Effects of particulate matter exposure on blood 5-hydroxymethylation: results from the Beijing truck driver air pollution study

Previous studies have reported epigenetic changes induced by environmental exposures. However, previous investigations did not distinguish 5-methylcytosine (5mC) from a similar oxidative form with opposite functions, 5-hydroxymethylcytosine (5hmC). Here, we measured blood DNA global 5mC and 5hmC by ELISA and used adjusted mixed-effects regression models to evaluate the effects of ambient PM₁₀ and personal PM_2.5 and its elemental components—black carbon (BC), aluminum (Al), calcium (Ca), potassium (K), iron (Fe), sulfur (S), silicon (Si), titanium (Ti), and zinc (Zn)—on blood global 5mC and 5hmC levels. The study was conducted in 60 truck drivers and 60 office workers in Beijing, China from The Beijing Truck Driver Air Pollution Study at 2 exams separated by one to 2 weeks. Blood 5hmC level (0.08%) was ∼83-fold lower than 5mC (6.61%). An inter-quartile range (IQR) increase in same-day PM₁₀ was associated with increases in 5hmC of 26.1% in office workers (P = 0.004), 20.2% in truck drivers (P = 0.014), and 21.9% in all participants combined (P < 0.001). PM₁₀ effects on 5hmC were increasingly stronger when averaged over 4, 7, and 14 d preceding assessment (up to 132.6% for the 14-d average in all participants, P < 0.001). PM₁₀ effects were also significant after controlling for multiple testing (family-wise error rate; FWER < 0.05). 5hmC was not correlated with personal measures of PM_2.5 and elemental components (FWER > 0.05). 5mC showed no correlations with PM₁₀, PM_2.5, and elemental components measures (FWER > 0.05). Our study suggests that exposure to ambient PM₁₀ affects 5hmC over time, but not 5mC. This finding demonstrates the need to differentiate 5hmC and 5mC in environmental studies of DNA methylation.     

Two-Dimensional Aerodynamic Models of Insect Flight for Robotic Flapping Wing Mechanisms of Maximum Efficiency

In the ＂modified quasi-steady＂ approach, two-dimensional （2D） aerodynamic models of flapping wing motions are analyzed with focus on different types of wing rotation and different positions of rotation axis to explain the force peak at the end of each half stroke. In this model, an additional velocity of the mid chord position due to rotation is superimposed on the translational relative velocity of air with respect to the wing. This modification produces augmented forces around the end of each stroke. For each case of the flapping wing motions with various combination of controlled translational and rotational velocities of the wing along inclined stroke planes with thin figure-of-eight trajectory, discussions focus on lift-drag evolution during one stroke cycle and efficiency of types of wing rotation. This ＂modified quasi-steady＂ approach provides a systematic analysis of various parameters and their effects on efficiency of flapping wing mechanism. Flapping mechanism with delayed rotation around quarter-chord axis is an efficient one and can be made simple by a passive rotation mechanism so that it can be useful for robotic application.     

Antitumor effects of MutT homolog 1 inhibitors in human bladder cancer cells

ABSTRACT

As standard second-line regimen has not been established for patients who are refractory to or relapse with cisplatin-based chemotherapy, an effective class of novel chemotherapeutic agents is needed for cisplatin-resistant bladder cancer. Recent publications reported that MutT homolog 1 (MTH1) inhibitors suppress tumor growth and induce impressive therapeutic responses in a variety of human cancer cells. Few studies investigated the cytotoxic effects of MTH1 inhibitors in human bladder cancer. Accordingly, we investigated the antitumor effects and the possible molecular mechanisms of MTH1 inhibitors in cisplatin-sensitive (T24) and – resistant (T24R2) human bladder cancer cell lines. These results suggest that TH588 or TH287 may induce cancer cell suppression by off-target effects such as alterations in the expression of apoptosis- and cell cycle-related proteins rather than MTH1 inhibition in cisplatin-sensitive and – resistant bladder cancer cells.

Abbreviations: MTH: MutT homolog; ROS: reactive oxygen species; CCK-8: cell counting kit-8; DCFH-DA: dichlorofluorescein diacetate; PARP: poly (ADP-ribose) polymerase     

Strategies for oral delivery of macromolecule drugs

Advances in biotechnology, gene manipulation, and protein engineering for macromolecule drugs, such as insulin, parathyroid hormone (PTH), calcitonin, human growth hormone, erythropoietin (EPO), and peptide YY (PYY) allow commercial production in large scale for diverse therapeutic uses. Other macromolecules, such as mucopolysaccharide heparin, have expanded markets through improvements in their pharmacokinetic and pharmacological effects. However, most products are available only as injectable forms and are limited to patients with no alternative therapeutic choices. Orally available macromolecule formulations are still unmet needs for improving patient compliance and expanding administration paradigms and indications. Oral delivery technologies including carrier systems, absorption enhancers, protease inhibitors, and modification by conjugating transporter or receptor recognition molecules have been developed and some are undergoing clinical studies. In this review, we discuss major obstacles for oral absorption of macromolecule drugs and summarize recent strategies to overcome the huddles related to enhancing intestinal permeation.     

sMEK1 enhances gemcitabine anti-cancer activity through inhibition of phosphorylation of Akt/mTOR

Recently, we reported that sMEK1 is down-regulated in cancer cells and tissues, and that it enhances the pro-proliferative effect as a novel pro-apoptotic protein. However, the biological mechanism of the sMEK1 tumor suppressor in the cellular signal pathway has not been well understood. In our current work, we examined whether sMEK1 could promote the cytotoxic activity of gemcitabine in the human ovarian carcinoma system. Initially, we attempted to use a treatment of gemcitabine traditional chemotherapeutic agent and over-expression of sMEK1 in OVCAR-3 cancer cells. The combined treatment of sMEK1 and gemcitabine was more effective at inhibiting cell proliferation than either chemotherapeutic agent treatment alone. In addition, sMEK1 actively contributes to cell migration through its ability to promote gemcitabine-inhibited cell migration in tumorigenesis. Cell cycle-related proteins are highly associated with the down-regulation of cyclin D1 and CDK4, and the promotion of p16 and p27 as a cyclin-dependent kinase inhibitor. At the same time, sMEK1 arrests cell cycle progression in the G(1)-G(0) phase, and activates p53 and p21 expression, whereas Bcl-2 and Bcl-xL protein expression is reduced. Additionally, sMEK1 and gemcitabine suppresses the phosphorylation of signaling modulators downstream of PI3K, such as PDK1 and Akt. The p53 and p21 promoter luciferase activities were promoted by either sMEK1 or gemcitabine, and sMEK1 and gemcitabine combined additively activated the promoter further. Furthermore, as expected, sMEK1 plus gemcitabine markedly reduced the phosphorylation of p70S6K and the phosphorylation of 4E-BP1, which is one of the best characterized targets of the mTOR complex cascade. Taken together, these results provide evidence that sMEK1 can effectively regulate the pro-apoptotic activity of gemcitabine through the up-regulation of p53 expression.