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PubMed | Key Laboratory of Transplant Engineering and Immunology and Sichuan University
Type: | Journal: International journal of nanomedicine | Year: 2016

Inflammatory response is a major cause of grafts dysfunction in islet transplantation. Hepatocyte growth factor (HGF) had shown anti-inflammatory activity in multiple diseases. In this study, we aim to deliver HGF by self-assembling peptide/heparin (SAP/Hep) hybrid gel to protect -cell from inflammatory injury. The morphological and slow release properties of SAPs were analyzed. Rat INS-1 -cell line was treated with tumor necrosis factor in vitro and transplanted into rat kidney capsule in vivo, and the viability, apoptosis, function, and inflammation of -cells were evaluated. Cationic KLD1R and KLD2R self-assembled to nanofiber hydrogel, which showed higher binding affinity for Hep and HGF because of electrostatic interaction. Slow release of HGF from cationic SAP/Hep gel is a two-step mechanism involving binding affinity with Hep and molecular diffusion. In vitro and in vivo results showed that HGF-loaded KLD2R/Hep gel promoted -cell survival and insulin secretion, and inhibited cell apoptosis, cytokine release, T-cell infiltration, and activation of NFB/p38 MAPK pathways in -cells. This study suggested that SAP/Hep gel is a promising carrier for local delivery of bioactive proteins in islet transplantation.


Xia J.,Key Laboratory of Transplant Engineering and Immunology | Xia J.,State Key Laboratory of Biotherapy | Zhou Y.,Key Laboratory of Transplant Engineering and Immunology | Ji H.,Key Laboratory of Transplant Engineering and Immunology | And 10 more authors.
Hepatology | Year: 2013

Histone deacetylases 1 and 2 (HDAC1 and HDAC2) are ubiquitously expressed in tissues, including the liver, and play critical roles in numerous physiopathological processes. Little is known regarding the role of HDAC1 and HDAC2 in liver regeneration. In this study we generated mice in which Hdac1, Hdac2 or both genes were selectively knocked out in hepatocytes to investigate the role of these genes in liver regeneration following hepatic injury induced by partial hepatectomy or carbon tetrachloride administration. The loss of HDAC1 and/or HDAC2 (HDAC1/2) protein resulted in impaired liver regeneration. HDAC1/2 inactivation did not decrease hepatocytic 5-bromo-2-deoxyuridine uptake or the expression of proliferating cell nuclear antigen, cyclins, or cyclin-dependent kinases. However, the levels of Ki67, a mitotic marker that is expressed from the mid-G1 phase to the end of mitosis and is closely involved in the regulation of mitotic progression, were greatly decreased, and abnormal mitosis lacking Ki67 expression was frequently observed in HDAC1/2-deficient livers. The down-regulation of either HDAC1/2 or Ki67 in the mouse liver cancer cell line Hepa1-6 resulted in similar mitotic defects. Finally, both HDAC1 and HDAC2 proteins were associated with the Ki67 gene mediated by CCAAT/enhancer-binding protein β. Conclusion: Both HDAC1 and HDAC2 play crucial roles in the regulation of liver regeneration. The loss of HDAC1/2 inhibits Ki67 expression and results in defective hepatocyte mitosis and impaired liver regeneration. © 2013 by the American Association for the Study of Liver Diseases.


Chen Y.,Curtin University Australia | Chen Y.,Key Laboratory of Transplant Engineering and Immunology | Carlessi R.,Curtin University Australia | Walz N.,Curtin University Australia | And 7 more authors.
Molecular and Cellular Endocrinology | Year: 2016

Pigment epithelium-derived factor (PEDF) is a multifunctional glycoprotein, associated with lipid catabolism and insulin resistance. In the present study, PEDF increased chronic and acute insulin secretion in a clonal rat β-cell line BRIN-BD11, without alteration of glucose consumption. PEDF also stimulated insulin secretion from primary mouse islets. Seahorse flux analysis demonstrated that PEDF did not change mitochondrial respiration and glycolytic function. The cytosolic presence of the putative PEDF receptor - adipose triglyceride lipase (ATGL) - was identified, and ATGL associated stimulation of glycerol release was robustly enhanced by PEDF, while intracellular ATP levels increased. Addition of palmitate or ex vivo stimulation with inflammatory mediators induced β-cell dysfunction, effects not altered by the addition of PEDF. In conclusion, PEDF increased insulin secretion in BRIN-BD11 and islet cells, but had no impact on glucose metabolism. Thus elevated lipolysis and enhanced fatty acid availability may impact insulin secretion following PEDF receptor (ATGL) stimulation. © 2016 Elsevier Ireland Ltd.


Kong L.,University of Sichuan | Zhou Y.,University of Sichuan | Zhou Y.,Key Laboratory of Transplant Engineering and Immunology | Bu H.,University of Sichuan | And 4 more authors.
Journal of Experimental and Clinical Cancer Research | Year: 2016

Background: Hepatocellular carcinoma (HCC) is associated with inflammation, and roughly 30 % of the global population shows serological evidence of current or past infection with hepatitis B or hepatitis C virus. Resident hepatic macrophages, known as Kupffer cells (KCs), are considered as the specific tumor-associated macrophages (TAMs) of HCC, and can produce various cytokines - most importantly interleukin (IL)-6 - to promote tumorigenesis of HCC. However, the roles of KCs and IL-6 in carcinogenesis in the liver are still unclear. Methods: We analyzed leukocyte-related peripheral blood data of 192 patients and constructed a mouse model in which the bone marrow was cleared out by irradiation and reconstructed using bone marrow donated from IL-6-deficient mice to further elucidate the hepatic pathological changes in response to toxic challenge and oncogenic gene mutation. Results: Peripheral monocyte counts and serum IL-6 levels were significantly higher in patients with HCC than in those without HCC. In addition, there was a significant difference in the levels of IL-6 among individuals with different histopathological grades. In mice with selective IL-6 ablation in monocytes/KCs, we observed decreased toxic liver injury, inflammatory infiltration, and systemic inflammation. In Mdr2-deficient mice, which spontaneously developed HCC, the loss of IL-6 in monocytes/KCs resulted in inhibition of IL-6/signal transducer and activator of transcription 3 signaling, decreased serum IL-6 levels, and delayed tumorigenesis. Conclusions: Our findings demonstrate that increased TAM-derived IL-6 had an amplifying effect on the inflammation response, thereby promoting the occurrence and development of HCC. © 2016 The Author(s).


Luo R.,Key Laboratory of Transplant Engineering and Immunology | Li L.,Key Laboratory of Transplant Engineering and Immunology | Du X.,University of Sichuan | Shi M.,Key Laboratory of Transplant Engineering and Immunology | And 7 more authors.
Gene | Year: 2015

The vascular system particularly endothelium is sensitive to ischemia-reperfusion (I/R) injury, which is a big challenge in surgical practices and many vascular disorders. In the present study, we reported the global gene expression changes in a 2-h ischemia and 4-h reperfusion injury induced in the hind limb vessels of rhesus monkeys (Macaca mulatta) using microarray technique. Results: The histological results showed abnormal morphology of endothelial cells after 2-h ischemia and the hematological detection found slightly extension of coagulation time after I/R treatment. Furthermore, we found distinct alterations in gene expression patterns during I/R process. These identified genes are mostly involved in inflammation, immune response, apoptosis, and cell stress signaling pathways. The significantly up-regulated genes included IL-6, regulator of G-protein signaling 8, selectin E, and metallothionein 2A, et al. Whist, the robustly down-regulated genes included NECAP endocytosis associated 2, transglutaminase 2, and fibronectin 1, et al. Conclusion: Our results indicate that inflammation, primarily characterized by gene expression changes of cytokines and chemokines is the most important event in the early stage of I/R injury in blood vessels. © 2015.


Wang D.,Key Laboratory of Transplant Engineering and Immunology | Liu J.,Key Laboratory of Transplant Engineering and Immunology | He S.,Key Laboratory of Transplant Engineering and Immunology | Wang C.,Key Laboratory of Transplant Engineering and Immunology | And 13 more authors.
Endocrine | Year: 2014

The objectives of the study were to improve the model system of diabetic nephropathy in nonhuman primates and assess the early renal damage. Diabetes was induced in monkeys by streptozotocin, and the animals were administered exogenous insulin to control blood glucose (BG). Animals were divided into four groups, including the normal group (N = 3), group A (streptozotocin diabetic model with control of BG < 10 mmol/L, N = 3), group B (streptozotocin diabetic model with control of BG between 15 and 20 mmol/L, N = 4), and group C (streptozotocin diabetic model with control of BG between 15 and 20 mmol/L and high-sodium and high-fat diet, N = 4). The following parameters were evaluated: (1) blood biochemistry and routine urinalysis, (2) color Doppler ultrasound, (3) angiography, (4) renal biopsy, and (5) renal fibrosis-related gene expression levels. Animals in group C developed progressive histologic changes with typical diabetic nephropathy resembling diabetic nephropathy in human patients and exhibited accelerated development of diabetic nephropathy compared with other nonhuman primate models. Significant changes in the expression of the Smad2/3 gene and eNOS in renal tissue were also observed in the early stage of diabetic nephropathy. In conclusion, our model is an excellent model of diabetic nephropathy for understanding the pathogenesis of diabetic nephropathy. © 2014, Springer Science+Business Media New York.


Ni R.,Soochow University of China | Ni R.,Lawson Health Research Institute | Ni R.,University of Western Ontario | Cao T.,Soochow University of China | And 10 more authors.
Free Radical Biology and Medicine | Year: 2016

Aims The mitochondria are important sources of reactive oxygen species (ROS) in the heart. Mitochondrial ROS production has been implicated in the pathogenesis of diabetic cardiomyopathy, suggesting that therapeutic strategies specifically targeting mitochondrial ROS may have benefit in this disease. We investigated the therapeutic effects of mitochondria-targeted antioxidant mito-TEMPO on diabetic cardiomyopathy. Methods The mitochondria-targeted antioxidant mito-TEMPO was administrated after diabetes onset in a mouse model of streptozotocin-induced type-1 diabetes and type-2 diabetic db/db mice. Cardiac adverse changes were analyzed and myocardial function assessed. Cultured adult cardiomyocytes were stimulated with high glucose, and mitochondrial superoxide generation and cell death were measured. Results Incubation with high glucose increased mitochondria superoxide generation in cultured cardiomyocytes, which was prevented by mito-TEMPO. Co-incubation with mito-TEMPO abrogated high glucose-induced cell death. Mitochondrial ROS generation, and intracellular oxidative stress levels were induced in both type-1 and type-2 diabetic mouse hearts. Daily injection of mito-TEMPO for 30 days inhibited mitochondrial ROS generation, prevented intracellular oxidative stress levels, decreased apoptosis and reduced myocardial hypertrophy in diabetic hearts, leading to improvement of myocardial function in both type-1 and type-2 diabetic mice. Incubation with mito-TEMPO or inhibition of Nox2-containing NADPH oxidase prevented oxidative stress levels and cell death in high glucose-stimulated cardiomyocytes. Mechanistic study revealed that the protective effects of mito-TEMPO were associated with down-regulation of ERK1/2 phosphorylation. Conclusions Therapeutic inhibition of mitochondrial ROS by mito-TEMPO reduced adverse cardiac changes and mitigated myocardial dysfunction in diabetic mice. Thus, mitochondria-targeted antioxidants may be an effective therapy for diabetic cardiac complications. © 2015 Elsevier Inc.


Deng S.,University of Sichuan | Jin T.,University of Sichuan | Zhang L.,Key Laboratory of Transplant Engineering and Immunology | Bu H.,University of Sichuan | Zhang P.,University of Sichuan
Molecular Medicine Reports | Year: 2016

Chronic renal allograft dysfunction (CRAD) is the most common cause of graft failure following renal transplantation. However, the underlying mechanisms remain to be fully elucidated. Immunosuppressants and hyperlipidemia are associated with renal fibrosis following longterm use. The present study aimed to determine the effects of tacrolimus (FK506) and lipid metabolism disorder on CRAD. In vitro and in vivo models were used for this investigation. Cells of the mouse proximal renal tubular epithelial cell strain, NRK52E, were cultured either with oxidized lowdensity lipoprotein (oxLDL), FK506, oxLDL combined with FK506, or vehicle, respectively. Changes in cell morphology and changes in the levels of lectinlike oxLDL receptor1 (LOX1), reactive oxygen species (ROS), hydrogen peroxide and fibrosisassociated genes were evaluated at 24, 48 and 72 h. In separate experiment, total of 60 SpragueDawley rats were divided randomly into four groups, which included a highfat group, FK506 group, highfat combined with FK506 group, and control group. After 2, 4 and 8 weeks, the serum lipid levels, the levels of oxLDL, ROS, and the expression levels of transforming growth factor (TGF)1 and connective tissue growth factor were determined. The in vitro and in vivo models revealed that lipid metabolism disorder and FK506 caused oxidative stress and a fibrogenic response. In addition, decreased levels of LOX1 markedly reduced the levels of TGF1 in the in vitro model. Taken together, FK506 and dyslipidemia were found to be associated with CRAD following transplantation.


PubMed | University of Sichuan, Key Laboratory of Transplant Engineering and Immunologyicine R and Key Laboratory of Transplant Engineering and Immunology
Type: | Journal: The Journal of biological chemistry | Year: 2016

The ATP-binding cassette transporter A1 (ABCA1), which promotes cholesterol efflux from cells and inhibits inflammatory responses, is highly expressed in the kidney. Research has shown that exendin-4, a glucagon-like peptide-1 receptor (GLP-1R) agonist, promotes ABCA1 expression in multiple tissues and organs; however, the mechanisms underlying exendin-4 induction of ABCA1 expression in glomerular endothelial cells are not fully understood. In this study we investigated the effect of exendin-4 on ABCA1 in glomerular endothelial cells of diabetic kidney disease (DKD) and the possible mechanism. We observed a marked increase in glomerular lipid deposits in tissues of patients with DKD and diabetic apolipoprotein E knockout (apoE-/-) mice by Oil Red O staining and biochemical analysis of cholesterol. We found significantly decreased ABCA1 expression in glomerular endothelial cells of diabetic apoE-/- mice and increased renal lipid, cholesterol, and inflammatory cytokine levels. Exendin-4 decreased renal cholesterol accumulation and inflammation and increased cholesterol efflux by upregulating ABCA1. In human glomerular endothelial cells (HRGECs), GLP-1R-mediated signaling pathways (e.g., Ca2+/calmodulin-dependent protein kinase, cAMP/protein kinase A (PKA), phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), and extracellular signal-regulated kinase (ERK1/2) were involved in cholesterol efflux and inflammatory responses by regulating ABCA1 expression. We propose that exendin-4 increases ABCA1 expression in glomerular endothelial cells, which plays an important role in alleviating renal lipid accumulation, inflammation, and proteinuria in mice with type 2 diabetes.


PubMed | Key Laboratory of Transplant Engineering and Immunology
Type: Journal Article | Journal: Hepatology (Baltimore, Md.) | Year: 2013

Histone deacetylases 1 and 2 (HDAC1 and HDAC2) are ubiquitously expressed in tissues, including the liver, and play critical roles in numerous physiopathological processes. Little is known regarding the role of HDAC1 and HDAC2 in liver regeneration. In this study we generated mice in which Hdac1, Hdac2 or both genes were selectively knocked out in hepatocytes to investigate the role of these genes in liver regeneration following hepatic injury induced by partial hepatectomy or carbon tetrachloride administration. The loss of HDAC1 and/or HDAC2 (HDAC1/2) protein resulted in impaired liver regeneration. HDAC1/2 inactivation did not decrease hepatocytic 5-bromo-2-deoxyuridine uptake or the expression of proliferating cell nuclear antigen, cyclins, or cyclin-dependent kinases. However, the levels of Ki67, a mitotic marker that is expressed from the mid-G1 phase to the end of mitosis and is closely involved in the regulation of mitotic progression, were greatly decreased, and abnormal mitosis lacking Ki67 expression was frequently observed in HDAC1/2-deficient livers. The down-regulation of either HDAC1/2 or Ki67 in the mouse liver cancer cell line Hepa1-6 resulted in similar mitotic defects. Finally, both HDAC1 and HDAC2 proteins were associated with the Ki67 gene mediated by CCAAT/enhancer-binding protein .Both HDAC1 and HDAC2 play crucial roles in the regulation of liver regeneration. The loss of HDAC1/2 inhibits Ki67 expression and results in defective hepatocyte mitosis and impaired liver regeneration.

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