Podcasts about hmgb1

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.06.527377v1?rss=1 Authors: Yin, Z., Wu, L., Zhang, Y., Sun, Y., Chen, J. W., Subudhi, S., Ho, W., Lee, G. Y., Wang, A., Gao, X., Ren, J., Zhu, C., Zhang, N., Ferraro, G. B., Muzikansky, A., Zhang, L., Stemmer-Rachamimov, A., Mao, J., Plotkin, S. R., Xu, L. Abstract: Patients with Schwannomatosis (SWN) overwhelmingly present with intractable, debilitating chronic pain. There are no effective therapies to treat SWN. The drivers of pain response and tumor progression in SWN are not clear. The pain is not proportionally linked to tumor size and is not always relieved by tumor resection, suggesting that mechanisms other than mechanical nerve compression exist to cause pain. SWN research is limited by the lack of clinically-relevant models. Here, we established novel patient-derived xenograft (PDX) models, dorsal root ganglia (DRG) imaging model, and combined with single-cell resolution intravital imaging and RNASeq, we discovered: i) schwannomas on the peripheral nerve cause macrophage influx into the DRG, via secreting HMGB1 to directly stimulate DRG neurons to express CCL2, the key macrophage chemokine, ii) once recruited, macrophages cause pain response via overproduction of IL-6, iii) IL-6 blockade in a therapeutic setting significantly reduces pain but has modest efficacy on tumor growth, iv) EGF signaling is a potential driver of schwannoma growth and escape mechanism from anti-IL6 treatment, and v) combined IL-6 and EGFR blockade simultaneously controlled pain and tumor growth in SWN models. Our findings prompted the initiation of phase II clinical trial (NCT05684692) for pain relief in patients with SWN. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

In this episode of the Epigenetics Podcast, we caught up with Akis Papantonis from the University Medical Center Göttingen to talk about his work on genome organisation mediated by RNA Polymerase II. The research of the Papantonis Laboratory focuses on investigating how environmental signalling stimuli are integrated by chromatin to control homeostatic to deregulated functional transitions. In more detail, the team is interested in how dynamic higher-order regulatory networks are influenced by the underlying linear DNA fiber. The ultimate goal of the laboratory is to understand general rules governing transcriptional and chromatin homeostasis and finally, how those rules might affect development, ageing or malignancies.   References Larkin, J. D., Cook, P. R., & Papantonis, A. (2012). Dynamic reconfiguration of long human genes during one transcription cycle. Molecular and cellular biology, 32(14), 2738–2747. https://doi.org/10.1128/MCB.00179-12 Diermeier, S., Kolovos, P., Heizinger, L., Schwartz, U., Georgomanolis, T., Zirkel, A., Wedemann, G., Grosveld, F., Knoch, T. A., Merkl, R., Cook, P. R., Längst, G., & Papantonis, A. (2014). TNFα signalling primes chromatin for NF-κB binding and induces rapid and widespread nucleosome repositioning. Genome biology, 15(12), 536. https://doi.org/10.1186/s13059-014-0536-6 Sofiadis, K., Josipovic, N., Nikolic, M., Kargapolova, Y., Übelmesser, N., Varamogianni-Mamatsi, V., Zirkel, A., Papadionysiou, I., Loughran, G., Keane, J., Michel, A., Gusmao, E. G., Becker, C., Altmüller, J., Georgomanolis, T., Mizi, A., & Papantonis, A. (2021). HMGB1 coordinates SASP-related chromatin folding and RNA homeostasis on the path to senescence. Molecular systems biology, 17(6), e9760. https://doi.org/10.15252/msb.20209760 Enhancer-promoter contact formation requires RNAPII and antagonizes loop extrusion. Shu Zhang, Nadine Übelmesser, Mariano Barbieri, Argyris Papantonis. bioRxiv 2022.07.04.498738; doi: https://doi.org/10.1101/2022.07.04.498738   Related Episodes Chromatin Organization During Development and Disease (Marieke Oudelaar) Biophysical Modeling of 3-D Genome Organization (Leonid Mirny) Hi-C and Three-Dimensional Genome Sequencing (Erez Lieberman Aiden)   Contact Epigenetics Podcast on Twitter Epigenetics Podcast on Instagram Epigenetics Podcast on Mastodon Active Motif on Twitter Active Motif on LinkedIn Email: podcast@activemotif.com

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.26.509535v1?rss=1 Authors: Uzay, B., Demir, B. D., Ozcan, S. Y., Kocak, E. E., Yemisci, M., Ozdemir, Y. G., Dalkara, T., Karatas, H. Abstract: Migraine is a neurological disorder characterized by episodes of severe headache. Cortical spreading depression (CSD), the electrophysiological equivalent of migraine aura, results in the opening of pannexin-1 megachannels that release ATP and triggers parenchymal neuroinflammatory signaling cascade in the cortex. Migraine symptoms suggesting subcortical dysfunction bring subcortical spread of CSD under the light. Here, we investigated the role of purinergic P2X7 receptors on the subcortical spread of CSD and its consequent neuroinflammation using a potent and selective P2X7 antagonist, JNJ-47965567. P2X7 antagonism had no effect on the CSD threshold and characteristics but increased the latency to hypothalamic voltage deflection following CSD showing that ATP acts as a mediator in the subcortical spread. P2X7 antagonism also prevented hypothalamic neuronal activation following CSD, revealed by bilateral decrease in hypothalamic c-fos positive neuron count. P2X7 antagonism further stopped the CSD-induced neuroinflammation revealed by decreased nuclear translocation of NF-kappa B-p65 in astrocytes and decreased HMGB1 release. Following CSD we observed an increase in neuronal cytoplasmic P2X7R signal in the cortex and subcortical structures (thalamus, hypothalamus, striatum, hippocampus) concordant with the neuroinflammation which is also prevented by P2X7R antagonism. In conclusion, our data suggest that P2X7R plays an imperative role in CSD-induced neuroinflammation, the subcortical spread of CSD, and CSD-induced hypothalamic neuronal activation hence can be a potential target in migraine treatment. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

In this week's episode we discuss the role of HEATR3 variants as a new cause of Diamond-Blackfan anemia, learn more about the long-term efficacy and safety of zanubrutinib in relapsed or refractory mantle cell lymphoma, and uncover an unexpected role for HMGB1 in anemia of inflammation by inhibiting erythropoietin signaling.

Aging-US published a Special Collection on Eye Disease which included "HMGB1 and Caveolin-1 related to RPE cell senescence in age-related macular degeneration" and reported that AMD is a major unmet medical need as it is estimated that more than 20 million patients will be affected by 2050 in the US alone. STGD is the most common hereditary macular dystrophy, mostly affecting young patients aged between 6 and 15 years old with a prevalence of 1/8,000-1/10,000. It is formed by the reaction of 2 all-trans retinal molecules with phosphatidylethanolamine generating N-retinylidene-PE, as a detoxication mechanism of retinal isomers including all-trans and 11-cis-retinal. Indeed, it has been shown that as early as in 3-month-old Abca4-/- Rdh8-/- mice, the amplitudes of scotopic A and B waves and flicker ERG are reduced. Dr. Jin Yang and Dr. Xiaorong Li both from The Tianjin Medical University Eye Hospital said, "Age-related macular degeneration (AMD) is the leading cause of vision loss in older adults worldwide." AMD can be classified into early-stage or late-stage AMD. The latter is characterized by neovascularization, geographic atrophy, or both. Conversely, early-stage AMD is characterized by a limited amount of drusen, which is mainly caused by lipid and protein accumulation and thought to contribute to atrophic changes. As the disease progresses, neovascular changes or geographic atrophy involving the macular area can be present in patients for years. Therefore, the authors explored the relationship between dry AMD and RPE dysfunction and senescence using proteomic mass spectrometry to examine differential expression in induced pluripotent stem cell-derived RPE cell lines with and without A2E treatment. They have previously demonstrated that the iPSC-derived RPE is phenotypically and functionally similar to the native RPE. In addition, the young status of iPSC-RPE may provide an excellent means for observing changes in protein expression during the process of RPE cell aging. A2E photo-oxidation products can cause oxidative stress, membrane permeation, telomere dysfunction and accelerated RPE senescence. Although A2E is clearly present in the retina, there are rather different opinions regarding its distribution. Ablonczy et al. showed that levels of A2E decreased from the periphery to the centre region in aging tissue of macaques and humans but A2E was localized mainly in the centre region of young mouse retina. The Yang/Li Research Team concluded in their Aging-US Research Output, "upregulation of HMGB1 and Caveolin-1 caused RPE cell senescence and suppressed migration and invasion, and β-catenin and Zo-1 accumulation was enhanced by A2E in RPE cells. In particular, the results showed a change in expression of HMGB1 and Caveolin-1, which suggests that they are prime gatekeepers in RPE cell senescence. The above results indicate that stabilizing expression of HMGB1 and Caveolin-1 is a potential therapeutic target to prevent the progression of RPE cell senescence." Full Text - https://www.aging-us.com/article/102039/text Correspondence to: Jin Yang email: yangjinchina324@gmail.com and Xiaorong Li email: lixiaorong@tmu.edu.cn Keywords: A2E, HMGB1, Caveolin-1, RPE cell senescence, AMD About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research as well as topics beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, cancer, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR among others), and approaches to modulating these signaling pathways. To learn more about Aging-US, please visit http://www.Aging-US.com or connect with @AgingJrnl Aging-US is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact 18009220957x105 MEDIA@IMPACTJOURNALS.COM

Tendinopathy is a debilitating tendon disorder that affects millions of Americans and costs billions of health care dollars every year. High mobility group box 1 (HMGB1), a known tissue damage signaling molecule, has been identified as a mediator in the development of tendinopathy due to mechanical overloading of tendons in mice. Metformin (Met), a drug approved by the Food and Drug Administration used for the treatment of type 2 diabetes, specifically inhibits HMGB1. This study tested the hypothesis that Met would prevent mechanical overloading-induced tendinopathy in a mouse model of tendinopathy created by intensive treadmill running (ITR). In conclusion, inhibition of HMGB1 by injections of Met prevented tendinopathy development due to mechanical overloading in the Achilles tendon in mice.   To view the article click here.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.25.266361v1?rss=1 Authors: De Leo, F., Giacomo, Q., De Marchis, F., Malisa, M. V., Bianchi, M. E., Musco, G. Abstract: HMGB1 is a key molecule that both triggers and sustains inflammation following infection or injury, and is involved in a large number of pathologies, including cancer. HMGB1 participates to the recruitment of inflammatory cells forming a heterocomplex with the chemokine CXCL12 (HMGB1/CXCL12), herewith activating the G-protein coupled receptor CXCR4. Thus, identification of molecules that disrupt this heterocomplex can offer novel pharmacological opportunities to treat inflammation related diseases. To identify new HMGB1/CXCL12 inhibitors we have performed a study on the ligandability of the single HMG boxes of HMGB1 followed by a virtual screening campaign on both HMG boxes using Zbc Drugs and three different docking programs (Glide, AutoDock Vina, AutoDock 4.2.6). The best poses in terms of scoring functions, visual inspection and predicted ADME properties were further filtered according to a pharmacophore model based on known HMGB1 binders and clustered according to their structures. Eight compounds representative of the clusters were tested for HMGB1 binding by NMR. We identified 5,5' methylenedi-2,3-cresotic acid (2a) as binder of both HMGB1 and CXCL12; 2a also targets the HMGB1/CXCL12 heterocomplex. In cell migration assays 2a inhibited the chemotactic activity of HMGB1/CXCL12 with IC50 in the subnanomolar range, the best documented up to now. These results pave the way for future structure activity relationship studies to optimize the pharmacological targeting of HMGB1/CXCL12 for anti-inflammatory purposes. Copy rights belong to original authors. Visit the link for more info

In this episode of the JSOM Podcast, Alex reviews the Combat Medics' Aid Bag Inventory by Schauer, et. al.; Josh breaks down a basic science article about biomarkers in evacuated patients and Rick Hines from the JSOMTC opines about freeze dried plasma by Cuenca, et. al. in our guest review. In addition, Dr. Jae Choi and Dr. Andriy Batchinsky provide in-depth information on their research into HMGB1 proteins. Visit our Social Media @jsomonline. https://jsom.us/Podcast.

Thu, 30 Jul 2015 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/18542/ https://edoc.ub.uni-muenchen.de/18542/1/Hoehne_Christopher_Ludwig.pdf Hoehne, Christopher Ludwig dd

In der hier vorliegenden Arbeit wurden die Interaktionen von Thrombozyten und myeloiden Zellen im intravaskulären und interstitiellen Raum in vivo bei steriler Inflammation untersucht. Diese Analysen fanden mittels intravitaler 2-Photonen Mikroskopie im Mausmodell statt. Im Ohrmodell wurde mit Hilfe eines Lasers eine Gewebsverletzung gesetzt, die eine sterile Entzündung erzeugt. In den postkapillären Venolen konnte gezeigt werden, dass durch den Laserstimulus eine Rekrutierung und enge Interaktion zwischen Plättchen, neutrophilen Granulozyten und Monozyten/Makrophagen ausgelöst wird. Innerhalb der postkapillären Venolen fördern kurzzeitige Kontakte zwischen Thrombozyten und myeloiden Leukozyten die Transmigration und Aktivierung der neutrophilen Granulozyten und der Monozyten. Die beiden letzteren Zellpopulationen des angeborenen Immunsystems beeinflussen sich auch gegenseitig und treten an bestimmten Stellen bevorzugt ins Gewebe über. Innerhalb des interstitiellen Gewebes konnten Bereiche definiert werden, in denen unterschiedliche Leukozytenmigrationsmuster, abhängig von der Entfernung zur Verletzung, stattfanden. Diese verschiedenen Bewegungsmuster zeigen sich auch auf zellulärer und molekularer Ebene. Die myeloiden Zellen wiesen in dem entfernteren Bereich um die Verletzung eine zielgerichtetere Bewegung auf als in direkter Umgebung zur Nekrose. Dort zeigte sich eine ungerichtete Migration auf die Verletzung hin. Dies ist auch durch die Fraktalkin- Freisetzung der Fibroblasten beeinflusst, die Monozyten im Bereich der postkapillären Venolen zurück halten. Außerdem zeigte sich ein Einfluss des Danger- associated molecular patterns HMGB1 auf die Monozyten/Makrophagen, welches direkt um die Nekrosezone freigesetzt wird. Zudem setzen neutrophile Granulozyten Faktoren frei, die eine essentielle Rolle spielen für die Migration der Monozyten/ Makrophagen. Gewebsmakrophagen treten im interstitiellen Raum in Kontakt mit migrierenden neutrophilen Granulozyten und schwächen deren Reaktion. Dabei kommt es jedoch zu einer Aktivierung des Gewebsmakrophagen, die nach mehreren Kontakten mit neutrophilen Granulozyten beginnen sich zu bewegen. In dieser Arbeit konnten mehrere Interaktionen zwischen Thrombozyten, neutrophilen Granulozyten und Monozyten/ Makrophagen während einer sterilen Entzündung entdeckt werden, die zu neuen Therapieansätzen für Krankheiten wie Trauma, Schlaganfall und Herzinfarkt führen könnten.

The cell type-, organ-, and species-specific expression of the Toll-like receptors (TLRs) are well described, but little is known about the respective expression profiles of their accessory molecules. We therefore determined the mRNA expression levels of LBP, MD2, CD36, CD14, granulin, HMGB1, LL37, GRP94, UNC93b1, TRIL, PRAT4A, AP3B1, AEP and the respective TLRs in human and mouse solid organs. Humans and mice displayed significant differences between their respective mRNA expression patterns of these factors. In addition, the expression profiles in transient tissue inflammation upon renal ischemia-reperfusion injury, in spleens and kidneys from mice with lupus-like systemic autoimmunity, and in progressive tissue fibrosis upon unilateral ureteral obstruction were studied. Several TLR co-factors were specifically regulated during the different phases of these disease entities, suggesting a functional involvement in the disease process. Thus, the organ-and species-specific expression patterns need to be considered in the design and interpretation of studies related to TLR-mediated innate immunity, which seems to be involved in the tissue injury phase, in the phase of tissue regeneration, and in progressive tissue remodelling.

Immunogene Zelltodmarker sind eine inhomogene Gruppe von Molekülen, die während Zelltodprozessen wie Apoptose, Nekrose oder weiteren Formen freigesetzt werden. Je nach Zusammensetzung des extrazellulären Milieus können diese „Danger associated molecular patterns“ (DAMPs) wie das „High mobility group box 1“ (HMGB1) Protein das Immunsystem stimulierend oder inhibierend beeinflussen. Bei Tumorerkrankungen scheint eine kontinuierliche Freisetzung von HMGB1, u.a. über eine Vermittlung durch den zellulären Bindungspartner „Receptor of advanced glycation end products“ (RAGE), zu einer Förderung des Tumorwachstums zu führen, während die pulsatile Freisetzung während zytotoxischer Therapie zu einer verbesserten antitumorösen Immunantwort beitragen könnte. Lösliches RAGE (sRAGE) kann hingegen die Effekte von extrazellulärem HMGB1 abpuffern. In diesem Review werden die strukturellen und funktionalen Charakteristika dieser immunogenen Zelltodmarker sowie ihre Rolle in der Pathophysiologie von nicht-malignen und malignen Erkrankungen vorgestellt; sodann wird ihre Relevanz als Serum-Biomarker für die Diagnose, die Prognoseabschätzung, die Prädiktion und das Monitoring des Ansprechens einer zytotoxischen Therapie bei Tumorpatienten beleuchtet. Bei Patienten mit verschiedenen Tumorerkrankungen wurden im Vergleich zu gesunden Personen erhöhte Serumkonzentrationen von HMGB1 und niedrigere sRAGE-Werte gefunden. Zudem waren hohe HMGB1- und niedrige sRAGE-Serumwerte vor und während einer zytotoxischen Therapie mit einem unzureichenden Ansprechen auf die Behandlung und einem kürzeren Überleben assoziiert. Diese Ergebnisse weisen die immunogenen Zelltodmarker HMGB1 und sRAGE als neue, vielversprechende Biomarker zur Abschätzung der Prognose, Stratifikation der Patienten und zum Therapiemonitoring bei Tumorpatienten aus.

Maurizio Capogrossi, Istituto Dermopatico della Immacolata, IDI, Patologia Vascolare, Rome, ITALY speaks on "HMGB1 and left ventricular remodeling after infarction". This seminar has been recorded by ICGEB Trieste

Maurizio Capogrossi, Istituto Dermopatico della Immacolata, IDI, Patologia Vascolare, Rome, ITALY speaks on "HMGB1 and left ventricular remodeling after infarction". This seminar has been recorded by ICGEB Trieste

Trotz des Einsatzes verschiedenster sehr potenter Antibiotika und Antiphlogistika in Verbindung mit einer ausgereiften Intensivmedizinischen Betreuung ist die Sepsis sowohl in der Human- als auch in der Tiermedizin heute immer noch eine der häufigsten Todesursachen. Die Immunpathogenese der Erkrankung ist gekennzeichnet durch eine systemische Entzündungsreaktion, hervorgerufen durch eine frühe Sekretion des Zytokins Tumor Nekrose Faktor alpha (TNFα). Im Vergleich zu TNFα gilt dagegen das erst kürzlich entdeckte Zytokin High Mobility Group Box 1 (HMGB1) als später proinflammatorischer Faktor. Um nun die Rolle dieser beiden Zytokine in der caninen Sepsis näher zu untersuchen, wurden neue sensitive Nachweismethoden etabliert und zusätzlich zwei bereits kommerziell erhältliche Substanzen aus der Humanmedizin zur Neutralisation von caninem TNFα in vitro getestet. Anhand bereits publizierter Sequenzen und mit Hilfe der Ensembl Datenbank konnten per PCR die Sequenzen für canines TNFα, TNFR1 (P60), HMGB1 und dessen Rezeptor RAGE kloniert und die Proteine rekombinant exprimiert werden. Die Bioaktivität und die Konzentration des rcanTNFα wurden in einem Zytotoxizitäts Assay mit der Zelllinie WEHI164 getestet. Die Bioaktivität des P60-Fc Fusionsproteins wurde durch seine neutralisierende Wirkung auf das zytotoxische rcanTNFα im gleichen Assay nachgewiesen. Mit Hilfe des P60-Fc Fusionsproteins und einem kommerziellen biotinylierten Ziege-anti-Hund TNFα Antikörper konnte ein entsprechender sensitiver ELISA aufgebaut werden. Gleichzeitig wurden ebenfalls im WEHI-Bioassay die zwei humanen anti-TNFα Therapeutika Infliximab und Ethanercept auf ihre Eigenschaft zur Bindung und Neutralisation von caninem TNFα hin getestet Nur Ethanercept konnte dabei das Zytokin binden und neutralisieren. Anschließend wurden Plasmaproben von 79 klinisch an Sepsis erkrankten Hunden analysiert und im TNFα ELISA quantifiziert. Keine der untersuchten Proben wies dabei jedoch einen erhöhten Spiegel an TNFα im Plasma auf. Aus diesem Grund wurden nun auch mit Hilfe zweier polyklonaler Seren gegen rcanHMGB1 und gegen eine spezifische Peptidsequenz des Zytokins ein Western Blot Verfahren und ein Capture ELISA für die Messung von HMGB1 aufgebaut. HMGB1 konnte dabei allerdings sowohl bei gesunden als auch bei sepsiskranken Hunden in vergleichbaren Mengen nachgewiesen werden.

In eukaryotic nuclei, the DNA double helix is wound up and condensed into chromatin through the interaction with histones and further proteins. Several factors regulate the chromatin structure, allow unfolding or condensation of the chromatin fibre and permit or restrict access to DNA. One prominent class of chromosomal regulators is represented by ATP-dependent chromatin remodelling complexes, which use the energy derived from ATPhydrolysis to break or alter histone-DNA contacts. The ATP-utilising Chromatin Assembly and Remodelling Factor (ACF) and the Chromatin Accessibility Complex (CHRAC) are two closely related ATP-dependent chromatin remodelling factors. ACF consists of the ATPase ISWI and ACF1, a large protein that influences both the quality and efficiency of ISWI activity. CHRAC contains ISWI and ACF1 as well, but in addition the two small histone fold proteins CHRAC14 and CHRAC16. In this work, the CHRAC14 and CHRAC16 subunits are characterised both structurally and functionally. The generation of a bicistronic expression plasmid allowed the expression and purification of highly pure recombinant CHRAC14-CHRAC16 in stoichiometric amounts. The crystal structure of the CHRAC14-CHRAC16 complex was solved at a resolution of 2.4 Å and demonstrates that the two proteins interact with each other via their histone fold motifs, thereby closely resembling the structure of histones H2A-H2B and NFYB-NFYC, the histone fold subunits of nuclear factor Y (NF-Y). Rat monoclonal antibodies against CHRAC14 and CHRAC16 were raised and characterised, but due to their poor affinity, they turned out to be only of limited use for the analysis of the two proteins. CHRAC14-CHRAC16 interact with the N-terminus of ACF1, including the conserved WAC motif. They have a weak affinity for DNA, and studies with CHRAC14-CHRAC16 deletion variants revealed that their C-termini play important but distinct roles in DNA binding. Finally, CHRAC14-CHRAC16 facilitate ACF-dependent nucleosome mobilisation, and their ability to enhance ACF activity depends on both the interaction with the ACF1 N-terminus and the dynamic binding to DNA. In the light of profound similarities to the effects of HMGB1 (high mobility group box protein 1) on nucleosome sliding, these data imply that the CHRAC14-CHRAC16 subcomplex operates as a ‘DNA chaperone’ and assists ACF1 and ISWI during ATPdependent nucleosome remodelling by providing a transient DNA binding surface. This work provides the basis for further experiments to gain more insights into the mechanistic details of CHRAC-dependent nucleosome remodelling and to explore the roles of CHRAC in the living cell.