メタボロミクス:オープンアクセス

Mutations in metabolic enzymes, especially Isocitrate dehydrogenase1/2, strongly implicate altered metabolism in tumorigenesis by generating 2-HG. 2-HG is an oncometabolite mostly identified in AML and glioma. Wild type IDH1 and IDH2 catalyze the interconversion of isocitrate and α-KG, which is a TCA cycle intermediate and an essential cofactor for many enzymes, while 2-HG produced by mutant of IDH1/2 functions as a competitive inhibitor of α-KG, leading to epigenetic alteration and disruption of PHDs-mediated protein hydroxylation. However how is 2-HG produced in non-IDH mutated cells is still not well defined. Recent studies demonstrated that the accumulation of 2-HG in non-IDH mutated cells might be due to many other cellular mechanisms, including MYC status, expression of IDH1/2, dysregulation of 2-HGDH and hypoxia. Here we review what is known about the molecular mechanisms of transformation by IDH mutations and the mechanisms of carcinogenic metabolites 2-HG accumulation in non-IDH mutated cells. We also discuss the strategies for separation of two enantiomers of 2-HG (D and L) and their implications for the identification of the cancer subtypes and the development of targeted therapies to treat different types of human malignancies.

Endophyte, Alternaria species-1 isolated from leaf part of Crotalaria pallida was selected in isolation, identification and purification of coumarin. HPLC, UV-spectrophotometry, FTIR, NMR and XRD studies were carried out on characterization of endophytic fungal coumarin. In vitro apoptotic activity was carried out against HeLa cervical cancer cell lines. The results of MTT studies, acridine staining activity revealed the coumarin as an effective in inducing apoptotic activity in HeLa cells. The coumarin significantly inhibited the proliferation of HeLa cells and it’s a concentration and time dependent manner. Significant elevation of caspase 3 and 9 and activity was observed in coumarin treated HeLa cells but no elevation or activity of caspase 7, 8, 10 was not observed. Coumarin has shown 0.156 μg/ml of significant IC50 value against viable of HeLa cell lines. Thus, coumarin exerts apoptotic activity by caspase dependent apoptosis by enhancing the caspase 3 and 9 and it degraded the DNA (avoided the further replication). This is the first report in internationally that coumarin isolated from endophyte, Alternaria species-1, purified and characterized and its role was identified in apoptotic activity.

Transplantation of Langerhans islets is a potential cure for diabetes mellitus. The main problem for routine clinical use remains the prevention of rejection without drastic side effects. Immuno-isolation is an experimental strategy to prevent graft rejection by separating the transplanted cells from the host immune system using a barrier device. The aim of the current study was to improve the physical features of encapsulated islets in a barium cross-linked ultra-high viscosity alginate by adding Poloxamer 188 (P188). Empty alginate capsules, and especially encapsulated islets, could be easily generated using UHV-P188 alginate because of its anti-foaming properties. Diabetic mice were used for evaluation of biocompatibility and graft function. Biocompatibility testing with empty capsules showed no inflammatory reaction or fibrotic overgrowth. The capsules remained intact in the intraperitoneal and intramuscular implant sites over a period of 4 weeks. Transplantation of encapsulated islets, however, led to a strong systemic inflammatory response with fibrotic overgrowth of the islet-containing capsules but no graft failure. This finding likely reflected the complementactivating property of P188. Our results clearly showed that the complex interaction of additives, xenogeneic tissue, and alginate with the host immune system could not be predicted by the behavior of the individual components. Furthermore, the mouse model described herein was an excellent tool to evaluate the physico-chemical properties and the in vivo biocompatibility and functionality of various additives. Our results will improve the biomaterials used for alginate microbeads in a clinical setting in the future.

Tellurium (Te) has been reported to be toxic to humans but its application in industries is growing at rapid pace. Mitochondria are responsible to generate the chemical energy to regulate the fuelling of cellular processes. The decay of the mitochondria in the brain cells is a primary cause of all neurodegenerative disorders from Parkinson's to dementia. Animals were divided into 5 groups; group 1st was control. Group 2nd received Te as sodium tellurite (4.15 mg, 1/20th of LD50) orally once daily for 15 days. Groups 3rd and 4th were pretreated with zingerone (50 and 100 mg/kg b. wt respectively once daily for 15 days) followed by 15 days treatment with Te (orally once daily). On day 16, after the completion of Te dosing, the animals were sacrificed and brains were taken out to isolate the mitochondria. The content of lipid peroxidation (LPO) was increased significantly and the content of glutathione and activities of antioxidant enzymes; glutathione peroxidase (GPx) glutathione reductase (GR), glutathione-S-transferase (GST), superoxide dismutase (SOD) and catalase (CAT) were decreased significantly in the brain mitochondria of Te treated group as compared to the brain mitochondria of control group and these changes were protected significantly and dose dependently with the treatment of zingerone in Te+Z1 and Te+Z2 groups. The above study indicates that the zingerone which is part of our diet may be used as the best tool for the prevention of Te toxicity.

Human sustainable space exploration could go further with the development of strategies and preparatory activities. Enormous scientific work has been done during the 21st century. MARS-500 project is one of unique preparatory activities, and was finished within 520 day isolation on the Earth. The full 520 day MARS mission simulation provided an opportunity to conduct a long-term, isolated experiment to observe metabolic changes due to people differences and its stability to duration variation. Six volunteers were selected from Russia, France, Italy, and China, and their urine specimens were collected in six periods. Then the subtle metabolic variations were investigated by nuclear magnetic resonance (NMR) at six different periods. We found that the metabotypes of six crews drifted out from the first period to the farthest third period, then reverted to the nearest sixth period in metabolic space, suggesting a property of resilience for metabolic phenotype. Furthermore, a set of 20 biomarkers, discriminating great changes in metabolic phenotypes well, were associated with emotion, muscle turnover, circadian rhythms, energy expenditure, lipid metabolism, oxidative activity, cognitive performance, and gut-microbial activities. In deeps, to analysis the data from MARS-500 project with two-way ANOVA, an interaction between factor of people differences and long-term isolation showed that the six crews each had a specific response to 520 days’ isolation. In this picture, accurate healthy management during future human space mission should aim at promoting his or her ability to
revert to his or her stable metabotype under a defined and isolated environment.

Current clinical studies on lipidomics have revealed some outcomes that could have a great effect on treating the possible pathophysiological mechanisms through new molecular targets rather than the phenotyping results of diseases. Bladder cancer is one of the leading cancers in the field of urology and a leading cause of cancer-related death. Beside its very common epidemiology, it is a highly heterogeneous disease. Non-muscle invasive bladder cancer definition includes a fully heterogeneous disease spectrum that involves Ta low grade and T1 high grade diseases, which are completely different for recurrence, progression and disease free survival rates. From this perspective, it is essential to research new target metabolites in an attempt to elucidate the underlying mechanisms to provide a more satisfactory and individualized approach in the diagnosis, treatment and prognosis for patients with bladder cancer. Lipids have many roles in cellular structure and function. They are structural scaffolds and mediators of signal transduction as well as serving as metabolic fuels. The development in lipidomic research are promising to identify new metabolites in this highly complex and heterogeneous cancer type but more studies are warranted to eluciadate the role of complex lipid metabolism in tumor pathophysiology as well as to find out targeted molecules for treatment and prognosis management in clinical settings.

Glutathione S-transferase (GST) is a generic term that describes a class of proteins involved in phase-II detoxification of endogenous compounds and xenobiotics. Regulation and function of GSTs have influences on cell growth, oxidative stress, as well as disease progression and prevention. Although not routinely assayed in clinical laboratories, the present review highlighted the application of GST activity in diagnostic pathology. Human GSTs are divided into three main families, namely, the cytosolic, mitochondrial and membranebound microsomal GSTs. The expression of GST isoforms in biologic systems may well be of relevance from a clinical and toxicity standpoints and applies in the renewed efforts in eradication and control of parasitic infections. A survey of frequency of polymorphism and measure of GST activity among human population groups are reliable and valuable diagnostic tools. The reliability of GST activity in diagnostic pathology is underscored in pathologic conditions/disorders whose etiologies are associated with overwhelming levels of oxidative stress and failure of GST-mediated detoxification mechanisms.

Recently, it has been a big issue to distinguish the dried roots of Cynanchum wilfordii and Cynanchum auriculatum in Korean herbal medicine market. Although C. wilfordii and C. auriculatum have similar morphology, the types and quantities of metabolites may differ depending on the species. Thus, in this study, UPLC-QTOF/MS based metabolomics was applied to discriminate the roots of C. wilfordii and C. auriculatum. In the optimal LC/MS conditions, 64 known metabolites were analyzed in the two species. PCA and PLS-DA of metabolic profile data was able to differentiate between C. wilfordii and C. auriculatum. Furthermore, OPLS-DA and S-plot were applied to find the potential biomarkers for the discrimination of C. wilfordii and C. auriculatum. Finally, 4 known and 10 unknown metabolites were determined as the biomarkers, and their repeatability and reliability were also validated. This indicated the metabolite profiling is a robust approach to find discriminating biomarkers of C. wilfordii and C. auriculatum.