Mechanism Exploration on the Immunoregulation of Allogeneic Heart Transplantation Rejection in Rats With Exosome miRNA and Proteins From Overexpressed IDO1 BMSCs.

Immunoregulation and indoleamine 2,3-dioxygenase 1 (IDO1) play pivotal roles in the rejection of allogeneic organ transplantation. This study aims to elucidate the immune-related functional mechanisms of exosomes (Exos) derived from bone marrow-derived mesenchymal stem cells (BMSCs) overexpressing IDO1 in the context of allogeneic heart transplantation (HTx) rejection. A rat model of allogeneic HTx was established. Exos were extracted after transfection with oe-IDO1 and oe-NC from rat BMSCs. Exos were administered via the caudal vein for treatment. The survival of rats was analyzed, and reverse transcription qualitative PCR (RT-qPCR) and immunohistochemistry (IHC) were employed to detect the expression of related genes. Histopathological examination was conducted using hematoxylin and eosin (HE) staining, and flow cytometry was utilized to analyze T-cell apoptosis. Proteomics and RNA-seq analyses were performed on Exos. The data were subjected to functional enrichment analysis using the R language. A protein interaction network was constructed using the STRING database, and miRWalk, TargetScan, and miRDB databases predicted the target genes, differentially expressed miRNAs, and transcription factors (TFs). Exos from BMSCs overexpressing IDO1 prolonged the survival time of rats undergoing allogeneic HTx. These Exos reduced inflammatory cell infiltration, mitigated myocardial damage, induced CD4 T-cell apoptosis, and alleviated transplantation rejection. The correlation between Exos from BMSCs overexpressing IDO1 and immune regulation was profound. Notably, 13 immune-related differential proteins (Anxa1, Anxa2, C3, Ctsb, Hp, Il1rap, Ntn1, Ptx3, Thbs1, Hspa1b, Vegfc, Dcn, and Ptpn11) and 10 significantly different miRNAs were identified. Finally, six key immune proteins related to IDO1 were identified through common enrichment pathways, including Thbs1, Dcn, Ptpn11, Hspa1b, Il1rap, and Vegfc. Thirteen TFs of IDO1-related key miRNAs were obtained, and a TF-miRNA-mRNA-proteins regulatory network was constructed. Exosome miRNA derived from BMSCs overexpressing IDO1 may influence T-cell activation and regulate HTx rejection by interacting with mRNA.

Bruceine D and Narclasine inhibit the proliferation of breast cancer cells and the prediction of potential drug targets.

BACKGROUND: Breast cancer is one of the most common female malignancies. This study explored the underlying mechanism through which the two plant compounds (Brucaine D and Narclasine) inhibited the proliferation of breast cancer cells. OBJECTIVE: The purpose of this study was to explore the effect of Brucaine D and Narclasine on breast cancer development and their potential drug targets. METHODS: GSE85871 dataset containing 212 samples and the hallmark gene set "h.all.v2023.1.Hs.symbols.gmt" were downloaded from the Gene Expression Omnibus (GEO) database and the Molecular Signatures Database (MSigDB) database, respectively. Principal component analysis (PCA) was applied to classify clusters showing similar gene expression pattern. Single sample gene set enrichment analysis (ssGSEA) was used to calculate the hallmark score for different drug treatment groups. The expressions of genes related to angiogenesis, glycolysis and cell cycle were detected. Protein-protein interaction (PPI) network analysis was performed to study the interaction of the hub genes. Then, HERB database was employed to identify potential target genes for Narclasine and Bruceine D. Finally, in vitro experiments were conducted to validate partial drug-target pair. RESULTS: PCA analysis showed that the significant changes in gene expression patterns took place in 6 drugs treatment groups (Narciclasine, Bruceine D, Japonicone A, 1beta-hydroxyalatolactone, Britanin, and four mixture drugs) in comparison to the remaining drug treatment groups. The ssGSEA pathway enrichment analysis demonstrated that Narciclasine and Bruceine treatments had similar enriched pathways, for instance, suppressed pathways related to angiogenesis, Glycolysis, and cell cycle, etc.. Further gene expression analysis confirmed that Narciclasine and Bruceine had a strong ability to inhibit these cell cycle genes, and that MYC, CHEK2, MELK, CDK4 and EZH2 were closely interacted with each other in the PPI analysis. Drug target prediction revealed that Androgen Receptor (AR) and Estrogen Receptor 1 (ESR1) were the targets for Bruceine D, and Cytochrome P450 3A4 enzyme (CYP3A4) was the target for Narciclasine. Cell experiments also confirmed the connections between Narciclasine and CYP3A4. CONCLUSION: The present study uncovered that Narciclasine and Bruceine D could inhibit the growth of breast cancer and also predicted the potential targets for these two drugs, providing a new therapeutic direction for breast cancer patients.

Prognosis analysis of necroptosis-related genes in colorectal cancer based on bioinformatic analysis.

Background: Colorectal cancer (CRC) is one gastrointestinal malignancy, accounting for 10% of cancer diagnoses and cancer-related deaths worldwide each year. Therefore, it is urgent to identify genes involved in CRC predicting the prognosis. Methods: CRC's data were acquired from the Gene Expression Omnibus (GEO) database (GSE39582 and GSE41258 datasets) and The Cancer Genome Atlas (TCGA) database. The differentially expressed necroptosis-related genes (DENRGs) were sorted out between tumor and normal tissues. Univariate Cox regression analysis and least absolute shrinkage and selectionator operator (LASSO) analysis were applied to selected DENRGs concerning patients' overall survival and to construct a prognostic biomarker. The effectiveness of this biomarker was assessed by the Kaplan-Meier curve and the receiver operating characteristic (ROC) analysis. The GSE39582 dataset was utilized as external validation for the prognostic signature. Moreover, using univariate and multivariate Cox regression analyses, independent prognostic factors were identified to construct a prognostic nomogram. Next, signaling pathways regulated by the signature were explored through the gene set enrichment analysis (GSEA). The single sample gene set enrichment analysis (ssGSEA) algorithm and tumor immune dysfunction and exclusion (TIDE) were used to explore immune correlation in the two groups, high-risk and low-risk ones. Finally, prognostic genes' expression was examined in the GSE41258 dataset. Results: In total, 27 DENRGs were filtered, and a necroptosis-related prognostic signature based on 6 DENRGs was constructed, which may better understand the overall survival (OS) of CRC. The Kaplan-Meier curve manifested the effectiveness of the prognostic signature, and the ROC curve showed the same result. In addition, univariate and multivariate Cox regression analyses revealed that age, pathology T, and risk score were independent prognostic factors, and a nomogram was established. Furthermore, the prognostic signature was most significantly associated with the apoptosis pathway. Meanwhile, 24 immune cells represented significant differences between two groups, like the activated B cell. Furthermore, 32 immune checkpoints, TIDE scores, PD-L1 scores, and T-cell exclusion scores were significantly different between the two groups. Finally, a 6-gene prognostic signature represented different expression levels between tumor and normal samples significantly in the GSE41258 dataset. Conclusion: Our study established a signature including 6 genes and a prognostic nomogram that could significantly assess the prognosis of patients with CRC.

Targeting Ferroptosis in Colorectal Cancer.

Ferroptosis is a unique way of regulating cell death (RCD), which is quite different from other programmed cell deaths such as autophagy. It presents iron overload, accumulation of reactive oxygen species (ROS), and lipid peroxidation. A ferroptotic cell usually has an intact cell structure as well as shrinking mitochondria with decreased or vanishing cristae, concentrated membrane density, and ruptured outer membrane. Recently, increasing investigations have discovered that tumor cells have a much greater iron demand than the normal ones, making them more sensitive to ferroptosis. In other words, ferroptosis may inhibit the progress of the tumor, which can be used in the therapy of tumor patients, especially for those with chemotherapy resistance. Therefore, ferroptosis has become one hot spot in the field of tumor research in recent years. Colorectal cancer (CRC) is one common type of gastrointestinal malignancy. The incidence of CRC appears to have an upward trend year by year since the enhancement of living standards. Although surgery and chemoradiotherapy have largely improved the prognosis of patients with CRC, some patients still appear to have severe adverse reactions and drug resistance. Moreover, much research has verified that ferroptosis has a necessary association with the occurrence and progression of gastrointestinal tumors. In this review, we provide a comprehensive evaluation of the main mechanisms of iron metabolism, lipid metabolism, and amino acid metabolism involved in the occurrence of ferroptosis, as well as the research progress of ferroptosis in CRC.

Effect of vitamin D on oxidative stress and serum inflammatory factors in the patients with type 2 diabetes.

The type 2 diabetes mellitus (T2DM) is an urgent global health problem. T2DM patients are in a state of high oxidative stress and inflammation. Vitamin D and glutathione (GSH) play crucial roles in antioxidation and anti-inflammation. However, T2DM patients have lower vitamin D and GSH levels than healthy persons. A randomized controlled trial was conducted to see the effect of the vitamin D supplementation on oxidative stress and inflammatory factors in T2DM patients. In this study, a total of 178 T2DM patients were randomly enrolled, 92 patients received regular treatment (T2DM group) and 86 patients in Vitamin D group received extra vitamin D 400 IU per day in addition to regular treatment. Serum vitamin D, GSH, GSH metabolic enzyme GCLC and GR, inflammatory factor MCP-1, and IL-8 levels were investigated. We found that the T2DM group has significantly higher concentrations of MCP-1 and IL-8 than those in the healthy donor group. After vitamin D supplementation for 90 days, T2DM patients had a 2-fold increase of GSH levels, from 2.72 ± 0.84 to 5.76 ± 3.19 µmol/ml, the concentration of MCP-1 decreased from 51.11 ± 20.86 to 25.42 ± 13.06 pg/ml, and IL-8 also decreased from 38.21 ± 21.76 to 16.05 ± 8.99 pg/ml. In conclusion, our study demonstrated that vitamin D could regulate the production of GSH, thereby reducing the serum levels of MCP-1 and IL-8, alleviating oxidative stress and inflammation, providing evidence of the necessity and feasibility of adjuvant vitamin D treatment among patients with T2DM. On the other hand, vitamin D and GSH levels have important diagnostic and prognostic values in T2DM patients.

The Double-Lumen Irrigation-Suction Tube in The Management of Incisional Surgical Site Infection After Enterocutaneous Fistula Excisions: An Observational Study.

BACKGROUND: This study aimed to investigate the effect of double-lumen irrigation-suction tube (DLIST) in the management of surgical site infections (SSIs) after enterocutaneous fistula (ECF) excisions. METHOD: From January 2016 to December 2017 medical records of patients with ECF excisions were reviewed. Patients with primary superficial SSI were divided into group a (treated with DLIST) and b (treated with delayed primary closures). Patients with primary deep SSI were divided into group A (treated with DLIST) and B (treated with vacuum-assisted closure [VAC]). The effect of the DLIST was evaluated. RESULTS: There were 32 in group a and 27 in group b. The therapeutic time and cost in group a were lower (13.13 ± 2.37 d vs. 24.89 ± 7.44 d; p < .001; $1456 ± 302 vs.$2784 ± 583; p < .001). There were 21 in group A and 23 in group B. While the therapeutic time of group A was longer, the cost was lower ($1717 ± 404 vs. $2636 ± 592; p < .001). CONCLUSIONS: Placing DLIST is an effective and cheap method to treat superficial SSI after ECF excisions. The cost of DLIST in treatment of deep SSI is lower, while the effect of VAC is better.

MiR-182-5p inhibits colon cancer tumorigenesis, angiogenesis, and lymphangiogenesis by directly downregulating VEGF-C.

MicroRNAs (miRNAs) are gene modulators essential for biological processes. However, the precise functions of miRNAs in growth and development of colon cancer are still elusive. To clarify their role, here we analyzed a miRNA microarray of colon cancer. MiR-182-5p was found markedly downregulated in colon cancer tissues and cells, and strongly correlated with pathological stage, differentiation, and lymphatic metastasis. In vitro, miR-182-5p overexpression repressed colon cancer cell proliferation, colony formation, migration, and invasion, and triggered G1 arrest and apoptosis. MiR-182-5p overexpression also downregulated vascular endothelial growth factor (VEGF)-C and inhibited the activity of a luciferase reporter containing the VEGF-C 3'-untranslated region. Moreover, miR-182-5p overexpression in colon cancer cells and human umbilical vein endothelial cells (HUVECs) downregulated VEGF-A as well as VEGF receptor (VEGFR)-2 and VEGFR-3, thereby inhibiting the phosphorylation of ERK and AKT. In vivo, miR-182-5p overexpression strikingly suppressed oncogenicity of SW620 cells as well as angiogenesis and lymphangiogenesis of xenograft tumors in nude mice. These data indicate that miR-182-5p regulates colon cancer tumorigenesis partially through modulating angiogenesis and lymphangiogenesis by targeting VEGF-C, and inhibiting ERK and AKT signaling pathways.

Transcatheter Arterial Embolization in the Treatment of Abdominal Bleeding in Patients Being Treated with Open Abdomen Due to Duodenal Fistula.

BACKGROUND: This study aimed to investigate the transcatheter arterial embolization (TAE) in treatment of abdominal bleeding in patients being treated with open abdomen due to duodenal fistula. METHODS: This was a retrospective study performed at our center. From January 2005 to November 2010, all patients with abdominal bleeding were treated with surgical hemostasis (SH) and included in SH group. From January 2012 to December 2018, all patients with a bleeding were treated with TAE and included in the TAE group. Clinical data were reviewed and compared between the two groups. The effect of TAE in the management of abdominal bleeding was evaluated. RESULTS: A total of 131 patients were enrolled, and there were 64 in the SH group and 67 in the TAE group. The success rate of hemostasis was higher in the TAE group (89.55% vs. 73.44%, adjusted OR = 4.065, 95% CI 1.336-12.336, P = 0.013). Moreover, the recognition rate of hemorrhagic vessels in the TAE group was higher (91.04 vs. 51.56; P < 0.001). The re-bleeding occurred in 20 patients, 7(11.67%) in the TAE group and 13(27.66%) in the SH group. The re-bleeding rate in SH group was higher (adjusted HR = 2.564, 95% CI 1.023-6.428, P = 0.045) CONCLUSIONS: TAE is an effective method in treatment of abdominal bleeding in patients being treated with open abdomen due to duodenal fistula.