT: Uric acid and purines (such as adenosine) regulate mood, sleep, activity, appetite, cognition, memory, convulsive threshold, social interaction, drive, and impulsivity. A link between purinergic dysfunction and mood disorders was first proposed a century ago. Interestingly, a recent nationwide population-based study showed elevated risk of gout in subjects with bipolar disorder (BD), and a recent meta-analysis and systematic review of placebo-controlled trials of adjuvant purinergic modulators confirmed their benefits in bipolar mania. Uric acid may modulate energy and activity levels, with higher levels associated with higher energy and BD spectrum. Several recent genetic studies suggest that the purinergic system - particularly the modulation of P1 and P2 receptor subtypes - plays a role in mood disorders, lending credence to this model. Nucleotide concentrations can be measured using brain spectroscopy, and ligands for in vivo positron emission tomography (PET) imaging of adenosine (P1) receptors have been developed, thus allowing potential target engagement studies. This review discusses the key role of the purinergic system in the pathophysiology of mood disorders. Focusing on this promising therapeutic target may lead to the development of therapies with antidepressant, mood stabilization, and cognitive effects.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 11/2014; PMID: 25445063. DOI:10.1016/j.pnpbp.2014.10.016 · 4.03 Impact Factor
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    ABSTRACT: Prevention of Graft-versus-Host-Disease (GvHD) by preserved Graft-versus-Leukaemia (GvL) effect is one of the major obstacles following allogeneic haematopoietic stem cell transplantation. Currently used drugs are associated with side effects and were not able to separate GvHD from the GvL-effect because of general T-cell suppression. This review focuses on murine models for GvHD and currently available treatment options involving antibodies and applications for the therapeutic use of aptamers as well as strategies for targeting immune responses by allogenic antigens.
    Journal of Cellular and Molecular Medicine 10/2014; 19(1). DOI:10.1111/jcmm.12416 · 3.70 Impact Factor

Publication Stats

2k Citations
361.28 Total Impact Points

Institutions

  • 2003–2015
    • University of São Paulo
      • Department of Biochemistry (IQ)
      San Paulo, São Paulo, Brazil
  • 2014
    • University of Texas Health Science Center at Houston
      • Center for Membrane Biology
      Houston, Texas, United States
  • 2006
    • University of Toronto
      Toronto, Ontario, Canada
  • 2001
    • University of Leipzig
      • Translational Centre for Regenerative Medicine (TRM)
      Leipzig, Saxony, Germany
  • 1998–2001
    • Cornell University
      • Department of Molecular Biology and Genetics
      Ithaca, New York, United States
    • Zentrum für Molekulare Neurobiologie Hamburg
      Hamburg, Hamburg, Germany
  • 1996
    • University of Hamburg
      • Center for Molecular Neurobiology (ZMNH)
      Hamburg, Hamburg, Germany