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.

Injectable and Thermosensitive Hydrogel with Platelet-Rich Plasma for Enhanced Biotherapy of Skin Wound Healing.

The rapid and effective healing of skin wounds resulted from severe injuries and full-layer skin defects remains a pressing clinical challenge in contemporary medical practice. The reduction of wound infection and rapid healing is helpful to rebuild and repair skin tissue. Here, a thermosensitive chitosan-based wound dressing hydrogel incorporating ß-glycerophosphate (GP), hydroxy propyl cellulose (HPC), graphene oxide (GO), and platelet-rich plasma (PRP) is developed, which exhibits the dual functions of antibacterial properties and repair promotion. GP and HPC enhance the mechanical properties through forming hydrogen bonding connection, while GO produces local heat under near-infrared light, leading to improved blood circulation and skin recovery. Notably, antibacterial properties against Pseudomonas aeruginosa, and control-release of growth factors from PRP are also achieved based on the system. In vitro experiments reveal its biocompatibility, and ability to promote cell proliferation and migration. Animal experiments demonstrate that the epithelial repair and collagen deposition can be promoted during skin wound healing in Sprague Dawley rats. Moreover, a reduction in wound inflammation levels and the improvement of wound microenvironment are observed, collectively fostering effective wound healing. Therefore, the composite hydrogel system incorporated with GO and PRP can be a promising dressing for the treatment of skin wounds.

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.

A review of platelet-rich plasma for enteric fistula management.

Enteric fistula (EF), a serious complication after abdominal surgery, refers to unnatural communication between the gastrointestinal tract and the skin or other hollow organs. It is associated with infection, massive fluid/electrolyte loss, and malnutrition, resulting in an unhealed course. Despite advances in surgical techniques, wound care, infection control, and nutritional support, EF remains associated with considerable morbidity and mortality. Autologous platelet-rich plasma (PRP) containing elevated platelet concentrations has been proposed to promote healing in many tissues. However, the mechanism of action of PRP in EF treatment remains unclear owing to its complicated clinical manifestations. In this review, we summarized the clinical approaches, outlined the principal cytokines involved in the healing effects, and discussed the advantages of PRP for EF therapy. In addition, we defined the mechanism of autologous PRP in EF management, which is essential for further developing EF therapies.

Effects of the interactions between platelets with other cells in tumor growth and progression.

It has been confirmed that platelets play a key role in tumorigenesis. Tumor-activated platelets can recruit blood cells and immune cells to migrate, establish an inflammatory tumor microenvironment at the sites of primary and metastatic tumors. On the other hand, they can also promote the differentiation of mesenchymal cells, which can accelerate the proliferation, genesis and migration of blood vessels. The role of platelets in tumors has been well studied. However, a growing number of studies suggest that interactions between platelets and immune cells (e.g., dendritic cells, natural killer cells, monocytes, and red blood cells) also play an important role in tumorigenesis and tumor development. In this review, we summarize the major cells that are closely associated with platelets and discuss the essential role of the interaction between platelets with these cells in tumorigenesis and tumor development.

Frizzled-3 suppression overcomes multidrug chemoresistance by Wnt/ß-catenin signaling pathway inhibition in hepatocellular carcinoma cells.

Multidrug resistance (MDR) is a major obstacle to the efficacy of hepatocellular carcinoma (HCC) chemotherapy. Previous studies have identified that low FZD3 predicted decreased survival after intraperitoneal versus intravenous-only chemotherapy in ovarian cancer. This study aimed to identify a potential target in HCC chemotherapy. The FZD3 expression variant in HCC cell lines was detected by RT-qPCR and western blotting. The FZD3 expression in the early recurrent HCC group (RE group) and the non-early recurrent HCC group (non-RE group) was measured by RT-qPCR. Then, the 50% inhibitory concentrations (IC50) in HCC cell lines were studied by MTT assay. TOP/FOP FLASH luciferase assay was performed to measure TCF-binding activities. We found that FZD3 was upregulated in three HCC cell lines, and the FZD3 expression was significantly higher in the RE group than in the non-RE group (P = 0.0344). A positive correlation between FZD3 and MDR1 was observed in HCC tissues (R2 = 0.6368, P = 0.0001). Then, we found that FZD3 knockdown significantly altered Huh-7 cell chemotherapeutic sensitivity to cisplatin [50.43 µM in the FZD3 siRNA (siFZD3) group vs 98.59 µM in the siRNA negative control (siNC) group; P = 0.007] or doxorubicin (7.43 µM in the siFZD3 group vs 14.93 µM in the siNC group; P = 0.017). TOP/FOP FLASH luciferase assay showed FZD3 could inhibit Wnt/ß-catenin signaling in HCC cells. Moreover, FZD3 expression knockdown in SNU-449 and Huh-7 cells markedly reduced ß-catenin and phosho-ß-catenin (S37) protein expression, and Cyclin D1, c-myc and MDR1 were significantly decreased. This is the first study to describe the significantly increased FZD3 expression in patients with early recurrent HCC. FZD3 knockdown led to increased sensitivity to chemotherapy by Wnt/ß-catenin signaling inhibition in HCC cell lines. Our study suggests FZD3 as a potential target for reversing chemoresistance in HCC.

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.

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.

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.

Current treatment approaches for COVID-19 and the clinical value of transfusion-related technologies.

COVID-19 is caused by SARS-CoV-2 which is a new enveloped virus that belongs to the Beta coronavirus genus. As a major health crisis, SARS-CoV-2 has infected over a million people around the world. There is currently no specific treatment available for patients with COVID-19 infection. Numerous potential therapies, including supportive intervention, immunomodulatory agents, antiviral therapy, and convalescent plasma transfusion, have been used in clinical practice. Herein, we summarize the current potential therapeutic approaches for diseases related to COVID-19 infection and discusses the clinical value of blood transfusion-related technologies used in COVID-19 treatment.

Genome-wide analysis of prognostic-related lncRNAs, miRNAs and mRNAs forming a competing endogenous RNA network in lung squamous cell carcinoma.

PURPOSE: As a type of cancer with the highest morbidity and mortality, lung squamous cell carcinoma (LUSC) has a very poor prognosis. Long-non-coding RNA (lncRNA) has recently attracted attentions because it can play the role of competing endogenous RNA (ceRNA) to inhibit microRNA (miRNA) functions. In this study, we aimed to find prognosis-related lncRNAs, miRNAs and mRNAs and construct a prognosis-related ceRNA network. METHODS: The original LUSC RNA-sequencing data and miRNA profiles data were downloaded from the cancer genome atlas (TCGA) database. Differentially expressed lncRNAs, miRNAs and mRNAs were then identified between patients with lymph node metastasis and no lymph node metastasis. Univariate Cox regression analysis was performed to find the survival-associated lncRNAs, miRNAs and mRNAs. Subsequently, prognostic-related ceRNA network was established. By multivariate Cox regression analysis, three lncRNA signatures and three mRNA signatures were developed and used for predicting LUSC patients' survival. RESULTS: A total of 224 lncRNAs, 160 miRNAs, 913 mRNAs were identified between samples with lymph node metastasis and no lymph node metastasis. Univariate Cox regression analysis showed that, among them, 28 lncRNAs, 8 miRNAs, 105 mRNAs were significantly associated with patients' overall survival time. Further pathway and enrichment analysis suggested that these mRNAs were associated with the regulation of transmembrane transport, regulation of blood circulation, plasma lipoprotein particle organization. Then we constructed a survival-related ceRNA network including 9 lncRNAs, 8 miRNAs and 23 mRNAs. Additionally, a multivariate Cox regression analysis demonstrated that three lncRNAs (AL161431.1, LINC02389, APCDD1L.DT) and three mRNAs (KLK6, SLITRK5, CCDC177) had a significant prognostic value. Risk score indicated that lncRNA signature and mRNA signature could independently predict overall survival in LUSC patients. CONCLUSION: The current study provided a better understanding of the ceRNA network in the progression of LUSC and laid a theoretical foundation for LUSC prognosis.

Identification of a miRNA-mRNA network associated with lymph node metastasis in colorectal cancer.

Lymph node metastasis is an important step in the progression of colorectal cancer (CRC); however, the underlying mechanisms are still unknown. The aim of the present study was to identify the gene expression pattern during lymph node metastasis in CRC and to identify upstream microRNAs (miRNAs) to explore the underlying mechanisms in detail. A total of 305 differently expressed genes (DEGs) were identified, including 227 upregulated genes and 78 downregulated genes in lymph node metastasis. Pathway and process enrichment analysis demonstrated that DEGs were significantly enriched in 'NABA CORE MATRISOME', 'extracellular matrix assembly', 'antimicrobial humoral response' and 'Toll-like receptor signaling' pathways. The top 10 hub genes were identified by protein-protein interaction network, and sub-networks revealed that these genes were involved in significant pathways, including 'neutrophil chemotaxis' and 'Smooth Muscle Contraction'. In addition, 73 mature differently expressed miRNAs associated with lymph node metastasis were identified, of which 48 were upregulated and 25 were downregulated. Six miRNAs were identified to regulate DEGs. Additionally, based on the relationship between miRNAs and transcription factors, a miRNA-TF-mRNA network was constructed. In conclusion, DEGs, miRNAs and their interactions and pathways were identified in lymph node metastasis in CRC, which provided insight into the mechanism of CRC metastasis and may be used to develop novel targets for CRC treatment.

[Research progress in thin flap and flap thinning technique].

OBJECTIVE: To review the historical origin and development of thin flap and flap thinning technique. METHODS: A wide range of domestic and foreign literatures on thin flaps and flap thinning technique were reviewed. The background, definition, methods, problems, challenges, and future development of thin flap and flap thinning technique were summarized and analysed. RESULTS: Thin flap and flap thinning technique play an important role in the development of flap surgery, leading flap surgery towards a more rational and refined direction. CONCLUSION: Thin flap and flap thinning technique are still hot topics in the future. With the development of thin flap and flap thinning technique, clinicians will have more "free" choices.

Increased platelet-to-lymphocytes ratio is associated with poor long-term prognosis in patients with pancreatic cancer after surgery.

Several studies reported platelet-to-lymphocytes ratio (PLR), neutrophil-to-lymphocyte ratio (NLR) and red blood cell distribution width (RDW) were associated with the mid-term survival or cancer stage in pancreatic cancer. However, the relationship between these markers and the long-term prognosis of pancreatic cancer is still unknown. We investigated the relationship between PLR, NLR, RDW, and the long-term prognosis of pancreatic cancer.We included 182 pancreatic cancer patients who received operation at Linzi District People 's Hospital between August 2010 and January 2017. PLR, NLR, and RDW control data was obtained from 150 health volunteers from January 2011 to January 2017. Blood biochemical data before operation, preoperative computed tomography information, and pathological data of the pancreatic cancer patients were retrospectively collected for further analysis. Independent long-term prognostic significance of PLR, NLR, and RDW were analyzed in pancreatic cancer patients.PLR, NLR, and RDW were significantly increased in pancreatic cancer group compared with the control. Receiver operating characteristic (ROC) curve analysis showed the optimal cut-off values of PLR, NLR, and RDW were 150, 1.73, and 13.2 respectively. Overall survival (OS) analysis showed pancreatic cancer patients with PLR≥150 (median time, 24 vs 37.5 months, P = .005) or RDW≥13.2 (median time, 27 months vs 37.5 months, P = .018) had lower postoperative 5 year OS compared with pancreatic cancer patients with PLR<150 or RDW<13.2. Univariate and multivariable Cox regression analysis for postoperative 5 year OS data showed PLR≥150 (HR = 2.451, 95% CI 1.215-4.947; P = .012) was still associated with the OS independently. Disease free survival (DFS) analysis showed pancreatic cancer patients with PLR≥150 (median time, 24 months vs 38 months, P = .002) or RDW≥13.2 (median time, 24 months vs 37.5 months, P = .006) had lower postoperative 5 year DFS compared with pancreatic cancer patients with PLR<150 or RDW<13.2. Univariate and multivariable Cox regression analysis for postoperative 5 year DFS data showed PLR≥150 (HR = 2.712, 95% CI 1.367-5.379; P = .004) was independently associated with the DFS.In the present study, we find hematological biomarkers PLR≥150 is an independently predictive risk factor for the postoperative long-term prognosis in pancreatic cancer patients. Our study may provide a convenient way for the prognostic assessment of pancreatic cancer patients.

Gallstone is correlated with an increased risk of idiopathic sudden sensorineural hearing loss: a retrospective cohort study.

OBJECTIVES: This study aims to test the hypothesis that gallstone disease (GSD) is a risk factor for the development of idiopathic sudden sensorineural hearing loss (ISSNHL). Research has shown risks of cardiovascular and cerebrovascular events in patients with GSD; however, well-conducted English studies on the association between GSD and the development of ISSNHL are lacking. DESIGN AND SETTING: Retrospective cohort study using the Taiwan Longitudinal Health Insurance Database. PARTICIPANTS: We compared 26,449 patients diagnosed with GSD between 1 January 2001 and 31 December 2007, with 52,898 age-matched, gender-matched and comorbidities propensity scores-matched controls. OUTCOME MEASURED: We followed each patient until the end of 2011 and evaluated the incidence of ISSNHL for at least 4 years after the initial GSD diagnosis. RESULTS: The incidence of ISSNHL was 1.42 times higher in the GS cohort than in the non-GS cohort (9.27 vs 6.52/10,000 person-years). Using Cox proportional hazard regressions, the adjusted HR was 1.44 (95% CI 1.19 to 1.74). In the cohort of patients with GSD who needed a cholecystectomy, 37 patients suffered from ISSNHL. Among those patients, 31 (83.7%) patients sustained ISSNHL before cholecystectomy and 6 (16.2%) patients sustained ISSNHL after cholecystectomy. CONCLUSIONS: A diagnosis of GSD may be an independent risk for ISSNHL. This finding suggests that an underlying vascular and inflammatory mechanism may contribute to the development of ISSNHL. Physicians may want to counsel patients with GSD to seek medical attention if they have hearing impairments, because patients may be at an increased risk of developing ISSNHL.