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Shi J.,University of Manitoba | Shi J.,Manitoba Institute of Child Health | Guobao W.,Key Laboratory for Organ Failure Research | Chen H.,Tianjin Medical University | And 4 more authors.
Polymer Chemistry | Year: 2014

In this study, we report a facile approach to develop an injectable hydrogel with an in situ and pH sensitive drug delivery system for cancer treatment. The hydrogel was based on modified chitosan and alginate. We conjugated doxorubicin (DOX) to succinated chitosan (S-chi) via a Schiff base between a ketone group in the DOX and an amine group in the S-chi, which led to a pH sensitive release of DOX upon the stimulus of an acidic tumor microenvironment. Hydrogel formed in minutes while DOX conjugated S-chi was mixed with oxidized alginate. The hydrogel structure was characterized by cryo-imaging, FTIR and a rheology test. The DOX release profiles were tested in response to different pH values. The MTT assay showed a low toxicity of the hydrogel. The gel in turn inhibited the growth of tumor cells MCF-7 effectively when loaded with DOX. Finally, the DOX laden hydrogel was injected into the xenograft breast tumor model and significantly inhibited tumor growth. © 2014 the Partner Organisations. Source


Zhou Q.,Key Laboratory for Organ Failure Research | Wu S.,Key Laboratory for Organ Failure Research | Jiang J.,Key Laboratory for Organ Failure Research | Tian J.,Key Laboratory for Organ Failure Research | And 14 more authors.
Nephrology | Year: 2012

Aim: Whether the burden of advanced oxidation protein products (AOPP) accumulation, a marker of oxidative stress, is affected by dialysis modality remains unclear. We compared the serum levels of AOPP in patients on haemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD) and tested the hypothesis that an accumulation of AOPP was an independent risk factor for cardiovascular disease. Methods: This was a cross-section study. A total of 2095 patients (1539 HD, 556 CAPD) were recruited from the nine largest dialysis centres in China. Persons in medical centres for disease screening were selected as controls. Patients maintained on HD were dialyzed twice or thrice weekly. CAPD patients used lactate-buffered, glucose-containing solutions. The patients' data were abstracted from the medical record. The serum levels of AOPP were determined by spectrophotometric detection. Results: The levels of AOPP were significantly elevated in both HD and CAPD patients compared to healthy controls. Accumulation of AOPP was more significant in HD compared to CAPD population. Meanwhile, AOPP accumulation was associated with the presence of ischaemic heart disease (IHD) only in HD, but not CAPD patients. A higher proportion of IHD was found in the HD population among those with higher levels of AOPP in each category of age and irrespective of the presence or absence of high triglyceride. Multivariate regression analysis indicated that accumulation of AOPP was an independent risk factor for IHD in HD population. Conclusion: Accumulation of AOPP was more significant in HD compared to CAPD patients. The level of AOPP was independently associated with IHD only in HD patients. These investigators examined the serum levels of advanced oxidation protein products (AOPP) in patients on haemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD) in a cross-section study and tested AOPP as an independent risk factor for cardiovascular disease. The levels of AOPP were significantly elevated in both HD and CAPD patients compared to healthy controls. However, accumulation of AOPP was more significant in HD compared to CAPD patients. Only in HD patients, the AOPP levels exhibit an association with ischaemic heart disease. © 2012 Asian Pacific Society of Nephrology. Source


Zhou L.L.,Key Laboratory for Organ Failure Research | Cao W.,Key Laboratory for Organ Failure Research | Xie C.,Key Laboratory for Organ Failure Research | Tian J.,Key Laboratory for Organ Failure Research | And 8 more authors.
Kidney International | Year: 2012

The accumulation of plasma advanced oxidation protein products (AOPPs) is prevalent in chronic kidney disease. We previously showed that accumulation of AOPPs resulted in podocyte apoptosis and their deletion by a cascade of signaling events coupled with intracellular oxidative stress. The transmembrane receptor that specifically transmits the AOPPs' signals to elicit cellular activity, however, remains unknown. Using co-immunoprecipitation and immunofluorescence, we found that AOPPs colocalized and interacted with the receptor of advanced glycation end products (RAGE) on podocytes. Blocking RAGE by anti-RAGE immunoglobulin G or its silencing by siRNA significantly protected podocytes from AOPPs-induced apoptosis both in vitro and in vivo and ameliorated albuminuria in AOPPs-challenged mice. AOPPs-induced activation of nicotinamide adenine dinucleotide phosphate oxidase and the excessive generation of intracellular superoxide were largely inhibited by anti-RAGE immunoglobulin G or RAGE siRNA. Moreover, blockade of RAGE decreased the activation of the p53/Bax/caspase-dependent proapoptotic pathway induced by AOPPs. Thus, AOPPs interact with RAGE to induce podocyte apoptosis and this, in part, may contribute to the progression of chronic kidney disease. © 2012 International Society of Nephrology. Source


Hou F.F.,Key Laboratory for Organ Failure Research | Zhou Q.G.,Key Laboratory for Organ Failure Research
Nephrology | Year: 2010

Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB) have become the cornerstone in the treatment of chronic kidney disease (CKD), as numerous lines of evidence have shown that these agents have a blood pressure lowing independent anti-proteinuric effect. However, despite the benefits of ACEI or ARB therapy, a substantial proportion of patients still experience renal morbidity and mortality. Considering the prognostic impact of proteinuria reduction, it is currently assumed that titration of ACEI or ARB for optimal anti-proteinuric effect would be a logical step towards improvement of renoprotection. Recent published studies, performed with higher than recommended doses of either ACEI or particularly ARB, suggest that the approach is associated with a further decrement in urinary protein excretion and probably improved renal outcome. Although most patients achieve their maximum benefit at standard doses, there is a residual group of patients who may do so at higher doses of renin-angiotensin system inhibitors. Because patients who would benefit from higher doses are not identifiable a priori, a titration process might be cogent in order to provide more robust anti-proteinuric benefit to such patients. © 2010 Asian Pacific Society of Nephrology. Source


Wu W.,Southern Medical University | Wang Y.,Southern Medical University | Wang Y.,Key Laboratory for Organ Failure Research | Shen S.,Southern Medical University | And 14 more authors.
Investigative Radiology | Year: 2013

OBJECTIVE: Ultrasound molecular imaging has the potential to detect activated platelets, thus identifying atherosclerotic plaque instability before onset of serious clinical events. However, it has not been well defined in inflammatory arterial thrombosis. We hypothesized that microbubbles (MBs) target glycoprotein IIb/IIIa (GP IIb/IIIa) could achieve a noninvasive in vivo detection of inflammatory thrombosis in large arteries through contrast-enhanced ultrasound (CEU) imaging. MATERIALS AND METHODS: Lipid shell-based gas-filled MBs were modified covalently with a cyclic Arg-Gly-Asp (RGD) peptide (MB-cRGD) targeted to activated GP IIb/IIIa or a negative control peptide (MB-CON) via thiol-maleimide coupling. Adherence of MB-cRGD and MB-CON to GP IIb/IIIa was determined in vitro by using a parallel plate flow chamber at variable shear stress (0.5-8 dynes/cm). Inflammatory platelet thrombosis was induced by periadvential application of arachidonic acid (AA) to one of the bilateral carotids of C57BL/6 mice (n = 20) and confirmed through intravital fluorescence microscopy. Attachment of MBs was determined in vivo with CEU imaging of bilateral carotids in the AA application mice with (n = 10) or without (n = 10) pretreatment of GP IIb/IIIa antagonist. The expression of integrin GP IIb/IIIa was assessed through immunohistochemistry. RESULTS: Microbubble-cRGD but not MB-CON had excellent affinity to GP IIb/IIIa under all shear stress conditions. Successful inflammatory platelet activation and thrombosis in AA application carotids were noted through intravital fluorescence microscopy. Contrast video intensity from adhered MB-cRGD in the thrombi was significantly higher than that from MB-CON (P < 0.05). Video intensity of MB-cRGD in the thrombi was suppressed significantly by preblocking with GP IIb/IIIa antagonist (P < 0.05) but not for MB-CON. Immunohistochemical finding demonstrates that expression of integrin GP IIb/IIIa in the thrombi was abundant; it was inhibited significantly through pretreatment with GP IIb/IIIa antagonist (P < 0.05). CONCLUSIONS: Cyclic RGD-modified MBs targeted to GP IIb/IIIa with CEU are capable of detecting inflammation-activated platelets and thrombosis in large arteries, thus providing a potential tool for identification of vulnerable atherosclerotic plaques. Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Source

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