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      Anti-Diabetic Effects of Madecassic Acid and Rotundic Acid

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          Abstract

          Anti-diabetic effects of madecassic acid (MEA) and rotundic acid (RA) were examined. MEA or RA at 0.05% or 0.1% was supplied to diabetic mice for six weeks. The intake of MEA, not RA, dose-dependently lowered plasma glucose level and increased plasma insulin level. MEA, not RA, intake dose-dependently reduced plasminogen activator inhibitor-1 activity and fibrinogen level; as well as restored antithrombin-III and protein C activities in plasma of diabetic mice. MEA or RA intake decreased triglyceride and cholesterol levels in plasma and liver. Histological data agreed that MEA or RA intake lowered hepatic lipid droplets, determined by ORO stain. MEA intake dose-dependently declined reactive oxygen species (ROS) and oxidized glutathione levels, increased glutathione content and maintained the activity of glutathione reductase and catalase in the heart and kidneys of diabetic mice. MEA intake dose-dependently reduced interleukin (IL)-1β, IL-6, tumor necrosis factor-α and monocyte chemoattractant protein-1 levels in the heart and kidneys of diabetic mice. RA intake at 0.1% declined cardiac and renal levels of these inflammatory factors. These data indicated that MEA improved glycemic control and hemostatic imbalance, lowered lipid accumulation, and attenuated oxidative and inflammatory stress in diabetic mice. Thus, madecassic acid could be considered as an anti-diabetic agent.

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          Attenuation by metallothionein of early cardiac cell death via suppression of mitochondrial oxidative stress results in a prevention of diabetic cardiomyopathy.

          We aimed to test whether attenuation of early-phase cardiac cell death can prevent diabetic cardiomyopathy. Our previous study showed that cardiac apoptosis as a major early cellular response to diabetes is induced by hyperglycemia-derived oxidative stress that activates a mitochondrial cytochrome c-mediated caspase-3 activation pathway. Metallothionein (MT) as a potent antioxidant prevents the development of diabetic cardiomyopathy. Diabetes was induced by a single dose of streptozotocin (STZ) (150 mg/kg) in cardiac-specific, metallothionein-overexpressing transgenic (MT-TG) mice and wild-type (WT) controls. On days 7, 14, and 21 after STZ treatment, cardiac apoptosis was examined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and caspase-3 activation. Cardiomyopathy was evaluated by cardiac ultrastructure and fibrosis in the diabetic mice 6 months after STZ treatment. A significant reduction in diabetes-induced increases in TUNEL-positive cells, caspase-3 activation, and cytochrome c release from mitochondria was observed in the MT-TG mice as compared to WT mice. Cardiac protein nitration (3-nitrotyrosine [3-NT]) and lipid peroxidation were significantly increased, and there was an increase in mitochondrial oxidized glutathione and a decrease in mitochondrial reduced glutathione in the WT, but not in the MT-TG, diabetic mice. Double staining for cardiomyocytes with alpha sarcomeric actin and caspase-3 or 3-NT confirmed the cardiomyocyte-specific effects. A significant prevention of diabetic cardiomyopathy and enhanced animal survival were observed in the MT-TG diabetic mice as compared to WT diabetic mice. These results suggest that attenuation of early-phase cardiac cell death by MT results in a significant prevention of the development of diabetic cardiomyopathy. This process is mediated by MT suppression of mitochondrial oxidative stress.
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            Activated protein C: biased for translation.

            The homeostatic blood protease, activated protein C (APC), can function as (1) an antithrombotic on the basis of inactivation of clotting factors Va and VIIIa; (2) a cytoprotective on the basis of endothelial barrier stabilization and anti-inflammatory and antiapoptotic actions; and (3) a regenerative on the basis of stimulation of neurogenesis, angiogenesis, and wound healing. Pharmacologic therapies using recombinant human and murine APCs indicate that APC provides effective acute or chronic therapies for a strikingly diverse range of preclinical injury models. APC reduces the damage caused by the following: ischemia/reperfusion in brain, heart, and kidney; pulmonary, kidney, and gastrointestinal inflammation; sepsis; Ebola virus; diabetes; and total lethal body radiation. For these beneficial effects, APC alters cell signaling networks and gene expression profiles by activating protease-activated receptors 1 and 3. APC's activation of these G protein-coupled receptors differs completely from thrombin's activation mechanism due to biased signaling via either G proteins or β-arrestin-2. To reduce APC-associated bleeding risk, APC variants were engineered to lack >90% anticoagulant activity but retain normal cell signaling. Such a neuroprotective variant, 3K3A-APC (Lys191-193Ala), has advanced to clinical trials for ischemic stroke. A rich data set of preclinical knowledge provides a solid foundation for potential translation of APC variants to future novel therapies. © 2015 by The American Society of Hematology.
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              Neutrophils and monocytes as potentially important sources of proinflammatory cytokines in diabetes.

              Neutrophils and monocytes play a central role in host defence. The invading leucocytes are capable of synthesizing and releasing a variety of proinflammatory mediators including cytokines. Given the importance of cytokines in the progression of chronic and acute inflammatory processes, we aimed to ascertain whether the release of interleukin (IL)-8, IL-1beta, tumour necrosis factor (TNF)-alpha and IL-1ra of neutrophils and monocytes was modified in diabetes. To this end, we measured the release of cytokines in suspensions of cell culture in basal and lipopolysaccharide (LPS)-stimulated conditions. In basal conditions, neutrophils of diabetics release 1.6, 3.2, 1.9 and 1.9-fold higher amounts of IL-8, IL-1beta, TNF-alpha and IL-1ra, respectively, than do healthy controls. Under our experimental conditions, this effect was more evident for neutrophils than for monocytes. Incremental cytokine production was also found to occur when neutrophils were stimulated with LPS. IL-8, IL-1beta and TNF-alpha increased, respectively, by 4.0, 1.7 and 2.8-fold. Although the effect was more marked for neutrophils, monocytes showed a tendency for increased cytokine production. The discovery of this increase in cytokines released by the neutrophils of diabetics contributes towards a clearer understanding of other deficiencies described for neutrophils in diabetes, such as the migration of neutrophils to inflammatory sites, phagocytes, release of lytic proteases, production of reactive oxygen species and apoptosis. The excessive production of cytokines may lead to inappropriate activation and tissue injury and even to increased susceptibility to invasive microorganisms. Thus, the increased responsiveness of neutrophils of diabetics demonstrated in this study may be considered part of the scenario of diabetes physiopathology.
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                Author and article information

                Journal
                Nutrients
                Nutrients
                nutrients
                Nutrients
                MDPI
                2072-6643
                02 December 2015
                December 2015
                : 7
                : 12
                : 10065-10075
                Affiliations
                [1 ]Department of Biological Science and Technology, China Medical University, Taichung City 40402, Taiwan; yuanmh@ 123456mail.cmu.edu.tw
                [2 ]Graduate Institute of Clinical Medical Science, China Medical University, Taichung City 40402, Taiwan; viennaspring0312@ 123456gmail.com
                [3 ]Division of Endocrinology and Metabolism, Department of Internal Medicine, China Medical University Hospital, Taichung City 40402, Taiwan
                [4 ]Shanghai Research Center for the Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; lhhu@ 123456simm.ac.cn
                [5 ]Department of Pathology, Chung Shan Medical University Hospital, Taichung City 40402, Taiwan; jasmine.lyl@ 123456gmail.com
                [6 ]Department of Health and Nutrition Biotechnology, Asia University, Taichung City 40402, Taiwan
                [7 ]Department of Nutrition, China Medical University, Taichung City 40402, Taiwan
                Author notes
                [* ]Correspondence: mcyin@ 123456mail.cmu.edu.tw ; Tel.: +886-4-2205-3366 (ext. 7510); Fax: +886-4-2206-2891
                Article
                nutrients-07-05512
                10.3390/nu7125512
                4690064
                26633490
                0a8e75f5-5e80-4866-8cf7-66de052aa0fb
                © 2015 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 09 November 2015
                : 23 November 2015
                Categories
                Article

                Nutrition & Dietetics
                madecassic acid,rotundic acid,diabetes,coagulation,anti-lipid
                Nutrition & Dietetics
                madecassic acid, rotundic acid, diabetes, coagulation, anti-lipid

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