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We examined the effects of a 2,2'-bipyridine containing natural product, collismycin C on high mobility group box 1 (HMGB1, septic mediator)-mediated septic responses and survival rate in a mouse sepsis model. Collismycin C inhibited the HMGB1 release and downregulated HMGB1-mediated inflammatory responses in human endothelial cells. Collismycin C also inhibited HMGB1-induced hyperpermeability and leukocyte migration in mice. In addition, collismycin C treatment reduced CLP-induced HMGB1 release and sepsis-related mortality and pulmonary damage in vivo . Our results indicate that collismycin C is a potential therapeutic agent for the treatment of severe vascular inflammatory diseases by inhibiting HMGB1 signaling pathway.

High mobility group box 1 (HMGB1) is recognized as a late mediator of sepsis, and the inhibition of HMGB1 release and recovery of vascular barrier integrity have emerged as attractive therapeutic strategies for the management of sepsis. We tested the hypothesis that aloin induces sirtuin 1 (SIRT1) and heme oxygenase (HO)-1, which inhibit HMGB1 release in lipopolysaccharide (LPS)-stimulated cells, thereby inhibiting HMGB1-induced hyperpermeability and increasing the survival of septic mice. Aloin was administered after LPS or HMGB1 challenge, and the antiseptic activity of aloin was determined from measurements of permeability, activation of pro-inflammatory proteins and production of markers for tissue injury in HMGB1-activated human umbilical vein endothelial cells (HUVECs) and a cecal ligation and puncture (CLP)-induced sepsis mouse model. Aloin significantly reduced HMGB1 release in LPS-activated HUVECs via SIRT1-mediated HMGB1 deacetylation and the PI3K/Nrf2/heme oxygenase (HO)-1 signaling axis. Aloin also suppressed the production of tumor necrosis factor (TNF)- α and interleukin (IL)-6, as well as the activation of nuclear factor (NF)- κ B and extracellular signal-regulated kinase 1/2 (ERK 1/2) by HMGB1. Moreover, aloin restored HMGB1-mediated vascular disruption and inhibited vascular hyperpermeability in mice. In addition, treatment with aloin reduced the CLP-induced release of HMGB1, sepsis-related mortality and tissue injury in vivo . Our results suggest that aloin reduces HMGB1 release and sepsis-related mortality by activating SIRT1 and PI3K/Nrf2/HO-1 signals, indicating that aloin has potential for the treatment of sepsis.

High mobility group box 1 (HMGB1) is considered a late mediator of sepsis and the inhibition of HMGB1-mediated severe inflammatory responses and restoration of endothelial integrity have emerged as attractive therapeutic strategies for the management of sepsis. Zingerone (ZGR), a phenolic alkanone isolated from ginger, has been reported to possess various pharmacological activities. We examined the effects of ZGR on HMGB1-mediated septic responses and survival rate in a mouse model of sepsis. ZGR was administered after HMGB1 challenge. The antiseptic activity of ZGR was determined from the measurements of permeability, leukocyte adhesion and migration, activation of pro-inflammatory proteins, and the production of tissue injury markers in HMGB1-activated HUVECs and mice. ZGR significantly reduced HMGB1 release in LPS-activated HUVECs via the SIRT1-mediated deacetylation of HMGB1. And, ZGR suppressed the production of TNF-α and IL-6 and the activation of NF-κB and ERK 1/2 by HMGB1. ZGR also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with ZGR reduced the CLP-induced release of HMGB1, sepsis-related mortality, and tissue injury in vivo. Our results indicated that ZGR might be useful in the treatment of sepsis by targeting HMGB1., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The screening of bioactive compound libraries can be an effective approach for repositioning FDA-approved drugs or discovering new treatments for human diseases. Inhibition of high mobility group box 1 (HMGB1) and restoration of endothelial integrity are emerging as an attractive therapeutic strategies in the management of severe sepsis or septic shock. Here, we examined the effects of methylthiouracil (MTU), used as antithyroid drug, by monitoring the effects on lipopolysaccharide (LPS)- or cecal ligation and puncture (CLP)-mediated release of HMGB1, and on the modulation of HMGB1-mediated inflammatory responses. The anti-inflammatory activities of MTU were determined by measuring permeability, leukocyte adhesion and migration, and the activation of pro-inflammatory proteins in HMGB1-activated HUVECs and mice. MTU inhibited the release of HMGB1 and downregulated HMGB1-dependent inflammatory responses in human endothelial cells. MTU also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with MTU reduced CLP-induced release of HMGB1 and sepsis-related mortality and pulmonary injury. Our results indicate that MTUs could be candidate therapeutic agents for various severe vascular inflammatory diseases via the inhibition of the HMGB1 signaling pathway., (Copyright © 2015 Elsevier Inc. All rights reserved.)

A certain nucleosomal protein-high mobility group box-1 (HMGB1)-has recently been established as a late mediator of sepsis, with a relatively wide therapeutic window for pharmacological intervention. Pelargonidin (PEL) is a well-known red pigment found in plants; it has important biological activities that are potentially beneficial for human health. In the present study, we investigated whether PEL can modulate HMGB1-mediated inflammatory responses in human umbilical vein endothelial cells (HUVECs) and in mice. The anti-inflammatory activities of PEL were determined by measuring permeability, leukocyte adhesion and migration, and activation of pro-inflammatory proteins in HMGB1-activated HUVECs and mice, as well as the beneficial effects of PEL on survival rate in the mouse sepsis model. The data showed that PEL had effectively inhibited lipopolysaccharide (LPS)-induced release of HMGB1 and suppressed HMGB1-mediated septic responses, such as hyperpermeability, adhesion and migration of leukocytes, and expression of cell adhesion molecules. Furthermore, PEL inhibited the HMGB1-mediated production of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), as well as the activation of nuclear factor-κB (NF-κB) and extracellular signal-regulated kinases 1 and 2 (ERK1/2). Collectively, these results indicate that PEL could be used to treat various severe vascular inflammatory diseases via the inhibition of the HMGB1 signaling pathway.

The nucleosomal protein high-mobility group box-1 (HMGB1), which has recently been established as a late mediator of lethal systemic inflammation, has a relatively wide therapeutic window for pharmacological interventions. Compounds produced by marine-derived microbes have been widely investigated for their potential use as bioactive natural products. Cyclic dipeptides, which are also known as diketopiperazines, are molecules that are frequently found in marine-derived microorganisms. While their pharmacological potential has been well established, their biological activities against septic responses have not yet been reported. Here, three diketopiperazines (1-3) isolated from two strains of marine-derived bacteria were investigated for their potential activities against HMGB1-mediated septic responses. The data showed that 1-3 effectively inhibited the lipopolysaccharide (LPS)-induced release of HMGB1 and suppressed the HMGB1-mediated septic responses, including hyperpermeability, leukocyte adhesion and migration, and cell adhesion molecule expression. In addition, 1-3 inhibited the HMGB1-mediated production of tumor necrosis factor-[Formula: see text] (TNF-[Formula: see text] and interleukin (IL)-6 and the activation of nuclear factor-[Formula: see text]B (NF-[Formula: see text]B) and extracellular signal-regulated kinase (ERK) 1 and ERK2. Collectively, these results indicated that 1-3 might act as potential therapeutic agents for various severe vascular inflammatory diseases through the inhibition of the HMGB1 signaling pathway.

High mobility group box 1 (HMGB1) was recently shown to be an important extracellular mediator of severe vascular inflammatory disease, sepsis. Lysozyme protects us from the ever-present danger of bacterial infection and binds to bacterial lipopolysaccharide (LPS) with a high affinity. Here, we show, for the first time, the anti-septic effects of lysozyme in HMGB1-mediated inflammatory responses in vitro and in vivo. The data showed that lysozyme posttreatment suppressed LPS-mediated release of HMGB1 and HMGB1-mediated cytoskeletal rearrangement. Lysozyme also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in human endothelial cells. In addition, lysozyme inhibited the HMGB1-mediated activation of Akt, nuclear factor-κB (NF-κB), extracellular regulated kinases (ERK) 1/2 and production of interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), and chemoattractant protein-1 (MCP-1) in HUVECs. Furthermore, lysozyme reduced the cecal ligation and puncture (CLP)-induced release of HMGB1, migration of leukocytes, septic mortality, and pulmonary damage in mice. Collectively, these results suggest lysozyme as a candidate therapeutic agent for the treatment of vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway.

In this Letter, we investigated the barrier protective effects of 3-N-(MeO)n-cinnamoyl carbazoles (BS 1; n=1, BS 2; n=2, BS 3; n=3) and 3-O-(MeO)3-cinnamoyl carbazole (BS 4) against high-mobility group box 1 (HMGB1)-mediated vascular disruptive responses in human umbilical vein endothelial cells (HUVECs) and in mice for the first time. Data showed that BS 2, BS 3, and BS 4, but not BS 1, inhibited HMGB1-mediated vascular disruptive responses and transendothelial migration of human neutrophils to HUVECs. BS 2, BS3, and BS 4 also suppressed HMGB1-induced hyperpermeability and leukocyte migration in mice. Interestingly, the barrier protective effects of BS 3 and BS 4 were better than those of BS 2. These results suggest that the number of methoxy groups substituted on the cinnamamide or cinnamate moiety of the 9H-3-carbazole derivative is an important pharmacophore for the barrier protective effects of these compounds., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Aim and Objective: The ubiquitous nuclear protein, high-mobility group box 1 (HMGB1), is released by activated macrophages and human umbilical vein endothelial cells (HUVECs) and functions as a late mediator of experimental sepsis. Polyozellin, which has been reported to have a variety of biological activities including antioxidant and anticancer activity, is the major active compound found in edible mushroom (Polyozellus multiplex). In this study, we investigated the antiseptic effects and underlying mechanisms of polyozellin against HMGB1-mediated septic responses in HUVECs and mice., Methods: The anti-inflammatory activities of polyozellin were determined by measuring permeability, human neutrophil adhesion and migration, and activation of proinflammatory proteins in HMGB1-activated HUVECs and mice., Results: According to the results, polyozellin effectively inhibited lipopolysaccharide (LPS)-induced release of HMGB1, and suppressed HMGB1-mediated septic responses, such as hyperpermeability, adhesion and migration of leukocytes, and expression of cell adhesion molecules. In addition, polyozellin suppressed the production of tumor necrosis factor-α and interleukin (IL)-6, and the activation of nuclear factor-κB and extracellular signal-regulated kinases 1/2 by HMGB1., Conclusion: Collectively, these results indicate that P. multiplex containing polyozellin could be commercialized as functional food for preventing and treatment of various severe vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway.

Inhibition of high mobility group box 1 (HMGB1) protein and restoration of endothelial integrity is emerging as an attractive therapeutic strategy in the management of sepsis. Here, three structurally related polyphenols found in the Chinese herb Huang Qui, baicalin (BCL), baicalein (BCN), and wogonin (WGN), were examined for their effects on lipopolysaccharide (LPS)- or cecal ligation and puncture (CLP)-mediated release of HMGB1 and on modulation of HMGB1-mediated inflammatory responses. According to our data, BCL, BCN, and WGN inhibited the release of HMGB1 and down-regulated HMGB1-dependent inflammatory responses in human endothelial cells. BCL, BCN, and WGN also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with BCL, BCN, and WGN reduced CLP-induced release of HMGB1 and sepsis-related mortality and pulmonary injury in mice. These results indicate that BCL, BCN, and WGN could be candidate therapeutic agents for various severe vascular inflammatory diseases owing to their inhibition of the HMGB1 signaling pathway., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Sepsis is a state of disrupted inflammatory homeostasis that is initiated by infection. High mobility group box 1 (HMGB1) protein acting as a late mediator of severe vascular inflammatory conditions, such as sepsis and endothelial cell protein C receptor (EPCR), is involved in vascular inflammation. Fisetin, an active compound from the family Fabaceae, was reported to have antiviral, neuroprotective, and anti-inflammatory activities. Here, we determined the anti-septic effects of fisetin on HMGB1-mediated inflammatory responses and on the shedding of EPCR in vitro and in vivo, for the first time. First, we monitored the effects of post-treatment fisetin on lipopolysaccharide (LPS) and cecal ligation and puncture (CLP)-mediated release of HMGB1 and HMGB1-mediated regulation of pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) and septic mice. Post-treatment fisetin was found to suppress LPS-mediated release of HMGB1 and HMGB1-mediated cytoskeletal rearrangements. Fisetin also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in septic mice. Fisetin induced potent inhibition of phorbol-12-myristate 13-acetate (PMA) and CLP-induced EPCR. Fisetin also inhibited the expression and activity of tumor necrosis factor-α converting enzyme, induced by PMA in endothelial cells. In addition, fisetin inhibited the production of tumor necrosis factor-α and the activation of AKT, nuclear factor-κB, and extracellular regulated kinases 1/2 by HMGB1 in HUVECs. Fisetin also down-regulated CLP-induced release of HMGB1, production of interleukin 1β, and reduced septic mortality. Collectively, these results suggest that fisetin may be a candidate therapeutic agent for the treatment of vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway.

Nuclear DNA-binding protein high mobility group box 1 (HMGB1) acts as a late mediator of severe vascular inflammatory conditions, such as sepsis. Activated factor X (FXa) is an important player in the coagulation cascade responsible for thrombin generation, and it influences cell signalling in various cell types by activating protease-activated receptors (PARs). However, the effect of FXa on HMGB1-induced inflammatory response has not been studied. First, we addressed this issue by monitoring the effects of post-treatment with FXa on lipopolysaccharide (LPS)- and cecal ligation and puncture (CLP)-mediated release of HMGB1 and HMGB1-mediated regulation of pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) and septic mice. Post-treatment with FXa was found to suppress LPS-mediated release of HMGB1 and HMGB1-mediated cytoskeletal rearrangements. FXa also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in septic mice. In addition, FXa inhibited the production of tumour necrosis factor-α and interleukin (IL)-1β. FXa also facilitated the downregulation of CLP-induced release of HMGB1, production of IL-6, and mortality. Collectively, these results suggest that FXa may be regarded as a candidate therapeutic agent for treating vascular inflammatory diseases by inhibiting the HMGB1 signalling pathway.

High mobility group box-1 (HMGB1) protein acts as a late mediator of severe vascular inflammatory conditions. Orientin has been known to have anxiolytic and antioxidative activities. However, the effect of orientin on HMGB1-induced inflammatory response has not been studied. We assessed this question by monitoring the effects of post-treatment orientin and its derivatives on lipopolysaccharide (LPS) and cecal ligation and puncture (CLP)-mediated release of HMGB1 and HMGB1-mediated regulation of pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) and septic mice. Post-treatment orientin was found to suppress LPS-mediated release of HMGB1 and HMGB1-mediated cytoskeletal rearrangements. Orientin inhibited HMGB1-mediated hyperpermeability and leukocyte migration in septic mice. Orientin also induced down-regulation of CLP-induced release of HMGB1 and mortality. Collectively, these results suggest that orientin may be regarded as a candidate therapeutic agent for treatment of vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway.

Exendin-4 (EX4) has been reported to attenuate myocardial ischemia and reperfusion (I/R) injury and inflammatory and oxidative responses. Nuclear DNA-binding protein high-mobility group box 1 (HMGB1) protein acts as a late mediator of severe vascular inflammatory conditions. However, the effect of EX4 on HMGB1-induced inflammatory response has not been studied. First, we accessed this question by monitoring the effects of posttreatment EX4 on lipopolysaccharide (LPS) and cecal ligation and puncture (CLP)-mediated release of HMGB1 and HMGB1-mediated regulation of proinflammatory responses in human umbilical vein endothelial cells (HUVECs) and septic mice. Posttreatment EX4 was found to suppress LPS-mediated release of HMGB1 and inhibited HMGB1-mediated hyperpermeability and leukocyte migration in septic mice. EX4 also induced downregulation of CLP-induced release of HMGB1, production of IL-6, and mortality. Collectively, these results suggest that EX4 may be regarded as a candidate therapeutic agent for treatment of vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway.

High mobility group box 1 (HMGB1) acts as a late mediator of vascular inflammatory conditions. Pellitorine (PT), an active amide compound from Asarum sieboldii, is known to possess antibacterial and anticancer properties. In this study, we investigated the anti-septic effects of PT against pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) induced by HMGB1 and the associated signaling pathways. According to our findings, treatment with PT resulted in inhibited release of HMGB1, down-regulation of HMGB1-dependent inflammatory responses in HUVECs, and inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with PT resulted in reduced cecal ligation and puncture (CLP)-induced release of HMGB1 and sepsis-related mortality. PT suppressed the production of tumor necrosis factor-α and interleukin 6 and the activation of nuclear factor-κB and extracellular regulated kinases 1/2 by HMGB1. Collectively, these results indicate the potential of PT as a candidate therapeutic agent for treatment of various severe vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway.

Objective and Design: High mobility group box 1 (HMGB1) protein acts as a late mediator of severe vascular inflammatory conditions. Rutin (RT), an active flavonoid compound, is well known to possess potent antiplatelet, antiviral and antihypertensive properties. In this study, we investigated the anti-inflammatory effects of RT against pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) induced by HMGB1 and the associated signaling pathways., Methods: The anti-inflammatory activities of RT were determined by measuring permeability, monocytes adhesion and migration, and activation of pro-inflammatory proteins in HMGB1-activated HUVECs and mice., Results: We found that RT potently inhibited HMGB1 release, down-regulated HMGB1-dependent inflammatory responses in human endothelial cells, and inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with RT resulted in reduced cecal ligation and puncture-induced release of HMGB1 and sepsis-related mortality. Further studies revealed that RT suppressed the production of tumor necrosis factor-α and interleukin 6 and the activation of nuclear factor-κB and extracellular regulated kinases 1/2 by HMGB1., Conclusion: Collectively, these results indicate that RT could be a candidate therapeutic agent for treatment of various severe vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway.

The ubiquitous nuclear protein High mobility group box 1 (HMGB1) is released by activated macrophages and human umbilical vein endothelial cells (HUVECs), and functions as a late mediator of experimental sepsis. Glyceollins (GCLs) are active compounds from Aspergillus sojae which have been reported for anti-cancer, anti-diabetes, and anti-inflammatory activities. We investigated here, the antiseptic effects and underlying mechanisms of GCLs against HMGB1-mediated septic responses in HUVECs and mice. According to the results, GCLs effectively inhibited lipopolysaccharide-induced release of HMGB1, and suppressed HMGB1-mediated septic responses, such as hyperpermeability, adhesion and migration of leukocytes, and expression of cell adhesion molecules. In addition, GCLs suppressed the production of tumor necrosis factor-α and interleukin 6 and activation of nuclear factor-κB and extracellular regulated kinases 1/2 by HMGB1. Collectively, these results indicate that GCLs could be a potential therapeutic agent for treatment of various severe vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

High mobility group box 1 (HMGB1) protein is a crucial cytokine that mediates response to infection, injury, and inflammation. Rosmarinic acid (RA) is an important component of the leaves of Perilla frutescens and has neuroprotective, anti-microbial, anti-oxidant, and anti-cancer effects but little is known of its effects on HMGB1-mediated inflammatory response. Here, we investigated this issue by monitoring the effects of RA on the lipopolysaccharide (LPS) or cecal ligation and puncture (CLP)-mediated release of HMGB1 and HMGB1-mediated modulation of inflammatory responses. RA potently inhibited the release of HMGB1 and down-regulated HMGB1-dependent inflammatory responses in human endothelial cells. RA also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. Furthermore, RA reduced CLP-induced HMGB1 release and sepsis-related mortality. Given these results, RA should be viewed as a candidate therapeutic agent for the treatment of various inflammatory diseases via inhibition of the HMGB1 signaling pathway., (Copyright © 2012 Wiley Periodicals, Inc.)

High mobility group box 1 (HMGB1) protein is a crucial nuclear cytokine that mediates inflammatory responses, whereas persicarin is an active compound from Oenanthe javanica that has been widely researched for its neuroprotective and antioxidant activities. However, little is known of the effects of persicarin on HMGB1-mediated inflammatory response. Here, we investigated this issue by monitoring the effects of persicarin on the lipopolysaccharide (LPS) and on the cecal ligation and puncture (CLP)-mediated releases of HMGB1 and the effects of persicarin on the HMGB1-mediated modulation of inflammatory response. Persicarin potently inhibited the release of HMGB1 and down-regulated HMGB1-dependent inflammatory responses in human endothelial cells, and inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. Furthermore, persicarin reduced CLP-induced HMGB1 release and sepsis-related mortality. Given these results, persicarin should be viewed as a candidate therapeutic for the treatment of severe vascular inflammatory diseases, such as, sepsis or septic shock., (Copyright © 2012 Wiley Periodicals, Inc.)

Nuclear DNA-binding protein high mobility group box 1 (HMGB1) protein acts as a late mediator of severe vascular inflammatory conditions, such as sepsis and septic shock. Epi-sesamin (ESM), an important component of Asarum sieboldii roots, is known to exhibit anti-allergic, anti-nociceptive, and anti-fungal effects. However, little is known of its effects on HMGB1-mediated inflammatory responses. Here, we investigated this issue by monitoring the effects of ESM on lipopolysaccharide (LPS) or cecal ligation and the puncture (CLP)-mediated release of HMGB1, and on modulation of HMGB1-mediated inflammatory responses. ESM potently inhibited HMGB1 release, down-regulated HMGB1-dependent inflammatory responses in human endothelial cells, and inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with ESM resulted in reduced CLP-induced release of HMGB1 and sepsis-related mortality. Of particular interest, ESM inhibition of HMGB1-mediated anti-inflammatory activity was more potent than that by sesamin (SM), likely due to differences between their three-dimensional structures. These results indicate that ESM could be a candidate therapeutic agent for treatment of various severe vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway., (Copyright © 2012 Elsevier Inc. All rights reserved.)

High mobility group box 1 (HMGB1) protein acts as a potent proinflammatory cytokine and is involved in the pathogenesis of several vascular diseases, such as, systemic vasculitis and sepsis. Emodin-6-O-β-D-glucoside (EG) is a new active compound from Reynoutria japonica, and its biologic activities have not been previously investigated. In this study, we first investigated the antiinflammatory activities of EG on HMGB1-mediated proinflammatory responses in human umbilical vein endothelial cells (HUVECs) and in a murine cecal ligation and puncture (CLP)-model of sepsis in mice. EG was found to suppress the release of HMGB1, the production of tumor necrosis factor (TNF)-α, and the activation of nuclear factor-κB (NF-κB) by HMGB1 in HUVECs, and to inhibit HMGB1-mediated hyperpermeability and leukocyte migration in mice. In the CLP model, HMGB1 was highly released, but this release was prevented by EG. Furthermore, EG also increased the survival times of CLP administered mice. Collectively, this study shows EG can protect barrier integrity and inhibit HMGB1-mediated inflammatory responses, which suggests a potential use as a therapy for sepsis or septic shock., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

High mobility group box 1 (HMGB1) protein is a crucial nuclear cytokine that elicits severe vascular inflammatory diseases. Oenanthe javanica (water dropwort) extract has anti-arrhythmic, neuroprotective and anti-diabetic activity. However, isorhamnetin-3-O-galactoside (I3G), an active compound from O. javanica, is not researched well for its biological activity. Here, we investigated the anti-inflammatory activities of I3G by monitoring the effects of I3G on the lipopolysaccharide (LPS) or cecal ligation and puncture (CLP)-mediated release of HMGB1 and HMGB1 or CLP-mediated modulation of inflammatory responses. I3G potently inhibited the release of HMGB1 and down-regulated HMGB1-dependent inflammatory responses in human endothelial cells. I3G also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. Further studies revealed that I3G suppressed the production of tumor necrosis factor-α and activation of nuclear factor-κB by HMGB1. In addition, I3G reduced CLP-induced HMGB1 release and sepsis-related mortality. Given these results, I3G should be viewed as a candidate therapeutic agent for the treatment of severe vascular inflammatory diseases such as sepsis or septic shock via inhibition of the HMGB1 signaling pathway., (Copyright © 2012 Wiley Periodicals, Inc.)

Withaferin A (WFA), an active compound from Withania somnifera, is widely researched for its anti-inflammatory, cardioactive and central nervous system effects. In this study, we first investigated the possible barrier protective effects of WFA against pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) and in mice induced by high mobility group box 1 protein (HMGB1) and the associated signaling pathways. The barrier protective activities of WFA were determined by measuring permeability, leukocytes adhesion and migration, and activation of pro-inflammatory proteins in HMGB1-activated HUVECs. We found that WFA inhibited lipopolysaccharide (LPS)-induced HMGB1 release and HMGB1-mediated barrier disruption, expression of cell adhesion molecules (CAMs) and adhesion/transendothelial migration of leukocytes to human endothelial cells. WFA also suppressed acetic acid-induced hyperpermeability and carboxymethylcellulose-induced leukocytes migration in vivo. Further studies revealed that WFA suppressed the production of interleukin 6, tumor necrosis factor-α (TNF-α) and activation of nuclear factor-κB (NF-κB) by HMGB1. Collectively, these results suggest that WFA protects vascular barrier integrity by inhibiting hyperpermeability, expression of CAMs, adhesion and migration of leukocytes, thereby endorsing its usefulness as a therapy for vascular inflammatory diseases., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The phlorotannins (phloroglucinol, eckol, and dieckol) are active compounds found in Eisenia bicyclis, and have been widely investigated for their antioxidant, anti-tumor, and anti-cancer activities. In this study, we investigated the protective effects of these phlorotannins against pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) and in mice treated by high mobility group box 1 protein (HMGB1), and the signaling pathways involved. The protective activities of the phlorotannins were determined by measuring permeability, leukocyte adhesion and migration, and the activations of pro-inflammatory proteins in HMGB1-activated HUVECs. We found that the phlorotannins inhibited; lipopolysaccharide (LPS)-induced HMGB1 release, HMGB1-mediated barrier disruption, the expressions of cell adhesion molecules (CAMs), and the adhesion/transendothelial migration of leukocytes to human endothelial cells. The phlorotannins also suppressed acetic acid induced-hyperpermeability and carboxymethylcellulose-induced leukocytes migration in vivo. Further studies revealed that the hydroxyl groups on dieckol positively regulated these vascular barrier protective effects. Collectively, these results suggest that phloroglucinol, eckol, and dieckol protect vascular barrier integrity by inhibiting hyperpermeability, the expressions of CAMs, and the adhesion and migration of leukocytes, which confirms their potential usefulnesses for the treatment of vascular inflammatory diseases., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

High mobility group box 1 (HMGB1) mediates proinflammatory responses in inflammatory diseases. Lycopene found in tomatoes and tomato products has anti-oxidant, anti-cancer and antiinflammatory effects. The potential anti-inflammatory roles of lycopene in HMGB1-mediated proinflammatory responses in both primary human umbilical vein endothelial cells (HUVECs) and animal were investigated. The anti-inflammatory effects of lycopene were determined including permeability, monocyte adhesion and migration, and activation of proinflammatory proteins and HMGB1 receptors on HMGB1 activated HUVECs. In the in vivo model, the anti-inflammatory effect of lycopene was assessed by monitoring vascular permeability and migration of leukocytes to the peritoneal cavity of mice injected with lycopene. Lycopene inhibited lipopolysaccharide (LPS)-mediated release of HMGB1, expression of HMGB1-mediated tumor necrosis factor (TNF)-secretory phospholipase A2 (sPLA2)-IIA, and HMGB1-mediated pro-inflammatory signaling responses in endothelial cells. It did this through down-regulation of cell surface expression of cell adhesion molecules (CAMs), HMGB1 receptors, toll-like receptor (TLR)-2, and -4, and receptors for advanced glycation end products (RAGE). These findings suggest that lycopene promotes barrier integrity, inhibits monocyte adhesion and migration to HMGB1 activating HUVECs by blocking activation of proinflammatory cytokines and expression of CAMs and HMGB1 receptors, thereby showing its usefulness as a therapy for vascular inflammatory diseases., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

As a late mediator of inflammation, high mobility group box 1 (HMGB1) protein up-regulates pro-inflammatory cytokines in several inflammatory diseases. Further, high plasma levels of HMGB1 correlate with poor prognosis and increased mortality in patients with severe inflammation. Oleanolic acid (OA), a triterpenoid known for its anti-inflammatory and anti-cancer properties, is commonly present in several medicinal plants but the effects of OA on HMGB1-mediated pro-inflammatory responses of human endothelial cells is not well-studied. In this study, we investigated this question by monitoring the effect of OA on lipopolysaccharide (LPS)-mediated release of HMGB1 and the HMGB1-mediated modulation of inflammatory responses in human umbilical vein endothelial cells (HUVECs). OA potently inhibited the release of HMGB1 by HUVECs as well as down-regulated HMGB1-dependent adhesion and migration of the monocytic cell line THP-1 to activated HUVECs. OA also down-regulated the cell surface expression of the receptor of HMGB1, thereby inhibiting HMGB1-dependent pro-inflammatory responses by inhibiting activation of nuclear factor-κB (NF-κB) and production of tumor necrosis factor-α (TNF-α) by HMGB1. Given these results, OA showed anti-inflammatory activities and could be a candidate as a therapeutic agent for various inflammatory diseases through the inhibition of the HMGB1 signaling pathway., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

High mobility group box 1 (HMGB1) protein is secreted by activated cells of the innate immune system and/or released by injured tissues and necrotic cells; HMGB1 up-regulates proinflammatory cytokines in several inflammatory diseases. Kaempferol-3-O-sophoroside (KP) was isolated from the leaves of cultivated mountain ginseng. KP has antitumor, antioxidative, antiallergic and antidiabetic activities, but the effects of KP on HMGB1-mediated proinflammatory responses have not been studied. In this study, we monitored the effect of KP on the lipopolysaccharide (LPS)-mediated release of HMGB1 and the HMGB1-mediated modulation of proinflammatory responses in human endothelial cells. We found that KP potently inhibited the release of HMGB1 by LPS and inhibited LPS- or HMGB1-mediated barrier permeability and expression of cell adhesion molecules. Further studies revealed that KP inhibited cell surface receptor of HMGB1, toll-like receptor (TLR) 2/4, but not the receptor for advanced glycation end products (RAGE). Collectively, these results suggest that KP possesses anti-inflammatory responses against HMGB1-mediated proinflammatory responses, thereby endorsing its usefulness as a therapy for vascular inflammatory diseases., (Copyright © 2011 Elsevier Ltd. All rights reserved.)