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      Multi-Targeted Molecular Effects of Hibiscus sabdariffa Polyphenols: An Opportunity for a Global Approach to Obesity

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          Abstract

          Improper diet can alter gene expression by breaking the energy balance equation and changing metabolic and oxidative stress biomarkers, which can result in the development of obesity-related metabolic disorders. The pleiotropic effects of dietary plant polyphenols are capable of counteracting by modulating different key molecular targets at the cell, as well as through epigenetic modifications. Hibiscus sabdariffa (HS)-derived polyphenols are known to ameliorate various obesity-related conditions. Recent evidence leads to propose the complex nature of the underlying mechanism of action. This multi-targeted mechanism includes the regulation of energy metabolism, oxidative stress and inflammatory pathways, transcription factors, hormones and peptides, digestive enzymes, as well as epigenetic modifications. This article reviews the accumulated evidence on the multiple anti-obesity effects of HS polyphenols in cell and animal models, as well as in humans, and its putative molecular targets. In silico studies reveal the capacity of several HS polyphenols to act as putative ligands for different digestive and metabolic enzymes, which may also deserve further attention. Therefore, a global approach including integrated and networked omics techniques, virtual screening and epigenetic analysis is necessary to fully understand the molecular mechanisms of HS polyphenols and metabolites involved, as well as their possible implications in the design of safe and effective polyphenolic formulations for obesity.

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          Flavonoids: biosynthesis, biological functions, and biotechnological applications

          Flavonoids are widely distributed secondary metabolites with different metabolic functions in plants. The elucidation of the biosynthetic pathways, as well as their regulation by MYB, basic helix-loop-helix (bHLH), and WD40-type transcription factors, has allowed metabolic engineering of plants through the manipulation of the different final products with valuable applications. The present review describes the regulation of flavonoid biosynthesis, as well as the biological functions of flavonoids in plants, such as in defense against UV-B radiation and pathogen infection, nodulation, and pollen fertility. In addition, we discuss different strategies and achievements through the genetic engineering of flavonoid biosynthesis with implication in the industry and the combinatorial biosynthesis in microorganisms by the reconstruction of the pathway to obtain high amounts of specific compounds.
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            Effects of abiotic stress on plants: a systems biology perspective

            The natural environment for plants is composed of a complex set of abiotic stresses and biotic stresses. Plant responses to these stresses are equally complex. Systems biology approaches facilitate a multi-targeted approach by allowing one to identify regulatory hubs in complex networks. Systems biology takes the molecular parts (transcripts, proteins and metabolites) of an organism and attempts to fit them into functional networks or models designed to describe and predict the dynamic activities of that organism in different environments. In this review, research progress in plant responses to abiotic stresses is summarized from the physiological level to the molecular level. New insights obtained from the integration of omics datasets are highlighted. Gaps in our knowledge are identified, providing additional focus areas for crop improvement research in the future.
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              A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity.

              Adiponectin secreted from adipocytes binds to adiponectin receptors AdipoR1 and AdipoR2, and exerts antidiabetic effects via activation of AMPK and PPAR-α pathways, respectively. Levels of adiponectin in plasma are reduced in obesity, which causes insulin resistance and type 2 diabetes. Thus, orally active small molecules that bind to and activate AdipoR1 and AdipoR2 could ameliorate obesity-related diseases such as type 2 diabetes. Here we report the identification of orally active synthetic small-molecule AdipoR agonists. One of these compounds, AdipoR agonist (AdipoRon), bound to both AdipoR1 and AdipoR2 in vitro. AdipoRon showed very similar effects to adiponectin in muscle and liver, such as activation of AMPK and PPAR-α pathways, and ameliorated insulin resistance and glucose intolerance in mice fed a high-fat diet, which was completely obliterated in AdipoR1 and AdipoR2 double-knockout mice. Moreover, AdipoRon ameliorated diabetes of genetically obese rodent model db/db mice, and prolonged the shortened lifespan of db/db mice on a high-fat diet. Thus, orally active AdipoR agonists such as AdipoRon are a promising therapeutic approach for the treatment of obesity-related diseases such as type 2 diabetes.
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                Author and article information

                Journal
                Nutrients
                Nutrients
                nutrients
                Nutrients
                MDPI
                2072-6643
                20 August 2017
                August 2017
                : 9
                : 8
                : 907
                Affiliations
                [1 ]Instituto de Biología Molecular y Celular (IBMC), Universidad Miguel Hernández (UMH), Edificio Torregaitán, Elche 03202, Spain; mherranz@ 123456umh.es (M.H.-L.); maria.olivares@ 123456umh.es (M.O.-V.); jant.encinar@ 123456umh.es (J.A.E.); e.barrajon@ 123456umh.es (E.B.-C.)
                [2 ]Department of Analytical Chemistry, University of Granada, Avda. Fuentenueva s/n, Granada 18071, Spain; ansegura@ 123456ugr.es
                [3 ]Research and Development of Functional Food Centre (CIDAF), PTS Granada, Avda. del Conocimiento s/n., Edificio BioRegión, Granada 18016, Spain
                [4 ]Unitat de Recerca Biomèdica, Hospital Universitari Sant Joan, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Reus 43201, Spain; jjoven@ 123456grupsagessa.com
                [5 ]CIBER: CB12/03/30038, Fisiopatología de la Obesidad y la Nutrición, CIBERobn, Instituto de Salud Carlos III (ISCIII), Palma de Mallorca 07122, Spain
                Author notes
                [* ]Correspondence: vmicol@ 123456umh.es ; Tel.: +34-96-665-8430
                Author information
                https://orcid.org/0000-0002-7219-3863
                Article
                nutrients-09-00907
                10.3390/nu9080907
                5579700
                28825642
                36becac5-1ece-4ced-8813-fb1a9e88b074
                © 2017 by the authors.

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

                History
                : 31 July 2017
                : 14 August 2017
                Categories
                Review

                Nutrition & Dietetics
                antioxidants,dietary supplementation,obesity,epigenetics,metabolic stress,polyphenols,metabolites,virtual screening,hibiscus sabdariffa

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