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Chen L.-S.,National Chung Cheng University | Wang M.,Chung Shan Medical University | Ou W.-C.,Central Taiwan University of Science and Technology | Fung C.-Y.,National Chung Cheng University | And 6 more authors.
Gene Therapy | Year: 2010

The JC virus (JCV) may infect human oligodendrocytes and consequently cause progressive multifocal leukoencephalopathy (PML) in patients with immune deficiency. In addition, the virus has also been detected in other human tissues, including kidney, B lymphocytes, and gastrointestinal tissue. The recombinant major structural protein, VP1, of JCV is able to self-assemble to form a virus-like particle (VLP). It has been shown that the VLP is capable of packaging and delivering exogenous DNA into human cells for gene expression. However, gene transfer is not efficient when using in vitro DNA packaging methods with VLPs. In this study, a novel in vivo DNA packaging method using the JCV VLP was used to obtain high efficiency gene transfer. A reporter gene, the green fluorescence protein, and a suicide gene, the herpes simplex virus thymidine kinase (tk), were encapsidated into VLPs in Escherichia coli. The VLP was used to specifically target human colon carcinoma (COLO-320 HSR) cells in a nude mouse model. Intraperitoneal administration of ganciclovir in the tk-VLP-treated mice greatly reduced tumor volume. These findings suggest that it will be possible to develop the JCV VLP as a gene delivery vector for human colon cancer therapy in the future. © 2010 Macmillan Publishers Limited All rights reserved.

Yu H.-P.,Chang Gung Memorial Hospital | Yu H.-P.,Chang Gung University | Hsieh P.-W.,Chang Gung University | Chang Y.-J.,Chang Gung University | And 3 more authors.
Free Radical Biology and Medicine | Year: 2011

Neutrophil activation after trauma-hemorrhagic shock (T/H) has been implicated in the development of multiple organ dysfunction (MOD). In this study, we report that a small chemical compound, 2-(2-fluorobenzamido)benzoic acid ethyl ester (EFB-1), exhibited a potent inhibitory effect on the formyl-l-methionyl-l-leucyl-l-phenylalanine (FMLP)-induced superoxide anion (O2 •-) release and CD11b expression by human neutrophils. Additionally, administration of EFB-1 in rats subjected to T/H caused a significant improvement in MOD. EFB-1 treatment induced an increase in cAMP formation and protein kinase (PK) A activity in FMLP-activated neutrophils, which occurred through the selective inhibition of cAMP-specific phosphodiesterase (PDE) activity but not an increase in adenylate cyclase function or cGMP-specific PDE activity. FMLP-induced phosphorylation of protein kinase B (AKT), but not calcium mobilization, was reduced by EFB-1. The inhibitory effects of EFB-1 on O2 •- production, CD11b expression, and AKT phosphorylation were reversed by PKA inhibitors (H89 and KT5720). Significantly, administration of EFB-1 (1 mg/kg body wt) attenuated the myeloperoxidase activity of the intestines, lungs, and liver and reduced the wet/dry weight ratio of the intestines and lungs and plasma alanine aminotransferase and aspartate aminotransferase levels in Sprague-Dawley rats after T/H. Therefore, EFB-1 is a new inhibitor of cAMP-specific PDE that potently suppresses O2 •- release and CD11b expression by human neutrophils and attenuates T/H-induced MOD in rats. © 2011 Elsevier Inc.

Hwang T.-L.,Chang Gung University | Wang C.-C.,Chang Gung University | Kuo Y.-H.,National Research Institute of Chinese Medicine | Huang H.-C.,China Medical University at Taichung | And 3 more authors.
Biochemical Pharmacology | Year: 2010

The pericarp of Sapindus mukorossi Gaertn is traditionally used as an expectorant in Japan, China, and Taiwan. Activated neutrophils produce high concentrations of the superoxide anion (O2 -) and elastase known to be involved in airway mucus hypersecretion. In the present study, the anti-inflammatory functions of hederagenin 3-O-(3,4-O-di-acetyl-α-l-arabinopyranoside)-(1→3)-α-l-rhamnopyranosyl-(1→2)-α-l-arabinopyranoside (SMG-1), a saponin isolated from S. mukorossi, and its underlying mechanisms were investigated in human neutrophils. SMG-1 potently and concentration-dependently inhibited O2 - generation and elastase release in N-Formyl-Met-Leu-Phe (FMLP)-activated human neutrophils. Furthermore, SMG-1 reduced membrane-associated p47phox expression in FMLP-induced intact neutrophils, but did not alter subcellular NADPH oxidase activity in reconstituted systems. SMG-1 attenuated FMLP-induced increase of cytosolic calcium concentration and phosphorylation of p38 MAPK, ERK, JNK, and AKT. However, SMG-1 displayed no effect on cellular cAMP levels and activity of adenylate cyclase and phosphodiesterase. Significantly, receptor-binding analysis showed that SMG-1 inhibited FMLP binding to its receptor in a concentration-dependent manner. In contrast, neither phorbol myristate acetate-induced O2 - generation and MAPKs activation nor thapsigargin-caused calcium mobilization was altered by SMG-1. Taken together, our results demonstrate that SMG-1 is a natural inhibitor of the FMLP receptor, which may have the potential to be developed into a useful new therapeutic agent for treating neutrophilic inflammatory diseases. © 2010 Elsevier Inc.

Lin S.-J.,Chang Gung Memorial Hospital at Chia Yi | Chen C.-L.,Chang Gung Memorial Hospital at Chia Yi | Peng K.-T.,Chang Gung Memorial Hospital at Chia Yi | Hsu W.-H.,Chang Gung Memorial Hospital at Chia Yi | Hsu W.-H.,Chang Gung University
Injury | Year: 2014

Objective Our study aimed to determine whether the displacement and morphology of a fragment in femur fracture with Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association/32-B/32-C (AO/OTA/32-B/32-C) classification affect the outcomes following closed reduction and internal fixation with an interlocking nail. Design This was a retrospective study. Setting The study was conducted at a Level III trauma centre. Patients A total of 50 consecutive patients presenting femoral shaft fracture with AO/OTA-type 32-B/32-C were included in the present study. Interventions Patients were divided into two groups according to the displacement of the fragments. In the large displacement group, patients were further subgrouped according to whether a reversed morphology of the fragment was present. Outcomes measurement The radiographic union score of femur (RUSF), the mean union time and the re-operation rate were assessed. Results The union rate of small- and large-gap groups at 12 months postoperatively was 75.9% and 21.1%, respectively (p = 0.000). The mean union time of those union cases in these two groups was 7.8 and 13.0 months, respectively (p = 0.000). The union rate of the non-reversed and reversed groups at 12 months postoperatively was 30% and 11.1%, respectively (p = 0.179). The mean RUSF at 12 months in the non-reversed and reversed groups was 8.8 and 8.3, respectively (p = 0.590). However, we found that patients presenting a reversed fragment had an increased risk of more than one re-operation (p = 0.030). Conclusions A fragmentary displacement of >1 cm in AO/OTA-type 32-B/32-C femoral shaft fracture after nailing affected bone healing. Among the large-gap group patients, an unreduced reverse fragment presented a negative prognostic factor for re-operation. Level of evidence Prognostic level III. © 2013 Elsevier Ltd.

Peng K.-T.,Chang Gung Memorial Hospital at Chia Yi | Peng K.-T.,Chang Gung University | Chen C.-F.,National Tsing Hua University | Chen C.-F.,Industrial Technology Research Institute of Taiwan | And 7 more authors.
Biomaterials | Year: 2010

Osteomyelitis characterized by an inflammatory response often leads to bone loss and the spread of bacterial infection to surrounding soft tissues. To overcome the side effects induced by the systemic antibiotic treatment for osteomyelitis, recent investigations have explored the use of antibiotic-loaded undegradable or biodegradable delivery implants at the infected bone. Here, we show a novel biodegradable thermosensitive implant composed of poly(ethylene glycol) monomethyl ether (mPEG) and poly(lactic-co-glycolic acid) (PLGA) copolymer as a sol-gel drug delivery system for treating bone infection. The physical properties of a series of mPEG-PLGA nanocomposites, including the critical micelle concentration (CMC), particle size, polyindex (PI), sol-gel transition, viscosity and degradation rate, have been characterized in vitro. This sol-to-gel drug delivery system could provide several advantages in treating osteomyelitis, including easy preparation, 100% encapsulated rate, near-linear sustained release of drugs, injectable design and in situ gelling at the target tissue. Similar to the undegradable teicoplanin-impregnated polymethylmethacylate (PMMA) bone cements, we showed that implantation of the mPEG-PLGA hydrogel containing teicoplanin was effective for treating osteomyelitis in rabbits as detected by the histological staining and immunoblotting analyses. The use of the mPEG-PLGA-based biodegradable hydrogels may hold great promise as a therapeutic strategy for other infected diseases. © 2010 Elsevier Ltd.

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