Isolation, Synthesis, and Antisepsis Effects of a <i>C</i>-Methylcoumarinochromone Isolated from <i>Abronia nana</i> Cell Culture

Lee, Wonhwa,Lee, Doohyun,Lee, Yuri,Lee, Taeho,Song, Kyung-Sik,Yang, Eun-Ju,Bae, Jong-Sup American Chemical Society and American Society of 2018 Journal of natural products Vol.81 No.5

<P>Only a few isoflavones have been isolated from plants of the genus <I>Abronia</I>. The biological properties of compounds isolated from <I>Abronia</I> species have not been well established, and their antisepsis effects have not been reported yet. In the present study, a new <I>C</I>-methylcoumarinochromone, was isolated from <I>Abronia nana</I> suspension cultures. Its structure was deduced as 9,11-dihydroxy-10-methylcoumarinochromone (boeravinone Y, <B>1</B>) by spectroscopic data analysis and verified by chemical synthesis. The potential inhibitory effects of <B>1</B> against high mobility group box 1 (HMGB1)-mediated septic responses were investigated. Results showed that <B>1</B> effectively inhibited lipopolysaccharide-induced release of HMGB1 and suppressed HMGB1-mediated septic responses, in terms of reduction of hyperpermeability, leukocyte adhesion and migration, and cell adhesion molecule expression. In addition, <B>1</B> increased the phagocytic activity of macrophages and exhibited bacterial clearance effects in the peritoneal fluid and blood of mice with cecal ligation and puncture-induced sepsis. Collectively, these results suggested that <B>1</B> might have potential therapeutic activity against various severe vascular inflammatory diseases <I>via</I> inhibition of the HMGB1 signaling pathway.</P> [FIG OMISSION]</BR>

Suppressive Effects of Ginsenoside Rh1 on HMGB1-Mediated Septic Responses

Lee, Wonhwa,Cho, Soo-Hyun,Kim, Ji-Eun,Lee, Changhun,Lee, Jee-Hyun,Baek, Moon-Chang,Song, Gyu-Yong,Bae, Jong-Sup World Scientific Publishing Company 2019 The American journal of Chinese medicine Vol.47 No.1

<P>High mobility group box 1 (HMGB1) is considered as 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. Ginsenoside Rh1, a protopanaxatriol type ginsenoside, is one of the major bioactive components of Korean red ginseng, which has been increasingly used for enhancing cognition and physical health worldwide. Ginsenoside Rh1 exhibits potent biological activities such as antistress, anti-oxidant, anti-inflammatory and immunomodulatory effects. We examined the effects of ginsenoside Rh1 on HMGB1-mediated septic responses and survival rate in a mouse model of sepsis. Ginsenoside-Rh1 was administered after the HMGB1 challenge. The antiseptic activity of ginsenoside Rh1 was determined by measuring the permeability, leukocyte adhesion and migration, activation of pro-inflammatory proteins in HMGB1-activated human umbilical vein endothelial cells (HUVECs) and mice, and the survival rate in a sepsis mouse model. Ginsenoside Rh1 significantly reduced HMGB1 release in lipopolysaccharide (LPS)-activated HUVECs. Furthermore, ginsenoside Rh1 suppressed the production of tumor necrosis factor (TNF)-<TEX>$ \alpha $</TEX>, interleukin (IL)-6, activation of nuclear factor (NF)-<TEX>$ \kappa $</TEX>B and extracellular signal-regulated kinase (ERK) 1/2 by HMGB1. Ginsenoside Rh1 also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with ginsenoside Rh1 reduced the cecal ligation and puncture (CLP)-induced release of HMGB1, sepsis-related mortality and tissue injury <I>in vivo</I>. Our results indicated that ginsenoside Rh1 might be useful in the treatment of sepsis by targeting HMGB1.</P>

Role of moesin in HMGB1-stimulated severe inflammatory responses

Lee, Wonhwa,Kwon, Oh Kwang,Han, Min-Su,Lee, You-Mie,Kim, Shin-Woo,Kim, Kyung-Min,Lee, Taeho,Lee, Sangkyu,Bae, Jong-Sup Thieme 2015 Thrombosis and Haemostasis Vol.114 No.2

<B>Summary</B><P>Sepsis is a life-threatening condition that arises when the body’s response to infection causes systemic inflammation. High-mobility group box 1 (HMGB1), as a late mediator of sepsis, enhances hyper-permeability, and it is therefore a therapeutic target. Despite extensive research into the underlying mechanisms of sepsis, the target molecules controlling vascular leakage remain largely unknown. Moesin is a cytoskeletal protein involved in cytoskeletal changes and para-cellular gap formation. The objectives of this study were to determine the roles of moesin in HMGB1-mediated vascular hyperpermeability and inflammatory responses and to investigate the mechanisms of action underlying these responses. Using siRNA knockdown of moesin expression in primary human umbilical vein endothelial cells (HUVECs), moesin was found to be required in HMGB1-induced F-actin rearrangement, hyperpermeability, and inflammatory responses. The mechanisms involved in moesin phosphorylation were analysed by blocking the binding of the HMGB1 receptor (RAGE) and inhibiting the Rho and MAPK pathways. HMGB1-treated HUVECs exhibited an increase in Thr558 phosphorylation of moesin. Circulating levels of moesin were measured in patients admitted to the intensive care unit with sepsis, severe sepsis, and septic shock; these patients showed significantly higher levels of moesin than healthy controls, which was strongly correlated with disease severity. High blood moesin levels were also observed in cecal ligation and puncture (CLP)-induced sepsis in mice. Administration of blocking moesin antibodies attenuated CLP-induced septic death. Collectively, our findings demonstrate that the HMGB1-RAGE-moesin axis can elicit severe inflammatory responses, suggesting it to be a potential target for the development of diagnostics and therapeutics for sepsis.</P>

Antiseptic Effects of New 3'-N-Substituted Carbazole Derivatives In Vitro and In Vivo.

Lee, Wonhwa,Kwak, Soyoung,Yun, Eunju,Lee, Jee Hyun,Na, MinKyun,Song, Gyu-Yong,Bae, Jong-Sup Kluwer Academic/Plenum Publishers 2015 INFLAMMATION Vol.38 No.4

<P>Inhibition of high-mobility group box 1 (HMGB1) protein and restoration of endothelial integrity are emerging as attractive therapeutic strategies in the management of sepsis. Here, new five structurally related 3'-N-substituted carbazole derivatives were examined for their effects on lipopolysaccharide (LPS)-mediated or cecal ligation and puncture (CLP)-mediated release of HMGB1 and on modulation of HMGB1-mediated inflammatory responses. We accessed this question by monitoring the effects of posttreatment carbazole derivatives on LPS- and CLP-mediated release of HMGB1 and HMGB1-mediated regulation of proinflammatory responses in human umbilical vein endothelial cells (HUVECs) and septic mice. The new 3'-N-substituted carbazole derivatives 1-5 inhibited the release of HMGB1 and downregulated HMGB1-dependent inflammatory responses in human endothelial cells. New compounds also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with each compound reduced CLP-induced release of HMGB1 and sepsis-related mortality and pulmonary injury in mice. These results indicate that the new 3'-N-substituted carbazole derivatives could be candidate therapeutic agents for various severe vascular inflammatory diseases owing to their inhibition of the HMGB1 signaling pathway.</P>

Research on theragnostic biomaterials for severe COVID-19

Wonhwa LEE 한국생물공학회 2021 한국생물공학회 학술대회 Vol.2021 No.10

The outbreak of highly contagious and deadly SARS-CoV-2, also known as Coronavirus Disease 2019 (COVID-19) has posed a serious threat to public health across the globe, calling for the development of effective diagnostic markers and therapeutics. Here, we report a highly reliable theragnostic biomarker, acetylated 676th lysine transforming growth factor beta-induced protein (TGFBIp K676Ac). The TGFBIp K676Ac was consistently elevated in the blood of SARS-CoV-2 pneumonia patients (n=113); especially in patients of intensive care unit (ICU) than non-ICU. Patients’ blood samples showed increased cytokines and lymphopenia, which are exemplary evidence of SARS-CoV-2 pneumonia. Treatment of TGFBIp neutralizing antibodies suppressed the cytokine storm. The increased level of TGFBIp K676 Ac in ICU patients implies that it can be used as a reliable theragnostic biomarker for SARS-CoV-2.

Protective effects of zingerone on lipopolysaccharide-induced hepatic failure through the modulation of inflammatory pathways

Lee, Wonhwa,Hwang, Mi-Hye,Lee, Yuri,Bae, Jong-Sup Elsevier 2018 Chemico-biological interactions Vol.281 No.-

<P><B>Abstract</B></P> <P>The aim of this study was to investigate the effects of zingerone (ZGR) on lipopolysaccharide (LPS)-induced liver failure in mice, and to elucidate underlying mechanisms. ZGR is a phenolic alkanone isolated from ginger, and has potential health benefits. Mice were treated intravenously with ZGR at 12 h after LPS treatment. LPS significantly increased mortality, serum levels of alanine transaminase, aspartate transaminase, and inflammatory cytokines, and toll-like receptor 4 (TLR4) protein expression; these effects of LPS were inhibited by ZGR. It also attenuated the LPS-induced activation of myeloid differentiation primary response gene 88 and TLR-associated activator of interferon-dependent signaling pathways of the TLR system. Our results suggest that ZGR protects against LPS-induced liver damage by inhibiting the TLR-mediated inflammatory pathway, indicating its potential to treat liver diseases.</P> <P><B>Highlights</B></P> <P> <UL> <LI> LPS-induced hepatic failure model in mice mimics the clinical hepatitis. </LI> <LI> ZGR suppressed LPS-induced mortality in vivo. </LI> <LI> ZGR attenuates LPS-induced liver damage by inhibition TLR signaling. </LI> <LI> ZGR could be used to treat liver diseases. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Anti-inflammatory effects of oleanolic acid on LPS-induced inflammation in vitro and in vivo.

Lee, Wonhwa,Yang, Eun-Ju,Ku, Sae-Kwang,Song, Kyung-Sik,Bae, Jong-Sup Kluwer Academic/Plenum Publishers 2013 INFLAMMATION Vol.36 No.1

<P>Oleanolic acid (OA) is a triterpenoid known for its anti-inflammatory and anti-cancer properties; however, the anti-inflammatory effects of OA on lipopolysaccharide (LPS)-mediated pro-inflammatory responses have not been studied. Here, we first investigated the possible anti-inflammatory effects of OA against pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) induced by LPS and the associated signaling pathways. We found that OA inhibited LPS-induced barrier disruption, expression of cell adhesion molecules (CAMs), and adhesion/transendothelial migration of monocytes to HUVECs. OA also suppressed acetic acid-induced hyperpermeability and carboxymethylcellulose-induced leukocyte migration in vivo. Further studies revealed that OA suppressed the production of tumor necrosis factor-α and activation of nuclear factor-κB by LPS. Collectively, these results suggest that OA has anti-inflammatory effects by inhibiting hyperpermeability, the expression of CAMs, and the adhesion and migration of leukocytes, thereby endorsing its usefulness as a therapeutic agent for vascular inflammatory diseases.</P>

Cudratricusxanthone A attenuates renal injury in septic mice

Lee, Wonhwa,Lee, Yuri,Jeong, Gil-Saeng,Ku, Sae-Kwang,Bae, Jong-Sup Elsevier 2017 Food and Chemical Toxicology Vol. No.

<P><B>Abstract</B></P> <P>As a natural compound extracted from the roots of <I>Cudrania tricuspidata</I> Bureau, Cudratricusxanthone A (CTXA) is known to possess hepatoprotective, anti-inflammatory, and anti-proliferative activities. This study was aimed to clarify the role of CTXA in modulating renal functional damage in a mouse model of sepsis and to elucidate its underlying mechanisms. We examined the renal protective effects of CTXA on cecal ligation and puncture (CLP)-induced renal damage by assessment of serum creatinine, blood urea nitrogen (BUN), lipid peroxidation, total glutathione, glutathione peroxidase activity, catalase activity, and superoxide dismutase activity. Post-treatment with CTXA resulted in a significant reduction in the deleterious renal functions by CLP, such as elevated BUN, creatinine, and urine protein. Induction of nitric oxide synthase and excessive production of nitric acid by CLP surgery were significantly reduced by post-treatment with CTXA via inhibiting nuclear factor-κB activation. Furthermore, the plasma levels of interleukin-6 and tumor necrosis factor-α were suppressed by CTXA post-treatment. Concurrently, CTXA treatment potently suppressed the CLP-induced septic lethality, rise of lipid peroxidation and markedly enhanced the antioxidant defense system by restoring the levels of superoxide dismutase, glutathione peroxidase, and catalase in kidney. The present results suggested that CTXA could protect against sepsis-triggered renal injury in mice.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Cudratricusxanthone A (CTXA), found in <I>Cudrania tricuspidata</I>, showed renal protection. </LI> <LI> CTXA inhibited CLP-induced elevated levels of BUN, creatinine, and urine protein. </LI> <LI> CTXA inhibited the productions of TNF-α and IL-6 by CLP. </LI> <LI> CTXA enhanced antioxidant defense and decreased lipid peroxidation. </LI> </UL> </P>

Ameliorative Effect of Vicenin-2 and Scolymoside on TGFBIp-Induced Septic Responses

Lee, Wonhwa,Ku, Sae-Kwang,Bae, Jong-Sup Springer-Verlag 2015 INFLAMMATION Vol.38 No.6

Factor Xa inhibits HMGB1-induced septic responses in human umbilical vein endothelial cells and in mice.

Lee, Wonhwa,Ku, Sae-Kwang,Bae, Jong-Sup F. K. Schattauer 2014 Thrombosis and Haemostasis Vol.112 No.4

<P>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.</P>