The Single-Nucleotide Polymorphism of miR-27a rs895819 and the Expression of miR-27a in Helicobacter pylori-Related Diseases and the Correlation with the Traditional Chinese Medicine Syndrome.

Aims: The study aims to explore the effects of the single-nucleotide polymorphism of miR-27a and its expression in Helicobacter pylori (H. pylori)-related diseases and the relationship between gastric pathology and traditional Chinese medicine (TCM). Methods: Subjects were classified into six histopathological groups and five TCM syndrome groups. All specimens underwent H. pylori detection through rapid urease test and methylene blue staining. Histopathological characteristics were observed by hematoxylin-eosin. The expression of miR-27a and its genotype were, respectively, detected by Quantitative Real-Time PCR and direct sequencing. Results: H. pylori promoted the malignant evolution of gastric mucosa and were involved in the formation of TCM syndrome. In H. pylori-positive patients, the frequency of miR-27a CT genotype at the rs895819 locus and its expression in the gastric cancer group were higher than those in other pathological groups. TCM syndrome had a close relationship with histopathological changes, and patients with spleen-qi deficiency syndrome had a higher risk of gastric cancer than other syndromes, regardless of H. pylori infection. Conclusion: The C allele at miR-27a rs895819 locus may be an oncogene in gastric cancer. High levels of miR-27a could play an important role in gastric malignant evolution, especially cancerization. There is a certain connection between TCM syndrome and pathological changes of the gastric mucosa to some extent, where patients with SQD syndrome had a higher risk of GC.

Functional gene polymorphisms and expression alteration of selected microRNAs and the risk of various gastric lesions in Helicobacter pylori-related gastric diseases.

Background: Helicobacter pylori (Hp) persistent infection is an important pathogenic factor for a series of chronic gastric diseases from chronic gastritis to gastric cancer. Genetic and epigenetic abnormalities of microRNAs may play a vital role in the pathological evolution of gastric mucosa in Helicobacter pylori-related gastric diseases (HPGD). This study aimed to investigate the relationship between miR-146a, miR-196a2, miR-149, miR-499 and miR-27a gene single nucleotide polymorphisms (SNPs) and their expressions with pathological changes in gastric mucosa, and to further analyze the interactions between SNPs and Hp. Methods: Subjects in this study included patients diagnosed with HPGD and healthy controls. MiR-146a rs2910164, miR-196a2 rs11614913, miR-149 rs2292832, miR-499 rs3746444 and miR-27a rs895819 were genotyped by direct sequencing. Fluorescence quantitative PCR was used to detect microRNA expressions. Gene-gene and gene-environment interactions were evaluated by multifactor dimensionality reduction (MDR) method. Results: we found that frequency distribution of miR-196a2 rs11614913 CT genotype in gastric precancerous lesion (GPL) group and gastric cancer (GC) group was significantly higher than normal control (NOR) group [adjusted OR = 6.16, 95%CI (1.46-26.03); adjusted OR = 11.83, 95%CI (1.65-84.72), respectively]. CT genotype and C allele of miR-27a rs895819 were associated with increased risk of GC [adjusted OR = 10.14, 95%CI (2.25-45.77); adjusted OR = 3.71, 95%CI(1.46-9.44), respectively]. The MDR analysis results showed that the interaction between miR-196a2 rs11614913 and Hp was associated with the risk of GPL (p = 0.004). Meanwhile, the expression level of miR-196a2 in GC group was significantly higher than NOR, chronic inflammation (CI) and early precancerous lesion (EPL) groups among Hp-positive subjects. And expressions of miR-499 and miR-27a in GC group were both higher than EPL group. Also, miR-27a expression in GC group was higher than CI and gastric atrophy (GA) groups. Conclusion: miR-196a2 rs11614913 and miR-27a rs895819 may affect the genetic susceptibility to GPL or GC. MiR-196a2 rs11614913 and Hp have a synergistic effect in the occurrence and development of GPL. The up-regulation of miR-499, miR-196a2 and miR-27a expression caused by Hp infection may be an important mechanism of gastric carcinogenesis.

RNA-binding protein HuR regulates translation of vitamin D receptor modulating rapid epithelial restitution after wounding.

Homeostasis of the intestinal epithelium is tightly regulated by numerous extracellular and intracellular factors including vitamin D and the vitamin D receptor (VDR). VDR is highly expressed in the intestinal epithelium and is implicated in many aspects of gut mucosal pathophysiology, but the exact mechanism that controls VDR expression remains largely unknown. The RNA-binding protein human antigen R (HuR) regulates the stability and translation of target mRNAs and thus modulates various cellular processes and functions. Here we report a novel role of HuR in the posttranscriptional control of VDR expression in the intestinal epithelium. The levels of VDR in the intestinal mucosa decreased significantly in mice with ablated HuR, compared with control mice. HuR silencing in cultured intestinal epithelial cells (IECs) also reduced VDR levels, whereas HuR overexpression increased VDR abundance; neither intervention changed cellular Vdr mRNA content. Mechanistically, HuR bound to Vdr mRNA via its 3'-untranslated region (UTR) and enhanced VDR translation in IECs. Moreover, VDR silencing not only inhibited IEC migration over the wounded area in control cells but also prevented the increased migration in cells overexpressing HuR, although it did not alter IEC proliferation in vitro and growth of intestinal organoids ex vivo. The human intestinal mucosa from patients with inflammatory bowel diseases exhibited decreased levels of both HuR and VDR. These results indicate that HuR enhances VDR translation by directly interacting with its mRNA via 3'-UTR and that induced VDR by HuR is crucial for rapid intestinal epithelial restitution after wounding.

Associations of Interleukin-1ß with H. pylori-Induced Gastric Atrophy and Syndrome of Dampness-Heat in the Spleen and Stomach in Subjects with H. pylori-Related Gastric Diseases.

H. pylori-related gastric diseases (HPGD) are a series of gastric mucosal benign and malignant lesions associated with H. pylori infection. Exploring the pathogenesis of HPGD will be of great significance to prevent and treat gastric malignancy. Traditional Chinese medicine (TCM) syndrome is the essence of TCM, reflecting the state of whole body. Potential similarities of TCM syndrome may provide a new perspective in understanding development and treatment of diseases. To seek an early warning signal for gastric malignant pathology and similarities of TCM syndrome from the viewpoint of molecular biology, we examined the relationships among H. pylori, gastric pathology, and TCM syndrome and effects of Interleukin-1ß (IL-1ß) gene polymorphisms and expression on gastric pathology and TCM syndrome in HPGD. The results indicated that detection of H. pylori with differentiation of TCM syndrome may have a predictive function to gastric pathology. H. pylori may lead to gastric atrophy via enhancing IL-1ß mRNA expression, and IL-1ß mRNA overexpression in gastric mucosa may be one of the generality characteristics for H. pylori-negative subjects with syndrome of dampness-heat in the spleen and stomach.

Interaction of Cyclooxygenase-2 with Helicobacter pylori Induces Gastric Chronic Nonresolving Inflammation and the Formation of Syndrome of Internal Block of Static Blood in Helicobacter pylori-Related Gastric Diseases.

Cyclooxygenase-2 (COX-2) is an inducible enzyme stimulated by various inflammatory factors (IFs). Chronic gastritis is a classic model of "inflammation-cancer transformation" and Helicobacter pylori-related gastric diseases (HPGD) are specific ones of this model. Traditional Chinese Medicine (TCM) syndromes could play a predictive role in gastric histopathological evolution. To search for early warning evidence about "inflammation-cancer transformation," this study is about to explore interaction of COX-2 with Helicobacter pylori (Hp) in HPGD with different TCM syndromes. All included subjects underwent endoscopy and biopsy. Hp infection was detected by rapid urease test and methylene blue staining. Histopathological characteristics and COX-2 expression in gastric mucosa (GM) were, respectively, observed by hematoxylin-eosin and Elivision™ plus. SPSS 18.0 and Stata 11.0 statistical software packages were used for statistical analysis. Results of immunohistochemical staining in this study showed COX-2 expression in Hp-positive patients was stronger than that in Hp-negative ones. Spearman' analysis indicated that degrees of both Hp infection and COX-2 expression were positively correlated with those of gastric inflammation and inflammatory activity. Compared with the relative normal group, both severe dysplasia group and gastric carcinoma group had more severe Hp infection and COX-2 expression. Compared with the nonsyndrome, syndrome of internal block of static blood (IBSB) had higher scores in semiquantitative analysis of COX-2 protein expression among TCM groups. Moreover, multivariate logistics regression analysis suggested that patients with Hp infection could increase the risk of IBSB. These results indicated that COX-2 interacting with Hp could play an important role in transforming gastric chronic nonresolving inflammation into carcinoma in subjects with HPGD, as well as inducing the formation of IBSB. HPGD together with IBSB could be an early warning evidence for GM with histopathological evolution from benign to malignant.

Efficacy of traditional Chinese Medicine for gastric precancerous lesion: A meta-analysis of randomized controlled trials.

OBJECTIVE: To evaluate efficacy of traditional Chinese medicine (TCM) for gastric precancerous lesion (GPL). METHOD: Literature retrieval was conducted in seven databases from their inception through Dec. 24th, 2018. The Cochrane collaboration, Review Manager (RevMan5.3) and GRADE profiler software were conducted for this meta-analysis. RESULTS: In primary outcomes, results of meta-analysis showed that TCM had superior to current routine pharmacotherapy (RP) in clinical efficacy, Helicobacter pylori (Hp) eradication rate, efficacy under endoscopy, and TCM syndrome efficacy. Meanwhile, no potential publication bias was detected by Begg's and Egger's tests. In secondary outcomes, compared with control groups, experimental groups were more positive effects on improvement of stomach distention, stomachache, and heartburn. CONCLUSION: Our findings indicated that TCM could have positive effects on GPL. However, further standardized RCTs of rigorous design should be required to obtain more forceful evidence.

Efficacy of Jianpi Liqi therapy for functional dyspepsia: A meta-analysis of randomized, positive medicine-controlled trials.

BACKGROUND: We performed this meta-analysis to assess the efficacy and safety of Jianpi Liqi therapy (JLT), a traditional Chinese medicine therapy, in treating functional dyspepsia (FD). METHODS: We systematically searched 13 databases from their inception to 15th, May 2019. Eligible studies were randomized controlled trials (RCTs) that compared JLT medicine with conventional pharmacotherapy (CP) in treating patients with FD. Cochrane Collaboration tool, Review Manager 5.3 and STATA 11.0, GRADE profiler 3.6 were used for evaluating risk of bias, analyzing, and assessing quality of evidence respectively. RESULTS: After exclusions, 15 RCTs including a total of 1451 participants were included for analysis. We found evidence that JLT had better efficacy than CP (domperidone, omeprazole, esomeprazole, mosapride, lansoprazole, compound digestive enzymes, lactasin tablets) for FD (OR 0.34; 95% CI 0.26, 0.45; P < .00001). Moreover, JLT had more improvement on symptoms including abdominal pain, abdominal distention, early satiety, belching, poor appetite, and fatigue compared with CP. In addition, serious adverse events were not observed in treatment courses. CONCLUSION: This meta-analysis suggested that JLT appears to have better efficacy in treating FD compared with CP. It may be an effective and safe therapy option for patients with FD. Though, more large-sample and strictly designed RCTs are needed to confirm our findings.PROSPERO registration number: CRD42019133241.

The Therapeutic Role of Xenobiotic Nuclear Receptors Against Metabolic Syndrome.

BACKGROUND: Diabetes, with an increased prevalence and various progressive complications, has become a significant global health challenge. The concrete mechanisms responsible for the development of diabetes still remain incompletely unknown, although substantial researches have been conducted to search for the effective therapeutic targets. This review aims to reveal the novel roles of Xenobiotic Nuclear Receptors (XNRs), including the Peroxisome Proliferator-Activated Receptor (PPAR), the Farnesoid X Receptor (FXR), the Liver X Receptor (LXR), the Pregnane X Receptor (PXR) and the Constitutive Androstane Receptor (CAR), in the development of diabetes and provide potential strategies for research and treatment of metabolic diseases. METHODS: We retrieved a large number of original data about these five XNRs and organized to focus on their recently discovered functions in diabetes and its complications. RESULTS: Increasing evidences have suggested that PPAR, FXR, LXR ,PXR and CAR are involved in the development of diabetes and its complications through different mechanisms, including the regulation of glucose and lipid metabolism, insulin and inflammation response and related others. CONCLUSION: PPAR, FXR, LXR, PXR, and CAR, as the receptors for numerous natural or synthetic compounds, may be the most effective therapeutic targets in the treatment of metabolic diseases.

The Role of E-cadherin in Helicobacter pylori-Related Gastric Diseases.

BACKGROUND: Helicobacter pylori (H. pylori)-related gastric diseases are a series of gastric mucosal disorders associated with H. pylori infection. Gastric cancer (GC) is widely believed to evolve from gastritis and gastric ulcer. As an important adhesion molecule of epithelial cells, E-cadherin plays a key role in the development of gastric diseases. In this review, we aim to seek the characteristic of E-cadherin expression at different stages of gastric diseases. METHODS: We searched plenty of databases for research literature about E-cadherin expression in H. pylori-related gastric diseases, and reviewed the relationship of E-cadherin and H. pylori, and the role of E-cadherin at different stages of gastric diseases. RESULTS: H. pylori was shown to decrease E-cadherin expression by various ways in vitro, while most of clinical studies have not found the relationship between H. pylori and E-cadherin expression. It is defined that poor outcome of GC is related to loss expression of E-cadherin, but it is still unclear when qualitative change of E-cadherin expression in gastric mucosa emerges. CONCLUSION: Expression level of E-cadherin in gastric cells may be a consequence of injury factors and body's selfrepairing ability. More studies on E-cadherin expression in gastric mucosa with precancerous lesions need to be performed, which may be potential and useful for early detection, prevention and treatment of GC.

Regulation of Intestinal Epithelial Barrier Function by Long Noncoding RNA uc.173 through Interaction with MicroRNA 29b.

The mammalian intestinal epithelium establishes a selectively permeable barrier that supports nutrient absorption and prevents intrusion by noxious luminal substances and microbiota. The effectiveness and integrity of the barrier function are tightly regulated via well-controlled mechanisms. Long noncoding RNAs transcribed from ultraconserved regions (T-UCRs) control diverse cellular processes, but their roles in the regulation of gut permeability remain largely unknown. Here we report that the T-UCR uc.173 enhances intestinal epithelial barrier function by antagonizing microRNA 29b (miR-29b). Decreasing the levels of uc.173 by gene silencing led to dysfunction of the intestinal epithelial barrier in cultured cells and increased the vulnerability of the gut barrier to septic stress in mice. uc.173 specifically stimulated translation of the tight junction (TJ) claudin-1 (CLDN1) by associating with miR-29b rather than by binding directly to CLDN1 mRNA. uc.173 acted as a natural decoy RNA for miR-29b, which interacts with CLDN1 mRNA via the 3' untranslated region and represses its translation. Ectopically expressed uc.173 abolished the association of miR-29b with CLDN1 mRNA and restored claudin-1 expression to normal levels in cells overexpressing miR-29b, thus rescuing the barrier function. These results highlight a novel function of uc.173 in controlling gut permeability and define a mechanism by which uc.173 stimulates claudin-1 translation, by decreasing the availability of miR-29b to CLDN1 mRNA.

Efficacy and safety of Modified Tongxie Yaofang in diarrhea-predominant irritable bowel syndrome management: A meta-analysis of randomized, positive medicine-controlled trials.

OBJECTIVE: To systematically evaluate the efficacy and safety of Modified Tongxie Yaofang (M-TXYF) for the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D). METHOD: Electronic databases including PubMed, Springer Link, EMBASE, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature (CBM), Wanfang, and Chinese Scientific Journals Database (VIP) were conducted from their inception through May 11, 2017 without language restrictions. Primary and secondary outcomes were estimated by 95% confidence intervals (CI). RevMan 5.3 and the Cochrane Collaboration's risk of bias tool were analyzed for this meta-analysis. RESULTS: Twenty-three literatures with a total of 1972 patients were included for the meta-analysis. The overall risk of bias evaluation was low. The pooled odds ratio showed that M-TXYF was significantly superior to routine pharmacotherapies (RP) in clinical therapeutic efficacy (OR 4.04, 95% CI 3.09, 5.27, P < 0.00001, therapeutic gain = 17.6%, number needed to treat (NNT) = 5.7). Moreover, compared with RP, M-TXYF showed that it can significantly reduce the scores of abdominal pain (standardized mean difference (SMD) -1.27; 95% CI -1.99, -0.56; P = 0.0005), abdominal distention (SMD -0.37; 95% CI -0.73, -0.01; P = 0.09), diarrhea (SMD -1.10; 95% CI -1.95, -0.25; P = 0.01), and frequency of defecation (SMD -1.42; 95% CI -2.19, -0.65; P = 0.0003). The differences of the adverse events between experiment and control groups had no statistical significance. CONCLUSION: This meta-analysis indicated that M-TXYF could be a promising Chinese herbal formula in treating IBS-D. However, considering the lack of higher quality of randomized controlled trials (RCTs), highly believable evidences should be required.

Systematic review and meta-analysis of traditional Chinese medicine in the treatment of constipation-predominant irritable bowel syndrome.

AIM: This meta-analysis analyzed the efficacy and safety of traditional Chinese medicine (TCM) for the treatment of irritable bowel syndrome with constipation (IBS-C). METHODS: We searched seven electronic databases for randomized controlled trials investigating the efficacy of TCM in the treatment of IBS-C. The search period was from inception to June 1, 2017. Eligible RCTs compared TCM with cisapride and mosapride. Article quality was evaluated with the Cochrane Risk Bias Tool in the Cochrane Handbook by two independent reviewers. Begg's test was performed to evaluate publication bias. Review Manager 5.3 and Stata 12.0 were used for analyses. RESULTS: Eleven eligible studies comprising a total of 906 participants were identified. In the primary outcome, TCM showed significant improvement in overall clinical efficacy compared with cisapride and mosapride (odds ratio [OR] = 4.00; 95% confidence interval [CI]: 2.74,5.84; P < 0.00001). In terms of secondary outcomes, TCM significantly alleviated abdominal pain (OR = 5.69; 95% CI: 2.35, 13.78; P = 0.0001), defecation frequency (OR = 4.38; 95% CI: 1.93, 9.93. P = 0.0004), and stool form (OR = 4.96; 95% CI: 2.11, 11.65; P = 0.0002) in the treatment group as compared to the control group. A lower recurrence rate was associated with TCM as compared to cisapride and mosapride (OR = 0.15; 95% CI: 0.08, 0.27; P < 0.00001). No adverse effects were observed during TCM treatment. CONCLUSIONS: TCM showed greater improvement in terms of clinical efficacy in the treatment of IBS-C than cisapride and mosapride, although it was not possible to draw a definitive conclusion due to the small sample size, high risk, and low quality of the studies. Large multi-center and long-term high-quality randomized control trials are needed.

The efficacy of Jianpi Yiqi therapy for chronic atrophic gastritis: A systematic review and meta-analysis.

Jianpi Yiqi therapy (JYT) is a classical therapy in treating chronic atrophic gastritis (CAG), but the clinical effects of it are still contentious. The purpose of this article is to evaluate the efficacy and safety of JYT for CAG. Seven electronic databases including PubMed, Embase, Springer Link, CNKI (China National Knowledge Infrastructure), VIP (Chinese Scientific Journals Database), Wan-fang database, and CBM (Chinese Biomedicine Database) were searched from their inception to November 1, 2016. 13 randomized controlled trials (RCTs) with a total of 1119 participants were identified for analysis. Meta-analyses demonstrated that both JYT (RR 1.41; 95% CI 1.27, 1.57; P < 0.00001) and JYT + western medicine (RR 1.27; 95% CI 1.17, 1.38; P < 0.00001) were more efficacious than only western medicine. Furthermore, JYT had potential improvement on traditional Chinese medicine (TCM) symptoms scores such as stomachache, stomach distention, belching, fatigue, et al. In addition, no serious adverse events were reported in the selected trials. The Cochrane Collaboration's risk of bias tool was evaluated for the weaknesses of methodological quality, while the quality level of Grades of Recommendations Assessment Development and Evaluation (GRADE) evidence classification indicated "Very low". This meta-analysis indicates that JYT may have potential effects on the treatment of patients with CAG. However, due to limitations of methodological quality and small sample size of the included studies, further standardized research of rigorous design should be needed.

Efficacy and Safety of Modified Banxia Xiexin Decoction (Pinellia Decoction for Draining the Heart) for Gastroesophageal Reflux Disease in Adults: A Systematic Review and Meta-Analysis.

Modified Banxia Xiexin decoction (MBXD) is a classical Chinese herbal formula in treating gastroesophageal reflux disease (GERD) for long time, but the efficacy of it is still controversial. This study is to evaluate the efficacy and safety of MBXD for the treatment of GERD in adults. The search strategy was carried out for publications in seven electronic databases. RevMan software version 5.3 and the Cochrane Collaboration's risk of bias tool were performed for this review. Twelve RCTs were included for the analysis. The results of overall clinical efficacy and efficacy under gastroscope demonstrated that MBXD was superior to conventional western medicine. Meanwhile, the results of subgroup analysis showed clinical heterogeneity between the two groups. However, there was no statistically significant difference in acid regurgitation between the two groups. But in the improvement of heartburn and sternalgia, the results showed statistically significant differences for the comparison between two groups. In addition, the adverse reactions of the experiment groups were not different from those of the control groups. This systematic review indicates that MBXD may have potential effects on the treatment of patients with GERD. But because the evidence of methodological quality and sample sizes is weak, further standardized researches are required.

Interleukin-12 and interferon-γ acting on damp-heat of spleen- stomach syndrome triggered by Helicobacter pylori.

OBJECTIVE: To investigate the expression of and interleukin-12 (IL-12) and interferon-γ (IFN-γ) in relation to the pathology of damp-heat of spleen-stomach syndrome (DHSS) induced by Helicobacter pylori (H. pylori) infection. METHODS: In total, 114 individual gastric mucosal specimens including 83 DHSS, 19 spleen-qi deficiency syndrome (SQD) and 12 from healthy volunteers (CON) were collected by gastroscopy. To explore the relationship between the two syndromes and H. pylori infection, individual samples were tested using rapid urease and methylene blue tests. Hematoxylin and eosin stained sections were examined to grade for the degree of inflammation and inflammatory activity, and expression of IL-12 and IFN-γ was investigated by immunohistochemistry. RESULTS: Statistically significant differences in the degree of inflammation and inflammatory activity were observed between the groups of specimens: DHSS, SQD and CON (P < 0.05). Additionally, greater intestinal metaplasia (IM) and dysplasia were observed in the DHSS group, especially those with H. pylori infection. Expression of both IFN-γ; and IL-12 was higher in DHSS samples infected with H. pylori than in uninfected samples and in the CON (P < 0.05) but not in the SQD (P > 0.05) groups. Intriguingly, in gastric specimens exhibiting IM and dysplasia, IL-12 translocated from the nucleus into the cytoplasm. CONCLUSION: Our findings suggest that IL-12 and IFN-γ are involved in DHSS pathology, but not in SQD, acting as healthy-Qi. DHSS is not just the consequence of those two cytokines but results from the cross-talk between a number of cytokines and/or other proteins, which may warrant further investigation in DHSS patients infected with H. pylori.