Finkduke2292

erent surgical specialities. Several areas for improvement have been identified, as some core prevention measures are not in common use.In addition to serving as an incretin-based treatment of type 2 diabetes mellitus (T2DM), glucagon-like peptide 1 (GLP-1) can also reverse cardiovascular diseases caused by vascular remodelling. However, a detailed mechanism underlying how GLP-1 reverses vascular remodelling remains unclear. Here, Spontaneous hypertension rats (SHR) were used as an in vivo model of vascular remodelling. Treatment with a GLP-1 receptor (GLP-1R) agonist Liraglutide or dipeptidyl peptidase 4 (DPP4) inhibitor Alogliptin decreased systolic blood pressure (SBP), diastolic blood pressure (DBP), thickness of vascular wall, and overall collagen levels in SHR. In vitro vascular remodelling can be induced by exposing rat aortic smooth muscle cells (RASMC) to angiotensin II (Ang II); GLP-1 treatment attenuated AngII induction of RASMC proliferation, migration, and excessive extracellular matrix (ECM) degradation. Downregulation of matrix metalloproteinase 1 (MMP1) enhanced the inhibitory effects of GLP-1, and extracellular regulated protein kinase 1/2 (ERK1/2) and nuclear factor kappa-B (NF-κB) signalling participated in these processes. These results provide a new mechanistic understanding of key therapeutic strategies for the treatment of vascular remodelling-related diseases.Oxidative stress (OS) is recognized as disturbance of cellular equilibrium between reactive oxygen species (ROS) formation and their elimination by antioxidant defense systems. One example of ROS-mediated damage is generation of potentially mutagenic DNA precursor, 8-oxodGTP. In human cells genomic 8-oxodGTP incorporation is prevented by the MutT homologue 1 (MTH1 or hMTH1 for human MTH1) protein. It is well established that malignant cells, including thyroid cancer cells, require hMTH1 for maintaining proliferation and cancerous transformation phenotype. Above observations led to the development of hMTH1 inhibitors as novel anticancer therapeutics. In the current study we present extensive analysis of oxidative stress responses determining sensitivity to hMTH1 deficiency in cultured thyroid cells. Amredobresib supplier We observe here that hMTH1 depletion results in downregulation of several glutathione-dependent OS defense system factors, including GPX1 and GCLM, making some of the tested thyroid cell lines highly dependent on glutathione levels. This is evidenced by the increased ROS burden and enhanced proliferation defect after combination of hMTH1 siRNA and glutathione synthesis inhibition. Moreover, due to the lack of data on hMTH1 expression in human thyroid tumor specimens we decided to perform detailed analysis of hMTH1 expression in thyroid tumor and peri-tumoral tissues from human patients. Our results allow us to propose here that anticancer activity of hMTH1 suppression may be boosted by combination with agents modulating glutathione pool, but further studies are necessary to precisely identify backgrounds susceptible to such combination treatment.Cerebral cavernous malformations (CCM) are lesions affecting brain capillaries that appear with a mulberry-like morphology. This shape results from the enlarged and tangled microvessels having defective endothelial cell junctions, few surrounding pericytes and dense extracellular collagen-rich matrix. Three genes KRIT1, CCM2 and PDCD10 are linked to disease onset. However, a variable percentage of patients harbour no mutations at these loci, encouraging hypothesis of further genetic factors involved in CCM pathogenesis. Here we present data obtained by transcriptome analysis on endothelial cells isolated by CCM specimens, with the aim to identify dysregulated pathways involved in lesion onset. Lesions belonged to two patients carried neither germline nor somatic mutations at the three CCM genes. By comparison with Human brain microvascular endothelial cells (HBMECs) expression profile, we identified 1325 differentially expressed genes (Bonferroni pValue less then 0.05) common for the two samples. Functional enrichment analysis clustered these genes in 80 terms related to neuroinflammation, extra-cellular matrix remodelling, cell junction impairment, reactive oxygen species metabolism. In addition, CCM genes expression values resulted slightly altered in only one of the two CCM endothelial cell samples when compared to HBMECs, suggesting as further genetic factors can contribute to CCM development. Following expression analysis, we suggests that the molecular shift from canonical to non-canonical Wnt pathway might be a key event in CCM pathogenesis. Moreover, our results provide novel potential genetic targets to investigate for the development of more selective therapies.

Docetaxel remains a main treatment for metastatic castration-resistant prostate cancer (mCRPC); however, the development of docetaxel resistance has been found in some mCRPC patients. The aim of this work is to identify an effective biomarker for predicting therapeutic effectiveness of docetaxel in mCRPC patients.

We examined DNA polymerase theta (POLQ) expression in The Cancer Genome Atlas (TCGA) database and Tissue microarray. Kaplan-Meier analyses were performed to estimate the prognostic significance of POLQ. A series of functional analyses were conducted in cell lines and xenograft models. Regulated pathways were predicted by Geneset Enrichment Analysis (GSEA) software and further investigated by luciferase reporter and RT-PCR assays.

We found that POLQ mRNA levels in CRPC tissues was significantly higher than that of other DNA polymerases in non-CRPC prostate tissues. POLQ upregulation was extensively detected in mCRPC and strongly predicted a poor prognosis. POLQ knockdown enhanced docetaxel sensitivity in a cell-based cytotoxicity assay and promoted the therapeutic effect on the tumor growth of metastatic PC-3M cells in xenograft models. The computational simulation by GSEA software significantly predicted the association between POLQ upregulation and the activation of E2F/G2M checkpoint-related pathways. Moreover, luciferase reporter and RT-PCR assays demonstrated that POLQ knockdown downregulated the transcriptional regulatory activity of E2F and repressed E2F/G2M checkpoint-regulated CDK1 in mCRPC cells.

Our results suggest that POLQ serves as a predictive factor for poor docetaxel response and provide a novel strategy to enhance the anticancer effects of docetaxel therapy by targeting POLQ in mCRPC patients.

Our results suggest that POLQ serves as a predictive factor for poor docetaxel response and provide a novel strategy to enhance the anticancer effects of docetaxel therapy by targeting POLQ in mCRPC patients.