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Influence of Tyrphostin AG490 on the expression of diabetes-associated markers in human adipocytes.

ABSTRACT: Tyrosine kinase inhibitors (TKi) hold promise as a treatment for a variety of disorders ranging from those in oncology to diseases thought as immune mediated. Tyrphostin AG490 is a potent Jak-Stat TKi shown effective in the prevention of allograft transplant rejection, experimental autoimmune disease, as well as the treatment of cancer. However, given its ability to modulate this important but pleiotropic intracellular pathway, we thought that it is important to examine its effects on glucose metabolism and expression of major transcription factors and adipokines associated with insulin insensitivity and diabetes. We investigated the metabolic effects of AG490 on glucose levels in vivo using an animal model of diabetes, nonobese diabetic (NOD) mice, and transcription factor expression through assessment of human adipocytes. AG490 treatment of young nondiabetic NOD mice significantly reduced blood glucose levels (p?=?0.002). In vitro, treatment of adipocytes with rosiglitazone, an insulin sensitizer that binds to peroxisome proliferator-activated receptor (PPAR) receptors and increases the adipocyte response to insulin, significantly increased the expression of the antidiabetic adipokine adiponectin. Importantly, the combination of rosiglitazone plus Tyrphostin AG490 further increased this effect and was specifically associated with significant upregulation of C-enhanced binding protein (C/EBP) (p?

SUBMITTER: Davoodi-Semiromi A

PROVIDER: S-EPMC4538928 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Influence of Tyrphostin AG490 on the expression of diabetes-associated markers in human adipocytes.

Davoodi-Semiromi Abdoreza A Wasserfall C H CH Hassanzadeh A A Cooper-DeHoff R M RM Wabitsch M M Atkinson M M

Immunogenetics 20121019 1

Tyrosine kinase inhibitors (TKi) hold promise as a treatment for a variety of disorders ranging from those in oncology to diseases thought as immune mediated. Tyrphostin AG490 is a potent Jak-Stat TKi shown effective in the prevention of allograft transplant rejection, experimental autoimmune disease, as well as the treatment of cancer. However, given its ability to modulate this important but pleiotropic intracellular pathway, we thought that it is important to examine its effects on glucose me ...[more]

PMID: 23081744

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Project description:The objective of the present study was to establish if individuals with Diabetes Mellitus (DM2) and periodontal diseases (gingivitis or periodontitis) presented an increase in the concentration of modified LDL (moLDL) and what is the influence of periodontal treatment on the decrease of moLDL particles with consequent improvement in the parameters of DM2. Twenty-four diabetic patients with periodontitis (Group 1) and twenty-four diabetic patients with gingivitis (Group 2) were followed up for a period of 12 months. Group 1 was treated with periodontal debridement, and Group 2 received supra-gingival scaling and prophylaxis. In both groups, periodontal clinical parameters: probing depth (PD), clinical attachment level (CAL), gingival resection (GR), bleeding on probing index (BOP) and plaque index; inflammatory serum markers (glycemia, A1c, total cholesterol, HDL-cholesterol (HDL-c), LDL-cholesterol (LDL-c), triglycerides and hs-CRP) and oxidized LDL (oxLDL) were measured at baseline, t = 6 and t = 12 months after treatment. Solutions of LDL were analyzed using the nonlinear optical Z-Scan and optical absorption techniques. The periodontal clinical parameters showed significant improvement (p < 0.05) in both Group after 12 months. For both groups, total cholesterol, HDL-c, LDL-c, triglycerides and A1c levels did not show significant reductions after periodontal therapy. hs-CRP levels in Group 1 presented a significant reduction after 12 months. The glycemic rate and the oxLDL concentrations did not show significant differences as a function of time. The optical measurements of LDL solutions revealed an improvement of the LDL-c quality in both groups. Periodontal debridement was able to improve periodontal parameters and the quality of LDL-c in diabetic patients but without changes in the oxLDL concentration in both groups. Considering the clinical relevance, the reduction of infectious and inflammatory sites present in the oral cavity through periodontal therapy may help with the control and prevention of hyperglycemia and precursors of cardiovascular diseases.

Project description:Although pancreatic cancer often invades peripancreatic adipose tissue, little information is known about cancer-adipocyte interaction. We first investigated the ability of adipocytes to de-differentiate to cancer-associated adipocytes (CAAs) by co-culturing with pancreatic cancer cells. We then examined the effects of CAA-conditioned medium (CAA-CM) on the malignant characteristics of cancer cells, the mechanism underlying those effects, and their clinical relevance in pancreatic cancer. When 3T3-L1 adipocytes were co-cultured with pancreatic cancer cells (PANC-1) using the Transwell system, adipocytes lost their lipid droplets and changed morphologically to fibroblast-like cells (CAA). Adipocyte-specific marker mRNA levels significantly decreased but those of fibroblast-specific markers appeared, characteristic findings of CAA, as revealed by real-time PCR. When PANC-1 cells were cultured with CAA-CM, significantly higher migration/invasion capability, chemoresistance, and epithelial-mesenchymal transition (EMT) properties were observed compared with control cells. To investigate the mechanism underlying these effects, we performed microarray analysis of PANC-1 cells cultured with CAA-CM and found a 78.5-fold higher expression of SAA1 compared with control cells. When the SAA1 gene in PANC-1 cells was knocked down with SAA1 siRNA, migration/invasion capability, chemoresistance, and EMT properties were significantly attenuated compared with control cells. Immunohistochemical analysis on human pancreatic cancer tissues revealed positive SAA1 expression in 46/61 (75.4%). Overall survival in the SAA1-positive group was significantly shorter than in the SAA1-negative group (P = .013). In conclusion, we demonstrated that pancreatic cancer cells induced de-differentiation in adipocytes toward CAA, and that CAA promoted malignant characteristics of pancreatic cancer via SAA1 expression, suggesting that SAA1 is a novel therapeutic target in pancreatic cancer.

Dataset Information

Influence of Tyrphostin AG490 on the expression of diabetes-associated markers in human adipocytes.

Publications

Influence of Tyrphostin AG490 on the expression of diabetes-associated markers in human adipocytes.

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