Although manganese (Mn) is an essential metal ion biological cofactor, high concentrations could potentially induce an accumulation in the brain and lead to manganism. However, there is no "gold standard" for manganism assessment due to a lack of objective biomarkers. We hypothesized that Mn-induced alterations are associated with metabolic responses to manganism. Here we use an untargeted metabolomics approach by performing ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) on control and Mn-treated rat plasma, to identify metabolic disruptions under high Mn exposure conditions. Sprague-Dawley rats had access to deionized drinking water that was either Mn-free or contained 200 mg Mn per L for 5 weeks. Mn-exposure significantly increased liver Mn concentration in comparison with the control, and also resulted in extensive necrosis and dissolved nuclei, which suggested liver damage from hepatic histopathology. Principal component analysis readily distinguished the metabolomes between the control group and the Mn-treated group. Using multivariate and univariate analysis, Mn significantly altered the concentrations of 36 metabolites (12 metabolites showed a remarkable increase in number and 24 metabolites reduced significantly in concentration) in the plasma of the Mn-treated group. Major alterations were observed for purine metabolism, amino acid metabolism and fatty acid metabolism. These data provide metabolic evidence and putative biomarkers for the Mn-induced alterations in plasma metabolism. The targets of these metabolites have the potential to improve our understanding of cell-level Mn trafficking and homeostatic mechanisms.
BackgroundThe expression of chemokine receptors CCR7 has been studied in relation to tumor dissemination and poor prognosis in a limited number of cancers. No such studies have been done on CCR7 expression in non-Hodgkin's lymphoma (T-NHL). Our aim in this paper is to investigate the association between CCR7 expression and progression and prognosis of T-NHL.Methods1) Analysis of clinical data: The specimens were obtained from 41 patients with T-NHL and 19 patients with lymphoid hyperplasia. Their corresponding clinicopathologic data were also collected. The expression levels of CCR7, MMP-2, and MMP-9 were examined by immunohistochemical staining. 2) Human T-NHL cell lines Hut 78 (cutaneous T-cell lymphoma) and Jurkat (adult T-cell leukemia/lymphoma) were cultured. The invasiveness of the two cell lines were measured with a Transwell invasion assay, and then used to study the effects of chemokine receptors on T-NHL invasion and the underlying molecular mechanism. The transcript and expression of CCR7 were evaluated using RT-PCR and western blotting.Results1) The higher CCR7 and MMP-9 expression ratios were significantly associated with multiple lesions and higher stage III/IV. Moreover, a positive correlation was observed between CCR7 and MMP-9 expression. 2) The Hut 78 cell line was more invasive than the Jurkat cells in the Transwell invasion assay. The transcript and expression levels of CCR7 were significantly higher in Hut78 than that of Jurkat cell line. The T-NHL cell lines were co-cultured with chemokine CCL21 which increased the invasiveness of T-NHL cell. The positive association between CCL21 concentration and invasiveness was found. 3) The stronger transcript and expression of PI3K, Akt and p- Akt were also observed in Hut78 than in Jurkat cell line.ConclusionsHigh CCR7 expression in T-NHL cells is significantly associated with lymphatic and distant dissemination as well as with tumor cell migration and invasion in vitro. Its underlying mechanism probably involves the PI3K/Akt signal pathway.
BackgroundKIF20A is well known as one of the key proteins in mitosis. Recently, a number of studies illustrated that KIF20A might function as an oncogene in some carcinomas. However, its expression levels and clinical value remained unclear in gastric cancer (GC).Patients and methodsIn this study, we investigated the expression of KIF20A in samples from GC patients and cell lines by quantitative real-time PCR and Western blot. The function of KIF20A in cell proliferation of GC cell lines was examined via cell viability and colony formation assays. Immunohistochemistry assay based on a tissue microarray consisting of 146 cases was performed to evaluate the prognostic value of KIF20A. The overall survival rate of 122 GC patients based on KIF20A expression was analyzed as well. Finally, using KIF20A inhibitor, genistein, and combining it with cisplatin or fluorouracil, the antitumor effects were studied.ResultsMost GC samples (56.76%) showed higher KIF20A expression level compared to their corresponding normal specimens, which demonstrated the potential oncogenic role of KIF20A in GC. The functional studies elucidated the essential role of KIF20A in GC cell proliferation. Besides, tissue microarray result showed that the expression level of KIF20A was significantly related to the histological grades (P=0.036). Furthermore, we found the expression of KIF20A was related to poor overall survival rate, which is coincident with the results from Kaplan–Meier plotter database. In addition, we found that a KIF20A inhibitor, genistein, could enhance the antitumor activity of cisplatin and fluorouracil, which might be considered as a chemosensitive agent in GC.ConclusionKIF20A can promote cell proliferation in GC, which might be used as an independent prognostic factor and a potential therapeutic target.
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