Background Mast cells have gained notoriety based on their detrimental contributions to IgE-mediated allergic disorders. Although mast cells express the vitamin D receptor (VDR), it is not clear to ...what extent 1α,25-dihydroxyvitamin D3 (1α,25OH2 D3 ) or its predominant inactive precursor metabolite in the circulation, 25-hydroxyvitamin D3 (25OHD3 ), can influence IgE-mediated mast cell activation and passive cutaneous anaphylaxis (PCA) in vivo. Objective We sought to assess whether the vitamin D3 metabolites 25OHD3 and 1α,25(OH)2 D3 can repress IgE-dependent mast cell activation through mast cell–25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) and mast cell–VDR activity. Methods We measured the extent of vitamin D3 suppression of IgE-mediated mast cell degranulation and mediator production in vitro , as well as the vitamin D3 –induced curtailment of PCA responses in WBB6F1 - KitW/W-v or C57BL/6J- KitW-sh/W-sh mice engrafted with mast cells that did or did not express VDR or CYP27B1. Results Here we show that mouse and human mast cells can convert 25OHD3 to 1α,25(OH)2 D3 through CYP27B1 activity and that both of these vitamin D3 metabolites suppressed IgE-induced mast cell–derived proinflammatory and vasodilatory mediator production in a VDR-dependent manner in vitro . Furthermore, epicutaneously applied vitamin D3 metabolites significantly reduced the magnitude of skin swelling associated with IgE-mediated PCA reactions in vivo ; a response that required functional mast cell–VDRs and mast cell–CYP27B1. Conclusion Taken together, our findings provide a mechanistic explanation for the anti-inflammatory effects of vitamin D3 on mast cell function by demonstrating that mast cells can actively metabolize 25OHD3 to dampen IgE-mediated mast cell activation in vitro and in vivo.
In order to improve the effect of continuous speech recognition, this paper combines the DTW algorithm to construct a continuous Russian speech recognition system and proposes a continuous Russian ...speech detection method based on VGDTW-MPCA with an unequal interval process. Moreover, considering the influence of the correlation between variables on the synchronization of the DTW algorithm, this paper constructs a DTW algorithm on a local data set to synchronize in different variable groups. Then, this paper integrates the obtained data into complete 3D data for modeling. It can be seen from the simulation research that the Russian continuous speech recognition system based on DTW proposed in this paper has a high continuous Russian speech recognition accuracy.
FOXO transcription factors are key tumor suppressors in mammalian cells. Until now, suppression of FOXOs in cancer cells was thought to be mainly due to activation of multiple onco-kinases by a ...phosphorylation-ubiquitylation-mediated cascade. Therefore, it was speculated that inhibition of FOXO proteins would naturally occur through a multiple step post-translational process. However, whether cancer cells may downregulate FOXO protein via an alternative regulatory mechanism is unclear. In the current study, we report that expression of miR-96 was markedly upregulated in breast cancer cells and breast cancer tissues compared with normal breast epithelial cells (NBEC) and normal breast tissues. Ectopic expression of miR-96 induced the proliferation and anchorage-independent growth of breast cancer cells, while inhibition of miR-96 reduced this effect. Furthermore, upregulation of miR-96 in breast cancer cells resulted in modulation of their entry into the G1/S transitional phase, which was caused by downregulation of cyclin-dependent kinase (CDK) inhibitors, p27(Kip1) and p21(Cip1), and upregulation of the cell-cycle regulator cyclin D1. Moreover, we demonstrated that miR-96 downregulated FOXO3a expression by directly targeting the FOXO3a 3'-untranslated region. Taken together, our results suggest that miR-96 may play an important role in promoting proliferation of human breast cancer cells and present a novel mechanism of miRNA-mediated direct suppression of FOXO3a expression in cancer cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Lipid rafts, specialized domains in cell membranes, function as physical platforms for various molecules to coordinate a variety of signal transduction processes. Flotinllin-1 (FLOT1), a marker of ...lipid rafts, is involved in the progression of cancer, but the precise mechanism remains unclear. The aim of the present study was to examine the role of FLOT1 on the tumorigenesis of breast cancer cells and its clinical significance in progression of the disease.
FLOT1 expression was analyzed in 212 paraffin-embedded, archived clinical breast cancer samples by using immunohistochemistry (IHC). The effect of FLOT1 on cell proliferation and tumorigenesis was examined in vitro and in vivo. Western blotting and luciferase reporter analyses were carried out to identify the effects of downregulating FLOT1 on expression of cell cycle regulators and transcriptional activity of FOXO3a.
IHC analysis revealed high expression of FLOT1 in 129 of the 212 (60.8%) paraffin-embedded archived breast cancer specimens. The overall expression level of FLOT1 significantly correlated with clinical staging and poor patient survival of breast cancer. Strikingly, we found that silencing FLOT1 inhibited proliferation and tumorigenicity of breast cancer cells both in vitro and in vivo, which was further shown to be mechanistically associated with suppression of Akt activity, enhanced transcriptional activity of FOXO3a, upregulation of cyclin-dependent kinase inhibitor p21(Cip1) and p27(Kip1), and downregulation of the CDK regulator cyclin D1.
FLOT1 plays an important role in promoting proliferation and tumorigenesis of human breast cancer and may represent a novel prognostic biomarker and therapeutic target for the disease.
In the current Tumour-Node-Metastasis (TNM) classification system for renal cell carcinoma (RCC), both renal sinus fat invasion (SFI) and perinephric fat invasion (PFI) are defined as T3a, suggesting ...that the prognosis should be similar for the two pathologic findings. Several studies, however, have reported a worse prognosis for SFI in patients with a T3a tumor. In order to compare the prognosis of these two pathologic findings (SFI versus. PFI) in a more comprehensive way, this meta-analysis was performed.
To identify relevant studies, Medline, Embase, Cochrane Library, and Scopus database were searched from the inception until October 2014. A meta-analysis was performed using Review Manager 5.2 and STATA 11. Pooled Odds ratio (OR) and/or hazard ratio (HR) with 95% confidence interval (CI) were calculated to examine the risk or hazard association.
A total of 6 studies including 1031 patients qualified for analysis. T3a RCC patients with SFI were significantly associated with poor cancer specific survival(CSS) (HR: 1.47, 95% CI: 1.19-1.83; P<0.001) compared to those with PFI. In T3aNx/N0M0 subgroup, SFI patients also showed a worse prognosis than those with PFI (CSS, HR: 1.94, 95% CI: 1.21-3.12; P = 0.006). T3a RCC patients with SFI had higher Furhman grade, greater possibility of lymph node metastasis, sarcomatoid differentiation and tumour necrosis. Main limitation is the relatively small number of included studies.
The present meta-analysis suggested that SFI is associated with worse CSS in patients with pT3a RCC. However, due to the small number of included studies, future studies with a large sample size are required to further verify our findings.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Astrocyte elevated gene-1 (AEG-1), upregulated in various types of human cancers, has been reported to be associated with the carcinogenesis of human cancer. However, the functional significance of ...AEG-1 in human esophageal squamous cell carcinoma (ESCC) remains unknown. In the present study, we showed the expression of AEG-1 was markedly upregulated in esophageal cancer cell lines and surgical ESCC specimens at both transcriptional and translational levels. Immunohistochemical analysis revealed that 80 of 168 (47.6%) paraffin-embedded archival ESCC specimens exhibited high levels of AEG-1 expression. Statistical analysis suggested the upregulation of AEG-1 was significantly correlated with the clinical staging of the ESCC patients (P = 0.001), T classification (P = 0.002), N classification (P = 0.034), M classification (P = 0.021) and histological differentiation (P = 0.035) and those patients with high AEG-1 levels exhibited shorter survival time (P < 0.001). Multivariate analysis indicated that AEG-1 expression might be an independent prognostic indicator of the survival of patients with ESCC. Furthermore, we found that ectopic expression of AEG-1 in ESCC cells could significantly enhance cell proliferation and anchorage-independent growth ability. Conversely, silencing AEG-1 by short hairpin RNAi caused an inhibition of cell growth and anchorage-independent growth ability on soft agar. Moreover, we demonstrated that the upregulation of AEG-1 could reduce the expression of p27Kip1 and induce the expression of cyclin D1 through the AKT/FOXO3a pathway. Our findings suggest that the AEG-1 protein is a valuable marker of ESCC progression and that the upregulation of AEG-1 plays an important role in the development and pathogenesis of human ESCC.
Background and Purpose
Podocyte injury plays a key role in the development of diabetic nephropathy (DN). We have recently shown that 11R‐VIVIT, an inhibitor of cell‐permeable nuclear factor of ...activated T‐cells (NFAT), attenuates podocyte apoptosis induced by high glucose in vitro. However, it is not known whether 11R‐VIVIT has a protective effect on DN, especially podocyte injury, under in vivo diabetic conditions. Hence, we examined the renoprotective effects of 11R‐VIVIT in diabetic db/db mice and the possible mechanisms underlying its protective effects on podocyte injury in vivo and in vitro.
Experimental Approach
Type 2 diabetic db/db mice received i.p. injections of 11R‐VIVIT (1 mg·kg−1) three times a week and were killed after 8 weeks. Immortalized mouse podocytes were cultured under different experimental conditions.
Key Results
11R‐VIVIT treatment markedly attenuated the albuminuria in diabetic db/db mice and also alleviated mesangial matrix expansion and podocyte injury. However, body weight, food and water intake, and glucose levels were unaffected. It also attenuated the increased NFAT2 activation and enhanced urokinase‐type plasminogen activator receptor (uPA receptor) expression in glomerulor podocytes. In cultured podocytes, the increased nuclear accumulation of NFAT2 and uPA receptor expression induced by high glucose treatment was prevented by 11R‐VIVIT or NFAT2‐knockdown; this was accompanied by improvements in the filtration barrier function of the podocyte monolayer.
Conclusions and Implications
The NFAT inhibitor 11R‐VIVIT might be a useful therapeutic strategy for protecting podocytes and treating DN. The calcinerin/NFAT2/uPA receptor signalling pathway should be exploited as a therapeutic target for protecting podocytes from injury in DN.
Calanthe fimbriata Franch. is a Tujia ethnic herb, which has traditionally been used to treat gastric ulcers, chronic hepatitis, etc. We explored the chemical constitutes, gastroprotective effects, ...and the active fraction of C. fimbriata, as well as elucidating the underlying mechanisms. Firstly, four in vitro antioxidant tests were applied to determine the oxidation resistance of C. fimbriata methanol extract and its fractions. The gastroprotective effects were evaluated in ethanol-induced gastric ulcer rats, gastric histopathology was visualized by H&E staining, and the acidity of gastric juice was measured by titrating with NaOH solution. The contents of malondialdehyde, catalase, superoxide dismutase, gastrin, and the activity of H+K+-ATPase were estimated using commercial kits. EtOAc fraction of C. fimbriata methanol extract (CfEF) exhibited significant gastroprotective effects by ameliorating stomach pathological changes and elevating the pH value of gastric juice. It also manifested remarkable antioxidant activities in vitro and in vivo. Using various chromatographic methods and spectroscopic techniques, 22 compounds were isolated and characterized from CfEF, in which alkaloids were the predominant components. All of these substances were derived from C. fimbriata for the first time. The results indicated that CfEF is a promising source of gastroprotective agents. The antioxidant activity of this herb, as well as prevention of gastrin secretion and inhibition of H+K+ -ATPase, was found to be the underlying mechanism of action.
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•The ethnic herb of Calanthe fimbriata had significantly anti-gastric ulcer effects in rats.•The EtOAc fraction was the active part of the anti-gastric ulcer.•The main chemical constituents of the active fraction were alkaloids.•The mechanisms of action were antioxidation and inhibition of gastric acid secretion.
Muscle invasive bladder cancer (MIBC) is often lethal and non-MIBC (NMIBC) can recur and progress, yet prognostic markers are currently inadequate. SAM68, a member of RNA-binding proteins, has been ...reported to contribute to progression of other cancers. The aim of this study is to investigate the potential utility of SAM68 in the progression and prognosis of bladder cancer.
Quantitative PCR and immunohistochemistry were utilized to examine the expression of SAM68 in ten pairs of MIBC and adjacent normal bladder urothelium, and eight pairs of MIBC and non-MIBC (NMIBC) tissues from the same patient. Moreover, SAM68 protein expression level and localization were examined by immunohistochemistry in 129 clinicopathologically characterized MIBC samples. Prognostic associations were determined by multivariable analysis incorporating standard prognostic factors.
SAM68 expression was elevated in MIBC tissues compared with adjacent normal bladder urothelium, and was increased at both transcriptional and translational levels in MIBC tissues compared with NMIBC tissues of the same patient. For MIBC, high expression and nucleus-cytoplasm co-expression of SAM68 were associated with higher T-stage, higher N-stage and worse recurrence-free survival. Five-year recurrence-free survival was 80% and 52.9% for MIBC patients with low and high SAM68 expression, respectively (p = 0.001). SAM68 nucleus-cytoplasm co-expression associated with worse 5-year recurrence-free survival rate (49.2%) than SAM68 expression confined to the nucleus (82.5%) or cytoplasm (75.5%) alone. On multivariable analysis SAM68 expression level, SAM68 nucleus-cytoplasm co-expression, T-stage, and N-stage were all independent prognostic factors for recurrence-free survival of MIBC patients.
SAM68 expression is increased in MIBC when compared to normal urothelium and NMIBC, and appears to be a potentially useful prognostic marker for MIBC.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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