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"Jian-min Si"
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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. By improving retinoic acid synthesis, a novel probiotic L. intestinalis exerts a protective effect against colitis. Retinoic acid triggers epithelial gene alteration, including SAA1, SAA2, and C/EBPA, to downregulate RORγt+ Th17 cells. L. intestinalis and its associated metabolite, retinoic acid, have potential therapeutic effects for suppressing colonic inflammation.
Journal Article
HOTAIR induces the ubiquitination of Runx3 by interacting with Mex3b and enhances the invasion of gastric cancer cells
BackgroundLong 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.MethodsRPISeq 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.ResultsWe 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.ConclusionsThese results uncovered the novel interaction between HOTAIR and Runx3, and provided potential therapeutic targets on the metastasis of gastric cancer.
Journal Article
Resveratrol Improves Brain-Gut Axis by Regulation of 5-HT-Dependent Signaling in the Rat Model of Irritable Bowel Syndrome
Irritable bowel syndrome (IBS) is at high risk of co-morbid depression and anxiety, which reduces patients' quality of life and increases the burden of health care costs. However, the pathophysiological mechanisms responsible for IBS still remain unknown. This study investigated the effects of resveratrol on stress-related depression, anxiety, intestinal and visceral dysfunction in rat model of IBS. Rats received chronic acute combining stress (CACS) for 22 days exhibited depression/anxiety-like behavior, visceral hypersensitivity and altered intestinal motility, as measured by the forced swimming, marble bury, abdominal withdrawal reflex (AWR) and intestinal tract motility (ITM) tests. These abnormalities were accompanied by reduced 5-hydroxytryptamine (5-HT) level in the hippocampus and increased 5-HT expression in the gut (ileum and colon) after CACS. Chronic treatment of IBS rats with resveratrol dose-dependently normalized CACS-induced both central nervous and peripheral dysfunction, which were consistent with its differentially regulating 5-HT contents in the brain and intestine. Pretreatment with the 5-HT
receptor antagonist NAN-190 hydrobromide (NAN-190) prevented such effects. While sub-threshold of 5-HT
receptor agonist 8-OH-DPAT potentiated the effects of low dose of resveratrol (10 mg/kg) on CACS-related behavioral abnormalities. Furthermore, resveratrol markedly increased PKA, p-cAMP-response element binding protein (p-CREB) and brain derived neurotrophic factor (BDNF) expression in the hippocampus of IBS rats, while decreased PKA, pCREB and BDNF levels were found in the ileum and colon. These effects were prevented by NAN-190, which were consistent with the behavioral changes. The present results suggested that resveratrol improved anti-IBS-like effects on depression, anxiety, visceral hypersensitivity and intestinal motility abnormality through regulating 5-HT
-dependent PKA-CREB-BDNF signaling in the brain-gut axis.
Journal Article
trans-Resveratrol Ameliorates Stress-Induced Irritable Bowel Syndrome-Like Behaviors by Regulation of Brain-Gut Axis
Irritable bowel syndrome (IBS) is a functional disorder characterized by abdominal pain and abnormalities in defecation associated with psychiatric disorders such as depression and anxiety due to the dysfunction of brain-gut axis. This study aims to determine whether
-Resveratrol affects chronic-acute combined stress (CACS)-induced IBS-like symptoms including depression, anxiety and intestinal dysfunction.
ICR male mice were exposed to the CACS for 3 weeks.
-Resveratrol were administrated daily (2.5, 5, and 10 mg/kg, i.g.) 30 min before CACS. Behavioral tests were performed to evaluate the treatment effects of
-Resveratrol on IBS. Hippocampus tissues were collected and processed Golgi staining and immuno-blot analysis. Ileum and colon tissues were collected and processed Hematoxylin and Eosin staining and immuno-blot analysis.
Administration with
-Resveratrol before CACS for 3 weeks significantly reversed CACS-induced depression- and anxiety-like behaviors and intestinal dysfunction in mice, which implied a crucial role of
-Resveratrol in treatment of IBS-like disorder. Furthermore,
-Resveratrol improved hippocampal neuronal remodeling, protected ileal and colonic epithelial barrier structure against CACS insults. The further study suggested that
-Resveratrol normalized phosphodiesterases 4A (PDE4A) expression and CREB-BDNF signaling that were disturbed by CACS. The increased pCREB and BDNF expression in the hippocampus were found, while decreased pCREB and BDNF levels were observed after treatment with
-Resveratrol.
The dual effects of
-Resveratrol on stress-induced psychiatric and intestinal dysfunction may be related to normalization of PDE4A expression and subsequent pCREB-BDNF signaling in the hippocampus, ileum and colon.
Journal Article
Parkin represses 6-hydroxydopamine-induced apoptosis via stabilizing scaffold protein p62 in PC12 cells
Aim： Parkin has been shown to exert protective effects against 6-hydroxydopamine （6-OHDA）-induced neurotoxicity in different models of Parkinson disease. In the present study we investigated the molecular mechanisms underlying the neuroprotective action of parkin in vitro. Methods. HEK293, HeLa and PC12 cells were transfected with parkin, parkin mutants, p62 or si-p62. Protein expression and ubiquitination were assessed using immunoblot analysis. Immunoprecipitation assay was performed to identify the interaction between parkin and scaffold protein p62. PC12 and SH-SY5Y cells were treated with 6-OHDA （200 pmol/L）, and cell apoptosis was detected using PI and Hoechst staining. Results： In HEK293 cells co-transfected with parkin and p62, parkin was co-immunoprecipitated with p62, and parkin overexpression increased p62 protein levels. In parkin-deficient HeLa cells, transfection with wild-type pakin, but not with ligase activity-deficient pakin mutants, significantly increased p62 levels, suggesting that parkin stabilized p62 through its E3 ligase activity. Transfection with parkin or p62 significantly repressed ERK1/2 phosphorylation in HeLa cells, but transfection with parkin did not repress ERK1/2 phosphorylation in p62-knockdown HeLa cells, suggesting that p62 was involved in parkin-induced inhibition on ERK1/2 phosphorylation. Overexpression of parkin or p62 significantly repressed 6-OHDA-induced ERK1/2 phosphorylation in PC12 cells, and parkin overexpression inhibited 6-OHDA-induced apoptosis in PC12 and SH-SY5Y cells. Conclusion： Parkin protects PC12 cells against 6-OHDA-induced apoptosis via ubiquitinating and stabilizing scaffold protein p62, and repressing ERK1/2 activation.
Journal Article
Converting a Microarray Signature into a Diagnostic Test: A Trial of Custom 74 Gene Array for Clarification and Prediction the Prognosis of Gastric Cancer
Gastric cancer (GC) is associated with high mortality rates and an unfavorable prognosis at advanced stages. In addition, there are no effective methods for diagnosing gastric cancer at an early stage or for predicting the outcome for the purpose of selecting patient-specific treatment options. Therefore, it is important to investigate new methods for GC diagnosis.
To facilitate its use in a diagnostic setting, a group of 74 genes with diagnostic and prognostic information was translated into a customized microarray containing a reduced set of 1,042 probes suitable for high throughput processing. In this report, we demonstrate for the first time that the custom mini-array can be used as a reliable diagnostic tool in gastric cancer. With an AUC value of 0.565 (95% CI 0.305-0.825) indicating a perfect test, the sensitivity and specificity of diagnosis from the ROC curve were calculated to be 70% and 80%, respectively.
The data clearly demonstrate the reproducibility and robustness of the small custom-made microarray. The array is an excellent tool for classifying and predicting the outcome of disease in gastric cancer patients.
Journal Article
Two-tube method for treatment of spontaneous esophageal rupture and concomitant mediastinal infection
Objective
Spontaneous esophageal rupture (SER) is a rare but life-threatening condition with high mortality. The prognosis of patients with SER treated with surgical intervention or the traditional “three-tube” method is controversial. Thus, the aim of this study was to evaluate the clinical efficacy, feasibility, and safety of a new “two-tube” method involving a trans-fistula drainage tube and a three-lumen jejunal feeding tube for the treatment of SER without concomitant pleural rupture.
Methods
From January 2007 to June 2016, patients with SER and managed with the “two-tube” method or other methods were retrospectively analyzed. Data collected included initial presentation, procedure time, duration of treatment, numbers of patients with eventual healing of leaks, and complications.
Results
The average procedure time for the “two-tube” method was 22.1 ± 5.5 minutes. In comparison with the control method, the “two-tube” method had a similar diagnosis time (3.6 ± 1.4 vs. 3.4 ± 1.4 days) but a significantly higher successful closure rate (94.4% vs. 63.6%) and shorter treatment time (38.2 ± 5.6 vs. 53.6 ± 16.9 days). No complications associated with performance of the “two-tube” method occurred.
Conclusion
The “two-tube” method is an effective and safe approach for patients with SER.
Journal Article
Endoscopic submucosal dissection for early gastric cancer in elderly patients: a meta-analysis
Background
The effectiveness of endoscopic submucosal dissection (ESD) has been increasingly reported. However, studies addressing the safety and application value of ESD in elderly patients with early gastric cancer (EGC) were still lacking. This meta-analysis was intended to evaluate the feasibility and safety of ESD in elderly patients with EGC.
Methods
A systematic search was conducted in PubMed, EBSCO, Cochrane Library, EMBASE, and Web of Science. Studies were screened out if data of elderly and non-elderly gastric cancer patients were reported separately. The qualities of included studies were assessed using Newcastle-Ottawa Quality Assessment Scale. The pooled odd ratios (ORs) with 95 % confidence intervals (CIs) were calculated. Statistical analysis was conducted using the Review Manager 5.2 (Cochrane Collaboration, Oxford, UK).
Results
Nine studies (eight in Japan, one in China), including a total of 30,100 lesions, met the inclusion criteria. The “en bloc” and histological complete resection rates of the elderly and non-elderly groups were similar [OR, 0.98, 95 % CI, 0.56 to 1.71;
P
= 0.93 and OR, 0.79, 95 % CI, 0.58 to 1.07;
P
= 0.13, respectively]. As for procedure-related complications, similar perforation rates [OR, 1.19, 95 % CI, 0.94 to 1.51;
P
= 0.15], and bleeding rates [OR, 1.13, 95 % CI, 0.83 to 1.56);
P
= 0.43] between the elderly and non-elderly groups were observed. Whereas, the elderly patients had a higher procedure-related pneumonia rate compared with non-elderly ones [OR, 2.18, 95 % CI, 1.55 to 3.08;
P
< 0.01].
Conclusions
The ESD procedure appears to be a safe technique in elderly patients with EGC while appropriate approach should be taken to avoid procedure-related pneumonia.
Journal Article
A probiotic treatment containing Lactobacillus, Bifidobacterium and Enterococcus improves IBS symptoms in an open label trial
Objective： To evaluate the efficacy and safety of live combined Bifidobacterium, Lactobacillus and Enterococcus capsules in treatment of irritable bowel syndrome, Methods： Eighty-fve patients [male 32, female 53; age （45.31±11,72） years] were given live combined Bifidobacterium, Lactobacillus and Enterococcus capsules 1260 mg/d t.i.d. ×4 weeks. Syndrome scales were used to evaluate the efficacy in gastrointestinal syndrome. Fecal flora was also measured before and after the treatment. Six bacteria were cultured and the colony forming units were counted in stool. SPSS was used for data analysis. Results： Seventy-four patients finished the follow-up. No side-effect was found. For treatment of irritable bowel syndrome, the effective rate of live combined Bifidobacterium, Lactobacillus and Enterococcus capsules was 56.8% in the second week, 74.3% in the fourth week and 73.0% in the sixth week. Single symptom was improved, especially in abdominal pain and stool character. The probiotica containing live combined Bifidobacterium, Lactobacillus and Enterococcus could increase bifidobacterium count （P〈0.01） and lactobacillus count （P〈0.05）; decrease bacteroides count （P〈0.05） and enterococci count （P〈0.01）; No obvious changes were observed in clostridium diffcile colonitis and enterobacteriaceae （P〉0.05）. Conclusion： The result of the study indicated that the administration of live combined Bifidobacterium, Lactobacillus and Enterococcus improved the symptom of irritable bowel syndrome and that there was a gradual increase of this effect. Thereafter conditions remained stable for 2 weeks. That improvement may be associated with alterations in gastrointestinal flora.
Journal Article