International Journal of Molecular Sciences Review Artemisia annua, a Traditional Plant Brought to Light 1, , 2, 3 Axelle Septembre-Malaterre * y, Mahary Lalarizo Rakoto y , Claude Marodon , Yosra Bedoui 4, Jessica Nakab 3, Elisabeth Simon 3, Ludovic Hoarau 3, Stephane Savriama 5, Dominique Strasberg 6 , Pascale Guiraud 1, Jimmy Selambarom 1 and Philippe Gasque 1,7 1 Unité de recherche Etudes Pharmaco-Immunologie (EPI), Université de La Réunion, CHU La Réunion site Félix Guyon, Allée des Topazes, CS11021, 97400 Saint Denis de La Réunion, France; [email protected] (P.G.); [email protected] (J.S.); [email protected] (P.G.) 2 Faculté de Médecine, Université d’Antananarivo, Campus Universitaire Ambohitsaina, BP 375, Antananarivo 101, Madagascar; [email protected] 3 APLAMEDOM Réunion, 1, rue Emile Hugot, Batiment B, Parc Technologique de Saint Denis, 97490 Sainte Clotilde, La Réunion, France; [email protected] (C.M.); [email protected] (J.N.); [email protected] (E.S.); [email protected] (L.H.) 4 INSERM, UMR 1188 Diabète athérothrombose Thérapies Réunion Océan Indien (DéTROI), Université de La Réunion, 97400 Saint Denis de La Réunion, France; [email protected] 5 EA929 Archéologie Industrielle, Histoire, Patrimoine/Géographie-Développement Environnement de la Caraïbe (AIHP-GEODE), Université des Antilles, Campus Schoelcher, BP7207, 97275 Schoelcher Cedex Martinique, France; [email protected] 6 Unité Mixte de Recherche Peuplements Végétaux et Bio-agresseurs en Milieu Tropical (PVBMT), Pôle de Protection des Plantes, Université de La Réunion, 7 Chemin de l’IRAT, 97410 Saint-Pierre, La Réunion, France; [email protected] 7 Laboratoire d’Immunologie Clinique et Expérimentale de la Zone de l’Océan Indien (LICE-OI) CHU La Réunion site Félix Guyon, Allée des Topazes, CS11021, 97400 Saint Denis de La Réunion, France * Correspondence: [email protected] These authors contributed equally to this work. y Received: 18 June 2020; Accepted: 13 July 2020; Published: 15 July 2020 Abstract: Traditional remedies have been used for thousand years for the prevention and treatment of infectious diseases, particularly in developing countries. Of growing interest, the plant Artemisia annua, known for its malarial properties, has been studied for its numerous biological activities including metabolic, anti-tumor, anti-microbial and immunomodulatory properties. Artemisia annua is very rich in secondary metabolites such as monoterpenes, sesquiterpenes and phenolic compounds, of which the biological properties have been extensively studied. The purpose of this review is to gather and describe the data concerning the main chemical components produced by Artemisia annua and to describe the state of the art about the biological activities reported for this plant and its compounds beyond malaria. Keywords: Artemisia annua; Asteraceae; biological properties; secondary metabolites 1. Introduction The family Asteraceae comprises a wide number of genera, of which the genus Artemisia is one of the largest and most widely distributed worldwide [1]. The genus Artemisia L. is heterogeneous and consists of over 500 species widely geographically distributed in all continents except Antarctica. The genus acclimatizes to any environment, from sea level to high altitudes [2]. However, most of Artemisia species grow preferentially in the Northern Hemisphere and at a lower level in the Southern Hemisphere [3,4]. Species of this genus can be perennial, biennial or annual grasses, shrubs or bushes Int. J. Mol. Sci. 2020, 21, 4986; doi:10.3390/ijms21144986 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 4986 2 of 34 that are generally aromatic, with erect or ascending stems. The leaves of these plants are alternate, often divided, rarely whole and with smooth edges. The origin of the scientific name of the genus ArtemisiaInt. J. Mol.stems Sci. 2020 from, 21 two, x FOR major PEER REVIEW interpretations. The first proposition addresses the name “Artemisia”2 of 37 fromArtemisia the Greek stems goddess from “Artemis” two major (Diana interpretations. for the Romans), The first Zeus’s proposition daughter addresses and Apollo’s the sister,name who was considered“Artemisia” thefrom protector the Greek of thegoddess wild animals“Artemis” and (D goddessiana for ofthe the Romans), hunt. TheZeus’s second daughter interpretation and assignsApollo’s the origin sister, of who the was name considered to the King the protector of Caria’s of (Mausolus)the wild animals sister and and goddess wife Artemisia,of the hunt. whoThe was crownedsecond Queen interpretation after her assigns husband’s the origin death. of The the name genus to Artemisia the King of is Caria’s commonly (Mausolus) known sister as “wormwood”. and wife Wormwood,Artemisia, though, who was strictly crowned speaking, Queen after refers her to husb Artemisiaand’s death. absinthium The genus L., Artemisia which is is one commonly of the most commonknown and as well-known“wormwood”. species Wormwood, of the though, genus strictly [5]. The speaking, type species refers to of Artemisia the genus absinthium Artemisia L., is the Artemisiawhich vulgaris is one of[ 6the]. Apartmost common from Artemisia and well-known annua L.,species other of verythe genus well-known [5]. The type species species of of the the genus genus Artemisia is the Artemisia vulgaris [6]. Apart from Artemisia annua L, other very well-known include Artemisia absinthium, Artemisia abrotanum and Artemisia afra. These species were used to treat species of the genus include Artemisia absinthium, Artemisia abrotanum and Artemisia afra. These fever and malaria, respectively, in China, Europe and Africa [7]. Artemisia verlotiorum Lamotte was species were used to treat fever and malaria, respectively, in China, Europe and Africa [7]. Artemisia introducedverlotiorum to, andLamotte is still was present introduced in, theto, and Mascarene is still present Islands. in, the Mascarene Islands. ArtemisiaArtemisia annua annua, (Figure, (Figure1) 1) commonly commonly named named as as“annual “annual absinthe” absinthe” is an annual is an annualherbaceous herbaceous herb, herb,hence hence its its name name “annua”. “annua”. The The plant plant is grown is grown in inAsia, Asia, India, India, Central Central and andEastern Eastern Europe, Europe, in the in the temperatetemperate regions regions of America,of America, Africa, Africa, Australia Australia and in in tropical tropical regions regions [3,7]. [3, 7It]. is It widely is widely used used as a as a dietarydietary spice, spice, herbal herbal tea andtea and medicinal medicinal plant plant in in the the mild mild climates climates ofof Asia,Asia, such as as China China and and Korea Korea [8]. [8]. FigureFigure 1. 1.Artemisia Artemisia annua annua [9]. [9 ]. The literatureThe literature describes describes a confusion a confusion over over the ancientthe ancient Chinese Chinese names names of the of speciesthe speciesArtemisia Artemisia annua L. and Artemisiaannua L and apiacea Artemisia hance apiacea, the hance latter, the being latter native being native to China, to China, indistinctly indistinctly referred referred as as “qing “qing hao”. The polymathhao”. The Shenpolymath Gua Shen (1031–1095) Gua (1031–1095) of the Song of the dynasty Song dynasty described described two di twofferent different varieties varieties of qing of hao, one withqing blue–greenhao, one with leaves, blue–green and anotherleaves, and with another yellowish–green with yellowish–green leaves in leaves autumn. in autumn. Based Based partly on this description,partly on this thedescription, physician the and physician natural and historian natural historian Li Shizhen Li Shizhen (1518–1593) (1518—1593) differentiated differentiated between qing haobetween (blue-green qing hao herb)(blue-green and huangherb) and hua huang hao (yellow hua hao blossom(yellow blossom herb) in herb) his encyclopedicin his encyclopedicClassified Classified Materia Medica (Ben cao gang mu) in 1596 [10]. Currently, Artemisia apiacea hance is identified Materia Medica (Ben cao gang mu) in 1596 [10]. Currently, Artemisia apiacea hance is identified as qing as qing hao, and Artemisia annua as huang hua hao [7]. Unlike Artemisia apiacea hance, Artemisia annua hao, and Artemisia annua as huang hua hao [7]. Unlike Artemisia apiacea hance, Artemisia annua has been has been introduced to many other countries in Europe, North America, and the tropics. Seed introducedvarieties to have many been other adapted countries by breeding in Europe, for lower North latitudes, America, and and cultivation the tropics. has been Seed successfully varieties have beenachieved adapted in by many breeding tropical for countries, lower latitudes, for example and in cultivation the Congo, India, has been and successfullyBrazil. In contrast. achieved Artemisia in many tropicalapiacea countries, hance is less for examplecommon and in the is rarely Congo, grown India, outside and China Brazil. [5]. In contrast. Artemisia apiacea hance is less commonArtemisia and isannua rarely has grown been used outside in traditional China [ 5medicine]. for many years in Asia and Africa for the Artemisiatreatment of annua malariahas and been fever, used in inthe traditional form of tea or medicine pressed juice for many [11,12]. years The current in Asia pharmacopoeia and Africa for the treatmentof the of People’s malaria Republic and fever, of China in the officially form of lists tea orthe