BACKGROUND: Chronic exposure to elevated levels of free fatty acids contributes to pancreatic β-cell dysfunction. Although it is well known that metformin induces cellular energy depletion and a concomitant activation of AMP-activated protein kinase (AMPK) through inhibition of the respiratory chain, previous studies have shown inconsistent results with regard to the action of metformin on pancreatic β-cells. We therefore examined the effects of metformin on pancreatic β-cells under lipotoxic stress.METHODS: NIT-1 cells and mouse islets were exposed to palmitate and treated with 0.05 and 0.5 mM metformin. Cell viability, glucose-stimulated insulin secretion, cellular adenosine triphosphate, reactive oxygen species (ROS) levels and Rho kinase (ROCK) activities were measured. The phosphorylation of AMPK was evaluated by Western blot analysis and mRNA levels of endoplasmic reticulum (ER) stress markers and NADPH oxidase (NOX) were measured by real-time quantitative polymerase chain reaction analysis.RESULTS: We found that metformin has protective effects on palmitate-induced β-cell dysfunction. Metformin at a concentration of 0.05 mM inhibits NOX and suppresses the palmitate-induced elevation of ER stress markers and ROS levels in a AMPK-independent manner, whereas 0.5 mM metformin inhibits ROCK activity and activates AMPK.CONCLUSION: This study suggests that the action of metformin on β-cell lipotoxicity was implemented by different molecular pathways depending on its concentration. Metformin at a usual therapeutic dose is supposed to alleviate lipotoxic β-cell dysfunction through inhibition of oxidative stress and ER stress.
Adenosine Triphosphate ; AMP-Activated Protein Kinases ; Animals ; Blotting, Western ; Cell Survival ; Electron Transport ; Endoplasmic Reticulum ; Endoplasmic Reticulum Stress ; Fatty Acids, Nonesterified ; Insulin ; Insulin-Secreting Cells ; Metformin ; Mice ; NADPH Oxidase ; Oxidative Stress ; Phosphorylation ; Polymerase Chain Reaction ; Reactive Oxygen Species ; rho-Associated Kinases ; RNA, Messenger

In this article, on page 230, Fig. 2A needs to be corrected.

OBJECTIVE: To evaluate engraftment by visualizing the location of human bone marrow-derived mesenchymal stem cells (hBM-MSCs) three-dimensionally in photothrombotic cerebral infarction (PTCI) models of rats. MATERIALS AND METHODS: Magnetic resonance imaging (MRI) of an agarose block containing superparamagnetic iron oxide (SPIO)-labeled hBM-MSCs was performed using a 3.0-T MRI, T2-(T2WI), T2*-(T2*WI), and susceptibility-weighted images (SWI). PTCI was induced in 6 rats, and 2.5 x 10(5) SPIO-labeled hBM-MSCs were infused through the ipsilateral internal carotid artery (ICA group) or tail vein (IV group). MRI was performed on days 1, 3, 7, and 14 after stem cell injection. Dark signal regions were confirmed using histology. Three-dimensional MRI reconstruction was performed using the clinical workflow solution to evaluate the engraftment of hBM-MSCs. Volumetric analysis of the engraftment was also performed. RESULTS: The volumes of SPIO-labeled hBM-MSCs in the phantom MRI were 129.3, 68.4, and 25.9 microL using SWI, T2*WI, and T2WI, respectively. SPIO-labeled hBM-MSCs appeared on day 1 after injection, encircling the cerebral infarction from the ventral side. Dark signal regions matched iron positive cells and human origin (positive) cells. The volume of the engraftment was larger in the ICA group on days 1, 3, and 7, after stem cell injection (p < 0.05 on SWI). SWI was the most sensitive MRI pulse sequence (p < 0.05). The volume of infarction decreased until day 14. CONCLUSION: The engraftment of SPIO-labeled hBM-MSCs can be visualized and evaluated three-dimensionally in PTCI models of rats. The engraftment volume was larger in the ICA group than IV group on early stage within one week.
Animals ; Cerebral Infarction/pathology/*radiography ; Contrast Media ; Dextrans ; Humans ; Imaging, Three-Dimensional/methods ; Magnetic Resonance Imaging/*methods ; Magnetite Nanoparticles ; Male ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stromal Cells/radiography ; Nanoparticles ; Neuroimaging/*methods ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Tomography, X-Ray Computed

BACKGROUND AND OBJECTIVES: We compared the efficacy and safety of valsartan and rosuvastatin combination therapy with each treatment alone in hypercholesterolemic hypertensive patients. SUBJECTS AND METHODS: Patients who met inclusion criteria were randomized to receive 1 of the following 2-month drug regimens: valsartan 160 mg plus rosuvastatin 20 mg, valsartan 160 mg plus placebo, or rosuvastatin 20 mg plus placebo. The primary efficacy variables were change in sitting diastolic blood pressure (sitDBP) and sitting systolic blood pressure (sitSBP), and percentage change in low-density lipoprotein-cholesterol (LDL-C) in the combination, valsartan, and rosuvastatin groups. Adverse events (AEs) during the study were analyzed. RESULTS: A total of 354 patients were screened and 123 of them were finally randomized. Changes of sitDBP by least squares mean (LSM) were -11.1, -7.2, and -3.6 mm Hg, respectively, and was greater in the combination, as compared to both valsartan (p=0.02) and rosuvastatin (p<0.001). Changes of sitSBP by LSM were -13.2, -10.8, and -4.9 mm Hg, and was greater in the combination, as compared to rosuvastatin (p=0.006) and not valsartan (p=0.42). Percentage changes of LDL-C by LSM were -52, -4, and -47% in each group, and was greater in the combination, as compared to valsartan (p<0.001), similar to rosuvastatin (p=0.16). Most AEs were mild and resolved by the end of the study. CONCLUSION: Combination treatment with valsartan and rosuvastatin exhibited an additive blood pressure-lowering effect with acceptable tolerability, as compared to valsartan monotherapy. Its lipid lowering effect was similar to rosuvatatin monotherapy.
Blood Pressure ; Drug Therapy, Combination ; Humans ; Least-Squares Analysis ; Rosuvastatin Calcium ; Valsartan

OBJECTIVE: This study aimed to evaluate the hypotheses that administration routes [intra-arterial (IA) vs. intravenous (IV)] affect the early stage migration of transplanted human bone marrow-derived mesenchymal stem cells (hBM-MSCs) in acute brain infarction. METHODS: Male Sprague-Dawley rats (n=40) were subjected to photothrombotic infarction. Three days after photothrombotic infarction, rats were randomly allocated to one of four experimental groups [IA group : n=12, IV group : n=12, superparamagnetic iron oxide (SPIO) group : n=8, control group : n=8]. All groups were subdivided into 1, 6, 24, and 48 hours groups according to time point of sacrifice. Magnetic resonance imaging (MRI) consisting of T2 weighted image (T2WI), T2* weighted image (T2*WI), susceptibility weighted image (SWI), and diffusion weighted image of rat brain were obtained prior to and at 1, 6, 24, and 48 hours post-implantation. After final MRI, rats were sacrificed and grafted cells were analyzed in brain and lung specimen using Prussian blue and immunohistochemical staining. RESULTS: Grafted cells appeared as dark signal intensity regions at the peri-lesional zone. In IA group, dark signals in peri-lesional zone were more prominent compared with IV group. SWI showed largest dark signal followed by T2*WI and T2WI in both IA and IV groups. On Prussian blue staining, IA administration showed substantially increased migration and a large number of transplanted hBM-MSCs in the target brain than IV administration. The Prussian blue-positive cells were not detected in SPIO and control groups. CONCLUSION: In a rat photothrombotic model of ischemic stroke, selective IA administration of human mesenchymal stem cells is more effective than IV administration. MRI and histological analyses revealed the time course of cell migration, and the numbers and distribution of hBM-MSCs delivered into the brain.
Animals ; Brain ; Brain Infarction ; Cell Movement ; Cerebral Infarction* ; Diffusion ; Humans* ; Infarction ; Infusions, Intravenous* ; Iron ; Lung ; Magnetic Resonance Imaging* ; Male ; Mesenchymal Stromal Cells* ; Rats* ; Rats, Sprague-Dawley ; Stroke ; Transplants

This study aimed to characterize and MRI track the mesenchymal stem cells labeled with chitosan-coated superparamagnetic iron oxide (Chitosan-SPIO). Chitosan-SPIO was synthesized from a mixture of FeCl2 and FeCl3. The human bone marrow derived mesenchymal stem cells (hBM-MSC) were labeled with 50 microg Fe/mL chitosan-SPIO and Resovist. The labeling efficiency was assessed by iron content, Prussian blue staining, electron microscopy and in vitro MR imaging. The labeled cells were also analyzed for cytotoxicity, phenotype and differentiation potential. Electron microscopic observations and Prussian blue staining revealed 100% of cells were labeled with iron particles. MR imaging was able to detect the labeled MSC successfully. Chitosan-SPIO did not show any cytotoxicity up to 200 microgram Fe/mL concentration. The labeled stem cells did not exhibit any significant alterations in the surface markers expression or adipo/osteo/chondrogenic differentiation potential when compared to unlabeled control cells. After contralateral injection into rabbit ischemic brain, the iron labeled stem cells were tracked by periodical in vivo MR images. The migration of cells was also confirmed by histological studies. The novel chitosan-SPIO enables to label and track MSC for in vivo MRI without cellular alteration.
Animals ; Brain Ischemia/chemically induced/pathology/therapy ; Cell Differentiation ; Chitosan/*chemistry ; Coordination Complexes/*chemistry/toxicity ; Ferric Compounds/*chemistry ; Humans ; Magnetic Resonance Imaging ; Magnetics ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stromal Cells/*chemistry/cytology ; Metal Nanoparticles/*chemistry ; Phenotype ; Rabbits

Therapeutic embolization is defined as the voluntary occlusion of one or several vessels, and this is achieved by inserting material into the lumen to obtain transient or permanent thrombosis in the downstream vascular bed. There are a number of indications for this approach in urological practice, in particular for the patients with parenchymatous or vascular kidney disease. In this review, we present the different embolization techniques and the principally employed occluding agents, and then we present the principal clinical indications and we discuss other pathologies that may benefit from this non-invasive therapy. The complications, side effects and main precautions associated with this approach are also described.
Adenocarcinoma/*therapy ; Aneurysm/therapy ; Angiomyolipoma/*therapy ; Embolization, Therapeutic/*methods ; Humans ; Kidney/injuries ; Kidney Diseases/*therapy ; Kidney Neoplasms/*therapy

PURPOSE: The purpose of this study was to evaluate multidetector row CT (MDCT) angiographic findings and their clinical significance for contrast extravasation into a spontaneous intracerebral hematoma (ICH). MATERIALS AND METHODS: MDCT angiographic studies and clinical records of 115 patients with spontaneous ICH were retrospectively reviewed. Cases were divided into two groups according to the presence or absence of contrast extravasation. The cases in the two groups were compared to determine the differences in radiological and clinical findings. The contrast extravasation group was divided into two subgroups according to radiological findings as follows: single or multiple dot-like contrast extravasation (Type A) and beaded-tubular (with or without dot-like extravasation) contrast extravasation (Type B). RESULTS: Contrast extravasation was seen in 38 patients (33%). It was associated with a larger hematoma volume, more frequent intraventricular hemorrhage (IVH) and subarachnoid hemorrhage (SAH), a shorter time interval from onset to the time of the CT scan, lower Glasgow coma scale (GCS), and a higher mortality rate. Type A and B contrast extravasation were observed in 16 (42%) and 22 (58%) patients, respectively. The rate of IVH and the clinical outcome of patients with Type B showed a significant correlation. CONCLUSION: Two types of contrast extravasation into an ICH show a significant difference in the rate of IVH and in clinical outcome. Detecting the presence of contrast extravasation and classifying them according to the morphologic patterns are important in predicting a prognosis.
Contrast Media ; Glasgow Coma Scale ; Hematoma* ; Hemorrhage ; Humans ; Mortality ; Prognosis ; Retrospective Studies ; Subarachnoid Hemorrhage ; Tomography, X-Ray Computed

PURPOSE: The aim of this study was to evaluate the CT findings of pulmonary fat embolism syndrome that was induced by triolein and oleic acid, along with its pathologic correlation. MATERIALS AND METHODS: 16 rabbits were included in this study. The rabbits in group I (n=8) were embolized with 0.2 mL triolein and the rabbits of group II (n=8) were embolized with 0.2 mL oleic acid through ear veins. HRCT scans were done prior to embolization and at 0.5, 4, 24, 48 and 72 hours post-embolization. The pathologic correlations were determined at 0.5, 24, 48 and 72 hours. RESULTS: At 24 hours, one group I rabbit showed abnormal CT findings that were composed of several 2-3 mm nodules and multiple ill-defined peripheral ground glass opacities. The pathologic finding of this rabbit at 48 hours was mainly intraarveolar edema. All the group II rabbits (n=8/8) showed ill-defined bilateral and peripheral ground glass opacities with (n=6/8) or without consolidations (n=2/8) on the 0.5 hour CT. All the rabbits (n=7/7) showed that the new ground glass opacities and ground glass opacities noted on the 0.5 hour CT were changed into consolidation. The margins of the ground glass opacities and consolidations were more sharpened on the 24 hours CT. All 6 rabbits (n=6/6) showed consolidations without ground glass opacities and the margins of the consolidations were more sharpened on the 48 hours CT. There was no significant interval change on the 72 hours CT. The pathologic findings of ground glass opacities were interstitial edema or mild intraalveolar edema. The pathologic findings of consolidation were intraalveolar edema, hemorrhage and coagulation necrosis. CONCLUSION: The CT findings after fat embolization using triolein and oleic acid were ill-defined peripheral ground glass opacities with/without consolidations. These findings occurred in only one triolein group with the time lag, but these findings were immediately and extensively seen in all group II rabbits. These CT findings may be important for making a diagnosis of pulmonary fat embolism syndrome.
Diagnosis ; Ear ; Edema ; Embolism, Fat* ; Glass ; Hemorrhage ; Necrosis ; Oleic Acid* ; Pulmonary Embolism ; Rabbits* ; Triolein* ; Veins

OBJECTIVE: To know the effect of adenosine 5'-triphosphate (ATP) on intracellular calcium level and cell proliferation in cervical cancer cells. METHODS: Study design: Four different human cervical cancer cell lines (Caski, C33A, HeLaS3 and SiHa) were used in this study. The change of intracellular calcium level, cell proliferation and the activity of proliferation- and calcium-related transcription factors by extracellular ATP were examined in these cell lines. RESULTS: Extracellular ATP induced calcium mobilization, cell proliferation and the activation of NF-kappa B in all cell lines used. CONCLUSION: These results suggest that calcium mobilization and NF-kappa B dependent signaling pathway play an important role in the cell proliferation by ATP in cervical cancer.
Adenosine Triphosphate ; Adenosine* ; Calcium* ; Cell Line ; Cell Proliferation ; Humans ; NF-kappa B* ; Transcription Factors ; Uterine Cervical Neoplasms*