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Insulin-resistance (IR) is one of the most important precursors of type 2 diabetes (T2D). Recent evidence suggests an association of depression with the onset of T2D. Accumulating evidence shows that depression and T2D share common biological origins, and DNA methylation examination might reveal the link between lifestyle, disease risk, and potential therapeutic targets for T2D. Here we hypothesize that integrative mining of IR and depression cohort data will facilitate predictive biomarkers identification for T2D. We utilized a newly proposed method to extract gene-level information from probe level data on genome-wide DNA methylation array. We identified a set of genes associated with IR and depression in clinical cohorts. By overlapping the IR-related nutraceutical-gene network with depression networks, we identified a common subnetwork centered with Vitamin D Receptor (VDR) gene. Preliminary clinical validation of gene methylation set in a small cohort of T2D patients and controls was established using the Sequenome matrix-assisted laser desorption ionization-time flight mass spectrometry. A set of sites in the promoter regions of VDR showed a significant difference between T2D patients and controls. Using a logistic regression model, the optimal prediction performance of these sites was AUC = 0.902，and an odds ratio = 19.76. Thus, monitoring the methylation status of specific VDR promoter region might help stratify the high-risk individuals who could potentially benefit from vitamin D dietary supplementation. Our results highlight the link between IR and depression, and the DNA methylation analysis might facilitate the search for their shared mechanisms in the etiology of T2D.

There is a body of evidence that the aging immune system is linked to cancer. In this study, with aging- and immune-related DNA methylation data, we investigated the DNA methylation regulation changes in promoters with other regions of genes during aging and their association with the immune-cell proportion in the circulating whole blood of individuals. The analyses for aging- and CD4+ T cell proportion-derived differential genes showed that ubiquitination plays an important role in the aging immune system and tumorigenesis. Therefore, starting from a set of pre-annotated ubiquitination genes, we found that among the differentially ubiquitinated genes, DZIP3, an E3 ubiquitin ligase with no reports on its function in immune cells and tumorigenesis, was significantly associated with both aging (P-value = 3.86e-06) and CD4+ T cell proportion (P-value = 1.97e-05) in circulating blood. By collecting a cohort of 100 colon cancer patients and 50 healthy individuals, we validated that the 1st exon DNA methylation of DZIP3 could predict the onset of early stage (AUC = 0.833, OR = 8.82) and all pTNM stages of colorectal cancer (AUC = 0.782, OR = 5.70). Thus, the epigenetically regulated ubiquitination machine plays an important role in immune aging and tumorigenesis.

ObjectiveThere is a body of evidence that the aging immune system is linked to cancer. Here, we hypothesized that ubiquitination might play a key gatekeeper role in immune system aging and tumorigenesis in CRC. Therefore, we will systematically study the DNA methylation of ubiquitination genes and screen candidate CRC marker that are correlated with both aging and immune cell compositions.DesignThrough aging- and immune-related DNA methylation data, we investigated the DNA methylation regulation changes in promoters with other regions of genes during aging and their association with the immune cell proportion in the circulating whole blood of healthy individuals. Then, by collecting a cohort of 100 colon cancer patients and 50 healthy individuals, we used nucleic acid mass spectrometry to test whether ubiquitination genes can be used as candidate markers for the early screening of CRC.ResultsThe biological analyses for aging- and CD4 T cell proportion-derived differential genes showed that they are associated with ubiquitination. Among them, DZIP3 was significantly associated with both aging (P-value = 3.86E-06) and CD4 T cell proportion (P-value = 1.97E-05) in circulating blood. Then, we validated that the 1st exon DNA methylation of DZIP3 could predict the onset of early stage CRC (AUC = 0.833, OR = 8.82) and all pTNM stages of CRC (AUC = 0.782, OR = 5.70).ConclusionsThe epigenetically regulated ubiquitination plays an important role in immune aging and tumorigenesis. DNA methylation characteristic of DZIP3 can be used as a promising marker of CRC early screening.Summary boxWhat is already known about this subject?The aging immune system is associated with cancer.Ubiquitination plays potent roles in regulating a variety of signals in both innate and adaptive immune cells.The abnormalities of ubiquitination are closely related to the occurrence of various tumors.Blood cell DNA methylome analysis provides a promising tool to probe the key components of immune cell dysregulation in aging and tumorigenesis.What are the new findings?The aging- and immune cell proportion-derived differential genes are associated with ubiquitination.The epigenetically regulated ubiquitination plays an important role in immune aging and tumorigenesis.DNA methylation characteristic of DZIP3, an E3 ubiquitin ligase with no reports on its function in immune cells and tumorigenesis, can be used as a promising markers of CRC early screening.How might it impact on clinical practice in the foreseeable future?The in-depth study for DNA methylome of ubiquitination will open up a new path for the study of CRC pathogenesis, diagnosis and treatment.In addition, DZIP3-focused screening technique only needs to extract the whole blood of individuals for MassARRAY analysis; the samples are easy to obtain, and the results are objective. Therefore, this method may have important applications in clinical CRC screening.

Tetramethylpyrazine (TMP), extracted from the Chinese herbal medicine Ligusticum wallichii franchat (chuan xiong in Chinese), is a potent anti-free radical and calcium antagonist. Correspondingly, two important hypotheses in the causation of cataracts are free radical toxicity and calcium ion overload. In this study we investigated the effect of TMP on lens opacification induced by sodium selenite in rats, addressing the potential of TMP eye drops to prevent and treat cataracts. Results showed that the extent of lens opacification in the untreated Normal Control group (NC group) was significantly less than that of selenite-injected untreated rats (MC group) on days 3, 5, 7 and 10 (p 0.001), while TMP treated selenite-injected rats (TMP group) had less lens opacification than the MC group on days 3, 5, 7 and 10 (p 0.05). Compared with the NC group, the MC group had significantly decreased activity of super-oxide dismutase (SOD), glutathione peroxidase (GSH-PX) and catalase (CAT) and significantly elevated malondialdehyde (MDA) and calcium ion content (p 0.001). Compared with the MC group, the activity of (SOD), (GSH-PX) and (CAT) were significantly higher while (MDA) and calcium ion levels were significantly lower in the TMP group at all time points (p 0.01). The findings demonstrate that the selenite-induced cataract rat models were successfully built and the TMP eye drops can delay lens opacification induced by sodium selenite in rats. The mechanism by which TMP preserves lens transparency from selenite treated animals is associated with the lenses' ability to maintain normal levels of activity of SOD, GSH-PX and CAT and normal concentrations of MDA and calcium ion.