Inhibition of METTL5 improves preimplantation development of mouse somatic cell nuclear transfer embryos.

In brief: Several factors affect the reprogramming efficiency of nuclear transfer embryos. This study shows that inhibiting 18S rRNA m6A methyltransferase METTL5 during nuclear transfer can improve the developmental rate of nuclear transfer embryos. Abstract: N6-methyladenosine (m6A) is one of the most important epigenetic modifications in eukaryotic RNAs, which regulates development and diseases. It is identified by several proteins. Methyltransferase-like 5 (METTL5), an enzyme that methylates 18S rRNA m6A, controls the translation of proteins and regulates pluripotency in embryonic stem cells. However, the functions of METTL5 in embryonic development have not been explored. Here, we found that Mettl5 was upregulated in somatic cell nuclear transfer (SCNT) embryos compared with normal fertilized embryos. Therefore, we hypothesized that METTL5 knockdown during the early stage of SCNT would improve the developmental rate of SCNT embryos. Notably, injection of Mettl5 siRNA (si-Mettl5) into enucleated oocytes during nuclear transfer increased the rate of development and the number of cells in blastocysts. Moreover, inhibition of METTL5 reduced the activity of phosphorylated ribosomal protein S6, decreased the levels of the repressive histone modification H3K27me3 and increased the expression of activating histone modifications H3K27ac and H3K4me3 and mRNA levels of some 2-cell-specific genes. These results expand our understanding of the role of METTL5 in early embryonic development and provide a novel idea for improving the efficiency of nuclear transfer cloning.

[Effect of baicalin on signal transduction and activating transcription factor expression in ulcerative colitis patients].

OBJECTIVE: To explore the intervention of baicalin on signal transduction and activating transcription factor expression of ulcerative colitis (UC) patients. METHODS: Recruited were UC patients at Outpatient Department of Digestive Disease, Inpatient Department of Digestive Disease, Center for Digestive Endoscopy of College City Branch, Guangdong Provincial Hospital of Traditional Chinese Medicine, and Southern Hospital affiliated to Southern Medical University from June 2010 to January 2011. They were assigned to the UC group (33 cases) and the diarrhea-predominant irritable bowel syndrome (IBS-D) group (30 cases). Another 30 healthy subjects were recruited as a healthy control group. Peripheral blood mononuclear cells (PBMCs) in vitro intervened by different concentrations baicalin were taken from UC patients. IL23R gene expressions in vitro intervened by different concentrations baicalin were detected using Q-PCR. Expressions of signal transducer and activator of transcription 4 (STAT4) , STAT6, phosphorylated-STAT4 (p-STAT4), and p-STAT6 were detected using Western blot. Serum levels of IFN-γ, IL-4, IL-6, and IL-10 were measured by ELISA. Effects of different concentrations baicalin on expressions of PBMCs, and levels of IFN-γ, IL-4, IL-10 of UC patients were also detected. RESULTS: Compared with the negative control group, 40 µmol baicalin obviously decreased IL23R gene expression of UC patients (P <0. 01). Compared with the healthy control group and the IBS-D group, p-STAT4/STAT4 ratios increased, p-STAT6/STAT6 ratios decreased, levels of IFN-γ, IL-4, IL-10 all increased in the US group (all P <0. 05). Compared with the negative control, 5 and 10 µmol baicalin groups, 20 and 40 moL baicalin obviously decreased p-STAT4/STAT4 ratios (all P <0. 05); 20 and 40 µmoL baicalin obviously increased p-STAT6/STAT6 ratios (all P <0. 05); 20 and 40 µmoL baicalin obviously lowered levels of IFN-γ and IL-4, and elevated IL-10 levels (all P <0. 05). CONCLUSION: 40 µmoL baicalin could in vitro inhibit p-STAT4/STAT4 ratios, adjust p-STAT6/STAT6 ratios and related cytokines, thereby balancing the immunity and relieving inflammatory reactions of UC.

A Spatially Stable Crystal-Particle Gel to Trap Patchouli Oil for Efficient Colonic Drug Delivery.

Patchouli oil has exhibited remarkable efficacy in the treatment of colitis. However, its volatility and potential irritancy are often drawbacks when extensively used in clinical applications. Oil gel is a semisolid and thermoreversible system that has received extensive interest for its solubility enhancement, inhibition of bioactive component recrystallization, and the facilitation of controlled bioactive release. Therefore, we present a strategy to develop an oil gel formulation that addresses this multifaceted problem. Notably, a patchouli oil gel formulation was designed to solidify and trap patchouli oil into a spatially stable crystal-particle structure and colonic released delivery, which has an advantage of the stable structure and viscosity. The patchouli oil gel treatment of zebrafish with colitis improved goblet cells and decreased macrophages. Additionally, patchouli oil gel showed superior advantages for restoring the tissue barrier. Furthermore, our investigative efforts unveiled patchouli oil's influence on TRP channels, providing evidence for its potential role in mechanisms of anti-inflammatory action. While the journey continues, these preliminary revelations provide a robust foundation for considering the adoption of patchouli oil gel as a pragmatic intervention for managing colitis.

QingChang-XiaoPi decoction ameliorates intestinal inflammation of ulcerative colitis by regulating the pathogenicity of Th17 cells.

BACKGROUND: QingChang-XiaoPi Decoction (QCXPY), a Chinese herbal prescription, has been employed in the treatment of ulcerative colitis (UC) in China. However, its molecular mechanism of action in UC remains unclear. PURPOSE: To elucidate the therapeutic effects of QCXPY against UC and reveal its mechanism of action. STUDY DESIGN: We conducted a single-arm observation to evaluate the clinical efficacy of QCXPY in patients with mild-to-moderate UC. Inclusion and exclusion criteria were established to ensure the eligibility of participants, with a focus on excluding patients with specific conditions or complications that could confound the results. METHODS: The expression of inflammatory factors in patients' serum was detected using a Luminex assay. The main components of QCXPY were identified using UHPLC-Q-TOF-MS. Network pharmacology was employed to predict potential therapeutic targets and their mechanisms of action. The efficacy of QCXPY was evaluated using a dextran sulfate sodium (DSS)-induced mouse model. Disease activity index (DAI), histopathological score, cytokine detection by ELISA, T-helper 17 (Th17) cell proportion by flow cytometry, expression of the IL-23/IL-17 axis, and changes in the levels of its downstream effectors were detected by immunohistochemistry, immunofluorescence, and western blotting. RESULTS: QCXPY could alleviate the symptoms of diarrhea, abdominal pain, abdominal distension, and purulent stool in patients with mild-to-moderate UC. Moreover, it reduced the expression of IL-6, IL-17, and IL-23 in serum; alleviated DSS-induced experimental colitis in mice; reduced DAI, pathological scores, and the expressions of IL-6, IL-17, and IL-23 in colon tissue; and decreased the proportion of pathogenic Th17 cells and the expression of STAT3 and phospho-STAT3. CONCLUSION: This study confirmed for the first time that QCXPY could alleviate intestinal symptoms, reduce the levels of serum inflammatory factors, and improve the quality of life of patients with mild-to-moderate UC. Its mechanism of action may involve reducing the secretion of inflammatory cytokines, moderating the pathogenicity of Th17 cells, and inhibiting STAT3 phosphorylation, thereby alleviating intestinal inflammation in UC.

The function of the gut microbiota-bile acid-TGR5 axis in diarrhea-predominant irritable bowel syndrome.

Imbalanced gut microbiota (GM) and abnormal fecal bile acid (BA) are thought to be the key factors for diarrhea-predominant irritable bowel syndrome (IBS-D), but the underlying mechanism remains unclear. Herein, we explore the influence of the GM-BA-Takeda G-protein-coupled receptor 5 (TGR5) axis on IBS-D. Twenty-five IBS-D patients and fifteen healthy controls were recruited to perform BA-related metabolic and metagenomic analyses. Further, the microbiota-humanized IBS-D rat model was established by fecal microbial transplantation (FMT) to investigate the GM-BA-TGR5 axis effects on the colonic barrier and visceral hypersensitivity (VH) in IBS-D. Finally, we used chenodeoxycholic acid (CDCA), an important BA screened out by metabolome, to evaluate whether it affected diarrhea and VH via the TGR5 pathway. Clinical research showed that GM associated with bile salt hydrolase (BSH) activity such as Bacteroides ovatus was markedly reduced in the GM of IBS-D, accompanied by elevated total and primary BA levels. Moreover, we found that CDCA not only was increased as the most important primary BA in IBS-D patients but also could induce VH through upregulating TGR5 in the colon and ileum of normal rats. TGR5 inhibitor could reverse the phenotype, depression-like behaviors, pathological change, and level of fecal BSH in a microbiota-humanized IBS-D rat model. Our findings proved that human-associated FMT could successfully induce the IBS-D rat model, and the imbalanced GM-BA-TGR5 axis may promote colonic mucosal barrier dysfunction and enhance VH in IBS-D. IMPORTANCE: Visceral hypersensitivity and intestinal mucosal barrier damage are important factors that cause abnormal brain-gut interaction in diarrhea-predominant irritable bowel syndrome (IBS-D). Recently, it was found that the imbalance of the gut microbiota-bile acid axis is closely related to them. Therefore, understanding the structure and function of the gut microbiota and bile acids and the underlying mechanisms by which they shape visceral hypersensitivity and mucosal barrier damage in IBS-D is critical. An examination of intestinal feces from IBS-D patients revealed that alterations in gut microbiota and bile acid metabolism underlie IBS-D and symptom onset. We also expanded beyond existing knowledge of well-studied gut microbiota and bile acid and found that Bacteroides ovatus and chenodeoxycholic acid may be potential bacteria and bile acid involved in the pathogenesis of IBS-D. Moreover, our data integration reveals the influence of the microbiota-bile acid-TGR5 axis on barrier function and visceral hypersensitivity.

Biomarkers prediction and immune landscape in ulcerative colitis: Findings based on bioinformatics and machine learning.

BACKGROUND: Ulcerative colitis (UC) presents diagnostic and therapeutic difficulties. The primary objective of this study is to identify efficacious biomarkers for diagnosis and treatment, as well as acquire a deeper understanding of the immuneological characteristics associated with the disease. METHODS: Datasets relating to UC were obtained from GEO database. Among these, three datasets were merged to create a metadata for bioinformatics analysis and machine learning. Additionally, one dataset specifically utilized for external validation. Least absolute shrinkage and selection operator (LASSO) and random forest (RF) were employed to screen signature genes. The artificial neural network (ANN) model and receiver operating characteristic (ROC) curve were used to assess the diagnostic performance of signature genes. The single sample gene set enrichment analysis (ssGSEA) was applied to reveal the immune landscape. Finally, the relationship between the signature genes, immune infiltration, and clinical characteristics was investigated through correlation analysis. RESULT: By intersecting the result of LASSO, RF and WGCNA, 8 signature genes were identified, including S100A8, IL-1B, CXCL1, TCN1, MMP10, GREM1, DUOX2 and SLC6A14. The biological progress of this gene mostly encompasses acute inflammatory response, aggregation and chemotaxis of leukocyte, and response to lipopolysaccharide by mediating IL-17 signaling pathway, NF-kappa B signaling pathway, TNF signaling pathway, NOD-like receptor signaling pathway. Immune infiltration analysis shows 25 immune cells are significantly elevated in UC samples. Moreover, these signature genes exhibit a strong correlation with various immune cells and a mild to moderate correlation with the Mayo score. CONCLUSION: S100A8, IL-1B, CXCL1, TCN1, MMP10, GREM1, DUOX2 and SLC6A14 have been identified as credible potential biomarkers for the diagnosis and therapy of UC. The immune response mediated by these signature biomarkers plays a crucial role in the occurrence and advancement of UC by means of the reciprocal interaction between the signature biomarkers and immune-infiltrated cells.

Biological role of long non-coding RNA KCNQ1OT1 in cancer progression.

Long non-coding RNAs (lncRNAs) are a type of RNAs that are more than 200 nucleotides without protein-coding potential. In recent years, more and more attention has been paid to the role of lncRNAs in cancer pathogenesis. LncRNA KCNQ1 overlapping transcript 1 (KCNQ1OT1) is located on chromosome 11p15.5 with a total length of 91 kb and is highly expressed in various malignancies, which is closely related to tumor growth, lymph node metastasis, survival cycle and recurrence rate. In addition, KCNQ1OT1 is involved in the regulation of PI3K/AKT and Wnt/ß-catenin signaling pathways. In this review, the mechanism and related progress of KCNQ1OT1 in different cancers were reviewed. It was found that KCNQ1OT1 can stabilize mRNA expression through sponging miRNA, which not only induced tumor cell proliferation, migration, invasion, drug resistance, epithelial-mesenchymal transition (EMT) and inhibited cell apoptosis in vitro, but also promoted tumor growth and metastasis in vivo. Therefore, as a new biomarker and therapeutic target, KCNQ1OT1 has broad prospects for the diagnosis and treatment of different cancers.

Shenling Baizhu Powder Alleviates TNBS-Induced Colitis in Rats by Improving Intestinal Epithelial Permeability and Inhibiting Inflammation Through the TLR5/MyD88/NF-κB Pathway.

Aim of the study: To evaluate the protective effect and mechanism of shenling baizhu powder (SBP) on TNBS-induced colitis. Methods: Rats were given TNBS to establish the model of colitis and subsequently treated with different doses of SBP or mesalamine (MES). In addition, the expression of the TLR5/MyD88/NF-κB signaling pathway and critical targets of the intestinal mucosal barrier was detected by immunochemical analysis techniques. Results: SBP significantly ameliorated the symptoms of TNBS-induced colitis in rats and reduced the secretion of pro-inflammatory cytokines. SBP could effectively strengthen epithelial barrier integrity in TNBS-induced colitis by increasing the secretion of mucin and tight junction and inhibiting apoptosis. Furthermore, we identified the crucial role of the TLR5/MyD88/NF-κB signaling pathway in exerting the therapeutic effect of SBP. Conclusion: The results of our study suggest that SBP has therapeutic effects on TNBS-induced colitis and potential value in treating and maintaining remission of colitis.

Comparison of five diarrhea-predominant irritable bowel syndrome (IBS-D) rat models in the brain-gut-microbiota axis.

The brain-gut-microbiota (BGM) axis is known to be essential for diarrhea-predominant irritable bowel syndrome (IBS-D). In order to evaluate the effects of IBS-D rat models (the central sensitization model, the peripheral sensitization model and the compound model) on the BGM axis, five models were induced in Wistar rats with 4% acetic acid (AD, dissolved 0.4 ml of AD in 9.6 ml of ultrapure water) + wrap restrain stress (WRS), 4% AD, colorectal distention (CRD), WRS, and neonatal maternal separation (NMS). Abdominal withdrawal reflex (AWR) scale scores and the moisture content of feces (MCF) were evaluated on the day of completing modeling. Body weight was measured every 7 days during modeling. Brain gut peptides, cytokine levels, the activity of spinal cord neurons, intestinal mucosal barrier function, and gut microbiota were determined after induction of IBS-D. We found intervention with 4% AD + WRS, 4% AD, CRD, WRS, and NMS induced a similar course of effects on the BGM axis. Among the five models, AWR scores (60 mmHg, 80 mmHg) were all increased. The levels of 5-hydroxytryptamine, corticotropin-releasing factor, substance P, and calcitonin gene-related protein in serum rapidly increased, whereas that of neuropeptide Y decreased. C-fos in the spinal cord showed increased neuronal activity. The intestinal permeability was increased and the composition and structure of gut microbiota were changed. In conclusion, the five models could cause changes in BGM axis, but the 4% AD + WRS model was closer to the changes BGM axis of post-inflammatory models of IBS-D.

Therapeutic targets and pharmacological mechanisms of Coptidis Rhizoma against ulcerative colitis: Findings of system pharmacology and bioinformatics analysis.

Evidence of the advantages of Coptidis Rhizoma (CR) for the treatment of ulcerative colitis (UC) is accumulating. However, research revealing the targets and molecular mechanisms of CR against UC is scarce. In this research, a bioinformatics analysis was performed to carry out the physicochemical properties and biological activities of phytochemicals in CR and analyze the binding activities, targets, biological functions and mechanisms of CR against UC. This research shows that the CR's key phytochemicals, which are named Coptisine, Berberrubine, Berlambine, Berberine, Epiberberine, Obacunone, Worenine, Quercetin, (R)-Canadine, Magnograndiolide, Palmatine and Moupinamide, have ideal physicochemical properties and bioactivity. A total of 1,904 potential phytochemical targets and 17,995 UC-related targets are identified, and we finally acquire 233 intersection targets between key phytochemicals and disease. A protein-protein interaction network of 233 common targets was constructed; and six hub targets were acquired with a degree greater than or equal to median, namely TP53, HSP90AA1, STAT3, ESR1, MYC, and RELA. The enrichment analysis suggested that the core targets may exert an impact on anti-inflammatory, immunoregulatory, anti-oxidant and anti-fibrosis functions mainly through the PI3K/ART signaling pathway, Th17 differentiation signaling pathway, inflammatory bowel disease signaling pathway, etcetera. Also, a molecular docking analysis shows that the key phytochemicals have strong affinity for binding to the core targets. Finally, the interaction network of CR, phytochemicals, targets, GO functions, KEGG pathways and UC is constructed. This study indicates that the key phytochemicals in CR have superior drug likeness and bioactivity, and the molecular mechanism of key phytochemicals against UC may be via the signaling pathway mentioned above. The potential and critical pharmacological mechanisms provide a direction for future research.

Efficacy and safety of Chinese medicine combined with balloon dilatation vs. balloon dilatation alone for achalasia patients: a systematic review and meta-analysis.

Background: Balloon dilatation is widely used for patients with achalasia; however, the efficacy and safety of Chinese medicine combined with balloon dilatation for achalasia patients is still unclear. Therefore, we conducted a meta-analysis to compare the treatment effectiveness of treatment with Chinese medicine plus balloon dilatation versus balloon dilatation alone for patients with achalasia. Methods: Randomized controlled trials (RCTs) compared the effectiveness of Chinese medicine plus balloon dilatation with balloon dilatation as examined in studies in the PubMed, Springer, Embase, Wiley-Blackwell, Chinese Journal Full-text Database, and the Cochrane library from their inception up to May 2019. The odds ratios (ORs) and weighted mean differences (WMDs) with corresponding 95% confidence intervals (CIs) were used to calculate categories and continuous outcomes using the random-effects model. The inclusion of studies according to the PICOS (participants, interventions, comparisons, outcomes) criteria, the assessment of risk of bias of included studies adhered to the Cochrane criteria guidelines. Results: The initial electronic searches produced 378 records, and 10 RCTs that recruited 504 achalasia patients were included in the final quantitative analysis. Except for other potential biases with moderate to high-risk bias of 20-40%, the other six items had a low-risk bias of 80-90%. Overall, we noted that patients who received the Chinese medicine plus balloon dilatation treatment had a greater incidence of improvement at 1 year (OR: 2.20; 95% CI: 1.45-3.33; P<0.001), and 5 years (OR: 1.83; 95% CI: 1.23-2.74; P=0.003), and reduced the risk of gastroesophageal reflux (OR: 0.42; 95% CI: 0.24-0.76; P=0.004) than patients who underwent balloon dilation only. However, patients who received the Chinese medicine plus balloon dilatation treatment did not have a greater risk of perforation (OR: 0.53; 95% CI: 0.24-1.19; P=0.123) compared with patients undergoing balloon dilation. Finally, Chinese medicine plus balloon dilatation was associated with high esophageal sphincter pressure (WMD: 2.01; 95% CI: 1.19-2.84; P<0.001) compared with patients who underwent balloon dilatation only. Conclusions: Chinese medicine plus balloon dilatation had better effects after treatment than balloon dilatation alone for achalasia patients. Given the risk of bias of included studies, the conclusion should be made with cautions.

Adverse and unconventional reactions related to immune checkpoint inhibitor therapy for cancer.

Immunotherapy is an emerging method for the treatment of cancer. Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block immune checkpoint pathways and release the body's anti-tumor immunity. They consist mainly of antibodies against cytotoxic T lymphocyte associated antigen-4 (CTLA-4), programmed death receptor 1 (PD-1), and programmed death ligand 1 (PD-L1). Although ICI therapy has been shown to be effective at treating cancer, it can also destroy immune tolerance and lead to organ toxicity. These unwanted side effects are known as immune related adverse events (irAEs). ICI treatment can also cause unconventional reactions such as pseudoprogression and hyperprogression. Pseudoprogression looks like an increase in the tumor parenchyma but is actually a temporary inflammation in the tumor; hyperprogression refers to the acceleration of tumor growth after the start of immunotherapy. Understanding the mechanisms of these two phenomena and distinguishing their differences are necessary for the effective prevention and treatment of unconventional reactions.

Biomarkers related to immune checkpoint inhibitors therapy.

Immune checkpoint inhibitors (ICIs) therapy is an emerging cancer treatment. During treatment it is necessary to monitor the patient at all times and respond to any adverse reactions that may occur, such as immune-related adverse events and unconventional reactions. Biomarkers, the biochemical indicators that mark changes in the structure or function of systems, organs, tissues, and cells, may be used to predict and design treatment for such reactions. Anti-tumor immunotherapy biomarkers can be derived from the tumors themselves (e.g. negative regulatory molecules and dynamic changes in genome sequence) or from the immune system (e.g. peripheral blood cell population counts, various cytokines, tumor-infiltrating lymphocytes, and intestinal microbes). The development of biomarkers is important for monitoring the effect of treatment, assessing the patient's response to ICIs, determining adverse reactions, and predicting the direction of disease development. In addition, organ toxicity and systemic events also have an impact on the therapeutic effect of ICIs.

Clinical evidence of acupuncture and moxibustion for irritable bowel syndrome: A systematic review and meta-analysis of randomized controlled trials.

Background: Acupuncture and moxibustion have been widely used in the treatment of Irritable Bowel Syndrome (IBS). But the evidence that acupuncture and moxibustion for IBS reduction of symptom severity and abdominal pain, and improvement of quality of life is scarce. Methods: PubMed, Embase, Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database (VIP), Wanfang Database, China Biomedical Literature Service System (SinoMed), and unpublished sources were searched from inception until June 30, 2022. The quality of RCTs was assessed with the Cochrane Collaboration risk of bias tool. The strength of the evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluation system (GRADE). Trial sequential analysis (TSA) was conducted to determine whether the participants in the included trials had reached optimal information size and whether the cumulative data was adequately powered to evaluate outcomes. Results: A total of 31 RCTs were included. Acupuncture helped reduce the severity of symptoms more than pharmaceutical drugs (MD, -35.45; 95% CI, -48.21 to -22.68; I 2 = 71%). TSA showed the cumulative Z score crossed O'Brien-Fleming alpha-spending significance boundaries. Acupuncture wasn't associated with symptom severity reduction (SMD, 0.03, 95% CI, -0.25 to 0.31, I 2 = 46%), but exhibited therapeutic benefits on abdominal pain (SMD, -0.24; 95% CI, -0.48 to -0.01; I 2 = 8%) compared to sham acupuncture. Moxibustion show therapeutic benefits compared to sham moxibustion on symptom severity (SMD, -3.46, 95% CI, -5.66 to -1.27, I 2 = 95%) and abdominal pain (SMD, -2.74, 95% CI, -4.81 to -0.67, I 2 = 96%). Acupuncture (SMD, -0.46; 95% CI, -0.68 to -0.24; I 2 = 47%) and the combination of acupuncture and moxibustion (SMD, -2.00; 95% CI, -3.04 to -0.96; I 2 = 90%) showed more benefit for abdominal pain compared to pharmacological medications as well as shams. Acupuncture (MD, 4.56; 95% CI, 1.46-7.67; I 2 = 79%) and moxibustion (MD, 6.97; 95% CI, 5.78-8.16; I 2 = 21%) were more likely to improve quality of life than pharmaceutical drugs. Conclusion: Acupuncture and/or moxibustion are beneficial for symptom severity, abdominal pain and quality of life in IBS. However, in sham control trials, acupuncture hasn't exhibited robust and stable evidence, and moxibustion's results show great heterogeneity. Hence, more rigorous sham control trials of acupuncture or moxibustion are necessary. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=262118, identifier CRD42021262118.

Chinese herbal compound prescriptions combined with Chinese medicine powder based on traditional Chinese medicine syndrome differentiation for treatment of chronic atrophic gastritis with erosion: a multi-center, randomized, positive-controlled clinical trial.

BACKGROUND: In this study, Chinese herbal compound prescriptions combined with Chinese medicine powder were evaluated for the treatment of chronic atrophic gastritis with erosion. METHODS: This multi-center, randomized, positive drug control clinical trial randomly assigned 216 patients with chronic atrophic gastritis with erosion to three groups: (1) control group: aluminum plus magnesium suspension thrice per day for 4 weeks; (2) test group 1: Chinese herbal compound prescriptions twice a day plus Sanqi (Panax notoginseng) powder twice a day for 4 weeks; (3) test group 2: Chinese herbal compound prescriptions twice a day plus Sanqi (Panax notoginseng) powder and Zhebeimu (Fritillaria thunbergii Miq.) powder twice a day for 4 weeks. The primary endpoint (improvement of gastric mucosal erosion; improvement of gastric mucosal pathology) and secondary endpoints (improvement of clinical symptoms scores; improvement of the patient-reported outcome [PRO] instrument for chronic gastrointestinal diseases) were assessed using endoscopy at week 4 following the treatment. Drug-related adverse events (AEs) and adverse drug reactions (ADRs) were also compared. RESULTS: The final analysis included 202 patients (control group, 63; test group 1, 69; test group 2, 70). At week 4, using within-group comparison, gastric mucosal erosion improved in each group following treatment with a significant difference (P < 0.05); there were no statistically significant differences in gastric mucosal erosion scores among the groups after treatment (P > 0.05); in terms of improvement of gastric mucosal erosion, the efficacy rate of the control group was 69.12%, the efficacy rate of the test group 1 was 73.24%, and the efficacy rate of the test group 2 was 69.01% and efficacy rate among the groups was not statistically significant (P > 0.05). As determined by acute inflammation, chronic inflammation, atrophy, intestinal metaplasia, and dysplasia, the pathological score (total score and the highest score) did not differ statistically among groups following treatment (P > 0.05); within the control group, the total scores of acute inflammation, chronic inflammation, atrophy, and intestinal metaplasia were significantly decreased (P < 0.05), but there was no significant improvement in dysplasia (P > 0.05); in the test group 1, chronic inflammation, atrophy, and intestinal metaplasia and dysplasia scores were significantly decreased (P < 0.05), but acute inflammation did not improve (P > 0.05); there was a significant reduction in the atrophy score in test group 2 (P < 0.05), but no improvement in the scores of acute inflammation, chronic inflammation, intestinal metaplasia, and dysplasia was observed (P > 0.05). Similarly, within the control group, the highest scores of acute inflammation, chronic inflammation, atrophy, and intestinal metaplasia were significantly decreased (P < 0.05), but there was no significant improvement in dysplasia (P > 0.05); there was a significant reduction in highest scores of atrophy, intestinal metaplasia, and dysplasia (P < 0.05) in test group 1, but the highest scores didn't not improve with acute inflammation and chronic inflammation (P > 0.05); there was a significant reduction in the highest atrophy score in test group 2 (P < 0.05), but no improvement in the highest scores of acute inflammation, chronic inflammation, intestinal metaplasia, and dysplasia was observed (P > 0.05). Compared to the control group, the main symptom scores and total symptom scores in the test groups were lower following treatment, with a statistically significant difference (P < 0.05); the analysis of covariance with center, erosion type, and group as factors was applied, and the comparison among the groups in dyspepsia, defecation, and total PRO instrument scores were statistically significant (P < 0.05). In the study period, AEs were reported in 3 (4.23%) patients in the test group 1 and 3 (4.41%) patients in the control group; ADRs were confirmed in 3 (4.23%) patients from the test group 1 and 2 (2.94%) from the control group. AEs and ADRs were not statistically significantly different among groups (AE, P = 0.2213; ADR, P = 0.2872). No serious AE or ADR was reported. CONCLUSIONS: This study has shown that both aluminum plus magnesium suspension and Chinese herbal compound prescriptions together with Panax notoginseng powder are capable of improving gastric mucosal erosion and reducing gastric mucosal pathological scores, and there were no statistically significant differences among the groups in primary endpoints, indicating that Chinese herbal therapy can achieve similar efficacy than antacids in terms of primary outcomes. The aluminum plus magnesium suspension is comparable to Chinese herbal therapy in improving atrophy and intestinal metaplasia, and is inferior to Chinese herbal therapy in improving dysplasia. In addition, the Chinese herbal therapy significantly outperforms the aluminum plus magnesium suspension in improving symptoms. Therefore, the overall clinical outcome of Chinese herbal compound prescriptions together with Panax notoginseng powder based on TCM syndrome patterns in the treatment of erosive gastritis is superior to that of antacids. Trial registration ChiCTR, ChiCTR-IPR-15005905. Registered 22 January 2015, https://www.chictr.org.cn/showproj.aspx?proj=10359.

Altered metabolome and microbiome features provide clues in understanding irritable bowel syndrome and depression comorbidity.

Irritable bowel syndrome (IBS) is one of the functional gastrointestinal disorders characterized by chronic and/or recurrent symptoms of abdominal pain and irregular defecation. Changed gut microbiota has been proposed to mediate IBS; however, contradictory results exist, and IBS-specific microbiota, metabolites, and their interactions remain poorly understood. To address this issue, we performed metabolomic and metagenomic profiling of stool and serum samples based on discovery (n = 330) and validation (n = 101) cohorts. Fecal metagenomic data showed moderate dysbiosis compared with other diseases, in contrast, serum metabolites showed significant differences with greater power to distinguish IBS patients from healthy controls. Specifically, 726 differentially abundant serum metabolites were identified, including a cluster of fatty acyl-CoAs enriched in IBS. We further identified 522 robust associations between differentially abundant gut bacteria and fecal metabolites, of which three species including Odoribacter splanchnicus, Escherichia coli, and Ruminococcus gnavus were strongly associated with the low abundance of dihydropteroic acid. Moreover, dysregulated tryptophan/serotonin metabolism was found to be correlated with the severity of IBS depression in both fecal and serum metabolomes, characterized by a shift in tryptophan metabolism towards kynurenine production. Collectively, our study revealed serum/fecal metabolome alterations and their relationship with gut microbiome, highlighted the massive alterations of serum metabolites, which empower to recognize IBS patients, suggested potential roles of metabolic dysregulation in IBS pathogenesis, and offered new clues to understand IBS depression comorbidity. Our study provided a valuable resource for future studies, and would facilitate potential clinical applications of IBS featured microbiota and/or metabolites.

The Chinese herbal formula Huoxiang Zhengqi for diarrhea-predominant irritable bowel syndrome (CHAIRS): a study protocol for a double-blinded randomized controlled trial.

BACKGROUND: Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common chronic digestive disease. Recent observational studies have reported that the Chinese herbal formula Huoxiang Zhengqi (HXZQ) can relieve IBS-D symptoms, but no high-level evidence is presented. Therefore, we want to evaluate the efficacy and safety of HXZQ for IBS-D patients. METHODS: This is a double-blind, randomized, placebo-controlled trial. The 212 eligible patients with IBS-D will be randomly assigned to receive either HXZQ oral liquid or a placebo, at a 1:1 ratio, for 4 weeks with a 4-week follow-up period. Adequate relief will be the primary outcome measures. IBS symptom severity score, IBS quality-of-life questionnaire, EQ-5D-5L, and Chinese medicine symptom questionnaire will be the secondary outcome measures. DISCUSSION: This trial aims to demonstrate the efficacy and safety of HXZQ for IBS-D, which is expected to be an effective IBS-D treatment. TRIAL REGISTRATION: The trial was registered with the Chinese Clinical Trial Registry, ChiCTR1900026837 . Registered on 24 October 2019.

Gut Microbiota-Bile Acid Crosstalk in Diarrhea-Irritable Bowel Syndrome.

The occurrence of diarrhea-predominant irritable bowel syndrome (IBS-D) is the result of multiple factors, and its pathogenesis has not yet been clarified. Emerging evidence indicates abnormal changes in gut microbiota and bile acid (BA) metabolism have a close relationship with IBS-D. Gut microbiota is involved in the secondary BA production via deconjugation, 7α-dehydroxylation, oxidation, epimerization, desulfation, and esterification reactions respectively. Changes in the composition and quantity of gut microbiota have an important impact on the metabolism of BAs, which can lead to the occurrence of gastrointestinal diseases. BAs, synthesized in the hepatocytes, play an important role in maintaining the homeostasis of gut microbiota and the balance of glucose and lipid metabolism. In consideration of the complex biological functional connections among gut microbiota, BAs, and IBS-D, it is urgent to review the latest research progress in this field. In this review, we summarized the alterations of gut microbiota in IBS-D and discussed the mechanistic connections between gut microbiota and BA metabolism in IBS-D, which may be involved in activating two important bile acid receptors, G-protein coupled bile acid receptor 1 (TGR5) and farnesoid X receptor (FXR). We also highlight the strategies of prevention and treatment of IBS-D via regulating gut microbiota-bile acid axis, including probiotics, fecal microbiota transplantation (FMT), cholestyramine, and the cutting-edge technology about bacteria genetic engineering.

Astragaloside IV Protects Ethanol-Induced Gastric Mucosal Injury by Preventing Mitochondrial Oxidative Stress and the Activation of Mitochondrial Pathway Apoptosis in Rats.

Alcohol consumption affects gastric mucosa by multiple and complex mechanisms depending either by direct contact of ethanol or by indirect biological damage induced by its metabolite acetaldehyde. The present study aims at further investigating the mechanism of ethanol-induced gastric mucosa injury and the protective effect of astragaloside IV (AS-IV) in an aspect of mitochondrial oxidative stress and mitochondrial pathway of apoptosis. Using an array of experimental approaches, we have shown that the development of mitochondrial oxidative stress and associated apoptosis play crucial roles in the pathogenesis of gastric injury induced by ethanol. AS-IV inhibits mitochondrial oxidative stress by scavenging accumulation of malondialdehyde and decreasing the consumption of glutathione. AS-IV also prevents ethanol-induced apoptosis by modulating the activity of caspase-3 and caspase-9, the expression of Bax/Bcl-2, and the release of cytochrome C and apoptosis inducing factor. Moreover, AS-IV reduces ethanol-mediated activation of caspase-8 and breakage of Bid. This study thus indicates that AS-IV prevented ethanol-induced gastric damage by blocking activation of mitochondrial oxidative stress and mitochondrial pathway of apoptosis induced by ethanol in the gastric mucosa.

Whole-genome sequencing reveals novel tandem-duplication hotspots and a prognostic mutational signature in gastric cancer.

Genome-wide analysis of genomic signatures might reveal novel mechanisms for gastric cancer (GC) tumorigenesis. Here, we analysis structural variations (SVs) and mutational signatures via whole-genome sequencing of 168 GCs. Our data demonstrates diverse models of complex SVs operative in GC, which lead to high-level amplification of oncogenes. We find varying proportion of tandem-duplications (TDs) among individuals and identify 24 TD hotspots involving well-established cancer genes such as CCND1, ERBB2 and MYC. Specifically, we nominate a novel hotspot involving the super-enhancer of ZFP36L2 presents in approximately 10% GCs from different cohorts, the oncogenic role of which is further confirmed by experimental data. In addition, our data reveal a mutational signature, specifically occurring in noncoding region, significantly enriched in tumors with cadherin 1 mutations, and associated with poor prognoses. Collectively, our data suggest that TDs might serve as an important mechanism for cancer gene activation and provide a novel signature for stratification.