Jatrorrhizine alleviates ulcerative colitis via regulating gut microbiota and NOS2 expression.

BACKGROUND: The natural protoberberine jatrorrhizine (JA) is reported to have several medicinal properties and a significant effect on the gut microbiota of mice. The regulation of gut microbiota is generally known to play an important role in the intestinal mucosal immune response to ulcerative colitis (UC). However, whether JA can be used in the treatment of UC is still unclear. Our study aimed to investigate the underlying therapeutic effects and mechanisms of JA in treating colitis. RESULTS: Compared with the DSS-induced colitis model group, the JA + DSS treated group had more significant improvements in weight loss, disease activity index score, colon length shortening, and pathological inflammation. 16s rRNA sequencing analysis showed that JA treatment protected colitis mice against DSS-induced disturbance of gut microbiota. At the phylum level, reductions in Deferribacteres and Proteobacteria were observed in the JA-treated group; At the genus level, the JA-treated group showed an increased relative abundance of Akkermansia and decreased abundance of Escherichia-Shigella, Desulfovibrio, Mucispirillum, etc. Network pharmacology was then used to screen out five drug-disease target genes (NOS2, ESR1, CALM1, CALM2, CALM3). Transcriptomics analysis further validated that the NOS2 expression was significantly reduced in colon tissue of JA-administered mice compared with DSS control mice. Additionally, analysis of correlation suggested that NOS2 expression was negatively correlated with the relative abundance of AKKermansia and positively correlated with Desulfovibrio, Rikenella. CONCLUSION: JA alleviates ulcerative colitis via regulating gut microbiota and NOS2 expression.

Artesunate exerts protective effects against ulcerative colitis via suppressing Toll­like receptor 4 and its downstream nuclear factor­κB signaling pathways.

Artesunate (ART) is a semi­synthetic derivative of artemisinin used in the treatment of patients with malaria, which has also been reported to have immunoregulatory, anticancer and anti­inflammatory properties. The aim of the present study was to investigate the possible beneficial effects of ART on ulcerative colitis (UC) rats and to detect the possible mechanisms underlying these effects. A UC rat model was established using dextran sulfate sodium (DSS). Rats were randomly divided into the following groups: Normal control, UC model group, UC rats treated with a low, medium or high dose of ART (10, 30 and 50 mg/kg/day, respectively), and the positive control group (50 mg/kg/day 5­aminosalicylic acid). The damage status of colonic mucosal epithelial tissue was investigated by hematoxylin and eosin staining, and then the weight, colon length and disease activity index (DAI) were measured. Western blotting and reverse transcription­quantitative polymerase chain reaction analysis were used to detect the levels of cytokines associated with UC and proteins associated with Toll­like receptor 4 (TLR4)­nuclear factor (NF)­κB pathway. ELISA was also performed to measure the levels of inflammatory cytokines. In addition, the viability and infiltration of RAW264.7 cells were examined using Cell Counting Kit­8 and Transwell assays. The results demonstrated that treatment with ART significantly alleviated the UC symptoms induced by DSS in the rat model, lowered the DAI, ameliorated pathological changes, attenuated colon shortening, inhibited the levels of pro­inflammatory mediators and myeloperoxidase activity, and increased hemoglobin expression. Additionally, inflammatory and apoptotic markers were found to be significantly downregulated following treatment with ART in UC rats and RAW264.7 cells. To the best of our knowledge, the present study is the first to demonstrate that ART exerts anti­inflammatory effects via regulating the TLR4­NF­κB signaling pathway in UC.

Long non-coding RNA DANCR, a prognostic indicator, promotes cell growth and tumorigenicity in gastric cancer.

Gastric cancer remains the third leading cause of cancer-related mortality worldwide, and proliferation of gastric cancer represents the major reason for its poor prognosis. Recent evidence indicates that long non-coding RNAs play crucial roles in development and progression of gastric cancer. Long non-coding RNA differentiation antagonizing non-protein coding RNA is upregulated in hepatic cell carcinoma, but the role of lncRNA differentiation antagonizing non-protein coding RNA in gastric cancer has not been explored. In this article, we found that differentiation antagonizing non-protein coding RNA is also upregulated in gastric cancer. Experiments revealed that silencing differentiation antagonizing non-protein coding RNA significantly inhibited gastric cancer cell proliferation in vitro and in vivo. Overexpression of differentiation antagonizing non-protein coding RNA notably increases gastric cancer cell proliferation. From RNA-seq and gene ontology annotations, we found that differentiation antagonizing non-protein coding RNA influences the gene expression programs in cell metabolic and cycle process. Taken together, our findings suggest that the long non-coding RNA differentiation antagonizing non-protein coding RNA promotes the proliferation of gastric cancer and is a potential prognostic biomarker and therapeutic target in gastric cancer.

High expression of long non-coding RNA CCAT2 indicates poor prognosis of gastric cancer and promotes cell proliferation and invasion.

BACKGROUND: Numerous studies have demonstrated that long non-coding RNAs (lncRNAs) have many biological functions and play crucial roles in various human cancers, including cancer development, metastasis and prognosis of cancer patients. CCAT2, a novel long non-coding RNA, has been identified as correlating with several different types of cancers. However, the role of lncRNA CCAT2 in gastric cancer (GC) patients is unknown. The purpose of our research was to investigate the function and prognostic significance of lncRNA CCAT2 expression in GC patients. METHODS: Expression of lncRNA CCAT2 was examined in 208 paired normal and cancerous gastric tissues. Molecular and cellular techniques were used to explore the biological function of lncRNA CCAT2 in GC cells. Kaplan-Meier method and Cox proportional hazards model were used to analyze the prognostic significance of lncRNA CCAT2 expression. RESULTS: The results showed that lncRNA CCAT2 was upregulated in GC tissues (P=0.000), and positively correlated with TNM stage (P=0.029), lymphatic invasion (P=0.042) and nervous invasion (P=0.024) in GC patients. Furthermore, we also found that high expression of lncRNA CCAT2 was an unfavorable prognostic factor in GC patients. Silencing of lncRNA CCAT2 inhibits gastric cancer cell proliferation and invasion. CONCLUSIONS: lncRNA CCAT2 may serve as a tumor promoter and a new predictive prognostic factor for human gastric cancer.

Faecalibacterium prausnitzii supernatant ameliorates dextran sulfate sodium induced colitis by regulating Th17 cell differentiation.

AIM: To explore the preventive and therapeutic effects of Faecalibacterium prausnitzii (F. prausnitzii) supernatant on dextran sulfate sodium (DSS) induced colitis in mice. METHODS: Forty C57BL/6J male mice were randomly divided into four groups: control group, model group, treatment group, and prevention group. Mice were weighed daily. On day 10, the colon length was measured, the colorectal histopathologic damage score (HDS) was assessed, and plasma interleukin (IL)-17A, IL-6, and IL-4 levels were detected by enzyme-linked immunosorbent assay. The expression of transcription factor retinoic acid-related orphan receptor-γt (RORγt) and IL-17A in colon inflammatory mucosa tissue were determined by immunohistochemical assay, and the expression levels of RORγt mRNA, IL-17A mRNA, and IL-6 mRNA were detected by real-time quantitative polymerase chain reaction (PCR). The proportion of Th17 in mononuclear cells in spleen was assayed by fluorescence activated cell sorter. RESULTS: When compared with the model group, the colon length (P < 0.05) and body weight (P < 0.01) in the treatment and prevention groups were significantly increased, and the colon HDS was decreased (P < 0.05 and P < 0.01). There was no statistical difference between the treatment group and prevention group. After treatment with F. prausnitzii supernatant, the plasma levels of IL-17A and IL-6 (P < 0.05), the protein and mRNA expression of IL-17A and RORγt, and the Th17 cell ratio of spleen cells (P < 0.01) were significantly decreased compared to the model group. Plasma IL-4 level in the prevention group was significantly higher than that in the model group (P < 0.05), but there was no significant difference between these two groups in the expression of IL-6 in both the plasma and colon mucosa tissues. CONCLUSION: F. prausnitzii supernatant exerts protective and therapeutic effects on DSS-induced colitis in mice, probably via inhibition of Th17 differentiation and IL-17A secretion in the plasma and colon mucosa tissues. It can also improve colitis in mice by downregulating IL-6 and prevent colitis by upregulating IL-4.

Associations between CD24 gene polymorphisms and inflammatory bowel disease: A meta-analysis.

AIM: To evaluate the relationships between CD24 gene polymorphisms and the risk of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD). METHODS: The PubMed, Web of Science and Cochrane Library databases were searched (up to May 30, 2014). The search terms "CD24", "inflammatory bowel disease", "Crohn's disease", "Ulcerative colitis", "IBD", "CD" or "UC"; and "polymorphism", "mutation" or "variant" were used. Association studies were limited to the English language, but no limitations in terms of race, ethnicity or geographic area were employed. Stata SE12 software was used to calculate the pooled odds ratios (ORs) with 95% confidence intervals (CIs). P < 0.05 was considered statistically significant. The information was independently extracted from each eligible study by two investigators. Two common polymorphisms, C170T (rs8734) and TG1527del (rs3838646), in the CD24 gene were assessed. RESULTS: A total of three case-control studies including 2342 IBD patients and 1965 healthy controls were involved in this meta-analysis. The patients and controls were from Caucasian cohorts. The three articles included in this meta-analysis all conformed to Hardy-Weinberg equilibrium. This meta-analysis revealed that there were no significant associations between the two CD24 polymorphisms and the risk for IBD (all P > 0.05). However, in a disease subgroup analysis, we found that the CD24 C170T polymorphism was associated with an increased risk of UC in a dominant model (OR = 1.79, 95%CI: 1.15-2.77, P = 0.009) and an additive model (OR = 1.87, 95%CI: 1.19-2.93, P = 0.007), but this relationship was not present for CD. The CD24 TG1570del polymorphism was significantly associated with CD in the additive model (OR = 1.24, 95%CI: 1.01-1.52, P = 0.037). CONCLUSION: Our findings provide evidence that the CD24 C170T polymorphism might contribute to the susceptibility to UC, and the CD24 TG1527del polymorphism might be associated with the risk of CD.

Comparison of two capture methods for endoscopic removal of large common bile duct stones.

BACKGROUND: Large common bile duct (CBD) stones remain a major challenge for endoscopists. The capture of large CBD stones is a limiting factor for successful removal. The aim of the study is to evaluate the efficacy and safety of stretching the basket out at the bottom of the stones to capture large CBD stones. PATIENTS AND METHODS: Sixty-five patients with large stones (>20 mm in diameter) were selected and randomly divided into Group A (33 cases) and Group B (34 cases). After appropriate sphincterotomy with balloon dilation, two different methods were used to capture stones. For Method A, the basket was inserted above a large stone and opened to capture it. For Method B, the basket was stretched out at the bottom of the large stone and opened slowly to capture it. RESULTS: The success rate of capturing stones was 33.3% in Group A and 94.1% in Group B (P<.05). There was no statistically significant difference in complication rate between the two groups (P>.05). CONCLUSIONS: The success rate for capturing large CBD stones can be increased by stretching the basket out at the bottom of the stones to capture the stone.

Changing trends in the proportions of small (≤ 2 cm) proximal and non-proximal gastric carcinomas treated at a high-volume tertiary medical center in China.

OBJECTIVE: Guided by the recently established histological criteria of the gastroesophageal junction (GEJ), we aimed to investigate and compare trends in the proportions of small (≤ 2 cm) proximal gastric carcinoma (PGC) vs non-PGC (NPGC) in Chinese patients over an 8-year period. METHODS: The study was conducted with consecutive surgical resected specimens of small PGC that was located within 3 cm below the GEJ and NPGC (located at all other gastric regions) treated at a single medical center in China. Differences in proportions between the two groups were compared. RESULTS: Among all 313 cases, 111 (35.5%) were classified as PGC and the remaining 202 (64.5%) as NPGC. Patients with PGC were significantly elder than those with NPGC, and none aged younger than 40 years. The proportions of PGC significantly and progressively increased from 16% in 2004 to 45% in 2011, in contrast to a steady decreasing trend for NPGC from 84% to 55% over the same period. The difference in trends between the two groups approached, but was not at a statistically significant level (P = 0.08). Proportions of small cancers in the gastric corpus and in female patients remained low and stable, in contrast to a significantly higher proportion in male patients (P < 0.05). CONCLUSIONS: Our data showed a significantly upward-shifting trend in the proportions of small PGC, primarily in elderly male patients, in contrast to a downward shifting trend in NPGC over the most recent 8-year period in Chinese patients.

Recent progress on the role of gut microbiota in the pathogenesis of inflammatory bowel disease.

In recent years investigations of inflammatory bowel disease (IBD) have advanced rapidly with regard to the relationship between the host immune response and gut microbiota. Patients with IBD have been shown to have an abnormal composition of gut microbiota and host immune dysregulation. Abnormal components of gut microbiota, to which the host mounts aberrant immune responses in genetically vulnerable individuals, appear to play a critical role in the pathogenesis of IBD. Therefore, inappropriate innate and adaptive host immune responses to abnormal components of gut microbiota and their products form the basis of IBD pathogenesis. Modern molecular genetic methods should be utilized to help to illuminate the pathogenetic mechanism of IBD and to develop personalized therapeutic strategies for this disease.

Folic acid prevents the initial occurrence of sporadic colorectal adenoma in Chinese older than 50 years of age: a randomized clinical trial.

Colorectal adenoma (CRA) is the precursor lesion of colorectal cancer (CRC). Several agents have been shown to be effective in the chemoprevention of CRA recurrence, but there has been little research on its primary prevention. Participants older than 50 years with no adenomas were recruited for our study and randomized to receive either 1 mg/day folic acid supplement or treatment without folic acid. After 3 years of follow-up, plasma folate and colonoscopy were evaluated. Seven hundred ninety-one participants (91.98%) completed the study. CRA occurred in 64 (14.88%) participants in the folic acid group and 132 (30.70%) in the control group [unadjusted risk ratio (RR), 0.49; 95% confidence interval (CI), 0.37-0.63; P < 0.01]; left-sided adenoma (unadjusted RR, 0.54; 95% CI, 0.38-0.76; P = 0.001) and advanced CRA (unadjusted RR, 0.36; 95% CI, 0.16-0.81; P = 0.01) were most common. There was no significance difference in the occurrence of three or more adenomas (unadjusted RR, 0.70; 95% CI, 0.36-1.77; P = 0.38) or right-sided adenoma (unadjusted RR, 0.55; 95% CI, 0.30-1.00; P = 0.07) between the two groups. Participants with low plasma folate may have a high risk of CRA. In conclusion, primary prevention with 1 mg/day folic acid supplementation could reduce the incidence of CRA, especially left-sided and advanced disease in those with no previous adenomas. People with differing baseline plasma folate levels should be given individualized treatment. Those with low plasma folate should be encouraged to take adequate supplements; plasma folate should be elevated to an effective therapeutic level, which may reduce the incidence of CRA.

How to diagnose and manage patients with Barrett's esophagus in China.

In order to prevent the development of Barrett's esophagus (BE)-related esophageal cancer in China and facilitate the communication of research results among different centers, we propose using standardized diagnostic criteria and taking a conservative approach to diagnose and manage BE patients. BE patients without dysplasia need to be treated medically. For low-grade dysplasia, an annual endoscopy with biopsies is recommended, along with medical therapy. For high-grade dysplasia and intramucosal carcinoma, an endoscopic or surgical intervention is suggested. All BE patients should be followed up closely.

Barrett's esophagus-related diseases remain uncommon in China.

Barrett's esophagus (BE)-related esophageal adenocarcinoma (EAC) has shown the fastest rise in incidence in Western countries; however, research data on BE-related diseases from China are inconclusive. We aimed to review and analyze the published results on these diseases in China. We searched PubMed and Chinese medical literature for key words: BE, EAC, Chinese and China. Relevant research papers along with the study results from our own groups were reviewed and analyzed. Using standardized criteria, columnar-lined esophagus (CLE) was found in as many as 29% of resection specimens in Chinese patients with proximal gastric cancer. However, BE with intestinal metaplasia was rare, ranging from 0.06% in the general population to <2% in referral patients. Risk factors included advancing age, hiatal hernia and probably gastroesophageal reflux disease and tobacco or alcohol abuse, but not male gender or obesity. At endoscopy, most CLE/BE were <2 cm in length, and appeared tongue-like and island-like. The long-segment BE was rare, especially in women. Population-based studies conducted in Taiwan and Hong Kong SAR, China showed that EAC was not only rare but also stable or had decreased in incidence over the past decade. By histopathology, EAC accounted for only 1% of all distal esophageal cancers and almost all gastroesophageal junction (GEJ) cancers were centered in the proximal stomach. BE-related diseases, except for CLE, are rare in China. The clinical significance and malignant potential of CLE in the Chinese population remain elusive. Further investigation on these diseases is in progress.

Epidemiological study of colorectal adenoma and cancer in symptomatic patients in China between 1990 and 2009.

OBJECTIVE: The best cure for colorectal cancer (CRC) lies on its early diagnosis and treatment. We aimed to provide the epidemiological features of advanced colorectal adenoma (A-CRA) and CRC in symptomatic patients and to determine whether the incidences of A-CRA and CRC increased simultaneously in China between 1990 and 2009. METHODS: A total of 157,943 patients who had undergone a colonoscopy from 1990 to 2009 were enrolled, of which 6,777 patients had A-CRA and 3,503 had CRC. They were compared with controls in a stratified analysis. The detection rates of A-CRA and CRC in the 1990s and 2000s were also compared. RESULTS: The detection rate of A-CRA increased 1.88-fold over the two decades, while that of CRC increased 0.66-fold. The percentages of patients with A-CRA and CRC who were elder than 50 years were significantly higher in the 2000s than those in the 1990s (P = 0.000). The changes of location of A-CRA and CRC during the two decades indicated a shift of lesions from the distal colon to proximal colon. CONCLUSION: There was a significant increase in detection rate of A-CRA in the 2000s, but CRC did not increase at a similar speed. Our results indicated that the early detection and removal of colorectal adenoma in symptomatic patients might decrease the incidence of CRC.

Expression of CD4+ forkhead box P3 (FOXP3)+ regulatory T cells in inflammatory bowel disease.

OBJECTIVE: Forkhead box P3 (FOXP3) plays an important role in the development and function of CD4(+) regulatory T (Treg) cells. In this study the percentage of CD4(+) FOXP3(+) Treg cells in peripheral blood mononuclear cells (PBMC) and the frequency of Treg cells in the colonic mucosa of patients with inflammatory bowel disease (IBD) were investigated. METHODS: The percentage of CD4(+) FOXP3(+) Treg cells in PBMC was analyzed by flow cytometry. Immunohistochemistry was used to examine the FOXP3(+) cells in the inflamed mucosa. Real-time polymerase chain reaction and Western blot were used to detect the expressions of FOXP3 mRNA and protein in PBMC and mucosal biopsy specimens of IBD patients, respectively. RESULTS: Together with the decrease of percentage of Treg cells in PBMC, we found that the frequency of Treg cells increased significantly in inflamed mucosa of active or inactive Crohn's disease (CD) and ulcerative colitis (UC). The expressions of FOXP3 mRNA and protein increased in inflamed mucosa when compared with those in healthy controls, especially the FOXP3 mRNA in patients with active CD or UC. Interestingly, the expression of FOXP3 protein in active UC was higher than that in active CD. CONCLUSIONS: There was a decrease of CD4(+) FOXP3(+) Treg cells in peripheral blood and an accumulation of Treg cells in inflamed mucosa. These data suggested that the suppressive function of Treg cells may be partially inhibited and this could be an important factor in the recurrence of disease, especially in UC.

The first year follow-up after colorectal adenoma polypectomy is important: a multiple-center study in symptomatic hospital-based individuals in China.

The recurrence of colorectal adenoma (CRA) is high. Although there are guidelines for colonoscopy surveillance after polypectomy in other countries, little is known about its recurrence rate and recurrence peak, especially in China. The aim of the present research is to investigate how long after polypectomy follow-up should take and to analyze risk factors of recurrence. 1208 patients who received polypectomies from five clinical research centers in four regions of China (Shanghai, Guangzhou, Nanjing and Beijing) were included. They were divided into 4 groups: group A (follow-up ≤ 1 year after polypectomy), group B (follow-up 2-3 years after polypectomy), group C (follow-up 4-5 years after polypectomy), and group D (follow-up > 5 years after polypectomy). The sex, age, adenoma location, size, number, and pathological characteristics were compared. On the whole, the recurrence rate was 59.46% in group A, 61.09% in group B, 78.07% in group C, and 87.12% in group D, which indicated an increased tendency with a prolonged follow-up duration. There was a significant difference between group A and C or D, and between group B and C or D (P<0.01), but there was no statistical difference between group A and B. Additionally, the recurrent patients in the first year had a recurrence rate of 97.33% in the first three years (59.46/61.09), which means that the peak of recurrence was almost entirely concentrated in the first year. The recurrence rate was higher in males and the elder. The risk factors included multiple numbers, villous feature, high-grade dysplasia of medium or smaller size and location in the distal colon. In conclusion, the peak of recurrence was almost totally concentrated in the first year; meanwhile, the first year follow-up is of critical importance in China. It may not be necessary to do the follow-up examination during the second and third years, but after three years, another colonoscopy should be undertaken.