Notes

Computerized quantification associated with epicardial adipose muscle volume.
These results demonstrate the comparable EDCs in iliac arteries of the adolescents are decreased in the adults, but relatively larger EDCs in adult SHRs can be a reflection of differential downregulation of TP and EP3 receptors during the transition from adolescence to adulthood. Also, our data suggest that blockade of both TP and EP3 receptors starting from the prehypertensive stage suppresses EDCs and the development of hypertension in SHRs.Neuroblastoma is an embryonal malignancy of early childhood arising from the embryonic sympatho-adrenal lineage of the neural crest. About half of all cases are currently classified as high-risk of disease recurrence, with an overall survival rate of less than 40% at 5 years despite intensive therapy. Recent studies on matched primary tumours and at the relapse revealed downregulation of genes transcriptionally silenced by YAP as significant association with neuroblastoma relapse. Here, we evaluated the pharmacological targeting of YAP/TAZ with the YAP/TAZ-TEAD inhibitor Verteporfin (VP) in Tumour Initiating Cells (TICs) derived from High-Risk Neuroblastoma patients. VP treatment suppresses YAP/TAZ expression, induces apoptosis and causes the re-organization of the cytoskeleton reducing cells migration and clonogenic ability. Moreover, VP reduces the percentage of side population cells and ABC transporters involved in drug resistance, and the percentage of stem cell subpopulations CD133+ and CD44+ of TICs. Finally, we demonstrated that VP sensitizes TICs to the standard drugs used for neuroblastoma therapy etoposide and cis-platin opening the way to use VP as drug repositioning candidate for recurrent neuroblastoma.5-Fluorouracil (5-FU) is the first-line chemotherapy drug for colorectal cancer but most of the patients get resistant to the drug on a longer course of treatment. After the successful use of immunotherapy in melanoma treatment, it was explored with enthusiasm in different types of solid cancers including colorectal cancer. Nivolumab and pembrolizumab (Programmed cell death-1 blocking antibodies) have shown efficacy in the mismatch repair deficient high microsatellite instability (dMMR-MSI-H) subtype of metastatic colorectal cancer (CRC) patients. Immunotherapy has shown long time remission in a subset of metastatic CRC patients. The molecular mechanism and emerging roles of immunotherapy in colorectal cancer are explored in this review article and future directions for the proper utilization of the development in immunobiology are suggested.The polyether ionophore salinomycin (SAL) has been found to selectively target breast cancer cells, including those with stem-like phenotype. On the other hand, SAL amides and esters obtained through derivatisation of the C1 carboxyl of the ionophore were found to exhibit anticancer properties, whilst reducing potential toxicity issues which often occur during standard chemotherapy. However, the studies on the activity and especially on the mechanisms of action of this class of semi-synthetic products against breast cancer cells are very limited. Therefore, in this work, we confirmed the anti-breast cancer activity of SAL, and further investigated the potential of its selected C1 amide and ester analogs to destroy breast cancer cells, including the highly aggressive triple-negative MDA-MB-231 cells. Importantly, SAL esters were found to be more potent than the native structure and their amide counterparts. Our data revealed that SAL ester derivatives, particularly compounds 5 and 7 (2,2,2-trifluoroethyl and benzotriazole ester of SAL, respectively), increase the level of p-eIF2α (Ser51) and IRE1α proteins. Akt inhibitor Additionally, an increased level of DNA damage indicators such as γH2AX protein and modified guanine (8-oxoG) was observed. These findings suggest that the apoptosis of MCF-7 and MDA-MB-231 cells induced by the most promising esters derived from SAL may result from the interaction between ER stress and DNA damage response mechanisms.Atherosclerosis is regarded as chronic inflammatory disease. The IL-6/STAT3 pathway plays an important role in inflammation. We previously described a small-molecule compound, Bazedoxifene, which target IL-6/STAT3 pathway and has been approved for clinical use for osteoporosis in postmenopausal women. The aim of this study is to evaluate the effect of Bazedoxifene in the progression of atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice. Five-week-old male ApoE-/- mice were fed with High-fat diet (HFD) containing 5 mg/kg Bazedoxifene or a matching control for 12 weeks. Oil red O (ORO) staining was used to detect plaque size; immunohistochemical staining was used to detect the presence of endothelial cells, vascular muscle cells and phosphorylated STAT3 (P-STAT3) in localized plaques. The potential underlying mechanisms in human umbilical vein endothelial cells (HUVECs) and vascular muscle cells (VSMCs) was detected by Western blot analysis, Wound healing assay and Elisa assay. In the ApoE-/- mice fed with HFD, daily Bazedoxifene administration effectively attenuated atherosclerotic plaque area (P less then 0.01), down-regulated IL-6 levels (P less then 0.01), decreased STAT3 phosphorylation, reduced VSMCs proliferation and increased endothelial coverage in aortic vessels. Interestingly, we found HUVECs lack of membrane IL-6 receptor (IL-6R) compared to VSMCs (P less then 0.01). Furthermore, we found that the soluble IL-6 receptor (sIL6R) participates in the activation of STAT3 induced by IL-6 or TNF-α in HUVECs and primary HUVECs. Bazedoxifene did not inhibit the growth of HUVECs while suppressing the proliferation of VSMCs. Bazedoxifene is an attractive novel therapeutic reagent for atherosclerosis diseases. This mechanism may be partially attributed to regulating IL-6/IL-6R/STAT3 signaling pathway.Fibrin clot structure and function are major determinants of thromboembolic diseases. The study aim was to determine the impact of epicatechin (a flavonoid with cardiovascular protective effects) on fibrin clot structure and permeability. Plasma samples from 12 healthy subjects were incubated with increasing concentrations of epicatechin. Turbidity of fibrin clot was analyzed by absorbance measurement at 405 nm. The fibrin clot nanostructure was determined by scanning spectrometry (wavelength from 500 to 800 nm) and fibrin fiber size by electron microscopy. Permeability was analyzed to assess the fibrin clot functional properties. Epicatechin addition increased the maximum absorbance from 0.34 ± 0.066 (vehicle) to 0.35 ± 0.077 (P = 0.1), 0.35 ± 0.072 (P less then 0.05) and 0.34 ± 0.065 (P = 0.5) for 1, 10 and 100 μM epicatechin, respectively. Epicatechin increased the fibrin clot fiber radius (nm) from 109.2 ± 3.2 (vehicle) to 108.9 ± 4.3 (P = 0.9), 110.0 ± 3.6 (P less then 0.05) and 109.5 ± 3.3 (P = 0.4), and the distance between protofibrils (nm) from 22.
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