Protein kinase TBK1/IKKε inhibitor Amlexanox improves cardiac function after acute myocardial infarction in rats.

BACKGROUND: The aim of this study was to study the effect of protein kinase TBK1 and IKKε inhibitor Amlexanox on cardiac function after acute myocardial infarction (AMI) in rats. METHODS: AMI model was established in rats. Experimental grouping: sham + dimethyl sulfoxide (DMSO) group, sham + Amlexanox group, AMI + DMSO group, AMI + Amlexanox group. 12 h after surgery, rats in the sham + Amlexanox group and AMI + Amlexanox group were given an intraperitoneal injection of Amlexanox at a dose of 25 mg/kg once a day for 7 consecutive days. The sham + DMSO group and the AMI + DMSO group were given the same amount of DMSO as a control. Ultrasound was used to detect changes in cardiac function in rats for 3 and 7 days after continuous administration, and real-time polymerase chain reaction was used to detect the transcription levels of ISGs and apoptosis in myocardial tissue. Hematoxylin-eosin and immunohistochemical staining were used to observe the inflammatory cell infiltration level and MOMA2 expression in myocardial tissue. Western blot was used to examine the TBK1 signaling pathway and its downstream protein expression. RESULTS: Amlexanox can improve left ventricular ejection fraction (LVEF) and short-axis shortening rate (FS) after AMI in rats, reduce remodeling of cardiomyopathy, and reduce inflammatory cell infiltration, thus reducing myocardial apoptosis. CONCLUSIONS: The protein kinases TBK1 and IKKε inhibitor Amlexanox can improve cardiac function in rats after AMI, reduce myocardial inflammatory response, reduce myocardial apoptosis, and then exert myocardial protection in vivo.

Interactions between the breast tissue microbiota and host gene regulation in nonpuerperal mastitis.

BACKGROUND: Nonpuerperal mastitis (NPM) causes considerable psychological distress in females, since it is difficult to diagnose and treat. A spectrum of etiological factors can lead to NPM. However, the pathogenesis of NPM remains unclear. Here, we aimed to dissect the role of host gene-microbe interactions in NPM. METHODS: We compared the breast tissue microbiome between NPM patients and controls using 16S rRNA sequencing. We also compared the gut microbiome between NPM patients and healthy controls. Moreover, we investigated whether the breast tissue microbiome was associated with an altered gut microbiome in patients with NPM. We analyzed differentially expressed genes in inflammatory tissues of mammary gland from patients with NPM and normal mammary gland tissues from patients with benign and non-infectious breast disease by RNA-sequencing (RNA-seq). Lastly, we explored the association of specific bacterial taxa with differential expression of immune-related genes and differences in infiltrating immune cells. RESULTS: The breast tissue microbiome from NPM and controls showed significant differences in community composition. The breast tissue shared a relatively small proportion of bacterial communities with the gut in patients with NPM. Ruminococcus (family Ruminococcaceae) of breast tissue was positively correlated with the differentially expression of immune-related genes between NPM patients and controls, including antigen processing and presentation genes (ICAM1, LGMN, THBS1, TAP1, HSPA1B and HSPA1A), cytokine receptor gene IL15RA, and chemokine gene CCN1. Rhizobium of breast tissue was negatively correlated with the differentially expression of the antigen processing and presentation gene HSPA6 between NPM patients and controls. We also found that Ruminococcus (family Ruminococcaceae), Coprococcus, and Clostridium of breast tissue positively correlated with the difference of CD8+ T cells between NPM patients and controls. CONCLUSIONS: We preliminarily explored the potential role of host-microbe interactions in NPM. We demonstrate cross-talk between the breast tissue microbiome and the gut microbiome in patients with NPM. We suggest that NPM microbiome composition influences the immune microenvironment of the disease by affecting the transcriptome. This is an exploratory study and further investigation of host-microbe interactions and its potential mechanism in NPM development are warranted.

Identification of genes and pathways related to breast cancer metastasis in an integrated cohort.

BACKGROUND: Breast cancer is the most common malignant disease in women. Metastasis is the most common cause of death from this cancer. Screening genes related to breast cancer metastasis may help elucidate the mechanisms governing metastasis and identify molecular targets for antimetastatic therapy. The development of advanced algorithms enables us to perform cross-study analysis to improve the robustness of the results. MATERIALS AND METHODS: Ten data sets meeting our criteria for differential expression analyses were obtained from the Gene Expression Omnibus (GEO) database. Among these data sets, five based on the same platform were formed into a large cohort using the XPN algorithm. Differentially expressed genes (DEGs) associated with breast cancer metastasis were identified using the differential expression via distance synthesis (DEDS) algorithm. A cross-platform method was employed to verify these DEGs in all ten selected data sets. The top 50 validated DEGs are represented with heat maps. Based on the validated DEGs, Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Protein interaction (PPI) networks were constructed to further illustrate the direct and indirect associations among the DEGs. Survival analysis was performed to explore whether these genes can affect breast cancer patient prognosis. RESULTS: A total of 817 DEGs were identified using the DEDS algorithm. Of these DEGs, 450 genes were validated by the second algorithm. Enriched KEGG pathway terms demonstrated that these 450 DEGs may be involved in the cell cycle and oocyte meiosis in addition to their functions in ECM-receptor interaction and protein digestion and absorption. PPI network analysis for the proteins encoded by the DEGs indicated that these genes may be primarily involved in the cell cycle and extracellular matrix. In particular, several genes played roles in multiple signalling pathways and were related to patient survival. These genes were also observed to be targetable in the CTD2 database. CONCLUSIONS: Our study analysed multiple cross-platform data sets using two different algorithms, helping elucidate the molecular mechanisms and identify several potential therapeutic targets of metastatic breast cancer. In addition, several genes exhibited promise for applications in targeted therapy against metastasis in future research.

Carbapenems vs alternative antibiotics for the treatment of complicated urinary tract infection: A systematic review and network meta-analysis.

BACKGROUND: Complicated urinary tract infections (cUTI) are universal reasons for hospitalization, and highly likely to develop into sepsis or septic shock. Carbapenem antibiotics with potentially higher efficacy or with fewer and milder side effects have increased in popularity, but evidence is limited by a scarcity of randomized controlled trials (RCTs) comparing different carbapenem antibiotics for cUTI. Network meta-analysis is a useful tool to compare multiple treatments when there is limited or no direct evidence available. OBJECTIVE: The aim of this study is to compare the efficacy and safety of different carbapenems with alternative antibiotics for the treatment of cUTI. METHODS: Pubmed, Medline, CENTRAL, and Embase were searched in November 2018. Studies of cUTI patients receiving carbapenem were included. We performed network meta-analysis to estimate the risk ratio (RR) and 95% credible interval (CrI) from both direct and indirect evidence; traditional meta-analysis was also performed. Primary outcomes were clinical and microbiological treatment success. RESULTS: A total of 19 studies and 7380 patients were included in the analysis. Doripenem (DOPM) was associated with lower clinical treatment success rates than other carbapenems. Although the efficacy of other carbapenems by RRs with 95% CrIs did not show statistical differences, the cumulative rank probability indicated that meropenem/vaborbactam (MV), ertapenem (ETPM), and biapenem (BAPM) had higher clinical and microbiological treatment success rates; imipenem/cilastatin (IC) and MV showed higher risk of adverse events (AEs). CONCLUSIONS: MV was associated with higher treatment success rates for cUTI, especially for cUTI caused by carbapenem-resistant uropathogens, but also with higher risk of AEs. Our findings suggest MV as a first-choice treatment of carbapenem-resistant cUTI. ETPM, BAPM, and meropenem (MEPM) is another reasonable choice for cUTI empiric therapy.