Clinical manifestation, lifestyle, and treatment patterns of chronic erosive gastritis: A multicenter real-world study in China.

BACKGROUND: Although chronic erosive gastritis (CEG) is common, its clinical characteristics have not been fully elucidated. The lack of consensus regarding its treatment has resulted in varied treatment regimens. AIM: To explore the clinical characteristics, treatment patterns, and short-term outcomes in CEG patients in China. METHODS: We recruited patients with chronic non-atrophic or mild-to-moderate atrophic gastritis with erosion based on endoscopy and pathology. Patients and treating physicians completed a questionnaire regarding history, endoscopic findings, and treatment plans as well as a follow-up questionnaire to investigate changes in symptoms after 4 wk of treatment. RESULTS: Three thousand five hundred sixty-three patients from 42 centers across 24 cities in China were included. Epigastric pain (68.0%), abdominal distension (62.6%), and postprandial fullness (47.5%) were the most common presenting symptoms. Gastritis was classified as chronic non-atrophic in 69.9% of patients. Among those with erosive lesions, 72.1% of patients had lesions in the antrum, 51.0% had multiple lesions, and 67.3% had superficial flat lesions. In patients with epigastric pain, the combination of a mucosal protective agent (MPA) and proton pump inhibitor was more effective. For those with postprandial fullness, acid regurgitation, early satiety, or nausea, a MPA appeared more promising. CONCLUSION: CEG is a multifactorial disease which is common in Asian patients and has non-specific symptoms. Gastroscopy may play a major role in its detection and diagnosis. Treatment should be individualized based on symptom profile.

Lactobacillus Intestinalis Primes Epithelial Cells to Suppress Colitis-Related Th17 Response by Host-Microbe Retinoic Acid Biosynthesis.

Gut microbiome is integral to the pathogenesis of ulcerative colitis. A novel probiotic Lactobacillus intestinalis (L. intestinalis) exerts a protective effect against dextran sodium sulfate-induced colitis in mice. Based on flow cytometry, colitis-associated Th17 cells are the target of L. intestinalis, which is supported by the lack of protective effects of L. intestinalis in T cell-null Rag1-/- mice or upon anti-IL-17-A antibody-treated mice. Although L. intestinalis exerts no direct effect on T cell differentiation, it decreases C/EBPA-driven gut epithelial SAA1 and SAA2 production, which in turn impairs Th17 cell differentiation. Cometabolism of L. intestinalis ALDH and host ALDH1A2 contributed to elevated biosynthesis of retinoic acid (RA), which accounts for the anti-colitis effect in RAR-α -mediated way. In a cohort of ulcerative colitis patients, it is observed that fecal abundance of L. intestinalis is negatively associated with the C/EBPA-SAA1/2-Th17 axis. Finally, L. intestinalis has a synergistic effect with mesalazine in alleviating murine colitis. In conclusion, L. intestinalis and associated metabolites, RA, have potential therapeutic effects for suppressing colonic inflammation by modulating the crosstalk between intestinal epithelia and immunity.

Lactobacillus johnsonii alleviates colitis by TLR1/2-STAT3 mediated CD206+ macrophagesIL-10 activation.

Imbalance of gut microbiota homeostasis is related to the occurrence of ulcerative colitis (UC), and probiotics are thought to modulate immune microenvironment and repair barrier function. Here, in order to reveal the interaction between UC and gut microbiota, we screened a new probiotic strain by 16S rRNA sequencing from Dextran Sulfate Sodium (DSS)-induced colitis mice, and explored the mechanism and clinical relevance. Lactobacillus johnsonii (L. johnsonii), as a potential anti-inflammatory bacterium was decreased colonization in colitis mice. Gavage L. johnsonii could alleviate colitis by specifically increasing the proportion of intestinal macrophages and the secretion of Il-10 with macrophages depleted model and in Il10-/- mice. We identified this subset of immune cells activated by L. johnsonii as CD206+ macrophagesIL-10. Mechanistically, L. johnsonii supplementation enhanced the mobilization of CD206+ macrophagesIL-10 through the activation of STAT3 in vivo and in vitro. In addition, we revealed that TLR1/2 was essential for the activation of STAT3 and the recognition of L. johnsonii by macrophages. Clinically, there was positive correlation between the abundance of L. johnsonii and the expression level of MRC1, IL10 and TLR1/2 in UC tissues. L. johnsonii could activate native macrophages into CD206+ macrophages and release IL-10 through TLR1/2-STAT3 pathway to relieve experimental colitis. L. johnsonii may serve as an immunomodulator and anti-inflammatory therapeutic target for UC.

A phosphatidic acid-binding lncRNA SNHG9 facilitates LATS1 liquid-liquid phase separation to promote oncogenic YAP signaling.

Long noncoding RNAs (lncRNAs) are emerging as a new class of important regulators of signal transduction in tissue homeostasis and cancer development. Liquid-liquid phase separation (LLPS) occurs in a wide range of biological processes, while its role in signal transduction remains largely undeciphered. In this study, we uncovered a lipid-associated lncRNA, small nucleolar RNA host gene 9 (SNHG9) as a tumor-promoting lncRNA driving liquid droplet formation of Large Tumor Suppressor Kinase 1 (LATS1) and inhibiting the Hippo pathway. Mechanistically, SNHG9 and its associated phosphatidic acids (PA) interact with the C-terminal domain of LATS1, promoting LATS1 phase separation and inhibiting LATS1-mediated YAP phosphorylation. Loss of SNHG9 suppresses xenograft breast tumor growth. Clinically, expression of SNHG9 positively correlates with YAP activity and breast cancer progression. Taken together, our results uncover a novel regulatory role of a tumor-promoting lncRNA (i.e., SNHG9) in signal transduction and cancer development by facilitating the LLPS of a signaling kinase (i.e., LATS1).

HOTAIR induces the ubiquitination of Runx3 by interacting with Mex3b and enhances the invasion of gastric cancer cells.

BACKGROUND: Long non-coding RNAs (LncRNAs) exert their functions mainly by binding to their corresponding proteins. Runt-related transcription factor 3 (Runx3) is an important transcription factor that functions as a tumor suppressor in gastric cancer. Whether there is an interplay between LncRNAs and Runx3 remains unclear. METHODS: RPISeq was applied to screen the LncRNAs that potentially bind to Runx3. The interaction between LncRNA HOX antisense intergenic RNA (HOTAIR) and Runx3 was validated by RNA Immunoprecipitation and RNA pull-down assays. The role of Mex3b in the ubiquitination of Runx3 induced by HOTAIR was assessed by immunoprecipitation. Pearson's correlation between HOTAIR mRNA expression and Runx3 protein expression was analyzed. Cell migration and invasion were explored by transwell assays. RESULTS: We found that HOTAIR was bound to Runx3 protein and identified the fragment of HOTAIR spanning 1951-2100 bp as the specific binding site. In addition, mex-3 RNA binding family member B (Mex3b) was an E3 ligase involved in HOTAIR-induced ubiquitous degradation of Runx3. Silencing the expression of HOTAIR or Mex3b attenuated the degradation of Runx3. In human gastric cancer tissues, HOTAIR was negatively associated with the expression level of Runx3 protein (Pearson coefficient - 0.501, p = 0.025). Inhibition of HOTAIR significantly suppressed gastric cancer cell migration and invasion through upregulating claudin1, which could be reversed by co-deficiency of Runx3. CONCLUSIONS: These results uncovered the novel interaction between HOTAIR and Runx3, and provided potential therapeutic targets on the metastasis of gastric cancer.

Emerging molecular basis of hematogenous metastasis in gastric cancer.

Lymphatic metastasis is commonly observed in gastric cancer (GC), but hematogenous metastasis is more likely responsible for the cancer-related mortality. Since Stephen Paget first introduced the "seed and soil hypothesis" a century ago, growing evidence recognizes that numerous essential secreted factors and signaling pathway effectors participate in the pre-metastatic niche formation and distant organ metastasis. The cross-talk between GC cells and surrounding microenvironment may consist of a series of interrelated steps, including epithelial mesenchymal transition, intravasation into blood vessels, circulating tumor cell translocation, and secondary organ metastasis. Secreted factors including vascular endothelial growth factor (VEGF), matrix metalloproteinases and cancer-derived extracellular vesicles, especially exosomes, are essential in formation of premetastatic niche. Circulating tumor cells and microRNAs represent as ''metastatic intermediates'' between primary tumors and sites of dissemination. Many biomarkers have been identified as novel metastatic markers and prognostic effectors. In addition, molecular therapy has been designed to target biomarkers such as growth factors (human epidermal growth factor receptor 2, VEGF) and chemokines, although they have not clearly proven to be effective in inhibiting GC metastasis in clinical trials. In this review, we will systematically discuss the emerging molecules and their microenvironment in hematogenous metastasis of GC, which may help us to find new therapeutic strategies in the future.

Noninvasive DNA methylation biomarkers in colorectal cancer: A systematic review.

OBJECTIVE: To summarize the current evidence on the biomarkers associated with DNA methylation in the screening and diagnosis of colorectal cancer (CRC). METHODS: A literature search was conducted on the databases of PubMed and Web of Science to identify articles published from 1 January 2000 to 6 June 2015 with language striction. Stuides focusing on the association between noninvasive biomarkers indicating DNA methylation and CRC were included. RESULTS: Altogether 74 studies were finally included in the study. Varied genetic markers in the feces and blood samples were hypermethylated in patients with CRC than in the healthy controls. Some of them could even be detected at the early stage of the tumors. The sensitivity of the genetic markers was superior to that of fecal occult blood test and carcinoembryonic antigen. Multitarget DNA assays using a combination of different methylated genes could improve the diagnostic sensitivity. CONCLUSIONS: Genetic markers might be minimally invasive, economical and accurate for the screening and surveillance of CRC. Large multicenter studies evaluating these biomarkers systematically and prospectively not only in CRC but also in other types of cancers are needed in the future.

Diagnostic performance of magnifying narrow-band imaging for early gastric cancer: A meta-analysis.

AIM: To investigate the performance of magnifying endoscopy with narrow-band imaging (ME-NBI) in the diagnosis of early gastric cancer (EGC). METHODS: Systematic literature searches were conducted until February 2014 in PubMed, EMBASE, Web of Science, Ovid, Scopus and the Cochrane Library databases by two independent reviewers. Meta-analysis was performed to calculate the pooled sensitivity, specificity and diagnostic odds ratio and to construct a summary receiver operating characteristic (ROC) curve. Subgroup analyses were performed based on the morphology type of lesions, diagnostic standard, the size of lesions, type of assessment, country and sample size to explore possible sources of heterogeneity. A Deeks' asymmetry test was used to evaluate the publication bias. RESULTS: Fourteen studies enrolling 2171 patients were included. The pooled sensitivity, specificity and diagnostic odds ratio for ME-NBI diagnosis of EGC were 0.86 (95%CI: 0.83-0.89), 0.96 (95%CI: 0.95-0.97) and 102.75 (95%CI: 48.14-219.32), respectively, with the area under ROC curve being 0.9623. Among the 14 studies, six also evaluated the diagnostic value of conventional white-light imaging, with a sensitivity of 0.57 (95%CI: 0.50-0.64) and a specificity of 0.79 (95%CI: 0.76-0.81). When using "VS" (vessel plus surface) ME-NBI diagnostic systems in gastric lesions of depressed macroscopic type, the pooled sensitivity and specificity were 0.64 (95%CI: 0.52-0.75) and 0.96 (95%CI: 0.95-0.98). For the lesions with a diameter less than 10 mm, the sensitivity and specificity were 0.74 (95%CI: 0.65-0.82) and 0.98 (95%CI: 0.97-0.98). CONCLUSION: ME-NBI is a promising endoscopic tool in the diagnosis of early gastric cancer and might be helpful in further target biopsy.

Cytomegalovirus: a probable cause of steroid-refractory ulcerative colitis.

Cytomegalovirus, regarded as a trigger of several autoimmune diseases, is an opportunistic pathogen. Patients with ulcerative colitis (UC) undergoing steroid treatment are susceptible to this infection. In the presence of cytomegalovirus, inflammation becomes more complex. Patients with active UC who are infected with cytomegalovirus are usually non-responders to steroid, while antiviral drugs could induce remission. Cytomegalovirus should be suggested as a probable cause of steroid-refractory UC based on the clinical data in the literatures.

Overt gastrointestinal bleeding because of hookworm infection.

Hookworm infection is a relatively common cause of anemia in endemic areas. The most common hookworm species are Ancylostoma duodenale and Necator americanus. In this report we present a case of overt gastrointestinal bleeding because of hookworm infection. Capsule endoscopy revealed many hookworms in the lumen of proximal jejunum where active bleeding was seen. The patient was successfully treated with Albendazole.

Irreformable hyponatremia: a case report of pituitary dysfunction with liver cirrhosis.

The diagnosis of pituitary dysfunction is very difficult in inpatients with liver cirrhosis, because the symptoms are intricate and similar. We here report a case of a male patient complaining of fatigue and anorexia for more than two years. On duration of hospital stay, hyponatremia was irreformable. Magnetic resonance imaging of the pituitary revealed the presence of cystic pituitary and abnormal signal in the left frontal lobe. The patient was also suspected to be infective endocarditis. Recognition of this unusual complication of this condition is important for the patients with chronic liver disease.

[DNA methylation of ZIC1 and KLOTHO gene promoters in colorectal carcinomas and its clinicopathological significance].

OBJECTIVE: To determine DNA methylation status of ZIC1 and KLOTHO gene in colorectal carcinomas and its relationship with clinicopathological features of patients. METHODS: The mRNA expression of ZIC1 and KLOTHO genes in colorectal carcinomas was detected by real-time quantitative RT-PCR, and the promoter methylation status was detected by methylation specific PCR (MSP). The relationship of ZIC1 and KLOTHO methylation status with clinicopathological features of colorectal carcinoma was analyzed. RESULT: The mRNA expression levels of ZIC1 and KLOTHO genes were significantly down-regulated in tumor tissues when compared to adjacent nontumor tissues (P<0.001). ZIC1 and KLOTHO methylation was detected in 80.0%(20/25) and 76.0%(19/25) of colorectal tumor tissues, respectively, and the both positive rate was 64.0%(16/25). CONCLUSION: The down-regulated expression of ZIC1 and KLOTHO in colorectal carcinoma may relate to promoter methylation. The detection of methylation of ZIC1 and KLOTHO gene potentially provides biomarkers for diagnosis of colorectal carcinoma.

Klotho, an anti-senescence related gene, is frequently inactivated through promoter hypermethylation in colorectal cancer.

The potential anti-senescence gene Klotho (KL) has been recently found to participate in the progression of several different human cancers including breast, lung, and cervical cancer. In this current study, we identified KL as a candidate tumor suppressor gene silenced through promoter hypermethylation in colorectal cancer (CRC). KL gene expression is found to be absent or reduced in colon cancer cell lines (5/6, 83.3%), which can be reversed by treatment with demethylation agent 5-aza-2'-deoxycytidine (Aza), but not HDAC inhibitor trichostatin A. In addition, KL expression is markedly downregulated in colorectal carcinoma tissues when compared to the adjacent nontumor tissues (n=25, p<0.001). The methylation of the KL gene promoter was frequently detected in primary tumor tissues (34/40, 85%) when compared with adjacent nontumor colon tissues. Furthermore, ectopic expression of KL led to the cell proliferation inhibition of colon cancer cell lines via the induction of cell apoptosis and S-phase cell cycle arrest. Taken together, our results suggest that KL is inactivated through promoter hypermethylation and potentially functions as a tumor suppressor gene in CRC.

[Small interfering RNA inhibits cell proliferation in gastric cancer cell lines highly expressing RegIα].

OBJECTIVE: To investigate the effect of small interfering RNA on cell proliferation and apoptosis in gastric cancer cell lines with high expression of RegIα. METHODS: Total RNA was isolated from six gastric cancer cell lines,and the expression of RegI α mRNA was detected by RT-PCR. RegI α RNAi expression vector was constructed and stably transfected into MKN45 and AGS cells with high RegI α expression, empty-vector was used as control. RegI α mRNA and protein expression was measured by RT-PCR and Western blot respectively in stable transfected cell lines. Cell proliferation and apoptosis were detected with MTT assay and flow cytometry. RESULT: RT-PCR results indicated that RegI α mRNA expression was significantly inhibited by RNAi in both cell lines compared with empty-vector. Western blot results showed that RegIα protein was down-regulated to (44 ± 4)% and (25 ± 4)% respectively in MKN45 and AGS cells compared to empty-vector. MTT results showed that cell growth was significantly inhibited in MKN45 and AGS cells. The apoptosis rate in MKN45 and AGS cells was remarkable increased compared to that of empty-vector (12.96 ± 0.50)% compared with (3.99 ± 0.30)% and (11.59 ± 1.10)% compared with (4.22 ± 0.40)% (P < 0.05). CONCLUSION: Small interfering RNA of RegI α gene can efficiently down-regulate RegI α expression in MKN45 and AGS cell lines, and further inhibit cell growth and induce cell apoptosis.

[Construction of RegIα over-expression vector and its effect on proliferation and apoptosis of gastric cancer cells].

OBJECTIVE: To construct RegIα over-expression vector and to evaluate the effect of RegIα on the proliferation and apoptosis of gastric cancer MKN28 cells in vitro. METHODS: Full sequence of RegIα cDNA was amplified from normal gastric tissue samples by RT-PCR and cloned into pIRES2-EGFP vector. RT-PCR and Western blot were performed to detect expression levels of RegIα in MKN28 cells. The effects of over-expression RegIα on cell proliferation was measured by MTT assay and apoptosis was detected by flow cytometry. RESULT: RegIα cDNA over-expression vector of pIRES2-RegIα-EGFP was successfully constructed. The expressions of RegIα in MKN28 cells, including mRNA and protein levels, were significantly increased after stable transfection, which resulted in cell proliferation and anti-apoptotic effect induced by H(2)O(2). CONCLUSION: The over-expression of RegIα can promote cell proliferation and reduce cell apoptosis when induced by H(2)O(2) in gastric cancer cells.

Muscovite reverses gastric gland atrophy and intestinal metaplasia by promoting cell proliferation in rats with atrophic gastritis.

OBJECTIVE: To detect whether muscovite exerts its protective role in the progression of atrophic gastritis (AG) and evaluate the possible mechanism. METHODS: AG rats were established and then randomly divided into groups administrated with different doses of muscovite for 8 weeks. Histological changes in gastric antrum and the number of parietal cells, chief cells, and G/D cells were observed. Serum gastrin and prostaglandin E2 (PGE2) were evaluated by enzyme-linked immunosorbent assay (ELISA). The expression of proliferating cell nuclear antigen (PCNA), epidermal growth factor receptor (EGFR), C-erbB-2, p21, p53, p16 and bcl-2 in gastric tissue were detected by immunohistochemistry. The concentrations of TNF-alpha and IL-1beta secreted by THP-1 cells were detected when incubated with different doses of muscovite. RESULTS: The grade of inflammation in muscovite groups was lower (p < 0.05), while the thickness and number of gastric glands were significantly elevated in muscovite groups (p < 0.01). The expression height of PCNA in the muscovite group was higher than in the AG group (p < 0.01). Immunohistochemistry results showed a positive expression rate of EGFR; p16 in muscovite-treated AG rats was increased (p < 0.05), while C-erbB-2 and p21 were decreased (p < 0.05). Serum gastrin and PGE2 were significantly elevated in the high-dose muscovite-treated rats (p < 0.05). In vitro studies showed that muscovite had a dose-dependent adsorption of TNF-alpha and IL-1beta. CONCLUSION: Muscovite could reverse gastric gland atrophy and intestinal metaplasia by promoting cell proliferation and revitalization in gastric mucosa in AG rats.

Therapeutic effects of rectal administration of muscovite on experimental colitis in rats.

BACKGROUND AND AIMS: The aim of this study was to investigate whether rectal administration of muscovite can ameliorate colonic inflammation in a rat model of experimental colitis, and its possible mechanism. METHODS: Female Sprague-Dawley (SD) rats with trinitrobenzene sulfonic acid (TNBS)-induced colitis were treated with rectal administration of muscovite or 5-aminosalicylic acid (5-ASA) daily for 14 days. The changes in body weight, macroscopic damage and histologic scores were subsequently evaluated. Gene expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), mucin2 (MUC2) and trefoil factor 3 (TFF3) in the colonic tissues was assessed by semiquantitative reverse transcription polymerase chain reaction (RT-PCR) while protein levels of TNF-alpha and IL-1beta were detected by ELISA. Mucin2 expression in colonic mucosa was detected by immunohistochemistry. The capacity of muscovite to adsorb cytokines in vitro was determined by the changes in the amount of TNF-alpha, IL-1beta secreted by lipopolysaccharide (LPS)-stimulated THP-1 cells and IL-8 secreted by LPS-stimulated HT-29 cells. RESULTS: Rectal administration of muscovite improved the loss of body weight, macroscopic and histologic scores of TNBS-induced colitis in a dose-dependent manner. Trinitrobenzene sulfonic acid-induced expression of TNF-alpha and IL-1beta was reduced by muscovite and 5-ASA treatment. Reduction of MUC2 expression in colitis rats was reversed by muscovite and 5-ASA treatment. However, the expression of TFF3 mRNA in colonic mucosa was not affected. In addition, we found muscovite inhibited the expression of TNF-alpha, IL-1beta secreted by THP-1 and IL-8 secreted by HT-29 cells in a dose-dependent manner. CONCLUSIONS: Our study demonstrated for the first time that rectal administration of muscovite can ameliorate colonic inflammation of TNBS-induced colitis. Further confirmatory studies are needed to prove that muscovite might be a potential therapeutic agent for the treatment of ulcerative colitis.