ABSTRACT
OBJECTIVE: This study aims to explore whether homeobox A11 antisense RNA (HOXA11-AS) could regulate inflammation induced by diabetic arteriosclerosis (DAA) via PI3K/AKT pathway. PATIENTS AND METHODS: Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was used to detect expressions of HOXA11-AS and proinflammatory genes in carotid endarterectomy samples of symptomatic and asymptomatic atherosclerosis (AS) patients, diabetes mellitus (DM), and non-DM patients. The above-mentioned genes in DM animal model and non-DM animal model were also detected. We detected the expression of HOXA11-AS in vascular smooth muscle cells (VSMCs) treated with platelet-derived growth factor (PDGF) or PDGF inhibitor imatinib, respectively. Subsequently, we applied cell transfection technology to interfere with the expression of HOXA11-AS in VSMCs. In vascular endothelial cells (VECs) and VSMCs, we detected the effect of HOXA11-AS on the expressions of genes related to the proliferation, migration, and cell cycle. Then, VSMCs were treated with tumor necrosis factor-α (TNF-α), and the expression of HOXA11-AS was examined in VSMCs. The effect of HOXA11-AS on TNF-α-induced inflammation in VSMCs was detected as well. Finally, we analyzed the effect of HOXA11-AS on PDGF-induced activation of PI3K/AKT pathway in VSMCs and VECs. RESULTS: HOXA11-AS expression was markedly increased in carotid endarterectomy specimens of symptomatic AS patients compared to that of asymptomatic AS patients. Expression levels of HOXA11-AS and pro-inflammatory genes were significantly elevated in carotid endarterectomy specimens of DM patients. Similarly, HOXA11-AS expression was also significantly increased in carotid arteries of DM mice compared with that of non-DM mice. PDGF could upregulate HOXA11-AS expression in VSMCs, which was reversed by PDGF inhibitor imatinib. HOXA11-AS knockdown could reduce the expressions of the proliferation-associated gene (PCNA) and the cycle-related genes (p21, p53), and also inhibited the proliferation and migration of VSMCs induced by PDGF. HOXA11-AS was upregulated by TNF-α. HOXA11-AS knockdown remarkably downregulated expressions of inflammation-related genes in VSMCs induced by TNF-α. In VECs, low expression of HOXA11-AS can inhibit the expression of TNF-α-induced pro-inflammatory genes and PDGF-induced vascular inflammation-related genes. Low expression of HOXA11-AS inhibited PDGF-induced activation of PI3K/AKT pathway in VSMCs and VECs. CONCLUSIONS: HOXA11-AS may participate in DAA by activating the PI3K/AKT pathway to regulate inflammation in VSMCs and VECs.
Subject(s)
Arteriosclerosis/genetics , Diabetic Angiopathies/etiology , Homeodomain Proteins/genetics , Animals , Cell Cycle/genetics , Cell Proliferation/genetics , Cells, Cultured , Down-Regulation , Endothelial Cells/metabolism , Humans , Inflammation/metabolism , Mice , Myocytes, Smooth Muscle/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Platelet-Derived Growth Factor/administration & dosage , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/genetics , Up-RegulationABSTRACT
BACKGROUND: To establish a tacrolimus-induced diabetes rat model and assess efficacy and safety of insulin glargine combined with repaglinide in Chinese patients with diabetes after liver transplantation. METHODS: Animal experiments and clinical trial were conducted. Animal experiments: Male SD rats were randomly divided into tacrolimus (4 mg/kg daily) and control group (saline). Rats were sacrificed after five months of treatment and blood was collected through heart puncture. Patients who underwent liver transplantation were selected and followed up regularly. If HbA1c was < 9%, repaglinide was administered; if HbA1c was > or = 9%, glargine plus repaglinide was administered. RESULTS: For rat model studies, in the tacrolimus group, fasting blood glucose (FBG) levels were increased after three months (p < 0.01). After five months, the insulin secretion index and the sensitivity index in the tacrolimus group was significantly lower than in the control group (p < 0.01). For studies of post-transplant diabetes mellitus (PTDM), eighty-six liver transplant recipients were enrolled. 51 were given repaglinide and 35 were given repaglinide combined with glargine. After treatment for 1, 6, and 12 months, FBG, post-prandial blood glucose (PPBG), and HbA1c levels decreased (p < 0.05) in both groups, and no statistically significant changes were observed in the liver and kidney function indicators (p > 0.05). No severe hypoglycemia episodes were reported. CONCLUSIONS: Tacrolimus caused islet cell necrosis, reduced insulin secretion, increased insulin resistance, and increased blood glucose in the model. The blood glucose levels increased in a time-dependent manner. Combination of glargine and repaglinide was effective and safe for Chinese patients with post liver transplant diabetes mellitus.
Subject(s)
Diabetes Mellitus/etiology , Immunosuppressive Agents/adverse effects , Liver Transplantation/adverse effects , Tacrolimus/adverse effects , Animals , Blood Glucose/analysis , Male , Rats , Rats, Sprague-DawleyABSTRACT
Ochrobactrum intermedium DN2 was used to degrade nicotine in tobacco waste extracts. The optimal temperature and pH of nicotine degradation by strain DN2 was 30-37 degrees C and 7.0, respectively. Under these optimal conditions, the average degradation rate of nicotine in a 30L fed-batch culture was 140.5 mg 1(-1) h(-1). The results of this study indicate that strain DN2 may be useful for reducing the nicotine content of reconstituted tobacco.
