Identification of potential tumor markers will help stratify and identify a tumor's malignant potential and its response to specific therapies. IL-6 has been reported to be a predictor in various ...cancers. Therefore, the present study was performed to highlight the role of IL-6 in improving treatment and determining prognosis of bladder cancer. The human bladder cancer cell lines HT1376 and HT1197 were selected for cell and animal experiments, in which biological changes after experimental manipulation of IL-6 were explored, including tumor behavior and related signaling in bladder cancer. In addition, clinical specimens from 85 patients with muscle-invasive, and 50 with non-muscle invasive bladder cancers were selected for immunohistochemical staining to evaluate the predictive capacity of IL-6 in relation to clinical outcome. The data revealed that IL-6 was overexpressed in the bladder cancer specimens compared with non-malignant tissues at both mRNA and protein levels. Positive staining of IL-6 was significantly correlated with higher clinical stage, higher recurrence rate after curative treatment, and reduced survival rate. Tumor growth and invasive capability were attenuated when IL-6 was blocked. The underlying changes included decreased cell proliferation, less epithelial-mesenchymal transition (EMT), decreased DNA methyltransferase 1 expression and attenuated angiogenesis. In conclusion, our findings showed that IL-6 could be a significant predictor for clinical stage and prognosis of bladder cancer. Moreover, targeting IL-6 may be a promising strategy for treating bladder cancer.
A central question is how specificity in cellular responses to the eukaryotic second messenger Ca(2+) is achieved. Plant guard cells, that form stomatal pores for gas exchange, provide a powerful ...system for in depth investigation of Ca(2+)-signaling specificity in plants. In intact guard cells, abscisic acid (ABA) enhances (primes) the Ca(2+)-sensitivity of downstream signaling events that result in activation of S-type anion channels during stomatal closure, providing a specificity mechanism in Ca(2+)-signaling. However, the underlying genetic and biochemical mechanisms remain unknown. Here we show impairment of ABA signal transduction in stomata of calcium-dependent protein kinase quadruple mutant plants. Interestingly, protein phosphatase 2Cs prevent non-specific Ca(2+)-signaling. Moreover, we demonstrate an unexpected interdependence of the Ca(2+)-dependent and Ca(2+)-independent ABA-signaling branches and the in planta requirement of simultaneous phosphorylation at two key phosphorylation sites in SLAC1. We identify novel mechanisms ensuring specificity and robustness within stomatal Ca(2+)-signaling on a cellular, genetic, and biochemical level.
Q Curvature on a Class of 3-Manifolds Hang, Fengbo; Yang, Paul C.
Communications on pure and applied mathematics,
April 2016, Volume:
69, Issue:
4
Journal Article
•A total of 76 (poly)phenol metabolites were quantifed after consumption of artichokes.•More than 80% of the phenolic metabolites were excreted after 4 h post-consumption.•The interindividual ...variability was high, especially for gut microbial metabolites.•3ʹ-Methylation exceeded 4ʹ-methylation in sous-vide artichoke (poly)phenol metabolism.•Hepatic beta-oxidation of 3ʹ,4ʹ-dihydroxycinnamic acid occurred, but was limited.
Artichokes are a rich source of (poly)phenols, mainly caffeoylquinic acids, but little is known about their bioavailability from this source. This study investigated the absorption, metabolism and excretion of (poly)phenols after sous-vide artichoke consumption (5776 µmol of (poly)phenols) by healthy volunteers. Seventy-six (poly)phenol metabolites were identified by UHPLC-MS/MS using authentic standards, including acyl-quinic acids plus C6–C3, C6–C1, C6–C2, C6–C1–N, C6–C0 metabolites, and their phase-II conjugates. The major metabolites were 3ʹ-methoxy-4ʹ-hydroxycinnamic acid, 3ʹ-methoxycinnamic acid-4ʹ-sulfate, and 4ʹ-hydroxycinnamic acid-3ʹ-sulfate, which appeared early in plasma (Tmax < 4 h); plus 3-(3ʹ-methoxy-4ʹ-hydroxyphenyl)propanoic acid, 3-(4ʹ-methoxyphenyl)propanoic acid-3ʹ-glucuronide, 3-(3ʹ-hydroxyphenyl) propanoic acid and hippuric acids, which appeared later (Tmax > 6 h). The 24 h urinary recovery averaged 8.9% (molar basis) of the (poly)phenols consumed. Hepatic beta-oxidation of 3ʹ,4ʹ-dihydroxycinnamic acid and methylated conjugates occurred, but was limited (<0.04%). 3ʹ-Methylation exceeded 4ʹ-methylation and interindividual variability was high, especially for gut microbial metabolites (up to 168-fold).
The aim of this study was to highlight the role of 1α,25-dihydroxyvitamin D3 (calcitriol) in esophageal squamous cell carcinoma (SCC). The human esophageal SCC cell lines CE81T and TE2 were selected ...for cellular and animal experiments to investigate the changes in tumor behavior after calcitriol supplementation and the underlying mechanisms. Moreover, we evaluated the relationship between calcitriol supplementation, myeloid-derived suppressor cell (MDSC) recruitment, IL6 levels, and tumor progression by a 4-nitroquinoline 1-oxide (4-NQO)-induced esophageal tumor animal model. In this study, we demonstrated that calcitriol supplementation inhibited aggressive tumor behavior both in vitro and in vivo. The underlying changes included increased cell death, a lower degree of epithelial-mesenchymal transition, and inhibited IL6 signaling. In the 4-NQO-induced esophageal tumor animal model, increased IL6 and MDSC recruitment were linked with invasive esophageal tumors. Supplementation with calcitriol attenuated the level of IL6, the induction of MDSCs, and the incidence of 4-NQO-induced invasive tumors. Moreover, the IL6-induced changes in C57 mice, including augmented MDSC recruitment, increased levels of ROS and p-Stat3 in MDSCs, and higher suppressive function of MDSCs in T-cell proliferation, which were abrogated by calcitriol supplementation. On the basis of our results, we concluded that calcitriol abrogated the IL6-induced aggressive tumor behavior and MDSC recruitment to inhibit esophageal tumor promotion. Therefore, we suggest that supplementation with vitamin D3 may be a promising strategy for the prevention and treatment of esophageal SCC.
The aim of this study was to explore specific molecular markers that could lead to new insights into the identification of innovative treatments. The role of DNMT3b and its predictive power in the ...prognosis of oral cancer were identified. Human oral cancer cell lines including SCC4 and SCC25 were selected for cellular experiments. Changes in tumor growth, aggressiveness and the responsible signaling pathway were investigated in vitro and in vivo. Furthermore, 125 oral cancer tissue specimens were analyzed using immunohistochemical staining on tissue microarray slides, and correlations calculated between the level of DNMT3b and the clinical outcome of patients. Our data revealed that inhibition of DNMT3b resulted in slower tumor growth, attenuated tumor invasion ability and epithelial mesenchymal transition, as determined by in vitro and in vivo experiments. Activated IL-6 signaling might be responsible to the induction of DNMT3b overexpression on oral cancer. Regarding clinical data, the incidence of DNMT3b immunoreactivity in oral cancer specimens was significantly higher than in non-malignant epithelium, and positively linked to expression of IL-6. Furthermore, expression of DNMT3b was significantly linked with the risk of lymph node involvement, disease recurrence and shorter survival in patients with pathological stage III-IV oral cancer. In conclusion, IL-6 -DNMT3b axis could be used to predict the prognosis of oral cancer in clinics, and targeting DNMT3b could represent a promising treatment strategy.
The gut microbiome converts dietary compounds that are absorbed in the gastrointestinal tract and further metabolized by the human host. Sulfated metabolites are a major compound class derived from ...this co-metabolism and have been linked to disease development. In the present multidisciplinary study, we have investigated human urine samples from a dietary intervention study with 22 individuals collected before and after consumption of a polyphenol rich breakfast. These samples were analyzed utilizing our method combining enzymatic metabolite hydrolysis using an arylsulfatase and mass spectrometric metabolomics. Key to this study is the validation of 235 structurally diverse sulfated metabolites. We have identified 48 significantly upregulated metabolites upon dietary intervention including 11 previously unknown sulfated metabolites for this diet. We observed a large variation in subjects based on their potential to sulfate metabolites, which may be the foundation for classification of subjects as high and low sulfate metabolizers in future large cohort studies. The reported sulfatase-based method is a robust tool for the discovery of unknown microbiota-derived metabolites in human samples.
•Comprehensive analysis of the sulfated metabolome as a signature for microbiome-host co-metabolism.•Discovery of 11 new metabolite markers for raspberries, soy milk and flaxseeds.•Structure validation of 130 sulfated metabolites (authentic standards, MS/MS fragmentation).•48 significantly upregulated sulfated metabolites upon dietary intervention.•Targeted analysis of individual sulfated metabolome changes based on 235 compounds.
Abstract
We present another proof of the sharp inequality for Paneitz operator on the standard three sphere, in the spirit of subcritical approximation for the classical Yamabe problem. To solve the ...perturbed problem, we use a symmetrization process which only works for extremal functions. This gives a new example of symmetrization for higher-order variational problems.
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