HMGB1-Binding Heptamer Confers Anti-Inflammatory Effects in Primary Microglia Culture

김일두,이자경 한국뇌신경과학회 2013 Experimental Neurobiology Vol.22 No.4

High mobility group box 1 (HMGB1) is an endogenous danger signal molecule. In the postischemic brain, HMGB1 is massivelyreleased during NMDA-induced acute damage and triggers inflammatory processes. In a previous study, we demonstrated thatintranasally delivered HMGB1 binding heptamer peptide (HBHP; HMSKPVQ) affords robust neuroprotective effects in theischemic brain after middle cerebral artery occlusion (MCAO, 60 minutes). In the present study, we investigated HBHP-inducedanti-inflammatory effects on microglia activation. In LPS-treated primary microglia culture, HMGB1 was rapidly released andaccumulated in culture media. Furthermore, LPS-conditioned media collected from primary microglia cultures (LCM) activatednaïve microglia and markedly induced NO and proinflammatory cytokines. However, the suppression of HMGB1 by siRNA-HMGB1, HMGB1 A box, or anti-HMGB1 antibody significantly attenuated LCM-induced microglial activation, suggesting thatHMGB1 plays a critical role in this process. A pull-down assay using biotin-labeled HBHP showed that HBHP binds directlyto HMGB1 (more specifically to HMGB1 A box) in LCM. In addition, HBHP consistently inhibited LCM-induced microglialactivation and suppressed the inductions of iNOS and proinflammatory cytokines. Together these results suggest that HBHP confersanti-inflammatory effects in activated microglia cultures by forming a complex with HMGB1.

Sirt1 S-nitrosylation induces acetylation of HMGB1 in LPS-activated RAW264.7 cells and endotoxemic mice

Kim, Young Min,Park, Eun Jung,Kim, Hye Jung,Chang, Ki Churl Elsevier 2018 Biochemical and biophysical research communication Vol.501 No.1

<P><B>Abstract</B></P> <P>Excessive inflammation plays a detrimental role in endotoxemia. A recent study indicated that alarmins such as high mobility group box 1 (HMGB1) have drawn attention as therapeutic targets of sepsis. Post-translational modification (i.e., acetylation of lysine residues) of HMGB1 leads to the release of HMGB1 into the cellular space, operating as a warning signal that induces inflammation. Sirtuin 1 (SIRT1) has been shown to negatively regulate HMGB1 hyperacetylation and its extracellular release in sepsis. Therefore, we hypothesized that the S-nitrosylation (SNO) of SIRT1 may disrupt the ability of SIRT1 to negatively regulate the hyperacetylation of HMGB1. As long as the S-nitrosylation of SIRT1 occurs during septic conditions, it may worsen the situation. We found that the activity of SIRT1 decreased as the SNO-SIRT1 levels increased, resulting in HMGB1 release by LPS in RAW264.7 cells. Both the iNOS inhibitor (1400 W) and silencing iNOS significantly inhibited SNO-SIRT1, allowing increases in SIRT1 activity that decreased the HMGB1 release by LPS. SNAP, a NO donor, significantly increased both SNO-SIRT1 levels and the HMGB1 release that was accompanied by decreased sirt1 activity. However, sirtinol, a Sirt1 inhibitor, by itself decreased Sirt1 activity compared to that of the control, so that it did not affect already increased SNO-SIRT levels by SNAP. Most importantly, in lung tissues of LPS-endotoxic mice, significantly increased levels of SNO-SIRT were found, which was inhibited by 1400 W treatment. Plasma nitrite and HMGB1 levels were significantly higher than those in the sham controls, and the elevated levels were significantly lowered in the presence of 1400 W. We concluded that the S-nitrosylation of Sirt1 under endotoxic conditions may uninhibit the acetylation of HMGB1 and its extracellular release.</P> <P><B>Highlights</B></P> <P> <UL> <LI> S-nitrosylation of SIRT1 (SNO-SIRT1) by NO resulted in HMGB1 release in LPS-activated RAW264.7 cells. </LI> <LI> The iNOS inhibitor (1400 W) and si-iNOS significantly inhibited SNO-SIRT1, which decreased the HMGB1 release by LPS. </LI> <LI> The levels of SNO-SIRT were significantly increased in LPS-injected mice lung, which was inhibited by 1400 W treatment. </LI> <LI> The SNO-SIRT1 under endotoxic conditions may uninhibit the acetylation of HMGB1 and its extracellular release. </LI> </UL> </P>

HMGB1 modulation in pancreatic islets using a cell-permeable A-box fragment

Hwang, Yong Hwa,Kim, Min Jun,Lee, Yong-Kyu,Lee, Minhyung,Lee, Dong Yun Elsevier 2017 Journal of controlled release Vol.246 No.-

<P><B>Abstract</B></P> <P>Although pancreatic islet implantation is an attractive strategy for curing diabetes mellitus, implanted cells are immunologically eliminated due to early islet graft loss. One of main issues in early islet graft loss is the secretion of high-mobility group-box-1 (HMGB1) protein from the damaged islet cells, which is known as a cytokine-like factor. Therefore, regulating the activity of HMGB1 protein offers an alternative strategy for improving outcomes of islet cell therapy. To this end, we first demonstrated that HMGB1 protein could be bound to its A-box fragment (HMGB1 A-box) with higher binding affinity, resembling anti-HMGB1 antibody. To be used as a pharmaceutical protein <I>ex vivo</I>, TAT-labeled HMGB1 A-box-His<SUB>6</SUB> (TAT-HMGB1A) was structurally modified for cellular membrane penetration. TAT-HMGB1A significantly reduced secretion of endogenous HMGB1 protein through interaction in the cytosol without any damage to the viability or functionality of the islets. When TAT-HMGB1A-treated islets were implanted into diabetic nude mice, they completely cured diabetes, as evidenced by stable blood glucose level. TAT-HMGB1A treatment could also reduce the marginal islet mass needed to cure diabetes. Furthermore, TAT-HMGB1A positively protected xenotransplanted islets from xenogeneic immune reactions. Collectively, cell-penetrable TAT-HMGB1A could be used to modulate HMGB1 activity to increase successful outcomes of <I>ex vivo</I> pancreatic islet cell therapy.</P> <P><B>Graphical abstract</B></P> <P> <I>Ex vivo</I> cell-permeable HMGB1 A-box fragment delivery into pancreatic islet could offer enhanced viability of islets from immune reactions, thereby supporting successful pancreatic islet transplantation to cure diabetes mellitus.</P> <P>[DISPLAY OMISSION]</P>

High mobility group B1(HMGB1)과 LPS의 염증유발효과 차이의 비교 및 HMGB1에 의한 IL-8 promoter 자극 기전의 규명

전은주 ( Eun Ju Jeon ),곽희원 ( Hee Won Kwak ),송주한 ( Ju Han Song ),이영우 ( Young Woo Lee ),정재우 ( Jae Woo Chung ),최재철 ( Jae Chul Choi ),신종욱 ( Jong Wook Shin ),박인원 ( In Won Park ),최병휘 ( Byoung Whui Choi ),김재열 ( 대한결핵 및 호흡기학회 2007 Tuberculosis and Respiratory Diseases Vol.62 No.4

배경: HMGB1은 염증반응의 후기에 분비되는 중요한 염증유발물질 중 하나이다. 본 연구에서는 기존에 염증유발물질로 잘 알려진 LPS와 새롭게 염증유발물질로 관심을 받고 있는 HMGB1의 염증유발작용을 생체 외 및 생체 내 실험을 통해 비교하고자 하였다. 또한 HMGB1의 자극에 의한 IL-8 promoter region의 활성화에 중요한 역할을 수행하는 전사인자들을 확인하고자 하였다. 방법: RAW264.7 세포에 LPS(100 ng/ml) 또는 HMGB1(500 ng/ml)을 투여하고 각각 0, 2, 4, 8, 12 그리고 24시간 뒤에 세포상층액의 TNF-α, MIP-2 그리고 IL-1β의 농도를 ELISA법으로 측정하였다. 생쥐의 복강에 LPS(5 mg/kg) 또는 HMGB1(2.5 mg/kg)을 주입하여 급성폐손상을 유발한 후에 폐의 사이토카인의 발현과 MPO 활성도를 측정하였다(LPS는 4시간 뒤, HMGB1은 24 시간 뒤). IL-8 promoter 부위에 있는 NF-IL6, NF-κB 그리고 AP-1에 대한 결합부위에 대해 돌연변이를 일으킨 후에 각각의 돌연변이체를 pIL-6luc에 결합시킨 뒤 RAW264.7 세포에 삽입하였다. 이 세포들을 36시간 배양한 후에 HMGB1(500 ng/ml)으로 자극하고, 한 시간 뒤에 세포를 녹인 후 luciferase 활성도를 측정하였다. 결과: LPS 투여 후에 RAW264.7 세포 배양상층액의 TNF-α농도는 24시간 뒤에, MIP-2 농도는 8시간 뒤에 최고치를 보였다. 한편 HMGB1 투여 후에는 TNF-α와 MIP-2 농도 모두 24시간 뒤에 최고치를 나타내었다. LPS 복강 내 투여 후 4시간 뒤에 생쥐의 폐의 TNF-α, MIP-2 그리고 IL-1β의 농도는 대조군에 비해 현저히 증가하였으나, HMGB1 복강 내 투여 후 24시간 뒤에 생쥐의 폐에서는 IL-1β의 농도만 약간 증가하였다. MPO 활성도는 LPS와 HMGB1 투여 후에 모두 증가하였으며, LPS 투여 후가 더 의미있게 증가하였다. NF-κB 돌연변이체와 AP-1 돌연변이체에서 luciferase 활성도가 의미있게 감소하였다. 결론: 이상의 결과를 살펴볼 때 HMGB1은 염증유발효과는 LPS에 비해 강도가 떨어지나 지속시간은 오래 계속되는 것으로 보이며, HMGB1에 의한 IL-8의 활성화에 NF-κB 뿐만 아니라 AP-1도 중요한 역할을 수행하는 것으로 판단된다. Background: High mobility group box 1 (HMGB1) is a novel, late mediator of inflammation. This study compared the pro-inflammatory effects of LPS and HMGB1. The transcriptional factors that play an important role in mediating the HMGB1-induced stimulation of IL-8 were also evaluated. Methods: RAW264.7 cells were stimulated with either LPS (100 ng/ml) or HMGB1 (500 ng/ml). The TNF-α, MIP-2 and IL-1β levels in the supernatant were evaluated by ELISA at 0, 2, 4, 8, 12 and 24h after stimulation. An acute lung injury was induced by an injection of LPS (5 mg/kg) or HMGB1 (2.5 mg/kg) into the peritoneum of the Balb/c mice. The lung cytokines and MPO activity were measured at 4h (for LPS) or 24h (for HMGB1) after the injection. The transcriptional factor binding sites for NF-IL6, NF-κB and AP-1 in the IL-8 promoter region were artificially mutated. Each mutant was ligated with pIL-6luc and transfected into the RAW264.7 cells. One hour after stimulation with HMGB1 (500 ng/ml), the cell lysate was analyzed for the luciferase activity. Results: The expression of MIP-2, which peaked at 8h with LPS stimulation, increased sequentially until 24h after HMGB1 stimulation. An intraperitoneal injection of HMGB1, which induced a minimal increased in IL-1β expression, provoked the accumulation of neutrophils the lung. A mutation of AP-1 as well as NF-κB in the IL-8 promoter region resulted in a lower luciferase activity after HMGB1 stimulation. Conclusion: The proinflammatory effects of HMGB1, particularly on IL-8, are mediated by both NF-κB and AP-1. (Tuberc Respir Dis 2007; 62: 299-307)

Medicinal Chemistry : Ginsenosides Inhibit HMGB1-induced Inflammatory Responses in HUVECs and in Murine Polymicrobial Sepsis

( Won Hwa Lee ),( Sae Kwang Ku ),( Tae Cheon Jeong ),( Sang Kyu Lee ),( Jong Sup Bae ) 영남대학교 약품개발연구소 2015 영남대학교 약품개발연구소 연구업적집 Vol.25 No.-

Asian ginseng is used as a treatment for cardiovascular diseases, ischemia, and cancers. High mobility group box 1 (HMGB1) protein acts as a late mediator of severe vascular inflammatory conditions. However, the effect of ginsenosides from Asian ginseng on HMGB1-induced inflammatory responses has not been studied. We addressed this question by monitoring the effects of ginsenoside treatmenet on lipopolysaccharide (LPS) and cecal ligation and puncture (CLP)-mediated release of HMGB1, and HMGB1-mediated regulation of proinflammatory responses. Ginsenoside treatment suppressed LPS-mediated relaease of HMGB1 and HMGB1-mediated cytoskeletal rearrangement. Ginsenosides also inhibited HMGB1-mendiated inflammatory responses. In addition, ginsenosides inhibited the production of tumor necrosis factor -α (TNF-α) and activation of protein kinase B (Akt), nuclear factor-kB(NF-kB), and extracellular-regulated kinases (ERK) 1/2 by HMGB1. Ginsenosides also decreased CLP-induced release of HMGB1, production of interleukin (IL) 1β/6, and mortality. These results suggested that ginsenosides may be potential therapeutic agents for treatment of vascular inflammatory diseases through inhibition of the HMGB1 signaling patheway.

HMGB1 Switches Alkylating DNA Damage-Induced Apoptosis to Necrosis

Su Yeon Lee(이수연),Eui Kyong Jeong(정의경),Hyun Min Jeon(전현민),Min Kyung Ju(주민경),Cho Hee Kim(김초희),Hye Gyeong Park(박혜경),Ho Sung Kang(강호성) 한국생명과학회 2011 생명과학회지 Vol.21 No.7

세포괴사는 세포막의 파열, HMGB1을 포함한 세포 내용물의 세포외부로의 방출 등을 수반하는 세포죽음이다. HMGB1은 핵 단백질로 전사조절자로 작용하지만 세포괴사에 의해 세포 밖으로 방출되면 염증을 유발하고 암을 촉진하는 cytokine으로 작용한다. HMGB1의 과발현은 암 발생 및 항암제 저항과 밀접한 연관성을 가지고 있지만, 그 기작에 대한 연구는 미흡한 실정이다. 본 연구에서는, HMGB1이 항암제에 의한 세포 죽음에 미치는 영향을 조사하였다. 그 결과, HMGB1은 MCF-7, MDA-MB231, MDA-MB361 세포에서 cisplatin에 의한 세포사멸을 억제하고 세포운명을 세포괴사로 바꾼다는 사실을 확인하였다. HMGB1의 세포사멸-세포괴사 전환 작용을 4-HC를 처리한 세포에서도 관찰되었다. 그러나, HMGB1은 docetaxel (DOC)에 의한 세포사멸에는 영향을 주지 않음을 확인하였다. MTS를 이용하여 항암제에 의한 세포 죽음에 미치는 영향을 조사한 결과, necrotic core가 형성된 8일째 MCF-7 MTS에서 cisplatin에 의한 세포사멸이 세포괴사로 바뀌는 반면, DOC에 의한 세포사멸은 세포괴사로 전환되지 않는 것을 확인하였다. 또한 spheroid에서 HMGB1 receptor인 RAGE의 발현이 증가함을 확인하였다. 이러한 결과를 통해, HMGB1이 alkylating agent에 의한 세포사멸을 세포괴사로 전환시킴을 알 수 있었다. 따라서, alkylating agent에 의한 항암제 효능을 나타내기 위해선, 이들 항암제의 부작용 즉 세포괴사를 억제하는 전략이 필요한 것으로 생각된다. Necrosis is characterized by the cell membrane rupture and release of the cellular contents, including high-mobility group box 1 protein (HMGB1), into the extracellular microenvironment. HMGB1 acts as a transcriptional regulator in nuclei, but exerts a pro-inflammatory and tumor-promoting cytokine activity when released into the extracellular space. Its overexpression is associated with tumor progression and chemoresistance. Thus, HMGB1 acts as a clinically important molecule in tumor biology. In this study, we examined whether HMGB1 affects cell death induced by anti-cancer drugs. Here we show that HMGB1 prevented cisplatin (alkylating agent)-induced apoptosis and switched the cell fate to necrosis in MCF-7, MDA-MB231, and MDA-MB361 cells. Similar apoptosis-to-necrosis switch effects of HMGB1 were observed in cells treated with 4-HC, another alkylating agent. In contrast, HMGB1 did not exert any significant effects on docetaxel (DOC)-induced apoptosis in MCF-7 cells. We also show that cisplatin-induced apoptosis was switched to necrosis in MCF-7 multicellular tumor spheroids (MTS) that were cultured for 8 days and had necrotic cores, but DOC-induced apoptosis was prevented without the apoptosis-to-necrosis switch. Finally, the levels of RAGE, a receptor of HMGB1, were increased with extended culture of MTS. These findings demonstrate that HMGB1 switches alkylating agent-induced apoptosis to necrosis, suggesting that the strategy to prevent necrosis occurring as an undesirable action of alkylating agent-based chemotherapy should be delineated to improve the efficacy of chemotherapy for cancer.

Suppressive effects of rare ginsenosides, Rk1 and Rg5, on HMGB1-mediated septic responses

Kim, Ji-Eun,Lee, Wonhwa,Yang, Sumin,Cho, Soo-Hyun,Baek, Moon-Chang,Song, Gyu-Yong,Bae, Jong-Sup Elsevier 2019 Food and chemical toxicology Vol.124 No.-

<P><B>Abstract</B></P> <P>High mobility group box 1 (HMGB1) is considered to be a late mediator of sepsis. The inhibition of HMGB1-mediated severe inflammatory response and restoration of endothelial integrity have emerged as attractive therapeutic strategies for the management of sepsis. Rare ginsenosides, Rk1 (<B>SB1</B>) and Rg5 (<B>SB2</B>), are among the main components of black ginseng and are prepared from ginsenoside Rd by steaming at 120 °C for 3 h. We examined the effects of <B>SB1</B> and <B>SB2</B> on HMGB1-mediated septic response and survival rate in a mouse model of sepsis. <B>SB1</B> and <B>SB2</B> were administered after challenge with HMGB1. <B>SB1</B> and <B>SB2</B> significantly reduced the release of HMGB1 in lipopolysaccharide (LPS)-activated primary human umbilical vein endothelial cells (HUVECS) via the SIRT1-mediated deacetylation of HMGB1. Moreover, <B>SB1</B> and <B>SB2</B> suppressed the production of TNF-α and IL-6 and the activation of NF-κB and ERK 1/2 by HMGB1. <B>SB1</B> and <B>SB2</B> also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with <B>SB1</B> and <B>SB2</B> reduced the cecal ligation and puncture-induced release of HMGB1, sepsis-related mortality, and tissue injury in vivo. Our results indicate that <B>SB1</B> and <B>SB2</B> might be useful in the treatment of sepsis by targeting HMGB1.</P> <P><B>Highlights</B></P> <P> <UL> <LI> HMGB1 is considered a late mediator of sepsis. </LI> <LI> Rare ginnsenosides, SB1 and SB2, are among the main components of black ginseng. </LI> <LI> SB1 and SB2 suppressed LPS-induced secretion of HMGB1. </LI> <LI> SB1 and SB2 reduced HMGB1-mediated septic responses. </LI> <LI> SB1 and SB2 reduced mortality and lung injury in mouse sepsis model. </LI> </UL> </P>

아연에 의한 신경세포사 과정에서 유출되는 HMGB1의 세포사 악화에 대한 영향

임채문(Chae-Moon Lim),김정빈(Jung-Bin Kim),이자경(Ja-Kyeong Lee) 대한해부학회 2008 Anatomy & Cell Biology Vol.41 No.1

High mobility group box 1 (HMGB1)은 염증유발 사이토 카인으로 작용하는 것이 보고되었으며, 허혈에 의한 뇌손상 과정에서도 HMGB1은 세포 밖으로 급격히 유출되고 유출된 HMGB1은 염증유발 사이토카인으로 작용하는 것으로 보고되었다. 한편, 허혈에 의한 뇌조직 손상 과정에서 아연이 중요한 역할을 한다는 것이 알려져 있다. 본 연구에서는 아연에 의해 유도되는 1차 배양 대뇌피질 신경세포 손상 과정에서 HMGB1이 세포 밖으로 유출되고, 유출된 HMGB1이 신경세포 사멸을 가속화시키는 과정을 조사하였다. 황산아연 200 μM을 1차 배양 대뇌피질 신경세포에 30분간 처리한 후 새로운 배양액에서 24시간 동안 배양하면, 세포생존율이 44.6±1.5%로 감소된다. 이 과정에서 과량의 HMGB1 세포 밖으로 빠져나와 배양액에 축적되는 것을 웨스턴 블롯과 이중면역형광염색법으로 확인하였다. 황산아연 200μM을 처리한 1차 배양 신경세포의 배양액을 24시간 후에 회수하여 농축한 후, 새로운 1차 배양 신경세포에 처리하면 세포생존율이 69.6±1.4%로 감소되는 것을 관찰하였다. 그러나 아연과 함께 아연의 chelator인 TPEN 1mM을 처리하거나 HMGB1 siRNA를 각각 처리한 세포의 배양액을 사용한 경우에는 배양액 처리에 의한 세포사 유도가 억제되었다. 또한, HMGB1 특이 항체나 HMGB1의 리간드 중의 하나로 알려진 RAGE의 특이 항체를 처리하면 세포생존율이 각각 81.0±4.0%, 79.0±4.0%로 회복되었다. 이와 같은 결 과는 아연에 의해 유도되는 신경세포 손상 과정에서 급격히 유출되는 HMGB1이 세포사멸을 유도, 악화시킬 가능성을 시사한다. As a nonhistone DNA-binding protein, high mobility group box 1 (HMGB1) is released in large amounts into the extracellular space immediately after ischemic insult and plays a role in the release of proinflammatory cytokines. Here, we the examined cytokine-like or signaling molecule-like function of extracellular HMGB1 in primary cortical cultures. We found that a large amount of HMGB1 was released following zinc-induced neuronal cell death in primary cortical cultures and that this extracellular HMGB1 might aggravate neuronal damage. The conditioned media collected from zinc-treated primary cortical cultures decreased neuronal cell survival to 69.6±1.4% of control values when added to fresh primary cortical cultures. In contrast, treatment with HMGB1-depleted conditioned media produced by cultures treated with an HMGB1 siRNA-expression vector suppressed the induction of neuronal death. A mutant HMGB1 siRNA-expression vector did not suppress the induction of neuronal death, demonstrating a role of HMGB1 in neuronal death. Moreover, HMGB1-depletion in media conditioned by cotreatment with anti-HMGB1 antibody or with anti-RAGE antibody, a potential receptor for HMGB1, recovered neuronal cell survival to 81.0±4.0% and 79.0±4.0%, respectively, when added to fresh primary cortical cultures. These results indicate that extracellular HMGB1 released after zinc treatment induces neuronal death, which might aggravate zinc toxicity.

High-mobility group box 1 is responsible for monosodium urate crystal-induced inflammation in human U937 macrophages

Choe, Jung-Yoon,Choi, Chang-Hyuk,Park, Ki-Yeon,Kim, Seong-Kyu Elsevier 2018 Biochemical and biophysical research communication Vol.503 No.4

<P><B>Abstract</B></P> <P>High-mobility group box 1 (HMGB1) was originally identified as a highly conserved non-histone DNA-binding factor and demonstrated to be a potent mediator in inflammatory diseases. We performed this study to investigate the role of HMGB1 in the pathogenesis of uric acid-induced inflammation in human U937 macrophages. To simulate uric acid-induced inflammation, human U937 macrophages were treated with monosodium urate (MSU) crystals. In addition to determining the effects of MSU crystal treatment on expression of various genes and proteins, cells were transfected with interfering RNA (siRNA) for HMGB1, or caspase-1 and then treated with MSU. Expression of interleukin-1β (IL-1β), IL-18, HMGB1, and caspase-1 was detected in human U937 cells and peripheral blood mononuclear cells (PBMCs) in gout patients and healthy controls by western blot analysis or quantitative real-time polymerase chain reaction. Transcript expression of IL-1β, IL-18, caspase-1, HMGB1 in PBMCs was significantly higher in active gout patients than inactive gout patients and healthy controls. The protein levels of these molecules were significantly increased by stimulation of U937 cells with 0.2 mg/ml MSU crystals. Stimulation of U937 cells with MSU crystals induced translocation of HMGB1 from the nucleus to the cytoplasm and its extracellular release. U937 cells transfected with caspase-1 siRNA had significantly lower HMGB1 expression in the cytoplasm and supernatant than non-transfected cells. Antioxidants, such as <I>N</I>-acetyl-<SMALL>L</SMALL>-cysteine and quercetin, markedly inhibited the nuclear-to-cytoplasmic translocation of HMGB1 and its release into the extracellular milieu. In conclusion, HMGB1, regulated by the enzymatic activity of caspase-1, is a crucial mediator in uric acid-induced inflammation.</P> <P><B>Highlights</B></P> <P> <UL> <LI> U937 cells with MSU crystals induced translocation of HMGB1 from the nucleus to the cytoplasm and its extracellular release. </LI> <LI> Activated caspase-1 could be responsible for translocation and releases of HMGB1 in inflammatory cells. </LI> <LI> HMGB1 is a crucial mediator of uric acid-induced inflammation. </LI> </UL> </P>

Zingerone reduces HMGB1-mediated septic responses and improves survival in septic mice

Lee, W.,Ku, S.K.,Bae, J.S. Academic Press 2017 Toxicology and applied pharmacology Vol.329 No.-

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 ½ 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.