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Yang S.-M.,A-Life Medical | Ka S.-M.,Graduate Institute of Aerospace and Undersea Medicine | Hua K.-F.,National Ilan University | Wu T.-H.,National Defense Medical Center | And 9 more authors.
Free Radical Biology and Medicine

High levels of reactive oxygen species (ROS), systemic T cell activation, and macrophage infiltration in the kidney are implicated in the acceleration and progression of IgA nephropathy (IgAN), the most frequent type of primary glomerulonephritis. However, the pathogenic mechanism of IgAN is still little understood, and it remains a challenge to establish a specific therapeutic strategy for this type of glomerular disorder. Recently, we showed that antroquinonol (Antroq), a pure active compound from Antrodia camphorata mycelium, inhibits renal inflammation and reduces oxidative stress in a mouse model of renal fibrosis. But the anti-inflammatory and immune-regulatory effects of Antroq on the acceleration and progression of primary glomerular disorders have not been determined. In this study, we show that Antroq administration substantially impeded the development of severe renal lesions, such as intense glomerular proliferation, crescents, sclerosis, and periglomerular interstitial inflammation, in mice with induced accelerated and progressive IgAN (AcP-IgAN). Further mechanistic analysis in AcP-IgAN mice showed that, early in the developmental stage of the AcP-IgAN model, Antroq promoted the Nrf2 antioxidant pathway and inhibited the activation of T cells and NLRP3 inflammasome. Significantly improved proteinuria/renal function and histopathology in AcP-IgAN mice of an established stage supported potential therapeutic effects of Antroq on the disease. In addition, Antroq was shown to inhibit activation of NLRP3 inflammasome in vitro by an IgA immune complex (IC) partly involving a reduced ROS production in IgA-IC-primed macrophages, and this finding may be helpful in the understanding of the mode of action of Antroq in the treated AcP-IgAN mice. © 2013 Elsevier Inc. Source

Wu T.-S.,Exploratory Research Laboratory | Wu T.-S.,Institute for Drug Evaluation Platform | Wang L.-C.,Chang Gung University | Liu S.-C.,Chang Gung University | And 12 more authors.
Journal of Immunology

Antivascular immunity may provide long-term protection by preventing neovascularization that precedes tumor progression. Although the tumorigenesis promoted by EBV-encoded oncogene latent membrane protein 1 derived from Taiwanese nasopharyngeal carcinoma (N-LMP1) has been demonstrated, the potential of N-LMP1 for inducing immune surveillance remains elusive. In this article, we describe the immunogenicity of N-LMP1 (1510) and its induction of antivascular immunity in a transplantable tumor model in immunocompetent BALB/c mice. The immunogenicity of N-LMP1 was evaluated on the basis of tumor rejection following immunization. The impact of the immunization on the dynamics of tumor angiogenesis was assessed by temporal noninvasive dynamic contrast-enhanced magnetic resonance imaging and was further confirmed by histologic study and vascular count. Through the experiments of in vivo depletion and adoptive transfer, CD4 T cells were identified as effectors that depend on IFN-γ for tumor prevention. The response was further verified by the identification of an MHC H-2 I-Ed-restricted peptide derived from N-LMP1 and by the immunization of mice with N-LMP1 peptide-loaded dendritic cells. These studies provide insight into N-LMP1-specific immunity in vivo, which suggests that CD4 T cells may play an important role in angiogenic surveillance against LMP1-associated cancer via tumor stroma targeting. Copyright © 2015 by The American Association of Immunologists, Inc. Source

Hou H.-Y.,Institute for Drug Evaluation Platform | Fu S.-H.,Academia Sinica, Taiwan | Liu C.-H.,Chang Gung University | Chen J.-P.,Chang Gung University | Ray-Sea Hsu B.,Chang Gung University
Polymer Journal

In this study, we examined the combined effect of two recombinant immunomodulator proteins, cytotoxic T-lymphocyte antigen-4-Ig (CTLA4Ig) and interleukin-1 receptor antagonist (IL1ra), on the survival of subcutaneous mouse islet grafts with temperature-sensitive hydrogel, poly(N-isopropylacrylamide) (pNIPAAm)-chitosan-hyaluronic acid (CPNHA), and gelatin microspheres in an allogeneic mouse model. The phase-transition temperature for the CTLA4Ig-grafted CPNHA (CPNCHA) was 28 °C. An in vitro cytotoxicity assay and in vivo tissue reactions showed that both CPNCHA and the gelatin microspheres were biocompatible, biodegradable and nontoxic. The survival of the allogeneic islets was prolonged when the grafts were transplanted into a subcutaneous matrix composed of CPNCHA and gelatin microspheres containing IL1ra relative to those implanted in CPNHA containing gelatin microspheres without an immunomodulator. In conclusion, our results suggest that the temperature-sensitive hydrogel, CPNCHA, is a suitable subcutaneous matrix for islet transplantation, and grafted CTLA4Ig and encapsulated IL1ra reduce immune rejection and prolong the survival of the functioning allogeneic islets. © 2014 The Society of Polymer Science, Japan (SPSJ) All rights reserved. Source

Wang C.-C.,National Sun Yat - sen University | Liu W.-S.,National Sun Yat - sen University | Liu W.-S.,Asia Pacific Biotech Developing Inc. | Chang F.-H.,Asia Pacific Biotech Developing Inc. | And 4 more authors.
Journal of Microbial and Biochemical Technology

Insulin resistance is one of the most important mechanisms of diabetes mellitus. Anti-oxidants had been proved to improve insulin resistance. However, the direct relation between anti-oxidants and glucose homeostasis is still elusive. Recently, we found that Lycogen ™ (extracts of Rhodobacter sphaeroides WL-APD911) has lycopene-like activity. Furthermore, Lycogen™ showed more potent anti-oxidative effect and less cytotoxicity than lycopene. To evaluate the effect of Lycogen™ on blood glucose levels, STZ-induced diabetic mice were randomly divided into four groups: (1) diabetes control group; (2) diabetes+Lycogen™ 50 mg/kg; (3) diabetes+Lycogen ™ 100 mg/kg; and (4) diabetes+Lycogen™ 200 mg/kg. After 7 days of trea™ent, the blood glucose level in the Lycogen™ 200 mg/kg group was significantly lower than the disease control group (p<0.01). In the oral glucose tolerance test, the blood glucose level was significantly lower in the Lycogen™ 200 mg/kg group than the disease control group (p<0.05). Our results confirmed that Lycogen™, a potent anti-oxidant, can significantly lower blood glucose levels in a diabetic mice model. © 2014 Wang CC, et al. Source

Hua K.-F.,National Ilan University | Yang S.-M.,National Defense Medical Center | Kao T.-Y.,National Ilan University | Chang J.-M.,Institute for Drug Evaluation Platform | And 6 more authors.

Renal reactive oxygen species (ROS) and mononuclear leukocyte infiltration are involved in the progressive stage (exacerbation) of IgA nephropathy (IgAN), which is characterized by glomerular proliferation and renal inflammation. The identification of the mechanism responsible for this critical stage of IgAN and the development of a therapeutic strategy remain a challenge. Osthole is a pure compound isolated from Cnidiummonnieri (L.) Cusson seeds, which are used as a traditional Chinese medicine, and is anti-inflammatory, anti-apoptotic, and anti-fibrotic both in vitro and in vivo. Recently, we showed that osthole acts as an anti-inflammatory agent by reducing nuclear factor-kappa B (NF-κB) activation in and ROS release by activated macrophages. In this study, we examined whether osthole could prevent the progression of IgAN using a progressive IgAN (Prg-IgAN) model in mice. Our results showed that osthole administration resulted in prevention of albuminuria, improved renal function, and blocking of renal progressive lesions, including glomerular proliferation, glomerular sclerosis, and periglomerular mononuclear leukocyte infiltration. These findings were associated with (1) reduced renal superoxide anion levels and increased Nrf2 nuclear translocation, (2) inhibited renal activation of NF-κB and the NLRP3 inflammasome, (3) decreased renal MCP-1 expression and mononuclear leukocyte infiltration, (4) inhibited ROS production and NLRP3 inflammasome activation in cultured, activated macrophages, and (5) inhibited ROS production and MCP-1 protein levels in cultured, activated mesangial cells. The results suggest that osthole exerts its reno-protective effects on the progression of IgAN by inhibiting ROS production and activation of NF-κB and the NLRP3 inflammasome in the kidney. Our data also confirm that ROS generation and activation of NF-κB and the NLRP3 inflammasome are crucial mechanistic events involved in the progression of the renal disorder. © 2013 Hua et al. Source

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