Résumé
ObjectiveTo investigate whether paeonol exerts a protective effect on mice with alcoholic liver injury by regulating the takeda G-protein-coupled receptor 5 （TGR5）/protein kinase A （PKA）/cAMP response binding element （CREB） signaling pathway mediated by Eubacterium. MethodC57BL/6 mice were randomly divided into five groups： normal group， model group， paeonol group （480 mg·kg-1）， antibiotic group （Abs group）， and antibiotic + paeonol group. Lieber-DeCarli liquid was used to feed C57BL/6 mice on the second day of modeling for 10 days. The blood lipids， liver function， inflammatory factors， and oxidative stress levels in mice were measured. Hematoxylin-eosin staining （HE） and oil red O staining were used to observe the morphological changes and fat accumulation in liver tissue. 16S rDNA sequencing was used to detect the diversity of intestinal microbiota in the blank， model， and paeanol groups. Western blot was used to detect the effect of paeonol on the expression levels of protein related to the signaling pathway of atresia band protein 1 （ZO-1）， Claudin-1， and TGR5/PKA/CREB in mouse ileal tissue. ResultCompared with those in the blank group， the blood lipids， liver function， oxidative stress levels， and the expression of inflammatory factors in the model group increased （P<0.01）， and the liver fat vacuoles were obvious. The ileal mucosa was seriously damaged， and the protein contents of ZO-1， Claudin-1， and TGR5/PKA/CREB in the ileal tissue decreased significantly （P<0.01）. The intestinal microbiota changed， and the proteobacteria phylum increased significantly. The ratio of Bacteroidetes to Firmicutes decreased. The relative abundance of Dubosiella newyorkensis， Lactobacillus， Bifidobacterium， and other genera decreased， while the relative abundance of Escherichia-Shigella， Morganella， Providencia， and Proteus increased significantly. Compared with the model group， paeonol significantly reduced the blood lipids， liver function， oxidative stress levels， and expression of inflammatory factors in mice with alcohol diet-induced liver injury （P<0.05）， decreased liver fat vacuoles， improved and restored the ileal intestinal barrier， and restored the normal structure of hepatocytes and ileal cells. The intestinal microbiota disorder caused by alcohol was improved， and the relative abundance of beneficial bacteria such as Eubacterium spp. was increased. The protein expression levels of ZO-1， Claudin-1， and TGR5/PKA/CREB in ileal tissue were increased （P<0.05）. ConclusionPaeonol has a protective effect on alcoholic liver injury in mice， and the mechanism of action is achieved by regulating the Eubacterium-mediated TGR5/PKA/CREB signaling pathway to ensure anti-inflammatory effect and improve the intestinal barrier.
Résumé
Objective To evaluate the efficacy of chemoradiotherapy alone and prognostic factors for locally advanced rectal cancer. Methods The clinical data of 47 patients with locally advanced rectal cancer who were admitted to our hospital and mostly treated with chemoradiotherapy alone from 2003 to 2010 were retrospectively analyzed. Three of the patients received radiotherapy alone. The Kaplan?Meier method was used to estimate overall survival (OS), progression?free survival (PFS), and distant metastasis?free survival ( DMFS ) rates, and the log?rank test was used for survival difference analysis and univariate prognostic analysis. The Cox regression model was used for multivariate prognostic analysis. Results In all patients, the 3?and 5?year OS rates were 53?2% and 33?2%, respectively, while the 3?and 5?year PFS rates were 37% and 31%, respectively. During the follow?up, 15 patients (32%) had local progression with PFS of 1?60 months (median PFS, 14 months);23 patients (49%) had distant metastasis with DMFS of 2?60 months ( median DMFS, 17 months) . Patients treated with high?dose radiotherapy had significantly lower 3?and 5?year local progression rates than patients treated with medium?dose radiotherapy ( 11% vs. 54%;11%vs. 57%;P=0?004). After chemoradiotherapy, 9 patients (19%) had clinical complete response (cCR), and the 3?and 5?year OS and PFS rates in those patients were all 8/9. The univariate analysis indicated that tumor distance from the anus and cCR were influencing factors for prognosis ( P= 0?026;P= 0?000 ) . However, the multivariate analysis showed that cCR was the only influencing factor for survival ( HR=12?24;95% CI, 1?64 ?91?29;P= 0?015 ) . Conclusions Chemoradiotherpay or radiotherapy alone is effective and safe in the treatment of patients with locally advanced rectal cancer who have to give up surgery or have unresectable tumors. High?dose radiotherapy may improve local control rate. Complete response to chemoradiotherapy predicts satisfactory treatment outcomes.