BACKGROUND: Liver failure in chronic hepatitis B (CHB) patients is a severe, life-threatening condition. Intestinal endotoxemia plays a significant role in the progress to liver failure. High mobility group box-1 (HMG...BACKGROUND: Liver failure in chronic hepatitis B (CHB) patients is a severe, life-threatening condition. Intestinal endotoxemia plays a significant role in the progress to liver failure. High mobility group box-1 (HMGB1) protein is involved in the process of endotoxemia. Regulatory T (Treg) cells maintain immune tolerance and contribute to the immunological hyporesponsiveness against HBV infection. However, the roles of HMGB1 and Treg cells in the pathogenesis of liver failure in CHB patients, and whether HMGB1 affects the immune activity of Treg cells are poorly known at present, and so were explored in this study. METHODS: The levels of HMGB1 expression were detected by ELISA, real-time RT-PCR, and Western blotting, and the percentage of CD4(+)CD25(+)CD127(low) Treg cells among CD4(+) cells was detected by flow cytometry in liver failure patients with chronic HBV infection, CHB patients, and healthy controls. Then, CD4(+)CD25(+)CD127(low) Treg cells isolated from the peripheral blood mononuclear cells from CHB patients were stimulated with HMGB1 at different concentrations or at various intervals. The effect of HMGB1 on the immune activity of Treg cells was assessed by a suppression assay of the allogeneic mixed lymphocyte response. The levels of forkhead box P3 (Foxp3) expression in Treg cells treated with HMGB1 were detected by RT-PCR and Western blotting. RESULTS: A higher level of HMGB1 expression and a lower percentage of Treg cells within the population of CIA(+) cells were found in liver failure patients than in CHB patients (82.6+/-20.1 mu g/L vs. 34.2+/-13.7 mu g/L; 4.55+/-1.34% vs. 9.52+/-3.89%, respectively). The immune activity of Treg cells was significantly weakened and the levels of Foxp3 expression were reduced in a dose- or time-dependent manner when Treg cells were stimulated with HMGB1 in vitro. CONCLUSIONS: The high level of HMGB1 and the low percentage of Treg cells play an important role in the pathogenesis of liver failure in patients with chronic HBV infection. Moreover, HMGB1 can weaken展开更多
AIM： To investigate the protective effects of ethyl py- ruvate （EP） on acute-on-chronic liver failure （ACLF） in rats. METHODS： An ACLF model was established in rats, and animals were randomly divided into normal...AIM： To investigate the protective effects of ethyl py- ruvate （EP） on acute-on-chronic liver failure （ACLF） in rats. METHODS： An ACLF model was established in rats, and animals were randomly divided into normal, mod- el and EP treatment groups. The rats in EP treatment group received EP （40 mg/kg） at 3 h, 6 h, 12 h and 24 h after induction of ACLF. Serum endotoxin, high mobility group box-1 （HMGB1）, alanine transaminase （ALT）, tumor necrosis factor-α （TNF-α）, interferon-α （IFN-γ）, interleukin （IL）-10 and IL-18 levels, changes of liver histology and HMGB1 expressions in liver tis- sues were detected at 48 h after induction of ACLF. The effects of EP on the survival of ACLF rats were also observed.RESULTS： Serum levels of endotoxin （0.394 ± 0.066 EU/mL vs 0.086±0.017 EU/mL, P 〈 0.001）, HMGB1 （35.42±10,86 μg/L vs 2.14 ± 0.27 μg/L, P 〈 0.001）, ALT （8415.87 ± 3567.54 IU/L vs 38.64 ± 8.82 IU/L, P 〈 0.001）, TNF-α （190.77 ± 12.34 ng/L vs 124.40 ± 4.12 ng/L, P 〈 0.001）, IFN-γ （715.38 ± 86.03 ng/L vs 398.66 ± 32.91 ng/L, P 〈 0.001）, IL-10 （6.85 ± 0.64 ng/L vs 3.49 ± 0.24 ng/L, P 〈 0.001） and IL-18 （85.19 ±3.49 ng/L vs 55.38 ±1.25 ng/L, P 〈 0.001） were significantly increased, and liver tissues presented se- vere pathological injury in the model group compared with the normal group, Howeverr EP administration significantly improved hepatic histopathology and re- duced the serum levels of endotoxin （0.155±0.045 EU/mL vs 0.394 ± 0.066 EU/mL vs P 〈 0.001） and in- flammatory cytokines （11.13 ± 2.58 μg/L vs 35.42 ± 10.86 μg/L for HMGB1, 3512.86 ± 972.67 IU/L vs 8415.87 ± 3567.54 IU/L for ALT, 128.55 ± 5.76 ng/L vs 190.77 ± 12.34 ng/L for TNF-α 438.16 ± 38.10 ng/L vs 715.38 ± 86.03 ng/L for IFN-γ 3.55 ± 0.36 ng/L vs 6.85 ± 0.64 ng/L for IL-10, and 60.35 ± 1.63 ng/L vs 85.19 ± 3.49 ng/L for IL-18, respectively, P 〈 0.001）, and the levels of HMGB1 in liver tissues re- gardless of treatment time after 展开更多
The present study aims to investigate the therapeutic effect and mechanism of glycyrrhizic acid(GA)in diabetic peripheral neuropathy(DPN).GA significantly mitigated nerve conduction velocity(NCV)deficit and morphologi...The present study aims to investigate the therapeutic effect and mechanism of glycyrrhizic acid(GA)in diabetic peripheral neuropathy(DPN).GA significantly mitigated nerve conduction velocity(NCV)deficit and morphological abnormality and reduced high-mobility group box-1(HMGB1)expression in the sciatic nerves of diabetic rats independent of blood glucose and body weight.Notably,GA alleviated the increase of HMGB1 and the decrease of cell viability in high glucose-stimulated RSC96 cells.Furthermore,GA obviously reduced the concentration of inflammatory cytokines in the sciatic nerves of diabetic rats and supernatants of high glucose-exposed RSC96 cells,then restored the decreased expression levels of nerve growth factor(NGF)and neuritin-1,and the increased expression levels of cleaved caspase-3 and neuron-specific enolase.Additionally,GA markedly inhibited receptor for advanced glycation end products(RAGE)expression,p38MAPK phosphorylation,and the nuclear translocation of NF-κBp65 in diabetic rats and high glucose-exposed RSC96 cells.The promotional effect of high glucose in RSC96 cells was diminished following Hmgb1 siRNA treatment.Our findings indicate that GA may exert neuroprotection on DPN by suppressing HMGB1,which lead to extenuation of inflammation response,balance of NGF,neuritin-1 and caspase-3,as well as inactivation of RAGE/p38MAPK/NF-κBp65 signaling pathway.展开更多
BACKGROUND: Acute liver failure(ALF) is a serious clinical syndrome with high mortality. Sodium butyrate has been shown to alleviate organ injury in a wide variety of preclinical models of critical diseases. The aim o...BACKGROUND: Acute liver failure(ALF) is a serious clinical syndrome with high mortality. Sodium butyrate has been shown to alleviate organ injury in a wide variety of preclinical models of critical diseases. The aim of this study was to investigate the protective effect of sodium butyrate on ALF in rats.METHODS: All rats were randomly divided into control,model and sodium butyrate treatment groups. Except the control group, the rats were induced ALF animal model by subcutaneous injection of human serum albumin+D- galactosamine+lipopolysaccharide. After induction of ALF,the rats in the treatment group received sodium butyrate(500mg/kg) at 12-hour or 24-hour time point. Fourty-eight hours after ALF induction, the animals were sacrificed and samples were harvested. Serum endotoxin, high mobility group box-1(HMGB1), liver function parameters, tumor necrosis factoralpha(TNF-α) and interferon-gamma(IFN-γ) were measured.The expression of HMGB1 and nuclear factor-kappa B(NF-κB)p65 protein in liver tissue was detected by Western blotting. The histological changes of liver and intestine were examined. The survival duration was also observed.RESULTS: Serum endotoxin, alanine aminotransferase, HMGB1,TNF-α and IFN-γ were significantly increased and the liver histology showed more severe histopathological injury in the model group compared with the control group(P<0.05).Compared to the model group, sodium butyrate treatment significantly improved the histopathological changes in the liver and intestine, reduced serum endotoxin and inflammatory cytokines, suppressed HMGB1 and NF-кB p65 proteins in liver tissue, and prolonged the survival duration regardless of treatment at 12 hours or 24 hours after induction of ALF(P<0.05).CONCLUSIONS: Sodium butyrate protected the liver from toxin-induced ALF in rats. The mechanisms may be due to direct hepatoprotection and decreased intestinal permeability.展开更多
Objective This study was performed to investigate the effect of high mobility group box-1 protein(HMGB1)on immune function of human T lymphocytes in vitro and explore its potential role in cell-mediated immune dysfunc...Objective This study was performed to investigate the effect of high mobility group box-1 protein(HMGB1)on immune function of human T lymphocytes in vitro and explore its potential role in cell-mediated immune dysfunction.Methods Fresh blood was obtained from healthy adult volunteers and peripheral blood mononuclear cells(PBMCs)were isolated,then rhHMGB1 was added to PBMCs.Four-color flow cytometric(FCM)analysis was used for the measurement of intracellular cytokine including interleukin IL-4 and interferon IFN-?ELISA kits were employed for the determination of IL-2 and sIL-2R protein levels in cell culture supernatants.Results(1)Different stimulating time and dosage of rhHMGB1 did not alter the number of IFN-αpositive cells(Th1).rhHMGB1 stimulation provoked a dose-dependent and time-dependent increase in Th2 subset and decrease in ratio of Th1 to Th2.(2)Compared with the untreated cells,when the cells were coincubated with rhHMGB1(10-100ng/ml)for 12 hrs,protein release of IL-2 and sIL-2R were significantly up-regulated.At 48 hrs,in contrast,protein production was relatively lower in cells after exposure to 100-1000 ng/ml rhHMGB1.Conclusions These findings demonstrated that HMGB1 has a dual influence on immune functions of human T lymphocytes.展开更多
In the face of the elevated incidence and mortality rate of septic shock in the ICU,this retrospective study seeks to investigate the indicative and predictive value of high-mobility group box 1(HMGB1)and miR-146b in ...In the face of the elevated incidence and mortality rate of septic shock in the ICU,this retrospective study seeks to investigate the indicative and predictive value of high-mobility group box 1(HMGB1)and miR-146b in patients with septic shock.Quantitative RTPCR was employed in this study to quantify the HMGB1 and miR-146b levels in plasma samples obtained from the patient group and healthy controls.The investigation involved the comparison between the two groups and tracking changes in the patient group over time.The finding revealed that upon admission,the patient group exhibited markedly elevated relative expression levels of HMGB1,which subsequently decreased over time.Conversely,the patient group displayed significantly reduced relative expression levels of miR-146b upon admission,which subsequently increased over time compared to the control group.Receiver operating characteristic(ROC)curves showed good predictive value for HMGB1 and miR-146b.The experimental results suggest that HMGB1 and miR-146b serve as valuable and convenient biomarkers for evaluating the severity of septic shock and predicting mortality.Additionally,it is proposed that serum miR-146b may be inducible and potentially exerts a negative regulatory effect on the expression of HMGB1.展开更多
Background Aerobic exercise can improve symptoms,reduce airway inflammation,and even ameliorate airway remodeling in asthmatic animals and patients.However,previous studies have focused mainly on the effect of aerobic...Background Aerobic exercise can improve symptoms,reduce airway inflammation,and even ameliorate airway remodeling in asthmatic animals and patients.However,previous studies have focused mainly on the effect of aerobic exercise on steroid-sensitive asthma （SSA）.The goals of this study were to determine the effect of low-intensity aerobic exercise training on airway hyperresponsiveness,inflammation,and remodeling in a rat model of steroid-resistant asthma （SRA） and to identify the potential mechanisms underlying these effects.Methods Endotoxin-free ovalbumin with or without lipopolysaccharide were applied to establish rat models of SRA and SSA,respectively.Airway hyperresponsiveness,inflammation,remodeling,expression of interleukin （IL）-25,IL-33,thymic stromal lymphopoietin （TSLP）,high mobility group box-1 （HMGB1）,and IL-17 in bronchoalveolar lavage fluid （BALF）,and the role of dexamethasone （DXM） were compared between these two asthmatic rat models.The effect of low-intensity aerobic exercise training and anti-HMGB1 treatment on airway hyperresponsiveness,inflammation,and remodeling in SRA rats also was evaluated.Results SRA rats developed neutrophil-dominated airway inflammation （（29.5±4.1）％ of the total cell numbers in BALF）,whereas SSA rats developed eosinophil-dominated airway inflammation （（24.0±6.1）％ of the total cell numbers in BALF）.Compared with SSA rats,SRA rats had more severe airway hyperresponsiveness,lower levels of IL-25 （（33.6±10.3） vs.（104.8±24.9） pg/ml）,IL-33 （（87.5±25.0） vs.（226.6±40.7） pg/ml）,and TSLP （（1 933.2±899.5） vs.（7 224.0±992.1） pg/ml）,and higher levels of HMGB1 （（21.2±4.5） vs.（5.4±1.6） ng/ml） and IL-17 （（780.5±261.7） vs.（291.4±76.4） pg/ml） in BALF （all P ＜0.05）.However,there was no significant difference in goblet cell hyperplasia,subepithelial collagen thickness,and airway smooth muscle remodeling between the two groups.Compared with control SSA rats,airway hyp展开更多
Background The extracellular release of the danger signal high mobility group box-1 （HMGB1） has been implicated in the pathogenesis and outcomes of sepsis. Understanding the mechanisms responsible for HMGB1 release ...Background The extracellular release of the danger signal high mobility group box-1 （HMGB1） has been implicated in the pathogenesis and outcomes of sepsis. Understanding the mechanisms responsible for HMGB1 release can lead to the identification of targets that may inhibit this process. The transcription factor interferon regulatory factor-1 （IRF-1） is an important mediator of innate immune responses and has been shown to participate in mortality associated with endotoxemia; however, its role in mediating the release of HMGB1 in these settings is unknown. Methods Male IRF-1 knockout （KO） and age matched C57BL/6 wild type （WT） mice were given intraperitoneal （IP） injections of lipopolysaccharide （LPS）. In some experiments, 96 hours survival rates were observed. In other experiments, mice were sacrificed 12 hours after LPS administration and sera were harvested for future analysis. In in vitro study, RAW 264.7 murine monocyte/macrophage-like cells or primary peritoneal macrophage obtained from IRF-1 KO and WT mice were cultured for LPS mediated HMGB1 release analysis. And the mechanism for HMGB1 release was analyzed by immune-precipitation. Results IRF-1 KO mice experienced less mortality, and released less systemic HMGB1 compared to their WT counterparts. Exogenous administration of recombinant HMGB1 to IRF-1 KO mice returned the mortality rate to that seen originally in IRF-1 WT mice. Using cultures of peritoneal macrophages or RAW264.7 cells, in vitro LPS stimulation induced the release of HMGB1 in an IRF-1 dependent manner. And the janus associated kinase （JAK）-IRF-1 signal pathway appeared to participate in the signaling mechanisms of LPS-induced HMGB1 release by mediating acetylation of HMGBI. Conclusion IRF-1 plays a role in LPS induced release of HMGB1 and therefore may serve as a novel target in sepsis~展开更多
Opioids,such as morphine,are the most potent drugs used to treat pain.Long-term use results in high tolerance to morphine.High mobility group box-1(HMGB1) has been shown to participate in neuropathic or inflammatory p...Opioids,such as morphine,are the most potent drugs used to treat pain.Long-term use results in high tolerance to morphine.High mobility group box-1(HMGB1) has been shown to participate in neuropathic or inflammatory pain,but its role in morphine tolerance is unclear.In this study,we established rat and mouse models of morphine tolerance by intrathecal injection of morphine for 7 consecutive days.We found that morphine induced rat spinal cord neurons to release a large amount of HMGB1.HMGB1 regulated nuclear factor κB p65 phosphorylation and interleukin-1β production by increasing Toll-like receptor 4receptor expression in microglia,thereby inducing morphine tolerance.Glycyrrhizin,an HMGB1 inhibito r,markedly attenuated chronic morphine tole rance in the mouse model.Finally,compound C(adenosine 5’-monophosphate-activated protein kinase inhibitor) and zinc protoporphyrin(heme oxygenase-1 inhibitor)alleviated the morphine-induced release of HMGB1 and reduced nuclear factor κB p65 phosphorylation and interleukin-1β production in a mouse model of morphine tolerance and an SH-SY5Y cell model of morphine tole rance,and alleviated morphine tolerance in the mouse model.These findings suggest that morphine induces HMGB1 release via the adenosine 5’-monophosphate-activated protein kinase/heme oxygenase-1 signaling pathway,and that inhibiting this signaling pathway can effectively reduce morphine tole rance.展开更多
目的探讨去整合素金属蛋白酶10(a disintegrin and metalloprotease 10,ADAM10)和高迁移率族蛋白B1(high mobility group box-1 protein,HMGB1)与声门型喉癌患者病理特征及预后关系分析。方法回顾性收集2017年3月~2020年12月于南京医科...目的探讨去整合素金属蛋白酶10(a disintegrin and metalloprotease 10,ADAM10)和高迁移率族蛋白B1(high mobility group box-1 protein,HMGB1)与声门型喉癌患者病理特征及预后关系分析。方法回顾性收集2017年3月~2020年12月于南京医科大学附属南京医院确诊及治疗的声门型喉癌患者50例(观察组),另取相对喉癌组织切缘0.5cm以上部位标本作为对照组。观察并比较ADAM10和HMGB1在两组中的阳性表达率,分析其阳性表达与声门型喉癌患者的病理特征关系。单因素分析影响声门型喉癌预后的危险因素,Cox多因素回归分析声门型喉癌患者不良预后的独立危险因素。结果ADAM10和HMGB1在观察组的阳性表达率均高于对照组,差异均有统计学意义(P<0.05)。声门型喉癌组织中的ADAM10与淋巴结转移和T分级差异比较有统计学意义,而与年龄、性别、饮酒史、吸烟史、分化程度差异比较无统计学意义(P>0.05);HMGB1与分化程度差异比较有统计学意义(P<0.05),而与年龄、性别、饮酒史、吸烟史、淋巴结转移、T分级差异比较无统计学意义(P>0.05)。单因素分析结果表明,淋巴结转移、T分级、分化程度、ADAM10、HMGB1是患者预后的影响因素。Cox多因素回归分析结果表明,淋巴结转移、T3+T4分级、低分化程度、ADAM10阳性、HMGB1阳性为声门型喉癌患者预后不良的独立影响因素(P<0.05)。结论ADAM10和HMGB1可作为声门型喉癌不良预后的风险评估指标。展开更多
Background:Sepsis is a common severe complication in major burn victims and is characterized by a dysregulated systemic response to inflammation.YTH domain family 2(YTHDF2),a wellstudied N6-methyladenosine(m6A)reader ...Background:Sepsis is a common severe complication in major burn victims and is characterized by a dysregulated systemic response to inflammation.YTH domain family 2(YTHDF2),a wellstudied N6-methyladenosine(m6A)reader that specifically recognizes and binds to m6A-modified transcripts to mediate their degradation,is connected to pathogenic and physiological processes in eukaryotes,but its effect on sepsis is still unknown.We aimed to discover the effects and mechanisms of YTHDF2 in sepsis.Methods:Quantitative reverse transcription-polymerase chain reaction(qRT-PCR)and western blot analyses were used to measure the expression of YTHDF2,the interleukin 6 receptor(IL-6R),high-mobility group box-1(HMGB1),Janus kinase 2(JAK2)and signal transducer and activator of transcription 1(STAT1)under different in vitro conditions.Enzyme-linked immunosorbent assays were utilized to evaluate the expression of HMGB1,IL-6,IL-1βand tumor necrosis factor-α.To confirm that YTHDF2 specifically targets IL-6R mRNA,RNA immunoprecipitation and dual-luciferase reporter assays were performed.Finally,we utilized a mouse model of lipopolysaccharide(LPS)-induced sepsis to verify the effects of YTHDF2 in vivo.Results:According to our findings,YTHDF2 was expressed at a low level in peripheral blood mononuclear cells from septic mice and patients as well as in LPS-induced RAW264.7 cells.Overexpression of YTHDF2 alleviated the inflammatory response by inhibiting HMGB1 release and JAK2/STAT1 signalling in LPS-stimulated cells.Mechanistically,YTHDF2 suppressed JAK2/STAT1 signalling by directly recognizing the m6A-modified site in IL-6R and decreasing the stability of IL-6R mRNA,thereby inhibiting HMGB1 release.In vivo experiments showed that YTHDF2 played a protective role in septic mice by suppressing the IL-6R/JAK2/STAT1/HMGB1 axis.Conclusions:In summary,these findings demonstrate that YTHDF2 plays an essential role as an inhibitor of inflammation to reduce the release of HMGB1 by inhibiting the IL-6R/JAK2/STAT1 pathway,indicating that YTHDF2 is a 展开更多
Objective： To investigate the possible mechanism of San-Cao Granule（SCG, 三草颗粒） mediating antiliver fibrosis. Methods： A total of 60 male Sprague-Dawley rats were randomly divided into the normal control group,...Objective： To investigate the possible mechanism of San-Cao Granule（SCG, 三草颗粒） mediating antiliver fibrosis. Methods： A total of 60 male Sprague-Dawley rats were randomly divided into the normal control group, porcine serum-treated group, ursodesoxycholic acid（UDCA, 60 mg/kg）, SCG（3.6 g/kg） group, SCG（1.8 g/kg） group and SCG（0.9 g/kg） group, with 10 rats in each group. Liver fibrosis was induced with porcine serum by intraperitoneal injection for 8 weeks, except for the normal control group. Then, the rats in the three SCG-treated groups and UDCA group were administered SCG and UDCA respectively for 4 weeks. The serum levels of alanine transaminase（ALT）, aspartate transaminase（AST）, albumin（ALB）, total bilirubin（TBIL）, hyaluronic acid（HA）, laminin（LN）, and type Ⅳcollagen（ⅣC） were examined using commercial kits and hepatic histopathology was examined with hematoxylin and eosin and Masson staining. Moreover, the protein expression levels of high mobility group box-1 protein（HMGB1）, transforming growth factor β1（TGF-β1）, phosphorylated mothers against decapentaplegic homolog 3（p-Smad3）, Smad7, toll-like receptor 4（TLR4）, myeloid differentiation factor 88（My D88）, nuclear factor-kappa B（NF-κB） and α-smooth muscle actin（α-SMA） were determined by western blot, immunohistochemistry and real time quantitativereverse transcription polymerase. Results： Both SCG（3.6 and 1.8 g/kg） and UDCA significantly ameliorated the liver fibrosis induced by porcine serum as indicated by retarding the serum levels increasing of ALT, AST, TBIL, HA, LN and ⅣC and preventing the serum level reducing of ALB compared with the model group（all P〈0.01）. Meanwhile, the collagen deposition was attenuated by SCG and UDCA treatment. Furthermore, SCG markedly reduced the expressions of HMGB1, TGF-β1, p-Smad3, TLR4, My D88, NF-κB and α-SMA, and enhanced the expression of the Smad7 compared with the model group（all P〈0.01）. Conclusion�展开更多
BACKGROUND High mobility group box-1 (HMGB1), recognized as a representative of damageassociated molecular patterns, is released during cell injury/death, triggering the inflammatory response and ultimately resulting ...BACKGROUND High mobility group box-1 (HMGB1), recognized as a representative of damageassociated molecular patterns, is released during cell injury/death, triggering the inflammatory response and ultimately resulting in tissue damage. Dozens of studies have shown that HMGB1 is involved in certain diseases, but the details on how injured hepatocytes release HMGB1 need to be elicited. AIM To reveal HMGB1 release mechanism in hepatocytes undergoing oxidative stress. METHODS C57BL6/J male mice were fed a high-fat diet for 12 wk plus a single binge of ethanol to induce severe steatohepatitis. Hepatocytes treated with H2O2 were used to establish an in vitro model. Serum alanine aminotransferase, liver H2O2 content and catalase activity, lactate dehydrogenase and 8-hydroxy-2- deoxyguanosine content, nicotinamide adenine dinucleotide (NAD+) levels, and Sirtuin 1 (Sirt1) activity were detected by spectrophotometry. HMGB1 release was measured by enzyme linked immunosorbent assay. HMGB1 translocation was observed by immunohistochemistry/immunofluorescence or Western blot. Relative mRNA levels were assayed by qPCR and protein expression was detected by Western blot. Acetylated HMGB1 and poly(ADP-ribose)polymerase 1 (Parp1) were analyzed by Immunoprecipitation. RESULTS When hepatocytes were damaged, HMGB1 translocated from the nucleus to the cytoplasm because of its hyperacetylation and was passively released outside both in vivo and in vitro. After treatment with Sirt1-siRNA or Sirt1 inhibitor (EX527), the hyperacetylated HMGB1 in hepatocytes increased, and Sirt1 activity inhibited by H2O2 could be reversed by Parp1 inhibitor (DIQ). Parp1 and Sirt1 are two NAD+-dependent enzymes which play major roles in the decision of a cell to live or die in the context of stress . We showed that NAD+ depletion attributed to Parp1 activation after DNA damage was caused by oxidative stress in hepatocytes and resulted in Sirt1 activity inhibition. On the contrary, Sirt1 suppressed Parp1 by negatively regulating its gene expression and deace展开更多
基金supported by a grant from the National Natural Science Foundation of China (No. 81071342)
文摘BACKGROUND: Liver failure in chronic hepatitis B (CHB) patients is a severe, life-threatening condition. Intestinal endotoxemia plays a significant role in the progress to liver failure. High mobility group box-1 (HMGB1) protein is involved in the process of endotoxemia. Regulatory T (Treg) cells maintain immune tolerance and contribute to the immunological hyporesponsiveness against HBV infection. However, the roles of HMGB1 and Treg cells in the pathogenesis of liver failure in CHB patients, and whether HMGB1 affects the immune activity of Treg cells are poorly known at present, and so were explored in this study. METHODS: The levels of HMGB1 expression were detected by ELISA, real-time RT-PCR, and Western blotting, and the percentage of CD4(+)CD25(+)CD127(low) Treg cells among CD4(+) cells was detected by flow cytometry in liver failure patients with chronic HBV infection, CHB patients, and healthy controls. Then, CD4(+)CD25(+)CD127(low) Treg cells isolated from the peripheral blood mononuclear cells from CHB patients were stimulated with HMGB1 at different concentrations or at various intervals. The effect of HMGB1 on the immune activity of Treg cells was assessed by a suppression assay of the allogeneic mixed lymphocyte response. The levels of forkhead box P3 (Foxp3) expression in Treg cells treated with HMGB1 were detected by RT-PCR and Western blotting. RESULTS: A higher level of HMGB1 expression and a lower percentage of Treg cells within the population of CIA(+) cells were found in liver failure patients than in CHB patients (82.6+/-20.1 mu g/L vs. 34.2+/-13.7 mu g/L; 4.55+/-1.34% vs. 9.52+/-3.89%, respectively). The immune activity of Treg cells was significantly weakened and the levels of Foxp3 expression were reduced in a dose- or time-dependent manner when Treg cells were stimulated with HMGB1 in vitro. CONCLUSIONS: The high level of HMGB1 and the low percentage of Treg cells play an important role in the pathogenesis of liver failure in patients with chronic HBV infection. Moreover, HMGB1 can weaken
基金Supported by The National Natural Science Foundation of China,No.81071342
文摘AIM： To investigate the protective effects of ethyl py- ruvate （EP） on acute-on-chronic liver failure （ACLF） in rats. METHODS： An ACLF model was established in rats, and animals were randomly divided into normal, mod- el and EP treatment groups. The rats in EP treatment group received EP （40 mg/kg） at 3 h, 6 h, 12 h and 24 h after induction of ACLF. Serum endotoxin, high mobility group box-1 （HMGB1）, alanine transaminase （ALT）, tumor necrosis factor-α （TNF-α）, interferon-α （IFN-γ）, interleukin （IL）-10 and IL-18 levels, changes of liver histology and HMGB1 expressions in liver tis- sues were detected at 48 h after induction of ACLF. The effects of EP on the survival of ACLF rats were also observed.RESULTS： Serum levels of endotoxin （0.394 ± 0.066 EU/mL vs 0.086±0.017 EU/mL, P 〈 0.001）, HMGB1 （35.42±10,86 μg/L vs 2.14 ± 0.27 μg/L, P 〈 0.001）, ALT （8415.87 ± 3567.54 IU/L vs 38.64 ± 8.82 IU/L, P 〈 0.001）, TNF-α （190.77 ± 12.34 ng/L vs 124.40 ± 4.12 ng/L, P 〈 0.001）, IFN-γ （715.38 ± 86.03 ng/L vs 398.66 ± 32.91 ng/L, P 〈 0.001）, IL-10 （6.85 ± 0.64 ng/L vs 3.49 ± 0.24 ng/L, P 〈 0.001） and IL-18 （85.19 ±3.49 ng/L vs 55.38 ±1.25 ng/L, P 〈 0.001） were significantly increased, and liver tissues presented se- vere pathological injury in the model group compared with the normal group, Howeverr EP administration significantly improved hepatic histopathology and re- duced the serum levels of endotoxin （0.155±0.045 EU/mL vs 0.394 ± 0.066 EU/mL vs P 〈 0.001） and in- flammatory cytokines （11.13 ± 2.58 μg/L vs 35.42 ± 10.86 μg/L for HMGB1, 3512.86 ± 972.67 IU/L vs 8415.87 ± 3567.54 IU/L for ALT, 128.55 ± 5.76 ng/L vs 190.77 ± 12.34 ng/L for TNF-α 438.16 ± 38.10 ng/L vs 715.38 ± 86.03 ng/L for IFN-γ 3.55 ± 0.36 ng/L vs 6.85 ± 0.64 ng/L for IL-10, and 60.35 ± 1.63 ng/L vs 85.19 ± 3.49 ng/L for IL-18, respectively, P 〈 0.001）, and the levels of HMGB1 in liver tissues re- gardless of treatment time after
基金supported by the National Natural Science Foundation of China (Grant No. 81700723)Research Project of Jiangsu 333 Engineering (Grant No. BRA2016232)Research Project of Jiangsu Provincial Commission of Health and Family Planning (Grant No. F201549/H201667)
文摘The present study aims to investigate the therapeutic effect and mechanism of glycyrrhizic acid(GA)in diabetic peripheral neuropathy(DPN).GA significantly mitigated nerve conduction velocity(NCV)deficit and morphological abnormality and reduced high-mobility group box-1(HMGB1)expression in the sciatic nerves of diabetic rats independent of blood glucose and body weight.Notably,GA alleviated the increase of HMGB1 and the decrease of cell viability in high glucose-stimulated RSC96 cells.Furthermore,GA obviously reduced the concentration of inflammatory cytokines in the sciatic nerves of diabetic rats and supernatants of high glucose-exposed RSC96 cells,then restored the decreased expression levels of nerve growth factor(NGF)and neuritin-1,and the increased expression levels of cleaved caspase-3 and neuron-specific enolase.Additionally,GA markedly inhibited receptor for advanced glycation end products(RAGE)expression,p38MAPK phosphorylation,and the nuclear translocation of NF-κBp65 in diabetic rats and high glucose-exposed RSC96 cells.The promotional effect of high glucose in RSC96 cells was diminished following Hmgb1 siRNA treatment.Our findings indicate that GA may exert neuroprotection on DPN by suppressing HMGB1,which lead to extenuation of inflammation response,balance of NGF,neuritin-1 and caspase-3,as well as inactivation of RAGE/p38MAPK/NF-κBp65 signaling pathway.
基金supported by a grant from the National Natural Science Foundation of China(81071342)
文摘BACKGROUND: Acute liver failure(ALF) is a serious clinical syndrome with high mortality. Sodium butyrate has been shown to alleviate organ injury in a wide variety of preclinical models of critical diseases. The aim of this study was to investigate the protective effect of sodium butyrate on ALF in rats.METHODS: All rats were randomly divided into control,model and sodium butyrate treatment groups. Except the control group, the rats were induced ALF animal model by subcutaneous injection of human serum albumin+D- galactosamine+lipopolysaccharide. After induction of ALF,the rats in the treatment group received sodium butyrate(500mg/kg) at 12-hour or 24-hour time point. Fourty-eight hours after ALF induction, the animals were sacrificed and samples were harvested. Serum endotoxin, high mobility group box-1(HMGB1), liver function parameters, tumor necrosis factoralpha(TNF-α) and interferon-gamma(IFN-γ) were measured.The expression of HMGB1 and nuclear factor-kappa B(NF-κB)p65 protein in liver tissue was detected by Western blotting. The histological changes of liver and intestine were examined. The survival duration was also observed.RESULTS: Serum endotoxin, alanine aminotransferase, HMGB1,TNF-α and IFN-γ were significantly increased and the liver histology showed more severe histopathological injury in the model group compared with the control group(P<0.05).Compared to the model group, sodium butyrate treatment significantly improved the histopathological changes in the liver and intestine, reduced serum endotoxin and inflammatory cytokines, suppressed HMGB1 and NF-кB p65 proteins in liver tissue, and prolonged the survival duration regardless of treatment at 12 hours or 24 hours after induction of ALF(P<0.05).CONCLUSIONS: Sodium butyrate protected the liver from toxin-induced ALF in rats. The mechanisms may be due to direct hepatoprotection and decreased intestinal permeability.
基金This study was supported by the National Natural Science Foundation of China(No.30672178)National Basic Research Program of China(No.2005CB522602)the National Natural Science Outstanding Youth Foundation of China(No.30125020).
文摘Objective This study was performed to investigate the effect of high mobility group box-1 protein(HMGB1)on immune function of human T lymphocytes in vitro and explore its potential role in cell-mediated immune dysfunction.Methods Fresh blood was obtained from healthy adult volunteers and peripheral blood mononuclear cells(PBMCs)were isolated,then rhHMGB1 was added to PBMCs.Four-color flow cytometric(FCM)analysis was used for the measurement of intracellular cytokine including interleukin IL-4 and interferon IFN-?ELISA kits were employed for the determination of IL-2 and sIL-2R protein levels in cell culture supernatants.Results(1)Different stimulating time and dosage of rhHMGB1 did not alter the number of IFN-αpositive cells(Th1).rhHMGB1 stimulation provoked a dose-dependent and time-dependent increase in Th2 subset and decrease in ratio of Th1 to Th2.(2)Compared with the untreated cells,when the cells were coincubated with rhHMGB1(10-100ng/ml)for 12 hrs,protein release of IL-2 and sIL-2R were significantly up-regulated.At 48 hrs,in contrast,protein production was relatively lower in cells after exposure to 100-1000 ng/ml rhHMGB1.Conclusions These findings demonstrated that HMGB1 has a dual influence on immune functions of human T lymphocytes.
基金Supported by the Natural Science Foundation of Hubei Province(2021CFB026)Scientific Research Project of Hubei Pathophysiological Society(2021HBAP002)+2 种基金Medical Service Capacity Building and Health Personnel Training Project of the Central Government(New Finance Society[2022]No.255)Key Project of Science and Technology Program of Nanshan District,Shenzhen(NS2022014)Wu Jieping Medical Foundation Clinical Research Project(320.6750.2021-11-12)。
文摘In the face of the elevated incidence and mortality rate of septic shock in the ICU,this retrospective study seeks to investigate the indicative and predictive value of high-mobility group box 1(HMGB1)and miR-146b in patients with septic shock.Quantitative RTPCR was employed in this study to quantify the HMGB1 and miR-146b levels in plasma samples obtained from the patient group and healthy controls.The investigation involved the comparison between the two groups and tracking changes in the patient group over time.The finding revealed that upon admission,the patient group exhibited markedly elevated relative expression levels of HMGB1,which subsequently decreased over time.Conversely,the patient group displayed significantly reduced relative expression levels of miR-146b upon admission,which subsequently increased over time compared to the control group.Receiver operating characteristic(ROC)curves showed good predictive value for HMGB1 and miR-146b.The experimental results suggest that HMGB1 and miR-146b serve as valuable and convenient biomarkers for evaluating the severity of septic shock and predicting mortality.Additionally,it is proposed that serum miR-146b may be inducible and potentially exerts a negative regulatory effect on the expression of HMGB1.
基金This study was supported by grants from the National Natural Science Foundation of China （No. 81070026）, the Key Project of Hunan Provincial Science and Technology Department （No. 2012FJ4375）, and the Open Innovation Platform of Hunan College （No. 10K076）.
文摘Background Aerobic exercise can improve symptoms,reduce airway inflammation,and even ameliorate airway remodeling in asthmatic animals and patients.However,previous studies have focused mainly on the effect of aerobic exercise on steroid-sensitive asthma （SSA）.The goals of this study were to determine the effect of low-intensity aerobic exercise training on airway hyperresponsiveness,inflammation,and remodeling in a rat model of steroid-resistant asthma （SRA） and to identify the potential mechanisms underlying these effects.Methods Endotoxin-free ovalbumin with or without lipopolysaccharide were applied to establish rat models of SRA and SSA,respectively.Airway hyperresponsiveness,inflammation,remodeling,expression of interleukin （IL）-25,IL-33,thymic stromal lymphopoietin （TSLP）,high mobility group box-1 （HMGB1）,and IL-17 in bronchoalveolar lavage fluid （BALF）,and the role of dexamethasone （DXM） were compared between these two asthmatic rat models.The effect of low-intensity aerobic exercise training and anti-HMGB1 treatment on airway hyperresponsiveness,inflammation,and remodeling in SRA rats also was evaluated.Results SRA rats developed neutrophil-dominated airway inflammation （（29.5±4.1）％ of the total cell numbers in BALF）,whereas SSA rats developed eosinophil-dominated airway inflammation （（24.0±6.1）％ of the total cell numbers in BALF）.Compared with SSA rats,SRA rats had more severe airway hyperresponsiveness,lower levels of IL-25 （（33.6±10.3） vs.（104.8±24.9） pg/ml）,IL-33 （（87.5±25.0） vs.（226.6±40.7） pg/ml）,and TSLP （（1 933.2±899.5） vs.（7 224.0±992.1） pg/ml）,and higher levels of HMGB1 （（21.2±4.5） vs.（5.4±1.6） ng/ml） and IL-17 （（780.5±261.7） vs.（291.4±76.4） pg/ml） in BALF （all P ＜0.05）.However,there was no significant difference in goblet cell hyperplasia,subepithelial collagen thickness,and airway smooth muscle remodeling between the two groups.Compared with control SSA rats,airway hyp
文摘Background The extracellular release of the danger signal high mobility group box-1 （HMGB1） has been implicated in the pathogenesis and outcomes of sepsis. Understanding the mechanisms responsible for HMGB1 release can lead to the identification of targets that may inhibit this process. The transcription factor interferon regulatory factor-1 （IRF-1） is an important mediator of innate immune responses and has been shown to participate in mortality associated with endotoxemia; however, its role in mediating the release of HMGB1 in these settings is unknown. Methods Male IRF-1 knockout （KO） and age matched C57BL/6 wild type （WT） mice were given intraperitoneal （IP） injections of lipopolysaccharide （LPS）. In some experiments, 96 hours survival rates were observed. In other experiments, mice were sacrificed 12 hours after LPS administration and sera were harvested for future analysis. In in vitro study, RAW 264.7 murine monocyte/macrophage-like cells or primary peritoneal macrophage obtained from IRF-1 KO and WT mice were cultured for LPS mediated HMGB1 release analysis. And the mechanism for HMGB1 release was analyzed by immune-precipitation. Results IRF-1 KO mice experienced less mortality, and released less systemic HMGB1 compared to their WT counterparts. Exogenous administration of recombinant HMGB1 to IRF-1 KO mice returned the mortality rate to that seen originally in IRF-1 WT mice. Using cultures of peritoneal macrophages or RAW264.7 cells, in vitro LPS stimulation induced the release of HMGB1 in an IRF-1 dependent manner. And the janus associated kinase （JAK）-IRF-1 signal pathway appeared to participate in the signaling mechanisms of LPS-induced HMGB1 release by mediating acetylation of HMGBI. Conclusion IRF-1 plays a role in LPS induced release of HMGB1 and therefore may serve as a novel target in sepsis~
基金supported by the National Natural Science Foundation of ChinaNos.81971047 (to WTL) and 82073910 (to XFW)+2 种基金the Natural Science Foundation of Jiangsu Province,No.BK20191253 (to XFW)Key R&D Program (Social Development) Project of Jiangsu Province,No.BE2019 732 (to WTL)Jiangsu Province Hospital (the First Affiliated Hospital of Nanjing Medical University) Clinical Capacity Enhancement Project,No.JSPH-511B2018-8 (to YBP)。
文摘Opioids,such as morphine,are the most potent drugs used to treat pain.Long-term use results in high tolerance to morphine.High mobility group box-1(HMGB1) has been shown to participate in neuropathic or inflammatory pain,but its role in morphine tolerance is unclear.In this study,we established rat and mouse models of morphine tolerance by intrathecal injection of morphine for 7 consecutive days.We found that morphine induced rat spinal cord neurons to release a large amount of HMGB1.HMGB1 regulated nuclear factor κB p65 phosphorylation and interleukin-1β production by increasing Toll-like receptor 4receptor expression in microglia,thereby inducing morphine tolerance.Glycyrrhizin,an HMGB1 inhibito r,markedly attenuated chronic morphine tole rance in the mouse model.Finally,compound C(adenosine 5’-monophosphate-activated protein kinase inhibitor) and zinc protoporphyrin(heme oxygenase-1 inhibitor)alleviated the morphine-induced release of HMGB1 and reduced nuclear factor κB p65 phosphorylation and interleukin-1β production in a mouse model of morphine tolerance and an SH-SY5Y cell model of morphine tole rance,and alleviated morphine tolerance in the mouse model.These findings suggest that morphine induces HMGB1 release via the adenosine 5’-monophosphate-activated protein kinase/heme oxygenase-1 signaling pathway,and that inhibiting this signaling pathway can effectively reduce morphine tole rance.
文摘目的探讨去整合素金属蛋白酶10(a disintegrin and metalloprotease 10,ADAM10)和高迁移率族蛋白B1(high mobility group box-1 protein,HMGB1)与声门型喉癌患者病理特征及预后关系分析。方法回顾性收集2017年3月~2020年12月于南京医科大学附属南京医院确诊及治疗的声门型喉癌患者50例(观察组),另取相对喉癌组织切缘0.5cm以上部位标本作为对照组。观察并比较ADAM10和HMGB1在两组中的阳性表达率,分析其阳性表达与声门型喉癌患者的病理特征关系。单因素分析影响声门型喉癌预后的危险因素,Cox多因素回归分析声门型喉癌患者不良预后的独立危险因素。结果ADAM10和HMGB1在观察组的阳性表达率均高于对照组,差异均有统计学意义(P<0.05)。声门型喉癌组织中的ADAM10与淋巴结转移和T分级差异比较有统计学意义,而与年龄、性别、饮酒史、吸烟史、分化程度差异比较无统计学意义(P>0.05);HMGB1与分化程度差异比较有统计学意义(P<0.05),而与年龄、性别、饮酒史、吸烟史、淋巴结转移、T分级差异比较无统计学意义(P>0.05)。单因素分析结果表明,淋巴结转移、T分级、分化程度、ADAM10、HMGB1是患者预后的影响因素。Cox多因素回归分析结果表明,淋巴结转移、T3+T4分级、低分化程度、ADAM10阳性、HMGB1阳性为声门型喉癌患者预后不良的独立影响因素(P<0.05)。结论ADAM10和HMGB1可作为声门型喉癌不良预后的风险评估指标。
基金The National Natural Science Foundation of China(82072171 and 81873935)provided funding for this work.
文摘Background:Sepsis is a common severe complication in major burn victims and is characterized by a dysregulated systemic response to inflammation.YTH domain family 2(YTHDF2),a wellstudied N6-methyladenosine(m6A)reader that specifically recognizes and binds to m6A-modified transcripts to mediate their degradation,is connected to pathogenic and physiological processes in eukaryotes,but its effect on sepsis is still unknown.We aimed to discover the effects and mechanisms of YTHDF2 in sepsis.Methods:Quantitative reverse transcription-polymerase chain reaction(qRT-PCR)and western blot analyses were used to measure the expression of YTHDF2,the interleukin 6 receptor(IL-6R),high-mobility group box-1(HMGB1),Janus kinase 2(JAK2)and signal transducer and activator of transcription 1(STAT1)under different in vitro conditions.Enzyme-linked immunosorbent assays were utilized to evaluate the expression of HMGB1,IL-6,IL-1βand tumor necrosis factor-α.To confirm that YTHDF2 specifically targets IL-6R mRNA,RNA immunoprecipitation and dual-luciferase reporter assays were performed.Finally,we utilized a mouse model of lipopolysaccharide(LPS)-induced sepsis to verify the effects of YTHDF2 in vivo.Results:According to our findings,YTHDF2 was expressed at a low level in peripheral blood mononuclear cells from septic mice and patients as well as in LPS-induced RAW264.7 cells.Overexpression of YTHDF2 alleviated the inflammatory response by inhibiting HMGB1 release and JAK2/STAT1 signalling in LPS-stimulated cells.Mechanistically,YTHDF2 suppressed JAK2/STAT1 signalling by directly recognizing the m6A-modified site in IL-6R and decreasing the stability of IL-6R mRNA,thereby inhibiting HMGB1 release.In vivo experiments showed that YTHDF2 played a protective role in septic mice by suppressing the IL-6R/JAK2/STAT1/HMGB1 axis.Conclusions:In summary,these findings demonstrate that YTHDF2 plays an essential role as an inhibitor of inflammation to reduce the release of HMGB1 by inhibiting the IL-6R/JAK2/STAT1 pathway,indicating that YTHDF2 is a
基金Supported by the Major Projects of the National Science and Technology(No.2012ZX10005010-002-002)the National Natural Science Foundation of China(No.81303120 and No.81173571)
文摘Objective： To investigate the possible mechanism of San-Cao Granule（SCG, 三草颗粒） mediating antiliver fibrosis. Methods： A total of 60 male Sprague-Dawley rats were randomly divided into the normal control group, porcine serum-treated group, ursodesoxycholic acid（UDCA, 60 mg/kg）, SCG（3.6 g/kg） group, SCG（1.8 g/kg） group and SCG（0.9 g/kg） group, with 10 rats in each group. Liver fibrosis was induced with porcine serum by intraperitoneal injection for 8 weeks, except for the normal control group. Then, the rats in the three SCG-treated groups and UDCA group were administered SCG and UDCA respectively for 4 weeks. The serum levels of alanine transaminase（ALT）, aspartate transaminase（AST）, albumin（ALB）, total bilirubin（TBIL）, hyaluronic acid（HA）, laminin（LN）, and type Ⅳcollagen（ⅣC） were examined using commercial kits and hepatic histopathology was examined with hematoxylin and eosin and Masson staining. Moreover, the protein expression levels of high mobility group box-1 protein（HMGB1）, transforming growth factor β1（TGF-β1）, phosphorylated mothers against decapentaplegic homolog 3（p-Smad3）, Smad7, toll-like receptor 4（TLR4）, myeloid differentiation factor 88（My D88）, nuclear factor-kappa B（NF-κB） and α-smooth muscle actin（α-SMA） were determined by western blot, immunohistochemistry and real time quantitativereverse transcription polymerase. Results： Both SCG（3.6 and 1.8 g/kg） and UDCA significantly ameliorated the liver fibrosis induced by porcine serum as indicated by retarding the serum levels increasing of ALT, AST, TBIL, HA, LN and ⅣC and preventing the serum level reducing of ALB compared with the model group（all P〈0.01）. Meanwhile, the collagen deposition was attenuated by SCG and UDCA treatment. Furthermore, SCG markedly reduced the expressions of HMGB1, TGF-β1, p-Smad3, TLR4, My D88, NF-κB and α-SMA, and enhanced the expression of the Smad7 compared with the model group（all P〈0.01）. Conclusion�
基金Supported by the National Natural Science Foundation of China,No.81503367 and No.81703832
文摘BACKGROUND High mobility group box-1 (HMGB1), recognized as a representative of damageassociated molecular patterns, is released during cell injury/death, triggering the inflammatory response and ultimately resulting in tissue damage. Dozens of studies have shown that HMGB1 is involved in certain diseases, but the details on how injured hepatocytes release HMGB1 need to be elicited. AIM To reveal HMGB1 release mechanism in hepatocytes undergoing oxidative stress. METHODS C57BL6/J male mice were fed a high-fat diet for 12 wk plus a single binge of ethanol to induce severe steatohepatitis. Hepatocytes treated with H2O2 were used to establish an in vitro model. Serum alanine aminotransferase, liver H2O2 content and catalase activity, lactate dehydrogenase and 8-hydroxy-2- deoxyguanosine content, nicotinamide adenine dinucleotide (NAD+) levels, and Sirtuin 1 (Sirt1) activity were detected by spectrophotometry. HMGB1 release was measured by enzyme linked immunosorbent assay. HMGB1 translocation was observed by immunohistochemistry/immunofluorescence or Western blot. Relative mRNA levels were assayed by qPCR and protein expression was detected by Western blot. Acetylated HMGB1 and poly(ADP-ribose)polymerase 1 (Parp1) were analyzed by Immunoprecipitation. RESULTS When hepatocytes were damaged, HMGB1 translocated from the nucleus to the cytoplasm because of its hyperacetylation and was passively released outside both in vivo and in vitro. After treatment with Sirt1-siRNA or Sirt1 inhibitor (EX527), the hyperacetylated HMGB1 in hepatocytes increased, and Sirt1 activity inhibited by H2O2 could be reversed by Parp1 inhibitor (DIQ). Parp1 and Sirt1 are two NAD+-dependent enzymes which play major roles in the decision of a cell to live or die in the context of stress . We showed that NAD+ depletion attributed to Parp1 activation after DNA damage was caused by oxidative stress in hepatocytes and resulted in Sirt1 activity inhibition. On the contrary, Sirt1 suppressed Parp1 by negatively regulating its gene expression and deace
