Curcumin ß-D-Glucuronide Plays an Important Role to Keep High Levels of Free-Form Curcumin in the Blood.

Curcumin, a polyphenol derived from the rhizome of the naturally occurring plant Curcuma longa, has various pharmacological actions such as antioxidant and anti-inflammatory effects. In this paper, we evaluated the role of its internal metabolite, curcumin ß-D-glucuronide (curcumin monoglucuronide, CMG), by investigating curcumin kinetics and metabolism in the blood. Firstly, we orally administered highly bioavailable curcumin to rats to elucidate its kinetics, and observed not only the free-form of curcumin, but also, curcumin in a conjugated form, within the portal vein. We confirmed that curcumin is conjugated when it passes through the intestinal wall. CMG, one of the metabolites, was then orally administered to rats. Despite its high aqueous solubility compared to free-form curcumin, it was not well absorbed. In addition, CMG was injected intravenously into rats in order to assess its metabolic behavior in the blood. Interestingly, high levels of free-form curcumin, thought to be sufficiently high to be pharmacologically active, were observed. The in vivo antitumor effects of CMG following intravenous injection were then evaluated in tumor-bearing mice with the HCT116 human colon cancer cell line. The tumor volume within the CMG group was significantly less than that of the control group. Moreover, there was no significant loss of body weight in the CMG group compared to the control group. These results suggest that CMG could be used as an anticancer agent without the serious side effects that most anticancer agents have.

Biodegradable honeycomb-patterned film composed of poly(lactic acid) and dioleoylphosphatidylethanolamine.

Honeycomb-patterned films have been reported to be useful for scaffolds of cell culture in tissue engineering. In the present study, we investigated a new compound, dioleoylphosphatidylethanolamine (DOPE), a naturally derived phospholipid having unsaturated fatty acid moieties, as a surfactant for fabricating honeycomb-patterned poly(d,l-lactide) (PLA) film. Only DOPE among commercially available phospholipids was useful as a surfactant, and it showed good solubility in PLA/chloroform solution and an excellent property for fabricating honeycomb-patterned film (the concentration of DOPE was from 0.2% to 20% by weight based on the weight of PLA). The pore size of the honeycomb was uniform, and all pores were interconnected with each other. The contact angle of water on the honeycomb-patterned film was affected by the amount of DOPE. Time-of-flight secondary ion mass spectrometer (TOF-SIMS) data suggested that DOPE was concentrated on the surface of the honeycomb-patterned film. To investigate cell proliferation and adhesion on the honeycomb-patterned film, NIH3T3 fibroblast cells were cultured on the film. The NIH3T3 cells adhered well on the honeycomb-patterned PLA film with DOPE (PLA-DOPE) and showed good cell proliferation compared to that on honeycomb-patterned PLA film fabricated with a copolymer (CAP) of dodecylacrylamide and omega-carboxyhexylacrylamide (PLA-CAP). These results suggest that the honeycomb-patterned PLA-DOPE can be applicable as a scaffold for cells with better profiles in comparison with PLA-CAP.

Expression of tissue transglutaminase and elafin in human coronary artery: implication for plaque instability.

BACKGROUND: the extracellular matrix (ECM) is an important determinant of plaque instability. Since tissue transglutaminase (tTG) and elafin act as stabilizing factors, they might play a crucial role in the pathogenesis of acute coronary syndrome. We examined their expression in human coronary arteries and the regulation of tTG expression in cultured vascular smooth muscle cells (SMCs). METHODS AND RESULTS: immunohistochemical studies on autopsy samples of human coronary arteries revealed the expression of tTG and elafin in the endothelium, medial SMCs, and the ECM in non-atherosclerotic coronary arteries. Their expression in SMCs, endothelium, and ECM was enhanced in atherosclerotic coronary arteries. In contrast, they were hardly detectable in accumulating macrophages or at the lipid core. Double staining demonstrated that elafin was co-localized with tTG. Moreover, some tTG-expressing cells were positive for TNF-alpha, suggesting that this cytokine might play an important role in the regulation of tTG. Treatment of cultured rat aortic SMCs with TNF-alpha increased their tTG mRNA, protein expression and enzyme activity. CONCLUSIONS: the expression of tTG and elafin increased in atherosclerotic coronary arteries. The investigation with cultured SMCs suggested that TNF-alpha might mediate the upregulation of tTG. Our findings may provide new insights into the mechanism of plaque instability and the pathogenesis of acute coronary syndrome.

A thin honeycomb-patterned film as an adhesion barrier in an animal model of glaucoma filtration surgery.

PURPOSE: To evaluate the effectiveness and safety of a thin honeycomb-patterned biodegradable film for glaucoma filtration surgery in rabbits. METHODS: A 7 microm-thick film made from poly(L-lactide-co-epsilon-caprolactone) was placed in the subconjunctival space in one eye of rabbits, with or without full thickness filtration surgery. The film had a honeycomb-patterned surface that faced the subconjunctival Tenon tissue and the other side was smooth. Filtration surgery was also performed in the fellow eye, which received either no adjunctive treatment or 0.4 mg/mL mitomycin C (MMC; n=6 each). Intraocular pressure (IOP) measurements and bleb evaluations using ultrasound biomicroscopy were performed periodically for 28 days after surgery followed by histologic observation. RESULTS: Postoperative IOPs of the film-treated eyes were significantly lower than that of control eyes from day 10 to day 28 (P<0.05), but were not significantly different from those of MMC-treated eyes. The subconjunctival filtration space, detected by ultrasound biomicroscopy, disappeared in 5 control eyes, 1 MMC-treated eye, but none of the film-treated eyes. A bleb leak occurred postoperatively in 2 MMC-treated eyes. Histologically, in eyes without filtration surgery, fibrotic tissue with the film partly attached to it was noted on the honeycomb side, but was minimal on the sclera that faced the smooth side of the film. In eyes with filtration surgery, the honeycomb-patterned film lined the inner bleb wall with minimal inflammatory reaction. CONCLUSIONS: The thin honeycomb-patterned film that attached to the inner bleb wall worked as an adhesion barrier in glaucoma filtration surgery in rabbits, which is worthy of further investigation.

Prevention of postoperative adhesions by a novel honeycomb-patterned poly(lactide) film in a rat experimental model.

Intraperitoneal adhesion is a serious problem concerning abdominal surgery. This study evaluated the performance of a honeycomb-patterned poly(lactide) (HCPLA) film as a physical barrier for preventing postoperative adhesion. HCPLA films were prepared using dioleoylphosphatidylethanolamine (DOPE) or a copolymer of dodecylacrylamide and omega-carboxyhexylacrylamide (CAP) as a surfactant (HCPLA-DOPE and HCPLA-CAP, respectively). In an in vivo adhesion prevention experiment, male Sprague-Dawley rats underwent standard cecum abrasion before midline laparotomy. We placed 2 cm x 2 cm HCPLA and flat films on the gliding interfaces; untreated rats formed the control group. After 1 week, adhesion was scored from 0 to 4. No significant difference was observed in the scores among groups, but macroscopic differences in adhesion prevention were observed. The adhesive strength of HCPLA-DOPE (18.1 +/- 1.2 g) to skinless chicken breast was significantly higher than that of the flat film (15.2 +/- 0.8 g, p < 0.05). Further, the adhesion score after 1 week for the HCPLA-DOPE group (1.6 +/- 0.2) was significantly lower than that for the control group (3.0 +/- 0.3, p < 0.05) but comparable to that for the Seprafilm group (1.4 +/- 0.3). These results demonstrated the potential of HCPLA-DOPE as a physical barrier for preventing postoperative adhesion.

Development of a novel temporary epicardial pacing wire with biodegradable film.

PURPOSE: A temporary epicardial pacing wire (TEPW) has been routinely placed in patients undergoing cardiac surgery. However, its fixation or removal occasionally causes troublesome complications. The aim of this study is to develop a novel TEPW using biodegradable film to fix the electrode to the epicardium without needle stabbing. DESCRIPTION: A biodegradable film was prepared with poly(L-lactide-co-epsilon-caprolactone). The film has a honeycomb-patterned structure that serves as a temporary adhesive for the myocardial surface, and the electrode was incorporated within the film. The novel TEPW was placed on the ventricular epicardium of dogs (group A, n = 5). As a control, conventional TEPW was inserted (group B, n = 6). The pacing threshold, R wave amplitude, impedance, and slew rate were measured at postoperative days 0, 1, 3, 5, 7, and 14, and complications after removal were checked. EVALUATION: All measurements in both groups were identified and differences were not observed. In addition, the novel TEPWs could be easily removed without related complications. CONCLUSIONS: This novel TEPW is safe and feasible for postoperative management of cardiac surgeries.

Oncostatin M, a cytokine released by activated mononuclear cells, induces epithelial cell-myofibroblast transdifferentiation via Jak/Stat pathway activation.

Interactions between inflammatory infiltrates and resident tubular epithelial cells may play important roles in the development of tubulointerstitial fibrosis, by promoting epithelial cell-myofibroblast transdifferentiation (EMT). Human proximal tubular epithelial cells transdifferentiated to myofibroblasts after treatment with activated PBMC conditioned medium. mRNA and protein levels for alpha-smooth muscle actin, collagen I, and fibronectin EDA(+) (markers for the myofibroblastic phenotype) were increased, whereas those for E-cadherin and cytokeratin 19 (markers for the epithelial phenotype) were decreased. cDNA microarray analysis was used to identify other changes in gene expression that might point to novel molecular mechanisms driving EMT. Of 1176 array genes, 61 demonstrated at least a twofold change at at least two consecutive time points, of the five time points examined (0.5, 4, 8, 16, and 48 h). Of these genes, 59% were upregulated and 41% were downregulated. The array indicated upregulation of expression of the oncostatin M (OSM)-specific receptor beta subunit from 4 to 48 h after exposure of kidney epithelial cells to activated PBMC conditioned medium, which contained high levels of OSM. In additional experiments, it was demonstrated that OSM induced EMT. OSM activated the Jak/Stat signaling pathway in epithelial cells, and a specific inhibitor of Jak2 blocked both its phosphorylation after exposure to OSM and the induction of alpha-actin and loss of cytokeratin 19 expression. Therefore, OSM is a novel inducer of EMT and is likely to be one of several cytokines produced by inflammatory infiltrates that contribute to this and subsequent tubulointerstitial fibrosis.