Background-Endothelial progenitor cells (EPCs) are thought to contribute to endothelial recovery after arterial injury.We therefore compared in vivo reendothelialization capacity of EPCs derived from patients with diabetes mellitus and healthy subjects. Moreover, we examined the effect of treatment with the peroxisome proliferator-activated receptor-␥ agonist rosiglitazone on oxidant stress, nitric oxide (NO) bioavailability, and the in vivo reendothelialization capacity of EPCs from diabetic individuals. Methods and Results-In vivo reendothelialization capacity of EPCs from diabetic patients (nϭ30) and healthy subjects (nϭ10) was examined in a nude mouse carotid injury model. Superoxide and NO production of EPCs was determined by electron spin resonance spectroscopy. Thirty patients with diabetes mellitus were randomized to 2 weeks of rosiglitazone (4 mg BID PO) or placebo treatment. In vivo reendothelialization capacity of EPCs derived from diabetic subjects was severely reduced compared with EPCs from healthy subjects (reendothelialized area: 8Ϯ3% versus 37Ϯ10%; PϽ0.001). EPCs from diabetic individuals had a substantially increased superoxide production and impaired NO bioavailability. Small-interfering RNA silencing of NAD(P)H oxidase subunit p47 phox reduced superoxide production and restored NO bioavailability and in vivo reendothelialization capacity of EPCs from diabetic patients. Importantly, rosiglitazone therapy normalized NAD(P)H oxidase activity, restored NO bioavailability, and improved in vivo reendothelialization capacity of EPCs from diabetic patients (reendothelialized area: placebo versus rosiglitazone, 8Ϯ1% versus 38Ϯ5%; PϽ0.001). Conclusions-In vivo reendothelialization capacity of EPCs derived from individuals with diabetes mellitus is severely impaired at least partially as a result of increased NAD(P)H oxidase-dependent superoxide production and subsequently reduced NO bioavailability. Rosiglitazone therapy reduces NAD(P)H oxidase activity and improves reendothelialization capacity of EPCs from diabetic individuals, representing a potential novel mechanism whereby peroxisome proliferatoractivated receptor-␥ agonism promotes vascular repair. association of reduced EPC numbers with peripheral artery disease and its severity in diabetic patients. 6,7 Experimental studies have demonstrated that EPCs promote endothelial repair after injury. 8 -10 In diabetic patients, however, an impaired migration capacity and tube formation of EPCs have been observed in vitro, 11,12 and a diabetesinduced delay in reendothelialization by EPCs has been described for diabetic mice, 13 raising the question of whether the in vivo reendothelialization capacity of human EPCs from patients with diabetes mellitus is altered. Moreover, mechanisms underlying EPC dysfunction in diabetic individuals remain largely unknown. In the present study, we therefore compared the in vivo reendothelialization capacity of EPCs derived from diabetic and healthy subjects and analyzed mechanisms of EPC dysfunction.Increased oxidant s...
Background-Statins may exert important pleiotropic effects, ie, improve endothelial function, independently of their impact on LDL cholesterol. In humans, however, pleiotropic effects of statins have never been unequivocally demonstrated because prolonged statin treatment always results in reduced LDL cholesterol levels. We therefore tested the hypothesis that similar reductions in LDL cholesterol with simvastatin and ezetimibe, a novel cholesterol absorption inhibitor, result in different effects on endothelial function. Methods and Results-Twenty patients with chronic heart failure were randomized to 4 weeks of simvastatin (10 mg/d) or ezetimibe (10 mg/d) treatment. Flow-dependent dilation (FDD) of the radial artery was determined by high-resolution ultrasound before and after intra-arterial vitamin C to determine the portion of FDD inhibited by radicals (⌬FDD-VC). Activity of extracellular superoxide dismutase, a major vascular antioxidant enzyme system, was determined after release from the endothelium by a heparin bolus injection. Endothelial progenitor cells were analyzed with an in vitro assay. Simvastatin and ezetimibe treatment reduced LDL cholesterol to a similar extent (15.6% versus 15.4%; PϭNS), whereas changes in mevalonate, the product of HMG-CoA-reductase, differed between groups (⌬mevalonate-simvastatin, Ϫ1.04Ϯ0.62 versus ⌬mevalonate-ezetimibe, 1.79Ϯ0.94 ng/mL; PϽ0.05 between groups). Importantly, FDD was markedly improved after simvastatin (10.5Ϯ0.6% versus 5.1Ϯ0.7%; PϽ0.01) but not after ezetimibe treatment (5.6Ϯ0.5% versus 5.8Ϯ0.6%; PϭNS). ⌬FDD-VC was substantially reduced after simvastatin but not after ezetimibe treatment. Extracellular superoxide dismutase activity was increased by Ͼ100% (PϽ0.05) after simvastatin but not ezetimibe treatment. Simvastatin treatment increased the number of functionally active endothelial progenitor cells, whereas ezetimibe had no effect. Conclusions-Four weeks of simvastatin treatment improves endothelial function independently of LDL cholesterol lowering, at least in part by reducing oxidant stress. Simvastatin may thereby exert important pleiotropic effects in
Ozone oxidative preconditioning is a prophylactic approach, which favors the antioxidant-prooxidant balance for preservation of cell redox state by the increase of antioxidant endogenous systems in both in vivo and in vitro experimental models. Our aim is to analyze the effect of ozone oxidative preconditioning on serum TNF-α levels and as a modulator of oxidative stress on hepatic tissue in endotoxic shock model (mice treated with lipopolysaccharide (LPS)). Ozone/oxygen gaseous mixture which was administered intraperitoneally (0.2, 0.4, and 1.2 mg/kg) once daily for five days before LPS (0.1 mg/kg, intraperitoneal). TNF-α was measured by cytotoxicity on L-929 cells. Biochemical parameters such as thiobarbituric acid reactive substances (TBARS), enzymatic activity of catalase, glutathione peroxidase, and glutathione-S transferase were measured in hepatic tissue. One hour after LPS injection there was a significant increase in TNF-α levels in mouse serum. Ozone/oxygen gaseous mixture reduced serum TNF-α levels in a dose-dependent manner. Statistically significant decreases in TNF-α levels after LPS injection were observed in mice pretreated with ozone intraperitoneal applications at 0.2 (78%), 0.4 (98%), and 1.2 (99%). Also a significant increase in TBARS content was observed in the hepatic tissue of LPS-treated mice, whereas enzymatic activity of glutathion-S transferase and glutathione peroxidase was decreased. However in ozone-treated animals a significant decrease in TBARS content was appreciated as well as an increase in the activity of antioxidant enzymes. These results indicate that ozone oxidative preconditioning exerts inhibitory effects on TNF-α production and on the other hand it exerts influence on the antioxidant-prooxidant balance for preservation of cell redox state by the increase of endogenous antioxidant systems.
Background and purpose: Intraglandular injection of botulinum toxin (BoNT) leads to a transient denervation of the submandibular gland and this is associated with reduced salivary secretion. The purpose of the present study was to verify whether temporary acinar atrophy occurs simultaneously with chemical denervation of the glands. Experimental approach: Tissue specimens of the right submandibular gland taken from 18 Wistar rats after intraglandular injection of BoNT A, BoNT B, or a combination of both were examined. As a sham control, an equivalent volume of saline was injected into the left submandibular gland. Morphometric measurements, immunohistochemistry, electron microscopy and western blot analysis were used to analyse the morphological and functional changes of the denervated glands. Key results: Morphological and ultrastructural analyses of the cell organelles and secretory granula showed a clear atrophy of the acini, which was more prominent in glands injected with the combination of BoNT/A and B. Morphometric measurements of the glandular acini revealed a significant reduction of the area of the acinar cells after injection of BoNT (P ¼ 0.031). The expression of amylase was significantly reduced in BoNT treated glands. Conclusions and implications: Intraglandular application of BoNT induces structural and functional changes of the salivary glands indicated by glandular atrophy. These effects may be due to glandular denervation induced by the inhibition of the soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptors (SNAREs) involved in acetylcholine release at the neuroglandular junction and also specially inhibition of those involved in exocytosis of the granula of the acinar cells.
The results support the important role of SOD and GPx in the protective effects of OOP against organ damage induced by fecal peritonitis in rats.
A robot's head is important both for directional sensors and, in human-directed robotics, as the single most visible interaction interface. However, designing a robot's head faces contradicting requirements when integrating powerful sensing with social expression. Furher, reactions of the general public show that current head designs often cause negative user reactions and distract from the functional capabilities.Therefore, this contribution presents a novel anthropomorphic robot head called "Flobi", which combines state-of-the-art sensing functionality with an exterior that elicits a sympathetic emotional response. It can display primary and secondary emotions in a human-like way, to enable intuitive human-robotinteraction. To facilitate further research on facial appearance, the exterior is fully modular and replaceable.While current state-of-the-art still requires trade-offs when integrating sensing and social expression, Flobi has been designed to enable service robotic applications, with highresolution, wide-angle stereo vision, gyroscope motion compensation and stereo audio. For ease of integration, the head is selfcontained, including 18 actuators, sensors and control boards, all in a human-head sized package.
Head and neck squamous cell carcinomas (HNSCC) represent a group of metastasizing tumors with a high mortality rate in man and animals. Since the biomolecule ozone was found to inhibit growth of various carcinoma cells in vitro we here applied the highly aggressive and lethal VX2 carcinoma HNSCC tumor model of the New Zealand White rabbit to test whether ozone exerts antitumorous effects in vivo. Therapeutic insufflation of medical ozone/oxygen (O 3 /O 2 ) gas mixture into the peritoneum (O 3 /O 2 -pneumoperitoneum) at an advanced stage of tumor disease led to a survival rate of 7/14 rabbits. Six of the seven surviving rabbits presented full tumor regression and the absence of local or distant lung metastases. Key words: HNSCC; immunosurveillance; metastasis; O 3 /O 2 -pneumoperitoneum; VX2 carcinoma Squamous cell carcinomas of the head and neck region (HNSCC) frequently metastasize and show a high mortality rate in man and animals. Being an accepted animal model for studying the progression and metastatic spread of HNSCC, the highly aggressive and lethal VX2 auricular carcinoma model of the New Zealand White (NZW) rabbit 1,2 was applied in our study. This tumor model was proven to be highly suitable to investigate new therapeutic approaches, since both the HNSCC and the VX2 carcinoma are similar in growth leading to early regional lymph node and subsequent distant metastatic spread. [3][4][5] As is true for many cancers HNSCC tumor cells somehow evade the body's immune system. This immune escape can partly be explained by the frequently observed downregulation or loss of MHC Class I determinants 6,7 and an increase in CD41CD251 regulatory T cells (T reg ) that are found responsible for depressed antitumor immunity. 8-10 Therefore, being able to activate the immunosurveillance toward HNSCC tumor cells should help in recognition and eradication of this tumor entity. Enhancing the immunosurveillance capacity is an emerging concept in recent cancer immunotherapies, 11-13 particularly those focusing on immunomodulators or upregulators of the immune response. 14 To augment the host's immune response against cancer cells, therapies with recombinant cytokines, dendritic cell immunization and tumor antigen vaccination as well as T cell-based immunotherapies are currently under investigation. [15][16][17]
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