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      The Antiaging Effect of Active Fractions and Ent-11α-Hydroxy-15-Oxo-Kaur-16-En-19-Oic Acid Isolated from Adenostemma lavenia (L.) O. Kuntze at the Cellular Level

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          Abstract

          Background: The extract of Adenostemma lavenia (L.) O. Kuntze leaves has anti-inflammatory activities and is used as a folk medicine to treat patients with hepatitis and pneumonia in China and Taiwan. The diterpenoid ent-11α-hydroxy-15-oxo-kaur-16-en-19-oic acid (11αOH-KA) is the major ingredient in the extract and has wide-spectrum biological activities, such as antitumor and antimelanogenic activities, as well as anti-inflammatory activity. However, the physical and biological properties of this compound as an antioxidant or antiaging agent have not been reported yet. Methods: In addition to in vitro assays, we monitored antioxidative and antiaging signals in Schizosaccharomyces pombe (yeast) and mouse melanoma B16F10 cells. Results: A. lavenia water and chloroform fractions showed antioxidant properties in vitro. The A. lavenia extracts and 11αOH-KA conferred resistance to H 2O 2 to S. pombe and B16F10 cells and extended the yeast lifespan in a concentration-dependent manner. These materials maintained the yeast mitochondrial activity, even in a high-glucose medium, and induced an antioxidant gene program, the transcriptional factor pap1 + and its downstream ctt1 +. Accordingly, 11αOH-KA activated the antioxidative transcription factor NF-E2-related factor 2, NRF2, the mammalian ortholog of pap1 +, in B16F10 cells, which was accompanied by enhanced hemeoxygenase expression levels. These results suggest that 11αOH-KA and A. lavenia extracts may protect yeast and mammalian cells from oxidative stress and aging. Finally, we hope that these materials could be helpful in treating COVID-19 patients, because A. lavenia extracts and NRF2 activators have been reported to alleviate the symptoms of pneumonia in model animals.

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          ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis.

          Benoît D'Autréaux, Michel B Toledano (2007)
          Reactive oxygen species (ROS) have been shown to be toxic but also function as signalling molecules. This biological paradox underlies mechanisms that are important for the integrity and fitness of living organisms and their ageing. The pathways that regulate ROS homeostasis are crucial for mitigating the toxicity of ROS and provide strong evidence about specificity in ROS signalling. By taking advantage of the chemistry of ROS, highly specific mechanisms have evolved that form the basis of oxidant scavenging and ROS signalling systems.
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            Basic principles and emerging concepts in the redox control of transcription factors.

            Regina Brigelius-Flohé, Leopold Flohé (2011)
            Convincing concepts of redox control of gene transcription have been worked out for prokaryotes and lower eukaryotes, whereas the knowledge on complex mammalian systems still resembles a patchwork of poorly connected findings. The article, therefore, reviews principles of redox regulation with special emphasis on chemical feasibility, kinetic requirements, specificity, and physiological context, taking well investigated mammalian transcription factor systems, nuclear transcription factor of bone marrow-derived lymphocytes (NF-κB), and kelch-like ECH-associated protein-1 (Keap1)/Nrf2, as paradigms. Major conclusions are that (i) direct signaling by free radicals is restricted to O(2)•- and •NO and can be excluded for fast reacting radicals such as •OH, •OR, or Cl•; (ii) oxidant signals are H(2)O(2), enzymatically generated lipid hydroperoxides, and peroxynitrite; (iii) free radical damage is sensed via generation of Michael acceptors; (iv) protein thiol oxidation/alkylation is the prominent mechanism to modulate function; (v) redox sensors must be thiol peroxidases by themselves or proteins with similarly reactive cysteine or selenocysteine (Sec) residues to kinetically compete with glutathione peroxidase (GPx)- and peroxiredoxin (Prx)-type peroxidases or glutathione-S-transferases, respectively, a postulate that still has to be verified for putative mammalian sensors. S-transferases and Prxs are considered for system complementation. The impact of NF-κB and Nrf2 on hormesis, management of inflammatory diseases, and cancer prevention is critically discussed.
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              KEAP1 E3 ligase-mediated downregulation of NF-kappaB signaling by targeting IKKbeta.

              Dung-Fang Lee, Hsu-Ping Kuo, Mo Liu … (2009)
              IkappaB kinase beta (IKKbeta) is involved in tumor development and progression through activation of the nuclear factor (NF)-kappaB pathway. However, the molecular mechanism that regulates IKKbeta degradation remains largely unknown. Here, we show that a Cullin 3 (CUL3)-based ubiquitin ligase, Kelch-like ECH-associated protein 1 (KEAP1), is responsible for IKKbeta ubiquitination. Depletion of KEAP1 led to the accumulation and stabilization of IKKbeta and to upregulation of NF-kappaB-derived tumor angiogenic factors. A systematic analysis of the CUL3, KEAP1, and RBX1 genomic loci revealed a high percentage of genome loss and missense mutations in human cancers that failed to facilitate IKKbeta degradation. Our results suggest that the dysregulation of KEAP1-mediated IKKbeta ubiquitination may contribute to tumorigenesis.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Antioxidants (Basel)
                Journal ID (iso-abbrev): Antioxidants (Basel)
                Journal ID (publisher-id): antioxidants
                Title: Antioxidants
                Publisher: MDPI
                ISSN (Electronic): 2076-3921
                Publication date (Electronic): 08 August 2020
                Publication date Collection: August 2020
                Volume: 9
                Issue: 8
                Electronic Location Identifier: 719
                Affiliations
                [1 ]Department of Chemistry, Faculty of Mathematics and Natural Sciences, IPB University, IPB Dramaga Campus, Bogor, West Java 16680, Indonesia; ilmiawati.aulia@ 123456gmail.com
                [2 ]Tropical Biopharmaca Research Center, IPB University, Taman Kencana Street No. 3, Bogor 16128, Indonesia
                [3 ]Department of Biology, Faculty of Mathematics and Natural Sciences, IPB University, IPB Dramaga Campus, Bogor, West Java 16680, Indonesia; rikaindriastuti@ 123456apps.ipb.ac.id (R.I.A.); muhammadprastyajuni2011@ 123456gmail.com (M.E.P.)
                [4 ]Graduate School of Natural Science and Technology, Gifu University; Gifu 501-1193, Japan; Z4521078@ 123456edu.gifu-u.ac.jp
                [5 ]Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University; Gifu 501-1193, Japan; w3032081@ 123456edu.gifu-u.ac.jp (M.S.); ahama@ 123456gifu-u.ac.jp (A.H.)
                Author notes
                [* ]Correspondence: ime@ 123456apps.ipb.ac.id (I.B.); htake@ 123456gifu-u.ac.jp (H.T.); Tel.: +62-251-8373561 (I.B.); +81-58-2307634 (H.T.)
                Author information
                https://orcid.org/0000-0003-1561-6943
                https://orcid.org/0000-0003-2500-1264
                https://orcid.org/0000-0002-1815-2964
                Article
                Publisher ID: antioxidants-09-00719
                DOI: 10.3390/antiox9080719
                PMC ID: 7464069
                PubMed ID: 32784463
                SO-VID: 66e60948-7e26-4247-9f1a-479b68964967
                Copyright © © 2020 by the authors.
                License:

                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
                Date received : 29 June 2020
                Date accepted : 06 August 2020
                Categories
                Subject: Article

                Keywords: antiaging,ent-11α-hydroxy-15-oxo-kaur-16-en-19-oic acid,adenostemma lavenia,pap1+ transcription factor,nrf2
                Data availability:
                Keywords: antiaging, ent-11α-hydroxy-15-oxo-kaur-16-en-19-oic acid, adenostemma lavenia, pap1+ transcription factor, nrf2

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