Pulmonary Protective Functions of Rare Ginsenoside Rg4 on Particulate Matter-induced Inflammatory Responses

Wonhwa Lee,Sae Kwang KU,Ji-Eun Kim,Ga-Eun Choi,Gyu Yong Song,Jong-Sup Bae 한국생물공학회 2019 Biotechnology and Bioprocess Engineering Vol.24 No.3

Inhalation of fine particulate matter (PM2.5) is associated with an increase in lung injury caused by the loss of integrity of the vascular barrier. The rare ginsenoside Rg4 is a main protopanaxatriol type ginsenoside of black ginseng (BG). The aim of this study was to investigate the beneficial effects of Rg4 on PM-induced lung endothelial cell (EC) barrier disruption and pulmonary inflammation. Permeability, leukocyte migration, activation of proinflammatory proteins, generation of reactive oxygen species (ROS), and histology were examined in PM2.5-treated EC and mice. Rg4 significantly scavenged PM2.5-induced ROS, inhibited ROS-induced activation of p38 mitogen-activated protein kinase (MAPK), activated Akt in purified pulmonary endothelial cells, which helped maintain endothelial integrity. Further, Rg4 reduced vascular protein leakage, leukocyte infiltration, and proinflammatory cytokine release in bronchoalveolar lavage fluids in PM-induced mouse lung tissues. Data suggested that Rg4 might exhibit protective effects in PM-induced inflammatory lung injury and vascular hyperpermeability.

Inhibitory effects of three diketopiperazines from marine-derived bacteria on endothelial protein C receptor shedding in human endothelial cells and mice

( Wonhwa Lee ),( Sae Kwang Ku ),( Hyukjae Choi ),( Jong Sup Bae ) 영남대학교 약품개발연구소 2016 영남대학교 약품개발연구소 연구업적집 Vol.26 No.-

Diketopiperazine is a natural products found from bacteria, fungi, marine sponges, gorgonian and red algae. They are cyclic dipeptides possessing relatively simple and rigid structures with chiral nature and various side chains. The compounds in this structure class have been known to possess diverse bioactivities including antibiotic ac-tivity, anti-cancer activity, neuroprotective activity, and anti-inflammatory activity. The endothelial cell protein C receptor (EPCR) plays an important role in the cytoprotective pathway and in the activation of protein C. Endo-thelial cell protein C receptor (EPCR) can be shed from the cell surface, which is mediated by tumor necrosis factor-a converting enzyme (TACE). However, little is known about the effects of dike to piperazine on EPCR shed-ding. We investigated this issue by monitoring the effects of diketopiperazine on phorbol-12-myristate 13-acetate (PMA)-, tumor necrosis factor (TNF)-a, and interleukin (1L)-l~-induced EPCR shedding in human umbil-ical vein endothelial cells (HUVECs), and cecal ligation and puncture (CLP)-mediated EPCR shedding in mice and underlying mechanism. Here, three (1-3) of diketopiperazines were isolated from two strains of marine-derived bacteria and 1-3 induced potent inhibition ofPMA-, TNF-a-, IL- W (in HUVECs), and CLP-induced EPCR shedding (in mice) via inhibition of phosphorylation of mitogen-activated protein kinases (MAPKs) such as p38,janus kinase (JNK), and extracellular signal-regulated kinase (ERK) 1/2.1-3 also inhibited the expression and activity of PM A-induced TACE in HUVECs suggesting that p38, ERK1/2, and JNK could be molecular targets of 1-3. These results demonstrate the potential of1-3 as an anti-EPCR shedding reagent against PMA-mediated and CLP--mediated EPCR shedding.

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.

[S6-2] Rational Operation and Management of GMP Factory

Wonhwa Jeong 한국식품영양과학회 2005 한국식품영양과학회 학술대회발표집 Vol.2005 No.10

Anti-Inflammatory Effects of Lysozyme Against HMGB1 in Human Endothelial Cells and in Mice.

Lee, Wonhwa,Ku, Sae-Kwang,Na, Dong Hee,Bae, Jong-Sup Kluwer Academic/Plenum Publishers 2015 INFLAMMATION Vol.38 No.5

<P>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.</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

Renal protective effects of aloin in a mouse model of sepsis

Lee, Wonhwa,Jeong, Gil-Saeng,Baek, Moon-Chang,Ku, Sae-Kwang,Bae, Jong-Sup Pergamon 2019 Food and Chemical Toxicology Vol. No.

<P><B>Abstract</B></P> <P>Aloin is the major anthraquinone glycoside obtained from the <I>Aloe</I> species and exhibits anti-inflammatory and anti-oxidative activities. However, the renal protective effects of aloin and underlying molecular mechanism remain unclear. This study was initiated to determine whether aloin could modulate renal functional damage in a mouse model of sepsis and to elucidate the underlying mechanisms. The potential of aloin treatment to reduce renal damage induced by cecal ligation and puncture (CLP) surgery in mice was measured 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 aloin resulted in a significant reduction in the deleterious renal functions by CLP, such as elevated BUN, creatinine, and urine protein. Moreover, aloin inhibited nuclear factor-κB activation and reduced the induction of nitric oxide synthase and excessive production of nitric acid. Aloin treatment also reduced the plasma levels of interleukin-6 and tumor necrosis factor-α, reduced lethality due to CLP-induced sepsis, increased lipid peroxidation, and markedly enhanced the antioxidant defense system by restoring the levels of superoxide dismutase, glutathione peroxidase, and catalase in kidney tissues. Our study suggested that aloin protects mice against sepsis-triggered renal injury.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Aloin, found in <I>Aloe</I> species, showed renal protection. </LI> <LI> Aloin inhibited CLP-induced elevated levels of BUN and creatinine. </LI> <LI> Aloin inhibited CLP-induced elevated levels of urine protein. </LI> <LI> Aloin inhibited the productions of TNF-α and IL-6 by CLP. </LI> <LI> Aloin enhanced antioxidant defense and decreased lipid peroxidation. </LI> </UL> </P>

Antithrombotic and antiplatelet activities of vicenin-2

Lee, Wonhwa,Bae, Jong-Sup Rapid Communications of Oxford Ltd 2015 Blood coagulation & fibrinolysis Vol.26 No.6

Cyclopia subternata is a medicinal plant commonly used in traditional medicine to relieve pain in physiological processes. However, there are limited modern data on its pharmacological effects and active components relating to its traditional use. Here, the anticoagulant and antiplatelet activities of vicenin-2 (VCN), an active compound in C. subternata, were determined. The anticoagulant activities were investigated by monitoring activated partial thromboplastin time (aPTT), prothrombin time (PT), and the activities of thrombin and activated factor X (FXa). The effects of VCN on the expression of plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) were evaluated in tumor necrosis factor (TNF)-α-activated human umbilical vein endothelial cells (HUVECs). Treatment with VCN resulted in prolonged aPTT and PT and inhibition of the activities of thrombin and FXa, as well as inhibited production of thrombin and FXa in HUVECs. In addition, VCN inhibited thrombin-catalyzed fibrin polymerization and platelet aggregation. VCN also elicited anticoagulant effects in mice. In addition, treatment with VCN resulted in significant reduction of the PAI-1 to t-PA ratio. Collectively, VCN possesses antithrombotic activities and offers a basis for development of a novel anticoagulant.

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>

Ameliorative Effect of Aspalathin and Nothofagin from Rooibos (<i>Aspalathus linearis</i>) on HMGB1-Induced Septic Responses<i>In Vitro</i>and<i>In Vivo</i>

Lee, Wonhwa,Kim, Kyung-Min,Bae, Jong-Sup World Scientific 2015 The American journal of Chinese medicine Vol.43 No.5

<P>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. Aspalathin (Asp) and nothofagin (Not), which have been reported to have anti-oxidant activity, are the two major active dihydrochalcones found in green rooibos. In this study, we investigated the antiseptic effects and underlying mechanisms of Asp and Not against HMGB1-mediated septic responses in HUVECs and mice. The anti-inflammatory activities of Asp and Not were determined by measuring permeability, monocyte adhesion and migration, and activation of proinflammatory proteins in HMGB1-activated HUVECs and mice. According to the results, Asp and Not 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, Asp and Not suppressed the production of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), the activation of nuclear factor-κB (NF-κB) and extracellular signal-regulated kinases 1 and 2 (ERK1/2) by HMGB1. Collectively, these results indicate that Asp and Not could be potential therapeutic agents for the treatment of various severe vascular inflammatory diseases via the inhibition of the HMGB1 signaling pathway.</P>