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Lou X.-D.,Fudan University | Wang H.-D.,Fudan University | Xia S.-J.,Fudan University | Skog S.,Sino Swed Molecular Bio Medicine Research Institute
Fudan University Journal of Medical Sciences

Diabetes mellitus and its associated micro- and macrovascular complications have posed a great threat to public health and become the main cause of morbidity and mortality burden to state economy. Recent studies have raised that epigenetics may play an important role in the pathology of diabetic vascular diseases, which refers to phenotype changes that are not related to the underlying DNA sequence, yet the alterations in gene expression can possibly be inherited into next generation. Furthermore, UKPDS and DCCT-EDIC demonstrate a phenomenon called metabolic memory, even if the blood glucose level is controlled in an ideal state, vascular inflammation still persists. Although epigenetics has not been fully elucidated, it provides a new insight into the pathogenesis of diabetes and is expected to become the targeted therapy for severe diseases. Source

Lou X.-D.,Fudan University | Wang H.-D.,Fudan University | Xia S.-J.,Fudan University | Xia S.-J.,Chongqing Medical University | And 2 more authors.
Archivum Immunologiae et Therapiae Experimentalis

This paper studies the expression of proinflammatory cytokines such as IL-1β, IL-6, TNF-α, and IFN-γ and anti-inflammatory cytokines such as IL-10 in diabetic rat aortas, the effects of resveratrol on these cytokines, and the potential epigenetic mechanisms involved. The experiment was performed on rats divided into four groups: normal group (NC), normal interventional group (NB), diabetic group (DM), and diabetic interventional group (DB). The NB and DB groups were treated with resveratrol. After more than 3 months, the rats' aortas were removed and analyzed for cytokines by using immunohistochemistry, Western blotting, real-time PCR, and methylation-specific PCR. Histological localization of these cytokines was mainly found in the arterial intima of diabetic rats. The protein and mRNA expression levels of IL-1β, IL-6, TNF-α, and IFN-γ were significantly higher in the DM group than in the NC group (p < 0.05), whereas in the resveratrol-treated groups (NB and DB), the levels were relatively lower than those in the corresponding groups. The DM group showed reduced levels of DNA methylation at the specific cytosine phosphate guanosine sites of IL-1β, IL-6, TNF-α, and IFN-γ, relative to those in the NC group (p < 0.01), and these levels were increased by resveratrol. In contrast, IL-10 was dramatically methylated and showed decreased expression in response to high glucose, and resveratrol reversed this effect. These results demonstrate that the inflammatory response is involved in diabetic macroangiopathy. Resveratrol inhibits the expression of proinflammatory cytokines and thus may have a protective effect on the aorta in hyperglycemia. Thus, DNA methylation, an epigenetic gene silencing signal, may be responsible for these two phenomena. © 2014 L. Hirszfeld Institute of Immunology and Experimental Therapy. Source

Xu Y.,Nanjing University | Xu Y.,Nanjing Southeast University | Liu B.,Nanjing University | Shi Q.-L.,Nanjing University | And 8 more authors.
International Journal of Clinical and Experimental Medicine

Objectives: The sensitivity and reliability of the biomarkers thymidine kinase 1 (TK1) and Ki-67 were studied in relation to clinical features and prognosis of survival for pathological-T1 (pT1) lung adenocarcinoma patients. Methods: TK1 and Ki-67 expression was determined in 80 patients with pT1 adenocarcinoma of the lung and in 20 specimens from normal lung tissues, using immunohistochemistry. Results: TK1 was found in most lung tumor cells both in the cytoplasm and the nuclei. The positive labelling index (LI) for total TK1 was significantly higher than that for Ki-67. There was a significant correlation between the LI of total TK1 and lymph node metastasis, degree of tumor invasion and pathologic stages, which was not found for Ki-67. In addition, the overall 5-year survival of patients was statistically significant different between low and high levels of TK1 expression, but not in cases of Ki-67. A multivariate analysis revealed that expression of TK1, lymph node involvement and TNM pathology staging could serve as independent prognostic factors for the disease progression of pT1 lung adenocarcinoma patients. Conclusions: Compared with Ki-67, TK1 is a more reliable proliferation index in pT1 adenocarcinoma of lung, which can evaluate the invasion and the prognosis of tumor. © 2014, E-Century Publishing Corporation. All rights reserved. Source

Luo P.,Wuhan University | Wang N.,Karolinska University Hospital | He E.,Karolinska University Hospital | He E.,Sino Swed Molecular Bio Medicine Research Institute | And 5 more authors.
Pathology and Oncology Research

The activity of the proliferation related enzyme thymidine kinase 1 (TK1) was reported to be 3-fold higher in extracts from normal kidney tissue as compare to renal carcinoma extracts [3]. To verify these unexpected results, determinations of the protein levels of TK1 in normal kidney and in samples from different types of renal cell carcinoma (RCC) were done with immunohistochemistry and Western blot analysis. Two anti-TK1 peptide antibodies reacting with different TK1 epitops were used. TK1 levels were high in tubule cells as compared to glomerulus cells and connective tissue cells, while an intermediary TK1 was observed in renal cell carcinoma (RCC) cells. Western blot analysis demonstrated high levels of TK1 in extract from normal kidney, and lower levels of TK1 in the RCC extracts. The specificity of TK1 staining was demonstrated in competition experiments with excess TK1 antigen. The high TK1 levels in normal kidney tubule cells suggest that they are in a form of activated G1-state. The relatively low TK1 level in RCC, representing TK1 expression in S-phase cells, is in accordance with the low overall proliferation rate of these tumors. These results suggest that cell cycle regulation of TK1 in normal tubule cells differ from that in other type of normal and malignant renal cells. © Arányi Lajos Foundation 2009. Source

Sun J.,Fudan University | Lou X.,Fudan University | Wang H.,Fudan University | Sollazzo A.,University of Stockholm | And 4 more authors.
International Journal of Diabetes in Developing Countries

The increased oxidative stress in diabetes is known to contribute to the development of diabetes. We investigate whether serum 8-hydro-2′-deoxyguanosine (8-oxo-dG) is associated with diabetes at the time of first diagnosis and evaluate whether it can be used as a reliable biomarker for the oxidative stress in diabetes. The study was designed as a case control study with two groups: patient with diabetes and control. The diabetes group consisted of a total of 28 patients consulting the hospital for the first time and definitely diagnosed for diabetes, and the control group was composed of 65 healthy subjects. Serum 8-oxo-dG was measured by a competitive enzyme-linked immunosorbent assay (ELISA) kit, specially developed to minimize cross-reaction of 8-oxo-dG antibody with serum guanosine. The average serum 8-oxo-dG levels in patients with diabetes and controls were 0.72 ± 0.41 and 0.24 ± 0.14 ng/mL, respectively, statistically significant (p < 0.001). The 8-oxo-dG value was significantly higher in women with diabetes, compared with men with diabetes (p = 0.028). The sensitivity and the specificity of the 8-oxo-dG ELISA assay were 0.80 and 0.96, respectively, and the ROC value was 0.93. This study suggests that increased oxidative stress has an important role in the pathogenesis of diabetes. Serum 8-oxo-dG may be a useful clinical biomarker for the early diagnosis of stress-related diseases, e.g. diabetes and its management. © 2015, Research Society for Study of Diabetes in India. Source

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