We also found a significantly inverse
We also found a significantly inverse correlation of OPRM1 CpG2-4 methylation level with HDL-C in Han male controls. Lipids are known to involve the inflammation pathway, Aβ formation and stability of neuron, whereby their abnormalities have been shown to increase the risk of AD , , . HDL-C, as the TC transporters, was decreased in MCI . The current findings revealed their negative associations of HDL-C with OPRM1 methylation in controls, mostly in males, this result might help explain the relationship of blood TC-related indexes with DNA methylation.
Our study has several limitations. Firstly, our study only involved a moderate number of MCI patients, and future studies with larger sample size may help confirm our findings. Secondly, the present case-control study only covers two populations from Xinjiang region. The current findings needed further validation in other ethnic populations. Thirdly, although promoter fragments of OPRK1 and OPRM1 were able to upregulate gene expression, the exact epigenetic mechanism of gene expression regulation required to be explored.
In conclusion, our findings suggested that OPRK1 and OPRM1 methylation might serve as blood biomarkers of MCI in Xinjiang Chinese. Specifically, OPRK1 hypermethylation was a MCI risk factor in Xinjiang female Han. OPRM1 CpG1 hypermethylation and CpG2-4 hypomethylation were associated with MCI risk in Xinjiang Uygur and Han, respectively. In addition, our results showed that OPRK1 promoter methylation was related to gender, ethnicity, aging and environmental changes, while OPRM1 promoter methylation was related to blood lipids and living regions.
Introduction A major limiting factor in cancer chemotherapy is the toxicity of cytotoxic drugs to normal tissues. Attempts to circumvent this problem have led to the tumour targeting approach, and Ivermectin to tumour-associated proteins have been used in the development of a number of targeted anti-tumour therapies including: immunotherapy, radioimmunotherapy and immunotoxin therapy 1, 2. Disadvantages identified with these first generation antibody-based therapies, for example poor tissue penetration and cellular heterogeneity in tumour antigen expression, led to the development of antibody-directed enzyme prodrug therapy (ADEPT) . In ADEPT, an inactive prodrug is converted to a highly cytotoxic agent at the tumour site by the action of an enzyme linked to an antibody directed at a tumour-associated antigen. The ZD2767 ADEPT system utilises the A5B7 F(ab)2- carboxypeptidase G2 (CPG2) antibody-enzyme conjugate (ZD2767C) which is targeted to carcinoembryonic antigen (CEA) -expressing tumours. The enzyme, CPG2, activates a di-iodophenol mustard glutamate prodrug (ZD2767P) to the potent di-iodophenol mustard (ZD2767D) via the cleavage of the carbamate bond (Fig. 1) 4, 5. There are also a number of other enzyme-drug combinations which are being developed as potential ADEPT systems 6, 7; however, the ZD2767 ADEPT system is one of the most advanced and is undergoing phase 1 clinical evaluation. Structurally, ZD2767D is similar to the classical nitrogen mustards melphalan and chlorambucil (Fig. 1), all 3 agents having a bifunctional bis-2-haloethyl aniline moiety. It is therefore possible pelvis cellular factors which are known to be determinants of nitrogen mustard activity may also be important in the cellular pharmacology of ZD2767D. Such mechanisms include: membrane transport, intracellular detoxification (both chemical and enzymatic) and repair of drug-induced damage 8, 9. To understand determinants of ZD2767D activity, the sensitivity of a panel of colorectal and non-small cell lung cancer (NSCLC) cell lines to ZD2767 was investigated, cell lines representative of tumour types known to express CEA in patients 10, 11. Chlorambucil was used as a comparator and the importance of bifunctionality was investigated by examining the activity of a monofunctional ZD2767D analogue (Fig. 1).