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      Polyphenol Stilbenes from Fenugreek ( Trigonella foenum-graecum L.) Seeds Improve Insulin Sensitivity and Mitochondrial Function in 3T3-L1 Adipocytes

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          Abstract

          Fenugreek ( Trigonella foenum-graecum L.) is a well-known annual plant that is widely distributed worldwide and has possessed obvious hypoglycemic and hypercholesterolemia characteristics. In our previous study, three polyphenol stilbenes were separated from fenugreek seeds. Here, we investigated the effect of polyphenol stilbenes on adipogenesis and insulin resistance in 3T3-L1 adipocytes. Oil Red O staining and triglyceride assays showed that polyphenol stilbenes differently reduced lipid accumulation by suppressing the expression of adipocyte-specific proteins. In addition, polyphenol stilbenes improved the uptake of 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG) by promoting the phosphorylation of protein kinase B (AKT) and AMP-activated protein kinase (AMPK). In present studies, it was found that polyphenol stilbenes had the ability to scavenge reactive oxygen species (ROS). Results from adenosine triphosphate (ATP) production and mitochondrial membrane potentials suggested that mitochondria play a critical role in insulin resistance and related signaling activation, such as AKT and AMPK. Rhaponticin, one of the stilbenes from fenugreek, had the strongest activity among the three compounds in vitro. Future studies will focus on mitochondrial biogenesis and function.

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          Most cited references27

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          Structure-radical scavenging activity relationships of phenolic compounds from traditional Chinese medicinal plants.

          Traditional Chinese medicinal plants associated with anticancer contain a wide variety of natural phenolic compounds with various structural features and possessing widely differing antioxidant activity. The structure-radical scavenging activity relationships of a large number of representative phenolic compounds (e.g., flavanols, flavonols, chalcones, flavones, flavanones, isoflavones, tannins, stilbenes, curcuminoids, phenolic acids, coumarins, lignans, and quinones) identified in the traditional Chinese medicinal plants were evaluated using the improved ABTS*+ and DPPH methods. Different categories of tested phenolics showed significant mean differences in radical scavenging activity. Tannins demonstrated the strongest activity, while most quinones, isoflavones, and lignans tested showed the weakest activity. This study confirmed that the number and position of hydroxyl groups and the related glycosylation and other substitutions largely determined radical scavenging activity of the tested phenolic compounds. The differences in radical scavenging activity were attributed to structural differences in hydroxylation, glycosylation and methoxylation. The ortho-dihydroxy groups were the most important structural feature of high activity for all tested phenolic compounds. Other structural features played a modified role in enhancing or reducing the activity. Within each class of phenolic compounds, the structure-activity relationship was elucidated and discussed. This study reveals the structure-activity relationships of a large series of representative natural phenolic compounds more systematically and fully than previous work. Structure-radical scavenging activity relationships of some natural phenolics identified in the medicinal plants were evaluated for the first time.
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            The role of mitochondria in insulin resistance and type 2 diabetes mellitus.

            Type 2 diabetes mellitus (T2DM) has been related to alterations of oxidative metabolism in insulin-responsive tissues. Overt T2DM can present with acquired or inherited reductions of mitochondrial oxidative phosphorylation capacity, submaximal ADP-stimulated oxidative phosphorylation and plasticity of mitochondria and/or lower mitochondrial content in skeletal muscle cells and potentially also in hepatocytes. Acquired insulin resistance is associated with reduced insulin-stimulated mitochondrial activity as the result of blunted mitochondrial plasticity. Hereditary insulin resistance is frequently associated with reduced mitochondrial activity at rest, probably due to diminished mitochondrial content. Lifestyle and pharmacological interventions can enhance the capacity for oxidative phosphorylation and mitochondrial content and improve insulin resistance in some (pre)diabetic cases. Various mitochondrial features can be abnormal but are not necessarily responsible for all forms of insulin resistance. Nevertheless, mitochondrial abnormalities might accelerate progression of insulin resistance and subsequent organ dysfunction via increased production of reactive oxygen species. This Review discusses the association between mitochondrial function and insulin sensitivity in various tissues, such as skeletal muscle, liver and heart, with a main focus on studies in humans, and addresses the effects of therapeutic strategies that affect mitochondrial function and insulin sensitivity.
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              PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis.

              New therapeutic approaches to counter the increasing prevalence of obesity and type 2 diabetes mellitus are in high demand. Deregulation of the phosphoinositide-3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue (AKT), mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK) pathways, which are essential for glucose homeostasis, often results in obesity and diabetes. Thus, these pathways should be attractive therapeutic targets. However, with the exception of metformin, which is considered to function mainly by activating AMPK, no treatment for the metabolic syndrome based on targeting protein kinases has yet been developed. By contrast, therapies based on the inhibition of the PI3K/AKT and MAPK pathways are already successful in the treatment of diverse cancer types and inflammatory diseases. This contradiction prompted us to review the signal transduction mechanisms of PI3K/AKT, MAPK and AMPK and their roles in glucose homeostasis, and we also discuss current clinical implications.
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                Author and article information

                Contributors
                Journal
                Oxid Med Cell Longev
                Oxid Med Cell Longev
                OMCL
                Oxidative Medicine and Cellular Longevity
                Hindawi
                1942-0900
                1942-0994
                2018
                5 June 2018
                : 2018
                : 7634362
                Affiliations
                1Center for Mitochondria and Healthy Aging, College of Life Sciences, Yantai University, Yantai 264005, China
                2Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, China
                3College of Pharmacy, Qinghai Nationalities University, Xining 810008, China
                4University of Chinese Academy of Sciences, Beijing 100049, China
                Author notes

                Academic Editor: Caio P. Fernandes

                Author information
                http://orcid.org/0000-0002-5743-0963
                http://orcid.org/0000-0002-7347-8561
                http://orcid.org/0000-0002-2234-4053
                Article
                10.1155/2018/7634362
                6008889
                30693063
                ace11aec-a295-4316-b1e0-c76dcd536475
                Copyright © 2018 Gang Li et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 24 November 2017
                : 6 April 2018
                : 15 May 2018
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 31470426
                Award ID: 31300292
                Funded by: Chinese Academy of Sciences
                Award ID: XDA12040320
                Funded by: Natural Science Foundation of Shandong Province
                Award ID: ZR2017MH024
                Funded by: Qinghai Provincial Science Foundation
                Award ID: 2016-ZJ-929Q
                Award ID: 2015-SF-121
                Funded by: Youth Innovation Promotion Association of the Chinese Academy of Sciences
                Categories
                Research Article

                Molecular medicine
                Molecular medicine

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