Therapeutic Evaluation of Bifidobacterium animalis subsp. lactis MH-02 as an Adjunctive Treatment in Patients with Reflux Esophagitis: A Randomized, Double-Blind, Placebo-Controlled Trial.

Proton pump inhibitors (PPIs) are currently routinely used for the treatment of reflux esophagitis (RE); however, with frequent symptom recurrence after discontinuation and limited clinical improvement in accompanying gastrointestinal symptoms. This study aims to explore the adjuvant therapeutic effect of Bifidobacterium supplement for RE patients. A total of 110 eligible RE patients were recruited and randomly assigned to the placebo and probiotic groups. All patients were treated with rabeprazole tablets and simultaneously received either Bifidobacterium animalis subsp. lactis MH-02 or placebo for 8 weeks. Patients who achieved clinical remission then entered the next 12 weeks of follow-up. RDQ, GSRS scores, and endoscopy were performed to assess clinical improvement, and changes in intestinal microbiota were analyzed with high-throughput sequencing. Our results revealed that MH-02 combined therapy demonstrated an earlier time to symptom resolution (50.98% vs. 30.61%, p = 0.044), a significant reduction in the GSRS score (p = 0.0007), and a longer mean time to relapse (p = 0.0013). In addition, high-throughput analyses showed that MH-02 combined therapy increased the α (p = 0.001) diversity of gut microbiota and altered microbial composition by beta diversity analysis, accompanied with significantly altered gut microbiota taxa at the genus level, where the abundance of some microbial genera including Bifidobacterium, Clostridium, and Blautia were increased, while the relative abundance of Streptococcus and Rothia were decreased (p < 0.05). Collectively, these results support the beneficial effects of MH-02 as a novel complementary strategy in RE routine treatment.

Correlations between genetically predicted lipid-lowering drug targets and inflammatory bowel disease.

BACKGROUND: Millions of individuals globally suffer from Inflammatory bowel diseases (IBDs). There is a dearth of large population-based investigations on lipid metabolism and IBDs, and it is unclear whether lipid-lowering drugs target IBDs causally. Consequently, the aim of this study was to investigate the effects of lipid-lowering medication targets on the occurrence and progression of IBDs. METHODS: Among the more than 400,000 participants in the UK Biobank cohort and the more than 170,000 participants in the Global Lipids Genetics Consortium, a total of nine genes linked to lipid-lowering drug targets were obtained (ABCG5/ABCG8, APOB, APOC3, LDLR, LPL, HMGCR, NPC1L1, PCSK9, and PPARA). IBD data were acquired from de Lange et al. (patients/sample size of IBDs: 25042/59957; ulcerative colitis (UC): 12366/45,975; Crohn's disease (CD): 12194/40,266) and the FinnGen cohort (patients/total sample size of IBDs: 4420/176,899; CD: 1520/171,906; UC: 3325/173,711). All four datasets were cross-combined for validation via Mendelian randomization analysis, and potential mediating factors were explored via mediation analysis. RESULTS: Genetically proxied APOC3 inhibition was related to increased IBD risk (odds ratio (95% confidence interval): 0.87 (0.80-0.95); P < 0.01) and UC risk (0.83 (0.73-0.94); P < 0.01). IBD and CD risk were reduced by genetic mimicry of LDLR and LPL enhancements, respectively (odds ratioLDLR: 1.18 (1.03-1.36); P = 0.018; odds ratioCD: 1.26 (1.11-1.43); P = 2.60E-04). Genetically proxied HMGCR inhibition was associated with increased CD risk (0.68 (0.50-0.94); P = 0.018). These findings were confirmed through Mendelian analysis of the cross-combination of four separate datasets. APOC3-mediated triglyceride levels may contribute to IBDs partly through mediated triglycerides, Clostridium sensu stricto 1, Clostridiaceae 1, or the Lachnospiraceae FCS020 group. LDLR enhancement may contribute to IBDs partly through increasing Lactobacillaceae. CONCLUSION: Vigilance is required to prevent adverse effects on IBDs (UC) for patients receiving volanesorsen (an antisense oligonucleotide targeting ApoC3 mRNA) and adverse effects on CD for statin users. LPL and LDLR show promise as candidate drug targets for CD and IBD, respectively, with mechanisms that are potentially independent of their lipid-lowering effects.

Exosomes with IR780 and Lenvatinib loaded on GPC3 single-chain scFv antibodies for targeted hyperthermia and chemotherapy in hepatocellular carcinoma therapy.

Exosomes (EXOs) are considered natural nanoparticles which have been widely used as carriers for the treatment and diagnosis of various diseases. However, due to the non-specific uptake, the unmodified EXOs cannot effectively deliver the vector to the target site. In this study, we used pDisplay vector to engineer Glypican-3 (GPC3) single-chain scFv antibody to the exosome surface, and the effect of engineered exosomes on the proliferation and migration of hepatocellular carcinoma (HCC) cells was determined by a series of in vitro experiments as well as in vivo mouse xenograft model and PDX model. Furthermore, we established an improved delivery system by engineering single-chain scFv antibody against GPC3 on the EXO surface for a more efficient HCC targeting. Moreover, the delivery system was loaded with IR780 and Lenvatinib for a combination of thermotherapy and chemotherapy. Our results revealed that the antibody-engineered exosomes enabled rapid imaging of HCC xenograft models post IR780 loading and showed significant anti-tumor photothermal therapy (PTT) effects after irradiation. Since dual loading of IR780 and Lenvatinib in exosomes required only a single injection and had a maximal efficacy against cancer cells, our findings highlight the clinical application of using GPC3 single-chain scFv antibody-engineered exosomes loaded with IR780 and Lenvartinib to achieve the imaging and the treatment of HCC from the combined effect of IR780-induced PTT and Lenvatinib-induced chemotherapy.

Disulfiram combined with chemoimmunotherapy potentiates pancreatic cancer treatment efficacy through the activation of cGAS-STING signaling pathway via suppressing PARP1 expression.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related mortality globally with limited effective treatment options. Although the combination of immunotherapy and chemotherapy has been attempted in clinical trials to treat PDAC, the results are not promising. Therefore, in this study, we explored the application of a novel combination strategy with disulfiram (DSF) to enhance the treatment efficacy of PDAC as well as its underlying molecular mechanism. We compared the antitumor effects between single agents and the combination therapy by using mouse allograft tumor model and found DSF combined with chemoimmunotherapy significantly suppressed the growth of subcutaneous PDAC allograft tumor in mice and prolonged the survival of mice. To further investigate the alterations in the immune microenvironment of tumors from different treatment groups, we employed flow cytometry and RNA-seq analysis to examine the composition of tumor-infiltrating immune cells as well as the expression level of a variety of cytokines. Our results revealed that the proportion of CD8 T cells was notably elevated and that multiple cytokines were upregulated in the combination therapy group. Furthermore, qRT-PCR results indicated that DSF could upregulate the mRNA levels of IFNα and IFNß, which could be reversed by STING pathway inhibitor. Mechanistically, we found that DSF activated STING signaling pathway through Poly (ADP-ribose) polymerases (PARP1) inhibition. Taken together, our findings highlight the potential clinical application of this novel combination strategy using DSF and chemoimmunotherapy in the treatment of patients with PDAC.

Mechanism of dact2 gene inhibiting the occurrence and development of liver fibrosis.

There are few reports about the relationship between dact2 and liver fibrosis. The inhibitory mechanism of dact2 in liver fibrosis is not clear, we need to further explore it. In this study has been shown that the dact2 gene can inhibit liver fibrosis. In this experiment, we used lentivirus as a vector to construct a lentivirus vector carrying the dact2 gene and packaged dact2 recombinant lentivirus and its control vector. HSC-T6 infected cells were observed. The effect of dact2 gene expression was activated by Wnt3a HSC-T6 cells. Immunoblot was used to detect α - SMA expression, TGF - ß 1, Smad3, Smad7, ß - Catenin and CyclinD1. The expression of MMP-2 and TIMP-1 was detected by real-time PCR. At the same time, dact2 recombinant lentivirus was injected into the tail vein. Carbon tetrachloride was used to establish the liver fibrosis model. After 7 weeks of modeling, the staining was used to observe the pathological changes of liver tissue, hydroxyproline was used to analyze the changes of collagen content in liver tissue, the expression of the protein was observed by immunohistochemistry, and the expression of fibrosis-related genes was detected by real-time PCR. Results showed that the dact2 gene expression could inhibit the activation of HSC-T6 cells and reduce the expression of TGF - ß 1. The percentage of Smad3, ß - Catenin and cyclinD1 protein was 50.02%, 46.73%, 47.58% and 37.50% respectively (P < 0.05).

LncRNA FGD5-AS1 functions as an oncogene to upregulate GTPBP4 expression by sponging miR-873-5p in hepatocellular carcinoma.

The long non-coding FGD5-AS1 (LncFGD5-AS1) has been reported to be a novel carcinogenic gene and participant in regulating tumor progression by sponging microRNAs (miRNAs). However, the pattern of expression and the biological role of FGD5-AS1 in hepatocellular carcinoma (HCC) remains largely unknown. The expression level of FGD5-AS1 in tumor tissues and cell lines was measured by RT-qPCR. CCK-8, EdU, flow cytometry, wound healing, and transwell chamber assays were performed to investigate the role of FGD5-AS1 in cell proliferation, apoptosis, migration, and invasion in HCC. Dual luciferase reporter, and RNA pull-down assays were performed to identify the regulatory interactions among FGD5-AS1, miR-873-5p and GTP-binding protein 4 (GTPBP4). We found that the expression of FGD5-AS1 was upregulated in HCC tissues and cell lines. Moreover, the knockdown of FGD5-AS1 suppressed cell proliferation, migration and invasion, and induced apoptosis in HCC cells. Further studies demonstrated that FGD5-AS1 could function as a competitive RNA by sponging miR-873-5p in HCC cells. Moreover, GTPBP4 was identified as direct downstream target of miR-873-5p in HCC cells and FGD5-AS1mediated the effects of GTPBP4 by competitively binding with miR-873-5p. Taken together, this study demonstrated the regulatory role of FGD5-AS1 in the progression of HCC and identified the miR-873-5p/GTPBP4 axis as the direct downstream pathway. It represents a promising novel therapeutic strategy for HCC patients.

Upregulation of MANCR predicts poor survival in patients with gastric cancer.

A previous study revealed that MANCR (mitotically associated long non-coding RNA) is implicated in breast cancer. The present study investigated the potential role of MANCR in gastric cancer (GC) and revealed that MANCR was upregulated in GC tissues compared with non-cancerous tissues. MANCR expression was not affected by clinical stages and a high MANCR expression level was associated with poor survival time. MicroRNA (miR)-101 was downregulated in cancer tissues compared with non-cancerous tissues and was inversely associated with MANCR expression. MANCR overexpression in GC cell lines in vitro resulted in miR-101 downregulation; however, miR-101 overexpression did not alter MANCR expression. Furthermore, MANCR overexpression promoted, while miR-101 overexpression inhibited GC cell proliferation. In addition, miR-101 overexpression decreased the effect of MANCR overexpression. The results obtained in the present study revealed that MANCR expression was associated with the survival of patients with GC, and MANCR overexpression in vitro may promote GC by downregulating miR-101 and increasing the proliferation of GC cells.