Enantioselective construction of triaryl-substituted all-carbon quaternary stereocenters via organocatalytic arylation of oxindoles with azonaphthalenes.

Azonaphthalenes have been verified as a class of effective arylation reagents in a variety of asymmetric transformations. Here a highly efficient approach to construct triaryl-substituted all-carbon quaternary stereocenters through chiral phosphoric acid-catalyzed enantioselective arylation of 3-aryl-2-oxindoles with azonaphthalenes is disclosed. This chemistry is scalable and displays excellent functional group tolerance, furnishing a series of 3,3-disubstituted 2-oxindole derivatives in good yields with excellent enantiocontrol. Preliminary mechanistic data suggest that the initially formed direct addition intermediate undergoes intramolecular annulation under acidic reaction conditions.

Mechanism research on the interaction regulation of Escherichia and IFN-γ for the occurrence of T2DM.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a major social and public health problem which may be induced by intestinal flora imbalance through inflammatory response, and the specific mechanism remains unclear. In this study, we aim to explore the interaction network of intestinal flora and cell inflammation in T2DM. METHODS: This a case-control study. Patients with T2DM was the case group and healthy people as control. The differences of cytokine expression levels between patients with T2DM and healthy controls were assessed by using flow cytometry. The diversity and abundance of intestinal flora were evaluated by using 16S rRNA three-generation full-length sequencing technology. RESULTS: A total of 29 patients with T2DM and 28 healthy controls were included for analysis. Compared with the healthy control group, the expression levels of plasma cytokine interleukin-2 (IL-2) (P=0.0000006), IL-6 (P=0.000193), tumor necrosis factor α (TNF-α) (P=0.016), interferon-γ (IFN-γ) (P=0.000036) and interleukin-17 (IL-17) (P=0.004) were significantly up-regulated in T2DM patients, and the abundance of Megamonas_funiformis (P=0.0016) and Escherichia (P=0.049) in the intestine were significantly increased. In contrast, the abundance of Bacteroides_stercoris (P=0.0068), Bacteroides_uniformis (P=0.033), and Phascolarctobacterium_faecium (P=0.033) were decreased in T2DM patients. Further, differentially expressed Escherichia had a positive correlation with IFN-γ (r=0.73) by Pearson correlation analysis. CONCLUSIONS: The interaction network between the intestinal bacteria Escherichia and the cytokine IFN-γ may drive inflammation in visceral adipose tissue (VAT), indicating insulin signal transduction can be inhibited in adipocytes to induce insulin resistance.

Tanshinone IIA combined with CsA inhibit myocardial cell apoptosis induced by renal ischemia-reperfusion injury in obese rats.

BACKGROUND: Acute myocardial injury (AMI), which is induced by renal ischemia-reperfusion (IR), is a significant cause of acute kidney injury (AKI)-related associated death. Obesity increases the severity and frequency of AMI and AKI. Tanshinone IIA (TIIA) combined with cyclosporine A (CsA) pretreatment was used to alleviate myocardial cell apoptosis induced by renal IR, and to determine whether TIIA combined with CsA would attenuate myocardial cell apoptosis by modulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats. METHODS: Male rates were fed a high fat diet for 8 weeks to generate obesity. AKI was induced by 30 min of kidney ischemia followed 24 h of reperfusion. Obese rats were given TIIA (10 mg/kg·d) for 2 weeks and CsA (5 mg/kg) 30 min before renal IR. After 24 h of reperfusion, the rats were anaesthetized, the blood were fetched from the abdominal aorta and kidney were fetched from abdominal cavity, then related indicators were examined. RESULTS: TIIA combined with CsA can alleviate the pathohistological injury and apoptosis induced by renal IR in myocardial cells. TIIA combined with CsA improved cardiac function after renal ischemia (30 min)-reperfusion (24 h) in obese rats. At the same time, TIIA combined with CsA improved mitochondrial function. Abnormal function of mitochondria was supported by decreases in respiration controlling rate (RCR), intracellular adenosine triphosphate (ATP), oxygen consumption rate, and mitochondrial membrane potential (MMP), and increases in mitochondrial reactive oxygen species (ROS), opening of the mitochondrial permeability transition pore (mPTP), mitochondrial DNA damage, and mitochondrial respiratory chain complex enzymes. The injury of mitochondrial dynamic function was assessed by decrease in dynamin-related protein 1 (Drp1), and increases in mitofusin1/2 (Mfn1/2), and mitochondrial biogenesis injury was assessed by decreases in PPARγ coactivator-1-α (PGC-1), nucleo respiratory factor1 (Nrf1), and transcription factor A of mitochondrial (TFam). CONCLUSION: We used isolated mitochondria from rat myocardial tissues to demonstrate that myocardial mitochondrial dysfunction occurred along with renal IR to induce myocardial cell apoptosis; obesity aggravated apoptosis. TIIA combined with CsA attenuated myocardial cell apoptosis by modulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats.

Correlation between alterations of gut microbiota and miR-122-5p expression in patients with type 2 diabetes mellitus.

BACKGROUND: To investigate the correlation between gut microbiota and circulating microRNAs (miRNAs) in patients with primary diagnosis of type 2 diabetes mellitus (T2DM) and to explore the possible mechanisms of miRNA-gut microbiota crosstalke network in the regulation of the insulin signaling pathway and glucose homeostasis in T2DM. METHODS: T2DM patients and normal controls were recruited. Fasting plasma and fecal samples were collected from the subjects, and their biochemical indexes including fasting blood glucose (FBG), glycated hemoglobin (HbAlc), cholesterol (TC), total triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and insulin were recorded. The variations in intestinal microbiota in the two groups were analyzed using 16S rRNA third-generation sequencing technology, and the differential expression of miRNAs between the groups was screened using miRNA high-throughput sequencing. The correlation and association between specifically changed intestinal microbiota and miRNA expressions were analyzed using a combination of bioinformatics analysis and statistical methods. Finally, 16S functional gene prediction analysis and target gene enrichment pathway analysis were carried out to predict relevant gut microbiota and miRNAs. RESULTS: Compared with normal controls, the biochemical indexes of HAlbc, FBG, TG, TC, LDL, HDL, and insulin were significantly different in T2DM patients (P<0.001, P<0.001, P=0.0125, P=0.98, P<0.001 P=0.022, and P=0.0013, respectively). The two groups also showed significantly different intestinal microbiota distribution and miRNA expression characteristics, including in the counts of Bacteriodes. uniformis and Phascolarctobacterium. Faecium (P=0.023, 0.031), which were negatively correlated (P=0.014, FC = -2.36) with the expression levels of serum miR-122-5p (r=-0.68, -0.60, P=0.01, 0.01). CONCLUSIONS: This study discovered specific gut microbiota and miRNA characteristics in patients with a primary diagnosis of T2DM. A negative correlation between miR-122-5p and the intestinal bacteria Bacteriodes. uniformis and Phascolarctobacterium. Faecium was also revealed, suggesting that the crosstalke between miRNA and gut microbiota may regulate the insulin secretion and signal transduction by controling key genes of glucose metabolism during the development of T2DM.

Comprehensive analysis of genes, pathways, and TFs in nonsmoking Taiwan females with lung cancer.

PURPOSE: The aim of this study was to investigate the molecular mechanism of lung cancer among nonsmoking Taiwan females. MATERIALS AND METHODS: By using the GSE19804 microarray data accessible from Gene Expression Omnibus (GEO) database, we identified differentially expressed genes (DEGs) between nonsmoking female lung cancer patients and healthy controls (!logFC! >1.5 and p-value < 0.05). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene ontology (GO) enrichment analysis was performed using Database for Annotation, Visualization and Integrated Discovery (DAVID). The Search Tool for the Retrieval of Interacting Genes (STRING) tool was utilized to build a protein-protein interaction (PPI) network, followed by the construction of a transcriptional regulatory network based on Transcription factor (TRANSFAC) database. RESULTS: As a result, 320 DEGs were identified between nonsmoking female patients with lung cancer and healthy controls. Pathway enrichment analysis showed significantly enriched pathways such as extracellular matrix (ECM)-receptor interaction and peroxisome proliferator-activated receptor (PPAR) signaling pathway, both of which were enriched with genes COL11A1 (encoding collagen XI alpha-1 chain protein), COL1A1, cluster of differentiation 36(CD36). GO enrichment analysis found that DEGs were significantly related to chemotaxis, vasculature development and cell adhesion GO terms. IL-6 was the node of the PPI network. Critical transcription factors (TFs) including CCAAT/enhancer-binding protein delta (CEBPD) and Rel/NF-κB were also identified. CONCLUSIONS: Our study revealed that ECM-receptor interaction, PPAR signaling pathways, and important biomolecules including COL11A1, COL1A1, CD36, IL-6, CEBPD, and Rel/NF-κB might be involved in lung cancer. This study might pave the way for the development and application of targeted therapeutics of lung cancer irrelevant to smoking.

Association between polymorphisms of DNA repair genes and survival of advanced NSCLC patients treated with platinum-based chemotherapy.

BACKGROUND: Single nucleotide polymorphism (SNP) in DNA repair genes can be used to explain the differences in survival of platinum-treated non-small cell lung cancer (NSCLC) patients regardless of their performance status. To define the role of DNA repair gene SNPs in NSCLC patients, we investigated the association between survival and 12 different SNPs of 9 DNA repair genes. METHODS: 340 patients were treated with platinum-based chemotherapy. Polymorphisms were detected by real time PCR with TaqMan probe, using genomic DNA extracted from peripheral blood samples. Multivariate logistic or Cox regression analyses were used to adjust for possible confounding variables. RESULTS: The median overall survival time was 15 months and it was significantly longer in patients harboring ERCC1 118 C/T or T/T allele: 18 months as compared to 13.8 months for the C/C allele (P=0.014). Subgroup analysis revealed that ERCC1 118 C/T or T/T was associated with increased survival in elderly patients (P=0.018), male (P=0.022), squamous carcinoma (P=0.003), smoker (P=0.076) and those treated with non-gemcitabine/cisplatin or carboplatin (non-GP/GC) regimen (P=0.023). XRCC3C/C was associated with better survival in non-gemcitabine/cisplatin treated patients (P=0.014). Both of CCNH-V270A C/C or C/T and XPD 751 A/A showed a significant longer survival in the squamous cell carcinoma subgroup (P=0.047 and P=0.034 respectively). CONCLUSION: Present data indicates that ERCC1 118 C/T or T/T might provide a better prognostic predictive marker of NSCLC patients treated with platinum-based chemotherapy, mainly in elderly subgroup, male, squamous carcinoma, smoker and those treated with non-GP/GC regimen.

ERCC1, RRM1 and BRCA1 mRNA expression levels and clinical outcome of advanced non-small cell lung cancer.

This study was to investigate whether the expressions of DNA repair genes ERCC1 (excision repair cross complementing 1), RRM1 (ribonucleotide reductase subunit M1) and BRCA1 (breast cancer 1) affected clinical outcome in patients with NSCLC. Patients with stage IIIb/IV NSCLC were given platinum-based chemotherapy. Messenger RNA expression levels of ERCC1, BRCA1 and RRM1 were determined by real-time polymerase chain reaction with TaqMan probes in the tumor. The relationship between these three genes with chemoresponse and overall survival was analyzed in this study. Eighty-five patients (median age 59, range 30-78) were enrolled into the study. Median overall survival (OS) was 13 months (range 10.8-15.2). Time to progression (TTP) was 6.1 months (range 5.5-6.7). Patients with low ERCC1 expression benefited more from a platinum-containing regimen (P=0.094). Patients with low RRM1 expression benefited more from a gemcitabine-containing regimen. Patients with high BRCA1 expression benefited more from an anti-tubulin-containing regimen (P=0.046). Partial response rate was 42.4%. A statistically significant difference in OS was seen in patients with low ERCC1 levels compared to patients with high ERCC1 ones. (16.5 vs. 10.0 months, P=0.045). A significant relationship was observed between the expression of ERCC1 and BRCA1 and TTP (6.5 vs. 5.1 months, P=0.001, 5.2 vs. 6.5, P=0.019, respectively). High expression of BRCA1 was associated with better survival in the anti-tubulin-containing regimen subgroup (8.7 vs. 13.0, P=0.035). ERCC1, RRM1 and BRCA1 are promising predictive and prognostic biomarkers in advanced non-small cell lung cancer.

High-level mRNA of excision repair cross-complementation group 1 gene is associated with poor outcome of platinum-based doublet chemotherapy of advanced nonsmall cell lung cancer patients.

BACKGROUND: DNA excision repair gene expression plays a pivotal role in the resistance of platinum-based doublet chemotherapy of nonsmall cell lung cancer (NSCLC) in clinical practice. The aim of this study was to investigate the relationship of the excision repair cross-complementation group 1 (ERCC1) mRNA level in fresh tumor tissue and the efficacy of platinum-based chemotherapy of NSCLC. PATIENTS AND METHODS: 100 patients diagnosed with NSCLC, including stage IIIB with malignant pleural effusion, stage IV, and recurrent disease, were enrolled in this study. Before clinical treatment, tumor biopsy specimens were collected, and total RNA was purified to analyze ERCC1 mRNA level by real-time polymerase chain reaction assay. All patients were treated with platinum-based third-generation doublet chemotherapy. RESULTS: Patient median age was 60 years. Forty-seven patients had NSCLC with low expression of ERCC1 mRNA, and 53 patients had high expression of ERCC1 mRNA. Although the ERCC1 mRNA level was not correlated with the response rate (p = .665) and progression-free survival (median, 6.4 months vs. 5.5 months; p = .446), the high level of ERCC1 mRNA demonstrated a significant association with poor overall survival (median, 11 months vs. 17 months; p = .02). High level of ERCC1 mRNA was an independent prognostic factor for poor overall survival (p < .001) along with lack of disease control (p < .001). CONCLUSIONS: High level of ERCC1 mRNA may serve as a useful prognostic factor for poor outcome in advanced NSCLC patients treated with platinum-based third-generation doublet chemotherapy and may provide important information to guide tailored therapy of NSCLC patients.