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ObjectiveTo investigate the expression levels of serum high-mobility group box 1 (HMGB1), soluble CD163 (sCD163), and prostaglandin E2 (PGE2) in patients with hepatitis B virus-related chronic-on-acute liver failure (HBV-ACLF), and to evaluate the value of the three indicators used alone or in combination in predicting prognosis. MethodsA total of 76 patients with HBV-ACLF who were hospitalized in Department of Infectious Diseases, The First Affiliated Hospital of Xinxiang Medical University, from July 1, 2022 to September 30, 2023 were enrolled, and according to the 28-day prognosis, they were divided into survival group with 48 patients and death group with 28 patients. General data were collected, Model for End-Stage Liver Disease (MELD) score was calculated, and ELISA was used to measure the serum levels of HMGB1, sCD163, and PGE2. The independent-samples t test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups; the chi-square test was used for comparison of categorical data between two groups. The Spearman rank correlation test was used to analyze the correlation of HMGB1, sCD163, and PGE2 with MELD score; the receiver operating characteristic (ROC) curve was used to analyze the value of HMGB1, sCD163, and PGE2 used alone or in combination in predicting the prognosis of HBV-ACLF patients. ResultsThere were significant differences between the two groups in total bilirubin, white blood cell count, the percentage of neutrophils, procalcitonin, serum amyloid A, interleukin-6, serum sodium, and serum creatinine (all P<0.05). Compared with the survival group, the death group had significantly higher serum levels of HMGB1 (Z=-2.997, P=0.003) and sCD163 (Z=-2.972, P=0.003), a significantly higher MELD score (t=-6.997, P<0.001), and a significantly lower serum level of PGE2 (Z=-4.909, P<0.001). The Spearman rank correlation test showed that HMGB1 and sCD163 were positively correlated with MELD score (r=0.431 and 0.319, both P<0.05), while PGE2 was negatively correlated with MELD score (r=-0.412, P<0.05). The ROC curve analysis showed that HMGB1, sCD163, and PGE2 used alone had an area under the ROC curve (AUC) of 0.717, 0.716, and 0.856, respectively, while the combination of the three indicators had the highest predictive value, with an AUC of 0.930, a sensitivity of 0.778, and a specificity of 0.920. ConclusionSerum HMGB1, sCD163, and PGE2 used alone or in combination have a good reference value in predicting the prognosis of HBV-ACLF patients, and the combination of the three indicators has the highest predictive value, which holds promise for further observation and research.
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Objective To investigate the effect of verbascoside(VB)on endothelial dysfunction in atherosclerotic(AS)rats by regulating high-mobility group protein B1(HMGB1)/receptor for advanced glycation endproducts(RAGE)/nuclear factor κB(NF-κB)signal pathway.Methods The rat model of AS was established by high fat feeding combined with vitamin D3 solution intraperitoneal injection.Rats were divided into the control group(n=10),the model group(n=12),the low(VB-L),medium(VB-M)and high dose(VB-H)VB groups(2,5 and 10 mg/kg,n=10),and the positive control group(simvastatin,5 mg/kg,n=10).The serum level of blood lipids was detected by automatic biochemical analyzer.Pathological changes of aorta were observed by HE staining.Serum levels of inflammatory factors and vascular endothelial cytokines were detected by enzyme-linked immunosorbent assay(ELISA).The level of oxidative stress in rats was detected by micro-method kit.The expression of HMGB1/RAGE signal pathway protein in aorta was detected by Western blot assay.Results Compared with the control group,the intima of aorta in the model group was thickened,plaque appeared in blood vessels,accompanied by lipid deposition and inflammatory cell infiltration.Serum levels of total cholesterol(TC),triglyceride(TG),low density lipoprotein cholesterol(LDL-C),tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),C-reactive protein(CRP),matrix metalloproteinase-9(MMP-9),endothelin-1(ET-1),visfatin,intercellular adhesion molecule-1(ICAM-1)and malondialdehyde(MDA),and HMGB1,RAGE and phosphorylation levels of NF-κB in aorta were obviously increased.Serum levels of high-density lipoprotein cholesterol(HDL-C),nitric oxide(NO),superoxide dismutase(SOD)and glutathione peroxidase(GSH-Px)were obviously decreased(P<0.05).Compared with the model group,pathological changes of rats were obviously improved in the VB-L,VB-M and VB-H groups and the simvastatin group.Serum levels of TC,TG,LDL-C,TNF-α,IL-1β,CRP,MMP-9,ET-1,visfatin,ICAM-1,MDA,and HMGB1,RAGE,phosphorylation levels of NF-κB in aorta were obviously decreased,and serum levels of HDL-C,NO,SOD and GSH-Px were obviously increased(P<0.05).Conclusion VB can down-regulate the expression of HMGB1/RAGE/NF-κB signal pathway protein,inhibit inflammation and oxidative stress in AS rats,and improve lipid metabolism and vascular endothelial function.
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Objective:To investigate the role and underlying mechanisms of inhibiting high mobility group box-1 (HMGB1) in the expression of matrix metalloproteinase-9 (MMP-9) in spinal cord astrocytes (AS) in rats after spinal cord injury (SCI).Methods:After an SCI model was established in Sprague-Dawley (SD) rats using a modified Allen's Weight-Dropping method and ethyl pyruvate (EP) or glycyrrhizin (GL) was used to inhibit the effect of HMGB1, the rats were divided into a sham group, an SCI group, an SCI+EP (50 mg/kg) group, and an SCI+GL (100 mg/kg) group. The expression levels of glial fibrillary acid protein (GFAP) and MMP-9 in spinal cord AS were observed. After the spinal cord AS in SD rats was cultured and incubated by the oxygen-glucose deprivation/reoxygenation (OGD/R) procedure, the expression of MMP-9 protein was detected at 6 h/R 6 h, 12 h, 24 h, and 48 h after OGD. The time point with the highest expression was chosen in the subsequent experiments as an OGD/R group. HMGB1 was inhibited by HMGB1 shRNA or EP to observe the effect of HMGB1 on the expression of MMP-9 protein in AS treated with OGD/R. Then, toll-like receptor 4 (TLR4) inhibitor, TIR-domain-containing adaptor inducing interferon- β (TRIF) inhibitor, and nuclear factor-kappa B (NF- κB) inhibitor were used to investigate the effects of TLR4/TRIF/NF- κB signaling pathway during the regulation of HMGB1 on MMP-9 in vitro. Results:Western blot showed that the expression of MMP-9 protein in the spinal cord was significantly increased in rats at 1 d after SCI, and the expression of MMP-9 protein in the SCI+EP group and the SCI+GL group was significantly lower than that in the SCI group ( P<0.001). Immunofluorescence showed that GFAP and MMP-9 proteins were co-localized in the spinal cord after SCI, and the expression of GFAP and MMP-9 proteins in the SCI+EP and SCI+GL groups was significantly lower than that in the SCI group ( P<0.05). Since the expression of MMP-9 protein in the spinal cord AS cultured in vitro was significantly higher in the OGD 6h/R 12h group than that in the normal group and the OGD 6h/R 6h, 24, and 48 h groups, the OGD 6h/R 12h was taken as the OGD/R group. The MMP-9 protein expression in AS in the OGD/R+HMGB1 shRNA group and the OGD/R+EP group was significantly lower than that in the OGD/R group ( P<0.001). In the cultured AS, moreover, inhibiting TLR4, TRIF, and NF- κB reduced MMP-9 protein expression after OGD 6 h/R 12 h when compared with that in the OGD/R group ( P<0.001). Conclusions:HMGB1 inhibition may result in a reduction in MMP-9 expression both in the spinal cord AS in SCI rats and in AS after OGD/R treatment in vitro. HMGB1 may regulate MMP-9 protein expression in AS after OGD/R treatment via the TLR4/TRIF/NF- κB signal pathway.
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Abstract Introduction: Serum level of high-mobility group box 1 protein is reportedly correlated with the severity of obstructive sleep apnea. Objective: We tried to evaluate the possibility of using the serum high-mobility group box 1 protein level as a biologic marker in obstructive sleep apnea patients. Methods: We generated a chronic intermittent hypoxia murine model that reflected human obstructive sleep apnea. Obstructive sleep apnea patients who underwent polysomnography were prospectively enrolled. Serum samples were obtained from mice and obstructive sleep apnea patients, and the serum high-mobility group box1 protein level was measured by enzyme-linked immunosorbent assay. Results: Serum high-mobility group box 1 protein level was 56.16 ± 30.33 ng/mL in chronic intermittent hypoxia and 18.63 ± 6.20 ng/mL in control mice (p<0.05). The mean apnea-hypopnea index and respiratory disturbance index values of enrolled obstructive sleep apnea patients were 50.35 ± 27.96 and 51.56 ± 28.53, respectively, and the mean serum high-mobility group box 1 protein level was 30.13 ± 19.97 ng/mL. The apnea-hypopnea index and respiratory disturbance index were not significantly correlated with the serum high-mobility group box 1 protein level (p>0.05). Instead, this protein level was significantly correlated with lowest arterial oxygen concentration (SaO2) (p<0.05). Conclusion: High-mobility group box 1 protein may be involved in the pathogenesis of obstructive sleep apnea, and the possibility of this protein being a useful biologic marker in obstructive sleep apnea should be further evaluated.
Resumo Introdução: O nível sérico da proteína de alta mobilidade do grupo Box-1 está relacionado com a gravidade da apneia obstrutiva do sono. Objetivo: Avaliar o uso do nível sérico da proteína de alta mobilidade do grupo Box-1 como um marcador biológico em pacientes com apneia obstrutiva do sono. Método: Geramos um modelo murino de hipóxia intermitente crônica que imita a apneia obstrutiva do sono em humanos. Pacientes com apneia obstrutiva do sono que fizeram polissonografia foram incluídos prospectivamente. Amostras de soro foram obtidas de camundongos e pacientes com apneia obstrutiva do sono e o nível sérico da proteína de alta mobilidade do grupo Box-1 foi medido por enzyme-linked immunosorbent assay. Resultados: O nível sérico da proteína de alta mobilidade do grupo Box-1 foi 56,16 ± 30,33 ng/mL em hipóxia intermitente crônica e 18,63 ± 6,20 ng/mL em camundongos controle (p < 0,05). Os valores médios do índice de apneia-hipopneia e do índice de distúrbio respiratório nos pacientes com apneia obstrutiva do sono foram 50,35 ± 27,96 e 51,56 ± 28,53, respectivamente, e o nível médio da proteína de alta mobilidade do grupo Box-1 foi 30,13 ± 19,97 ng/mL. O índice de apneia-hipopneia e o índice de distúrbio respiratório não foram significantemente associados com o nível da proteína de alta mobilidade do grupo Box-1 p> 0,05). Em vez disso, esse nível de proteína foi significantemente associado com o valor mais baixo da concentração arterial de oxigênio (SaO2) (p <0,05). Conclusão: A proteína de alta mobilidade do grupo Box-1 pode estar envolvida na patogênese da apneia obstrutiva do sono e a possibilidade de que essa proteína possa ser um marcador biológico útil na apneia obstrutiva do sono deve ser avaliada mais detalhadamente.
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Tumor immunogenic cell death is a type of regulatory cell death, which is driven by stress including chemotherapy drugs, radiotherapy, oncolytic virus, nano carrier drugs and photodynamic force. It can induce specific immune response to tumor death cell antigen. The further study can provide theoretical basis and new ideas for anti-tumor immunity and clinical immunotherapy of tumor.
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Inflammation plays an important part in neonatal hypoxic-ischemic brain damage (HIBD). High mobility group box-1 protein (HMGB1), a neuroinflammatory trigger, has a dual effect on HIBD: in the acute stage, it amplifies the ischemic tissue injury; in the later stage, it is involved in the neurovascular repair and reconstruction. The significance of HMGB1 in the pathogenesis of HIBD is still not fully understood. This review summarizes the role of HMGB1 in HIBD, including its effects on neurons, glial cells and blood-brain barrier, and the underlying mechanisms as well as the progress in research on HMGB1 in immature brain, hoping to provide new ideas for neuroprotection in HIBD.
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Objective:To investigate the effect of acteoside on the expressions of high mobility group box 1 (HMGB1) and nuclear factor-κB (NF-κB) in the renal tissue of diabetic nephropathy mice.Methods:Among 20 healthy 8-week old C57BL/6J mice, 5 mice were randomly selected as normal control group, the rest were established as type 1 diabetes mellitus (T1DM) models by a single intraperitoneal injection of streptozocin (STZ, 150 mg/kg). T1DM mice were randomly divided into three groups: 5 mice without treatment, 5 mice treated with acteoside and 5 mice treated with irbesartan. After continuous administration for 8 weeks, serum, urine, and kidney tissue were collected for biochemical, pathological, and related mRNA and protein detection. The renal tubular epithelial cells (NRK-52E cells) were divided into control group (1 g/L glucose), high glucose group (4.5 g/L glucose) and high glucose+acteoside group (4.5 g/L glucose+32 μmol/L acteoside). Real-time PCR and Western blotting were used to assess the expressions of HMGB1 and NF-κB after 48 hours and 72 hours culturing.Results:Compared with normal control group, blood glucose, 24-hour quantitative urinary protein, blood urea nitrogen (BUN), serum creatinine (Scr) and blood and urine HMGB1 were significantly increased in model group (all P<0.05), along with interstitial inflammatory cell infiltration and messangial matrix expantion, and the expressions of HMGB1 and NF-κB were significantly enhanced (all P<0.05). Compared with model group, histopathologic changes were alleviated and the mRNA and protein expression levels of HMGB1 and NF-κB were lower in the acteoside group (all P<0.05), while the blood glucose level was maintained at high level ( P>0.05), excluding reduced quantitative 24-hour urinary protein, BUN, Scr, and serum and urine HMGB1 (all P<0.05). Compared with control group, the mRNA and protein expressions of HMGB1 and NF-κB were increased in high glucose group of NRK-52E cells (all P<0.05). Compared with high glucose group, the mRNA and protein expressions of HMGB1 and NF-κB in high glucose+acteoside group were down-regulated (all P<0.05). Conclusion:Acteoside may alleviate the nephropathy in STZ-induced diabetic nephropathy mice by down-regulating the expressions of HMGB1 and NF-κB.
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Objective@#To investigate the expression and clinicopathological significance of high mobility group box protein B1 (HMGB1) protein in breast cancer.@*Methods@#The expression of HMGB1 protein in 26 normal breast tissues and 417 invasive breast cancer tissues diagnosed at Dongyang People′s Hospital, Zhejiang Province from 2016 to 2018 were detected by immunohistochemical EnVision method. The relationship between nuclear and cytoplasmic HMGB1 protein expression and clinicopathologic features of breast cancer patients were analyzed.@*Results@#The nuclear and cytoplasmic expression of HMGB1 protein was 80.8% (337/417) and 16.8% (70/417) respectively in breast cancer, and was 46.2%(12/26) and 0(0/26) respectively in normal breast tissue. Both nuclear and cytoplasmic expression of HMGB1 protein in breast cancer were significantly higher than normal breast tissue (P<0.001, P=0.046, respectively). The nuclear expression of HMGB1 protein was also higher in high grade, estrogen receptor (ER) negative, progesterone receptor (PR) negative (P=0.006, P=0.004, P<0.001, respectively); whereas the cytoplasmic expression of HMGB1 protein was also higher in high grade, estrogen receptor (ER) negative, progesterone receptor (PR) negative (P<0.001 in all) breast cancers. Multivariate logistic regression model showed that nuclear HMGB1 expression correlated with histologic grade (OR=2.188, 95%CI=1.078-4.443, P=0.030), while cytoplasmic HMGB1 expression correlated with histologic grade (OR=3.031, 95%CI=1.600-5.742, P=0.001), ER (OR=0.129, 95%CI=0.034-0.494, P=0.003) and TNM staging (OR=3.820, 95%CI=1.042-14.001, P=0.043). Multivariate analysis of Cox proportional hazard model showed that nuclear HMGB1 expression was an independent risk factor for the overall survival of breast cancer patients (HR=0.366, 95%CI=0.138-0.972, P=0.044).@*Conclusion@#Nuclear and cytoplasmic HMGB1 proteins are related to multiple poor prognostic factors in breast cancer, and may be a potential biomarker for breast cancer treatment.
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Abstract Objective: To investigate the expression of High Mobility Group Box 1 (HMGB1) and Heat Shock Protein-70 (HSP-70) during orthodontic tooth movement (OTM) after (-)- Epigallocatechin-3-Gallate (EGCG) in East Java Green Tea (Camelia Sinensis) Methanolic Extract (GTME) administration in vivo. Material and Methods: 28 Wistar rats (Rattus Novergicus) was used and divided into 4 groups accordingly: K- without EGCG and OTM; K+ with OTM, without EGCG for 14 days; T1with OTM for 14 days and EGCG for 7 days; treatment group 2 (T2) with OTM and EGCG for 14 days. OTM animal model was achieved through the installation of the OTM device by means of NiTi close coil spring with 10g force placed between the first incisor and first maxillary molars. The samples were terminated on Day 14. The pre-maxillary was isolated for the immunohistochemical examination. Analysis of Variance (ANOVA) then continued with Tukey Honest Significant Difference (HSD) (p<0.05) was performed to analyze the data. Results: The highest HMGB1 and HSP-70 expression were found in the K+ group pressure side, meanwhile the lowest HMGB1 and HSP-70 expression were found in K- group tension side in the alveolar bone. There was a significant decrease of HMGB1 and HSP-70 expression in T2 compared to T1 and K+ with significant between groups (p<0.05; p=0.0001). Conclusion: The decreased expression of HMGB1 and HSP-70 in alveolar bone of OTM wistar rats due to post administration of GTME that consisted EGCG.
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Animaux , Rats , Mouvement dentaire/instrumentation , Rat Wistar , Protéine HMGB1 , Protéines du choc thermique , Antioxydants/usage thérapeutique , Thé , Os et tissu osseux , Immunohistochimie , Analyse de variance , Modèles animaux , Incisive , Indonésie , MolaireRésumé
High mobility group protein B1 (HMGB1) is encoded by HMGB1 gene and is a highly conserved non-histone chromosomal binding protein widely present in the nucleus. It plays an important role in DNA replication and repair of eukaryotic cells. As a delayed inflammatory mediator, HMGB1 secreted or released extracellularly mediates inflammatory response in sepsis, autoimmune diseases, malignant tumors, liver-related diseases, and so on. In recent years, the studies of HMGB1 gene polymorphism have provided a theoretical basis for further clarifying the pathogenesis of diseases. These studies provided early predictions of disease susceptibility for early intervention and provided the basis for precise prevention and treatment of diseases. In this paper, the correlation between HMGB1 and clinical disease susceptibility and prognosis was reviewed.
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Objective@#To investigate the predictive value of serum high-mobility group box-1 protein (HMGB1) for hemorrhage transformation (HT) after intravenous thrombolysis in patients with acute ischemic stroke.@*Methods@#From February 2017 to September 2019, patients with acute ischemic stroke underwent intravenous thrombolysis in Lixin County People's Hospital, Bozhou, Anhui Province were enrolled prospectively. In the morning of the day after admission, fasting blood was collected to detect the level of serum HMGB1. Twenty-four hours after intravenous thrombolysis, CT reexamination was performed to determine whether HT occurred. The demographic and baseline clinical data were compared between the HT group and the non-HT group. Multivariate logistic regression analysis was used to determine the independent risk factors for HT after thrombolysis. Receiver operating characteristic (ROC) curve was used to analyze the predictive value of serum HMGB1 level to HT.@*Results@#A total of 182 patients were enrolled in the study, including 22 in the HT group and 160 in the non-HT group. The age, fasting blood glucose, serum HMGB1 level, and the proportion of history of atrial fibrillation and regular antiplatelet medication before onset in the HT group was significantly higher than those in the non-HT group, and the differences were statistically significant (all P<0.05). Multivariate logistic regression analysis showed that the increased serum HGMB1 level (odds ratio [OR] 2.145, 95% confidence interval[CI] 1.467-3.138; P=0.002), taking antiplatelet drugs regularly before onset (OR 5.496, 95% CI 1.700-17.768; P=0.004) and increased baseline fasting blood glucose level (OR 1.333, 95% CI 1.024-1.736; P=0.033) were the independent risk factors for HT after intravenous thrombolysis. ROC curve analysis showed that the area under the curve of serum HMGB1 level predicting HT after intravenous thrombolysis was 0.788 (95% CI 0.721-0.845; P<0.001). The sensitivity and specificity were 72.73% and 82.50%, respectively, when the best cutoff value was 7.97 μg/L.@*Conclusion@#The increased baseline HMGB1 level may predict the risk of HT after intravenous thrombolysis in patients with acute ischemic stroke.
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Objective To investigate the effects of budesonide (BUN) on high mobility group protein 1 (HMGB1)/toll-like receptor 4 (TLR4) / nuclear factor κB (NF-κB) pathway in neonatal mice with hyperoxia-induced bronchopulmonary dysplasia (BPD).Methods 80 mice were randomly divided into control group,model group,low,medium and high dose BUN groups,with 16 mice in each group.Mice in the control group were exposed to air,and mice in model group and BUN low,medium and high dose groups were exposed to 60% oxygen to establish BPD model;After 24 hours of modeling,the control group and model group were inhaled with normal saline every day.The low,middle and high dose BUN groups inhaled (1,2,4 ml) BUN,respectively,12 h/times,and continued to inhale until the mice were executed.On the 7th and 14th days of the model establishment,hematoxylin-eosin (HE) staining was used to observe the morphological changes of lung tissue;the levels of interleukin (IL)-1β,IL-6,tumor necrosis factor-α (TNF-α),malondialdehyde (MDA) and superoxide dismutase (SOD) in lung tissues were detected by enzyme-linked immunosorbent assay (ELISA);the levels of HMGB1,TLR4 and NF-κB in lung tissue were detected by real-time fluorescence quantitative polymerase chain reaction (qRT-PCR) and protein immunoblotting (WB).Results In the model group,the lung tissue structure was severely damaged and the alveolar volume was enlarged to form bullae on the 7th and 14th day.In low,middle and high dose groups,with the increase of BUN concentration,the lung tissue deformation gradually improved and the alveolar structure gradually became intact.Compared with the control group,the number of radial alveoli in the lung tissues of the model group decreased at 7th and 14th days;SOD activity decreased;the expression levels of IL-1β,IL-6,TNF-α,MDA,HMGB1,TLR4 and NF-κB mRNA and protein were increased (P <0.05).Compared with the model group,the number of radial alveoli and SOD activity in lung tissues of BUN groups increased gradually at 7th and 14th days,while the levels of IL-1β,IL-6,TNF-α,MDA,HMGB1,TLR4and NF-κB decreased gradually at different doses (P < 0.05).Conclusions BUN may inhibit the levels of inflammatory factors and oxidative stress by regulating HMGB1/TLR4/NF-κB pathway to achieve the protective effect on BPD neonatal mice.
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Objectives To determine the association between serum levels of high-mobility group box-1 (HMGB1),insulin-like growth factor-1 (IGF-1),vascular endothelial growth factor 165 (VEGF165) and occurrence and development of diabetic nephropathy (DN).Methods A total of 136 patients diagnosed as diabetic nephropathy (DN group) in Huai'an First People's Hospital between January 2016 to January 2018 were randomly selected in the study,including microalbuminuria group (n=62),macroalbuminuria group (n=50) and renal insufficiency group (n=24).Meanwhile,115 healthy examiners during the same period were collected as normal control group.Serum glucose,serum total cholesterol (TC),serum triglyceride (TG),high density lipoprotein cholesterol (HDL-C),low density lipoprotein cholesterol (LDL-C) and urinary albumin/urine creatinine ratio (UAlb/Cr) were detected inall subjects.Enzyme-linked immunosorbent assay (ELISA) was adopted to detect the serum concentrations of HMGB1,IGF-1 and VEGF165.Pearson correlation test was used to analyze the correlation between serum HMGB1,IGF-1 and VEGF165.Logistic ordered multi-classification regression was used to analyze the risk factors of DN progression,and the receiver operating characteristic curve (ROC) was drawn to evaluate the clinical predictive value of HMGB1,IGF-1 and VEGF165 in the progression of DN.Results The concentrations of serum HMGB1,IGF-1 and VEGF165 in DN patients were significantly higher than those in the control group (all P < 0.05).There was a positive association between HMGB1 and IGF-1,HMGB1 and VEGF165,IGF-1 and VEGF165 (all P < 0.01).Logistic regression analysis showed that elevated levels of HMGB1,IGF-1 and VEGF165 were independent risk factors for DN progression (OR=5.50,1.05,1.24,all P < 0.05).The sensitivity,specificity and area under ROC curve of combined detection of HMGB1,IGF-1 and VEGF165 were higher than HMGB1,IGF-1 and VEGF165 alone (AUC=0.989,0.984,0.942,0.878,P < 0.05).Conclusions The serum levels of HMGB1,IGF-1 and VEGF165 are related to the severity of DN.The clinical predictive value of combined detection of HMGB1,IGF-1 and VEGF165 for DN progression is superior to that of single index detection of HMGB1,IGF-1 and VEGF165.
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Objective To investigate the potential role of Sestrin2 (SESN2) in regulating the apoptosis of dendritic cells (DCs) induced by high mobility group box-1 protein (HMGB1).Methods DCs (the murine DC cell line DC2.4) were cultured with or without HMGB1 stimulation (cultured with 10ng/ml HMGB1 for 8,24 and 48 hours,or cultured with HMGB1 for 48 hours at different concentrations of 1,10 and 100ng/ml,respectively,n=4).The protein level of SESN2,cleaved-caspase-3 and Bcl-2 were analyzed with Western blotting.Localization of SESN2 in cells was observed under confocal laser microscope (LSCM).Cell apoptosis was analyzed with flow cytometry.In addition,DC2.4 cells were transfected with lentivirus containing SESN2 LV-RNA,SESN2 siRNA sequence expressing plasmids or blank vector (NC,NS,n=4).These cells were then stimulated with HMGB1 (100ng/ml)for 48 hours,and the apoptosis was accessed as mentioned above.Results Compared with the control group,the expression of SESN2 was obviously up-regulated after HMGB1 (10ng/ml) stimulation for 24 and 48 hours (P<0.05).In a dose-dependent response,the expression of SESN2 was markedly enhanced in treatment with 1,10,100ng/ml HMGB1 for 48 hours (P<0.05).Compared with the control group (7.35% ± 1.33%),the percentage of apoptosis was significantly increased with 10,100ng/ml HMGB1 for 48 hours [(17.02% ± 4.85%,17.48% ± 4.04%,respectively,P<0.05 or P<0.01].After transfection,compared with blank vector group,the apoptosis of SESN2 siRNA group obviously elevated [(65.96% ± 2.50%) vs.(50.01% ± 2.07%),P<0.05],and cleaved-caspase-3 expression significantly increased while Bcl-2 expression obviously decreased.In SESN2 LV-RNA group,the apoptosis significantly decreased [(35.57% ± 1.69%) vs.(49.04% ± 4.87%),P<0.05],and cleaved-caspase-3 expression decreased and Bcl-2 expression obviously increased compared with blank vector group (P<0.05).Conclusion SESN2 has a protective effect against HMGB 1 induced apoptosis of D C2.4 cells.
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ObjectiveTo investigate the correlation of serum high-mobility group box 1 (HMGB1) level with hepatic inflammatory activity, liver fibrosis degree, and liver function parameters in chronic hepatitis B patients. MethodsA total of 73 patients with chronic hepatitis B and liver cirrhosis were enrolled as subjects. Liver biopsy was performed to determine inflammatory activity and liver fibrosis degree, liver function parameters and serum HMGB1 level were measured, and the correlation between HMGB1 level and other indices was analyzed. The t-test was used for comparison between two groups, and a linear correlation analysis was performed to investigate the correlation between two indices. ResultsThe patients with chronic hepatitis B and liver cirrhosis had a significantly higher HMGB1 level than the healthy control group (29.46±7.54 ng/ml vs 16.86±3.48 ng/ml, t=5.668, P<0.01). The G3-G4 group had a significantly higher HMGB1 level than the G1-G2 group (t=4.441, P<0.01), while there was no significant difference in HMGB1 level between the S1-S2 group and the S3-S4 group (t=0.658, P>0.05). Serum HMGB1 level was positively correlated with alanine aminotransferase (r=0.256 6, P=0028 4) and aspartate aminotransferase (r=0.471 9, P<0.000 1), while it was not correlated with albumin or total bilirubin (both P>005). ConclusionSerum HMGB1 level is closely correlated with hepatic inflammatory activity.
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PURPOSE: The high mobility group box 1 (HMGB1) protein has roles in apoptosis and immune responses by acting as a ligand for receptor for advanced glycation end products (RAGE), Toll-like receptors (TLRs), and triggering receptor expressed on myeloid cells 1. In particular, HMGB1/RAGE is involved in tumor metastasis by inducing matrix metalloproteinase 2 (MMP2) and MMP9 expression. We investigated the associations between genetic variations in HMGB1-related genes and disease-free survival (DFS) and overall survival (OS) in Korean female breast cancer patients. METHODS: A total of 2,027 patients in the Seoul Breast Cancer Study were included in the analysis. One hundred sixteen single nucleotide polymorphisms (SNPs) were extracted from eight genes. A multivariate Cox proportional hazards model was used to estimate the hazard ratio and 95% confidence interval (CI) of each SNP. The effects of the SNPs on breast cancer prognosis were assessed at cumulative levels with polygenic risk scores. RESULTS: The SNPs significantly associated with DFS were rs243867 (hazard ratio, 1.26; 95% CI, 1.05–1.50) and rs243842 (hazard ratio, 1.24; 95% CI, 1.03–1.50); both SNPs were in MMP2. The SNPs significantly associated with OS were rs243842 in MMP2 (hazard ratio, 1.33; 95% CI 1.03–1.71), rs4145277 in HMGB1 (hazard ratio, 1.29; 95% CI, 1.00–1.66), rs7656411 in TLR2 (hazard ratio, 0.76; 95% CI, 0.60–0.98), and rs7045953 in TLR4 (hazard ratio, 0.50; 95% CI, 0.29–0.84). The polygenic risk score results for the DFS and OS patients showed third tertile hazard ratios of 1.72 (95% CI, 1.27–2.34) and 2.75 (95% CI, 1.79–4.23), respectively, over their first tertile references. CONCLUSION: The results of the present study indicate that genetic polymorphisms in HMGB1-related genes are related to breast cancer prognosis in Korean women.
Sujets)
Femelle , Humains , Récepteur spécifique des produits finaux de glycosylation avancée , Apoptose , Tumeurs du sein , Région mammaire , Survie sans rechute , Prédisposition génétique à une maladie , Variation génétique , Protéine HMGB1 , Matrix metalloproteinase 2 , Cellules myéloïdes , Métastase tumorale , Polymorphisme génétique , Polymorphisme de nucléotide simple , Pronostic , Modèles des risques proportionnels , Séoul , Récepteurs de type TollRésumé
Objective: To investigate the effects of high mobility group box-1 protein (HMGB1) exocrine promoted by G protein-coupled estrogen receptor (GPER) in cancer-associated fibroblast (CAF) combined with the small molecule compound G1 on the autophagy and proliferation of breast cancer MCF-7 cells. Methods: The GPER-shRNA lentiviral vector specifically interfering GPER gene expression was constructed and used to infect CAF (CAF-shGPER), while the CAF infected with a negative control lentivirus was used as the control (CAF-shNC). The expression levels of GPER mRNA and protein in CAF-shNC and CAF-shGPER cells were detected by real-time fluorescent quantitative PCR and Western blotting, respectively. The GPER-specific agonist G1 was used to treat the CAF-shNC and CAF-shGPER cells, respectively. Then the expression levels of HMGB1 mRNA and protein in CAF-shNC, CAF-shGPER, CAF-shNC+G1 and CAF-shGPER+G1 cells were detected by real-time fluorescent quantitative PCR and Western blotting, respectively. The secretion of HMGB1 protein in the conditioned medium of four groups was detected by enzyme-linked immunosorbent assay (ELISA). The conditioned medium of four groups was collected and used to treat MCF-7 cells. Then the expression levels of Beclin1, p62 and LC3 proteins in MCF-7 cells were detected by Western blotting, while the proliferation of MCF-7 cells was detected by CCK-8 assay. Results: After the lentivirus carrying GPER-shRNA was stably infected into CAF, the expressions of GPER mRNA and protein were significantly inhibited (both P<0.01). The expressions of HMGB1 mRNA and protein in CAF-shNC cells were significantly up-regulated by GPER specific agonist G1 (both P<0.05), while the secretion of HMGB1 was increased in the conditioned medium (P<0.05); However, the above effects of G1 were opposite in CAF-shGPER cells. Furthermore, the exocrine HMGB1 in conditioned medium up-regulated the expressions of Beclin1 and LC3 proteins (both P<0.01), down-regulated the expression of p62 protein (P<0.01), and increased the autophagy and proliferation abilities of MCF-7 cells (both P<0.01). Conclusion: The small molecule compound G1 can promote the expression of GPER in CAF in tumor microenvironment and increase the secretion of cytokine HMGB1, thus induce the autophagy of MCF-7 cells and promote the growth of MCF-7 cells.
Résumé
Nilotinib as a tyrosine kinase inhibitor has been recently used to improve the liver fibrosis process, but the exact mechanisms still require further clarification. In this study, we investigated the anti-fibrotic effects of Nilotinib via RAGE/HMGB1axis and antioxidant mechanisms. This experimental study was performed in the Hamadan University of Medical Sciences, Iran, from May 2015 to December 2016. Liver fibrosis was induced in Wistar male rats by CCL₄. Rats were gavaged daily with Nilotinib (10 mg/kg). RAGE, HMGB1, TNF-α and TGF-β mRNA expression were evaluated by quantitative RT-PCR. TNF-α protein levels were measured using the immunoassay method. Thiol groups, carbonyl groups, nitric oxide levels and glutathione peroxidase activity were measured by spectrophotometric methods.The results showed that Nilotinib decreased TNF-α, TGF-β, RAGE and HMGB1 mRNA expression (p<0.001) in the liver tissues of the fibrosis group. Nilotinib also decreased carbonyl groups and nitric oxide levels and increased thiol groups and glutathione peroxidase activity in the fibrosis groups. The histopathological changes were found to be attenuated by Nilotinib. In conclusion, Nilotinib can improve liver fibrosis and open new mechanisms of the anti-fibrotic properties of Nilotinib.
Sujets)
Animaux , Humains , Mâle , Rats , Fibrose , Expression des gènes , Glutathione peroxidase , Protéine HMGB1 , Dosage immunologique , Iran , Cirrhose du foie , Foie , Méthodes , Monoxyde d'azote , Stress oxydatif , Protein-tyrosine kinases , Fureur , ARN messagerRésumé
Objective@#To investigate the effects of hydrogen on the lung damage of mice at early stage of severe burn.@*Methods@#One hundred and sixty ICR mice were divided into sham injury, hydrogen, pure burn, and burn+ hydrogen groups according to the random number table, with 40 mice in each group. Mice in pure burn group and burn+ hydrogen group were inflicted with 40% total body surface area full-thickness scald (hereafter referred to as burn) on the back, while mice in sham injury group and hydrogen group were sham injured. Mice in hydrogen group and burn+ hydrogen group inhaled 2% hydrogen for 1 h at post injury hour (PIH) 1 and 6, respectively, while mice in sham injury group and pure burn group inhaled air for 1 h. At PIH 24, lung tissue of six mice in each group was harvested, and then pathological changes of lung tissue were observed by HE staining and the lung tissue injury pathological score was calculated. Inferior vena cava blood and lung tissue of other eight mice in each group were obtained, and then content of high mobility group box 1 (HMGB1) and interleukin-6 (IL-6) in serum and lung tissue was determined by enzyme-linked immunosorbent assay. Activity of superoxide dismutase (SOD) in serum and lung tissue was detected by spectrophotometry. After arterial blood of other six mice in each group was collected for detection of arterial partial pressure of oxygen (PaO2), the wet and dry weight of lung tissue were weighted to calculate lung wet to dry weight ratio. The survival rates of the other twenty mice in each group during post injury days 7 were calculated. Data were processed with one-way analysis of variance, LSD test and log-rank test.@*Results@#(1) At PIH 24, lung tissue of mice in sham injury group and hydrogen group showed no abnormality. Mice in pure burn group were with pulmonary interstitial edema, serious rupture of alveolar capillary wall, and infiltration of a large number of inflammatory cells. Mice in burn+ hydrogen group were with mild pulmonary interstitial edema, alveolar capillary congestion accompanied by slight rupture and bleeding, and the number of infiltration of inflammatory cells was smaller than that in pure burn group. The lung tissue injury pathological scores of mice in sham injury group, hydrogen group, pure burn group, and burn+ hydrogen group were (0.7±0.5), (0.8±0.5), (6.1±1.0), and (2.8±0.8) points, respectively. The lung tissue injury pathological score of mice in pure burn group was significantly higher than that in sham injury group (P<0.001). The lung tissue injury pathological score of mice in burn+ hydrogen group was significantly lower than that in pure burn group (P<0.001). (2) At PIH 24, the content of HMGB1 and IL-6 in serum and lung tissue of mice in hydrogen group was close to that in sham injury group (with P values above 0.05). The content of HMGB1 and IL-6 in serum and lung tissue of mice in pure burn group was significantly higher than that in sham injury group (with P values below 0.001). The content of HMGB1 and IL-6 in serum and lung tissue of mice in burn+ hydrogen group was significantly lower than that in pure burn group (with P values below 0.001). (3) At PIH 24, the activity of SOD in serum and lung tissue of mice in hydrogen group was close to that in sham injury group (with P values above 0.05). The activity of SOD in serum and lung tissue of mice in pure burn group was significantly lower than that in sham injury group (with P values below 0.001). The activity of SOD in serum and lung tissue of mice in burn+ hydrogen group was significantly higher than that in pure burn group (with P values below 0.001). (4) At PIH 24, there was no statistically significant difference in PaO2 among the mice in four groups (F=0.04, P>0.05). (5) At PIH 24, the ratios of lung wet to dry weight of mice in sham injury, hydrogen, pure burn, and burn+ hydrogen groups were 3.52±0.22, 3.61±0.24, 7.24±0.32, and 5.21±0.41, respectively. The ratio of lung wet to dry weight of mice in pure burn group was significantly higher than that in sham injury group (P<0.001). The ratio of lung wet to dry weight of mice in burn+ hydrogen group was significantly lower than that in pure burn group (P<0.001). (6) The survival rates of mice in sham injury group and hydrogen group during post injury days 7 were 100%. Compared with those in sham injury group, survival rates of mice in pure burn group from post injury days 3 to 7 were significantly decreased (with P values below 0.05). Compared with those in pure burn group, survival rates of mice in burn+ hydrogen group from post injury days 5 to 7 were significantly increased (with P values below 0.05).@*Conclusions@#Hydrogen can significantly alleviate the infiltration of inflammatory cells and improve the pathological lesions of lung tissue of mice with severe burn. It has the effects of reducing inflammatory reaction and inhibiting oxidative stress, further showing the protective effect on the lung of burn mice.
Résumé
High mobility group box 1 (HMGB1) is a pivotal mediator of sepsis progression. Remifentanil, an opioid agonist, has demonstrated anti-inflammatory effects in septic mice. However, it is not yet known whether remifentanil affects the expression of HMGB1. We investigated the effects of remifentanil on HMGB1 expression and the underlying mechanism in septic rats. Forty-eight male Sprague-Dawley rats were randomly divided into 3 groups; a sham group, a cecal ligation and puncture (CLP) group, and a CLP with remifentanil treatment (Remi) group. The rat model of CLP was used to examine plasma concentrations of proinflammatory cytokines, tissue HMGB1 mRNA and the activity of nuclear factor (NF)-κB in the liver, lungs, kidneys, and ileum. Pathologic changes and immunohistochemical staining of NF-κB in the liver, lungs, and kidneys tissue were observed. We found that remifentanil treatment suppressed the level of serum interleukin (IL)-6 and tumor necrosis factor (TNF)-α 6 hours after CLP, and serum HMGB1 24 hours after CLP. HMGB1 mRNA levels and the activity of NF-κB in multiple organs decreased by remifentanil treatment 24 hours after CLP. Remifentanil treatment also attenuated nuclear expression of NF-κB in immunohistochemical staining and mitigated pathologic changes in multiple organs. Altogether, these results suggested that remifentanil inhibited expression of HMGB1 in vital organs and release of HMGB1 into plasma. The mechanism was related to the inhibitory effect of remifentanil on the release of proinflammatory cytokines and activation of NF-κB.