VASN promotes colorectal cancer progression by activating the YAP/TAZ and AKT signaling pathways via YAP.

Colorectal cancer (CRC) is one of the most common gastrointestinal malignancies. Vasorin (VASN) has been reported to be critical in tumor development and angiogenesis. However, VASN has not been reported in CRC, and its role is unclear. In this study, VASN expression is upregulated in CRC compared with the normal tissues, and VASN expression positively correlates with N stage and poor overall survival by analysis of different datasets and 32 CRC clinicopathologic samples. Overexpression of VASN significantly promotes CRC cell progression, including proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), while knockdown of VASN inhibits CRC progression. We found that VASN was associated with the YAP/TAZ and PI3K/AKT pathways by gene set enrichment analysis (GSEA) and gene ontology (GO) analysis. Notably, western blotting, immunofluorescence staining and co-immunofluorescence (co-IP) confirmed that VASN could interact with YAP and activate the YAP/TAZ and PTEN/PI3K/AKT pathways, and knockdown of YAP reversed this effect. Importantly, our findings indicate that VASN interacts with YAP to inhibit YAP phosphorylation and stimulates CRC proliferation, migration, and invasion through activation of the YAP/TAZ-TEAD target gene CTGF and PTEN/PI3K/AKT pathways. Our results also show that knockdown of YAP reverses the cellular phenotype induced by increased VASN. In conclusion, our study reveals that VASN acts as an oncogene to stimulate tumor progression in CRC, providing new insights into the molecular mechanisms of CRC development and representing a possible novel biomarker for CRC.

The Short Health Scale: A Valid and Reliable Quality-of-Life Scale for Mainland Chinese Patients with Inflammatory Bowel Disease.

Background: The aim of our study was to translate and validate the mainland Chinese version of the short health scale (SHS), a disease-specific quality-of-life (QoL) scale for patients with inflammatory bowel disease (IBD). Methods: The SHS was translated and validated according to the standard process: a translation and back-translation procedure and a reliability and validation study. Patients with IBD were enrolled, and their QoL was assessed using the SHS, the short inflammatory bowel disease questionnaire (SIBDQ), and the Bristol stool form scale. Reliability (internal consistency reliability, split-half reliability, and test-retest reliability) and validity analyses were performed to evaluate the psychometric characteristics of the SHS. The impacts of different severity of major symptoms on QoL were analyzed by comparing the scores of SHS. Results: A total of 112 patients with IBD (69 with ulcerative colitis and 43 with Crohn's disease) completed the mainland Chinese version of the SHS, and 34 patients completed the SHS a second time within one to two weeks. Cronbach's alpha value of the SHS was 0.90, and its split-half coefficient was 0.83. Intraclass correlation coefficients of the four items ranged from 0.52 to 0.72. All four items of the SHS were significantly associated with the corresponding domains of the SIBDQ, with correlation coefficients ranging from -0.52 to -0.69 (p < 0.001). The results of confirmatory factor analysis indicated a good fit of the one-factor model, with comparative fit index (CFI) = 0.878, normed fit index (NFI) = 0.874, incremental fit index (IFI) = 0.880, and goodness of fit index (GFI) = 0.842. The patients with severe symptoms had higher scores in the SHS than those with no or mild symptoms. Conclusions: The SHS was simple and quick to be used. The SHS had good validity and reliability and was suitable for evaluating the QoL of patients with IBD in mainland China.

Translation and evaluation of the simplified Chinese version of the rating form of IBD patient concerns.

BACKGROUND: Inflammatory bowel disease (IBD) has become a global public health problem. The prevalence of IBD in China increased annually in past two decades. METHODS: This study was to translate and validate the rating form of IBD patients' concerns (RFIPC), and to describe disease-related worries and concerns of patients with IBD. The simplified Chinese version of the RFIPC was developed according to translation and back-translation procedure. Patients with IBD were consecutively enrolled from the First Affiliated Hospital of Guangzhou University of Chinese Medicine. The participants were assessed using the RFIPC and the Short Inflammatory Bowel Disease Questionnaire (SIBDQ). Internal consistency, test-retest reliability, measurement error, confirmatory factor analysis (CFA) and correlation of the RFIPC with the SIBDQ were performed to evaluate the psychometric characteristics of the RFIPC. RESULTS: A total of 116 patients with IBD, 73 with ulcerative colitis (UC) and 43 with Crohn's disease (CD), were enrolled in this study. Thirty-seven of them recompleted the questionnaires for the second time between 7 and 14 days after the first interview. The results of CFA indicated the original structure of the RFIPC was reasonable. Cronbach's alpha value of the RFIPC were 0.97. The intraclass correlation coefficients of four domains ranged from 0.85 to 0.92. The standard error of measurement was 7.10. The correlation coefficients between total score of the RFIPC and the SIBDQ score ranged from - 0.54 to - 0.70. Median total score of the RFIPC was 39.4 (IQR 24.0-59.3). Patients with severe symptoms reported higher scores of the RFIPC. The uncertain nature of disease, having surgery, having an ostomy bag, developing cancer, feeling out of control, being a burden on others and financial difficulties were highest concerns of patients with IBD. Comparing with patients with UC, patients with CD had more concerns of the ability to have children and being treated as different (P < 0.05). CONCLUSIONS: The simplified Chinese version of RFIPC is a valid and reliable tool. It could be used for assessing disease-related worries and concerns of patients with IBD in China. Specific concerns of patients with UC and CD are different, therefore, health workers should consider the specific needs of UC and CD patients.

Mass Cytometry and Single-Cell Transcriptome Analyses Reveal the Immune Cell Characteristics of Ulcerative Colitis.

Background: The pathogenesis of ulcerative colitis (UC) is closely related to immunity. The immune characteristic differences between active UC (UCa) and inactive UC (UCin) have not been completely explained. Mass cytometry (CyTOF) and single-cell RNA sequencing (scRNA-seq) were used to analyze the immune cells of UCa, UCin and healthy control (HC) subjects to determine the specific immune characteristics. Methods: The immune cell subsets among UCa, UCin, HC were distinguished using CyTOF analysis. scRNA-seq analysis was used to validate the results of CyTOF. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to understand the roles of differential immune cell subsets. Results: After CyTOF analysis and validation of scRNA-seq analysis, differential immune cell subsets mainly contained TNF+IL-17A++ effector memory (EM) Tregs, CXCR3+CTLA4+ EM Tregs, CXCR3++CCR7+ B cells, HLA-DR+CCR7+ dendritic cells (DCs) and CTLA-4+ natural killer (NK) cells. In comparison to HC, CCR6+TNF+CD161+ EM T cells were highly enriched in UCa and UCin. Besides, UCa was characterized by an increase in CD38+TNF+ EM Tregs, CXCR3+CCR4+ naïve B cells, HLA-DR+CD14+IL21+ macrophages/monocytes, HLA-DR+CCR7+ DCs, AHR+CD14+ cytotoxic NK (cNK) cells and CD8A+IFNG+ cNK cells. Decreases in CD38+CD27+ plasmablasts, CXCR3+CD38+ regulatory NK cells, and CXCR3+CCR7+ tolerant NK cells in UCa were discovered. Conclusions: Novel immune cell subsets which was used to distinguish UCa, UCin and HC were identified. This information might be utilized to distinguish the patients with UCa and UCin.

Diurnal pattern of salivary alpha-amylase and cortisol under citric acid stimulation in young adults.

Background: Saliva composition has diurnal variations. Citric acid stimulation plays a major role in the change of salivary flow rate and salivary composition. However, diurnal variations and sex differences in salivary alpha-amylase (sAA), pH, salivary flow rate (SFR), and salivary cortisol before and after citric acid stimulation remain unclear. Methods: We recruited 30 healthy volunteers, including 15 women (24.7 ± 1.0 years old) and 15 men (25.3 ± 1.3 years old). At four time points (T1, 7:00; T2, 10:00; T3, 16:00; and T4, 20:00), saliva was collected from healthy volunteers before and after citric acid stimulation; and sAA, pH, SFR and salivary cortisol were measured and compared between men and women. Results: There were circadian fluctuations in sAA activity, SFR, pH, and cortisol level both before and after citric acid stimulation, and the diurnal fluctuations of these indexes were not affected by citric acid stimulation. There were significant differences in salivary cortisol between men and women before and after acid stimulation in T1. Neither SFR nor pH showed sex-related differences before or after acid stimulation. The variation trend of sAA activity was contrary to that of cortisol, with a significant negative correlation. Conclusions: Our data suggest that sAA and cortisol showed diurnal fluctuation, and the variation characteristics of male and female under resting state and acid stimulation were basically the same. The variation trend of salivary alpha-amylase activity was opposite to that of cortisol, with significant negative correlation. Our findings may enable the selection of the correct sampling time for research and the selection of appropriate sampling strategies in studies investigating chronic psychosocial conditions.

Spinster homolog 2 in cancers, its functions and mechanisms.

Spinster homolog 2 (SPNS2) is a multi-transmembrane transporter, widely located in the cell membrane and organelle membranes. It transports sphingosine-1-phosphate (S1P) into the extracellular space and the circulatory system, thus alters the concentration and the distribution of S1P, sphingosine-1-phosphate receptor (S1PRs) and S1P related enzymes, meaning that it exerts its functions via S1P signaling pathways. Studies also show that ectopic SPNS2 mediates parts of the physiological process of the cells. As of now, SPNS2 has been reported to participate in physiological processes such as angiogenesis, embryonic development, immune response and metabolisms. It is also associated with the transformation from inflammation to cancer as well as the proliferation and metastasis of cancer cells. In this review, we summarize the functions and the mechanisms of SPNS2 in the pathogenesis of cancer to provide new insights for the diagnosis and the treatments of cancer.

Modified Sijunzi decoction in the treatment of ulcerative colitis in the remission phase: study protocol for a series of N-of-1 double-blind, randomised controlled trials.

BACKGROUND: Modified Sijunzi decoction (SJZD) has been used to treat ulcerative colitis (UC) in remission. However, more rigorous clinical trials are necessary to evaluate its effectiveness. Therefore, a series of single-case randomised controlled trials (N-of-1 trials) is proposed to compare the efficacy of modified SJZD with mesalazine for treating UC in remission. METHODS: This is a single-site, hospital-based, double-blind N-of-1 trial for 10 single subjects. Three cycles of N-of-1 trials are planned. There are two treatment periods in each cycle. Modified SJZD combined with mesalazine placebo or mesalazine combined with modified SJZD placebo will be randomised during each 8-week treatment period. There is no washout period in the study. Subjects will be selected by the researcher strictly in accordance with the inclusion and exclusion criteria. DISCUSSION: Paired t tests and mixed-effect models will be used to analyse the visual analogue scale (VAS) for clinical symptoms and the quality of life questionnaire responses. The findings will be interpreted with caution. We anticipate that the results will show that modified SJZD is effective for patients with UC in remission. TRIAL REGISTRATION: Chinese Clinical Trial Register, ID: ChiCTR1900024086. Registered on 24 June 2019.

Prognostic Value of Mismatch Repair Genes for Patients With Colorectal Cancer: Meta-Analysis.

DNA mismatch repair was proposed to play a pivotal role in the development and prognosis of colorectal cancer. However, the prognostic value of mismatch repair on colorectal cancer is still unknown. The PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched. The articles about mismatch repair (including hMLH1, hMSH2, hMSH3, hMSH6, hPMSH1, and hPMSH2) deficiency for the prognosis of patients with colorectal cancer were included in the study. The hazard ratio and its 95% confidence interval were used to measure the impact of mismatch repair deficiency on survival time. Twenty-one articles were included. The combined hazard ratio for mismatch repair deficiency on overall survival was 0.59 (95% confidence interval: 0.50-0.69) and that on disease-free survival was 0.57 (95% confidence interval: 0.43-0.75). In subgroup analysis, there were a significant association between overall survival and mismatch repair deficiency in Asian studies (hazard ratio: 0.67; 95% confidence interval: 0.50-0.91) and Western studies (hazard ratio: 0.56; 95% confidence interval: 0.46-0.67). For disease-free survival, the hazard ratios in Asian studies and Western studies were 0.55 (95% confidence interval: 0.38-0.81) and 0.62 (95% confidence interval: 0.50-0.78), respectively. Our meta-analysis indicated that mismatch repair could be used to evaluate the prognosis of patients with colorectal cancer.

Effective dispersion of multi-walled carbon nanotubes in aqueous solution using an ionic-gemini dispersant.

A promising ionic-gemini molecule, 4, 4'-di (n-tetradecyl) diphenylmethane disulfate salt (DSDM), is reported for effective dispersion of multi-walled carbon nanotubes (MWCNTs) in aqueous medium in the present investigation. The dispersibility and stability of the DSDM-modified MWCNTs were characterized by UV-vis spectrophotometer, Raman spectroscopy, Fourier transform infrared spectroscopy, transmission electron microscopy and zeta potential measurements. The hydrophobic interaction between alky chains and carbon nanotubes as well as the π-π-stacking interaction between benzene rings and carboatomic rings in MWCNTs enables a successful modification of DSDM onto the MWCNT surface. The dispersed MWCNTs individually existed in dispersion with no structural damage, indicating a much better performance than the MWCNTs dispersed by the sodium dodecylbenzene sulfonate (SDBS), a frequently reported single-chain ionic dispersant. Surface potential measurements showed that the DSDM-modified MWCNTs were negatively charged, giving rise to electrostatic repulsion between the MWCNTs in aqueous solution. A better MWCNT dispersion effect was observed with the increase in MWCNT surface potential, and the dispersion with high MWCNT surface potential presents high dispersion stability with no agglomeration appeared for more than 5 months. The magnesium (Mg) matrix composite fabricated based on the DSDM-dispersed MWCNTs demonstrated excellent mechanical properties compared to pure Mg. Our research may provide an alternative way to improve the mechanical properties of composites.

miR-155 targets Est-1 and induces ulcerative colitis via the IL-23/17/6-mediated Th17 pathway.

BACKGROUND: Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) affecting millions of people worldwide. miR-155 has been reported to be upregulated in various inflammatory diseases and is a positive regulator of the T-cell response. IL-17 secreting helper T (Th17) cells have been heavily implicated in tissue-specific immune pathology, including UC. METHODS AND RESULTS: Therefore, we targeted miR-155 and investigated its expression levels in a DSS-induced UC mouse model, revealing increased expression. Est-1 expression was found to have decreased, but the levels of IL-23/17/6 were raised significantly and Th17 had experienced an obvious increase. We overexpressed miR-155 using a lentiviral treatment. Increased miR-155 expression induced a more severe damage to colon tissues. In this case, the level of Est-1 decreased even further, thereby enhancing IL-23/17/6-mediated Th17 differentiation. CONCLUSION: miR-155 seems to target Est-1 and induces UC via the IL-23/17/6-mediated Th17 pathway.

Anti-inflammatory effect of Chang-An-Shuan on TNBS-induced experimental colitis in rats.

BACKGROUND: Inflammatory bowel disease (IBD), denominated by Crohn's disease and ulcerative colitis, is often associated with abdominal pain, diarrhea and bloody stool. The standard protocols for treating colitis conditions are not satisfactory; thus, complementary and alternative medicines have been increasingly accepted by IBD sufferers worldwide. In this study, we aimed to elucidate the anti-inflammatory effect of Chang-An-Shuan (CAS), a 6-herb Chinese medicinal formula, on 2, 4, 6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats and the underlying mechanisms. METHODS: Sprague-Dawley rats were administered with rectal gavage of 2.5% TNBS in 50% ethanol for the induction of experimental colitis which is considered as a model for Crohn's disease. Upon the TNBS induction, rats were given CAS at 0.5 g/kg/day or 5 g/kg/day for 10 days. The application of salicylazosulfapyridine (0.5 g/kg/day) was served as a positive reference drug for the colitis condition. The efficacy and mechanistic action of CAS were evaluated by means of histopathological and biochemical approaches such as histological staining, real-time polymerase chain reaction, Western blotting analysis and enzyme-linked immunosorbent assay. RESULTS: Oral administration of CAS at 5 g/kg/day, but not 0.5 g/kg/day, significantly ameliorated the severity of TNBS-induced colitis as evidenced by the reduced loss of body weight, alleviated diarrhea and decreased bloody stool. While lowering the disease activity index, the administration of CAS lessened mucosal lesions thus mucosal integrity of the colitis rats was notably improved. Further, the CAS treatment also significantly suppressed the mRNA and protein levels of pro-inflammatory cytokines, namely interleukin-1ß and tumor necrosis factor-α while enhancing the level of anti-inflammatory cytokine IL-10 in the TNBS-treated rats. Importantly, the ameliorative effect of CAS was related to an inhibition of the nuclear factor-κB (NF-κB) signaling pathway by downregulating the expression levels of NF-κBp-65, p-38 and p-AKT. CONCLUSIONS: We suggest that CAS is a potential alternative remedial approach for treating IBD conditions, and the anti-inflammatory effect of CAS is associated with the down-regulation of the NF-κB signaling pathway and the balanced production of pro- and anti-inflammatory cytokines.

Adalimumab for Moderately to Severely Active Ulcerative Colitis: A Systematic Review and Meta-Analysis.

BACKGROUND: Evidence-based studies are increasingly being focused on evaluating the efficacy and safety of adalimumab (ADA) for moderately to severely active ulcerative colitis (UC). However, the dosage pattern of ADA for UC management is still not clear. OBJECTIVE: A meta-analysis was conducted to evaluate the efficacy and safety of different ADA dosage regimens for moderately to severely active UC. METHODS: The Medline, EMBASE, ISI Web of Knowledge, and Cochrane databases were searched from their inception to January 2015. Randomized controlled trials (RCTs) comparing ADA with placebo were eligible for initial inclusion. The efficacy and side effects were evaluated for ADA 160/80 (ADA 160/80 mg at weeks 0/2 and then 40 mg at weeks 4 and 6), and ADA 80/40 (ADA 80/40 mg at weeks 0/2 and then 40 mg at weeks 4 and 6) induction therapy, with ADA 40 mg every other week (EOW) for maintenance therapy of 52 weeks. The pooled risk ratio (RR) and its 95 % confidence interval (CI) were calculated. RESULTS: Three RCTs were included. All of the studies were considered to have a low risk of bias. ADA 160/80 was more effective than placebo for induction of clinical remission (RR 1.62, 95 % CI 1.15-2.29), clinical response (RR 1.37, 95 % CI 1.19-1.59), mucosal healing (RR 1.27, 95 % CI 1.08-1.50), and inflammatory bowel disease questionnaire (IBDQ) response (RR 1.22, 95 % CI 1.05-1.43) and did not increase adverse events (RR 1.10, 95 % CI 0.95-1.27). Compared with placebo, ADA 80/40 did not show significant differences for induction of clinical remission and clinical response and did not increase adverse events. ADA 40 mg EOW was superior to placebo in maintaining clinical remission (RR 2.38, 95 % CI 1.57-3.59), clinical response (RR 1.69, 95 % CI 1.29-2.21), mucosal healing (RR 1.69, 95 % CI 1.26-2.28), and IBDQ response (RR 1.73, 95 % CI 1.28-2.34). Compared with placebo, ADA 40 mg EOW increased adverse events (RR 1.28, 95 % CI 1.06-1.54). CONCLUSION: ADA 160/80 was a safe and effective treatment for induction management of moderately to severely active UC, but the benefits of ADA 80/40 application were limited. ADA 40 mg EOW was effective for maintenance management of UC. Additional well designed RCTs are needed to confirm these results.

Probiotics can improve the clinical outcomes of hepatic encephalopathy: An update meta-analysis.

INTRODUCTION: Although the efficacy of probiotics has been extensively studied in hepatic encephalopathy (HE), the results remain controversial. The objective of this study is to identify and update the association between probiotics and HE. METHODS: Up to December 2014, we searched Medline, Embase, Web of Science, Cochrane CENTRAL, and SinoMed of China for all relevant articles about probiotics and HE. Jadad score was used to evaluate the quality of studies. Pooled relative risk (RR), publication bias and heterogeneity were assessed. RESULTS: Nine studies met the inclusion criteria. Probiotics was associated with improvement of minimal HE and prophylaxis of overt HE [RR 1.52; 95% confidence intervals (95% CI) 1.00-2.33]. Studies with probiotics showed reduction of ammonia concentration [standard mean difference (SMD) -0.32, 95% CI -0.54 to -0.11]. Probiotics could reduce physical and psychosocial sickness impact profile (SIP) score with weight mean difference (WMD) -3.13 (95% CI -4.10 to -2.17) and WMD -3.50 (95% CI -4.91 to -2.08), respectively. Similar result was obtained with total SIP score (WMD -4.83; 95% CI -6.24 to -3.43). Reduction of severe adverse events, defined as minimal HE developing into overt HE, hospitalizations, infections or unrelated emergency room (ER) visits, was observed in HE with probiotics (RR 0.59; 95% CI 0.39-0.90). CONCLUSION: Our pooled results indicated that probiotics was associated with improvement of minimal HE, prophylaxis of overt HE, and reduction of SIP score and severe adverse events. Large well-designed randomised controlled trials are needed to confirm these results.

MiR-29a promotes intestinal epithelial apoptosis in ulcerative colitis by down-regulating Mcl-1.

OBJECTIVE: While it's widely accepted that the etiology of ulcerative colitis (UC) involves both genetic and environmental factors, the pathogenesis of ulcerative colitis is still poorly understood. Intestinal epithelial apoptosis is one of the most common histopathological changes of UC and the expression of a number of apoptosis genes may contribute to the progression of UC. MicroRNAs have recently emerged as powerful regulators of diverse cellular processes and have been shown to be involved in many immune-mediated disorders such as psoriasis, rheumatoid arthritis, lupus, and asthma. A unique microRNA expression profile has been identified in UC, suggesting that, microRNAs play an important role in the pathogenesis of UC. We investigated the role of miR-29a in intestinal epithelial apoptosis in UC. METHODS: The expression of miR-29a and Mcl-1, an anti-apoptotic BCL-2 family member, was evaluated in both UC patients and UC mice model induced by dextran sodium sulfate (DSS). The apoptosis rate of intestinal epithelial cells was also evaluated. RESULTS: In UC patients and DSS-induced UC in mice, the expression of miR-29a and Mcl-1, were up-regulated and down-regulated, respectively. We identified a miR-29a binding site (7 nucleotides) on the 3'UTR of mcl-1 and mutation in this binding site on the 3'UTR of mcl-1 led to mis-match between miR-29a and mcl-1. Knockout of Mcl-1 caused apoptosis of the colonic epithelial HT29 cells. In addition, miR-29a regulated intestinal epithelial apoptosis by down-regulating the expression of Mcl-1. CONCLUSION: miR-29a is involved in the pathogenesis of UC by regulating intestinal epithelial apoptosis via Mcl-1.

Association of interleukin-17F 7488 single nucleotide polymorphism and inflammatory bowel disease in the Chinese population.

OBJECTIVE: The functional polymorphism of interleukin (IL)-17F 7488 A > G was found to be associated with autoimmune inflammatory diseases and also high IL-17F intestinal expression in inflammatory bowel disease (IBD) was detected. The purpose of this study was to investigate the association between the polymorphism and IBD in the Chinese population and to elucidate potential interactions between IL-17F genotypes and clinical phenotypes. MATERIAL AND METHODS: DNA was extracted from peripheral blood cells of 148 ulcerative colitis (UC), 134 Crohn's disease (CD) patients and 373 age- and gender-matched healthy controls. The IL-17F 7488 A > G polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequencing. RESULTS: In UC patients, the homozygous GG genotype frequency was significantly lower than that in the controls (0.0% versus 3.8%, p=0.014); Compared to that of wild-type AA patients, the AG heterozygous carriers have a later onset (43.3+/-11.1 years versus 34.6+/-14.8 years, p = 0.012) and a significantly higher incidence of mild severity (94.1% versus 61.0%, p = 0.009, OR = 0.96, 95% CI = 0.94-0.96), respectively, indicating that subjects with the GG genotype have a slightly decreased risk of 0.96 times for UC compared with that of other genotypes. Further analysis also revealed that G carrier subjects were more likely to present mild severity and had 10.2 times higher incidence of getting mild severity than those with AA genotype (OR = 10.2, 95% CI = 1.3-81.0). CONCLUSIONS: This study shows that IL-17F 7488 A > G polymorphism is associated with weak UC protection in the Chinese population. The clinical phenotypes of UC are also affected by this polymorphism.