Month: June 2020

Importantly, special care should be taken to schedule radiation therapy appropriately, as our data show that the use of vasodilators result in increased hypoxia, which could decrease radiotherapy efficacy in patients that demonstrate a “steal” effect. Generalized arterial calcification of infancy is a severe ectopic mineralization disorder affecting primarily the arterial blood vessels in humans. The disease is often diagnosed by prenatal ultrasound, and the affected individuals in most cases die within the first year of life from cardiovascular complications. GACI is inherited in an autosomal recessive fashion, and most cases are due to mutations in the ENPP1 gene, which encodes ectonucleotide pyrophosphatase/ phosphodiesterase 1, an enzyme that hydrolyses ATP to AMP and inorganic pyrophosphate. Under physiological conditions, PPi serves as a powerful anti-mineralization factor, and with reduced ENPP1 activity in GACI, the ratio of inorganic phosphate to PPi increases creating a promineralization environment and allowing ectopic tissue mineralization to ensue. There is currently no effective treatment for GACI. A number of mouse models recapitulating the clinical features of human diseases with vascular mineralization have been described. One of them, the asj mouse, was recently identified as a result of ENU treatment in The Jackson Laboratory Neuromutagenesis Program. These mice were originally noted to demonstrate a stiff posture, abnormalities in the front legs, and a progressive, SU5416 ageassociated stiffening of the joints.. Collectively, under normal physiologic conditions, there is a complex pro-mineralization/anti-mineralization network that is required to maintain the normal homeostatic ratio of PPi/Pi. Mutations in many of the genes controlling this ratio have been shown to result in ectopic mineralization of the soft connective tissues, particularly in the skin and the arterial blood vessels. For example, mutations in the ENPP1 gene result in GACI, mutations in the ABCC6 gene underlie PXE, and patients with mutations in the NT5E gene, which encodes CD73, develop arterial calcification due to CD73 deficiency. A number of animal models, particularly targeted and spontaneous mutant mice, have been extremely helpful in providing pathomechanistic information on ectopic mineralization in human diseases. In this study, we describe a novel mutant mouse, asj-2J, which was identified in the colony breeding program of The Jackson Laboratory. This mouse was noted to have extensive mineralization of the dermal sheath of vibrissae as well as arterial blood vessels, and the mice developed a phenotypic gait due to periarticular mineral deposits. The mineralization phenotype could be significantly accelerated by placing the mice on “acceleration diet”, enriched in phosphate and low in magnesium. The phenotypic similarity of these mutant mice with a previously described asj mouse prompted us to test the hypothesis that asj-2J mice were allelic, and complementation studies supported the notion that both mice had mutations in the same gene, Enpp1. Previous studies have demonstrated that asj mice harbor a homozygous missense mutation V246D.

In cells that are exposed to hypoxia or lack functional VHL, HIF-a subunits accumulate and bind to HIF-b, forming heterodimers which transcriptionally activate a number of genes whose products are involved in cell adaptation to hypoxia and regulation of angiogenesis, which is one of the key processes in tumorigenesis. Several lines of evidence suggest that the function of VHL is likely to extend beyond its crucial role in oxygen signal transduction, and the loss of its function may result in deregulation of several signalling pathways that have key roles in biological processes such as cell proliferation, cell survival, cell invasion and metastasis. Aberrant expression of VHL tumor suppressor gene has been reported in a number of human malignancies, including kidney, colon, breast, gastric cancer and MEN2- associated medullary thyroid cancer. Arguments that prompted us to study the possible involvement of the VHL gene in PTC are: VHL gene is expressed, and VHL protein is detectable immunohistochemically in thyroid follicular epithelial cells and endothelial cells, the expression of VHL protein in nonneoplastic and neoplastic thyroid lesions correlates with tumor differentiation, clinicopathological correlations of VHL with PTC remain largely unknown. Therefore, we aimed this study at evaluation of the association between VHL status, and a AMN107 variety of demographic and cancer characteristics in a group of 264 Serbian patients admitted to our reference center for PTC from 1992 to 2008. Our work is the first large-scale study of this kind so far. Various tumor suppressor genes, oncogenes, and intricate networks of signaling cascades have been investigated previously in thyroid tumors. VHL protein is widely expressed in human tissues and its best documented tumor suppressor function is the negative regulation of hypoxia-inducible target genes involved in angiogenesis, erythropoiesis and energy metabolism. Accumulating evidence suggests that VHL may also have HIF-independent and tissue-specific tumor suppressor functions since it has been implicated in diverse cellular processes, including regulation of the extracellular matrix and cell invasion, cytoskeletal stability and cell-cycle control and differentiation. Several studies suggest that VHL plays a critical role in regulating apoptotic pathways in renal cell carcinoma. According to a recent report, VHL may be a positive regulator of TP53, providing insight into another potential mechanism by which VHL loss of function may contribute to carcinogenesis. The role of VHL in thyroid cancer development is obscure. Since it has been reported that normal follicular epithelium shows a strong expression of VHL protein and that a differential expression of VHL protein in nonneoplastic and neoplastic thyroid lesions is in proportion to the level of tumor differentiation, it is reasonable to assume that VHL may be involved in the development of the most common type of thyroid cancer, PTC. These reports prompted us to investigate the possible role of VHL as a classic tumor suppressor gene and a potential association of its expression level with the development and clinicopathological features of PTC.

Among them, SMOC1, KCNC4, PDE4DIP and COL14A1 have been reported to associate with a variety of tumors. SMOC1 is SPARC related modular calcium binding 1 and has been found a correlation with malignant progression, such as brain tumor, colorectal cancer and breast cancer. KCNC4 is a potassium voltage-gated channel and the expression increase of Kv3.4 can promote the proliferation of OSCC. PDE4DIP is a tumor marker for diagnose and establish a prognosis in patients with esophageal squamous cell carcinoma. COL14A1 may be involved in the basement membrane regulation, providing specific molecular bridges between fibrils and other matrix components. However, our work revealed that BRI3 is closely related with this SAR131675 nifedipine effect on breast cancers. BRI3 participates in tumor necrosis factor- induced cell death. Silencing of BRI3 expression clearly suppressed the phosphorylation of Erk, and consequently the proliferation and migration of MDA-MB-231 cells, suggesting that the BRI3-Erk signaling pathway is involved in regulation of this nifedipine effect on breast cancers. As another mechanism underlining nifedipine promoting the breast cancer cell migration, up-regulation of ANGPTL7 was found in response to the nifedipine treatment. ANGPTL7 is a member of angiopoietin family as vascular regulators which functions as a general endothelial cell survival factor and modulates endothelial cell adhesion. Previous work has shown that ANGTL can cause the gap between endothelial cells resulting in the metastasis of breast cancers. MicroRNAs are small, single-stranded, non-coding RNAs that regulate gene expression. Their dysregulation therefore contributes to cancer cells’ proliferation and migration. For example, miRNA-10b initiated breast tumor invasion and metastasis. miRNA-135a promoted breast cancer cell migration and invasion by targeting HOXA10. Restoration of miRNA-145 suppresses prostate cancer cell proliferation, migration and invasion by targeting FSCN1. In our study, expression of miRNA-524-5p decreased after cells were treated with nifedipine and miRNA-524-5p regulated the expression of BRI3 gene. Thus the effects of nifedipine on breast cancer is carried out by miRNA-524-5pBRI3–Erk signaling pathway. The women occupy about 1/3 in all the hypertension patients. Some of them are suffering or are genetically easier to develop breast cancers. Thus it is urged that prescription of nifedipine to women should be seriously caution. Nifedipine is dangerous for patients with breast cancers and it may worsen the situation. As a result, doctors should be aware of the fact that nifedipine promotes the breast cancers and avoid nifedipine for the women especially who suffer both breast cancer and hypertension. The deposition of Ab in the brain is a principal target in many AD treatment strategies. A current hot topic in the field is using immunotherapy to reduce and eliminate Ab deposition. The concomitant reduced b-amyloid burden is associated with restored cognitive function. The Ab vaccine has been shown to decrease and eliminate Ab deposition in the brains of AD transgenic mice and to impair behavioral and cognitive disorders in experimental mice.

Increased the risk of breast carcinoma among older women. Clinic observation on the complication of nifedipine commonly led to mental symptoms and male breast hypertrophy. However, there are other studies showing that CCBs had no relation with cancers. Besides these reports, amlodipine, diltiazem and verapamil were even found to inhibit the growth of breast cancer in themodel of nude mice as well as the meningioma growth. According to the statistics, about 45% of hypertension patients are women. Dihydropyridine e.g. nifedipine accounts for 1/10 of compounds which are daily used in the clinic treatment of hypertension and associated cardiac diseases. It is therefore critical to understand whether CCBs can promote breast cancers and what is the mechanism underlining this cancinoma provocation. In this study, we found and confirmed that nifedipine, but not verapamil, could promote breast cancer both invivo and invitro. Nifedipine decreased miRNA-524-5p, resulting in the up-regulation of brain protein I3. Erk pathway was consequently activated and led to the proliferation and migration of breast cancer cells. Ibrutinib Silencing BRI3 reversed the promoting effect of nifedipine on the breast cancer. In this study, we found that nifedipine significantly stimulated breast cancer growth in the nude mice without any effects on the mice weight. In vivo imaging of tumor tissue in nude mice showed that nifedipine treated mice had stronger and wider range of fluorescence, suggesting tumors were more active and easier to migrate. The pathological section confirmed the hypothesis. CMC-Na groups had complete envelopes and large tumor cells necrosis in the middle of tumors; whereas cancer cells invaded skeletal muscles in the nifedipine treatment groups. Additionally, nifedipine promoted the proliferation and migration of both MDAMB-231 and MCF-7 cells by in-vitro and in-vivo assay. However, verapamil, another calcium channel blocker, didn’t have the similar effects in nude mice. Previous studies have resulted in a controversial conclusion on whether CCBs promote cancer cells. Our results confirmed that nifedipine can potentiate the breast cancers. With respect to the possible mechanism, i modulation was excluded in the first instance. MDA-MB-231 cells don’t express the CACNA1C and CACNA1D subtypes, which is consistent with the previous report. Moreover, that 1 mM nifedipine failed to alter i, ruled out the connection between calcium and the promotion effect of nifedipine. The lack of expression of voltage gated calcium channels in breast cancer cells likely counts upon the rationale that blockers of VGCCs should have no effect on breast cancers. Inconsistent to most previous studies, nifedipine exerts the distinct effect from verapamil, suggesting the specificity of nifedipine on its promotion outcome instead of the character of general blockers of CCBs. Verapamil was even reported to inhibit the growth of cancer cell. Different compound structures and binding motifs may explain the different effects of CCBs on cancer cells. Nifedipine activated the phosphorylation of Erk in MDA-MB-231 cells both invivo and invitro, which suggests it functions through Erk signaling pathway.

The increased level of 5mC in the cerebellum of BTBR T+tf/J mice found in this study may be attributed to the presence of oxidative DNA lesions and a marked upregulation of de novo DNA methyltransferases Dnmt3a and Dnmt3b. Many current reports link the increase in 5hmC content in DNA to the demethylating function of TET enzymatic oxidation of 5mC. The results of the present study demonstrate that an increased level of 5hmC in the cerebellum of BTBR T+tf/J mice occurred without changes in the Tet1 and Tet2 expression. This corresponds to similar findings in the mouse hippocampus during aging. A parallel elevation of 5mC and 5hmC in DNA in the cerebellum of BTBR T+tf/J mice and individuals with autism suggest that the increase in 5hmC level is not due to its role as an intermediate during demethylation of DNA. A significant positive correlation between the 8-oxoG and 5hmC in both mouse and human cerebellum suggests that the mechanism of DNA methylation alterations found in this study may be a consequence of an altered cellular redox status and oxidative stress. In conclusion, the results of our study demonstrate that oxidative DNA lesions and an altered pattern of DNA methylation are important molecular features of the autism cerebellar phenotype. The data presented herein point that diminished expression of Ogg1 in the cerebellum of BTBR T+tf/J mice caused by single nucleotide variation in the Ogg1 gene might be a driving force that promotes the accumulation of 8-oxodG in DNA. Similar alterations in 8-oxodG in cerebellar tissue from humans with autism and BTBR T+tf/J mouse model warrant future large-scale studies to specifically address the role genetic alterations OGG1 in pathogenesis of autism in human population. The study of microbial ecology associated with dairy fermentations is fundamental to understand the bases of important traits of dairy products. Traditionally, microbial dynamics in dairy fermentations have been studied with methods based on SP600125 129-56-6 cultivation on selective media followed by phenotypic and/or molecular characterization. These approaches highlighted the role and activity, in cheese manufacturing and ripening, of two microbial groups: starter lactic acid bacteria, with primary function of producing sufficient lactic acid during cheese manufacturing to reduce the pH of the milk; and non-starter LAB, generally adventitious contaminants which grow later, during cheese ripening, with an impact on flavour development. In the last years, approaches to study microorganisms in dairy products have undoubtedly changed. Culture-dependent approaches have shown limitations in terms of recovery rate, mainly related to the lack of knowledge of the real conditions under which most of bacteria are growing in their natural habitat, and the difficulty to develop media for cultivation accurately resembling these conditions. Thus, the cultivable populations may not totally represent the community, and the actual microbial diversity could be misinterpreted. For these reasons, the trend is now towards the use of culture-independent methods because they are believed to overcome problems associate.