Clinical characteristics and change trend of patients with Crohn′s disease at different onset times of perianal lesions / 中华消化杂志

Objective:To investigate the clinical characteristics and change trend of patients with perianal lesions before or after Crohn′s disease (CD) diagnosed.Methods:From January 2008 to September 2018, at The Tenth People′s Hospital Affiliated to Tongji University, the clinical data of 747 hospitalized CD patients were retrospectively collected, 293 patients were PCD patients. The clinical characteristics of PCD patients before or after CD diagnosed were analyzed and the change trend was followed. T test, Mann-Whitney U test, and Chi-square test were performed for statistical analysis. Multivariate logistic regression analysis was used to analyze factors associated with perianal lesions onset time. Spearman correlation analysis was used to analyze the change trend of clinical characteristics. Results:Before CD diagnosis, 86.3% (253/293) PCD patients had perianal lesions. The median follow-up time (range) was 72 months (36 to 108 months). Compared with the patients presented with perianal lesions after CD diagnosis, the onset age of patients with perianal lesions before CD diagnosis was younger ((36.0±12.6) years vs. (24.2±10.2) years), and the rates of male (62.5%, 25/40 vs. 77.9%, 197/253), non-structuring and non-penetrating type (32.5%, 13/40 vs. 56.9%, 144/253) and perianal surgery (55.0%, 22/40 vs.76.7%, 194/253) were high, but low rate of abdominal surgery (37.5%, 15/40 vs. 13.0%, 33/253), and the differences were statistically significant ( t=2.630, χ2=4.442, 8.379, 8.379 and 15.081; all P<0.05). The results of logistic multivariate analysis showed that before CD diagnosis, non-structuring and non-penetrating type was more common than structuring type (odds ratio ( OR)=0.447, 95% confidence interval ( CI) 0.207 to 0.962, P=0.039) and penetrating type ( OR=0.264, 95% CI 0.089 to 0.780, P=0.016). The short disease duration of CD ( OR=0.981, 95% CI 0.968 to 0.995, P=0.008), structuring type ( OR=2.239, 95% CI 1.040 to 4.822, P=0.039) and penetrating type ( OR=3.788, 95% CI 1.281 to 11.198, P=0.016) were the risk factors of perianal lesions after CD diagnosed. The number of PCD patients ( r=0.964, P<0.01) and the proportion of biological agents ( r=0.879, P<0.01) increased with years, while PCD duration ( r=-0.828, P<0.01) and the rate of abdominal surgery significantly decreased with years ( r=-0.882, P<0.01). The proportion of biological agents was negatively correlated with the rate of abdominal surgery ( r=-0.770, P=0.006). Conclusions:The perianal lesions should be closely monitored in adult CD patients with short disease duration, structuring type and penetrating type for early diagnosis and treatment. Biological agents can improve the clinical outcomes of PCD.

HMGB1 increases radiosensitivity by interacting with HDAC1 / 中华放射医学与防护杂志

Objective To study the nuclear protein association of high-mobility group box-1 (HMGB1) and histone deacetylase 1 (HDAC1),and the effect of interaction on radiosensitivity in human breast cancer cells.Methods The protein-protein interaction was determined by immunoprecipitationWestern blot and glutathione-S-transferase capture assays.Cell growth was examined by MTT (methyl thiazolyl tetrazolium)assay and clonogenic assay.Histone deacetylase activity was analyzed by histone deacetylase assay.Results A significant increase of HMGB1 protein and radiosensitivity was observed in MDA-MB-231 and MDA-MB-468 cells transfected with a pCMV-Tag2B expression vector carrying with a full-length of HMGB1 cDNA.HMGB1 binding to HDAC1 was demonstrated as GST (glutathione Stransferase)-pull down and immunoprecipitation Western blot assay,and the association was elevated by irradiation.An LXCXE motif was required for the HMGB1-HADC1 interaction and HMGB1 radiosensitization.A significant difference of IC50 value was observed,for example,1.8 and 2.2 Gy (wtHMGB1 transfectants,P ＜ 0.05),3.6 and 3.8 Gy (HMGB1/C103F transfectants,P ＞ 0.05),both compared with 3.9 and 4.1 Gy (pCMV-Tag2B transfectants) in MDA-MB-231 and MDA-MB-468 cells,respectively.A specific HDAC1 inhibitor trichostatin A markedly reduced the HMGB1-mediated radiosensitivity,0.5 Gy in the presence of trichostatin A versus 1.8 Gy in absence of trichostatin A in MDA-MB-231 transfectants,1.2 Gy (with trichostatin A) versus 2.2 Gy (without trichostatin A) in MDA-MB-468 transfectants,P ＜ 0.05.Histone deacetylase activity was also detected in immunoprecipitates prepared from these cells with antibodies to HMGB1,and this activity was abolished by the histone trichostatin A.Conclusions These results suggest a previous unanticipated role for HDAC1 in modification of HMGB1-mediated radiosensitivity by its direct interaction with HMGB1.

Regulation of HMGB1 release by inflammasomes

High mobility group box 1 (HMGB1) is an evolutionarily conserved non-histone chromatin-binding protein. During infection or injury, activated immune cells and damaged cells release HMGB1 into the extracellular space, where HMGB1 functions as a proinflammatory mediator and contributes importantly to the pathogenesis of inflammatory diseases. Recent studies reveal that inflammasomes, intracellular protein complexes, critically regulate HMGB1 release from activated immune cells in response to a variety of exogenous and endogenous danger signals. Double stranded RNA dependent kinase (PKR), an intracellular danger-sensing molecule, physically interacts with inflammasome components and is important for inflammasome activation and HMGB1 release. Together, these studies not only unravel novel mechanisms of HMGB1 release during inflammation, but also provide potential therapeutic targets to treat HMGB1-related inflammatory diseases.

Effect of HMGB1 on human hepatoma cell line-HepG2 proliferation / 中南大学学报(医学版)

OBJECTIVE@#To investigate the effect of high mobility group box-1 protein (HMGB1) on the proliferative activity of human hepatoma cell line HepG2 and its potential regulating mechanism.@*METHODS@#The cultured HepG2 cells were treated with recombinant HMGB1 (0, 10, 50, and 100 ng/mL, respectively) for 24 h. Cell proliferation was observed by MTT analysis. Western blot and reverse transcriptase-polymerase chain reaction were used to detect the expression of proliferating cell nuclear antigen (PCNA) and cyclin D1 protein and mRNA, respectively.@*RESULTS@#Compared with the control group, HMGB1 at 10, 50, and 100 ng/mL obviously increased HepG2 cells proliferation, cyclin D1 and PCNA protein and mRNA expression after the treatment for 24 h, respectively (P<0.05). Anti-HMGB1 significantly inhibited the proliferation and cyclin D1 and PCNA mRNA and protein expression of HMGB1 on HepG2 cells (P<0.05).@*CONCLUSION@#Proliferation of HMGB1 on HepG2 cells may be associated with increasing cyclin D1 and PCNA expression. Anti-HMGB1 may have a therapeutic effect on hepatocellular carcinoma.

Serum level of HMGB1 in patients with hepatitis B and its clinical significance / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To investigate whether there is a possible role of pro-inflammatory cytokine high mobility group box protein 1 (HMGB1) causing liver failure in severe hepatitis B patients.</p><p><b>METHODS</b>Serum HMGB1 levels of chronic hepatitis B (CHB) patients with different clinical conditions were measured and the correlations between HMGB1 and TBil or PTA were analyzed. (1) 54 chronic hepatitis B patients in different clinical conditions were enrolled in our study. Their serum TBil and PTA levels were detected by routine methods. (2) Their serum HMGB1 levels were also detected. 100 KD super-filtration columns were used to get rid of large proteins in the serum and 10 KD columns were used to condense the protein. Western blot was used to determine HMGB1 levels, and correlations between HMGB1 and TBil or PTA were analyzed.</p><p><b>RESULTS</b>The detection rates of serum HMGB1 were 100% (23/23), 90% (9/10), and 55% (6/11) in 23 patients with hepatic failure, 10 patients with chronic severe hepatitis B, and 11 patients with chronic moderate hepatitis B respectively. The concentration of serum HMGB1 levels in these three groups was (83.4+/-21.3), (78.1+/-19.5) and (60.3+/-14.3) microg/L respectively. Serum HMGB1 was not detected in normal healthy controls and hardly detected in convalescent and mild hepatitis patients. There were positive correlations between HMGB1 and TBil and negative correlations between HMGB1 and PTA.</p><p><b>CONCLUSION</b>HMGB1 levels in serum were closely associated with disease severity in chronic hepatitis B patients. HMGB1 may play a key role in the pathogenesis of chronic severe hepatitis B and liver failure.</p>