Blockade of high mobility group box 1 involved in the protective of curcumin on myocardial injury in diabetes in vivo and in vitro

IUBMB Life ◽  
2020 ◽  
Vol 72 (5) ◽  
pp. 931-941 ◽  
Author(s):  
Xueyun Yan ◽  
Peier Xu ◽  
Le Zhou ◽  
Jinyue Lu ◽  
Haihua Tang ◽  
...  
Keyword(s):  
Myocardial Injury ◽  
High Mobility ◽  
High Mobility Group

scholarly journals Defective Calmodulin-Mediated Nuclear Transport of the Sex-Determining Region of the Y Chromosome (SRY) in XY Sex Reversal

2005 ◽  
Vol 19 (7) ◽  
pp. 1884-1892 ◽  
Author(s):  
Helena Sim ◽  
Kieran Rimmer ◽  
Sabine Kelly ◽  
Louisa M. Ludbrook ◽  
Andrew H. A. Clayton ◽  
...  
Keyword(s):  
Y Chromosome ◽  
Nuclear Import ◽  
High Mobility ◽  
Sex Reversal ◽  
High Mobility Group ◽  
Missense Mutations ◽  
Nuclear Localization Signals ◽  
Xy Sex Reversal

Abstract The sex-determining region of the Y chromosome (SRY) plays a key role in human sex determination, as mutations in SRY can cause XY sex reversal. Although some SRY missense mutations affect DNA binding and bending activities, it is unclear how others contribute to disease. The high mobility group domain of SRY has two nuclear localization signals (NLS). Sex-reversing mutations in the NLSs affect nuclear import in some patients, associated with defective importin-β binding to the C-terminal NLS (c-NLS), whereas in others, importin-β recognition is normal, suggesting the existence of an importin-β-independent nuclear import pathway. The SRY N-terminal NLS (n-NLS) binds calmodulin (CaM) in vitro, and here we show that this protein interaction is reduced in vivo by calmidazolium, a CaM antagonist. In calmidazolium-treated cells, the dramatic reduction in nuclear entry of SRY and an SRY-c-NLS mutant was not observed for two SRY-n-NLS mutants. Fluorescence spectroscopy studies reveal an unusual conformation of SRY.CaM complexes formed by the two n-NLS mutants. Thus, CaM may be involved directly in SRY nuclear import during gonadal development, and disruption of SRY.CaM recognition could underlie XY sex reversal. Given that the CaM-binding region of SRY is well-conserved among high mobility group box proteins, CaM-dependent nuclear import may underlie additional disease states.

scholarly journals Induction of high-mobility group Box-1 in vitro and in vivo by respiratory syncytial virus

2018 ◽  
Vol 83 (5) ◽  
pp. 1049-1056 ◽  
Author(s):  
Sara Manti ◽  
Terri J Harford ◽  
Carmelo Salpietro ◽  
Fariba Rezaee ◽  
Giovanni Piedimonte
Keyword(s):  
Respiratory Syncytial Virus ◽  
High Mobility ◽  
High Mobility Group ◽  
Syncytial Virus

Levobupivacaine inhibits lipopolysaccharide-induced high mobility group box 1 release in vitro and in vivo

2014 ◽  
Vol 192 (2) ◽  
pp. 582-591 ◽  
Author(s):  
Yunfen Ge ◽  
Shuangfei Hu ◽  
Yunlong Zhang ◽  
Wenyuan Wang ◽  
Qiong Xu ◽  
...  
Keyword(s):  
High Mobility ◽  
High Mobility Group ◽  
Release In Vitro

scholarly journals High mobility group box 1 promotes endothelial cell angiogenic behavior in vitro and improves muscle perfusion in vivo in response to ischemic injury

2012 ◽  
Vol 55 (1) ◽  
pp. 180-191 ◽  
Author(s):  
Ulka Sachdev ◽  
Xiangdong Cui ◽  
Guiying Hong ◽  
Seung Namkoong ◽  
Jenny M. Karlsson ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
High Mobility ◽  
Ischemic Injury ◽  
High Mobility Group ◽  
Muscle Perfusion

scholarly journals High Mobility Group A1 (HMGA1) Epigenetic Regulators Induce ETV5 Networks in Relapsed B-Cell Leukemia and Provide Novel Therapeutic Targets

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 707-707
Author(s):  
Jung-Hyun Kim ◽  
Liping Li ◽  
Zixin Zhang ◽  
Katharina Hayer ◽  
Lingling Xian ◽  
...  
Keyword(s):  
Stem Cells ◽  
Gene Silencing ◽  
B Cell ◽  
Cell Lines ◽  
High Mobility ◽  
High Mobility Group ◽  
Transcriptional Networks ◽  
Hmga1 Expression

Abstract Introduction: Despite advances in therapy for B-cell acute lymphoblastic leukemia (B-ALL), relapsed disease remains the leading cause of death in children with cancer. The gene encoding the High Mobility Group A1 (HMGA1) chromatin regulator is highly expressed in stem cells and diverse malignancies where high levels portend poor outcomes. We discovered that transgenic mice misexpressing Hmga1 in lymphoid cells develop leukemic transformation by amplifying transcriptional networks involved in stem cell function, proliferation, and inflammation (Hillion et al, Cancer Res 2008, Schuldenfrei et al, BMC Genomics 2011, Xian et al, Nature Commun 2017). In pediatric B-ALL (pB-ALL), HMGA1 is overexpressed with highest levels in blasts from early relapse (Roy et al, Leuk Lymphoma 2013). Together, these findings suggest that HMGA1 is required for leukemogenesis and drives relapse through epigenetic reprogramming. We therefore sought to: 1) test the hypothesis that HMGA1 is required for leukemogenesis and relapse in pB-ALL, and, 2) elucidate targetable mechanisms mediated by HMGA1. Methods: To elucidate the function of HMGA1 and downstream targets, we employed CRISPR/Cas9 gene inactivation and lentiviral-mediated gene silencing via delivery of short hairpin RNA (shRNA) targeting 2 sequences per gene in cell lines from relapsed pB-ALL, including REH, which harbor the TEL-AML1 fusion, and 697, which harbor the E2A-PBX1 fusion. We assessed leukemia phenotypes in vitro and leukemic engraftment in vivo. To dissect molecular mechanisms, we performed RNA sequencing (RNAseq) and applied in silico pathway analysis. To validate these pathways in human pB-ALL, we assessed gene expression and clinical outcomes in independent cohorts. The Broad Institute Connectivity Map (CMAP) was applied to identify drugs to target HMGA1 networks. Results: HMGA1 is overexpressed in pB-ALL in independent cohorts with highest levels at relapse. Decreasing HMGA1 expression via CRISPR/Cas9 inactivation or shRNA-mediated gene silencing in relapsed pB-ALL cell lines (REH, 697) disrupts proliferation, decreases the frequency of cells in S phase concurrent with increases in G0/G1, enhances apoptosis, and impairs clonogenicity. To assess HMGA1 function in vivo, we compared leukemogenesis following tail vein injection of pB-ALL cell lines with or without HMGA1 depletion in immunodeficient mice (NOD/SCID/IL2 receptor gamma null). Survival was prolonged in mice injected with either pB-ALL cell line (REH, 697) after HMGA1 depletion. Further, leukemic cells that ultimately engraft show increased HMGA1 expression relative to the pool of injected cells with HMGA1 silencing, suggesting that escape from HMGA1 silencing was required for engraftment. RNAseq revealed transcriptional networks governed by HMGA1 that regulate proliferation (G2M checkpoint, E2F), RAS/ERK signaling, hematopoietic stem cells, and ETV5 (ETS variant 5 transcription factor) targets. Given its association with aggressive ALL harboring the BCR-ABL fusion, we focused on the ETV5 gene. CRISPR/Cas9 inactivation or gene silencing of ETV5 in relapsed pB-ALL cell lines (REH, 697) decreases proliferation and clonogenicity in vitro, while delaying leukemogenesis in vivo. Further, restoring ETV5 expression in pB-ALL cell lines with HMGA1 silencing partially rescues anti-leukemogenic effects of HMGA1 depletion. Mechanistically, HMGA1 binds to AT-rich regions within the ETV5 promoter (-0.7 kb and -0.2 kb) and recruits active histone marks (H3K27Ac, H3K4me3, H3K4me1) to induce ETV5. Epigenetic drugs predicted to target HMGA1-ETV5 networks synergize with HMGA1 silencing in cytotoxicity assays with pB-ALL cell lines. Most importantly, HMGA1 and ETV5 are co-expressed and up-regulated in primary blasts from children with pB-ALL with highest levels at relapse, thus underscoring the significance of this pathway in relapsed pediatric B-ALL. Conclusions: We discovered a previously unknown epigenetic program whereby HMGA1 up-regulates ETV5 networks by binding to chromatin and recruiting active histone marks to the ETV5 promoter. Both HMGA1 and ETV5 are up-regulated at relapse. Finally, the HMGA1-ETV5 axis can be targeted by epigenetic drugs (HDAC inhibitors) that synergize with HMGA1 depletion. Our findings reveal the HMGA1-ETV5 axis as a key molecular switch in relapsed pB-ALL and rational therapeutic target to treat or prevent relapse. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Indirect regulation of HMGB1 release by gasdermin D

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Allen Volchuk ◽  
Anna Ye ◽  
Leon Chi ◽  
Benjamin E. Steinberg ◽  
Neil M. Goldenberg
Keyword(s):  
Bone Marrow ◽  
Knockout Mice ◽  
Extracellular Space ◽  
High Mobility ◽  
High Mobility Group ◽  
Inflammasome Activation ◽  
Inflammatory Stimuli ◽  
Lps Treatment

Abstract The protein high-mobility group box 1 (HMGB1) is released into the extracellular space in response to many inflammatory stimuli, where it is a potent signaling molecule. Although research has focused on downstream HMGB1 signaling, the means by which HMGB1 exits the cell is controversial. Here we demonstrate that HMGB1 is not released from bone marrow-derived macrophages (BMDM) after lipopolysaccharide (LPS) treatment. We also explore whether HMGB1 is released via the pore-forming protein gasdermin D after inflammasome activation, as is the case for IL-1β. HMGB1 is only released under conditions that cause cell lysis (pyroptosis). When pyroptosis is prevented, HMGB1 is not released, despite inflammasome activation and IL-1β secretion. During endotoxemia, gasdermin D knockout mice secrete HMGB1 normally, yet secretion of IL-1β is completely blocked. Together, these data demonstrate that in vitro HMGB1 release after inflammasome activation occurs after cellular rupture, which is probably inflammasome-independent in vivo.

Protective Effect of Ginsenoside Rb1 Nanoparticles Against Contrast-Induced Nephropathy by Inhibiting High Mobility Group Box 1 Gene/Toll-Like Receptor 4/NF-κB Signaling Pathway

2021 ◽  
Vol 17 (10) ◽  
pp. 2085-2098
Author(s):  
Shuai Zhou ◽  
Shan Lu ◽  
Sen Guo ◽  
Luosha Zhao ◽  
Zhanying Han ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Protective Effect ◽  
High Mobility ◽  
High Mobility Group ◽  
Ginsenoside Rb1 ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Contrast Induced Nephropathy

With the progress made in the widespread application of interventional radiology procedures, there has been an increasing number of patients who suffer from cardiovascular diseases and go through imaging and interventional treatment with iodine contrast medium (ICM) year by year. In turn, there has been an increasing amount of concern over acute kidney injury (AKI) brought about by ICM. As evidenced by numerous studies, the initiation of inflammatory response plays a critical role in the development of ICM-induced AKI. Correspondingly, the strategy of targeting renal inflammatory response and cytokine release could provide an effective solution to mitigating the ICM-induced AKI. Moreover, Ginsenoside Rb1 (GRb1) constitutes one of the major active components of ginseng and features a wide range of vital biological functions. Judging from the research findings, GRb1 could impose antioxidant and anti-inflammatory effects on cardiovascular diseases, in addition to lung, liver and kidney diseases. However, reports on whether GRb1 could impose a protective effect against contrast-induced nephropathy (CIN) are absent. In this study, we have examined the therapeutic effects imposed by GRb1 as well as the potential molecular mechanism by establishing an in vivo and in vitro model of CIN. In addition, we have set up a mouse model of CIN through sequential intravenous injection of indomethacin, N(ω)-nitro-Larginine methyl ester (L-NAME), and iopromide. To further enhance the bioavailability of GRb1, we have encapsulated GRb1 with polyethylene glycol (PEG)/poly lactic-co-glycolic acid (PLGA) nanocarriers to generate GRb1 nanoparticles (NPs) conducting the in vivo experiments. During the in vitro experiments, we have adopted GRb1 to treat NRK-52E cells or cells transfected with the high mobility group box 1 gene (HMGB1) overexpression plasmid. As shown by the in vivo experimental results, GRb1 NPs could evidently improve the renal dysfunction in CIN, diminish the extent of apoptosis of tubular epithelial cells, and reduce the expression of high mobility group box 1 (HMGB1) and cytokines (tumor necrosis factor (TNF-α), interleukin (IL) 6 and IL-1β). In addition, GRb1 NPs are found to be capable of preventing the activation of Toll-like receptor 4 (TLR4)/NF-κB signaling pathway triggered by contrast medium. The in vitro experimental results have exactly confirmed the findings of the in vivo experiments. In the meantime, through the observation of the in vitro assays, overexpression of HMGB1 can partially counteract the beneficial effects imposed by GRb1. Judging from our research data, GRb1 could impose a protective effect against CIN by inhibiting inflammatory response via HMGB1/TLR4/NF-κB pathway, whereas HMGB1 constitutes a critical molecular target of GRb1.

High-mobility group box-1 gene, a potent proinflammatory mediators, is upregulated in more degenerated human discs in vivo and its receptor upregulated by TNF-α exposure in vitro

2015 ◽  
Vol 98 (3) ◽  
pp. 427-430 ◽  
Author(s):  
Helen E. Gruber ◽  
Gretchen L. Hoelscher ◽  
Synthia Bethea ◽  
Jane Ingram ◽  
Michael Cox ◽  
...  
Keyword(s):  
High Mobility ◽  
High Mobility Group ◽  
Proinflammatory Mediators ◽  
Tnf Α
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