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Zandong Yang

Publications and source records attributed to Zandong Yang.

13 recordsLinked to original sources
PubMed2006

Combined treatment with lisofylline and exendin-4 reverses autoimmune diabetes.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease leading to near complete pancreatic beta-cell destruction. New evidence suggests that beta-cell regeneration is possible, but ongoing autoimmune damage prevents restoration of beta-cell mass. We tested the hypothesis that simultaneously blocking autoimmune cytokine damage and supplying a growth-promoting stimulus for beta-cells would provide a novel approach to reverse T1DM. Therefore, in this study we combined lisofylline to suppress autoimmunity and exendin-4 to enhance beta-cell proliferation for treating autoimmune-mediated diabetes in the non-obese diabetic (NOD) mouse model. We found that this combined therapy effectively reversed new-onset diabetes within a week of therapy, and even maintained euglycemia up to 145 days after treatment withdrawal. The therapeutic effect of this regimen was associated with improved beta-cell metabolism and insulin secretion, while reducing beta-cell apoptosis. It is possible that such combined therapy could become a new strategy to defeat T1DM in humans.

Animals↗
PubMed2006

Genistein acutely stimulates insulin secretion in pancreatic beta-cells through a cAMP-dependent protein kinase pathway.

Although genistein, a soy isoflavone, has beneficial effects on various tissues, it is unclear whether it plays a role in physiological insulin secretion. Here, we present evidence that genistein increases rapid glucose-stimulated insulin secretion (GSIS) in both insulin-secreting cell lines (INS-1 and MIN6) and mouse pancreatic islets. Genistein elicited a significant effect at a concentration as low as 10 nmol/l with a maximal effect at 5 micromol/l. The effect of genistein on GSIS was not dependent on estrogen receptor and also not related to an inhibition of protein tyrosine kinase (PTK). Consistent with its effect on GSIS, genistein increases intracellular cAMP and activates protein kinase A (PKA) in both cell lines and the islets by a mechanism that does not involve estrogen receptor or PTK. The induced cAMP by genistein, at physiological concentrations, may result primarily from enhanced adenylate cyclase activity. Pharmacological or molecular intervention of PKA activation indicated that the insulinotropic effect of genistein is primarily mediated through PKA. These findings demonstrated that genistein directly acts on pancreatic beta-cells, leading to activation of the cAMP/PKA signaling cascade to exert an insulinotropic effect, thereby providing a novel role of soy isoflavones in the regulation of insulin secretion.

Animals↗
PubMed2005

Lisofylline: a potential lead for the treatment of diabetes.

Lisofylline (LSF), a synthetic modified methylxanthine, was originally designed and tested as an agent to reduce mortality during serious infections associated with cancer chemotherapy. Experimental studies and several clinical trials showed that LSF inhibited the generation of phosphatidic acid and free fatty acids. LSF also blocked the release of pro-inflammatory cytokines in oxidative tissue injury, in response to cancer chemotherapy and in experimental sepsis. Recent research has revealed a new potential to extend the therapeutic application of LSF especially for diabetes mellitus. These new studies demonstrate multiple actions of LSF in the regulation of immune cell function and autoimmune response by inhibition of IL-12 signalling and cytokine production. Supporting the new potential for LSF is the discovery of beneficial effects in protecting pancreatic beta cells and in preventing autoimmunity. In this article, these new observations about LSF are reviewed and a strategy proposed for using this compound in new clinical applications. LSF may, thus, have therapeutic value in the prevention of autoimmune disorders, including Type 1 diabetes, and autoimmune recurrence following islet transplantation, and in preservation of beta cell functional mass during islet isolation.

Animals↗
PubMed2005

Viral IL-10-mediated immune regulation in pancreatic islet transplantation.

Protection of transplanted pancreatic islet grafts in recipients with autoimmune diabetes depends on the suppression of autoimmune recurrence and allogeneic rejection. The aim of this study was to investigate the efficiency of viral IL-10 gene delivery in the prevention of autoimmune recurrence following islet transplantation. We evaluated the effectiveness of a systemically delivered adeno-associated viral vector (AAV vIL-10) carrying viral IL-10 in protecting islet engraftment. We observed significant prolongation of graft survival after treatment with AAV vIL-10 when using islets from donors lacking autoimmunity. We found that the mechanism of vIL-10-mediated protection was associated with suppression of T cell activation and that donor immune cells that were simultaneously transferred with the islet grafts could induce autoimmune recurrence. AAV vIL-10 gene transfer suppressed previously activated T cells and protected grafted islets from autoimmune-mediated destruction. We conclude that vIL-10 can regulate autoimmune activity and that transfer of its gene may have potential for therapeutic islet transplantation.

Adenoviridae↗
PubMed2005

Inflammatory blockade improves human pancreatic islet function and viability.

The pathogenesis of pancreatic beta-cell death in diabetes mellitus is still under investigation. Inflammation is likely to be one of the factors responsible for beta-cell death during disease development. In this study, we have used a novel antiinflammatory compound, Lisofylline (LSF), to investigate the role of inflammatory blockade in protecting human pancreatic islets. LSF is a small synthetic molecule that reduces inflammatory cytokine production and action, improves beta-cell mitochondrial metabolism, and regulates immune activities. The present study has demonstrated that the treatment of human islets with LSF not only allows the retention of glucose responsiveness and insulin secretion in the presence of multiple proinflammatory cytokines, but also enhances basal insulin secretion of beta cells in vitro. LSF also significantly reduces islet apoptosis, protects beta cells from proinflammatory cytokine damage, and maintains cellular viability. In a mouse transplantation model, insulin independence could be reached in diabetic recipient mice by implantation of 30% fewer islets when LSF was used in islet culture compared to the control group. These results demonstrate that LSF profoundly enhances beta-cell function, and suggest the potential of using inflammatory blockade, such as LSF, to improve beta-cell function for islet transplantation.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

The novel anti-inflammatory agent lisofylline prevents autoimmune diabetic recurrence after islet transplantation.

BACKGROUND: Pancreatic islet transplantation has become a promising treatment for type 1 diabetes. However, autoimmune reactivity destroys engrafted islets in type 1 diabetic recipients. The authors' previous studies demonstrated that a novel anti-inflammatory agent, lisofylline (LSF), suppressed autoimmune reactivity and protected nonobese diabetic (NOD) mice from diabetes. In this study, the authors investigated the potential of LSF in preventing autoimmune diabetes recurrence after islet transplantation. METHODS: Spontaneously diabetic NOD mice received NOD severe combined immunodeficiency islet transplants and were treated with daily LSF injections at 50 mg/kg for 3 weeks. Blood glucose levels were monitored. Serum cytokine levels were measured at 1 and 3 weeks after engraftment. Nephrectomy of the islet-implanted kidney was performed in LSF-treated recipients. Histology of islet grafts was assessed at the end of the study. The effect of LSF on beta-cell function was studied in vitro. RESULTS: Without immunosuppressants and insulin, the LSF-treated recipient mice maintained euglycemia significantly longer than the saline-treated recipients (mean, >65 days in the LSF-treated group vs. 6 days in saline controls; P=0.0004). Serum levels of interferon-gamma were markedly reduced in LSF-treated recipients at 1 and 3 weeks posttransplant. Diabetes recurred in the LSF-treated recipients after removing the islet-implanted kidneys. Immunohistochemistry showed retention of insulin-positive cells in the grafts of the LSF-treated recipients. LSF preserved beta-cell insulin secretory function in the presence of inflammatory cytokines in vitro. CONCLUSIONS: This study demonstrates that autoimmune diabetes recurrence after islet transplantation could be prevented by treatment with LSF. LSF and its analogues may have the potential to prevent islet autoimmune destruction in clinical transplantation.

Animals↗
PubMed2004

Autoimmune diabetes is blocked in Stat4-deficient mice.

Signal transducers and activators of transcription (STAT) proteins are activated in response to many cytokines, growth factors and hormones. STAT4 mediates IL-12 signaling and regulates T helper 1 (Th1) cell differentiation. Both IL-12 and Th1 cell activation participate in the development of autoimmune diabetes. In this study, we investigated the role of STAT4 in autoimmune diabetes. We crossbred Stat4 deficient (Stat4-/-) mice with nonobese diabetic (NOD) mice to generate the Stat4-/- NOD model. In Stat4-/- NOD mice, serum levels of both IFN-gamma and IL-2 were significantly reduced as compared to the controls. Insulin secretion in pancreatic islets was preserved in Stat4-/- NOD mice. Significantly, disruption of Stat4 activation completely prevented the development of spontaneous diabetes in NOD mice. This study reveals the important role of STAT4 in autoimmune diabetes pathogenesis.

Animals↗
PubMed2003

Rosiglitazone reduces the accelerated neointima formation after arterial injury in a mouse injury model of type 2 diabetes.

BACKGROUND: Hyperglycemia (HG) and hyperinsulinemia (HI) may be factors enhancing the atherosclerotic complications of diabetes. We hypothesized that specific feeding of C57BL/6 apolipoprotein (apo) E-/- mice would alter their metabolic profiles and result in different degrees of neointima (NI) formation. We additionally hypothesized that an insulin-sensitizing agent (rosiglitazone) would prevent the development of type 2 diabetes and reduce neointima formation after carotid wire injury measured at 28 days. METHODS AND RESULTS: Fasting glucose and insulin levels were elevated in the Western diet (WD) group, with a trend toward higher insulin levels and euglycemia in the fructose diet (FD)--fed mice. NI formation was exaggerated in the WD group compared with the FD or chow control groups. In the WD mice given rosiglitazone, glucose and insulin levels remained normal and NI formation was significantly reduced, as was NI macrophage content. CONCLUSIONS: These findings demonstrate that apoE-/- mice fed a WD develop type 2 diabetes with an exaggerated NI response to injury. FD mice maintain euglycemia but develop insulin resistance, with an intermediate degree of NI growth compared with chow diet controls. Rosiglitazone prevents the development of hyperglycemia and hyperinsulinemia and normalizes the insulin release profile in the apoE-/-, WD-fed mouse and significantly reduces NI formation by 65% after carotid wire injury while reducing macrophage infiltration. These data support the hypothesis that type 2 diabetes in the setting of elevated cholesterol accelerates the response to vascular injury and suggest that agents that improve insulin sensitivity may have therapeutic value in reducing restenosis in type 2 diabetes.

Animals↗
PubMed2003

The immune modulator FYT720 prevents autoimmune diabetes in nonobese diabetic mice.

FTY720 is a novel immune regulatory drug derived from the fungal sphingosine analog ISP-1 (myriocin). FTY720 causes a redistribution of lymphocytes from circulation to secondary lymphoid tissues. Type 1 diabetes is an autoimmune disorder caused by cellular-mediated destruction of insulin-producing pancreatic beta cells in the islets of Langerhans. Indeed, local infiltration of islets by mononuclear cells is the hallmark of Type 1 diabetes. Based on both FTY720's action and the involvement of cellular infiltration in the disease progression, we tested FTY720 for its ability to prevent autoimmune diabetes in diabetes-prone, nonobese diabetic (NOD) mice. We found that treatment with FTY720 completely prevented NOD mice from developing autoimmune diabetes. The FTY720-treated animals showed both reduced numbers of circulating lymphocytes and sharply diminished cellular infiltration of pancreatic islets. These results suggest that FTY720 may be effective in prevention of autoimmune diabetes or in slowing its progression.

Animals↗
PubMed2003

The novel anti-inflammatory compound, lisofylline, prevents diabetes in multiple low-dose streptozotocin-treated mice.

INTRODUCTION: Proinflammatory cytokines play an important role in the development of type 1 diabetes. Lisofylline (LSF) is a novel anti-inflammatory compound that specifically inhibits proinflammatory cytokine production and action. AIM: To investigate the effect of LSF on diabetes prevention. METHODOLOGY: A mouse with diabetes induced by multiple low doses of streptozotocin (STZ) can be used as an animal model for type 1 diabetes. In this study, we used this method to induce diabetes in C57BL/6J mice. The daily LSF treatment started 5 days before STZ injections and lasted for 2 weeks. The incidence of diabetes was monitored. Insulin secretion was assessed in pancreatic islets isolated from experimental mice. Cytokine production was measured in mouse sera. Islet apoptosis was assessed quantitatively. RESULTS: In LSF-treated mice, there was a significant reduction of diabetes incidence (25% vs. 91.6%). This protection was associated with suppression of systemic levels of IFN-gamma and TNF-alpha, inhibition of macrophage infiltration in islets, restoration of islet insulin secretion, and reduction of beta-cell apoptosis. CONCLUSIONS: This study suggests that treatment with LSF suppresses proinflammatory cytokines and protects beta-cells from inflammation. LSF may be useful for prevention of type 1 diabetes and other disorders associated with excessive proinflammatory cytokines.

Animals↗
PubMed2002

Suppression of autoimmune diabetes by viral IL-10 gene transfer.

Th1 cell activation and cytokine production shift the balance between Th1 and Th2, favoring the up-regulation of proinflammatory activity that leads to destruction of insulin-producing pancreatic beta cells in type 1 diabetes. Th2-type cytokines, such as IL-10, have immune regulatory function. Administration of IL-10, or IL-10 gene transfer, prevents autoimmune diabetes in nonobese diabetic (NOD) mice. However, constant administration of purified rIL-10 is not practical for long-term therapy to prevent diabetes. In this study, we transferred the BCRF-1 gene, an open reading frame in the Epstein-Barr viral genome with remarkable homology to mouse IL-10 (viral IL-10 or vIL-10), by an adeno-associated viral (AAV) vector to NOD mice to attain sustained vIL-10 gene expression. Like endogenous mouse IL-10, vIL-10 has potent immunoregulatory and immunosuppressive functions, but can be specifically distinguished from endogenous mouse IL-10 for monitoring of the transgene expression. A single systemic administration of AAV vIL-10 significantly reduced insulitis and prevented diabetes development in NOD mice. This protective effect correlated with sustained transgene expression and protein production. Moreover, splenocytes from the treated mice blocked diabetes transfer to NOD recipients, suggesting that vIL-10 induces an active suppression of autoimmunity. This study provides evidence to support the possibility of using vIL-10 gene therapy to prevent type 1 diabetes.

Adoptive Transfer↗
PubMed2002

Lisofylline, a novel antiinflammatory agent, protects pancreatic beta-cells from proinflammatory cytokine damage by promoting mitochondrial metabolism.

Proinflammatory cytokine-mediated pancreatic beta-cell dysfunction is a key pathological event in type I diabetes mellitus. Lisofylline (LSF), an anti-inflammatory agent, has been shown to protect pancreatic islets from IL-1 beta-induced inhibitory effects on insulin release. However, the mechanism of LSF action is not known. Increasing evidence suggests that the mitochondria play an important role in regulating the beta-cell insulin release capacity and the control of cellular viability. To examine the direct effects of LSF on beta-cells, insulin-secreting INS-1 cells were exposed to a combination of recombinant IL-1 beta, TNF alpha, and IFN gamma with or without LSF for 18 h. Basal and glucose-stimulated static insulin release were measured using RIA. INS-1 cell viability was determined using in situ terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling and LIVE/DEAD dual fluorescence labeling. To evaluate INS-1 mitochondrial function, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) metabolism, change in mitochondrial membrane potential, and intracellular ATP levels were assessed. Cytokine addition reduced basal (7.8 +/- 0.30 vs. 10.0 +/- 0.46 ng/ml.h; P < 0.005), glucose-stimulated insulin secretion (11.6 +/- 0.86 vs. 17.4 +/- 1.86 ng/ml.h; P < 0.005), and MTT metabolism in INS-1 cells. Over 40% of the cytokine-treated beta-cells exhibited nuclear DNA breakage, whereas the control cell death rate remained at 1-2%. Simultaneous application of LSF and cytokines to INS-1 cells restored insulin secretion, MTT metabolism, mitochondrial membrane potential, and cell viability to control levels. LSF increased beta-cell MTT metabolism as well as insulin release and glucose responsiveness. In summary, proinflammatory cytokines lead to a reduction of glucose-induced insulin secretion, mitochondrial activity, and viability in INS-1 cells. LSF at concentrations achievable in vivo protected beta-cells from the cytokine effects. The mechanism of LSF-induced protection may be by promoting mitochondrial metabolism.

Adenosine Triphosphate↗