Activation of aldehyde dehydrogenase 2 slows down the progression of atherosclerosis via attenuation of ER stress and apoptosis in smooth muscle cells.

Aldehyde dehydrogenase 2 (ALDH2) is a key mitochondrial enzyme in the metabolism of aldehydes and may have beneficial cardiovascular effects for conditions such as cardiac hypertrophy, heart failure, myocardial I/R injury, reperfusion, arrhythmia, coronary heart disease and atherosclerosis. In this study we investigated the role of ALDH2 in the progression of atherosclerosis and the underlying mechanisms, with a focus on endoplasmic reticulum (ER) stress. A clinical study was performed in 248 patients with coronary heart disease. The patients were divided into two groups according to their ALDH2 genotype. Baseline clinical characteristics and coronary angiography were recorded, and the coronary artery Gensini score was calculated. Serum levels of 4-hydroxy-2-nonenal (4-HNE) were detected. The clinical study revealed that the mutant ALDH2 genotype was an independent risk factor for coronary heart disease. ALDH2 gene polymorphism is closely associated with atherosclerosis and the severity of coronary artery stenosis. Serum levels of 4-HNE were significantly higher in patients with the mutant ALDH2 genotype than in patients with the wild-type ALDH2 genotype. As an in vitro model of atherosclerosis, rat smooth muscle cells (SMCs) were treated with oxygenized low-density lipoprotein (ox-LDL), which significantly elevated the levels of ER markers glucose-regulated protein78 (GRP78), protein kinase R-like ER kinase (PERK), phosphorylated eukaryotic translation initiation factor α subunit (p-eIF2α), activating transcription factor-4 (ATF-4), CEBP homologous protein (CHOP) and 4-HNE in the cells. All the ox-LDL-induced responses were significantly attenuated in the presence of Alda-1 (an ALDH2 activating agent), and accentuated in the presence of daidzin (an ALDH2 inhibitor). Furthermore, pretreatment with ALDH2 activator Alda-1 significantly decreased ox-LDL-induced apoptosis. Similarly, overexpression of ALDH2 protected SMCs against ox-LDL-induced ER stress as well as ER stress-induced apoptosis. These findings suggest that ALDH2 may slow the progression of atherosclerosis via the attenuation of ER stress and apoptosis in smooth muscle cells.

Auto-Induction Effect of Chloroxoquinoline on the Cytochrome P450 Enzymes of Rats Associated with CYP 3A and 1A.

To investigate the auto-induction of cytochrome P450 (CYP450) by Chloroxoquinoline (CXL), a novel anticancer drug. Three experiments related to the induction of CYP450 were performed: a) In vitro use of the rat fresh hepatocytes model; b) In vivo 'cocktail' of CYP450 probe model; c) Pharmacokinetic (PK) study of the single and multiple doses. Some typical CYP enzyme probes and inducers were used in these experiments and were all determined by HPLC-MS/MS. The expression levels of CYP3A and CYP1A mRNA were analyzed by the real time polymerase chain reaction (RT-PCR) technique. The PK studies showed that the area under the curve (AUC0-t) and the peak concentration (Cmax) of the multiple doses were approximately 2.4-fold and 1.9-fold lower than those of the single dose, respectively (p < 0.05). Subsequent studies were conducted to study the possible induction of CXL on CYP 450. The in vivo 'cocktail' administration of CYP450 probe model indicated that 5 d pretreatment with CXL resulted in a mean 4.6 times increase in the metabolites/probe plasma ratios for CYP 3A and a 336% increase for CYP 1A than those of the negative control (p < 0.05). The induction effect of CXL on CYP450 was further evaluated on rat hepatocytes with four concentrations (1, 10, 50 and 100 µmol/L). Compared with the negative control, the mRNA levels of CYP 1A2 increased significantly in rat hepatocytes after treatment with 10, 50 and 100 µmol/L CXL (p < 0.05). While significant inductions of CYP 3A1 were observed in the entire treated groups. The results of the present study demonstrate enhanced and induced expression of CYP 3A and CYP 1A in response to CXL exposure in rats, suggesting that CXL is an auto-inducer of CYP 3A and CYP 1A.

Glucose- and pH-responsive nanogated ensemble based on polymeric network capped mesoporous silica.

In this paper, a glucose and pH-responsive release system based on polymeric network capped mesoporous silica nanoparticles (MSN) has been presented. The poly(acrylic acid) (PAA) brush on MSN was obtained through the surface-initiated atom transfer radical polymerization (SI-ATRP) of t-butyl acrylate and the subsequent hydrolysis of the ester bond. Then the PAA was glycosylated with glucosamine to obtain P(AA-AGA). To block the pore of silica, the P(AA-AGA) chains were cross-linked through the formation of boronate esters between 4,4-(ethylenedicarbamoyl)phenylboronic acid (EPBA) and the hydroxyl groups of P(AA-AGA). The boronate esters disassociated in the presence of glucose or in acidic conditions, which lead to opening of the mesoporous channels and the release of loaded guest molecules. The rate of release could be tuned by varying the pH or the concentration of glucose in the environment. The combination of two stimuli exhibited an obvious enhanced release capacity in mild acidic conditions (pH 6.0).

Highly efficient antibacterial surface grafted with a triclosan-decorated poly(N-hydroxyethylacrylamide) brush.

This work presented a highly efficient antibacterial Ti-surface which was grafted with poly(N-hydroxyethylacrylamide) (PHEAA) brush and further decorated with triclosan (TCS). The modified surfaces were characterized using contact angle measurements, X-ray photoelectron spectroscopy, and attenuated total reflectance Fourier transform infrared. The antibacterial performance of the modified surfaces was evaluated using the Streptococcus mutans and Actinomyces naeslundii attachment test. The Ti surface with PHEAA brush (Ti-PHEAA) was able to resist the adhesion of the bacteria, while the TCS-decorated Ti surface (Ti-TCS) showed the capability of killing the bacteria adhered on the surface. As we coupled the TCS to the PHEAA brush, the surface showed highly efficient antibacterial performance due to the combination of the resistance to the bacteria adhesion and its activity of killing bacteria.

Regioselective synthesis of cytarabine monopropionate by using a fungal whole-cell biocatalyst in nonaqueous medium.

The utilization of a dehydrated fungal biocatalyst of Aspergillus oryzae cells was successfully performed to achieve efficient acylation modification of a polar nucleoside cytarabine (ara-C). Organic solvents showed evident influence on the reaction catalyzed by the A. oryzae whole-cells. Except for hexane-pyridine, the catalytic activity and regioselectivity of the whole-cells clearly increased with increasing the polarity of the hydrophobic organic solvents used. The effects of some crucial factors on the reaction were further examined. The best reaction medium, hydrophobic solvent concentration, vinyl propionate/ara-C ratio, reaction temperature and shaking speed were confirmed as isopropyl ether (IPE)-pyridine, 30% (v/v), 90, 30 °C and 140-180 rpm, respectively. The cell biocatalyst also showed good thermal stabilities in both IPE-pyridine and hexane-pyridine systems. In addition, the desired 3'-O-propional derivative of ara-C was synthesized with the yields of 88.3% and regioselectivity (>70%). The resulting biocatalytic system appears to be an effective alternative, and can thus be employed for application in highly regioselective modification of nucleoside analogues.