High mobility group box 1 (HMGB1)

Top PDF High mobility group box 1 (HMGB1):

Redox Modification of Cysteine Residues Regulates the Cytokine Activity of High Mobility Group Box-1 (HMGB1)

Redox Modification of Cysteine Residues Regulates the Cytokine Activity of High Mobility Group Box-1 (HMGB1)

High mobility group box 1 (HMGB1) is a nuclear protein with extracellular inflammatory cytokine activity. It is released passively during cell injury and necrosis, and secreted actively by immune cells. HMGB1 contains three conserved redox-sensitive cysteine residues: C23 and C45 can form an intramolecular disulfide bond, whereas C106 is unpaired and is essential for the interaction with Toll-Like Receptor (TLR) 4. However, a comprehensive characterization of the dynamic redox states of each cysteine residue and of their impacts on innate immune responses is lacking. Using tandem mass spectrometric analysis, we now have established that the C106 thiol and the C23-C45 disulfide bond are required for HMGB1 to induce nuclear NF- κ B translocation and tumor necrosis factor (TNF) production in macrophages. Both irreversible oxidation to sulphonates and complete reduction to thiols of these cysteines inhibited TNF production markedly. In a proof of concept murine model of hepatic necrosis induced by aceta- minophen, during inflammation, the predominant form of serum HMGB1 is the active one, containing a C106 thiol group and a disulfide bond between C23 and C45, whereas the inactive form of HMGB1, containing terminally oxidized cysteines, accumu- lates during inflammation resolution and hepatic regeneration. These results reveal critical posttranslational redox mechanisms that control the proinflammatory activity of HMGB1 and its inactivation during pathogenesis.
Show more

10 Read more

Poly(ADP-Ribosyl)ation of High Mobility Group Box 1 (HMGB1) Protein Enhances Inhibition of Efferocytosis

Poly(ADP-Ribosyl)ation of High Mobility Group Box 1 (HMGB1) Protein Enhances Inhibition of Efferocytosis

Phagocytosis of apoptotic cells by macrophages, known as efferocytosis, is a critical process in the resolution of inflammation. High mobility group box 1 (HMGB1) protein was first described as a nuclear nonhistone DNA-binding protein, but is now known to be secreted by activated cells during inflammatory processes, where it participates in diminishing efferocytosis. Although HMGB1 is known to undergo modification when secreted, the effect of such modifications on the inhibitory actions of HMGB1 during effe- rocytosis have not been reported. In the present studies, we found that HMGB1 secreted by Toll-like receptor 4 (TLR4) stimulated cells is highly poly(ADP-ribosyl)ated (PARylated). Gene deletion of poly(ADP)-ribose polymerase (PARP)-1 or pharmacological inhi- bition of PARP-1 decreased the release of HMGB1 from the nucleus to the extracellular milieu after TLR4 engagement. Preincuba- tion of macrophages or apoptotic cells with HMGB1 diminished efferocytosis through mechanisms involving binding of HMGB1 to phosphatidylserine on apoptotic cells and to the receptor for advanced glycation end products (RAGE) on macrophages. Prein- cubation of either macrophages or apoptotic cells with PARylated HMGB1 inhibited efferocytosis to a greater degree than expo- sure to unmodified HMGB1, and PARylated HMGB1 demonstrated higher affinity for phosphatidylserine and RAGE than unmodified HMGB1. PARylated HMGB1 had a greater inhibitory effect on Ras-related C3 botulinum toxin substrate 1 (Rac-1) activation in macrophages during the uptake of apoptotic cells than unmodified HMGB1. The present results, showing that PARylation of HMGB1 enhances its ability to inhibit efferocytosis, provide a novel mechanism by which PARP-1 may promote inflammation.
Show more

11 Read more

High expression of high mobility group box 1 (hmgb1) predicts poor prognosis for hepatocellular carcinoma after curative hepatectomy

High expression of high mobility group box 1 (hmgb1) predicts poor prognosis for hepatocellular carcinoma after curative hepatectomy

High mobility group box 1(HMGB1), an evolutionarily ancient protein, is a nuclear DNA-binding protein that loosely binds to chromatin and presents in almost all eukaryotic cells [5]. The nuclear role of HMGB1 is not only to integrate and stabilize nucleosome by means of making DNA bending and facilitating the bind of several regulatory protein complexes to DNA, such as the nu- clear factor-κB (NF-κB), p53, p73 transcriptional com- plexes [6,7], but also to facilitate the integration of transposons [8], to regulate transcriptional activation [9]. Moreover, HMGB1 can be released from necrotic cells, activated macrophages, mature dendritic cells and nat- ural killer cells to mediate late systemic inflammation which makes it one of the main prototypes of the emer- ging damage-associated molecular pattern molecules [10-12]. HMGB1 plays corresponding roles in cells through its receptors: RAGE (receptor for advanced gly- cation end-products) and TLRs (Toll like receptors). Re- cent studies have revealed that the binds of HMGB1 and RAGE or TLRs are involved in the activation of several pathways, such as NF-κB pathway, PI3K/AKT pathway, as well as signal transduction through AKT, ERK and p38 [13-16].
Show more

10 Read more

The presence of high mobility group box-1 and soluble receptor for advanced glycation end-products in juvenile idiopathic arthritis and juvenile systemic lupus erythematosus

The presence of high mobility group box-1 and soluble receptor for advanced glycation end-products in juvenile idiopathic arthritis and juvenile systemic lupus erythematosus

Although the pathogenesis of sJIA and cSLE remains unclear, a novel studies seem to point in the direction of innate, rather than adaptive immune response [4,5]. As shown during the past couple of decades, activation of innate immune system seems to rely on a special class of molecules, namely damage-associated molecular pat- terns (DAMP) or alarmins [6-10]. A prototype of alar- mins, high-mobility group box-1 (HMGB1), released to the extracellular space from activated or necrotic cells, acts as a key molecule of innate immunity [11,12]. Re- cently, Garcia-Romo and collegues have demonstrated that in cSLE, HMGB1 is released during NETosis, a form of regulated cell death that occurs with neutrophils (neutrophil extracellular traps, NET). As it has been shown in this study, HMGB1 itself can also induce NETosis and play an important role as a proinflamma- tory mediator in cSLE [13].
Show more

9 Read more

Signaling of High Mobility Group Box 1 (HMGB1) through Toll-like Receptor 4 in Macrophages Requires CD14

Signaling of High Mobility Group Box 1 (HMGB1) through Toll-like Receptor 4 in Macrophages Requires CD14

High mobility group box 1 (HMGB1) is a DNA-binding protein that possesses cytokinelike, proinflammatory properties when re- leased extracellularly in the C23–C45 disulfide form. HMGB1 also plays a key role as a mediator of acute and chronic inflammation in models of sterile injury. Although HMGB1 interacts with multiple pattern recognition receptors (PRRs), many of its effects in injury models occur through an interaction with toll-like receptor 4 (TLR4). HMGB1 interacts directly with the TLR4/myeloid differentiation protein 2 (MD2) complex, although the nature of this interaction remains unclear. We demonstrate that optimal HMGB1-dependent TLR4 activation in vitro requires the coreceptor CD14. TLR4 and MD2 are recruited into CD14-containing lipid rafts of RAW264.7 macrophages after stimulation with HMGB1, and TLR4 interacts closely with the lipid raft protein GM1. Furthermore, we show that HMGB1 stimulates tumor necrosis factor (TNF)-α release in WT but not in TLR4 –/– , CD14 –/– , TIR domain-containing adapter-inducing
Show more

11 Read more

Anti high mobility group box 1 monoclonal antibody treatment provides protection against influenza A virus (H1N1) induced pneumonia in mice

Anti high mobility group box 1 monoclonal antibody treatment provides protection against influenza A virus (H1N1) induced pneumonia in mice

represented a promising novel strategy against influenza infection. In this study, we focused on high mobility group box-1 (HMGB1), originally identified as a ubiquitous DNA-binding protein [12], which is now also recognized as a damage-associated molecular pattern molecule [13]. HMGB1 has been proposed to be a crucial mediator in the pathogenesis of many diseases, including sepsis [14], autoimmunity [15], acute lung inflammation [16] and several severe viral infections [17–19]. HMGB1 can be released passively from necrotic cells and/or actively secreted by macrophages or monocytes into the extracellular milieu [20]. Extracellular HMGB1 can elicit the production of proinflammatory cytokines that induce inflammatory responses through several immune recep- tors, including the toll-like receptor 4 (TLR4) [21] and the receptor for advanced glycation end product (RAGE) [22, 23]. Moreover, intranuclear HMGB1 has also been reported to play a significant role in the replication of influenza viruses [24].
Show more

9 Read more

Emerging Role of High-Mobility Group Box 1 (HMGB1) in Liver Diseases

Emerging Role of High-Mobility Group Box 1 (HMGB1) in Liver Diseases

liver injury), to advanced fibrosis and cir- rhosis (permanent damage/injury to the liver). The initial theory for the pathogen- esis of NAFLD was the “two-hit” hypoth- esis (66). The “first hit,” hepatic triglyc- eride accumulation (also called steatosis), sensititizes the liver to injury by “second hits,” such as those from cytokines, endo- toxin, adipokines, mitochondrial dysfunc- tion and oxidative stress, which result in de novo lipogenesis and increased release of free fatty acid and abnormal lipid dep- osition in the liver (67). Emerging evi- dence suggests that HMGB1-TLR4- MyD88 signaling is involved in the progression of NAFLD in the early stage (Figure 4B) (68). Knockout of TLR4 and its cytosolic adapter protein MyD88 in mice decreases serum HMGB1 level and suppresses high-fat diet–induced liver dysfunction. The accumulation of free HMGB1 in the plasma may further en- hance inflammation and liver damage. Treatment with HMGB1-neutralizing an- tibody inhibits free fatty acid–induced proinflammatory cytokines (for example, TNF and IL-6) production (68). These studies indicate that HMGB1 serves as an important mediator to accelerate local liver damage and systemic inflammation during the early stage of NAFLD.
Show more

10 Read more

Recent Developments in the Role of High-Mobility Group Box 1 in Systemic Lupus Erythematosus

Recent Developments in the Role of High-Mobility Group Box 1 in Systemic Lupus Erythematosus

An important feature of SLE is the pro- duction of autoantibodies against several different nuclear and cytoplasmic pro- teins. Indeed, also antibodies to HMGB1 were found in SLE, which seems specific to the disease, since these antibodies were not found in patients with systemic vasculitis (50,56,57). Interference of these antibodies with detection of serum HMGB1 by enzyme-linked immunosor- bent assay (ELISA) was noted (50,58), and it seems that the best way to detect HMGB1 in the serum of SLE patients is by immunoblot. The presence of anti- HMGB1 antibodies correlates with serum HMGB1, SLEDAI and anti-dsDNA anti- bodies (50), indicating that these antibod- ies might have a pathogenic role. In sep- sis, however, a protective role of anti-HMGB1 antibodies was found (59), initiating a debate about the role of these antibodies. Epitope mapping of the anti- HMGB1 antibodies revealed that the ma- jority of the antibodies reacted against box A (56), indicating that box A is not a treatment option for SLE. It might be ex- pected that box A in lupus will be neu- tralized. In contrast, in animal models in other diseases in which anti-HMGB1 an- tibodies are not present, such as sepsis, administration of box A is beneficial (60).
Show more

8 Read more

Chlorogenic Acid Attenuates High Mobility Group Box 1 (HMGB1) and Enhances Host Defense Mechanisms in Murine Sepsis

Chlorogenic Acid Attenuates High Mobility Group Box 1 (HMGB1) and Enhances Host Defense Mechanisms in Murine Sepsis

relevant animal model for sepsis and has been a mainstay of basic sepsis research. In the CLP model, chlorogenic acid given at 20 mg/kg was a potent and effi- cacious therapy. The effect of chloro- genic acid was equivalent to the efficacy conferred by ethyl pyruvate, an HMGB1 inhibitor, which we also used in the cur- rent study. Chlorogenic acid ameliorated multiorgan dysfunction, enhanced bacte- rial elimination and inhibited the actions of LPS. Multiorgan dysfunction is the critical cause of death in patients with sepsis. Levels of LDH, BUN, creatinine and AST peaked 12 h after the induction of sepsis, whereas ALT peaked 24 h after CLP. The time-dependent profile of CLP- induced enzymes shows the differences in the vulnerability of various organs af- fected by sepsis. Histological analysis also confirmed that CLP was associated with substantially increased inflamma- tory cell infiltration and congestion. Al- though leukocyte migration to the site of infection is crucial for the local control of bacterial growth and the prevention of bacterial dissemination, during the sep- tic response, excessive cellular infiltrates cause direct tissue damage by releasing lysosomal enzymes and superoxide- derived free radicals (28). The tissue damage induced by oxygen free radicals may lead to organ dysfunction. The pre- viously reported potent antioxidant ac- tivity of chlorogenic acid may have pro- vided protection against sepsis-induced multiorgan dysfunction (4). In addition to the ICAM-1 expression of the surface of cells, increased levels of circulating soluble form of ICAM-1 were found in septic patients and correlated with severity of sepsis, as well as subsequent organ failure and eventual outcome (29). The results of this study indicated that increased cellular adhesion, an impor- tant contributor to septic pathophysiol- ogy, was reversed by chlorogenic acid administration, and this decrease in cel- lular adhesion protected vital organs from sepsis-induced damage and dys- function. Defects in monocyte function play an important role in sepsis-induced mortality. Enhanced in vivo bacterial
Show more

12 Read more

Systemic release of high mobility group box 1 (HMGB1) protein is associated with severe and fatal Plasmodium falciparum malaria

Systemic release of high mobility group box 1 (HMGB1) protein is associated with severe and fatal Plasmodium falciparum malaria

Extracellular HMGB1 is believed to act as a danger signal and initiates a host immune response resulting in increased pro-inflammatory production. Using a peripheral blood mononuclear cell (PBMC)-P. falciparum co-culture ap- proach, P. falciparum-PEs were shown in this study to in- duce HMGB1 release from human PBMCs, which may account for elevated plasma/serum levels observed in mal- aria patients. It was hypothesized that malaria-induced re- lease of HMGB1 from immune effector cells could be involved in the propagation of inflammation leading to malaria-associated immunopathology. If so, HMGB1-based strategies might represent a novel therapeutic approach for severe P. falciparum infection, as proposed for sepsis [5]. In the P. berghei ANKA murine model, the development of ECM is highly dependent on host genetics and immune re- sponse to infection. Mice lacking key inflammatory media- tors, such as IFN-γ and members of the TNF superfamily (e g, LTα), are protected against the development of ECM
Show more

9 Read more

High Mobility Group box-1 (HMGB1) Protein As a Biomarker for Acute Cholecystitis

High Mobility Group box-1 (HMGB1) Protein As a Biomarker for Acute Cholecystitis

High mobility group box protein 1 (HMGB1) is a highly conserved protein, ubiquitously expressed in the nucleus of all vertebrate cells. The intranuclear functions of this protein have been well established. More recently, evidence has shown this protein to have extracellular functions involved in inflammatory responses and is considered a pro- inflammatory cytokine (7, 8). The extracellular release of the HMGB1 cytokine can occur either passively or actively. The nuclei of necrotic or damaged cells can result in the passive release of extracellular HMGB1, or activated macrophages, monocytes, and pituicytes can actively secrete HMGB1 into the extracellular environment (8, 9). Several studies have demonstrated HMGB1 levels to be increased in immune-mediated diseases and conditions such as sepsis (10, 11), lung inflammation (12), acute appendicitis (13, 14) and rheumatoid arthritis (15, 16).
Show more

6 Read more

High mobility group box 1 (HMGB1) and anti HMGB1 antibodies and their relation to disease characteristics in systemic lupus erythematosus

High mobility group box 1 (HMGB1) and anti HMGB1 antibodies and their relation to disease characteristics in systemic lupus erythematosus

In accordance with Li et al. , HMGB1 levels were cor- related positively with SLEDAI. The study by Li et al. , did not demonstrate an association of HMGB1 with spe- cific organ involvement [29]. HMGB1 has been impli- cated in the pathogenesis of kidney diseases in patients with lupus nephritis and antineitrophil cytoplasmic anti- body-associated vasculitis with renal involvement, and also has been shown to promote granulomatous nephri- tis in an adenine-fed rat model [31,37-41]. In this model it was shown that granuloma formation was associated with high HMGB1 expression and up-regulation of HMGB1 receptors such as RAGE and TLR4. Therefore, we investigated if levels of HMGB1 are related to kidney involvement in SLE. Serum HMGB1 levels were higher in patients with renal involvement compared to patients without renal involvement. In chronic kidney disease, HMGB1 has been shown to correlate with renal func- tion [37]. This could not be demonstrated in our SLE patients as no correlation could be demonstrated between the presence of HMGB1 and renal function parameters, such as serum creatinine, and eGRF. How- ever, we could observe a positive correlation between serum HMGB1 levels and proteinuria. Such association has been shown in a murine adenovirus accelerated SLE model [42]. Interestingly, antagonizing HMGB1 by administration of anti-HMGB1 mAb IA-4 in this model markedly inhibited proteinuria and led to kidney protec- tion. Combined, all these data indicate that HMGB1 might be an important molecule involved in renal pathology.
Show more

9 Read more

Extracellular High-Mobility Group Box 1 Protein (HMGB1) as a Mediator of Persistent Pain

Extracellular High-Mobility Group Box 1 Protein (HMGB1) as a Mediator of Persistent Pain

Dissecting the mechanisms of HMGB1 translocation and its compartment- specific roles is critical to advance the understanding of HMGB1 in physiology and pathophysiology. Whereas the DNA binding domains contain two nuclear lo- calization signals and two nonclassical nuclear export signals (31), HMGB1 lacks a secretory signal peptide and therefore cannot be actively secreted through clas- sical endoplasmic reticulum–Golgi path- ways (6). In activated monocytes and macrophages, HMGB1 is acetylated and accumulates in cytoplasmic vesicles, and exocytosis of HMGB1 via nonclassical vesicle-mediated secretory pathways has been demonstrated (25). HMGB1 release is also regulated by other posttransla- tional modifications including methyla- tion (32) and phosphorylation by calcium/calmodulin-dependent protein kinase and protein kinase C (PKC) (33–35). Recent studies show that during pyroptosis, Janus kinase/signal trans- ducer and activator of transcription (JAK/STAT1)-mediated acetylation is critical in the initial nucleus to cytosol shuttling, and the subsequent extracellu- lar release is controlled by NLRP3 in- flammasome and dsRNA- activated pro- tein kinase R (PKR) (28,36). Still, although it is clear that immune cells ac- tively release HMGB1 into the extracellu- lar space and the details surrounding this is starting to emerge, the mechanism of how other cells, including sensory neurons and spinal glial cells, regulate HMGB1 release in response to different signals remains largely unknown.
Show more

10 Read more

Urine levels of HMGB1 in Systemic Lupus Erythematosus patients with and without renal manifestations

Urine levels of HMGB1 in Systemic Lupus Erythematosus patients with and without renal manifestations

Introduction: Lupus nephritis (LN) is a severe and frequent manifestation of systemic lupus erythematosus (SLE). Its pathogenesis has not been fully elucidated but immune complexes are considered to contribute to the inflammatory pathology in LN. High Mobility Group Box 1 (HMGB1) is a nuclear non-histone protein which is secreted from different types of cells during activation and/or cell death and may act as a pro-inflammatory mediator, alone or as part of DNA- containing immune complexes in SLE. Urinary excretion of HMGB1 might reflect renal inflammatory injury. To assess whether urinary HMGB1 reflects renal inflammation we determined serum levels of HMGB1 simultaneously with its urinary levels in SLE patients with and without LN in comparison to healthy controls (HC). We also analyzed urinary HMGB1 levels in relation with clinical and serological disease activity.
Show more

11 Read more

Inflammasomes: Pandora’s box for sepsis

Inflammasomes: Pandora’s box for sepsis

Notes: (A) This part figure shows the induction of NLRP3 inflammasomes during sepsis in macrophages, causing their death, release of high-mobility group box 1 protein (HMGB1), microparticles (consisting of IL-1β, NLRP3, ASC, and CASP1) binding to endothelial cells and stimulating the induction of higher expression of adhesion molecules (ICAM-1 and vCAM-1), causing profound infiltration of neutrophils at the site of infection, which leads to increased tissue or organ damage and death of endothelial cells, in turn leading to increased circulating levels of ICAM-1 and vCAM-1, MOF, and finally death of the septic patient. MCC950, an NLRP3 inflammasome inhibitor, caused inhibition of increased expression of ICAM-1 and vCAM-1 on the endothelial cells and prevented MOF. (B) This part figure shows increased circulating levels of ATP and its metabolite called adenosine act via different receptors called P2X 7 and A 2A Rs expressed on the neutrophils, DCs, and macrophages. The binding then activates the NLRP3
Show more

26 Read more

Emerging roles for HMGB1 protein in immunity, inflammation, and cancer

Emerging roles for HMGB1 protein in immunity, inflammation, and cancer

Abstract: High-mobility group box 1 (HMGB1) protein is a member of the highly conserved non-histone DNA binding protein family. First identified in 1973, as one of a group of chromatin- associated proteins with high acidic and basic amino acid content, it was so named for its char- acteristic rapid mobility in polyacrylamide gel electrophoresis. HMGB1 was later discovered to have another function. It is released from a variety of cells into the extracellular milieu to act on specific cell-surface receptors. In this latter role, HMGB1 is a proinflammatory cytokine that may contribute to many inflammatory diseases, including sepsis. Therefore, HMGB1 regulates intracellular cascades influencing immune cell functions, including chemotaxis and immune modulation. The bioactivity of the HMGB1 is determined by specific posttranslational modifications that regulate its role in inflammation and immunity. During tumor development, HMGB1 has been reported to play paradoxical roles in promoting both cell survival and death by regulating multiple signaling pathways. In this review, we focus on the role of HMGB1 in physiological and pathological responses, as well as the mechanisms by which it contributes to immunity, inflammation, and cancer progression.
Show more

9 Read more

HMGB1: Endogenous Danger Signaling

HMGB1: Endogenous Danger Signaling

While foreign pathogens and their products have long been known to activate the innate immune system, the recent rec- ognition of a group of endogenous molecules that serve a similar function has provided a framework for understanding the overlap between the inflammatory responses activated by pathogens and injury. These endogenous molecules, termed alarmins, are normal cell constituents that can be released into the extracellular milieu during states of cellular stress or dam- age and subsequently activate the immune system. One nuclear protein, High mobility group box-1 (HMGB1), has received par- ticular attention as fulfilling the functions of an alarmin by being involved in both infectious and non-infectious inflammatory conditions. Once released, HMGB1 signals through various receptors to activate immune cells involved in the immune process. Although initial studies demonstrated HMGB1 as a late mediator of sepsis, recent findings indicate HMGB1 to have an important role in models of non-infectious inflammation, such as autoimmunity, cancer, trauma, and ischemia reperfusion injury. Further- more, in contrast to its pro-inflammatory functions, there is evidence that HMGB1 also has restorative effects leading to tissue re- pair and regeneration. The complex functions of HMGB1 as an archetypical alarmin are outlined here to review our current un- derstanding of a molecule that holds the potential for treatment in many important human conditions.
Show more

9 Read more

PubMedCentral-PMC5420377.pdf

PubMedCentral-PMC5420377.pdf

Over the past decade, the innate immune system has emerged as a critical component in the development of alcohol use disorders and other addictions. Microglia, the resident macrophage-like innate immune cells of the central nervous system, have only recently been discovered to play a critical role in brain homeostasis with key roles in neuronal differen- tiation, synapse formation, and neurocircuitry. It was only recently discovered that on embryonic day 8 in mice, meso- dermal progenitor yolk sac cells migrate to brain to form mi- croglia that persist throughout life as unique brain cells, dis- tinct from the neuro-ectodermal cells that form neurons and other glia (e.g., astrocytes and oligodendrocytes) (Ginhoux et al. 2010, 2013). Originating from the mesoderm, microglia express a multitude of innate immune signaling receptors and molecules. One microglia-associated receptor system, the toll- like receptor (TLR) superfamily (i.e., interleukin-1 receptor/ toll-like receptor), mounts proinflammatory responses to path- ogens by sensing large molecules containing lipids, sugars, protein, and nucleic acid components. Initial studies suggested that only microglia are involved in TLR signaling, but more recent studies suggest that all brain cell types are involved in this signaling (Crews and Vetreno 2016). Toll-like receptors activate signaling cascades that converge on nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a key innate immune nuclear transcription factor that promotes expression of proinflammatory cytokines, including tumor ne- crosis factor α (TNFα), interleukin-1β (IL-1β), IL-6, and monocyte chemoattractant protein-1 (MCP-1). Recent studies in brain, which is normally a sterile environment, indicate that endogenous TLR agonists may comprise an important signal- ing pathway between microglia, other glia, and neurons. The ubiquitously expressed nuclear protein, high-mobility group box 1 (HMGB1), is a cytokine-like molecule expressed in all cell types that upon release can directly activate TLRs and enhance the response of other innate immune signaling mole- cules at their respective receptors (see Fig. 1). Human and preclinical animal studies find that stress (Frank et al. 2015), alcohol (Crews and Vetreno 2014), and other drugs of abuse (Hutchinson et al. 2010; Northcutt et al. 2015) increase
Show more

16 Read more

The differentiation of mesenchymal stem cells to vascular cells regulated by the HMGB1/RAGE axis: its application in cell therapy for transplant arteriosclerosis

The differentiation of mesenchymal stem cells to vascular cells regulated by the HMGB1/RAGE axis: its application in cell therapy for transplant arteriosclerosis

In this scenario, we have been exploring ways of improv- ing the efficacy of MSC transplantation with a special focus on the regulation of cell differentiation that would promote endothelial regeneration. The current study aimed to evaluate whether the differentiation of MSCs to vascular cells would be influenced by high mobility group box 1 (HMGB1) and whether it could be used to provide favor- able outcomes of MSC-based therapy for transplant ar- teriosclerosis. HMGB1 is an evolutionarily abundant and highly conserved DNA binding protein, and is passively re- leased from necrotic cells or actively secreted by inflamma- tory cells to the extracellular milieu upon cell stress to regulate innate and adaptive immunity. HMGB1 stimulates the immune response, at least in part, through interaction with its principal binding partner, receptor for advanced glycation end-product (RAGE). Both HMGB1 and RAGE are highly expressed in atherosclerotic plaques to acceler- ate the progression of atherosclerosis [15]. Moreover, the HMGB1/RAGE axis is instrumental in promoting acute and chronic rejection [16–23]. Despite its proinflammatory properties, HMGB1 promotes tissue repair by recruiting
Show more

15 Read more

Efficacy of recombinant human soluble thrombomodulin for the treatment of acute exacerbation of idiopathic pulmonary fibrosis: a single arm, non-randomized prospective clinical trial

Efficacy of recombinant human soluble thrombomodulin for the treatment of acute exacerbation of idiopathic pulmonary fibrosis: a single arm, non-randomized prospective clinical trial

Thrombomodulin is a membranous protein found on the surface of vascular endothelial cells. It directly inhibits clotting activity through the formation of a complex with thrombin and further suppresses blood coagulation through its activation of protein C. Thrombomodulin has anti-inflammatory as well as high mobility group box 1 (HMGB1) inhibitory and anticoagulant activities [10, 11]. Recombinant human soluble thrombomodulin (rhTM) demonstrates anticoagulation effects superior to hep- arin for the treatment of disseminated intravascular coagulation (DIC) [12] and improves the outcomes and respiratory functions in patients with sepsis-induced acute respiratory distress syndrome (ARDS) [13]. Fur- thermore, Ebina et al. reported reduced expression of thrombomodulin on the surface of vascular endothelial cells in autopsy cases of AE-IPF [14]. Based on these findings, we conducted a clinical study to examine the efficacy of rhTM treatment of AE-IPF.
Show more

8 Read more

Show all 10000 documents...