Cyclophilin E (CypE) Functions as a Positive Regulator in Osteoblast Differentiation by Regulating the Transcriptional Activity of Runx2.

Cyclophilin E (CypE) belongs to the cyclophilin family and exhibits peptidyl-prolyl cis-trans isomerase (PPIase) activity. It participates in various biological processes through the regulation of peptidyl-prolyl isomerization. However, the specific role of CypE in osteoblast differentiation has not yet been elucidated. In this study, we first discovered the positive impact of CypE on osteoblast differentiation through gain or loss of function experiments. Mechanistically, CypE enhances the transcriptional activity of Runx2 through its PPIase activity. Furthermore, we identified the involvement of the Akt signaling pathway in CypE's function in osteoblast differentiation. Taken together, our findings indicate that CypE plays an important role in osteoblast differentiation as a positive regulator by increasing the transcriptional activity of Runx2.

Deubiquitinase USP17 Regulates Osteoblast Differentiation by Increasing Osterix Protein Stability.

Deubiquitinases (DUBs) are essential for bone remodeling by regulating the differentiation of osteoblast and osteoclast. USP17 encodes for a deubiquitinating enzyme, specifically known as ubiquitin-specific protease 17, which plays a critical role in regulating protein stability and cellular signaling pathways. However, the role of USP17 during osteoblast differentiation has not been elusive. In this study, we initially investigated whether USP17 could regulate the differentiation of osteoblasts. Moreover, USP17 overexpression experiments were conducted to assess the impact on osteoblast differentiation induced by bone morphogenetic protein 4 (BMP4). The positive effect was confirmed through alkaline phosphatase (ALP) expression and activity studies since ALP is a representative marker of osteoblast differentiation. To confirm this effect, Usp17 knockdown was performed, and its impact on BMP4-induced osteoblast differentiation was examined. As expected, knockdown of Usp17 led to the suppression of both ALP expression and activity. Mechanistically, it was observed that USP17 interacted with Osterix (Osx), which is a key transcription factor involved in osteoblast differentiation. Furthermore, overexpression of USP17 led to an increase in Osx protein levels. Thus, to investigate whether this effect was due to the intrinsic function of USP17 in deubiquitination, protein stabilization experiments and ubiquitination analysis were conducted. An increase in Osx protein levels was attributed to an enhancement in protein stabilization via USP17-mediated deubiquitination. In conclusion, USP17 participates in the deubiquitination of Osx, contributing to its protein stabilization, and ultimately promoting the differentiation of osteoblasts.

Metallothionein 3 Inhibits 3T3-L1 Adipocyte Differentiation via Reduction of Reactive Oxygen Species.

Metallothionein 3 (MT3), also known as a neuronal growth-inhibitory factor, is a member of the metallothionein family and is involved in a variety of biological functions, including protection against metal toxicity and reactive oxygen species (ROS). However, less is known about the role of MT3 in the differentiation of 3T3-L1 cells into adipocytes. In this study, we observed that MT3 levels were downregulated during 3T3-L1 adipocyte differentiation. Mt3 overexpression inhibited adipocyte differentiation and reduced the levels of the adipogenic transcription factors C/EBPα and PPARγ. Further analyses showed that MT3 also suppressed the transcriptional activity of PPARγ, and this effect was not mediated by a direct interaction between MT3 with PPARγ. In addition, Mt3 overexpression resulted in a decrease in ROS levels during early adipocyte differentiation, while treatment with antimycin A, which induces ROS generation, restored the ROS levels. Mt3 knockdown, on the other hand, elevated ROS levels, which were suppressed upon treatment with the antioxidant N-acetylcysteine. Our findings indicate a previously unknown role of MT3 in the differentiation of 3T3-L1 cells into adipocytes and provide a potential novel target that might facilitate obesity treatment.

Cyclophilin A Promotes Osteoblast Differentiation by Regulating Runx2.

Cyclophilin A (CypA) is a ubiquitously expressed and highly conserved protein with peptidyl-prolyl cis-trans isomerase activity that is involved in various biological activities by regulating protein folding and trafficking. Although CypA has been reported to positively regulate osteoblast differentiation, the mechanistic details remain largely unknown. In this study, we aimed to elucidate the mechanism of CypA-mediated regulation of osteoblast differentiation. Overexpression of CypA promoted osteoblast differentiation in bone morphogenic protein 4 (BMP4)-treated C2C12 cells, while knockdown of CypA inhibited osteoblast differentiation in BMP4-treated C2C12. CypA and Runx2 were shown to interact based on immunoprecipitation experiments and CypA increased Runx2 transcriptional activity in a dose-dependent manner. Our results indicate that this may be because CypA can increase the DNA binding affinity of Runx2 to Runx2 binding sites such as osteoblast-specific cis-acting element 2. Furthermore, to identify factors upstream of CypA in the regulation of osteoblast differentiation, various kinase inhibitors known to affect osteoblast differentiation were applied during osteogenesis. Akt inhibition resulted in the most significant suppression of osteogenesis in BMP4-induced C2C12 cells overexpressing CypA. Taken together, our results show that CypA positively regulates osteoblast differentiation by increasing the DNA binding affinity of Runx2, and Akt signaling is upstream of CypA.

YY2 Promotes Osteoblast Differentiation by Upregulating Osterix Transcriptional Activity.

Yin Yang 2 (YY2) is a paralog of YY1, a well-known multifunctional transcription factor containing a C-terminal zinc finger domain. Although the role of YY1 in various biological processes, such as the cell cycle, cell differentiation and tissue development, is well established, the function of YY2 has not been fully determined. In this study, we investigated the functional role of YY2 during osteoblast differentiation. YY2 overexpression and knockdown increased and decreased osteoblast differentiation, respectively, in BMP4-induced C2C12 cells. Mechanistically, YY2 overexpression increased the mRNA and protein levels of Osterix (Osx), whereas YY2 knockdown had the opposite effect. To investigate whether YY2 regulates Osx transcription, the effect of YY2 overexpression and knockdown on Osx promoter activity was evaluated. YY2 overexpression significantly increased Osx promoter activity in a dose-dependent manner, whereas YY2 knockdown had the opposite effect. Furthermore, vectors containing deletion and point mutations were constructed to specify the regulation site. Both the Y1 and Y2 sites were responsible for YY2-mediated Osx promoter activation. These results indicate that YY2 is a positive regulator of osteoblast differentiation that functions by upregulating the promoter activity of Osx, a representative osteogenic transcription factor in C2C12 cells.

The Diagnosis Performance of the TCM Syndromes of Irritable Bowel Syndrome by Gastroenterologists Based on Modified Simple Criteria Compared to TCM Practitioners: A Prospective, Multicenter Preliminary Study.

PURPOSE: Traditional Chinese medicine (TCM) including Chinese patent medicine has been widely used to treat irritable bowel syndrome (IBS). Syndrome differentiation is the essence of TCM. However, the diagnostic ability of gastroenterologists to detect TCM syndromes in IBS in China remains unknown. The aim of this study was to investigate the ability of gastroenterologists to diagnose the TCM syndromes of IBS based on modified simple criteria compared with TCM practitioners. METHODS: Patients meeting the Rome III criteria for IBS-D or IBS-C were recruited from six tertiary referral centers between January 2016 and December 2017. After learning the diagnosis criteria of the TCM syndromes in IBS, gastroenterologists first diagnosed the syndromes of the enrolled patients. Subsequently, the patients were diagnosed by TCM practitioners. The rate of agreement between the gastroenterologists and TCM practitioners was analyzed. In addition, demographic data and the distribution of TCM syndrome types in IBS were also analyzed. RESULTS: A total of 178 patients (93 males and 85 females), including 131 patients with IBS-D and 47 patients with IBS-C, were enrolled in this study. The rate of agreement of the syndrome diagnosis between the gastroenterologists and TCM practitioners was 84.3%. The diagnosis consistency rates among IBS-D patients and IBS-C patients were 87.0% and 76.5%, respectively. The most common TCM syndrome type in IBS-D patients was liver depression and spleen deficiency syndrome (27.5%), followed by spleen-yang deficiency syndrome (19.8%). Dryness and heat in intestine syndrome was the most common TCM syndrome in IBS-C patients (57.4%). CONCLUSIONS: Gastroenterologists had good diagnostic agreement with TCM practitioners for diagnosing TCM syndrome types in IBS after learning the diagnostic criteria. This knowledge can aid gastroenterologists in selecting suitable Chinese patent medicine to treat IBS.

Quercetin Suppresses AOM/DSS-Induced Colon Carcinogenesis through Its Anti-Inflammation Effects in Mice.

Colorectal cancer (CRC) is the fourth leading cause of tumor-related deaths worldwide. In this study, we explored the in vivo effects of quercetin, a plant flavonol from the flavonoid group of polyphenols with antioxidant effects, on colon carcinogenesis induced by azoxymethane/dextran sodium sulfate (AOM/DSS). Thirty mice were randomly assigned into three groups: the control group, the AOM/DSS group, and the quercetin+AOM/DSS group. CRC was induced by AOM injection and a solution of 2% DSS in the drinking water. In the AOM/DSS-induced colon cancer mice model, quercetin treatment dramatically reduced the number and size of colon tumors. In addition, quercetin significantly restored the leukocyte counts by decreasing the inflammation caused by AOM/DSS. We also observed that the expression of oxidative stress markers, such as lipid peroxide (LPO), nitric oxide (NO), superoxide dismutase (SOD), glucose-6-phosphate (G6PD), and glutathione (GSH), could be reduced by quercetin, suggesting that the anti-inflammatory function of quercetin comes from its antioxidant effect. Moreover, potential biomarkers were identified with serum metabolite profiling. Increased levels of 2-hydroxybutyrate, 2-aminobutyrate, and 2-oxobutyrate and decreased levels of gentian violet, indole-3-methyl acetate, N-acetyl-5-hydroxytryptamine, indoxyl sulfate, and indoxyl were also found in the AOM/DSS-treated mice. However, quercetin treatment successfully decreased the levels of 2-hydroxybutyrate, 2-aminobutyrate, 2-oxobutyrate, endocannabinoids, and sphinganine and increased the levels of gentian violet, N-acetyl-5-hydroxytryptamine, indoxyl sulfate, and indoxyl. Together, our data demonstrated that quercetin could maintain relatively potent antitumor activities against colorectal cancer in vivo through its anti-inflammation effect.

Clostridium butyricum, a butyrate-producing probiotic, inhibits intestinal tumor development through modulating Wnt signaling and gut microbiota.

Gut microbiota dysbiosis is closely involved in intestinal carcinogenesis. A marked reduction in butyrate-producing bacteria has been observed in patients with colorectal cancer (CRC); nevertheless, the potential benefit of butyrate-producing bacteria against intestinal tumor development has not been fully investigated. We found that Clostridium butyricum (C. butyricum, one of the commonly used butyrate-producing bacteria in clinical settings) significantly inhibited high-fat diet (HFD)-induced intestinal tumor development in Apcmin/+ mice. Moreover, intestinal tumor cells treated with C. butyricum exhibited decreased proliferation and increased apoptosis. Additionally, C. butyricum suppressed the Wnt/ß-catenin signaling pathway and modulated the gut microbiota composition, as demonstrated by decreases in some pathogenic bacteria and bile acid (BA)-biotransforming bacteria and increases in some beneficial bacteria, including short-chain fatty acid (SCFA)-producing bacteria. Accordingly, C. butyricum decreased the fecal secondary BA contents, increased the cecal SCFA quantities, and activated G-protein coupled receptors (GPRs), such as GPR43 and GPR109A. The anti-proliferative effect of C. butyricum was blunted by GPR43 gene silencing using small interfering RNA (siRNA). The analysis of clinical specimens revealed that the expression of GPR43 and GPR109A gradually decreased from human normal colonic tissue to adenoma to carcinoma. Together, our results show that C. butyricum can inhibit intestinal tumor development by modulating Wnt signaling and gut microbiota and thus suggest the potential efficacy of butyrate-producing bacteria against CRC.

Dietary Quercetin Increases Colonic Microbial Diversity and Attenuates Colitis Severity in Citrobacter rodentium-Infected Mice.

Disturbed balance between microbiota, epithelial cells, and resident immune cells within the intestine contributes to inflammatory bowel disease (IBD) pathogenesis. The Citrobacter rodentium-induced colitis mouse model has been well documented. This model allows the analysis of host responses to enteric bacteria and facilitates improved understanding of the potential mechanisms of IBD pathogenesis. The current study evaluated the effects of dietary 30 mg/kg quercetin supplementation on C. rodentium-induced experimental colitis in C57BL/6 mice. Following dietary quercetin supplementation, the mice were infected with 5 × 108 CFU C. rodentium, and the pathological effects of C. rodentium were measured. The results showed that quercetin alleviated the effects of C. rodentium-induced colitis, suppressed the production of pro-inflammatory cytokines, such as interleukin (IL)-17, tumor necrosis factor alpha, and IL-6 (p < 0.05), and promoted the production of IL-10 in the colon tissues (p < 0.05). Quercetin supplementation also enhanced the populations of Bacteroides, Bifidobacterium, Lactobacillus, and Clostridia and significantly reduced those of Fusobacterium and Enterococcus (p < 0.05). These findings indicate that dietary quercetin exerts therapeutic effects on C. rodentium-induced colitis, probably due to quercetin's ability to suppress pro-inflammatory cytokines and/or modify gut microbiota. Thus, these results suggest that quercetin supplementation is effective in controlling C. rodentium-induced inflammation.

Effect of Quercetin Monoglycosides on Oxidative Stress and Gut Microbiota Diversity in Mice with Dextran Sodium Sulphate-Induced Colitis.

The pathogenesis of inflammatory bowel disease (IBD) is linked to an intricate association of environmental, microbial, and host-related factors. This study examined the potential effects of dietary addition of two preparations from onion, one comprising quercetin aglycone alone (Q: 0.15% polyphenols, quercetin aglycone:quercetin monoglycosides, 98:2) and another comprising quercetin aglycone with monoglycosides (Q+MQ: 0.15% total polyphenols, quercetin aglycone:quercetin monoglycosides, 69:31), on dextran sodium sulphate- (DSS-) induced colitis in mice. The results revealed a significant decrease in the body weight gain of the mice with DSS-induced colitis, which was counteracted by the dietary Q or Q+MQ supplementation. Meanwhile, the oxidative stress indicated by myeloperoxidase (MPO), reduced glutathione (GSH), malondialdehyde (MDA), and serum nitrate (NO) concentrations was higher in mice with DSS-induced colitis than in the control group mice, but dietary Q or Q+MQ supplementation counteracted this trend. The colitis mice demonstrated reduced Chao1, angiotensin-converting enzyme (ACE), and Shannon indices and an increased Simpson index, but the colitis mice receiving dietary Q or Q+MQ exhibited higher Chao1, ACE, and Shannon indices and a reduced Simpson index. In conclusion, this research showed that even at a low dose, dietary Q or Q+MQ supplementation counteracts DSS-induced colitis in mice, indicating that Q or Q+MQ may be used as an adjuvant therapy for IBD patients.

A review of the relationship between the gut microbiota and amino acid metabolism.

New evidence has emerged in recent years to suggest a strong link between the human gut microbiota, its metabolites, and various physiological aspects of hosts along with important pathophysiological dimensions of diseases. The research indicates that the gut microbiota can facilitate metabolite production in two ways: first, the resident species of the gut microbiota use the amino acids produced from food or the host as elements for protein synthesis, and second, conversion or fermentation are used to drive nutrient metabolism. Additionally, the gut microbiota can synthesize several nutritionally essential amino acids de novo, which is a potential regulatory factor in amino acid homeostasis. The primary objective of this review is to summarize the current literature relating to the ways in which microbial amino acids contribute to host amino acid homeostasis.

Does neutrophil-to-lymphocyte ratio predict 1-year mortality in patients with primary biliary cholangitis? Results from a retrospective study with validation cohort.

OBJECTIVES: Neutrophil-to-lymphocyte ratio (NLR) has been used to predict prognosis in various liver diseases, but its role in primary biliary cholangitis (PBC) is not clarified. We aimed to investigate the prognostic usefulness of NLR for 1-year mortality in PBC. METHODS: The study recruited a retrospective cohort with 88 patients with PBC and a prospective validation cohort with 63 participants who were followed-up for 1 year. NLR and other laboratory measurements were analysed by multivariate regression model for identifying independent factors for early mortality. The cut-off threshold of NLR was determined by calculating the area under the receiver operating characteristics curve (AUROC) and used in a subsequent Kaplan-Meier survival analysis. RESULTS: Univariate and multivariate analyses showed that Mayo Risk Score (MRS), serum creatinine and NLR were independent indicators for mortality. NLR yielded significantly higher AUROC (0.86) than those of platelet-to-lymphocyte ratio (0.58, p=0.03), but comparable with MRS (0.87, p=0.88). Spearman's correlation analysis represented a positive correlation between escalating NLR and aggravating Child-Pugh grade (r=0.44, p<0.001). Patients with NLR <2.18 exhibited higher survival (with 100% sensitivity and 67.1% specificity) within 1 year follow-up duration, and NLR ≥2.18 was indicative of higher mortality (log-rank test, p<0.001). In addition, these results were internally confirmed by a validation cohort. CONCLUSION: NLR is closely related to short-term mortality in patients with PBC.

Endoscopic submucosal dissection for gastric adenomyoma: A rare entity of 15 cases among 571 patients with gastric submucosal eminence lesions.

Gastric adenomyoma (GA) is a kind of rare gastric submucosal eminence lesions. As the malignant transformation cannot be ruled out, surgery and laparoscopic resection are usually considered. The aim of this study is to evaluate the therapeutic effect and safety of endoscopic submucosal dissection (ESD) for GA.All of the patients with gastric submucosal eminence lesions who underwent ESD from June 2008 to June 2015 in General Hospital, Tianjin Medical University, China, were identified, and patients with GA, which was confirmed by pathological evaluation, were enrolled for further analysis.Among the 571 patients who received ESD, 15 cases with uncertain diagnosis before the procedure were finally confirmed as GA. The mean age of these 15 patients was 46.93 ±â€Š15.56 years (range: 18-73). Most of the lesions were located in antrum (12/15 patients), with 2 in the body of stomach and 1 in cardia, respectively. The mean size of the lesions was 1.47 ±â€Š0.67 cm (range: 0.4-3.0). According to the endoscopic ultrasonography, the lesions of 14 patients originated from submucosa and 1 originated from superficial muscularis, totally with mixed echoes changes. En bloc complete resection was achieved in all of the lesions. No perforation, intraoperative bleeding, delayed bleeding, and mortalities occurred. No recurrence or metastasis was found during 1 to 67 months.ESD appears to be a feasible, safe, and effective treatment for GA with clinical presentation of gastric submucosal eminence lesions.

Clinical features of upper gastrointestinal serrated lesions: An endoscopy database analysis of 98746 patients.

AIM: To analyse the clinical features of patients with the serrated lesions in the upper gastrointestinal tract (UPGI) tract. METHODS: Patients who underwent routine esophagogastroduodenoscopy (EGD) at the Digestive Endoscopy Centre of General Hospital, Tianjin Medical University between January 2011 and December 2015 were consecutively recruited. Patients with UPGI serrated lesions were consecutively identified. The patients' demographics and histopathology were recorded. The colorectal findings for patients who underwent colonoscopy simultaneously or within six months were also extracted from the colonoscopy database. In addition, we analysed differences in colorectal neoplasia detection between the study patients and randomly selected patients matched for age and gender who did not exhibit serrated lesions and who also underwent colonoscopy in the same period. RESULTS: A total of 21 patients out of 98746 patients (0.02%) who underwent EGD were confirmed to have serrated lesions with predominantly crenated, sawtooth-like configurations. The mean age of the 21 patients was (55.3 ± 17.2) years, and 11 patients were male (52.4%). In terms of the locations of the serrated lesions, 17 were found in the stomach (including 3 in the cardia, 9 in the corpus and 5 in the antrum), 3 were found in the duodenum, and 1 was found in the esophagus. Serrated lesions were found in different mucosal lesions, with 14 lesions were detected in polyps (8 hyperplastic polyps and 6 serrated adenomas with low grade dysplasia), 3 detected in Ménétrier gastropathy, 3 detected in an area of inflammation or ulcer, and 1 detected in the intramucosal carcinoma of the duodenum. In addition, colonoscopy data were available for 18 patients, and a significantly higher colorectal adenoma detection rate was observed in the UPGI serrated lesions group than in the randomly selected age- and gender-matched group without serrated lesions who also underwent colonoscopy in the same period (38.9% vs 11.1%, OR = 5.091, 95%CI: 1.534-16.890, P = 0.010). The detection rate of advanced adenoma was also higher in the UPGI serrated lesions group (22.2% vs 4.2%, OR = 6.571, 95%CI: 1.322-32.660, P = 0.028). CONCLUSION: Serrated lesions in the UPGI were detected in various mucosal lesions with different pathological morphologies. Moreover colonoscopy is recommended for the detection of concurrent colorectal adenoma for these patients.

Detection Rate, Distribution, Clinical and Pathological Features of Colorectal Serrated Polyps.

BACKGROUND: Colorectal serrated polyp is considered as histologically heterogeneous lesions with malignant potential in western countries. However, few Asian studies have investigated the comprehensive clinical features of serrated polyps in symptomatic populations. The aim of the study was to evaluate the features of colorectal serrated polyps in a Chinese symptomatic population. METHODS: Data from all consecutive symptomatic patients were documented from a large colonoscopy database and were analyzed. Chi-square test or Fisher's exact test and logistic regression analysis were used for the data processing. RESULTS: A total of 9191 (31.7%) patients were detected with at least one colorectal polyp. The prevalence of serrated polyps was 0.53% (153/28,981). The proportions of hyperplastic polyp (HP), sessile serrated adenoma/polyp (SSA/P), and traditional serrated adenoma (TSA) of all serrated polyps were 41.2%, 7.2%, and 51.6%, respectively, which showed a lower proportion of HP and SSA/P and a higher proportion of TSA. Serrated polyps appeared more in males and elder patients while there was no significant difference in the subtype distribution in gender and age. The proportions of large and proximal serrated polyps were 13.7% (21/153) and 46.4% (71/153), respectively. In total, 98.9% (89/90) serrated adenomas were found with dysplasia. Moreover, 14 patients with serrated polyps were found with synchronous advanced colorectal neoplasia, and large serrated polyps (LSPs) (odds ratio: 3.446, 95% confidence interval: 1.010-11.750, P < 0.05), especially large HPs, might have an association with synchronous advanced neoplasia (AN). CONCLUSIONS: The overall detection rate of colorectal serrated polyps in Chinese symptomatic patient population was low, and distribution pattern of three subtypes is different from previous reports. Moreover, LSPs, especially large HPs, might be associated with an increased risk of synchronous AN.

Endoscopic submucosal dissection for silent gastric Dieulafoy lesions mimicking gastrointestinal stromal tumors: Report of 7 cases-a case report series.

BACKGROUND: Dieulafoy lesion is a rare but serious cause of gastrointestinal hemorrhage. However, some cases can be occasionally found without bleeding during the endoscopic screening, and the management remains unclear. The aim of this article was to report the efficacy and safety of endoscopic submucosal dissection (ESD) for silent gastric Dieulafoy lesions, which presented as protrusion lesions mimicking gastrointestinal stromal tumors (GISTs). METHODS: Data from the patients with gastric protrusion lesions who underwent ESD from September 2008 to April 2016 in General Hospital, Tianjin Medical University, China were recorded. Seven cases with pathological diagnosis of Dieulafoy lesion without bleeding were enrolled for further analysis. RESULTS: A total of 7 patients (2 males and 5 females) with mean age of 57.7 ±â€Š4.15 years were pathologically diagnosed as Dieulafoy lesion. Four of the lesions were located in gastric antrum, 2 in the fundus, and 1 in the body of stomach, respectively. The mean sizes of the Dieulafoy lesions under white light endoscopy and endoscopic ultrasonography (EUS) were 1.06 ±â€Š0.28 and 0.84 ±â€Š0.29 cm. The origins of these lesions were submucosa (6/7, 85.7%) and muscularis propria (1/7, 14.3%). Three of them appeared with mixed echo under EUS, 3 with hypoechogenicity, and 1 with hyperechogenicity. En bloc complete resection was achieved in all the lesions by ESD with average time of 76.00 ±â€Š16.86 minutes, and no intraoperative bleeding happened. In addition, all patients were followed up for 1 to 53 months, and no recurrence or long-term complications was observed. CONCLUSION: Therefore, ESD can be an effective and safe treatment for silent gastric Dieulafoy lesions with clinical presentations of submucosal protrusion lesions mimicking GISTs.

Berberine Inhibits Intestinal Polyps Growth in Apc (min/+) Mice via Regulation of Macrophage Polarization.

Antitumor effect of berberine has been reported in a wide spectrum of cancer, however, the mechanisms of which are not fully understood. The aim of this study was to investigate the hypothesis that berberine suppresses tumorigenesis in the familial adenomatous polyposis (FAP) by regulating the macrophage polarization in Apc (min/+) mouse model. Berberine was given to Apc (min/+) mice for 12 weeks. Primary macrophages were isolated; after berberine treatment, the change in signaling cascade was determined. The total number and size of polyps were reduced remarkably in berberine group, compared with control group. A significant decrease in protein levels of F4/80, mannose receptor (MR), and COX-2 in stroma of intestinal polyps and an increase in the level of iNOS were observed after berberine treatment. The mRNA level of MR and Arg-1 in berberine group was significantly lower than those in IL-10 or IL-4 group, while no significant difference in mRNA levels of iNOS and CXCL10 was observed. The migration and invasiveness assays in vitro showed that berberine could reduce the capability of migration and invasiveness. These findings suggest that berberine attenuates intestinal tumorigenesis by inhibiting the migration and invasion of colorectal tumor cells via regulation of macrophage polarization.

Systematic Review: Adverse Events of Fecal Microbiota Transplantation.

BACKGROUND: Fecal microbiota transplantation (FMT) is a microbiota-based therapy that shows therapeutic potential in recurrent or refractory Clostridium difficile infections and other intestinal or extra-intestinal disorders. Nonetheless, adverse events (AEs) remain a major challenge in the application of FMT. AIM: To review the AEs of FMT and to address the concerns of safety during the procedure. METHODS: Publications were retrieved in the databases of Medline, Embase and Cochrane Library. AEs were classified according to their causality with FMT or their severity. RESULTS: A total of 7562 original articles about FMT were identified in this study, 50 of them fulfilled the inclusion criteria. Totally 78 kinds of AEs were revealed enrolled in these 50 selected publications. The total incidence rate of AEs was 28.5%. Among the 42 publications, 5 kinds were definitely and 38 kinds were probably related to FMT. The commonest FMT-attributable AE was abdominal discomfort, which was reported in 19 publications. For upper gastrointestinal routes of FMT, 43.6% (89/204) patients were compromised by FMT-attributable AE, while the incidence dropped to 17.7% (76/430) for lower gastrointestinal routes. In contrast, the incidences of serious adverse events (SAEs) were 2.0% (4/196) and 6.1% (40/659) for upper and lower gastrointestinal routes, respectively. A total of 44 kinds of SAEs occurred in 9.2% patients, including death (3.5%, 38/1089), infection (2.5%, 27/1089), relapse of inflammatory bowel diseases (0.6%, 7/1089) and Clostridium difficile infection (0.9%, 10/1089). CONCLUSION: Consequently, both AEs and SAEs are not rare and should be carefully monitored throughout FMT. However, high quality randomized controlled trials are still needed for the more definite incidence of AEs of FMT.

Potential role of TRIM3 as a novel tumour suppressor in colorectal cancer (CRC) development.

OBJECTIVE: Colorectal cancer (CRC) is the third leading cause of cancer-related mortality in the United States. Recent cancer genome-sequencing efforts and complementary functional studies have led to the identification of a collection of candidate 'driver' genes involved in CRC tumorigenesis. Tripartite motif (TRIM3) is recently identified as a tumour suppressor in glioblastoma but this tumour-suppressive function has not been investigated in CRC. MATERIAL AND METHODS: In this study, we investigated the potential role of TRIM3 as a tumour suppressor in CRC development by manipulating the expression of TRIM3 in two authentic CRC cell lines, HCT116 and DLD1, followed by various functional assays, including cell proliferation, colony formation, scratch wound healing, soft agar, and invasion assays. Xenograft experiment was performed to examine in vivo tumour-suppressive properties of TRIM3. RESULTS: Small-interfering RNA (siRNA) mediated knockdown of TRIM3 conferred growth advantage in CRC cells. In contrast, overexpression of TRIM3 affected cell survival, cell migration, anchorage independent growth and invasive potential in CRC cells. In addition, TRIM3 was found to be down-regulated in human colon cancer tissues compared with matched normal colon tissues. Overexpression of TRIM3 significantly inhibited tumour growth in vivo using xenograft mouse models. Mechanistic investigation revealed that TRIM3 can regulate p53 protein level through its stabilisation. CONCLUSIONS: TRIM3 functions as a tumour suppressor in CRC progression. This tumour-suppressive function is exerted partially through regulation of p53 protein. Therefore, this protein may represent a novel therapeutic target for prevention or intervention of CRC.