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Article | WPRIM | ID: wpr-832394


Background@#Endothelial-to-mesenchymal transition (EndMT) contributes to inflammatory conditions inducing conversion of endothelial cells (ECs) into activated fibroblasts, promoting fibrotic diseases. Pro-inflammatory cytokine is the most potent inducer of EndMT. We investigated inhibition of interleukin-1β (IL-1β)-induced EndMT by gemigliptin, a dipeptidyl peptidase-IV inhibitor. @*Methods@#We exposed human umbilical vein endothelial cells (HUVECs) to 10 ng/mL IL-1β/20 μM gemigliptin and analyzed the expression of endothelial, smooth muscle, mesenchymal, and osteoblastic markers, bone morphogenetic protein (BMP), Smad, and non-Smad signaling pathway proteins. @*Results@#Morphological changes showed gemigliptin blocked IL-1β-induced EndMT, upregulated EC markers, and downregulated smooth muscle and mesenchymal markers. IL-1β activation of HUVECs is initiated by the BMP/Smad and non-smad BMP signaling pathways. Gemigliptin inhibited IL-1β induction of BMP2 and 7, activin receptor type IA, BMP receptor type IA, and BMP receptor type II. Reversal of IL-1β-mediated inhibition of BMP-induced Smad1/5/8, Smad2, and Smad3 phosphorylation by gemigliptin suggests involvement of the Smad pathway in gemigliptin action. In the non-Smad BMP pathway, gemigliptin treatment significantly increased the deactivation of extracellular regulated protein kinase (ERK), p38, and JNK by IL-1β. Gemigliptin treatment suppressed BMP-2-induced expression of key osteoblastic markers including osterix, runt-related transcription factor 2, and hepcidin during IL-1β-induced EndMT. @*Conclusion@#We demonstrated a novel protective mechanism of gemigliptin against fibrosis by suppressing IL-1β-induced EndMT.

Article in English | WPRIM | ID: wpr-717359


BACKGROUND: Whether pancreatic steatosis has a local or systemic effect, like ectopic fat of other major organs, remains unknown. Data on the influence of pancreatic steatosis on microvascular complication are rare. Therefore, we investigated the relationship between pancreatic steatosis and diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM). METHODS: The attenuation of three pancreatic regions (head, body, and tail) and the spleen (S) in 186 patients with T2DM was measured using non-enhanced computed tomography imaging. We used three parameters for the assessment of pancreatic steatosis (‘P’ mean: mean attenuation of three pancreatic regions; P–S: difference between ‘P’ mean and ‘S’; P/S: the ‘P’ mean to ‘S’ ratio). The presence of DR was assessed by an expert ophthalmologist using dilated fundoscopy. RESULTS: The average P mean was 29.02 Hounsfield units (HU), P–S was −18.20 HU, and P/S was 0.61. The three pancreatic steatosis parameters were significantly associated with the prevalence of DR in non-obese T2DM patients. In the non-obese group, the odds ratios of P mean, P–S, and P/S for the prevalence of DR, after adjustment for age, sex, and glycosylated hemoglobin level, were 2.449 (P=0.07), 2.639 (P=0.04), and 2.043 (P=0.02), respectively. CONCLUSION: In this study, pancreatic steatosis was significantly associated with DR in non-obese patients with T2DM. Further studies are necessary to clarify the causal relationship between pancreatic steatosis and the development of DR.

Diabetes Mellitus, Type 2 , Diabetic Retinopathy , Fats , Glycated Hemoglobin A , Humans , Odds Ratio , Pancreas , Prevalence , Spleen
Article in English | WPRIM | ID: wpr-728538


Here, we investigated whether hyperglycemia and/or free fatty acids (palmitate, PAL) aff ect the expression level of bone morphogenic protein 4 (BMP4), a proatherogenic marker, in endothelial cells and the potential role of BMP4 in diabetic vascular complications. To measure BMP4 expression, human umbilical vein endothelial cells (HUVECs) were exposed to high glucose concentrations and/or PAL for 24 or 72 h, and the effects of these treatments on the expression levels of adhesion molecules and reactive oxygen species (ROS) were examined. BMP4 loss-of-function status was achieved via transfection of a BMP4-specific siRNA. High glucose levels increased BMP4 expression in HUVECs in a dose-dependent manner. PAL potentiated such expression. The levels of adhesion molecules and ROS production increased upon treatment with high glucose and/or PAL, but this eff ect was negated when BMP4 was knocked down via siRNA. Signaling of BMP4, a proinflammatory and pro-atherogenic cytokine marker, was increased by hyperglycemia and PAL. BMP4 induced the expression of infl ammatory adhesion molecules and ROS production. Our work suggests that BMP4 plays a role in atherogenesis induced by high glucose levels and/or PAL.

Atherosclerosis , Diabetes Mellitus , Diabetic Angiopathies , Endothelial Cells , Fatty Acids, Nonesterified , Glucose , Human Umbilical Vein Endothelial Cells , Humans , Hyperglycemia , Reactive Oxygen Species , RNA, Small Interfering , Transfection
Article in English | WPRIM | ID: wpr-727368


Alcohol consumption increases the risk of type 2 diabetes. However, its effects on prediabetes or early diabetes have not been studied. We investigated endoplasmic reticulum (ER) stress in the pancreas and liver resulting from chronic alcohol consumption in the prediabetes and early stages of diabetes. We separated Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a type-2 diabetic animal model, into two groups based on diabetic stage: prediabetes and early diabetes were defined as occurrence between the ages of 11 to 16 weeks and 17 to 22 weeks, respectively. The experimental group received an ethanol-containing liquid diet for 6 weeks. An intraperitoneal glucose tolerance test was conducted after 16 and 22 weeks for the prediabetic and early diabetes groups, respectively. There were no significant differences in body weight between the control and ethanol groups. Fasting and 120-min glucose levels were lower and higher, respectively, in the ethanol group than in the control group. In prediabetes rats, alcohol induced significant expression of ER stress markers in the pancreas; however, alcohol did not affect the liver. In early diabetes rats, alcohol significantly increased most ER stress-marker levels in both the pancreas and liver. These results indicate that chronic alcohol consumption increased the risk of diabetes in prediabetic and early diabetic OLETF rats; the pancreas was more susceptible to damage than was the liver in the early diabetic stages, and the adaptive and proapoptotic pathway of ER stress may play key roles in the development and progression of diabetes affected by chronic alcohol ingestion.

Alcohol Drinking , Animals , Body Weight , Diet , Eating , Endoplasmic Reticulum , Endoplasmic Reticulum Stress , Ethanol , Fasting , Glucose , Glucose Tolerance Test , Liver , Models, Animal , Pancreas , Prediabetic State , Rats , Rats, Inbred OLETF
Article in English | WPRIM | ID: wpr-42484


BACKGROUND: Insulin-mediated glucose uptake in insulin target tissues is correlated with interstitial insulin concentration, rather than plasma insulin concentration. Therefore, insulin delivery to the interstitium of target tissues is very important, and the endothelium may also play an important role in the development of insulin resistance. METHODS: After treating bovine aortic endothelial cells with angiotensin II (ATII), we observed the changes in insulin binding capacity and the amounts of insulin receptor (IR) on the cell membranes and in the cytosol. RESULTS: After treatment of 10(-7)M ATII, insulin binding was decreased progressively, up to 60% at 60 minutes (P<0.05). ATII receptor blocker (eprosartan) dose dependently improved the insulin binding capacity which was reduced by ATII (P<0.05). At 200 microM, eprosartan fully restored insulin binding capacity, althogh it resulted in only a 20% to 30% restoration at the therapeutic concentration. ATII did not affect the total amount of IR, but it did reduce the amount of IR on the plasma membrane and increased that in the cytosol. CONCLUSION: ATII decreased the insulin binding capacity of the tested cells. ATII did not affect the total amount of IR but did decrease the amount of IR on the plasma membrane. Our data indicate that ATII decreases insulin binding by translocating IR from the plasma membrane to the cytosol. The binding of insulin to IR is important for insulin-induced vasodilation and transendothelial insulin transport. Therefore, ATII may cause insulin resistance through this endothelium-based mechanism.

Acrylates , Angiotensin II , Angiotensins , Cell Membrane , Cytosol , Endothelial Cells , Endothelium , Glucose , Imidazoles , Insulin , Insulin Resistance , Plasma , Receptor, Insulin , Thiophenes , Vasodilation
Article in Korean | WPRIM | ID: wpr-656981


BACKGROUND AND OBJECTIVES: To make stem cell therapy successful as one of treatment options for sensorineural hearing loss, it is essential to culture and obtain sufficient amounts of adult neural stem cells, as well as separating them from adult auditory organs. This study was designed to investigate the proportion of cultured adult neural stem cells and its differentiated cells from guinea pig spiral ganglion. MATERIALS AND METHOD: The spiral ganglions from guinea pigs of 3-6 month age were obtained. The tissues were digested with 0.25 % trypsin and 10 mg/mL of DNase I, cells were then cultured with neurobasal medium (DMEM/F12 containing B27 supplement, L-glutamin, gentamycin) and added with 20 ng/mL of epidermal growth factor and 10 ng/mL of fibroblast growth factor. After 3 passages of culture, neural stem cells and differentiated cells were analyzed with the flow cytometric method. RESULTS: We concluded that neural stem cells were successfully cultured from spiral ganglions and these cells were in process of differentiation into neurons and Schwann cells. The results of flow cytometric analysis of cells in culture medium showed that 1.7% of cells (cell count of 24,300) expressed nestin, 3.45% polysialylated neural cell adhesion molecule, 7.19% (cell count of 66,300) neural cell adhesion molecule, and 3.57% beta III tubulin. CONCLUSION: Though obtaining adult neural stem cells from adult spiral ganglion was successful, the cell count was small. Further studies on the subject of making proper culture medium are needed to obtain adequate amounts of adult neural stem cells.

Adult , Animals , Cell Count , Deoxyribonuclease I , Epidermal Growth Factor , Fibroblast Growth Factors , Flow Cytometry , Guinea , Guinea Pigs , Hearing Loss, Sensorineural , Humans , Intermediate Filament Proteins , Nerve Tissue Proteins , Neural Cell Adhesion Molecules , Neural Stem Cells , Neurons , Schwann Cells , Spiral Ganglion , Stem Cells , Trypsin , Tubulin