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Dive into the research topics where Shisan Bao is active.

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Featured researches published by Shisan Bao.


Circulation | 2005

Reconstituted High-Density Lipoproteins Inhibit the Acute Pro-Oxidant and Proinflammatory Vascular Changes Induced by a Periarterial Collar in Normocholesterolemic Rabbits

Stephen J. Nicholls; Gregory J. Dusting; Belinda Cutri; Shisan Bao; Grant R. Drummond; Kerry-Anne Rye; Philip J. Barter

Background—HDLs have antiinflammatory and antioxidant properties in vitro. This study investigates these properties in vivo. Methods and Results—Chow-fed, normocholesterolemic New Zealand White rabbits received a daily infusion of (1) saline, (2) reconstituted HDL (rHDL) containing 25 mg apolipoprotein (apo) A-I and 50 mg of either 1-palmitoyl-2-linoleoyl phosphatidylcholine (PLPC) or 1,2-dipalmitoyl phosphatidylcholine (DPPC), (3) 25 mg lipid-free apoA-I, or (4) 50 mg of either PLPC–small unilamellar vesicles (SUVs) or DPPC-SUVs on each of 3 consecutive days. Nonocclusive carotid periarterial collars were implanted after the second dose of treatment. Forty-eight hours after insertion of the collars, the arteries were removed and analyzed for the presence of reactive oxygen species, the infiltration of neutrophils, and the expression of adhesion proteins and chemokines. Insertion of the periarterial collar induced a 4.1-fold increase in presence of vascular wall reactive oxygen species. This effect was completely abolished in the animals infused with rHDL. The periarterial collar was associated with a dense infiltration of the arterial wall by polymorphonuclear leukocytes. This infiltration was inhibited by 73% to 94% in the animals infused with rHDL, by 75% in the animals infused with lipid-free apoA-I, and by 51% to 65% in animals infused with SUVs. There were no significant differences between the effects of PLPC and DPPC in either the rHDL or SUVs. Endothelial expression of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1 was also increased by the collar insertion and inhibited by rHDL, lipid-free apoA-I, and, to a lesser extent, also by the SUVs. Conclusions—Infusion of rHDL, apoA-I, and phospholipid-SUVs inhibits the early pro-oxidant and proinflammatory changes induced by a periarterial collar in normocholesterolemic rabbits.


Science Translational Medicine | 2014

Therapeutic Inflammatory Monocyte Modulation Using Immune-Modifying Microparticles

Daniel R. Getts; Rachael L. Terry; Meghann Teague Getts; Celine Deffrasnes; Marcus Müller; Thomas Myles Ashhurst; Belal Chami; Derrick P. McCarthy; Huiling Wu; Jin Ma; Aaron Martin; Lonnie D. Shae; Paul K. Witting; Geoffrey S. Kansas; Joachim E. Kühn; Wali Hafezi; Iain L. Campbell; D. J. Reilly; Jana M. Say; Louise J. Brown; Melanie Y. White; Stuart J. Cordwell; Steven J. Chadban; Edward B. Thorp; Shisan Bao; Stephen D. Miller; Nicholas J. C. King

Negatively charged immune-modifying microparticles bind to the scavenger receptor MARCO on inflammatory monocytes, resulting in their apoptosis and reduced inflammatory damage in a range of diseases. A New Frontier in Immune Modulation Inflammatory monocytes markedly potentiate the immune pathology observed in many diseases, yet no therapy exists that specifically inhibits these cells. The therapeutic accessibility of monocytes in the bloodstream and their inherent propensity to engulf particulate material suggest that highly negatively charged microparticles might provide a readily translatable solution to this problem. These microparticles, referred to as immune-modifying microparticles (IMPs), may be derived from numerous compounds, including the biodegradable polymer poly(lactic-co-glycolic acid) (PLGA-IMP), already used in humans for inter alia dissolvable sutures. Getts et al. now show that upon infusion, IMPs bind to a receptor with a positive domain on inflammatory monocytes, resulting in monocyte sequestration in the spleen and apoptosis through a similar pathway observed for senescing leukocytes. This safe monocyte clearance pathway culminated in substantially reduced inflammatory tissue damage in mouse models of West Nile virus encephalitis, experimental autoimmune encephalomyelitis, peritonitis, colitis, and myocardial infarction. Together, the data suggest that IMPs could transform the treatment of acute inflammation. Indeed, phase 1/2 testing is planned to begin in 2014, with rapid translation supported by the availability of clinical-grade PLGA. Inflammatory monocyte-derived effector cells play an important role in the pathogenesis of numerous inflammatory diseases. However, no treatment option exists that is capable of modulating these cells specifically. We show that infused negatively charged, immune-modifying microparticles (IMPs), derived from polystyrene, microdiamonds, or biodegradable poly(lactic-co-glycolic) acid, were taken up by inflammatory monocytes, in an opsonin-independent fashion, via the macrophage receptor with collagenous structure (MARCO). Subsequently, these monocytes no longer trafficked to sites of inflammation; rather, IMP infusion caused their sequestration in the spleen through apoptotic cell clearance mechanisms and, ultimately, caspase-3–mediated apoptosis. Administration of IMPs in mouse models of myocardial infarction, experimental autoimmune encephalomyelitis, dextran sodium sulfate–induced colitis, thioglycollate-induced peritonitis, and lethal flavivirus encephalitis markedly reduced monocyte accumulation at inflammatory foci, reduced disease symptoms, and promoted tissue repair. Together, these data highlight the intricate interplay between scavenger receptors, the spleen, and inflammatory monocyte function and support the translation of IMPs for therapeutic use in diseases caused or potentiated by inflammatory monocytes.


Arteriosclerosis, Thrombosis, and Vascular Biology | 2005

Impact of Short-Term Administration of High-Density Lipoproteins and Atorvastatin on Atherosclerosis in Rabbits

Stephen J. Nicholls; Belinda Cutri; Stephen G. Worthley; Patrick Kee; Kerry-Anne Rye; Shisan Bao; Philip J. Barter

Objective—This study investigates effects of short-term administration of high-density lipoproteins (HDL) and a statin on atherosclerosis in cholesterol-fed rabbits. Effects of HDL apolipoprotein and phospholipid composition have also been investigated. Methods and Results—Aortic atherosclerosis was established over 17 weeks in 46 rabbits by balloon denudation and cholesterol feeding. During the past 5 days of the cholesterol-feeding period, animals received: (1) no treatment; (2) oral atorvastatin 5 mg/kg on each of the 5 days; or (3) infusions of HDL (8 mg/kg apolipoprotein A-I) on days 1 and 3 of the treatment phase. After euthanization, lesion size and composition were assessed by histological and immunohistochemical analysis. HDL (but not atorvastatin) reduced lesion size by 36% (P<0.05). The ratio of smooth muscle cells to macrophages in the lesions increased 2.6-fold in animals infused with HDL (P<0.05) and 4-fold in those receiving atorvastatin (P<0.01). HDL and atorvastatin reduced matrix metalloproteinase (MMP)-9 expression by 42% (P<0.05) and 45% (P<0.03), respectively. HDL increased thrombomodulin expression 2-fold (P<0.03). The beneficial effects on lesion area and plaque cellular composition were influenced by HDL phospholipid and apolipoprotein composition. Conclusion—Infusing small amounts of HDL rapidly reduces lesion size and is comparable to atorvastatin in promoting a stable plaque phenotype.


Immunology | 2000

Interferon‐γ plays a critical role in intestinal immunity against Salmonella typhimurium infection

Shisan Bao; Kenneth W. Beagley; Jie Shen; Alan J. Husband

Salmonella bacteria are a major cause of food‐borne infectious diarrhoea and there is great interest in understanding the pathogenesis of Salmonella infection and in vaccine development. Potential vaccines include the aromatic mutants of S. typhimurium. Such non‐lethal Aro mutants have also been useful for studying Salmonella infections in mouse models. Studies of systemic infection, using these Aro mutants, in both normal and cytokine gene knockout mice, indicate that interferon‐γ (IFN‐γ) plays a key role in the resolution of Salmonella infection. The present studies have investigated the outcome of oral infection in mice with attenuated Salmonella because this infection route mimics natural infection in humans. In IFN‐γ gene knockout (IFN‐γ–/–) mice, intestinal immunity was impaired and oral challenge resulted in disseminated septicaemia 2 weeks later. No dissemination of infection was seen in wild‐type mice. In wild‐type mice, both CD4 and CD8 cell numbers increased in the gut following Salmonella challenge, together with increased expression of major histocompatibility complex (MHC) II and vascular cell adhesion molecule‐1 (VCAM‐1). No such changes were seen in IFNγ–/– mice. Following oral challenge, antilipopolysaccharide (LPS) and antiphosphoryl choline antibodies increased by more than 100‐fold in both serum and faecal pellet extracts of IFNγ–/– mice compared with wild‐type mice. Our data show that IFN‐γ production is essential for resolution of enteric Salmonella infection and that antibody has little effect on this process.


Molecular and Cellular Biology | 2008

Targeted Disruption of the Basic Kruppel-Like Factor Gene (Klf3) Reveals a Role in Adipogenesis†

Nancy Sue; Briony H. A. Jack; Sally A. Eaton; Richard C. M. Pearson; Alister P. W. Funnell; Jeremy Turner; Robert Czolij; Gareth Denyer; Shisan Bao; Juan Carlos Molero-Navajas; Andrew C. Perkins; Yuko Fujiwara; Stuart H. Orkin; Kim S. Bell-Anderson; Merlin Crossley

ABSTRACT Krüppel-like factors (KLFs) recognize CACCC and GC-rich sequences in gene regulatory elements. Here, we describe the disruption of the murine basic Krüppel-like factor gene (Bklf or Klf3). Klf3 knockout mice have less white adipose tissue, and their fat pads contain smaller and fewer cells. Adipocyte differentiation is altered in murine embryonic fibroblasts from Klf3 knockouts. Klf3 expression was studied in the 3T3-L1 cellular system. Adipocyte differentiation is accompanied by a decline in Klf3 expression, and forced overexpression of Klf3 blocks 3T3-L1 differentiation. Klf3 represses transcription by recruiting C-terminal binding protein (CtBP) corepressors. CtBPs bind NADH and may function as metabolic sensors. A Klf3 mutant that does not bind CtBP cannot block adipogenesis. Other KLFs, Klf2, Klf5, and Klf15, also regulate adipogenesis, and functional CACCC elements occur in key adipogenic genes, including in the C/ebpα promoter. We find that C/ebpα is derepressed in Klf3 and Ctbp knockout fibroblasts and adipocytes from Klf3 knockout mice. Chromatin immunoprecipitations confirm that Klf3 binds the C/ebpα promoter in vivo. These results implicate Klf3 and CtBP in controlling adipogenesis.


Diabetes | 2008

Intravitreal Triamcinolone Acetonide Inhibits Breakdown of the Blood-Retinal Barrier through Differential Regulation of VEGF-A and its Receptors in Early Diabetic Rat Retinas

Xinyuan Zhang; Shisan Bao; Donna Lai; Robert W. Rapkins; Mark C. Gillies

OBJECTIVE To elucidate the mechanism of the unique beneficial effect of intravitreal steroid therapy on diabetic macular edema, we investigated the effect of locally administered triamcinolone acetonide (TA) on the expression of vascular endothelial growth factor (VEGF)-A and its receptors in retinas of rats with streptozotocin (STZ)-induced diabetes. We then correlated the expression of these proteins with breakdown of the blood-retinal barrier (BRB). RESEARCH DESIGN AND METHODS Thirty-two eyes of 16 diabetic and nondiabetic rats were divided into four groups. TA was injected into the vitreous of the right eye, and saline was injected into the left eye (control) 3.5 weeks after induction of diabetes. Retinas were harvested 48 h following treatment. mRNA and protein expression of VEGF-A, VEGF-A receptor 1 (fms-like tyrosine kinase [FLT]-1), and VEGF-A receptor 2 (fetal liver kinase [FLK]-1) were determined by real-time RT-PCR and immunohistochemistry. BRB permeability was quantitated by measuring extravasated endogenous albumin and retinal thickness. RESULTS Diabetes-induced retinal thickness and albumin extravasation were significantly reduced in TA-treated diabetic retinas to a level similar to that in sham-treated nondiabetic eyes. A close correlation between albumin leakage and increased expression of both Vegf-a and Flk-1 was noted in the diabetic retinas. TA downregulated the expression of Vegf-a and Flk-1 but upregulated the expression of Flt-1. TA did not alter the expression of these genes in nondiabetic retinas. CONCLUSIONS Intravitreal injection of TA stabilizes the BRB in association with regulation of Vegf-a, Flk-1, and Flt-1 expression in retinas in the early stages of diabetes.


Arteriosclerosis, Thrombosis, and Vascular Biology | 2010

Nonenzymatic Glycation Impairs the Antiinflammatory Properties of Apolipoprotein A-I

Estelle Nobecourt; Fatiha Tabet; Gilles Lambert; Rajesh Puranik; Shisan Bao; Ling Yan; Michael J. Davies; Bronwyn E. Brown; Alicia J. Jenkins; Gregory J. Dusting; David J. Bonnet; Linda K. Curtiss; Philip J. Barter; Kerry-Anne Rye

Objective—The goal of this study was to investigate the effects of nonenzymatic glycation on the antiinflammatory properties of apolipoprotein (apo) A-I. Methods and Results—Rabbits were infused with saline, lipid-free apoA-I from normal subjects (apoA-IN), lipid-free apoA-I nonenzymatically glycated by incubation with methylglyoxal (apoA-IGlyc in vitro), nonenzymatically glycated lipid-free apoA-I from subjects with diabetes (apoA-IGlyc in vivo), discoidal reconstituted high-density lipoproteins (rHDL) containing phosphatidylcholine and apoA-IN, (A-IN)rHDL, or apoA-IGlyc in vitro, (A-IGlyc in vitro)rHDL. At 24 hours postinfusion, acute vascular inflammation was induced by inserting a nonocclusive, periarterial carotid collar. The animals were euthanized 24 hours after the insertion of the collar. The collars caused intima/media neutrophil infiltration and increased endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). ApoA-IN infusion decreased neutrophil infiltration and VCAM-1 and ICAM-1 expression by 89%, 90%, and 66%, respectively. The apoA-IGlyc in vitro infusion decreased neutrophil infiltration by 53% but did not reduce VCAM-1 or ICAM-1 expression. ApoA-IGlyc in vivo did not inhibit neutrophil infiltration or adhesion molecule expression. (A-IGlyc in vitro)rHDL also inhibited vascular inflammation less effectively than (A-IN)rHDL. The reduced antiinflammatory properties of nonenzymatically glycated apoA-I were attributed to a reduced ability to inhibit nuclear factor-&kgr;B activation and reactive oxygen species formation. Conclusion—Nonenzymatic glycation impairs the antiinflammatory properties of apoA-I.


Molecular Immunology | 2000

Transcutaneous immunization induces mucosal and systemic immunity: a potent method for targeting immunity to the female reproductive tract

Christine M. Gockel; Shisan Bao; Kenneth W. Beagley

Female BALB/c mice were immunized with tetanus toxoid (TT) admixed with cholera toxin by direct application to shaved skin (Transcutaneous immunization, TCI). Tetanus toxoid-specific IgG and IgA in serum, saliva, vaginal lavage and fecal pellets were assayed by ELISA. Tetanus toxoid specific antibody-secreting cell (ASC) numbers were also determined by immunohistochemistry in sections of vagina, uterus, salivary gland and small intestine of immunized mice. TCI elicited significant levels of TT-specific IgG in serum, saliva and vaginal lavage, with the greatest increases over background seen in saliva (80-400 fold) and vaginal lavage (2-87 fold). TCI induced only modest levels of IgA in any of the samples tested (range 2-7 fold increase). In the absence of cholera toxin, application of TT alone did not result in detectable TT-specific antibodies in mucosal secretions. ASCs were found in all tissues following TCI. Cells were most frequent in uterus and vaginal tissues with ASC numbers less frequent in small intestine and salivary gland. This suggests that local production, rather than transudation from serum, is a major contributor of antibody in reproductive tract secretions. Further studies focussed on the role of sex hormones and immune induction following TCI. Animals immunized at the stage of oestrus cycle at which estrogen is abundant (Estrus), showed significantly lower levels of TT-specific IgG in vaginal lavage samples. Collectively, these data confirm the findings of Glenn and colleagues (1998), who showed TCI using cholera toxin can elicit high levels of serum IgG to both the toxin and co-administered antigen and further demonstrates that this route of immunization is particularly effective at eliciting humoral immunity in saliva and in the female reproductive tract.


PLOS ONE | 2013

Expression of tryptophan 2,3-dioxygenase and production of kynurenine pathway metabolites in triple transgenic mice and human Alzheimer's disease brain.

Wei Wu; Joseph A. Nicolazzo; Li Wen; Roger S. Chung; Roger Stankovic; Shisan Bao; Chai K. Lim; Bruce J. Brew; Karen M. Cullen; Gilles J. Guillemin

To assess the role of the kynurenine pathway in the pathology of Alzheimers disease (AD), the expression and localization of key components of the kynurenine pathway including the key regulatory enzyme tryptophan 2,3 dioxygenase (TDO), and the metabolites tryptophan, kynurenine, kynurenic acid, quinolinic acid and picolinic acid were assessed in different brain regions of triple transgenic AD mice. The expression and cell distribution of TDO and quinolinic acid, and their co-localization with neurofibrillary tangles and senile β amyloid deposition were also determined in hippocampal sections from human AD brains. The expression of TDO mRNA was significantly increased in the cerebellum of AD mouse brain. Immunohistochemistry demonstrated that the density of TDO immuno-positive cells was significantly higher in the AD mice. The production of the excitotoxin quinolinic acid strongly increased in the hippocampus in a progressive and age-dependent manner in AD mice. Significantly higher TDO and indoleamine 2,3 dioxygenase 1 immunoreactivity was observed in the hippocampus of AD patients. Furthermore, TDO co-localizes with quinolinic acid, neurofibrillary tangles-tau and amyloid deposits in the hippocampus of AD. These results show that the kynurenine pathway is over-activated in AD mice. This is the first report demonstrating that TDO is highly expressed in the brains of AD mice and in AD patients, suggesting that TDO-mediated activation of the kynurenine pathway could be involved in neurofibrillary tangles formation and associated with senile plaque. Our study adds to the evidence that the kynurenine pathway may play important roles in the neurodegenerative processes of AD.


Diabetologia | 2011

TNF-related apoptosis-inducing ligand (TRAIL) protects against diabetes and atherosclerosis in Apoe / mice

B. A. Di Bartolo; Jeng Yie Chan; Martin R. Bennett; Siân P. Cartland; Shisan Bao; B. E. Tuch; Mary M. Kavurma

Aims/hypothesisTNF-related apoptosis-inducing ligand (TRAIL) is implicated in the regulation of diabetes and is reduced in patients with cardiovascular disease. Although TRAIL receptors are widespread, and TRAIL can promote cell proliferation and apoptosis, it is not known how TRAIL might protect against diabetes and atherosclerosis.MethodsWe examined the development of atherosclerosis and diabetes in Apoe−/−, Trail (also known as Tnfsf10)−/−Apoe−/− and Trail−/− mice that were fed a high-fat diet. Plasma cholesterol, triacylglycerol, glucose and insulin, as well as changes in various metabolic enzymes and regulators were assessed. Glucose and insulin tolerance tests were performed. Pancreatic islets were examined for insulin and beta cell dysfunction (apoptosis and macrophage infiltration).ResultsCompared with Apoe−/− mice, Trail−/−Apoe−/− and Trail−/− mice exhibited several features of diabetes, including increased weight, hyperglycaemia, reduced plasma insulin, impaired glucose tolerance, beta cell dysfunction, reduced islet insulin, macrophage infiltration and increased apoptosis. Trail−/−Apoe−/− mice had increased plasma cholesterol, triacylglycerol, and VLDL- and LDL-cholesterol, and increased expression of genes involved in cholesterol synthesis and lipogenesis. Trail−/−Apoe−/− mice also had increased atherosclerosis, with several features of plaque instability.Conclusions/interpretationWe show for the first time that TRAIL deficiency promotes numerous features of diabetes that are typical of human disease, and are associated with reduced insulin and pancreatic inflammation/apoptosis. TRAIL also regulates cholesterol and triacylglycerol homeostasis in Apoe−/− mice by increasing the expression of genes involved in (1) cholesterol synthesis and absorption, and (2) triacylglycerol production.

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Kenneth W. Beagley

Queensland University of Technology

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Qing Xie

Shanghai Jiao Tong University

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Hui Wang

Shanghai Jiao Tong University

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Xiaogang Xiang

Shanghai Jiao Tong University

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M. Ng

Royal Prince Alfred Hospital

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Lanyi Lin

Shanghai Jiao Tong University

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Jie Lu

Shanghai Jiao Tong University

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