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    Endothelial cell pyroptosis plays an important role in Kawasaki disease via HMGB1/RAGE/cathespin B signaling pathway and NLRP3 inflammasome activation. Jia Chang,Zhang Jian,Chen Huanwen,Zhuge Yingzhi,Chen Huiqiao,Qian Fanyu,Zhou Kailiang,Niu Chao,Wang Fangyan,Qiu Huixian,Wang Zhenquan,Xiao Jian,Rong Xing,Chu Maoping Cell death & disease Kawasaki disease (KD) is the most common cause of pediatric cardiac disease in developed countries, and can lead to permanent coronary artery damage and long term sequelae such as coronary artery aneurysms. Given the prevalence and severity of KD, further research is warranted on its pathophysiology. It is known that endothelial cell damage and inflammation are two essential processes resulting in the coronary endothelial dysfunction in KD. However, detailed mechanisms are largely unknown. In this study, we investigated the role of pyroptosis in the setting of KD, and hypothesized that pyroptosis may play a central role in its pathophysiology. In vivo experiments of patients with KD demonstrated that serum levels of pyroptosis-related proteins, including ASC, caspase-1, IL-1β, IL-18, GSDMD and lactic dehydrogenase (LDH), were significantly increased in KD compared with healthy controls (HCs). Moreover, western blot analysis showed that the expression of GSDMD and mature IL-1β was notably elevated in KD sera. In vitro, exposure of human umbilical vein endothelial cells (HUVECs) to KD sera-treated THP1 cells resulted in the activation of NLRP3 inflammasome and subsequent pyroptosis induction, as evidenced by elevated expression of caspase-1, GSDMD, cleaved p30 form of GSDMD, IL-1β and IL-18, and increased LDH release and TUNEL and propidium iodide (PI)-positive cells. Furthermore, our results showed that NLRP3-dependent endothelial cell pyroptosis was activated by HMGB1/RAGE/cathepsin B signaling. These findings were also recapitulated in a mouse model of KD induced by Candida albicans cell wall extracts (CAWS). Together, our findings suggest that endothelial cell pyroptosis may play a significant role in coronary endothelial damage in KD, providing novel evidence that further elucidates its pathophysiology. 10.1038/s41419-019-2021-3
    Calycosin attenuates severe acute pancreatitis-associated acute lung injury by curtailing high mobility group box 1 - induced inflammation. Zhu Chang-Ju,Yang Wan-Guang,Li De-Jian,Song Yao-Dong,Chen San-Yang,Wang Qiao-Fang,Liu Yan-Na,Zhang Yan,Cheng Bo,Wu Zhong-Wei,Cui Zong-Chao World journal of gastroenterology BACKGROUND:Acute lung injury (ALI) is a common and life-threatening complication of severe acute pancreatitis (SAP). There are currently limited effective treatment options for SAP and associated ALI. Calycosin (Cal), a bioactive constituent extracted from the medicinal herb Radix Astragali exhibits potent anti-inflammatory properties, but its effect on SAP and associated ALI has yet to be determined. AIM:To identify the roles of Cal in SAP-ALI and the underlying mechanism. METHODS:SAP was induced two intraperitoneal injections of L-arg (4 g/kg) and Cal (25 or 50 mg/kg) were injected 1 h prior to the first L-arg challenge. Mice were sacrificed 72 h after the induction of SAP and associated ALI was examined histologically and biochemically. An model of lipopolysaccharide (LPS)-induced ALI was established using A549 cells. Immunofluorescence analysis and western blot were evaluated in cells. Molecular docking analyses were conducted to examine the interaction of Cal with HMGB1. RESULTS:Cal treatment substantially reduced the serum amylase levels and alleviated histopathological injury associated with SAP and ALI. Neutrophil infiltration and lung tissue levels of neutrophil mediator myeloperoxidase were reduced in line with protective effects of Cal against ALI in SAP. Cal treatment also attenuated the serum levels and mRNA expression of pro-inflammatory cytokines tumor necrosis factor-α, interleukin-6, IL-1β, HMGB1 and chemokine (CXC motif) ligand 1 in lung tissue. Immunofluorescence and western blot analyses showed that Cal treatment markedly suppressed the expression of HMGB1 and phosphorylated nuclear factor-kappa B (NF-κB) p65 in lung tissues and an model of LPS-induced ALI in A549 cells suggesting a role for HGMB1 in the pathogenesis of ALI. Furthermore, molecular docking analysis provided evidence for the direct interaction of Cal with HGMB1. CONCLUSION:Cal protects mice against L-arg-induced SAP and associated ALI by attenuating local and systemic neutrophil infiltration and inflammatory response inhibition of HGMB1 and the NF-κB signaling pathway. 10.3748/wjg.v27.i44.7669
    Oleuropein-Rich Olive Leaf Extract Attenuates Neuroinflammation in the Alzheimer's Disease Mouse Model. ACS chemical neuroscience Alzheimer's disease (AD) is the most common form of dementia among several neurodegenerative disorders afflicting the elderly. AD is characterized by the deposition of extracellular amyloid-β (Aβ) plaques, disrupted blood-brain barrier (BBB), and neuroinflammation. Several studies have demonstrated the health benefits of olive oil and olive leaf extract (OLE) due to their polyphenolic content. The main phenolic compound in OLE is glycosylated oleuropein (OLG), while the aglycon form of oleuropein (OLA) exists in much lower amounts. This work aimed to evaluate the effect of a low dose of OLG-rich OLE and the mechanism(s) that contributed to the observed beneficial effects against Aβ pathology in the homozygous 5xFAD mouse model. Mice were fed with OLE-enriched diet (695 μg/kg body weight/day) for 3 months, starting at 3 months old. Overall findings demonstrated that OLE reduced neuroinflammation by inhibiting the NF-κB pathway and suppressing the activation of NLRP3 inflammasomes and RAGE/HMGB1 pathways. In addition, OLE reduced total Aβ brain levels due to increased clearance and reduced production of Aβ and enhanced BBB integrity and function, which collectively improved the memory function. Thus, the consumption of OLE as a dietary supplement is expected to stop and/or slow the progression of AD. 10.1021/acschemneuro.2c00005
    High mobility group B1 levels in sepsis and Disseminated Intravascular Coagulation. Eskici Zeynep M,Açıkgöz Şerefden,Pişkin Nihal,Mungan Görkem,Can Murat,Güven Berrak,Köktürk Fürüzan Acta biochimica Polonica Cytokines trigger coagulant and fibrinolytic systems in sepsis to result in Disseminated Intravascular Coagulation (DIC) that is an important complication and leads to disseminated hemorrhages and multi-organ failure. High Mobility Group B1 DNA Binding (HMGB1) protein is a cytokine taking part in systemic inflammatory response. The objective of this study was to investigate HMGB1 levels in groups of septic patients with and without DIC.Twenty-one septic patients without DIC and 12 septic patients with DIC from the Intensive Care Unit (ICU) were included in the study. In addition, 20 patients admitted to the ICU without sepsis or DIC and 20 healthy volunteers served as controls. Levels of HMGB1, prothrombin time, activated partial thromboplastin time, fibrinogen, D-dimer, protein C, protein S, anti-thrombin III (ATIII), platelet (thrombocyte) and leukocyte count were determined. Levels of fibrinogen, protein C, ATIII and platelet count were significantly lower and D-dimer was significantly higher in the group with sepsis plus DIC compared to the group with sepsis without DIC. Levels of HMGB1 were higher in the group with sepsis and DIC compared to the group with sepsis; however, the difference was not statistically significant and the levels of HGMB1 of both groups were significantly higher compared to ICU and healthy control groups. HMGB1 levels were not significantly different in survivor and non survivor patients. HMGB1 levels did not differ in lower respiratory tract infection (LRTI) and urinary tract infection (UTI) in regard to the etiology of sepsis.
    High-mobility-group box protein 1A box reduces development of sodium laurate-induced thromboangiitis obliterans in rats. Kong Xiangqian,Yuan Hai,Wu Xuejun,Zhang Jingyong,Zhou Hua,Wang Maohua,Liu Yang,Jin Xing Journal of vascular surgery OBJECTIVE:High-mobility-group box protein 1 (HMGB1), as a late mediator of inflammation, plays a key role in inflammatory responses by inducing and extending the production of proinflammatory cytokines. The effect of HGMB1 in the inflammatory disease thromboangiitis obliterans (TAO) is unknown. We aimed to investigate the role of HMGB1 in sodium laurate-induced TAO in rats. METHODS:Male Wistar rats were randomly divided into five groups (n=8 each) for treatment: normal, sham-operated, TAO model, and low-dose (15 mg/kg) or high-dose (30 mg/kg) recombinant A box (rA box) infection (administered intraperitoneally once daily for 15 days). The TAO model was induced by sodium laurate and graded by gross appearance on day 15 after femoral artery injection. Histologic changes were measured by histopathology in rat femoral arteries. Plasma levels of HMGB1, thromboxane B2, 6-keto-prostaglandin F1-α, and blood cell counts and blood coagulation levels were measured. Expression of HMGB1, receptor for advanced glycation end-products (RAGE), interleukin-6, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 was assessed by immunohistochemistry and immunofluorescence, Western blot analysis, and quantitative reverse-transcription polymerase chain reaction. RESULTS:The typical signs and symptoms of TAO were observed on day 15 after sodium laurate injection. The expression of HMGB1, RAGE, interleukin-6, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 was markedly increased in rat femoral arteries. Plasma levels of HMGB1 and thromboxane B2 were elevated, but the level of 6-keto-prostaglandin F1-α was decreased. Blood was in a hypercoagulable state, and prothrombin, thrombin, and activated partial thromboplastin times were all significantly shortened, whereas fibrinogen level was increased in TAO rats compared with sham-operated rats. These effects were terminated by the HMGB1 antagonist rA box. CONCLUSIONS:HMGB1 is involved in the inflammatory state in a model of TAO induced by sodium laurate in rats, probably via its receptor RAGE. As the antagonist of HMGB1, rA box can attenuate the development of TAO, which may be a potential therapeutic target for the treatment of TAO. 10.1016/j.jvs.2012.06.083
    Low shear stress induced HMGB1 translocation and release via PECAM-1/PARP-1 pathway to induce inflammation response. Qin Wei-dong,Mi Shao-hua,Li Chen,Wang Gui-xia,Zhang Jian-ning,Wang Hao,Zhang Fan,Ma Yang,Wu Da-wei,Zhang Mingxiang PloS one Low shear stress (LSS) plays a critical role in the site predilection of atherosclerosis through activation of cellular mechanosensors, such as platelet endothelial cell adhesion molecule 1 (PECAM-1). Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme that regulates the expression of various inflammatory cytokines. The nuclear enzyme high mobility group box 1 (HMGB1) can induce inflammation response by binding to toll-like receptor 4 (TLR4). In the present study, we aimed to investigate the role and mechanism of HMGB1 in LSS induced inflammation in human umbilical vein endothelial cells (HUVECs). HUVECs were stimulated by undisturbed shear stress (USS, 1 Pa) and LSS (0.4 Pa) in our experiments. Gene expression was inhibited by small interfering RNA (siRNA). ICAM-1 expression was regulated by LSS in a time dependent manner. LSS can induce HMGB1 translocation from nucleus to cytoplasm and release. Compared with the USS, LSS could increase the protein expression of PECAM-1 and PARP-1 as well as the secretion of TNF-α and IL-1β. LSS induced the translocation of HMGB1 from nucleus to cytoplasm. Inhibition of HGMB1 reduced LSS-induced inflammatory response. Inhibition of PARP-1 suppressed inflammatory response through inhibiting TLR4 expression and HMGB1 translocation. PECAM-1 inhibition reduced LSS-induced ICAM-1 expression, TNF-α and IL-1β secretion, and monocytes adhesion. LSS can induce inflammatory response via PECAM-1/PARP-1/HMGB1 pathway. PARP-1 plays a fundamental role in HMGB1 translocation and TLR4 expression. Inhibition of PARP-1 may shed light on the treatment of HMGB1 involved inflammation during atherosclerosis. 10.1371/journal.pone.0120586
    HMGB1 Neutralizing Antibody Attenuates Cardiac Injury and Apoptosis Induced by Hemorrhagic Shock/Resuscitation in Rats. Zhou Yu,Li Yan,Mu Tong Biological & pharmaceutical bulletin High-mobility group box 1 (HMGB1) and its natural receptor, Toll-like receptor-4 (TLR4), are involved in various infectious or noninfectious diseases including hemorrhagic shock. HMGB1 neutralizing antibody (anti-HMGB1 monoclonal antibody (mAb)) treatment was shown to alleviate ischemia-reperfusion injury effectively. The aim of this study was to explore whether and by what mechanisms anti-HMGB1 mAb attenuates hemorrhagic shock and resuscitation (HS/R)-induced cardiac injury. Employing rat HS/R models, we found that anti-HMGB1 mAb treatment improved HS/R-induced cardiac function deterioration, attenuated cardiac enzyme elevation, improved ATP loss, and protected cardiac tissue. Anti-HMGB1 mAb also inhibited the production of inflammatory factors interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α). Moreover, anti-HMGB1 mAb reduced apoptotic responses by suppressing activated caspase-3 and reversing apoptotic gene expression of capase-3, Bax, and Bcl-2 in rat cardiac tissue. Moreover, anti-HMGB1 mAb decreased HS/R-induced HMGB1 and TLR4 expression elevation. We further confirmed that anti-HMGB1 mAb inhibited lipopolysaccharide-activated HGMB1 and TLR4 expression and decreased inflammatory factors IL-1β, IL-6, and TNF-α at the cellular level. It was concluded that anti-HMGB1 mAb treatment protects rats from cardiac injury induced by HS/R, and the beneficial effects may be related to its inhibitory effects on the HMGB1-TLR4 axis. 10.1248/bpb.b15-00026
    The protective effect of dexmedetomidine on LPS-induced acute lung injury through the HMGB1-mediated TLR4/NF-κB and PI3K/Akt/mTOR pathways. Meng Lu,Li Longyun,Lu Shan,Li Kai,Su Zhenbo,Wang Yunyun,Fan Xiaodi,Li Xuyang,Zhao Guoqing Molecular immunology The aim of present study was to evaluate the protective effects of dexmedetomidine (DEX) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and investigate its possible mechanisms mediated by HMGB1. In vivo, pulmonary pathology observation and myeloperoxidase (MPO) activity were also examined to evaluate the protective effect of DEX in the lungs. Tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) in bronchoalveolar lavage fluid (BALF), serum and lung tissues LPS-induced rats were detected. The oxidative indices including superoxide dismutase (SOD), Malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) in serum were also determined. Additionally, nitric oxide (NO), TNF-α, IL-6 and IL-1β, MDA, SOD and GSH-Px in the supernatants of LPS-induced BEAS-2B cells were measured. Furthermore, we detected the protein expression of high mobility group box-1 protein (HMGB1), Toll-like receptor 4 (TLR4), myeloid differentiating factor 88 (MyD88), inhibitor of NF-κB (IκBα), p-IκBα, nuclear factor kappa-B (NF-κB), p-NF-κB, phosphatidylinositol 3'-kinase (PI3K), p-PI3K, protein kinase B (Akt), p-Akt, mammalian target of rapamycin (mTOR) and p-mTOR in LPS-induced ALI rats and LPS-induced BEAS-2B cells. Immunohistochemical and immunofluorescence analyses of HMGB1 in lung tissues or BEAS-2B cells were also conducted to evaluate the mechanisms of DEX. DEX effectively attenuated pulmonary pathology, and ameliorated the levels of MPO, SOD, MDA, GSH-Px, TNF-α, IL-6, IL-1β and NO in LPS-stimulated rats and BEAS-2B cells. Additionally, treatment with DEX inhibited the expression of HMGB1, TLR4, MyD88, p-IκB, p-NF-κB, p-PI3K, p-Akt and p-mTOR in vivo and in vitro. Immunohistochemical and immunofluorescence analyses also showed that DEX suppressed HMGB1 levels in lung sections and BEAS-2B cells. Treatment with glycyrrhizin, an inhibitor of HMGB1, confirmed that HMGB1 was involved in the mechanism of DEX on LPS-induced ALI. The transfection of HGMB1 siRNA also confirmed these findings in vitro. In conclusion, the present study showed that DEX exerted a protective effect on LPS-induced ALI rats likely through the HMGB1-mediated TLR4/NF-κB and PI3K/Akt/mTOR pathways. 10.1016/j.molimm.2017.12.008
    MicroRNA-34c suppresses proliferation of vascular smooth muscle cell via modulating high mobility group box protein 1. Chen Li-Bo,An Zhe,Zheng Hai-Kuo,Wang Xin-Peng,Shan Rui-Ting,Mao Cui-Ying,Zhang Wen-Qi Journal of clinical laboratory analysis BACKGROUND:Atherosclerosis is the most frequent pathological process that causes cardiovascular diseases. OBJECTIVE:The present study aimed to confirm miRNAs associated with atherosclerosis and explore the molecular mechanism of miR-34c and its target high mobility group box protein 1 (HMGB1) in the control of growth of smooth muscle cells in the development of atherosclerosis. METHODS:Real-time PCR was firstly performed to confirm miRNA correlation with atherosclerosis, and computational analysis and luciferase assay were performed to explore the target of miR-34c, Western blot, and real-time PCR were also utilized to reveal the effect of whether high glucose (HG) and miR-34c affect miR-34c, HMGB1 levels, NF-κB p65 and TNF-α levels, and the role of miR-34c on vascular smooth muscle cells (VSMCs) viability induced by HG. Students' unpaired t test was performed to compare data between two groups. RESULTS:MiR-34c level was associated with atherosclerosis with different expression between VSMCs treated with high glucose or normal VSMCs. Then, HMGB1 is a virtual target of miR-34c with predicted binding site resided in HMGB1 3'UTR and further verified by that miR-34c remarkably reduced luciferase activity of wild HMGB1 3'UTR under a concentration-dependent fashion, and miR-34c cannot influence luciferase activity of mutant HMGB1 3'UTR. CONCLUSIONS:The results suggested miR-34c might be a novel therapeutic strategy in the management of atherosclerosis by suppressing the expression of HGMB1 and its downstream effectors. 10.1002/jcla.23293