molecules

Review Phytochemicals with Added Value from Morella and Myrica Species

Gonçalo P. Rosa 1,2 , Bruno J. C. Silva 3, Ana M. L. Seca 1,2,3 , Laila M. Moujir 4 and Maria Carmo Barreto 2,3,* 1 LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal; [email protected] (G.P.R.); [email protected] (A.M.L.S.) 2 cE3c—Centre for Ecology, Evolution and Environmental Changes/Azorean Biodiversity Group, Rua Mãe de Deus, 9501-321 Ponta Delgada, Portugal 3 Faculty of Sciences and Technology, University of Azores, Rua Mãe de Deus, 9501-321 Ponta Delgada, Portugal; [email protected] 4 Departamento de Bioquímica, Microbiología, Biología Celular y Genética, Facultad de Farmacia, Universidad de La Laguna, Avda Astrofísico Francisco Sánchez, s/n., 38200 La Laguna, Spain; [email protected] * Correspondence: [email protected]

Academic Editor: Derek J. McPhee



 Received: 27 November 2020; Accepted: 17 December 2020; Published: 21 December 2020

Abstract: Terrestrial plants, due to their sessile nature, are highly exposed to environmental pressure and therefore need to produce very effective molecules that enable them to survive all the threats. Myrica and Morella (Myricaceae) are taxonomically close genera, which include species of trees or shrubs with edible fruits that exhibit relevant uses in traditional medicine. For instance, in Chinese or Japanese folk medicine, they are used to treat diarrhea, digestive problems, headache, burns, and skin diseases. A wide array of compounds isolated from different parts of Myrica and/or Morella species possess several biological activities, like anticancer, antidiabetic, anti-obesity, and cardio-/neuro-/hepatoprotective activities, both in vitro and in vivo, with myricanol, myricitrin, quercitrin, and betulin being the most promising. There are still many other compounds isolated from both genera whose biological activities have not been evaluated, which represents an excellent opportunity to discover new applications for those compounds and valorize Morella/Myrica species.

Keywords: Morella; Myrica; myricanol; myricitrin; in vitro; in vivo

1. Introduction Nature is an important source of new biologically active compounds and molecules with very diverse and unique biological properties and chemical structures, several of them being commercialized as medicines [1]. This diversity is the result of a long and selective evolutionary pressure [2], that led to an array of different biosynthetic pathways producing primary and, in particular, secondary metabolites with a large variety of basic skeletons and functional groups, which have been huge contributors to the improvement of human health [3]. That evolutionary pressure is more intense in plants and other sessile organisms because, since they are unable to move, they are more exposed to the action of herbivores, pathogens. and/or variable sunlight conditions, and therefore need to produce very effective molecules that enable them to survive all of these threats [4]. That fact, allied to the extraordinary biological and chemical diversity within plants, offers a particularly rich potential in biologically active compounds that can be used to provide lead compounds for the production of medications for treating various diseases from migraine to cancer. Twenty-five percent of all prescribed drugs are derived from plants, and of the

Molecules 2020, 25, 6052; doi:10.3390/molecules25246052 www.mdpi.com/journal/molecules Molecules 2020, 25, 6052 2 of 33

252 drugs considered as basic and essential by the World Health Organization, 11% are exclusively of plant origin and a significant number are drugs obtained from natural precursors by semi-synthesis. Thus, medicinal plants and their derived natural compounds are still an increasing topic of investigation and interest [5,6]. The members of the Myrica and Morella genera are woody shrubs or tree pioneers in nitrogen-poor soils such as sandy soil or gravelly sites, because they are actinorhizal plants able to fix nitrogen through nitrogen-fixing root nodules induced by soil actinomycetes of the genus Frankia, with which they establish a symbiotic relationship [7]. In addition to the economic interest of these species as sources of paper and rope from the bark, as fuel wood, for biomass production, and land reclamation, they are also appreciated because their fruits that can be eaten raw and are used in the production of jams, syrups, and juices [8], and their applications in traditional medicine are also noteworthy. The Myrica genus comprised, before 2002, circa 97 species with a wide distribution in both temperate and sub-tropical regions [8,9]. Macdonald [10] presented various reasons for splitting this genus in two, Myrica and Morella, with his arguments only being accepted in 2002 [11]. A taxonomic key was published to allow the simple discrimination between species of the two genera [12]. The splitting of the Myrica genus led to many of the species previously belonging to the Myrica genus being reclassified and included in the Morella genus, which can cause problems when trying to correlate the discovery of secondary metabolites with the plant of origin. Many studies published before 2005 report the isolation of secondary metabolites from Myrica species which are now classified as Morella species, causing misleading reports on secondary metabolites found for the first time in the genus. Another issue is the fact that more recent publications use the previous scientific name, that consequently can lead to a compound not being properly detected in a literature survey. To prevent this from happening, the present work covers the secondary metabolites isolated from both genera and their respective biological activities. The botanical names of the species used in the present work are the ones currently accepted by the International Plant Names Index (IPNI) database, even if in the original publication the former name was used. In this case, the former name will appear in brackets.

2. Biological Activities Exhibited by Secondary Metabolites from Morella and Myrica Species Several of the secondary metabolites isolated from Morella and Myrica species have been studied to evaluate their potential application in human health. Silva et al. [13] reviewed compounds isolated from Morella and Myrica species exhibiting antioxidant and anti-inflammatory activities, reporting the antioxidant potential of various compounds as well as pertinent structure/activity relationships that could direct future research in order to obtain new, more active, and safer molecules. Therefore, this section is focused on other biological activities exhibited by compounds isolated from species of the Morella and Myrica genera. There are two bioactive compounds, myricetin and arjunolic acid, isolated, among others, from Myrica esculenta Buch.-Ham. Ex D. Don [14], whose biological activities have already been revised by Gupta et al. [15] and Gosh et al. [16], ranging from antidiabetic to antibacterial, anticancer, or anti-inflammatory. For that reason, those compounds will not be addressed in this work.

2.1. In Vitro Activities In vitro studies represent the first step in the evaluation of the pharmacological effects of compounds. They are a simpler and cheaper way to assess the bioactivities of the tested compounds and yield very important and relevant information to direct further investigations on the full pharmacological potential of a compound. The results of in vitro tests performed with compounds isolated from Morella and Myrica are summarized in Table1, where the compounds are organized by family. MoleculesMolecules2020 2020, 25, 25, 6052, x FOR PEER REVIEW 3 of 33 3 of 33 Molecules 2020, 25, x FOR PEER REVIEW 3 of 33

Table 1. In vitro biological activities exhibited by compounds from Morella and Myrica species. Table 1. In vitro biological activities exhibited by compounds from Morella and Myrica species. Table 1. In vitro biological activities exhibited by compounds from Morella and Myrica species. Compound Origin Biological Activities CompoundCompound Methanol extractOrigin of Myrica Origin rubra (Lour.) Biological Activities Biological Activities MethanolMethanolSiebold extract extract & of ofZucc.Myrica Myrica bark rubrarubra [17] (Lour.)(Lour.) Siebold & Zucc. Anti-tuberculosis [19] Myricanone (1) Hexane extractSiebold of & Morella Zucc.bark bark cerifera [[17]17 (L.)] Small Minimum inhibitory concentrationAnti-tuberculosis (MIC) = >150 [19]Anti-tuberculosis µg/mL (Ethambutol[19 MIC] = (Myrica cerífera) bark [18] 6.25 µg/mL). Myricanone (1) HexaneHexane extract extract of ofMorella Morella ceriferacerifera (L.) Small Small (MyricaMinimum cerífera) inhibitory concentrationMinimum (MIC) inhibitory = >150 µg/mL concentration (Ethambutol (MIC) MIC == >150 µg/mL Methanol extract of Morella adenophora Cytotoxic activity [25] Myricanone (1) (Myrica cerífera)bark bark [[18]18] 6.25 µg/mL).(Ethambutol MIC = 6.25 µg/mL). (Hance) J. Herb. roots [19] A549 cell line EC50 = 3.22 µg/mL (Fluorouracil EC50 = not shown). MethanolMethanol extract extract of ofMorella Morella adenophoraadenophora (Hance) J. Herb. Cytotoxic activity [25]Cytotoxic activity [25] Chloroform(Hance) and methanol J. Herb. roots extract [19] of Morella IncreaseA549 in cell apoptotic line EC rate50 = 3.22to 34.9% µg/mL at 5.0(Fluorouracil µg/mL (4.13% EC50 on = not untreated shown). cells). roots [19] A549 cell line EC50 = 3.22 µg/mL (Fluorouracil EC50 = not shown). arborea (Hutch.) Cheek twigs [20] Antimelanogenesis activity [26] ChloroformChloroform and and methanol methanol extractextract of MorellaMorella arboreaIncrease(Hutch.) in apoptoticIncrease rate to in 34.9% apoptotic at 5.0 rateµg/mL to (4.13% 34.9% on at 5.0untreatedµg/mL cells). (4.13% on untreated cells). 95% EtOHarborea extract (Hutch.) of Morella Cheek nanatwigs (A. [20] Chev.) Melanin content in B16Antimelanogenesis mouse melanoma activity cells at [26] 25 µg/mL: 23.5 ± 3.4% arborea (Hutch.)Cheek Cheek twigstwigs [20] [20] AntimelanogenesisAntimelanogenesis activity [26] activity [26] 95% EtOH extractJ. Herb. of Morellaroots [21] nana (A. Chev.) Melanin content in B16(arbutin mouse 25 melanoµg/mL:ma 77.4 cells ± 2.9%). at 25 µg/mL: 23.5 ± 3.4% 95% EtOH extract of Morella nana (A. Chev.) J. Herb. Melanin content in B16 mouse melanoma cells at 25 µg/mL: 23.5 3.4% Hexane extractJ. Herb. of Morella roots cerifera [21] (L.) Small Cell viability at 25 µg/mL:(arbutin 17.7 25 ±µg/mL: 1.7% (arbutin 77.4 ± 2.9%). 25 µg/mL: 102.0 ± 1.5%). ± roots [21] (arbutin 25 µg/mL: 77.4 2.9%). Hexane extract(Myrica of cerífera) Morella twigs cerifera [22] (L.) Small Cell viability at 25 µg/mL:Cytotoxic 17.7 ± 1.7% activity (arbutin [27] 25 µg/mL: 102.0 ± 1.5%).± Hexane extract of Morella cerifera (L.) Small (Myrica cerífera) Cell viability at 25 µg/mL: 17.7 1.7% (arbutin 25 µg/mL: 102.0 1.5%). Ethanol (95%Myrica extract cerífera) of Morella twigs [22] cerifera (L.) HepG2Cytotoxic cell line: EC activity50 = 32.46 [27] µg/mL. ± ± twigs [22] Cytotoxic activity [27] EthanolSmall 95% (Myrica extract cerífera) of Morella bark cerifera [23] (L.) WRL-68 cell line: atHepG2 100 µg/mL cell line: cell EC viability50 = 32.46 was µg/mL. 89.27% (non-tumor cell Ethanol 95% extract of Morella cerifera (L.) Small µ MethanolSmall extract (Myrica of cerífera) Myrica galebark L. [23] (Myrica WRL-68 cell line: at 100 µg/mL cellline). viabilityHepG2 was cell 89.27% line: EC (non-tumor50 = 32.46 cellg /mL. (Myrica cerífera) bark [23] Methanolgale var extract tormentosa of Myrica L.) branches gale L. ( [24]Myrica WRL-68 cell line:line).at 100 µg/mL cell viability was 89.27% (non-tumor Methanol extract of Myrica gale L. (Myrica gale var 5-Deoxymyricanone (2) gale var tormentosa L.) branches [24] cell line). tormentosa L.) branches [24] 5-Deoxymyricanone (2) 5-Deoxymyricanone (2)

Methanol extract of Morella adenophora Anti-tuberculosis [19] MethanolMethanol(Hance) extract extract J. ofHerb. ofMorella Morella roots adenophora adenophora[19] (Hance) J. Herb.MIC = 25.8 µg/mLAnti-tuberculosis (Ethambutol MIC [19]Anti-tuberculosis = 6.25 µg/mL). [19] (Hance) J. Herb.roots roots [[19]19] MIC = 25.8 µg/mLMIC (Ethambutol= 25.8 µ gMIC/mL = (Ethambutol6.25 µg/mL). MIC = 6.25 µg/mL).

12-Hydroxymyricanone (3) 12-Hydroxymyricanone12-Hydroxymyricanone (3 ()3 ) OH Methanol extract of Morella adenophora H CO OH Methanol extract of Morella adenophora (Hance) J. Herb. 3 Methanol(Hance) extract J. Herb. of Morellaroots roots adenophora[[19]19] H CO Anti-tuberculosis [19] 3 EthanolEthanol 80%(Hance) 80% extracts extracts J. Herb. ofof rootsMorella [19] nana nana (A.(A. Chev.) J. Herb. Anti-tuberculosis [19] Ethanol Chev.)80% extracts J.Herb. of roots Morella [28] nana (A. MIC = 35.8 µg/mLAnti-tuberculosis (Ethambutol MIC[19] = 6.25 µg/mL). H3CO roots [28] MIC = 35.8 µg/mL (Ethambutol MIC = 6.25 µg/mL). MethanolChev.) extract J.Herb. of Myrica roots gale [28] L. (Myrica MIC = 35.8 µg/mL (Ethambutol MIC = 6.25 µg/mL). H3HOCO O Methanol extract of Myrica gale L. (Myrica gale var Methanolgale var extract tormentosa of Myrica L.) branches gale L. ( [24]Myrica HO O tormentosa L.) branches [24] HO O gale var tormentosa L.) branches [24] OH OH

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Table 1. Cont.

Compound Origin Biological Activities Molecules 2020, 25, x FOR PEER REVIEW 4 of 33 Inhibition of muscle atrophy and dysfunction [30] Inhibition of muscleC2C12 atrophy myotubes and dysfunction treated with [30] 10 µM myricanol and C2C12 myotubes treated with 10 µM myricanoldexamethasone and dexamethasone showed: showed: ↑ myosin heavy chain expression (0.89 against 0.33 on cells treated only myosin heavy chain↑ expression (0.89 against 0.33 on cells treated only with dexamethasone),with dexamethasone), ↓ atrogin-1 expressionatrogin-1 (1.53 against expression 2.31 on cells (1.53 treated against only 2.31 with on cells treated only ↓ dexamethasone),with dexamethasone), ↓ MuRF1 expression (0.99MuRF1 against expression 1.55 on cells (0.99 treated against only 1.55 with on cells treated only ↓ dexamethasone),with dexamethasone), ↑ ATP production (5.84ATP nM/mg production protein (5.84against nM 3.83/mg nM/mg protein protein against on cells 3.83 nM/mg protein on ↑ treated only withcells dexamethasone), treated only with dexamethasone), Methanol extract of Myrica rubra (Lour.) ↑ mitochondrial contentmitochondrial (116.38% against content 68.12% (116.38% on cells againsttreated only 68.12% withon cells treated only ↑ MethanolSiebold extract and of Myrica Zucc. bark rubra [17](Lour.) Siebold and Zucc. dexamethasone),with dexamethasone), Hexane extract of Morellabark cerifera [17 (L.)] Small ↑ mitochondrial O2 consumptionmitochondrial (223.77 pmol/min O2 consumption against 166.59 (223.77 pmol/min pmol /min against Myricanol (4) ↑ Hexane extract(Myrica of Morellacerífera) bark cerifera [18](L.) Small (Myrica cerífera) on cells treated166.59 only pmol with/min dexamethasone). on cells treated only with dexamethasone). Myricanol (4) Methanol extract of Morellabark [adenophora18] Mitigation of lipidMitigation accumulation oflipid in 3TS-L1 accumulation adipocytes in[31] 3TS-L1 adipocytes [31] Methanol(Hance) extract J. ofHerb.Morella rootsadenophora [19] (Hance)Treatment J. Herb. with 5Treatment µM myricanol with increased 5 µM myricanol AMPK activation increased in 50% AMPK when activation in 50% when Methanol extract of Myricaroots esculenta [19] Buch.- compared to the untreatedcompared cells. to the untreated cells. Methanol extractHam. Ex of D.Myrica Don leaves esculenta [14] Buch.-Ham.Decrease Ex D. of Don 28% in lipid accumulationDecrease of 28%when in compared lipid accumulation to the untreated when cells. compared to the Chloroform and methanolleaves extract [14 of] Morella Neuroprotective effects [32]untreated cells. Chloroformarborea and (Hutch.) methanol Cheek extract twigs of[20]Morella arborea80% (Hutch.)increase in N2a cells viability treated withNeuroprotective 0.84 mM and 100 eff ectsmM [H322O] 2 95% EtOH extract ofCheek Morella twigsnana (A. [20 Chev.)] (against80% increase cells treated in N2a only cells with viability H2O2). treated with 0.84 mM and 100 mM J. Herb. roots [21] 40% reduction of intracellular ROS in N2a cells treated with 0.84 mM and 100 95% EtOH extract of Morella nana (A. Chev.) J. Herb. H2O2 (against cells treated only with H2O2). Dichloromethane: methanolroots (1:1) [21 ]extract of mM H2O2 when40% compared reduction with of intracellular the cells treated ROS only in with N2a H cells2O2. treated with 0.84 mM and Morella arborea (Hutch.) Cheek bark and stem Intracellular calcium concentration of 777.81 nM in N2a cells treated with Dichloromethane: methanol (1:1) extract of Morella arborea 100 mM H2O2 when compared with the cells treated only with H2O2. [29] 0.84 mM and 100 mM H2O2 (3045.51 nM in cells treated only with H2O2). (Hutch.) Cheek bark and stem [29] Intracellular calcium concentration of 777.81 nM in N2a cells treated with Ethanol 95% extract of Morella cerifera (L.) Antitumor activity [18] Ethanol 95% extract of Morella cerifera (L.) Small bark [23] 0.84 mM and 100 mM H2O2 (3045.51 nM in cells treated only with H2O2). Small bark [23] HL60 cell-line: IC50 = 5.3 ± 0.7 µM (Cisplatin EC50 = 4.2 ± 1.1 µM). Antitumor activity [18] A549 cell-line: IC50 = 16.5 ± 0.8 µM (Cisplatin EC50 = 18.4 ± 1.9 µM). HL60 cell-line: IC50 = 5.3 0.7 µM (Cisplatin EC50 = 4.2 1.1 µM). SK-BR-3 cell-line: EC50 = 14.8 ± 5.5 µM (Cisplatin± EC50 = 18.8 ± 0.6 µM). ± A549 cell-line: IC = 16.5 0.8 µM (Cisplatin EC = 18.4 1.9 µM). Anti tuberculosis50 [19] ± 50 ± SK-BR-3 cell-line: EC = 14.8 5.5 µM (Cisplatin EC = 18.8 0.6 µM). MIC = 30 µg/mL (Ethambutol50 MIC = 6.25± µg/mL). 50 ± Cytotoxic activity [33]Anti tuberculosis [19] MIC = 30 µg/mL (Ethambutol MIC = 6.25 µg/mL). A549 cell line EC50 = 4.85 µg/mL (Fluorouracil EC50 = not shown). Antimelanogenesis activityCytotoxic [26] activity [33] Melanin content inA549 B16 mouse cell line melano EC50ma= cells4.85 atµ g25/mL µg/mL: (Fluorouracil 3.8 ± 0.4% EC50 = not shown). (arbutin 25 µg/mL:Antimelanogenesis 77.4 ± 2.9%). activity [26] Cell viability at 25Melanin µg/mL: content8.8 ± 0.2% in (arbutin B16 mouse 25 µg/mL: melanoma 102.0 ± cells1.5%). at 25 µg/mL: 3.8 0.4% ± (arbutin 25 µg/mL: 77.4 2.9%). ± Cell viability at 25 µg/mL: 8.8 0.2% (arbutin 25 µg/mL: 102.0 1.5%). ± ±

Molecules 2020, 25, 6052 5 of 33

Molecules 2020, 25, x FOR PEER REVIEW 5 of 33 Molecules 2020, 25, x FOR PEER REVIEW 5 of 33 Table 1. Cont. Molecules 2020, 25, x MyricanolFOR PEER 11-sulphate REVIEW (5) 5 of 33 Myricanol 11-sulphate (5) MyricanolCompound 11-sulphate (5) Origin Biological Activities Myricanol 11-sulphate (5) Protection against glutamate-induced damage [17] Methanol extract of Myrica rubra (Lour.) PC12 cell line:Protection 5 µM of against myricanol glutamate-induced 11-sulphate maintained damage 72.09[17] ± 2.09% of MethanolSiebold extract and of Zucc. Myrica bark rubra [17] (Lour.) PC12cell cellviability line:Protection 5after µM 24of againsthmyricanol exposure glutamate-induced 11-su to glutamate.lphate maintained (Cells damage treated 72.09[17] only ± 2.09% with of MethanolSiebold extract and of Zucc. Myrica bark rubra [17] (Lour.) Protection against glutamate-induced damage [17] Methanol extract of Myrica rubra (Lour.) SieboldPC12cell and cellviability Zucc. line: 5after µMglutamate 24of hmyricanol exposure showed 11-su to glutamate. viabilitylphate maintained of (Cells 50%). treated 72.09 only ± 2.09% with of Siebold and Zucc. bark [17] PC12 cell line: 5 µM of myricanol 11-sulphate maintained 72.09 2.09% of bark [17] cell viability afterglutamate 24 h exposure showed to glutamate. viability of (Cells 50%). treated only with ± cell viability after 24 h exposure to glutamate. (Cells treated only with glutamate showed viability of 50%). glutamate showed viability of 50%).

Porson (6)

Porson (6) PorsonPorson ( (66)) Methanol extract of Morella adenophora Methanol(Hance) extract J. Herb. of Morella roots adenophora [19] Methanol95%Methanol EtOH(Hance) extractextract extract J. of ofHerb. of MorellaMorella Morella roots nana adenophora [19] (A. Chev.) (Hance) J. Herb. 95% EtOH(Hance) extractJ. Herb. J. of Herb. Morellarootsroots roots [21] nana [[19]19 (A.] Chev.) Anti-tuberculosis [19] 95% EtOH extract of Morella nana (A. Chev.) J. Herb. 95%Methanol EtOH extractextractJ. Herb. ofof MorellaMyricaroots [21] galenana L. (A. (Myrica Chev.) MIC = 40 µg/mLAnti-tuberculosis (Ethambutol MIC [19]Anti-tuberculosis = 6.25 µg/mL). [19] roots [21] Methanolgale var extract tormentosaJ. Herb. of Myricaroots L.) branches[21] gale L. ( [24]Myrica MIC = 40 µg/mLAnti-tuberculosis (EthambutolMIC = 40 µ MICg /[19]mL = (Ethambutol6.25 µg/mL). MIC = 6.25 µg/mL). EthylMethanolMethanolgale acetate var extract tormentosa extractextract of Myricaof of L.) MyricaMyrica branches gale gale galeL. (L [24]Myrica. L.stems (Myrica gale var MIC = 40 µg/mL (Ethambutol MIC = 6.25 µg/mL). Ethylgale acetate var tormentosa extracttormentosa[34] of L.) Myrica branchesL.) branchesgale L [24]. stems [24 ] EthylEthyl acetate acetate extract extract[34] of Myrica of Myrica gale L. galestemsL. stems [34] [34]

Myricananin C (7)

MyricananinMyricananin C C (7 (7) ) Myricananin C (7) MethanolMethanol extract extract of ofMorella Morella adenophora (Hance) J. Herb. Methanol(Hance) extract J. Herb. of Morellaroots roots adenophora [[19]19] Anti-tuberculosis [19]Anti-tuberculosis [19] EthanolEthanolMethanol(Hance) 80% 80% extract extract extract J. Herb. of ofMorellaof Morellaroots adenophora [19] nana nana (A.(A. Chev.) J. Herb. MIC = 55.5 µg/mLAnti-tuberculosisMIC (Ethambutol= 55.5 µ MICg [19]/mL = (Ethambutol6.25 µg/mL). MIC = 6.25 µg/mL). Ethanol(Hance) 80% extract J. Herb. of Morellaroots [19] nana (A. MIC = 55.5 µg/mLAnti-tuberculosis (Ethambutol MIC [19] = 6.25 µg/mL). Chev.) J. Herb. rootsroots [28] [28] Molecules 2020, 25, x FOR PEER REVIEW EthanolChev.) 80% extract J. Herb. of rootsMorella [28] nana (A. MIC = 55.5 µg/mL (Ethambutol MIC = 6.25 µg/mL). 6 of 33 Chev.) J. Herb. roots [28] (+)-Galeon (8)

(+)-Galeon (8)

Methanol extract of Morella adenophora Methanol(Hance) extract J. ofHerb.Morella rootsadenophora [19] (Hance) J. Herb. roots [19] Methanol extract of Myrica gale L. (Myrica Anti-tuberculosis [19]Anti-tuberculosis [19] Methanol extract of Myrica gale L. (Myrica gale var gale var tormentosa L.) branches [35] MIC = 15.0 µg/mLMIC (Ethambutol= 15.0 µ MICg/mL = (Ethambutol6.25 µg/mL). MIC = 6.25 µg/mL). Ethyl acetate extracttormentosa of MyricaL.) branches gale L. stems [35 ] Ethyl acetate extract[34] of Myrica gale L. stems [34]

α-Glucosidase Inhibition [36]

IC50 = 0.231 ± 0.033 mg/mL (Acarbose IC50 = 1.457 ± 0.144 mg/mL). Quercitrin (9) Antiviral Activity [37] Neuraminidase inhibition: IC50 = 311.76 µM (Oseltamivir acid IC50 = 280 µM). Myeloperoxidase inhibition [38] IC50 = 2.0 ± 0.2 µM Prevention of metal toxicity effects [39] Methanol extract of Myrica rubra (Lour.) Almost 100% HepG2 cell line viability when treated with 1 µM + 15 µM Siebold and Zucc. bark [17] MeHg (50% viability when only treated with 15 µM MeHg). Methanol extract of Morella adenophora Almost 100% HepG2 cell line viability when treated with 1 µM + 40 µM (Hance) J. Herb. roots [19] Pb(NO3)2 (50% viability when only treated with 40 µM Pb(NO3)2). About 50% PC12 cell line viability when treated with 1 µM + 10 µM MeHg (65% viability when only treated with 10 µM MeHg). Almost 90% PC12 cell line viability when treated with 1 µM + 350 µM Pb(NO3)2 (60% viability when only treated with 350 µM Pb(NO3)2). Anti-tuberculosis [19] MIC = >150 µg/mL (Ethambutol MIC = 6.25 µg/mL).

Molecules 2020, 25, x FOR PEER REVIEW 6 of 33

(+)-Galeon (8)

Molecules 2020, 25, 6052 Methanol extract of Morella adenophora 6 of 33 (Hance) J. Herb. roots [19] Methanol extract of Myrica gale L. (Myrica Anti-tuberculosis [19] gale var tormentosa L.) branches [35] MIC = 15.0 µg/mL (Ethambutol MIC = 6.25 µg/mL). Ethyl acetate extract of Myrica galeTable L. stems 1. Cont. [34] Compound Origin Biological Activities

α α-Glucosidase Inhibition-Glucosidase [36] Inhibition [36] IC = 0.231 0.033 mg/mL (Acarbose IC = 1.457 0.144 mg/mL). IC50 = 0.231 ± 0.03350 mg/mL (Acarbose IC50 = 1.457 ± 0.144 mg/mL).50 Quercitrin (9) ± ± Antiviral Activity [37]Antiviral Activity [37] Quercitrin (9) Neuraminidase inhibition:Neuraminidase IC50 = 311.76 µM inhibition: (Oseltamivir IC acid50 = IC311.7650 = 280µ MµM). (Oseltamivir acid Myeloperoxidase inhibition IC[38]50 = 280 µM). IC50 = 2.0 ± 0.2Myeloperoxidase µM inhibition [38] Molecules 2020, 25, x FOR PEER REVIEW 7 of 33 Prevention of metal toxicity effectsIC =[39]2.0 0.2 µM Methanol extract of Myrica rubra (Lour.) 50 ± Methanol extract of Myrica rubra (Lour.) SieboldAlmost and Zucc. 100% HepG2 cell line viabilityPrevention when treated of metal with toxicity1 µM + 15 e ffµMects [39] Siebold and Zucc. bark [17] bark [17] MeHgProtection (50% viability against when glutamate-induced only treated with damage 15 µM [17] MeHg). Methanol extract of Morella adenophora Almost 100% HepG2 cell line viability when treated with 1 µM + 15 µM Methanol extract of Morella adenophora (Hance)PC12Almost J. Herb.cell line:100% 10 HepG2 µM of cell myricitrin line viability maintained when treated73.15 ± 3.23%with 1 ofµM cell + 40viability µM (Hance) J. Herb. roots [19] MeHg (50% viability when only treated with 15 µM MeHg). roots [19] after Pb(NO24 h exposure3)2 (50%Almost to viability glutamate. 100% when (Cells HepG2 only treated treated cell lineonly with viabilitywith 40 µM glutamate Pb(NO when3 )showed treated2). with 1 µM + 40 µM About 50% PC12 cell line viabilityonly viability when oftreated 50%). with 1 µM + 10 µM MeHg Pb(NO3)2 (50% viability when only treated with 40 µM Pb(NO3)2). Protection against(65% viability Abouthypoxia/reoxygenatio 50%when PC12 only celltreatedn line(R/H) with viability injury 10 µM in when MeHg).cardiomyocyte treated with [43] 1 µM + 10 µM MeHg H9c2Almost cells pretreated 90% PC12 forcell 12 line h (65%with viability 40 viability µM when had treated whena survival onlywith rate 1 treated µM of 87.48+ 350 with ±µM 7.68% 10 µ M MeHg). (survival rate of untreated cells = 65.48 ± 6.42%). Pb(NO3)2 (60% Almostviability 90%when PC12 only treated cell line with viability 350 µM when Pb(NO treated3)2). with 1 µM + 350 µM 50% decrease of LDH levels secreted to culture medium in the cells Pb(NOAnti-tuberculosis) (60% viability [19] when only treated with 350 µM Pb(NO ) ). pretreated for 12 h with 403 2µM when compared with untreated cells. 3 2 MIC = >150 µg/mL (Ethambutol MICAnti-tuberculosis = 6.25 µg/mL). [19] Pretreatment with 40 µM inhibited intracellular ROS generation in 50% MIC = >150 µg/mL (Ethambutol MIC = 6.25 µg/mL). when compared to untreated cells. Reduction of 50% in the apoptoticProtection rate on against cells treated glutamate-induced with 40 µM when damage [17] comparedPC12 cell with line: the 10 untreatedµM of myricitrin cells. maintained 73.15 3.23% of cell ± Pretreatment with 40viability µM decreased after 24 the h caspase-3 exposure activity to glutamate. in 25% when (Cells treated only with Myricitrin (10) compared with the untreated cells. Methanol extract of Myrica rubra (Lour.) glutamate showed only viability of 50%). Myricitrin (10) Pretreatment with 40 µM increased the Bcl-2/Bax expression ratio to 1.28 ± MethanolSiebold extract and of Myrica Zucc. bark rubra [17](Lour.) Siebold and Zucc. Protection against hypoxia/reoxygenation (R/H) injury in 0.31 (0.46 ± 0.12 in untreated cells. Methanol extract of Morellabark [adenophora17] cardiomyocyte [43] Protection against advanced glycation end products (AGEs) injury in Methanol(Hance) extract J. ofHerb.Morella rootsadenophora [19] (Hance) J. Herb. H9c2 cells pretreated for 12 h with 40 µM had a survival rate of cardiomyocyte [44] Toluene extract of the rootsroot-bark [19 ]Morella 87.48 7.68% (survival rate of untreated cells = 65.48 6.42%). Pretreatment with 25 µg/mL led± to H9c2 cells viability of 78.94 ± 4.52% (60.34 ± Toluenecerifera extract (L.) Small of the (Myrica root-bark cerifera)Morella [40] cerifera (L.) Small 50% decrease of LDH levels secreted to culture medium in the cells ± 6.52% when treated only with 400 µg/mL AGEs). Methanol extract of(Myrica Myrica cerifera)esculenta [Buch.-40] pretreated for 12 h with 40 µM when compared with untreated cells. Pretreatment with 25 µg/mL µM decreased phospho-IKK-β expression in Methanol extractHam. Ex of D.Myrica Don leaves esculenta [14] Buch.-Ham. Ex D. Don Pretreatment with 40 µM inhibited intracellular ROS generation in 50% about 40%, when compared with the untreated cells. 80% Acetone extract of Myricaleaves rubra [14] (Lour.) when compared to untreated cells. Pretreatment with 25 µg/mL decreased TNF-α expression in about 50%, 80% AcetoneSiebold extract and Zucc. of Myrica leaves [41] rubra (Lour.) Siebold and Reduction of 50% in the apoptotic rate on cells treated with 40 µM when when compared with the untreated cells. Benzene extract (afterZucc. petroleum leaves ether) [41] of compared with the untreated cells. Pretreatment with 25 µg/mL decreased intracellular ROS generation in about BenzeneMorella extract cerifera (after(L.) Small petroleum (Myrica cerifera) ether) of Morella cerifera Pretreatment with 40 µM decreased the caspase-3 activity in 25% when 50%, when compared with the untreated cells. (L.) Smallroot ( Myricabark [42] cerifera) root bark [42] compared with the untreated cells. Pretreatment with 25 µg/mL markedly attenuated the inhibition of NQO-1, γ µ -GCS, Pretreatmentand HO-1 expression with 40 inducedM increased by AGEs. the Bcl-2/Bax expression ratio to 1.28 0.31 (0.46 0.12 in untreated cells. Pretreatment with 25 µg/mL decreased caspase-3± and caspase-9± activity in 3 and 2-fold, respectively,Protection when against compared advanced with the glycation untreated end cells. products (AGEs) injury in Pretreatment with 25 µg/mL decreased apoptoticcardiomyocyte rate in about 7%,[44 ]when compared with the untreated cells. Pretreatment with 25 µg/mL led to a 2-fold decrease in the expression of Bax compared with the untreated cells. Pretreatment with 25 µg/mL led to a 2-fold increase in the expression of Bcl-2 compared with the untreated cells. Pretreatment with 25 µg/mL led to a 33% decrease in the expression of collagen-1 compared with the untreated cells. Prevention of atherosclerosis [45] Pretreatment with 40 µM in oxidized low-density lipoprotein (ox-LDL) exposed human umbilical vein endothelial cells (HUVECs):

Molecules 2020, 25, 6052 7 of 33

Table 1. Cont.

Compound Origin Biological Activities Pretreatment with 25 µg/mL led to H9c2 cells viability of 78.94 4.52% ± (60.34 6.52% when treated only with 400 µg/mL AGEs). ± Pretreatment with 25 µg/mL µM decreased phospho-IKK-β expression in about 40%, when compared with the untreated cells. Pretreatment with 25 µg/mL decreased TNF-α expression in about 50%, when compared with the untreated cells. Pretreatment with 25 µg/mL decreased intracellular ROS generation in about 50%, when compared with the untreated cells. Pretreatment with 25 µg/mL markedly attenuated the inhibition of NQO-1, γ -GCS, and HO-1 expression induced by AGEs. Pretreatment with 25 µg/mL decreased caspase-3 and caspase-9 activity in 3 and 2-fold, respectively, when compared with the untreated cells. Pretreatment with 25 µg/mL decreased apoptotic rate in about 7%, when compared with the untreated cells. Pretreatment with 25 µg/mL led to a 2-fold decrease in the expression of Bax compared with the untreated cells. Pretreatment with 25 µg/mL led to a 2-fold increase in the expression of Bcl-2 compared with the untreated cells. Pretreatment with 25 µg/mL led to a 33% decrease in the expression of collagen-1 compared with the untreated cells. Prevention of atherosclerosis [45] Pretreatment with 40 µM in oxidized low-density lipoprotein (ox-LDL) exposed human umbilical vein endothelial cells (HUVECs): Increased cell viability (70.75 8.44% against 50.25 7.95% in the ± ± untreated cells); Reduction of apoptotic cells (15.58 4.65% against 23.89 3.65% in the ± ± untreated cells); 3-fold reduction of intracellular ROS levels when compared with untreated cells; ~33% reduction on caspase-3 activity when compared with untreated cells. Anti-tuberculosis [19] MIC = >150 µg/mL (Ethambutol MIC = 6.25 µg/mL). Protection against acrylamide induced oxidative stress [46] Acrylamide induced Caco-2 cells treated with 40 µg/mL presented a viability of 80% (untreated cells had a viability of 50%). Neuroprotective activity [47] Pretreatment with 10µM prevents PC12 cell death induced by 6-hydroxydopamine (6-OHDA) (untreated cells presented 25% of cell mortality). Molecules 2020, 25, x FOR PEER REVIEW 8 of 33

Increased cell viability (70.75 ± 8.44% against 50.25 ± 7.95% in the untreated cells); Reduction of apoptotic cells (15.58 ± 4.65% against 23.89 ± 3.65% in the untreated cells); 3-fold reduction of intracellular ROS levels when compared with untreated cells; ~33% reduction on caspase-3 activity when compared with untreated cells. Anti-tuberculosis [19] MIC = >150 µg/mL (Ethambutol MIC = 6.25 µg/mL). Protection against acrylamide induced oxidative stress [46] Molecules 2020, 25, 6052 Acrylamide induced Caco-2 cells treated with 8 of 33 40 µg/mL presented a viability of 80% (untreated cells had a viability of 50%). Table 1. Cont. Neuroprotective activity [47] Pretreatment with 10µM prevents PC12 cell death induced by 6- hydroxydopamine Compound Origin Biological Activities (6-OHDA) (untreated cells presented 25% of cell mortality). Pretreatment withPretreatment 10µM decreased with cytochrome 10µM decreased C release cytochrome by almost 60% C release by almost 60% when compared withwhen the compareduntreated group. with the untreated group. Pretreatment with 10µMPretreatment decreased with caspas 10e-3µM activity decreased release caspase-3 by almost activity 50% release by almost when compared50% with when the untreated compared group. with the untreated group. Pretreatment with 10µMPretreatment decreased with the apoptotic 10µM decreased rate activity the by apoptotic almost 50% rate activity by almost when compared50% with when the untreated compared group. with the untreated group. Antidiabetic activityAntidiabetic [48] activity [48] α-glucosidase inhibition:α-glucosidase IC50 = 1.1 inhibition: ± 0.06 µM IC = 1.1 0.06 µM 50 ± (acarbose: IC50 = 43(acarbose: ± 1.6 µM). IC = 43 1.6 µM). 50 ± β-amylase inhibition:β-amylase IC50 = 1.9 inhibition: ± 0.02 µM. IC = 1.9 0.02 µM. 50 ± (acarbose: IC50 = 19(acarbose: ± 1.6 µM). IC = 19 1.6 µM). 50 ± AntimelanogenesisAntimelanogenesis activity [26] activity [26] Melanin content Melaninin B16 mouse content melano in B16ma cells mouse at 25 melanoma µg/mL: 69.9 cells ± 2.3% at 25 µg/mL: 69.9 2.3% (arbutin 25 µg/mL: 77.4 ± 2.9%). ± (arbutin 25 µg/mL: 77.4 2.9%). Cell viability at 25 µg/mL: 102.9 ± 3.3% (arbutin 25 µg/mL: 102.0 ± ±1.5%). Cell viability at 25 µg/mL: 102.9 3.3% (arbutin 25 µg/mL: 102.0 1.5%). Myrigalone A (11) ± ± Myrigalone A (11) 50% acetone extract of Myrica gale L. seeds 50% acetone extract[49] of Myrica gale L. seeds [49] Uncoupling activity [53] MethanolMethanol extract extract of of MyricaMyrica gale gale L. leavesL. leaves and and fruits [34], Uncoupling activity [53] Increases mitochondrial respiration rate by 87 ± 8 natoms O/min/mg (DNP 36 fruits [34], fruitsfruits [50], [50 seeds], seeds [51] [ 51] Increases mitochondrial respiration rate by 87 8 natoms O/min/mg Molecules 2020, 25, x FOR PEER REVIEW ± 3 natoms O/min/mg) at 45 µM. 9± of 33 DiethylDiethyl ether extract ether extractof the fruit of theexudate fruit of exudate of (DNP 36 3 natoms O/min/mg) at 45 µM. Molecules 2020, 25, x FOR PEER REVIEW ± 9 of 33 Myrica Myricagale L. [52] gale L. [52] Myrigalone B (12)

Myrigalone B (12) 50% Acetone extract of Myrica gale L. seeds Antidiabetic activity [48] Myrigalone B (12) 50% Acetone extract[49] of Myrica gale L. seeds Antidiabetic activity [48] 50% Acetone extract of Myrica gale L. seedsα-glucosidase [49] inhibition:Antidiabetic IC50 = 19 ± 1.0 activity µM (acarbose: [48] IC50 = 43 ± 1.6 µM). Methanol extract of [49]Myrica gale L. seeds [54] α-glucosidase inhibition: IC = 19 1.0 µM Methanol extract of Myrica gale L. seedsα [54-glucosidaseβ-amylase] inhibition: inhibition: IC IC50 50= 8.3= 19 ± ±1.3 1.0 µM µM (acarbose: (acarbose: IC IC5050 = =19 43 ± ±1.650 1.6 µM). µM). MethanolDichloromethane extract of extract Myrica of gale Morella L. seeds serrata [54] µ ± β-amylase inhibition: ICUncoupling50 = 8.3 ± 1.3 activity µM(acarbose: (acarbose: [53] ICIC50 == 1943 ± 1.61.6 µM).M). DichloromethaneDichloromethane(Lam.) Killick extractextract leaves of of MorellaMorella [55] serrata serrata (Lam.) Killick ± Increases mitochondrialβ-amylase respirationUncoupling inhibition: rate activity by IC 4050 [53]± =10 8.3 natoms1.3 O/min/mgµM (acarbose: (DNP IC50 = 19 1.6 µM). Diethyl ether(Lam.) extract Killick of leavesthe fruit [55] [55 exudate ] of ± ± Increases mitochondrial36 ± respiration 3 natoms O/min/mg) rate by 40Uncoupling ±at 10 45µM. natoms O/min/mg activity [53 (DNP] DiethylDiethyl etherMyrica extract ether gale extractof the L. [52] fruit of theexudate fruit of exudate of Increases36 ± 3 natoms mitochondrial O/min/mg) at respiration 45µM. rate by 40 10 natoms O/min/mg Myrica Myricagale L. [52] gale L. [52] ± (DNP 36 3 natoms O/min/mg) at 45µM. Myrigalone D (13) ± MyrigaloneMyrigalone D D (13 (13) ) 50% acetone extract of Myrica gale L. seeds 50%50% acetone acetone extract extract[49] of Myrica of Myrica gale L. galeseedsL. seeds [49] Uncoupling activityUncoupling [53] activity [53] [49] Uncoupling activity [53] MethanolMethanol extract extract of ofMyrica Myrica gale L. seeds seeds [54] [54 ] andIncreases leaves mitochondrial [34] Increases respiration mitochondrial rate by 14 ± 2 respiration natoms O/min/mg rate by (DNP 14 362 natoms O/min/mg Methanol extractand of leaves Myrica [34] gale L. seeds [54] Increases mitochondrial± 3respiration natoms O/min/mg) rate by 14 at ± 245 natoms µM. O/min/mg (DNP± 36 From the Myrica gale L. fruits [53] (DNP 36 3 natoms O/min/mg) at 45 µM. From theand Myrica leaves gale [34] L. fruits [53] ± 3 natoms O/min/mg) at± 45 µM. From the Myrica gale L. fruits [53]

Myrigalone H (14) Myrigalone H (14)

Diethyl ether extract of the fruit exudate of Uncoupling activity [53] Diethyl etherMyrica extract gale of the L. [52] fruit exudate of Increases mitochondrial respirationUncoupling rate activity by 17 ±[53] 3 natoms O/min/mg (DNP 36 MyricaMyrica gale L. galefruit L. exudate [52] [56] Increases mitochondrial± 3respiration natoms O/min/mg) rate by 17 at ± 345 natoms µM. O/min/mg (DNP 36 Myrica gale L. fruit exudate [56] ± 3 natoms O/min/mg) at 45 µM.

Myrigalone G (15) Myrigalone G (15) Antidiabetic activity [48] 50% acetone extract of Myrica gale L. seeds α-glucosidase inhibition:Antidiabetic IC50 = 7 ± 1.4 activity µM (acarbose: [48] IC50 = 43 ± 1.6 µM). 50% acetone extract[49] of Myrica gale L. seeds αβ-glucosidase-amylase inhibition: inhibition: IC IC50 =50 33= 7 ± ± 6.6 1.4 µM µM (acarbose: (acarbose: IC IC5050 = = 19 43 ± ± 1.6 1.6 µM). µM). Diethyl ether extract[49] of the fruit exudate of β-amylase inhibition: ICUncoupling50 = 33 ± 6.6 activityµM (acarbose: [53] IC50 = 19 ± 1.6 µM). Diethyl etherMyrica extract gale of the L. [52] fruit exudate of Increases mitochondrial respirationUncoupling rate activity by 71 ±[53] 5 natoms O/min/mg (DNP 36 Myrica gale L. [52] Increases mitochondrial± 3respiration natoms O/min/mg) rate by 71 at ± 545 natoms µM. O/min/mg (DNP 36 ± 3 natoms O/min/mg) at 45 µM.

Molecules 2020, 25, x FOR PEER REVIEW 9 of 33 Molecules 2020, 25, x FOR PEER REVIEW 9 of 33 Myrigalone B (12) Myrigalone B (12) 50% Acetone extract of Myrica gale L. seeds Antidiabetic activity [48] 50% Acetone extract[49] of Myrica gale L. seeds α-glucosidase inhibition:Antidiabetic IC50 = 19 ± 1.0 activity µM (acarbose: [48] IC50 = 43 ± 1.6 µM). Methanol extract of Myrica[49] gale L. seeds [54] α-glucosidaseβ-amylase inhibition: inhibition: IC IC50 =50 8.3= 19 ± ±1.3 1.0 µM µM (acarbose: (acarbose: IC IC50 50= =19 43 ± ±1.6 1.6 µM). µM). MethanolDichloromethane extract of extract Myrica of gale Morella L. seeds serrata [54] β-amylase inhibition: ICUncoupling50 = 8.3 ± 1.3 activity µM (acarbose: [53] IC50 = 19 ± 1.6 µM). Dichloromethane(Lam.) Killick extract leaves of Morella [55] serrata Increases mitochondrial respirationUncoupling rate activity by 40 [53]± 10 natoms O/min/mg (DNP Diethyl ether(Lam.) extract Killick of leavesthe fruit [55] exudate of Increases mitochondrial36 ± respiration3 natoms O/min/mg) rate by 40 at± 10 45µM. natoms O/min/mg (DNP Diethyl etherMyrica extract gale of theL. [52] fruit exudate of 36 ± 3 natoms O/min/mg) at 45µM. Myrica gale L. [52]

Myrigalone D (13) Myrigalone D (13) 50% acetone extract of Myrica gale L. seeds 50% acetone extract[49] of Myrica gale L. seeds Uncoupling activity [53] Molecules 2020, 25, 6052 Methanol extract of Myrica[49] gale L. seeds [54] Increases mitochondrial respirationUncoupling rate activity by 14 ± [53] 2 natoms O/min/mg (DNP 36 9 of 33 Methanol extractand of leaves Myrica [34] gale L. seeds [54] Increases mitochondrial± 3respiration natoms O/min/mg) rate by 14 at ± 452 natoms µM. O/min/mg (DNP 36 From the andMyrica leaves gale [34] L. fruits [53] ± 3 natoms O/min/mg) at 45 µM. From the Myrica gale L. fruits [53] Table 1. Cont.

Myrigalone H (14) Compound Origin Biological Activities Myrigalone H (14) Myrigalone H (14) Diethyl ether extract of the fruit exudate of Uncoupling activity [53] DiethylDiethyl etherMyrica extract ether gale extractof theL. [52] fruit of theexudate fruit of exudate Increases of mitochondrial respirationUncoupling rate activity by 17Uncoupling ± [53] 3 natoms O/min/mg activity (DNP[53] 36 Myrica gale L. [52] Increases mitochondrial respiration rate by 17 ± 3 natoms O/min/mg (DNP 36 Myrica gale L. Myricafruit exudate gale L. [56] [52 ] Increases± 3 natoms mitochondrial O/min/mg) at 45 respiration µM. rate by 17 3 natoms O/min/mg Myrica gale L. fruit exudate [56] ± 3 natoms O/min/mg) at 45 µM. ± Myrica gale L. fruit exudate [56] (DNP 36 3 natoms O/min/mg) at 45 µM. ±

Myrigalone G (15) MyrigaloneMyrigalone G G (15 (15) ) Antidiabetic activityAntidiabetic [48] activity [48] 50% acetone extract of Myrica gale L. seeds α-glucosidase inhibition:Antidiabetic IC50 = 7 ± 1.4 activity µM (acarbose: [48] IC50 = 43 ± 1.6 µM). α-glucosidase inhibition: IC50 = 7 1.4 µM (acarbose: IC50 = 43 1.6 µM). 50%50% acetone acetone extract extract[49] of Myrica of Myrica gale L. galeseedsL. seedsαβ [-glucosidase49-amylase] inhibition: inhibition: IC 50IC =50 33 = 7± ±6.6 1.4 µM µM (acarbose: (acarbose: IC IC±5050 = =19 43 ± ±1.6 1.6 µM). µM). ± β-amylase inhibition: IC50 = 33 6.6 µM (acarbose: IC50 = 19 1.6 µM). Diethyl ether[49] extract of the fruit exudate ofβ-amylase inhibition: IC50 = 33 ± 6.6 µM (acarbose: IC± 50 = 19 ± 1.6 µM). ± Diethyl ether extract of the fruit exudate of Uncoupling activityUncoupling [53] activity [53] Diethyl etherMyrica extract Myricagale of theL. [52] fruit gale L.exudate [52] of Increases mitochondrial respirationUncoupling rate activity by 71 ± [53] 5 natoms O/min/mg (DNP 36 Increases mitochondrial respiration rate by 71 5 natoms O/min/mg Myrica gale L. [52] Increases mitochondrial± 3respiration natoms O/min/mg) rate by 71 at ± 455 natoms µM. O/min/mg (DNP± 36 (DNP 36 3 natoms O/min/mg) at 45 µM. Molecules 2020, 25, x FOR PEER REVIEW ± 3 natoms O/min/mg) at± 45 µM. 10 of 33

Anti-osteosarcoma activity [57] Anti-osteosarcomaMG-63 activity cell [57] line: EC50 = 14.54 µM. MG-63 cell line: EC50HOS = 14.54 cell µM. line: EC50 = 11.70 µM. Betulin (16) HOS cell line: EC50 = 11.70Antitumor µM. activity [58] Betulin (16) Antitumor activity [58] NCI-H460 cell line: EC50 = 2.8 0.4 µM NCI-H460 cell line: EC50 = 2.8 ± 0.4 µM (Podophyllotoxin: EC50 = 22 ± 6 ±µM). (Podophyllotoxin: EC50 = 22 6 µM). HT29-MTX cell line: EC50 = 1.6 ± 0.4 µM (Podophyllotoxin: EC50 = 24 ± 3± µM). HT29-MTX cell line: EC50 = 1.6 0.4 µM Antitumor activity [18] ± (Podophyllotoxin: EC50 = 24 3 µM). 50 50 ± HexaneHexane extract extract of ofMorella Morella ceriferacerifera (L.) Small Small (MyricaHL60 cerifera) cell-line: EC = 15.2 ± 2.3 µM (CisplatinAntitumor EC = 4.2 activity ± 1.1 µM).[18] (Myrica cerifera) bark [18] A549 cell-line: EC50 = 5.2 ± 3.0 µM (Cisplatin EC50 = 18.4 ± 1.9 µM). bark [18] HL60 cell-line: EC50 = 15.2 2.3 µM (Cisplatin EC50 = 4.2 1.1 µM). SK-BR-3 cell-line: EC50 = 3.1 ± 0.6 µM (Cisplatin ±EC50 = 18.8 ± 0.6 µM). ± A549 cell-line: EC = 5.2 3.0 µM (Cisplatin EC = 18.4 1.9 µM). Hepatoprotective 50activity [59]± 50 ± SK-BR-3 cell-line: EC = 3.1 0.6 µM (Cisplatin EC = 18.8 0.6 µM). Pretreatment with 25 µM in ethanol-induced50 ± HSC-T6 cells: 50 ± Hepatoprotective activity [59] Decrease in the expression levels of collagen-I (35%), α-SMA (25%) and TLR4 (60%), whenPretreatment compared with with untreated 25 µM incells. ethanol-induced HSC-T6 cells: ~30% increase inDecrease phosphorylation in the expression of STAT3, when levels compared of collagen-I with the (35%), α-SMA (25%) and untreatedTLR4 (60%), group. when compared with untreated cells. Myriceric acid A (17) ~30% increase in phosphorylation of STAT3, when compared with the untreated group.

Methanol extract of Morella cerifera (L.) Small Anti-hypertension activity [60] (Myrica cerifera) twigs [60] and branches [61] Endothelin 1 receptor antagonist: IC50 = 11 ± 2 nM.

Molecules 2020, 25, x FOR PEER REVIEW 10 of 33

Anti-osteosarcoma activity [57] MG-63 cell line: EC50 = 14.54 µM. Betulin (16) HOS cell line: EC50 = 11.70 µM. Antitumor activity [58] NCI-H460 cell line: EC50 = 2.8 ± 0.4 µM (Podophyllotoxin: EC50 = 22 ± 6 µM). HT29-MTX cell line: EC50 = 1.6 ± 0.4 µM (Podophyllotoxin: EC50 = 24 ± 3 µM). Antitumor activity [18] Hexane extract of Morella cerifera (L.) Small HL60 cell-line: EC50 = 15.2 ± 2.3 µM (Cisplatin EC50 = 4.2 ± 1.1 µM). (Myrica cerifera) bark [18] A549 cell-line: EC50 = 5.2 ± 3.0 µM (Cisplatin EC50 = 18.4 ± 1.9 µM). SK-BR-3 cell-line: EC50 = 3.1 ± 0.6 µM (Cisplatin EC50 = 18.8 ± 0.6 µM). Molecules 2020, 25, 6052 10 of 33 Hepatoprotective activity [59] Pretreatment with 25 µM in ethanol-induced HSC-T6 cells: Decrease in the expression levels of collagen-I (35%), α-SMA (25%) and TLR4 Table 1. Cont. (60%), when compared with untreated cells. ~30% increase in phosphorylation of STAT3, when compared with the Compound Originuntreated group. Biological Activities Myriceric acid A (17) Myriceric acid A (17)

MethanolMethanol extract extract of Morella of Morella cerifera cerifera (L.) Small(L.) Small (Myrica Anti-hypertension Anti-hypertensionactivity [60] activity [60] (Myrica cerifera)cerifera) twigstwigs [60] [ 60and] andbranches branches [61] [61] Endothelin 1 receptorEndothelin antagonist: 1 receptor IC50 = 11 antagonist: ± 2 nM. IC = 11 2 nM. 50 ±

Molecules 2020, 25, x FOR PEER REVIEW 11 of 33 Molecules 2020, 25, x FOR PEER REVIEW 11 of 33 3β-trans-p-Coumaroyloxy-2α,23-dihydroxyolean-12-en-28-oic 3β3-βtrans-trans-p-Coumaroyloxy-2-p-Coumaroyloxy-2acidα ,23-dihydroxyolean-12-en-28-oic(18)α ,23-dihydroxyolean -12-en-28-oicacid ( acid18) (18)

Methanol extract of Morella adenophora Anti-tuberculosis [19] MethanolMethanol(Hance) extract extract J. ofHerb.Morella of Morella rootsadenophora [19] adenophora (Hance) J. Herb. MIC = 45 µg/mLAnti-tuberculosis (Ethambutol MICAnti-tuberculosis [19] = 6.25 µg/mL). [19] (Hance) J. Herb.roots roots [19 [19]] MIC = 45 µg/mLMIC (Ethambutol= 45 µg /MICmL (Ethambutol= 6.25 µg/mL). MIC = 6.25 µg/mL).

(R)-4-(5-Hydroxy-7-(4-hydroxyphenyl)heptyl)-2- (R)-4-(5-Hydroxy-7-(4-hydroxyphenyl)heptyl)-2(R)-4-(5-Hydroxy-7-(4-hydroxyphenyl)heptyl)-2-methoxyphenol (19) -methoxyphenolmethoxyphenol ((1919))

MethanolMethanol extract extract of ofMorella Morella adenophoraadenophora (Hance) J. Herb. Anti-tuberculosis [19]Anti-tuberculosis [19] Methanol(Hance) extract J. Herb. of rootsMorella roots [[19]19 adenophora] MIC = 52 µg/mLAnti-tuberculosis (EthambutolMIC = 52 µ gMIC/mL [19] = (Ethambutol6.25 µg/mL). MIC = 6.25 µg/mL). (Hance) J. Herb. roots [19] MIC = 52 µg/mL (Ethambutol MIC = 6.25 µg/mL).

Corchoionoside C (20) Corchoionoside C (20)

Methanol extract of Myrica esculenta Buch.- Angiotensin I-converting enzyme [14] MethanolHam. extract Ex D. ofDon Myrica leaves esculenta [14] Buch.- 29.97 ± 4.77% ACE 1 Angiotensininhibition at I-converting100 µM (Captopril enzyme 88.64 [14] ± 2.57 at 4.6 µM). Ham. Ex D. Don leaves [14] 29.97 ± 4.77% ACE 1 inhibition at 100 µM (Captopril 88.64 ± 2.57 at 4.6 µM).

Molecules 2020, 25, x FOR PEER REVIEW 11 of 33

3β-trans-p-Coumaroyloxy-2α,23-dihydroxyolean-12-en-28-oic acid (18)

Methanol extract of Morella adenophora Anti-tuberculosis [19] (Hance) J. Herb. roots [19] MIC = 45 µg/mL (Ethambutol MIC = 6.25 µg/mL).

(R)-4-(5-Hydroxy-7-(4-hydroxyphenyl)heptyl)-2- methoxyphenol (19)

Methanol extract of Morella adenophora Anti-tuberculosis [19] Molecules 2020, 25, 6052 (Hance) J. Herb. roots [19] MIC = 52 µg/mL (Ethambutol MIC = 6.25 µg/mL). 11 of 33

Table 1. Cont.

CorchoionosideCompound C (20) Origin Biological Activities Corchoionoside C (20)

Angiotensin I-converting enzyme [14] MethanolMethanol extract extract of ofMyrica Myrica esculentaesculenta Buch.-Buch.-Ham. Ex D. Don Angiotensin I-converting enzyme [14] Ham. Ex D. Don leaves [14] 29.97 ± 4.77% ACE 1 29.97inhibition4.77% at 100 ACE µM (Captopril 1 inhibition 88.64 at ± 100 2.57µ atM 4.6 (Captopril µM). 88.64 2.57 at leaves [14] ± ± 4.6 µM). Molecules 2020, 25, x FOR PEER REVIEW 12 of 33 Molecules 2020, 25, x FOR PEER REVIEW 12 of 33

(6S,9R)-Roseoside (21) (6S(6,9SR,9)-RoseosideR)-Roseoside (21 ()21 ) AntimelanogenesisAntimelanogenesis activity [62] activity [62] Antimelanogenesis activity [62] Inhibition of melanogenesisInhibition in B16 of melanogenesis mouse melanoma in cells B16 at mouse 100 µM: melanoma 62.7 ± cells at 100 µM: Inhibition of melanogenesis in B16 mouse melanoma cells at 100 µM: 62.7 ± Methanol extract of Myrica esculenta Buch.- 3.1% (arbutin 10062.7 µM: 3.1%70.3 ± (arbutin 5.5%). 100 µM: 70.3 5.5%). MethanolMethanol extract extract of Myrica of esculentaMyrica Buch.- esculenta Buch.-Ham. Ex3.1% D. Don(arbutin 100 µM: 70.3 ± 5.5%). ± ± Ham. Ex D. Don leaves [14] Cell viability at 100Cell µM: viability 95.0 ± 2.2% at 100 (arbutinµM: 95.0 100 µM:2.2% 87.5 (arbutin± 2.8%). 100 µM: 87.5 2.8%). Ham. Ex D. Don leaves [14]leaves [14] Cell viability at 100 µM: 95.0 ± 2.2% (arbutin 100 µM: 87.5 ± 2.8%). ± ± Angiotensin I-convertingAngiotensin enzyme I-converting [14] Angiotensin enzyme I-converting [14] enzyme [14] 25.63 ± 1.35% ACE25.63 1 inhibition ± 1.35% ACEat 100 1µM 25.63inhibition (Captopril1.35% at 88.64 100ACE ±µM 2.57 (Captopril 1at inhibition4.6 µM). 88.64 at ± 100 2.57µ Mat 4.6 (Captopril µM). 88.64 2.57 at ± µ ± 4.6 M).

Myricadenin A (22) MyricadeninMyricadenin A A ( (2222) )

MethanolMethanol extract extract of Morella of adenophoraMorella adenophora (Hance) J. Herb.Anti-tuberculosis [19] Anti-tuberculosis [19] (Hance) J. Herb. roots [19]roots [19] MIC = 80.0 µg/mL (Ethambutol MIC =MIC 6.25 µg/mL).= 80.0 µg/mL (Ethambutol MIC = 6.25 µg/mL). Methanol extract of Morella adenophora Anti-tuberculosis [19] (Hance) J. Herb. roots [19] MIC = 80.0 µg/mL (Ethambutol MIC = 6.25 µg/mL).

D-Glcpy = D-glucopyranoside.d-Glcpy = d-glucopyranoside.

D-Glcpy = D-glucopyranoside.

Molecules 2020, 25, 6052 12 of 33

As seen in Table1, bioactive compounds are found in every part of the plant, from roots to the leaves, and the same compound can be found in members of both genera, which shows a close chemotaxonomic relationship, resulting from the taxonomic reorganization of the previous genus Myrica [12]. A variety of compounds are present, including diarylheptanoids, dihydrochalcones, triterpenoids and flavonoids, but the majority of the bioactive compounds obtained from Morella and Myrica genera are cyclic diarylheptanoids, a class of compounds known by their wide array of biological activities [63]. From the analysis of Table1 it is also clear that the compounds which have been more widely studied are myricanone (1), myricanol (4), quercitrin (9), myricitrin (10), and betulin (16), so details about the most interesting works and compounds from Table1 will be discussed in the following paragraphs. Myricanone (1) presents cytotoxic activity against A549 and HepG2 cell-lines with EC50 of 3.22 µg/mL [25], and 32.46 µM[27], respectively. Myricanone (1) increases the apoptotic rate of A549 tumor cells from 4.13% in untreated cells to 34.9% (after treatment) in a dose-dependent manner, and significantly inhibits colony formation in A-549, by inducing cell-cycle arrest in G1 phase [25]. Although the authors indicate that fluorouracil was used as positive control, and that myricanone (1) is more active than the positive control [25], the EC50 of fluorouracil is not presented, which hinders a more realistic assessment of the potency of myricanone effects against A549 cells. Myricanol (4) showed cytotoxic activity against HL60 (leukemia), A549 (lung), and SK-BR-3 (breast) cell-lines, with IC50 similar or lower (Table1) than the positive control cisplatin [ 18]. The author also demonstrated that induced apoptosis cell via mitochondrial (caspase 3, 8, and 9 were activated) and death receptor pathway in HL-60 cell, suggesting its potential anticancer activity. Similar results were obtained by Dai et al. [33] against A-549 cells. Myricanol (4) also presents a very interesting activity by inhibiting muscle atrophy and dysfunction caused by dexamethasone in C2C12 myotubes [33]. As seen in Table1, pretreatment with 4 induces a variety of processes that lead to or are a reflex of the direct activation of Sirtuin-1 [30], a protein that regulates skeletal muscle remodeling, which directly deacetylates and therefore activates PGC-1α to regulate mitochondrial biogenesis [64], induces autophagy to enhance degraded protein clearance and modulates FoxOs transcriptional activity to reduce atrogin-1 and MuRF1 expression, which are responsible for protein degradation, and consequently control loss of muscle mass and function [65]. Since there are only a few molecules approved for the treatment of muscle atrophy, and the majority come with very undesirable side effects like insulin resistance, sodium retention, or possibility of thromboembolisms [66], there is a need to find alternative molecules capable of treating this condition. The results shown by myricanol (4) turn it into a good candidate for that alternative. Additionally, myricanol shows neuroprotective effects in N2a neuronal cells exposed to H2O2 [32]. Pretreatment with 0.84 mM of 4 increased 80% of cell viability, decreased 40% of intracellular reactive oxygen species (ROS) formation and reduced intracellular calcium concentrations, compared with the H2O2 group. Quercitrin (9) is one of the most studied among the compounds from Morella and Myrica genera. Despite most of the studies being performed with quercitrin isolated from other sources, the fact that this compound has also been isolated in Morella and Myrica genera, namely Morella adenophora (Hance) J. Herb. [19], is in itself an added value to the biological importance of these genera. Compound 9 is a potent α-glucosidase inhibitor, an enzymatic target used to evaluate antidiabetic effect. It has an IC50 four times lower than acarbose, a commercial inhibitor, which indicates the great potential of quercitrin as a hypoglycemic agent for diabetes treatment [36]. Mercury and lead are considered as threats to human organisms, due to their low elimination rate and high accumulation, which have nefarious effects in several physiological functions, especially of liver and nervous system [67,68]. A study carried out by Aldana et al. [39] demonstrated the capacity of quercitrin (9) as cytoprotective agent for the HepG2 cell line against both metals. However, on PC12 cells, quercitrin was only able to protect against the effects of lead [39]. Further investigations are necessary to explain the cytoprotective mechanism of the compound. Molecules 2020, 25, 6052 13 of 33

Quercitrin (9) also presents a moderate antiviral activity by inhibition of neuraminidase (NA) [37], a viral enzyme common in human influenza viruses, which is essential for the virus release from infected cells to the neighboring cells of the respiratory tract [69]. It has also been reported that quercitrin (9) inhibits the activity of myeloperoxidase, with an IC50 of 2.0 µM[38], a result that hints at its possible role in reducing endothelial dysfunction and consequently that the protective effect of 9 should be evaluated in an atherosclerosis model. A great number of the studies reviewed about the pharmacological activities of myricitrin (10) focused on its effects against cardiovascular problems [43–45]. Qin et al. [45] suggest that myricitrin treatment protected human umbilical vein endothelial cells (HUVECs) against the effects of oxidized low-density lipoprotein (ox-LDL), which results in reduced atherosclerotic plaque formation. It was also found that 40 µM myricitrin protects H9c2 cardiomyocytes against hypoxia/reoxygenation injury, increasing cell-survival from 65.48% in untreated cells to 87.48% (Table1)[ 43]. In addition, there was a reduction in the expression of pro-apoptotic factors, like caspase-3 or Bax, and an increase in the expression of anti-apoptotic factors, like Bcl-2. Likewise, the authors formulated that myricitrin (10) might exert its cardioprotective effects via stimulation of the expression of heat shock protein 90, whose activation promotes the anti-apoptotic PI3-K/Akt signaling pathway [43]. In a model of diabetic cardiomyopathy injury, Zhang et al. [44] found that pretreatment with 53.8 µM of myricitrin significantly decreased advanced glycation end products (AGEs)-induced inflammatory cytokine expression, limited an increase in ROS levels, and reduced cell apoptosis, fibrosis, and hypertrophy in H9c2 cells (Table1). Overall, the protective e ffects of myricitrin could be attributed to its antioxidant and anti-inflammatory effects, as well as its ability to activate the Akt signaling pathway [43,44]. The anti-ROS activity of 10 is also responsible for the neuroprotective activities reported by Shen et al. [17] and Wang et al. [47] as observable by the effects described in Table1. Myricitrin (10) is also a potent α-glucosidase (IC50 = 1.1 µM) and β-amylase inhibitor (IC50 = 1.9 µM), being 20- and 10-fold more active than acarbose, respectively [48]. Myricanone (1), myricanol (4), and myricitrin (10) were found to inhibit melanogenesis in B16 mouse melanoma cells (Table1)[ 26]. The melanin content found after exposure to the compounds was lower than the positive control, arbutin. However, the mechanism by which this occurred was different. For myricanone (1) and myricanol (4), it was due to their cytotoxic effects on the B16 cells, while 10 exerted its antimelanogenesis effect without killing the B16 cells, similar to the effect of arbutin [26]. Respiration uncoupling seems to be implicated in numerous physiological and pathological processes like autophagy, regulation of ROS production, protein secretion, capacity to carry out physical exercise, and adipose tissue biology [70]. As seen in Table1, a series of dihydrochalcones, which have been isolated from various species of Morella and Myrica, possess the ability to uncouple the mitochondrial respiratory chain. Myrigalone A (11) and myrigalone G (15) were the best uncouplers, increasing the respiratory rate more than two-fold with respect to the positive control, 2,4-dinitrophenol (DNP) [53]. Although respiratory uncouplers may have some therapeutic interest, they must be evaluated for their safety, and there are no records of such study on the safety of myrigalones 11–15 as respiratory chain uncoupling agents. Myrigalone B (12) and myrigalone G (15) inhibited α-glucosidase activity with IC50 of 19 and 7 µM, respectively, which is lower than the positive control, acarbose (43 µM). For β-amylase inhibition, 12 was again the most active with an IC50 of 8.3 µM against 33 µM obtained with compound 15 (Table1)[ 48]. In this case myrigalone B (12) was still more active than acarbose, but not myrigalone G(15), since the IC50 of acarbose for β-amylase inhibition was 19 µM. Despite their potential as antidiabetic compounds, 12 and 15 are still less active inhibitors than myricitrin (10). Another very interesting compound found in Morella/Myrica genera is betulin (16), which has presented a wide array of antitumor activities (Table1). Lin et al. [ 57] reported the anticancer activity against two lines of osteosarcoma, MG-63 and HOS cell lines, with an IC50 of 14.54 and 11.70 µM, respectively. Unfortunately, no positive control was used to compare with the potency of botulin (16). Molecules 2020, 25, 6052 14 of 33

The authors found that the effect of 16 in osteosarcoma cell lines is through the induction of apoptosis and autophagy to suppress cell viability, as well as by the inhibition of mTOR signaling. Betulin (16) is also very active against the NCi-H460 (IC50 = 2.8 µM) and HT29-MTX (IC50 = 1.6 µM) cell lines, being much more active than the positive control podophyllotoxin (22 and 24 µM against these two cell lines, respectively) [58]. Compound 16 was also found to be active against A549 and SK-Br-3 cell lines, with a more potent effect than cisplatin (Table1), but is less potent against the HL60 cell-line [ 18]. Betulin (16) also exerts hepatoprotective activity against continuous ethanol exposure [59]. Ethanol-induced HSC-T6 cells treated with 25 µM of 16 suffered a decrease in the expression levels of collagen-I and α-SMA, which indicates that betulin (16) reduces ethanol-induced hepatic fibrosis. The expression levels of TLR4 were decreased after betulin pretreatment and there was an increased activation of STAT3. This modulation of TLR4 and STAT3 pathways is proposed as the mechanism through which 16 protects the hepatocytes against fibrosis. A good number of the compounds from Table1 were tested for their anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv, (+)-Galeon (8) being the most active compound with a minimum inhibitory concentration (MIC) of 15 µg/mL. However, this value was still higher than the one obtained with the positive control, ethambutol, which has an MIC of 6.25 µg/mL [19]. The second-best compound, 5-deoxymyricanone (2), has an MIC of 25.8 µg/mL, which is more than four times the MIC of the positive control, so it cannot be considered very active. Morella/Myrica compounds show remarkable pharmacological potential, with a variety of interesting in vitro activities. For further understanding of their full potential and clarification of mechanisms of action, their activities must be confirmed in vivo. The following section focuses on what is already known about the effects of compounds isolated from Morella/Myrica in living organisms.

2.2. In Vivo Tests In vivo studies are necessary to understand the actual potential of compounds as future therapeutic agents. A few compounds isolated from Morella/Myrica genera reached the in vivo stage of evaluation of their pharmacological effects, which means that research teams recognize their potential and want to prove their full pharmacological value. The main results of those studies are summarized in Table2, and the most relevant aspects are discussed below. As expected, the three compounds which have been more extensively studied in vitro and which were reported to be bioactive were the ones selected by researchers to be evaluated concerning their in vivo activity (Table2). These compounds are myricanol ( 4), myricitrin (10), and betulin (16), and many of the in vivo studies found in the present literature survey aimed to confirm or to clarify the mechanisms of action found on the in vitro studies. A dosage of 5 mg/kg of myricanol (4) administered to C57BL/6 mice with dexamethasone-induced muscle wasting led to a reduction of muscle loss in both quadriceps and gastrocnemius muscle (Table2). In addition, the mice from the treated group showed an improvement of grip strength of about 50 g and almost doubled the forced swim time when compared with the untreated group [30]. Muscle atrophy was inhibited, with muscle fiber diameter increasing almost by 25% when compared with the untreated group. As observed in the in vitro tests, myricanol (4) also prevents dexamethasone-induced muscle atrophy and weakness by activating SIRT1 to reduce muscle protein degradation, enhance autophagy, and promote mitochondrial biogenesis and function in mice [30]. Molecules 2020, 25, 6052 15 of 33

Table 2. In vivo biological activities exhibited by compounds from Morella and Myrica species.

Compound Model Dose Activity Myricanol (4) C57BL/6 mice 5 mg/kg Protection against muscle atrophy [30] Reduction of quadriceps muscle mass loss (1.36 0.02% b/w against 1.18 0.06% b/w on the ± ± untreated group). Reduction of gastrocnemius muscle mass loss (0.87 0.08% b/w against 0.78 0.05% b/w on ± ± the untreated group). Improvement of grip strength (120.58 7.93 g against 70.90 04.59 g on the untreated group). ± ± Increase in forced swim time (83.75 15.19 s against 48.80 11.43 s on the untreated group). ± ± Inhibition of muscle atrophy (~25% increase in muscle fiber diameter when compared with untreated group). C57BL/6J 25 mg/kg Anti-obesity and diabetic activity [71] Reduction of body weight and body fat gain under high fat diet when compared with untreated group. Decrease in serum total cholesterol, triglycerides, LDL-cholesterol, and LDL/HDL ratio (~33%). 50% reduction of fasting insulin levels when compared with untreated group. ~2-fold increase in insulin sensitivity when compared with untreated group. Increased levels of phosphorylation of IRS-1 (2.5-fold), AKT (3-fold), and GSK-3β (1.5-fold) when compared with untreated group. 35% decrease in adipocyte diameter when compared with untreated group. ~33% increase in irisin serum levels when compared with untreated group. Zebrafish 1 µM Anti-obesity activity [31] 66% decrease in lipid accumulation under high-fat diet, when compared with the untreated group (positive control AICAR (5 µM): 75% decrease). ~70–80% reduction of PPAR-γ,C/EBPα, SREB-1 and aP2 expression when compared with the untreated group (similar values obtained with the positive control). BALB/c nude mice 40 mg/kg Antitumor activity [72] 39.4% reduction on A549 xenograft tumor volume after 14 days, when compared with untreated group. ~33% increase in the expression levels of Bax when compared with untreated group. Decrease in the expression levels of Bcl-2 (25%), vascular endothelial growth factor (VEGF) (20%), and Survivin (33%) when compared with untreated group. 20% increase on the number of apoptotic tumor cells when compared with untreated group. Molecules 2020, 25, 6052 16 of 33

Table 2. Cont.

Myricitrin (10) ApoE -/- mice 50 mg/kg Prevention of atherosclerosis [45] ~25% reduction of serum levels of Ox-LDL (similar reduction in the positive control group treated with 2 g/kg of probucol). 22% reduction on aortic wall thickness when compared to the untreated group. Complete inhibition of calcification on aortic arch. (Calcification observed in the untreated group). 26% reduction on atherosclerotic plaque area when compared with the untreated group. ~20% reduction of caspase-3 expression in aortic arch. BALB/cN mice 100 mg/kg Hepatoprotective activity [73] Protection against CCl4 intoxication. Reduction in body weight change ( 12.9 0.8% against 19.6 2.3% on the untreated group. − ± ± Reduction of ALT serum levels (481 53 U/L against 2126 268 U/L on the untreated group). ± ± Reduction of AST serum levels (592 74 U/L against 2538 322 U/L on the untreated group). ± ± Reduction of liver lipids peroxidation. Increase on glutathione levels (46.1 3.4 µmol/g protein against 28.6 2.8 µmol/g protein on ± ± the untreated group). ~25% decrease in necrotic areas on the liver when compared with untreated group. 5-fold increase on CYP2E1 expression when compared with the untreated group. BALB/c mice 300 mg/kg Protection against diabetic cardiomyopathy [44] ~20–25% improvement in cardiac function of diabetic mice when compared with untreated group. Decrease on abnormalities in the arrangement of cardiac fibers and morphology of cardiomyocytes when compared with untreated group. Inhibition of collagen network destruction and reduction of fibrotic alterations of the hearth. 2-fold reduction in the expression of TGF-β1 when compared with the untreated group. 8-fold reduction in the expression levels of collagen-1. Reduction on serum levels of IL-6 (35.72 pg/mL against 112.41 pg/mL in the untreated group). Reduction on serum levels of TNF-α (24.83 pg/mL against 56.21 pg/mL in the untreated group). Decrease of Bax/Bcl-2 ratio (35-fold), caspase-3 (5-fold), and caspase-9 (4-fold) expression levels, when compared with the untreated group. BALB/c mice 50 mg/kg Neuroprotective activity [74] In LPS-stimulated mice: ~2-fold increase on the expression levels of PSD-95 and TH, when compared with untreated group. Reduction on expression levels of IL-1β (3-fold), IL-6 (2-fold), TNF-α (2-fold), and MCP-1 (2-fold), when compared with the untreated group. Reduction on the expression levels of COX-2 (3-fold) and iNOS (2-fold), when compared with the untreated group. Suppression of LPS-stimulated p38 (4-fold), ERK (4-fold), and JNK (2-fold) activation. Molecules 2020, 25, 6052 17 of 33

Table 2. Cont.

Betulin (16) C57BL/6 mice 20 mg/kg Hepatoprotective activity [75] Decrease of liver/body weight ratio in alcoholic mice, when compared with untreated group. Decrease in serum levels of ALT (66%), AST (33%), and TG (50%), when compared with the untreated group. Decrease on expression levels of collagen-I (20%), SREBP-1 (25%), and α-SMA (50%), when compared with untreated group. Increased phosphorylation of LKB1 (15%) and AMPK (25%) when compared with untreated group. 7-fold increase in SIRT-1 expression when compared with untreated group. C57BL/6 mice 50 mg/kg Hepatoprotective activity [47] Decrease in serum levels of ALT (50%), AST (50%), and TG (33%) in ethanol induced fatty-liver mice, when compared with the untreated group. Decrease in expression levels of SREBP-1 (75%), CYP2E1 (60%), and TLR4 (60%), when compared with the untreated group. ~30% increase in phosphorylation of STAT3, when compared with the untreated group. Molecules 2020, 25, 6052 18 of 33

In another study, myricanol (4) at a dosage of 25 mg/kg, when fed to C57BL/6J mice simultaneously with a high fat diet (HFD), was able to reduce body weight and body fat accumulation, when compared with mice fed only with the HFD [71]. Furthermore, compound 4 administration led to a 33% decrease in lipids serum levels and a 50% reduction of fasting insulin levels, which can be explained by the 2-fold increase observed in the insulin sensitivity on the treated group (Table2). Other e ffects of 4 in the HFD-fed mice were the activation of a series of pathways, like adenosine monophosphate-activated protein kinase (AMPK), leading to the suppression of adipogenesis and induction of lipolysis and lipid combustion in adipocytes, or insulin receptor substrate 1 (IRS-1), which leads to mitochondrial biogenesis, increases mitochondrial oxidative metabolism, and benefits adenosine triphosphate (ATP) synthesis. Myricanol (4) also increases irisin serum levels, which induces mitochondrial oxidative metabolism, mitochondrial uncoupling, fatty acid oxidation in skeletal muscle [76], and increases energy expenditure in human adipocytes, resulting in reduced lipid accumulation [77]. Altogether, these data show this compound could be developed as a candidate for the treatment of insulin resistance and obesity. The effect of myricanol on lipid accumulation was confirmed by Shen et al. [31], but in a zebrafish model, with their findings showing the inhibition of lipid accumulation by suppressing adipogenic factors, including peroxisome proliferator activated receptor γ (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα). Myricanol (4) also decreased tumor growth in xenografted BALB/c nude mice at a dosage of 40 mg/kg, by activating the expression levels of pro-apoptotic factors within the tumor cells and downregulating the protein expression of Bcl-2, VEGF, HIF-1α, and survivin, thus increasing the apoptotic rate of tumor cells [72]. These effects led to a reduction in tumor volume of 39.4% after 14 days when compared with the untreated mice, showing the great potential of myricanol to become an anticancer drug. In a murine model of atherosclerosis, a dosage of 50 mg/kg of myricitrin prevented the formation of Ox-LDL, which represented a reduction of 25% in serum levels of that atherosclerosis promoter [45]. A similar reduction was found in the mice treated with the positive control, probucol, but at a 40-fold higher dose than that of myricitrin, which means the latter is much more effective. By reducing the levels of Ox-LDL, myricitrin (10) led to a reduction of 20% in the expression of caspase-3 in the aortic arch, thus reducing endothelial cell apoptosis. This resulted in a complete inhibition of calcification in the aortic arch of treated mice, and a reduction on the atherosclerotic plaque area (Table2)[45]. The in vivo investigation of the effects of myricitrin in a model of diabetic cardiomyopathy demonstrated that oral administration of a dosage of 300 mg/kg/day for 8 weeks remarkably decreased the expression of enzymes associated with cardiomyopathy, as well as the expression of inflammatory cytokines and apoptotic proteins [44]. This led to 20–25% improvement of diastolic dysfunction and attenuated histological abnormalities, by inhibiting the destruction of the collagen network, which reduces the fibrotic alterations of the heart. Mechanistically, the authors found that myricitrin (10) attenuated diabetes-induced Nrf2 inhibition via the regulation of Akt and extracellular-signal-related kinase (ERK) phosphorylation in the diabetic heart. Another in vivo study showed that a dosage of 50 mg/kg of myricitrin (10) improved neuron injury and increased the expressions levels of PSD-95 protein and tyrosine hydroxylase TH protein in lipopolysaccharide (LPS)-stimulated BALB/c mice [74]. Loss of these proteins is found in Parkinson’s disease [78], so the fact that myricitrin increases their expression hints for a possible role in the prevention of this disease. In addition, myricitrin (10) decreased the production of pro-inflammatory factors including IL-1β, IL-6, and TNFα, decreased the level of chemokine MCP-1, and suppressed the expressions of COX-2 and iNOS (Table2). Meanwhile, myricitrin suppressed HMGB1, TLR4, and MyD88 expression in the nigrostriatum of LPS-stimulated mice, and inhibited NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways activated by LPS [74]. These effects show that myricitrin (10) is efficient in protecting the brain against inflammation and all the nefarious effects it causes. Molecules 2020, 25, 6052 19 of 33

Myricitrin (10) at a dosage of 100 mg/kg significantly ameliorated CCl4-induced hepatotoxicity in BALB/cN mice [73]. Treatment with this compound caused an increase in serum aspartate transaminase (AST) and alanine transaminase (ALT) levels and prevented histopathological changes in the liver (Table2). Hepatic oxidative stress was reduced by myricitrin ( 10), as evidenced by the decrease in lipid peroxidation, with concomitant increase in glutathione (GSH) level and cytochrome P450 2E1 (CYP2E1) expression. Furthermore, cyclooxygenase-2 (COX-2) and tumor necrosis factor-alpha (TNF-a) overexpression in the liver was reduced, suggesting the suppression of inflammation [73]. Myricitrin (10) also improved the regeneration of hepatic tissue after CCl4-intoxication, as evidenced by increased proliferating cell nuclear antigen (PCNA) expression. The results presented by Domitrovic et al. [73] suggest that the anti-inflammatory and antioxidant effects of myricitrin (10) are responsible for its hepatoprotective activity. In fact, all the myricitrin (10) in vivo studies presented in Table2 strongly indicate that 10 exerts its protective effects through the blockage of inflammation, oxidative stress, and apoptosis [44,45,73,74], which confirms myricitrin (10) as a potential candidate for the treatment and prevention of a wide array of disorders related to oxidative stress and inflammation. Betulin (16) in vivo studies focused on its hepatoprotective effects against both chronic alcohol consumption [75] or acute ethanol induced fatty liver [47]. In the model of chronic consumption, administration of 20 mg/kg of betulin (16) to alcoholic C57BL/6 mice attenuated the increases in serum aminotransferase and triglyceride levels, while significantly inhibiting SREBP-1 expression and activating LKB1-AMPK phosphorylation [75]. Additionally, betulin (16) enhanced the sirtuin 1 (SIRT1) expression mediated by ethanol. Taken together, betulin alleviates alcoholic liver injury possibly through blocking the regulation of SREBP-1 on fatty acid synthesis and activating SIRT1-LKB1-AMPK signaling pathway. In the acute ethanol-induced fatty liver model, administration of 50 mg/kg of betulin (16) to C57BL/6 mice induced a decrease in serum levels of hepatic enzymes and triglycerides [47]. The expression of SREBP-1, a transcription factor that promotes fatty acid synthesis [79] and whose activation by ethanol leads to fat accumulation on the liver, is reduced by betulin (16) to 75% of the expression levels presented by the untreated groups [47]. Betulin (16) administration also significantly decreased the expression levels of CYP2E1 and TLR4 and increased the activation of STAT3 (Table2), thus impairing the ethanol induced pro-inflammatory response and, consequently reducing liver steatosis and fibrosis [47].

3. Other Phytochemicals Identified in Morella and Myrica Species Many other secondary metabolites whose therapeutic application was not evaluated yet have been isolated in the last decades from Morella and Myrica species, constituting a pool of natural compounds structurally diverse with scientific interest, in which a research gap exists and which it is important to evaluate. These compounds are compiled in Table3. The pharmacological potential of the compounds presented in Table3 has not been evaluated so far by the researchers who have studied Morella and Myrica species. It should be noted that the isolation and structural elucidation are the first steps to describing the metabolomic profile of a species or genus, helping to assess their potential as a source of commercially valuable phytochemicals, adding value to the species, as well as finding alternative sources of pharmacologically active metabolites. The compounds listed in Table3 belong to several families, like chalcones, dihydrochalcones, flavonoids, diterpenoids, triterpenoids, and diarylheptanoids, the latter two being the families with the highest number of compounds isolated. A similar tendency had already been observed in Table1, where it was observed that diarylheptanoids were the most represented family, which indicates that Morella and Myrica genera are a good source of this family of compounds. Since many of the unstudied compounds compiled in Table3 share many structural features with some of the most active compounds that have already been assessed for their biological activities, there is plenty of potential for finding new added value compounds to increase the value of species from Morella/Myrica genera. Molecules 2020, 25, 6052 20 of 33

Molecules 2020, 25, x FOR PEER REVIEW 20 of 33 Molecules 2020, 25, x FOR PEER REVIEW 20 of 33 Molecules 2020, 25, x FOR PEER REVIEW 20 of 33 MoleculesTable 2020 3. Other, 25, x FOR secondary PEER REVIEW metabolites isolated from Morella/Myrica genera. 20 of 33 Molecules 2020, 25, x FOR PEER REVIEW 20 of 33 Molecules 2020, 25, x FORTable PEER 3. Other REVIEW secondary metabolites isolated from Morella/Myrica genera. 20 of 33 Molecules 2020, 25, x FORTable PEER 3. Other REVIEW secondary metabolites isolated from Morella/Myrica genera. 20 of 33 MoleculesName 2020, 25, x FORTable PEER 3. Other REVIEW secondary Structure metabolites isolated from Extract, Morella Species,/Myricaand genera. Part of Plant 20 of 33 Molecules 2020Name, 25, x FORTable PEER 3. Other REVIEW secondary Structure metabolites isolated from Morella Extract,/Myrica Species, genera. and Part of Plant 20 of 33 Molecules 2020Name, 25, x FORTable PEER 3. Other REVIEW secondary Structure metabolites isolated from Morella Extract,/Myrica Species, genera. and Part of Plant 20 of 33 Name Table 3. Other secondary Structure metabolites isolated from Morella Extract,/Myrica Species, genera. and Part of Plant Name Table 3. Other secondary Structure metabolites isolated from Morella Extract,/Myrica Species, genera. and Part of Plant Name Table 3. Other secondary Structure metabolites isolated from Morella Extract,/Myrica Species, genera. and Part of Plant Name Table 3. Other secondary Structure metabolites isolated from Morella Extract,/Myrica Species, genera. and Part of Plant 20,40-Dihydroxy-62′,4′-Dihydroxy-60-methoxy-3Name ′-methoxy-Table0,50 3. Other secondary Structure metabolites isolated fromDichloromethaneDichloromethane Morella Extract,/Myrica Species, extract extractgenera. and of Morella Part of Morella of serrata Plant (Lam.) 2′,4′-Dihydroxy-6Name ′-methoxy- Structure Dichloromethane Extract, Species, extract and of Morella Part of serrata Plant (Lam.) -dimethylchalcone23′,4′,5′-Dihydroxy-6′-dimethylchalconeName (23 )′-methoxy- (23) Structure Dichloromethaneserrata Extract,(Lam.) Species,Killick extract Killick leaves and of leaves Morella Part [55] of [55 serrataPlant] (Lam.) 23′,4′,5′-Dihydroxy-6′-dimethylchalcone′-methoxy- (23) DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) 23′,4′,5′-Dihydroxy-6′-dimethylchalconeName ′-methoxy- (23) Structure Dichloromethane Extract, Species,Killick extract leaves and of Morella Part [55] of serrata Plant (Lam.) 23′,4′,5′-Dihydroxy-6′-dimethylchalcone′-methoxy- (23) DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) 23′,4′,5′-Dihydroxy-6′-dimethylchalcone′-methoxy- (23) DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) 23′,4′,5′-Dihydroxy-6′-dimethylchalcone′-methoxy- (23) DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) 23′,4′,5′-Dihydroxy-6′-dimethylchalcone′-methoxy- (23) DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) 23′,4′,5′-Dihydroxy-6′-dimethylchalcone′-methoxy- (23) DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) 3′,5′-dimethylchalcone (23) Killick leaves [55] 3′,5′-dimethylchalcone (23) DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) Aurentiacin A (24) DichloromethaneDichloromethane extract extract of Morella of Morella serrata (Lam.) AurentiacinAurentiacin A (24) A (24) DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) Aurentiacin A (24) Dichloromethaneserrata (Lam.)Killick extract Killick leaves of leaves Morella [55] [ 55serrata] (Lam.) Aurentiacin A (24) DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) Aurentiacin A (24) DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) Aurentiacin A (24) DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) Aurentiacin A (24) DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) Aurentiacin A (24) DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) Aurentiacin A (24) 2′,6′-Dihydroxy-4′-methoxy- DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) 2′,6′-Dihydroxy-4Aurentiacin A′-methoxy- (24) DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) 23′,6′-methyl-dihydrochalcone′-Dihydroxy-4′-methoxy- DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) 2 ,6 -Dihydroxy-423′,6′-methyl-dihydrochalcone′-Dihydroxy-4-methoxy′-methoxy- DichloromethaneDichloromethaneKillick extract extract leaves of Morella of[55]Morella serrata (Lam.) 0 0 23′,6′-methyl-dihydrochalcone′-Dihydroxy-40 (25) ′-methoxy- DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) 23′′,6-methyl-dihydrochalcone′-Dihydroxy-4(25) ′-methoxy-25 Dichloromethaneserrata Killick extract leaves of Morella [55] serrata (Lam.) -30-methyl-dihydrochalcone23′,6′-methyl-dihydrochalcone′-Dihydroxy-4(25) ′-methoxy- ( ) Dichloromethane(Lam.)Killick extract Killick leaves of leaves Morella [55] [55 serrata] (Lam.) 23′,6′-methyl-dihydrochalcone′-Dihydroxy-4(25) ′-methoxy- DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) 23′,6′-methyl-dihydrochalcone′-Dihydroxy-4(25) ′-methoxy- DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) 23′′,6-methyl-dihydrochalcone′-Dihydroxy-4(25) ′-methoxy- DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) 3′-methyl-dihydrochalcone Methanol extract of Myrica gale L. seeds [54] (25) DichloromethaneMethanol extractKillick extract of Myricaleaves of Morella [55]gale L. serrata seeds (Lam.)[54] 3′-methyl-dihydrochalcone(25) MethanolMethanolFrom extract extracttheKillick Myrica of of leavesMyrica Myricagale L. [55]gale fruits gale L. seeds L.[53] [54] Myrigalone(25) E (26) MethanolFrom extract theKillick Myrica of Myricaleaves gale L. [55]gale fruits L. seeds [53] [54] Myrigalone(25) E (26) DichloromethaneMethanolFrom extract theseeds Myricaextract of [ 54Myrica gale]of Morella L. gale fruits L. serrata seeds [53] (Lam.)[54] Myrigalone E (26) DichloromethaneMethanolFrom extract the Myrica extract of Myrica gale of Morella L. gale fruits L. serrata seeds [53] (Lam.)[54] MyrigaloneMyrigalone E (26) E (26) DichloromethaneFromMethanolFrom the Myricaextract theKillick Myricaextract of gale Myricaleaves galeofL. Morellafruits L. [55]gale fruits L. [serrata53 seeds [53]] (Lam.)[54] Myrigalone E (26) DichloromethaneMethanolFrom extract theKillick Myricaextract of Myricaleaves galeof Morella L. [55]gale fruits L. serrata seeds [53] (Lam.)[54] Myrigalone E (26) DichloromethaneMethanolFrom extract theKillick Myricaextract of Myricaleaves galeof Morella L.[55]gale fruits L. serrata seeds [53] (Lam.)[54] Myrigalone E (26) DichloromethaneDichloromethaneMethanolFrom extract theKillick Myricaextract of extract leavesMyrica galeof Morella L.of [55]gale fruitsMorella L. serrata seeds [53] (Lam.)[54] Myrigalone E (26) DichloromethaneFrom the Myrica extract gale of Morella L. fruits serrata [53] (Lam.) Myrigalone E (26) serrata (Lam.)Killick Killick leaves leaves [55] [55] DichloromethaneFrom theKillick Myricaextract leaves galeof Morella L.[55] fruits serrata [53] (Lam.) Myrigalone E (26) DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) Myrigalone P (27) Methanol extractKillick of leavesMyrica [55]gale L. seeds [54] Myrigalone P (27) Methanol extractKillick of Myricaleaves [55]gale L. seeds [54] Myrigalone P (27) Methanol extract of Myrica gale L. seeds [54] Myrigalone P (27) MethanolMethanol extract extract of of MyricaMyrica gale gale L. seedsL. [54] MyrigaloneMyrigalone P (27) P (27) Methanol extract of Myrica gale L. seeds [54] Myrigalone P (27) Methanol extractseeds of [ 54Myrica] gale L. seeds [54] Myrigalone P (27) Methanol extract of Myrica gale L. seeds [54] Myrigalone P (27) Methanol extract of Myrica gale L. seeds [54] Myrigalone P (27) Methanol extract of Myrica gale L. seeds [54] Myrigalone P (27) Methanol extract of Myrica gale L. seeds [54]

Uvangoletin (28) Methanol extract of Myrica gale L. seeds [54] Uvangoletin (28) Methanol extract of Myrica gale L. seeds [54] Uvangoletin (28) Methanol extract of Myrica gale L. seeds [54] Uvangoletin (28) Methanol extract of Myrica gale L. seeds [54] Uvangoletin (28) MethanolMethanol extract extract of of MyricaMyrica gale gale L. seedsL. [54] UvangoletinUvangoletin (28) (28) Methanol extract of Myrica gale L. seeds [54] Uvangoletin (28) Methanol extract of Myrica gale L. seeds [54] Uvangoletin (28) Methanol extractseeds of [ 54Myrica] gale L. seeds [54] Uvangoletin (28) Methanol extract of Myrica gale L. seeds [54]

Uvangoletin (28) Methanol extract of Myrica gale L. seeds [54] Fruit exudate from the Myrica gale L. fruits Angoletin (29) Fruit exudate from the Myrica gale L. fruits Angoletin (29) Fruit exudate from[53,56] the Myrica gale L. fruits Angoletin (29) Fruit exudate from[53,56] the Myrica gale L. fruits Angoletin (29) Fruit exudate from[53,56] the Myrica gale L. fruits Angoletin (29) Fruit exudate from[53,56] the Myrica gale L. fruits Angoletin (29) FruitFruit exudate exudate from[53,56] the the MyricaMyrica gale gale L. fruits AngoletinAngoletin (29) (29) Fruit exudate from[53,56] the Myrica gale L. fruits Angoletin (29) Fruit exudateL. fruits from[53,56] [ 53the,56 Myrica ] gale L. fruits Angoletin (29) Fruit exudate from[53,56] the Myrica gale L. fruits Angoletin (29) [53,56] [53,56] Dichloromethane extract of Morella serrata (Lam.) Dichloromethane extract of Morella serrata (Lam.) Demethoxymatteucinol (30) DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) Demethoxymatteucinol (30) DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) Demethoxymatteucinol (30) DichloromethaneMethanol extractKillick extract of Myricaleaves of Morella [55]gale L. serrata seeds (Lam.)[54] Demethoxymatteucinol (30) DichloromethaneMethanol extractKillick extract of Myricaleaves of Morella [55]gale L. serrata seeds (Lam.)[54] Demethoxymatteucinol (30) DichloromethaneDichloromethaneMethanol extractKillick extract of extract Myricaleaves of Morella of [55]galeMorella L. serrata seeds (Lam.)[54] Demethoxymatteucinol (30) DichloromethaneMethanol extractKillick extract of Myricaleaves of Morella [55]gale L. serrata seeds (Lam.)[54] Demethoxymatteucinol (30) DichloromethaneMethanolserrata (Lam.) extractKillick extract Killick of Myricaleaves of leaves Morella [55]gale [L. 55serrata seeds] (Lam.)[54] DemethoxymatteucinolDemethoxymatteucinol (30) (30) DichloromethaneMethanol extractKillick extract of Myricaleaves of Morella [55]gale L. serrata seeds (Lam.)[54] Demethoxymatteucinol (30) MethanolMethanol extract extractKillick of of leavesMyricaMyrica [55]gale gale L. seedsL. [54] Demethoxymatteucinol (30) Methanol extractKillick of Myricaleaves [55]gale L. seeds [54] Methanol extractseeds of [Myrica54] gale L. seeds [54] Methanol extract of Myrica gale L. seeds [54]

Dichloromethane extract of Morella serrata (Lam.) Cryptostrobin (31) Dichloromethane extract of Morella serrata (Lam.) Cryptostrobin (31) DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) Cryptostrobin (31) DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) Cryptostrobin (31) DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) Cryptostrobin (31) DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) Cryptostrobin (31) DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) Cryptostrobin (31) DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) Cryptostrobin (31) DichloromethaneDichloromethaneKillick extract extract leaves of Morella of[55]Morella serrata (Lam.) CryptostrobinCryptostrobin (31) (31) DichloromethaneKillick extract leaves of Morella [55] serrata (Lam.) Cryptostrobin (31) serrata (Lam.)Killick Killick leaves leaves [55] [55] Killick leaves [55]

Demethoximatteucinol-7- Demethoximatteucinol-7- Methanol extract of Myrica gale L. seeds [54] Demethoximatteucinol-7-methoxy (32) Methanol extract of Myrica gale L. seeds [54] Demethoximatteucinol-7-methoxy (32) Methanol extract of Myrica gale L. seeds [54] Demethoximatteucinol-7-methoxy (32) Methanol extract of Myrica gale L. seeds [54] Demethoximatteucinol-7-methoxy (32) Methanol extract of Myrica gale L. seeds [54] Demethoximatteucinol-7-methoxy (32) Methanol extract of Myrica gale L. seeds [54] Demethoximatteucinol-7-methoxy (32) Methanol extract of Myrica gale L. seeds [54] Demethoximatteucinol-7-methoxy (32) Methanol extract of Myrica gale L. seeds [54] Demethoximatteucinol-7-methoxy (32) MethanolMethanol extract extract of of MyricaMyrica gale gale L. seedsL. [54] Demethoximatteucinol-7-methoxymethoxy (32) (32) Methanol extract of Myrica gale L. seeds [54] methoxy (32) seeds [54]

Molecules 2020, 25, 6052 21 of 33

Table 3. Cont. Molecules 2020, 25, x FOR PEER REVIEW 21 of 33 Molecules 2020, 25, x FOR PEER REVIEW 21 of 33 MoleculesName 2020, 25, x FOR PEER REVIEW Structure Extract, Species, and Part of Plant 21 of 33 Molecules 2020, 25, x FOR PEER REVIEW 21 of 33 Molecules 2020, 25, x FOR PEER REVIEW 21 of 33

Myricetin Methanol extract of Myrica gale L. Myricetin 3-O-6′’-galloyl-β- Methanol extract of Myrica gale L. (Myrica gale O Myricetinβ 3-O-6′’-galloyl-β- MethanolMyrica extract gale of Myricatormentosa gale L. (Myrica gale 3- -6”-galloyl-MyricetinD-galactopyranoside-D-galactopyranoside 3-O-6′’-galloyl- (33β) - Methanol( var extract tormentosavar of Myrica L.) branches gale L.L.) ([24]Myrica gale MyricetinD-galactopyranoside(33) 3-O-6′’-galloyl- (33β) - Methanolvar extract tormentosabranches of Myrica L.) [24 branches] gale L. ( Myrica[24] gale MyricetinD-galactopyranoside 3-O-6′’-galloyl- (33β) - Methanolvar extract tormentosa of Myrica L.) branches gale L. ( Myrica[24] gale D-galactopyranoside (33) var tormentosa L.) branches [24] D-galactopyranoside (33) var tormentosa L.) branches [24]

Gallocatechin-4-α-8- Gallocatechin-4-α-8- Aerial parts of Myrica gale L. [80] Gallocatechin-4-αGallocatechin-4--8-epicatechinepicatechin (34α) (-8- 34) AerialAerial parts parts of Myrica of Myrica gale galeL. L. [80 [80]] Gallocatechin-4-epicatechin (34α)-8- Aerial parts of Myrica gale L. [80] Gallocatechin-4-epicatechin (34α)-8- Aerial parts of Myrica gale L. [80] epicatechin (34) Aerial parts of Myrica gale L. [80] epicatechin (34)

Gallocatechin-4-α-8- Gallocatechin-4-α-8- Aerial parts of Myrica gale L. [80] Gallocatechin-4-αepigallocatechinGallocatechin-4--8-epigallocatechin α(35-8-) Aerial parts of Myrica gale L. [80] Gallocatechin-4-epigallocatechinα (35-8-) AerialAerial parts parts of Myrica of Myrica gale galeL. L. [80 [80]] (Gallocatechin-4-epigallocatechin35) α (35-8-) Aerial parts of Myrica gale L. [80] epigallocatechin (35) Aerial parts of Myrica gale L. [80] epigallocatechin (35)

Methanol extract of Morella adenophora (Hance) J. Adenodimerin B (36) Methanol extract of Morella adenophora (Hance) J. Adenodimerin B (36) MethanolMethanol extractHerb. extract of Morella roots of Morella adenophora[19] (Hance) J. Adenodimerin B (36) Methanol extractHerb. of Morella roots adenophora [19] (Hance) J. AdenodimerinAdenodimerin B (36) B (36) Methanoladenophora extractHerb. of(Hance) Morella roots J.adenophora [19] Herb. (Hance) J. Adenodimerin B (36) Herb. roots [19] rootsHerb. [ 19roots] [19]

Methanol extract of Morella adenophora (Hance) J. Adenodimerin C (37) Methanol extract of Morella adenophora (Hance) J. Adenodimerin C (37) Methanol extractHerb. of Morella roots adenophora[19] (Hance) J. Adenodimerin C (37) MethanolMethanol extractHerb. extractof Morella roots of adenophora Morella[19] (Hance) J. Adenodimerin C (37) Methanol extractHerb. of Morella roots adenophora [19] (Hance) J. AdenodimerinAdenodimerin C (37) C (37) adenophoraHerb.(Hance) roots J.[19] Herb. Herb. roots [19] roots [19]

Molecules 2020, 25, 6052 22 of 33

Table 3. Cont. Molecules 2020, 25, x FOR PEER REVIEW 22 of 33 Molecules 2020, 25, x FOR PEER REVIEW 22 of 33 MoleculesName 2020, 25, x FOR PEER REVIEW Structure Extract, Species, and Part of Plant 22 of 33 Molecules 2020, 25, x FOR PEER REVIEW 22 of 33 Molecules 2020, 25, x FOR PEER REVIEW 22 of 33 Molecules 2020, 25, x FOR PEER REVIEW 22 of 33 Molecules 2020, 25, x FOR PEER REVIEW 22 of 33

Gallocatechin-(4-α-8)- Gallocatechin-(4-Gallocatechin-(4-α-8)-gallocatechinα-8)- gallocatechin-(4-Gallocatechin-(4-αα-8)--8)- AerialAerial parts parts of Myrica of Myrica gale galeL. L. [80 [80]] -(4-α-8)-gallocatechinGallocatechin-(4-gallocatechin-(4- (38) α-8)--8)- Aerial parts of Myrica gale L. [80] Gallocatechin-(4-gallocatechin-(4-gallocatechin (38α-8)-)-8)- Aerial parts of Myrica gale L. [80] Gallocatechin-(4-gallocatechin-(4-gallocatechin (38α-8)--8)-) Aerial parts of Myrica gale L. [80] Gallocatechin-(4-gallocatechin-(4-gallocatechin (38αα-8)--8)-) Aerial parts of Myrica gale L. [80] gallocatechin-(4-gallocatechin (38α-8)-) Aerial parts of Myrica gale L. [80] gallocatechin-(4-gallocatechin (38α-8)-) Aerial parts of Myrica gale L. [80] gallocatechin (38) gallocatechin (38)

Ethanol 80% extracts of Morella nana (A. Chev.) J. Myricananin B (39) EthanolEthanol 80%80% extracts extracts of Morella of Morella nana (A. Chev.) J. MyricananinMyricananin B (39) B (39) Ethanol 80% extractsHerb. of roots Morella [28] nana (A. Chev.) J. Myricananin B (39) Ethanolnana 80% extractsHerb. of roots Morella [28] nana (A. Chev.) J. Myricananin B (39) Ethanol(A. 80% Chev.) extractsHerb. J. of Herb. roots Morella [28] roots nana [28 (A.] Chev.) J. Myricananin B (39) Ethanol 80% extractsHerb. of roots Morella [28] nana (A. Chev.) J. Myricananin B (39) Ethanol 80% extractsHerb. of roots Morella [28] nana (A. Chev.) J. Myricananin B (39) Herb. roots [28] Herb. roots [28]

Ethanol 80% extracts of Morella nana (A. Chev.) J. Myricananin E (40) Ethanol 80% extracts of Morella nana (A. Chev.) J. Myricananin E (40) EthanolEthanol 80%80% extractsHerb. extracts of roots Morella of [28]Morella nana (A. Chev.) J. Myricananin40 E (40) Ethanol 80% extractsHerb. of roots Morella [28] nana (A. Chev.) J. MyricananinMyricananin E ( ) E (40) Ethanol 80% extractsHerb. of roots Morella [28] nana (A. Chev.) J. Myricananin E (40) Ethanolnana (A. 80% Chev.) extractsHerb. J. Herb.of roots Morella [28] roots nana [28 (A.] Chev.) J. Myricananin E (40) Ethanol 80% extractsHerb. of roots Morella [28] nana (A. Chev.) J. Myricananin E (40) Herb. roots [28] Herb. roots [28]

80% ethanol extracts of Morella nana (A. Chev.) J. Myricananin F (41) * 80% ethanol extracts of Morella nana (A. Chev.) J. Myricananin F (41) * 80% ethanol extractsHerb. of roots Morella [81] nana (A. Chev.) J. Myricananin F (41) * 80%80% ethanol ethanol extractsHerb. extracts of roots Morella of [81]Morella nana (A. Chev.) J. Myricananin F (41) * 80% ethanol extractsHerb. of roots Morella [81] nana (A. Chev.) J. MyricananinMyricananin F (41)* F (41) * 80% ethanol extractsHerb. of roots Morella [81] nana (A. Chev.) J. Myricananin F (41) * 80%nana ethanol(A. Chev.) extractsHerb. J. Herb.of roots Morella [81] roots nana [81 (A.] Chev.) J. Myricananin F (41) * Herb. roots [81] Herb. roots [81]

80% ethanol extracts of the of Morella nana (A. Myricananin G (42) 80% ethanol extracts of the of Morella nana (A. Myricananin G (42) 80% ethanolChev.) extracts J. Herb. of the roots of Morella [81] nana (A. Myricananin G (42) 80%80% ethanol ethanolChev.) extracts extracts J. Herb. of the roots of of the Morella [81] of nana (A. Myricananin G (42) 80% ethanolChev.) extracts J. Herb. of the roots of Morella [81] nana (A. MyricananinMyricananin G (42) G (42) 80%Morella ethanol nanaChev.) extracts(A. J. Herb. Chev.) of the roots of J. Morella Herb. [81] nana (A. Myricananin G (42) 80% ethanolChev.) extracts J. Herb. of the roots of Morella [81] nana (A. Myricananin G (42) Chev.) J. Herb. roots [81] Chev.)roots J. [Herb.81] roots [81]

80% ethanol extracts of Morella nana (A. Chev.) J. Myricananin H (43) 80% ethanol extracts of Morella nana (A. Chev.) J. Myricananin H (43) 80% ethanol extractsHerb. of roots Morella [81] nana (A. Chev.) J. Myricananin H (43) 80% ethanol extractsHerb. of roots Morella [81] nana (A. Chev.) J. Myricananin H (43) 80% ethanol extractsHerb. of roots Morella [81] nana (A. Chev.) J. Myricananin H (43) 80%80% ethanol ethanol extractsHerb. extracts of roots Morella of [81]Morella nana (A. Chev.) J. Myricananin43 H (43) 80% ethanol extractsHerb. of roots Morella [81] nana (A. Chev.) J. MyricananinMyricananin H ( ) H (43) Herb. roots [81] nana (A. Chev.)Herb. J. Herb. roots roots[81] [81]

Ethanol 80% extracts of Morella nana (A. Chev.) J. Myricatomentogenin (44) Ethanol 80% extracts of Morella nana (A. Chev.) J. Myricatomentogenin (44) Ethanol 80% extractsHerb. of roots Morella [81] nana (A. Chev.) J. Myricatomentogenin (44) Ethanol 80% extractsHerb. of roots Morella [81] nana (A. Chev.) J. Myricatomentogenin (44) Ethanol 80% extractsHerb. of roots Morella [81] nana (A. Chev.) J. Myricatomentogenin (44) Ethanol 80% extractsHerb. of roots Morella [81] nana (A. Chev.) J. Myricatomentogenin (44) Ethanol 80% extractsHerb. of roots Morella [81]Morella nana (A. Chev.) J. Myricatomentogenin (44) Ethanol 80% extracts of Myricatomentogenin (44) Herb. roots [81] nana (A. Chev.)Herb. J. Herb. roots roots[81] [81]

Molecules 2020, 25, 6052 23 of 33

Table 3. Cont. Molecules 2020, 25, x FOR PEER REVIEW 23 of 33 Molecules 2020, 25, x FOR PEER REVIEW 23 of 33 MoleculesName 2020, 25, x FOR PEER REVIEW Structure Extract, Species, and Part of Plant 23 of 33 Molecules 2020, 25, x FOR PEER REVIEW 23 of 33 MoleculesMolecules 2020 2020, ,25 25, ,x x FOR FOR PEER PEER REVIEW REVIEW 2323 of of 33 33 Molecules 2020, 25, x FOR PEER REVIEW 23 of 33

Methanol extract of Morella Methanol extract of Morella adenophora (Hance) J. Methanoladenophora extract (Hance)of Morella J. adenophora Herb. (Hance) J. βMyricanone 5-O-β-D- Methanol extractHerb. of Morella roots adenophora[19] (Hance) J. Myricanone 5-O- Myricanone-D-glucopyranoside 5-O-β-D- Methanol extractHerb. of Morella roots adenophora [19] (Hance) J. Myricanoneglucopyranoside 5-O- β(45-D-) MethanolMethanol80% ethanol extract extract extractroots Herb.of of Morella Morellaof [19 rootsMorella] adenophora adenophora[19] nana (A. (Hance) (Hance) Chev.) J. J. (Myricanoneglucopyranoside45) 5-O-β (-D-45) Methanol80% ethanol extract extractHerb. of Morella of roots Morella adenophora [19] nana (A. (Hance) Chev.) J.J. MyricanoneMyricanoneglucopyranoside 5- 5-OO--β β(-D-45-D-) 80%80% ethanol ethanol extract extractHerb.Herb. of roots roots ofMorellaMorella [19][81][19] nana nana (A. Chev.) J. Myricanoneglucopyranoside 5-O-β (-D-45) 80% ethanol extractHerb. of rootsMorella [19][81] nana (A. Chev.) J. glucopyranosideglucopyranoside ( (4545)) 80%80%(A. ethanol ethanol Chev.) extract extract J.Herb. Herb. of of Morella rootsMorella roots [81] nana nana [ 81 ](A. (A. Chev.) Chev.) J. J. glucopyranoside (45) 80% ethanol extractHerb. of rootsMorella [81] nana (A. Chev.) J. Herb.Herb. roots roots [81] [81] Herb. roots [81]

Acerogenin 2-methyl ether 80% ethanol extract of Morella nana A. Chev.) J. Acerogenin 2-methyl ether 80% ethanol ethanol extract extract of ofMorellaMorella nana nana A. Chev.) J. Acerogenin( 462-methyl) ether 80% ethanol extractHerb. of roots Morella [81] nana A. Chev.) J. AcerogeninAcerogenin 2-methyl ether(2-methyl46) (46 )ether 80% ethanol extractHerb. of roots Morella [81] nana A. Chev.) J. AcerogeninAcerogenin (2-methyl 2-methyl46) ether ether 80%80% A.ethanol ethanol Chev.) extract extract J.Herb. Herb. of of rootsMorella Morella roots [81] nana nana [ 81] A. A. Chev.) Chev.) J. J. Acerogenin( 2-methyl46) ether 80% ethanol extractHerb. of roots Morella [81] nana A. Chev.) J. ((4646)) Herb.Herb. roots roots [81] [81] (46) Herb. roots [81]

95% EtOH extract of Morella nana A. Chev.) J. Myricananone (47) 95% EtOH extract of Morella nana A. Chev.) J. Myricananone (47) 95%95% EtOH EtOH extract extractHerb. of ofrootsMorellaMorella [21] nana nana A. Chev.) J. Myricananone (47) 95% EtOH extractHerb. of Morellaroots [21] nana A. Chev.) J. MyricananoneMyricananone (47) (47) 95%95% EtOH EtOH extract extractHerb. of of Morella Morellaroots [21] nana nana A. A. Chev.) Chev.) J. J. MyricananoneMyricananone ( (4747)) 95%A. EtOH Chev.) extract J.Herb. Herb. of Morellaroots roots [21] nana [ 21] A. Chev.) J. Myricananone (47) Herb.Herb. roots roots [21] [21] Herb. roots [21]

95% EtOH extract of Morella nana A. Chev.) J. Myricananadiol (48) 95% EtOH extract of Morella nana A. Chev.) J. Myricananadiol (48) 95% EtOH extractHerb. of rootsMorella [21] nana A. Chev.) J. Myricananadiol (48) 95%95% EtOH EtOH extract extractHerb. of ofMorellarootsMorella [21] nana nana A. Chev.) J. Myricananadiol48 (48) 95%95% EtOH EtOH extract extractHerb. of of Morella Morellaroots [21] nana nana A. A. Chev.) Chev.) J. J. MyricananadiolMyricananadiolMyricananadiol ( ) ( (4848)) 95% EtOH extractHerb. of Morellaroots [21] nana A. Chev.) J. Myricananadiol (48) A. Chev.) J.Herb.Herb. Herb. roots roots roots [21] [21] [21 ] Herb. roots [21]

Methanol extract of Morella adenophora (Hance) J. Methanol extract of Morella adenophora (Hance) J. Myricanol 11-O-β-D- MethanolHerb.Methanol roots extract [19] extract of Dichloromethane: Morella of Morellaadenophora methanol (Hance) J. Myricanol 11-O-β-D- MethanolHerb. roots extract [19] of Dichloromethane: Morella adenophora methanol (Hance) J. Myricanolxylopyranosyl 11-O -(β49-D-) MethanolMethanol(1:1)adenophoraHerb. extract roots extract extract in (Hance)[19] of of ofMorella Dichloromethane: Morella Morella J. arborea Herb. adenophora adenophora (Hutch.) roots methanol (Hance) (Hance) Cheek J. J. Myricanolxylopyranosyl 11-O- (β49-D-) Methanol(1:1)Herb. extract roots extract in [19] of of MorellaDichloromethane: Morella arborea adenophora (Hutch.) methanol (Hance) Cheek J. Myricanol 11-O-β-MyricanolMyricanolDxylopyranosyl-xylopyranosyl 11- 11-OO- -β(β49-D--D-) ( 49) (1:1)Herb.[Herb.19 ]extract Dichloromethane: roots roots in [19] [19] barkof Dichloromethane:Morella Dichloromethane: and stem arborea methanol [29 ](Hutch.) methanol methanol Cheek Myricanolxylopyranosyl 11-O -(β49-D-) (1:1)Herb. extract roots in [19] barkof MorellaDichloromethane: and stem arborea [29 (Hutch.)] methanol Cheek xylopyranosylxylopyranosyl ( (4949)) (1:1)(1:1)(1:1) extract extract extract in in of barkof in Morella Morella of andMorella stemarborea arborea [29 arborea (Hutch.) ](Hutch.) Cheek Cheek xylopyranosyl (49) (1:1) extract in barkof Morella and stem arborea [29 (Hutch.)] Cheek barkbark and and stem stem [29 [29]] (Hutch.) Cheekbark bark and andstem stem[29] [29]

Methanol extract of Myrica gale L. (Myrica gale Myricatomentoside I (50) Methanol extract of Myrica gale L. (Myrica gale Myricatomentoside I (50) Methanolvar extract tormentosa extract of ofMyrica L.)Myrica branches galegale L. ([35]MyricaL. gale Myricatomentoside I (50) Methanolvar extract tormentosa of Myrica L.) branches gale L. ( Myrica[35] gale MyricatomentosideMyricatomentoside I (50) I (50) MethanolMethanol(Myricavar extract extract galetormentosavar of of Myrica Myricatormentosa L.) branches gale gale L. L.L.) ( (Myrica[35]Myrica gale gale MyricatomentosideMyricatomentoside I I ( (5050)) Methanolvar extract tormentosa of Myrica L.) branches gale L. ( [35]Myrica gale Myricatomentoside I (50) varvar tormentosa branchestormentosa L.) [L.)35 branches branches] [35] [35] var tormentosa L.) branches [35]

Methanol extract of Myrica gale L. (Myrica gale Myricatomentoside II (51) Methanol extract of Myrica gale L. (Myrica gale Myricatomentoside II (51) Methanolvar extract tormentosa of Myrica L.) branches gale L. ([35]Myrica gale Myricatomentoside II (51) Methanolvar extract tormentosa extract of ofMyrica L.)Myrica branches galegale L. ( Myrica[35]L. gale Myricatomentoside II (51) MethanolMethanolvar extract extract tormentosa of of Myrica Myrica L.) branches gale gale L. L. ( (Myrica[35]Myrica gale gale MyricatomentosideMyricatomentosideMyricatomentoside II (51) II II ( (5151)) Methanol(Myricavar extract tormentosa gale var of Myricatormentosa L.) branches gale L.L.) ( [35]Myrica gale Myricatomentoside II (51) varvar tormentosa tormentosa L.) L.) branches branches [35] [35] var tormentosabranches L.) [35 branches] [35]

Methanol extract of Myrica gale L. (Myrica gale 12-Dehydroporson (52) Methanol extract of Myrica gale L. (Myrica gale 12-Dehydroporson (52) Methanolvar extract tormentosa of Myrica L.) branches gale L. ([24]Myrica gale 12-Dehydroporson (52) Methanolvar extract tormentosa of Myrica L.) branches gale L. ( Myrica[24] gale 12-Dehydroporson (52) MethanolMethanolvar extract extract tormentosa extract of of Myrica ofMyrica L.)Myrica branches gale gale galeL. L. ( (Myrica[24]MyricaL. gale gale 12-Dehydroporson12-Dehydroporson ( (5252)) Methanolvar extract tormentosa of Myrica L.) branches gale L. ( [24]Myrica gale 12-Dehydroporson (52) Myricavarvar tormentosa galetormentosatormentosa L.) L.) branches branches [24] [24] 12-Dehydroporson (52) ( var tormentosavar L.) branchesL.) [24] branches [24]

Molecules 2020, 25, 6052 24 of 33

Table 3. Cont. Molecules 2020, 25, x FOR PEER REVIEW 24 of 33 MoleculesName 2020, 25, x FOR PEER REVIEW Structure Extract, Species, and Part of Plant 24 of 33 MoleculesMolecules 2020 2020, ,25 25, ,x x FOR FOR PEER PEER REVIEW REVIEW 2424 of of 33 33

Dichloromethane:Dichloromethane: methanol methanol (1:1) (1:1) extract of Molecules 2020, 25, x FOR PEER REVIEW Dichloromethane: methanol (1:1) extract24 of of 33 MyricarborinMyricarborin (53) (53) extractMorella arborea of Morella (Hutch.) arborea Cheek(Hutch.) bark and stem Myricarborin (53) MorellaDichloromethane:Dichloromethane: arborea (Hutch.) methanol methanol Cheek (1:1) (1:1)bark extract extractand stem of of [29] MyricarborinMyricarborin ( (5353)) MorellaMorellaCheek arborea arborea bark (Hutch.) (Hutch.) and[29] stem Cheek Cheek [29 bark bark] and and stem stem Molecules 2020, 25, x FOR PEER REVIEW [29][29] 24 of 33 Molecules 2020, 25, x FOR PEER REVIEW 24 of 33 Dichloromethane: methanol (1:1) extract of Myricarborin (53) Morella arborea (Hutch.) Cheek bark and stem [29] Myricanene A 5-O-α-L- Dichloromethane: methanol (1:1) extract of MyricaneneMyricanene A A 5-O→-α-L- MethanolMethanol extract extract of Morella of Morellaadenophora (Hance) J. arabinofuranosylMyricaneneMyricarborin A 5- (1 (O53-)α6)- -L-β- MethanolDichloromethane: extract of Morella methanol adenophora (1:1) extract (Hance) of J. 5-O-α-L-arabinofuranosylarabinofuranosylMyricanene A 5- (1O→-α6)--L-β- MethanolMorellaadenophora arborea extract Herb.(Hutch.)(Hance) of Morella roots Cheek J. [19]adenophora Herb. bark and (Hance) stem J. D-glucopyranosideMyricarborin (53→ )( 54) MethanolMorella arborea extract (Hutch.)Herb. of Morella roots Cheek adenophora[19] bark and (Hance) stem J. β arabinofuranosylarabinofuranosylD-glucopyranoside (1 (1→ (6)-546)-)β β-- [29] (1 6)- -D-glucopyranoside (54) rootsHerb.Herb. [[29]19 roots roots] [19] [19] → D-glucopyranosideD-glucopyranoside ( (5454)) Myricanene A 5-O-α-L- Methanol extract of Morella adenophora (Hance) J. arabinofuranosyl (1→6)-β- Herb. roots [19] D-glucopyranoside (54) Myricanene A 5-O-α-L- Methanol extract of Myrica esculenta Buch.-Ham. MyricaneneMyresculoside A 5-O (-55α-L-) MethanolMethanol extract extract of MorellaMyrica of esculentaMyricaadenophora Buch.-Ham. (Hance) J. arabinofuranosylMyresculoside (1 (→556)-) β- MethanolMethanol extract extractex D.of of DonMorella Myrica leaves adenophora esculenta [14] Buch.-Ham. (Hance) J. MyresculosidearabinofuranosylMyresculoside (55) (1 →(556)-) β- Methanolesculenta extractBuch.-Ham.ex D.Herb. of Don Myrica roots leaves exesculenta [19] D. [14] Don Buch.-Ham. D-glucopyranosideMyresculoside (55 (54) ) exHerb. D. Don roots leaves [19] [14] D-glucopyranoside (54) exleaves D. Don [14 leaves] [14]

Methanol extract of Myrica esculenta Buch.-Ham. Myresculoside (55) ex D. Don leaves [14] (1S,2S,4R)-2-Hydroxy-1,8- (1S,2S,4R)-2-Hydroxy-1,8- Methanol extract of Myrica esculenta Buch.-Ham. cineole(1S,2S β,4-D-glucopyranosideR)-2-Hydroxy-1,8- Methanol extract of Myrica esculenta Buch.-Ham. cineole(1S,2MyresculosideS β,4-D-glucopyranosideR)-2-Hydroxy-1,8- (55) MethanolMethanolMethanol extract extractex D. extractof of DonMyrica Myrica leaves of esculenta Myricaesculenta [14] Buch.-Ham. Buch.-Ham. (1S,2S,4R)-2-Hydroxy-1,8-cineoleMyresculoside(56) (55) Methanol extractex D. of Don Myrica leaves esculenta [14] Buch.-Ham. cineolecineole β β-D-glucopyranoside-D-glucopyranoside(56) esculenta Buch.-Ham.ex D. Don leaves ex D.[14] Don β-D-glucopyranoside (56) exex D. D. Don Don leaves leaves [14] [14] ((5656)) leaves [14] (1S,2S,4R)-2-Hydroxy-1,8- Methanol extract of Myrica esculenta Buch.-Ham. cineole β-D-glucopyranoside Methanol extract of Morella adenophora (Hance) J. Methanol extractex D. of DonMorella leaves adenophora [14] (Hance) J. (56) Herb. roots [19] MethanolMethanol extract extractHerb. of of Morella Morella roots adenophora[19]adenophora (Hance) (Hance) J. J. ChloroformMethanol and extract methanol of Morella extract of Morella (1S,2S,4R)-2-Hydroxy-1,8- Chloroform andHerb.Herb. methanol roots roots [19] [19]extract of Morella (1S,2S,4R)-2-Hydroxy-1,8- Methanoladenophoraarborea extract (Hutch.) (Hance)of Myrica Cheek J.esculenta Herb. twigs Buch.-Ham. [20] cineole β-D-glucopyranoside MethanolChloroformChloroformarborea extract and (Hutch.)and of methanolMyricamethanol Cheek esculenta extract extract twigs Buch.-Ham. of[20]of Morella Morella cineole β-D-glucopyranoside Hexane extractex rootsof D. Morella Don [19 leaves] cerifera [14] (L.) Small twigs (56) HexaneMethanol arboreaextractarborea extractex (Hutch.) of (Hutch.)D. ofMorella Don Morella leavesCheek Cheek cerifera adenophora [14]twigs twigs (L.) Small[20] [20] (Hance) twigs J. (56) HexaneChloroform extractand of Morella methanol[23] cerifera extract (L.) Small twigs Taraxerol (57) Hexane extract ofHerb. Morella [23]roots cerifera [19] (L.) Small twigs Taraxerol (57) Benzeneof Morella extract arborea of Myrica(Hutch.)[23] gale L. Cheek (Myrica gale var Taraxerol (57) BenzeneChloroform extract and of Myricamethanol[23] gale extract L. (Myrica of Morella gale var Taraxerol (57) Benzene extracttormentosatwigs of Myrica [20 L.)] stems gale L. [82] (Myrica gale var MethanolBenzenearborea extract extracttormentosa (Hutch.) of of Myrica Morella L.) Cheek stemsgale adenophora L.twigs [82] (Myrica [20] (Hance) gale var J. HexaneBenzene extractextracttormentosa of of MorellaMorella L.) stems cerifera cerifera [82] (L.) Small MethanolHexaneBenzene extract extract extracttormentosa ofHerb. of Morella of Morella Morella rootsL.) cerifera stems adenophora [19] cerifera [82](L.) (L.) Small (Hance) Small twigs J. Benzene(L.)(Myrica extract Small cerifera of twigs Morella) root [23 ceriferabark] [42] (L.) Small ChloroformBenzene(Myrica extract andHerb. cerifera ofmethanol Morella roots[23]) root [19] extractcerifera bark [42] (L.)of Morella Small TaraxerolTaraxerol (57) (57) ExtractBenzene of(Myrica extractthe bark cerifera ofof Myrica) root barkesculenta gale [42]L. Buch.- BenzeneChloroformExtractarborea extract (ofMyrica the and (Hutch.) barkof cerifera methanolMyrica of MyricaCheek) root gale extract bark L.esculentatwigs (Myrica [42] of [20] Morella Buch.- gale var Extract(Myrica of galetheHam. barkvar ex tormentosaof D. Myrica Don [83] esculentaL.) Buch.- HexaneExtractarborea extract of tormentosatheHam. (Hutch.) of bark Morella ex of D.L.) CheekMyrica cerifera Donstems twigs[83]esculenta [82](L.) [20]Small Buch.- twigs stemsHam. ex [82 D.] Don [83] HexaneBenzene extract extractHam. of Morella of ex Morella[23] D. cerifera Don cerifera [83] (L.) (L.)Small Small twigs Taraxerol (57) Benzene(Myrica extract cerifera of[23]Morella) root bark cerifera [42] Taraxerol (57) Benzene extract of Myrica gale L. (Myrica gale var Benzene(L.) Small extract ( Myricaof Myrica cerifera gale L.) ( rootMyrica gale var ExtractChloroform of tormentosathe and bark methanol of L.) Myrica stems extract esculenta [82] of Morella Buch.- Chloroformtormentosa andbark methanol [42 L.)] stems extract [82] of Morella Benzenearborea extractHam. (Hutch.) of ex Morella D. Cheek Don cerifera [83]twigs (L.) [20] Small ChloroformChloroformExtractarborea of and (Hutch.)and the methanol methanol bark Cheek of Myrica extract extract twigs of[20]of Morella Morella Taraxerone (58) Benzene(Myrica extract cerifera of Morella) root cerifera bark [42] (L.) Small Taraxerone (58) Benzenearborea extract (Hutch.) of Morella Cheek cerifera twigs (L.) [20] Small Taraxerone (58) Benzeneesculentaarborea(Myrica extract (Hutch.)Buch.-Ham. cerifera of Morella )Cheek root cerifera bark ex twigs D. [42] (L.) [20] Small Taraxerone (58) Extract (ofMyrica the bark cerifera of Myrica) root bark esculenta [42] Buch.- BenzeneBenzene(Myrica extract extractDon cerifera of of [Morella 83Morella)] root cerifera ceriferabark [42] (L.) (L.) Small Small Extract of theHam. bark exof D.Myrica Don esculenta[83] Buch.- Chloroform((MyricaMyricaHam. and cerifera cerifera methanol ex D.)) Donroot root extract bark[83] bark [42] [42]of Morella arborea (Hutch.) Cheek twigs [20] Taraxerone (58) ChloroformBenzene extract and of methanol Morella cerifera extract (L.) Small

ofChloroformMorella(Myrica arborea and cerifera methanol(Hutch.)) root extract bark Cheek [42] of Morella ChloroformChloroform andand methanolmethanol extractextract ofof MorellaMorella Chloroformarborea twigs (Hutch.)and methanol [20 Cheek] extract twigs [20]of Morella TaraxeroneTaraxerone (58) (58) Chloroformarboreaarborea (Hutch.)and(Hutch.) methanol CheekCheek extract twigstwigs [20]of[20] Morella Taraxerone (58) BenzeneBenzeneBenzenearborea extract extract (Hutch.) of ofMyrica of MorellaMorella Cheek gale cerifera L. ceriferatwigs (Myrica (L.) [20] Small gale var Myricadiol (59) BenzeneBenzenearborea extract extract (Hutch.) of ofMyrica Morella Cheek gale cerifera L. twigs (Myrica (L.) [20] Small gale var Myricadiol (59) Benzene(L.) Small (extractMyricatormentosa (Myrica ofcerifera Myrica L.) cerifera) root stems gale bark L.) [82] root (Myrica [42] gale var Myricadiol (59) Benzene (extractMyricatormentosa of cerifera Myrica L.)) root stemsgale bark L. [82] (Myrica [42] gale var Myricadiol (59) Hexane extract barkof Morella [42] cerifera (L.) Small twigs HexaneChloroform extracttormentosatormentosa and of Morella methanol L.) L.) cerifera stems stems extract [82] (L.)[82] ofSmall Morella twigs [23] HexaneHexane arboreaextract extract (Hutch.)of of Morella Morella[23] Cheek cerifera cerifera twigs (L.) (L.) [20]Small Small twigs twigs [23] Benzene extract of Myrica[23] gale L. (Myrica gale var Myricadiol (59) ChloroformChloroformtormentosa and and methanol methanol L.) stems extract extract [82] of Morella HexaneofChloroformMorella arboreaextract arborea and (Hutch.)of Morella methanol(Hutch.) Cheek cerifera extract twigs Cheek (L.) of [20]Small Morella twigs Benzenearborea extract (Hutch.)twigs of Myrica [20[23] Cheek] gale L.twigs (Myrica [20] gale var Myricadiol (59) BenzeneBenzene extract extract of Myrica of Myrica gale L.gale (MyricaL. gale var MyricadiolMyricadiol (59) (59) tormentosa L.) stems [82] Hexane(Myrica extracttormentosa gale of varMorellatormentosa L.) ceriferastems [82] (L.)L.) Small twigs Hexane extract stemsof Morella [[23]82 ]cerifera (L.) Small twigs [23] Hexane extract of Morella cerifera (L.) Small twigs [23]

Molecules 2020, 25, 6052 25 of 33

Table 3. Cont. MoleculesMolecules 20202020,, 2525,, xx FORFOR PEERPEER REVIEWREVIEW 2525 ofof 3333 MoleculesMoleculesMoleculesName 2020 20202020,, , 25 2525,, , x xx FOR FORFOR PEER PEERPEER REVIEW REVIEWREVIEW Structure Extract, Species, and Part of Plant 252525 of ofof 33 3333 Molecules 2020, 25, x FOR PEER REVIEW 25 of 33

Chloroform and methanol extract ChloroformChloroform andand methanolmethanol extractextract ofof MorellaMorella AlphitolicAlphitolicAlphitolic acid (60 acidacid) ((6060)) ChloroformofChloroformChloroformMorella arborea and andand methanol methanolmethanol(Hutch.) extract extractextract Cheek of ofof Morella MorellaMorella AlphitolicAlphitolicAlphitolic acid acidacid ( (60(6060)) ) Chloroformarboreaarborea (Hutch.)(Hutch.)and methanol CheekCheek extract twigstwigs [20]of[20] Morella Alphitolic acid (60) arboreaarboreaarborea (Hutch.) twigs(Hutch.)(Hutch.) [20 Cheek CheekCheek] twigs twigstwigs [20] [20][20] arborea (Hutch.) Cheek twigs [20]

ChloroformChloroform andand and methanolmethanol methanol extractextract extract ofof MorellaMorella MaslinicMaslinic acidacid ((6161)) ChloroformChloroformChloroform and andand methanol methanolmethanol extract extractextract of ofof Morella MorellaMorella MaslinicMaslinicMaslinicMaslinic acid (61 acid acid)acid ( (61(6161)) ) ofChloroformMorellaarboreaarborea arborea (Hutch.)(Hutch.)and methanol(Hutch.) CheekCheek extract twigstwigs Cheek [20]of[20] Morella Maslinic acid (61) arboreaarboreaarborea (Hutch.) (Hutch.)(Hutch.) Cheek CheekCheek twigs twigstwigs [20] [20][20] arborea twigs(Hutch.) [20 Cheek] twigs [20]

MethanolMethanol extractextract extract ofofof MorellaMorellaMorella ceriferacerifera cerifera (L.)(L.) SmallSmall MyricericMyriceric acidacid CC ((6262)) MethanolMethanolMethanol extract extractextract of ofof Morella MorellaMorella cerifera ceriferacerifera (L.) (L.)(L.) Small SmallSmall MyricericMyricericMyricericMyriceric acid C ( acid acid62acid) C CC ( (62(6262)) ) Methanol(L.) Small((Myrica Myricaextract ( Myrica cerifera ceriferaof Morella)) cerifera twigstwigs cerifera [60][60]) (L.) Small Myriceric acid C (62) ((Myrica(MyricaMyrica cerifera ceriferacerifera)) ) twigs twigstwigs [60] [60][60] (Myricatwigs cerifera [60] ) twigs [60]

MethanolMethanol extractextract extract ofofof MorellaMorellaMorella ceriferacerifera cerifera (L.)(L.) SmallSmall MyricericMyriceric acidacid BB ((6363)) MethanolMethanolMethanol extract extractextract of ofof Morella MorellaMorella cerifera ceriferacerifera (L.) (L.)(L.) Small SmallSmall MyricericMyricericMyricericMyriceric acid B ( acid 63acidacid) B BB ( (63(6363)) ) Methanol(L.) Small((Myrica Myricaextract ( Myrica cerifera ceriferaof Morella)) cerifera twigstwigs cerifera [60][60]) (L.) Small Myriceric acid B (63) ((Myrica(MyricaMyrica cerifera ceriferacerifera)) ) twigs twigstwigs [60] [60][60] (Myricatwigs cerifera [60] ) twigs [60]

Methanol extract of Morella cerifera MethanolMethanol extractextract ofof MorellaMorella ceriferacerifera (L.)(L.) SmallSmall MyricericMyricericMyriceric acid D (acidacid64) DD ((6464)) MethanolMethanolMethanol(L.) Small extract extractextract ( Myrica of ofof Morella MorellaMorella cerifera cerifera ceriferacerifera) (L.) (L.)(L.) Small SmallSmall MyricericMyricericMyriceric acid acidacid D DD ( (64(6464)) ) Methanol((Myrica Myricaextract cerifera ceriferaof Morella)) twigstwigs cerifera [60][60] (L.) Small Myriceric acid D (64) ((Myrica(MyricaMyricatwigs cerifera ceriferacerifera [60])) ) twigs twigstwigs [60] [60][60] (Myrica cerifera) twigs [60]

Myrica gale BenzeneBenzeneBenzene extractextract extract ofof MyricaMyrica of galegale L.L. ((MyricaMyricaL. galegale varvar SerratenedioneSerratenedioneSerratenedione (65) ((6565)) BenzeneBenzeneBenzene(Myrica extract extractextract gale of ofofvar Myrica MyricaMyricatormentosa gale galegale L. L.L. ( (Myrica(MyricaMyricaL.) gale galegale var varvar SerratenedioneSerratenedioneSerratenedione ( (65(6565)) ) Benzene extracttormentosatormentosa of Myrica L.)L.) stems stemsgale L. [82][82] (Myrica gale var Serratenedione (65) tormentosatormentosatormentosastems [ L.) 82L.)L.) ] stems stemsstems [82] [82][82] tormentosa L.) stems [82]

BenzeneBenzeneBenzene extractextract extract ofof MyricaMyrica of Myrica galegale L.L. gale ((MyricaMyricaL. galegale varvar SerratenediolSerratenediol ((6666)) BenzeneBenzeneBenzene extract extractextract of ofof Myrica MyricaMyrica gale galegale L. L.L. ( (Myrica(MyricaMyrica gale galegale var varvar SerratenediolSerratenediolSerratenediolSerratenediol (66) ( (66(6666)) ) Benzene(Myrica extracttormentosatormentosa gale ofvar Myrica tormentosa L.)L.) stems stemsgale L. [82][82] (MyricaL.) gale var Serratenediol (66) tormentosatormentosatormentosa L.) L.)L.) stems stemsstems [82] [82][82] tormentosastems [ 82L.)] stems [82]

Molecules 2020, 25, 6052 26 of 33

Table 3. Cont. Molecules 2020, 25, x FOR PEER REVIEW 26 of 33 MoleculesName 2020, 25, x FOR PEER REVIEW Structure Extract, Species, and Part of Plant 26 of 33 Molecules 2020, 25, x FOR PEER REVIEW 26 of 33 Molecules 2020, 25, x FOR PEER REVIEW 26 of 33

Benzene extract of Myrica gale L. Benzene extract of Myrica gale L. (Myrica gale var MyricolalMyricolal (67) (67) Benzene(Myrica extract gale ofvar Myricatormentosa gale L. (MyricaL.) gale var Myricolal (67) Benzene extracttormentosa of Myrica L.) galestems L. [82](Myrica gale var Myricolal (67) Benzene extracttormentosastems of Myrica [ 82L.)] stemsgale L. [82] (Myrica gale var Myricolal (67) tormentosa L.) stems [82] tormentosa L.) stems [82]

MethanolMethanol extract extract of Myrica of esculentaMyrica Buch.-Ham. Arjunglucoside (68) Methanol extract of Myrica esculenta Buch.-Ham. ArjunglucosideArjunglucoside (68) (68) Methanolesculenta extractBuch.-Ham.ex D. of Don Myrica leaves exesculenta D. [14] Don Buch.-Ham. Arjunglucoside (68) Methanol extractex D. of Don Myrica leaves esculenta [14] Buch.-Ham. Arjunglucoside (68) exleaves D. Don [14 leaves] [14] ex D. Don leaves [14]

Methanol extract of Myrica esculenta Buch.-Ham. 3-epi-Ursolic acid (69) ** MethanolMethanol extract extractof Myrica of esculentaMyrica Buch.-Ham. 3-epi-Ursolic acid (69) ** Methanol extractex D. of Don Myrica leaves esculenta [14] Buch.-Ham. 3-epi-Ursolic3-epi acid-Ursolic (69 acid) ** (69) ** Methanolesculenta extractBuch.-Ham.ex D. of Don Myrica leaves exesculenta D.[14] Don Buch.-Ham. 3-epi-Ursolic acid (69) ** ex D. Don leaves [14] exleaves D. Don [14 leaves] [14]

3-O-(E)-Caffeoyl-ursolic acid Methanol extract of Myrica esculenta Buch.-Ham. 3-O-(E)-Caffeoyl-ursolic acid Methanol extract of Myrica esculenta Buch.-Ham. 3-O-(E)-Caffeoyl-ursolic(70) ** acid MethanolMethanol extractex extractD. of Don Myrica leaves of esculentaMyrica [14] Buch.-Ham. 3-O-(E)-Caffeoyl-ursolic(70) ** acid Methanol extractex D. of Don Myrica leaves esculenta [14] Buch.-Ham. 3-O-(E)-Caffeoyl-ursolic(70 acid) ** (70) ** esculenta Buch.-Ham.ex D. Don leaves ex D. [14] Don (70) ** ex D. Don leaves [14] leaves [14] * The stereochemistry was defined by Jahanban-Esfahlan et al. [84]; ** The name was corrected based * The stereochemistry was defined by Jahanban-Esfahlan et al. [84]; ** The name was corrected based *in The the stereochemistrystructure presented was indefined the original by Jahanban-Esfah paper since ursoniclan et al. acid [84]; has ** aThe ketone name group was corrected at C-3; L-Araf based = * The stereochemistryin* The the was stereochemistrystructure defined presented by Jahanban-Esfahlan was in defined the original by etJahanban-Esfah al.paper [84]; since ** The ursoniclan name et al. wasacid [84]; corrected has ** aThe ketone basedname group inwas the correctedat structure C-3; L-Araf based = inL-arabinofuranosyl; the structure presented D-Glcpy in th e= originalD-glucopyranoside; paper since ursonic Xyl acid= D -xylopyranosyl;has a ketone group Galloyl at C-3; =L -Araf3,4,5- = presented in theLin-arabinofuranosyl; original the structure paper presented since D-Glcpy ursonic in th e= acid originalD-glucopyranoside; has apaper ketone since group ursonic Xyl at = C-3;acid D-xylopyranosyl; hasL-Araf a ketone= L-arabinofuranosyl group Galloyl at C-3; = L -Araf;3,4,5- = Ltrihydroxybenzoyl;-arabinofuranosyl; ApiD-Glcpy = −β-D -Apiofuranosyl;= D-glucopyranoside; Caffeoyl Xyl= 3-hydroxycoumaroyl. = D-xylopyranosyl; Galloyl = 3,4,5- D-Glcpy = D-glucopyranosidetrihydroxybenzoyl;L-arabinofuranosyl;; Xyl = D Api -xylopyranosyl;D-Glcpy = −β-D -Apiofuranosyl;= DGalloyl-glucopyranoside;= 3,4,5-trihydroxybenzoyl Caffeoyl =Xyl 3-hydroxycoumaroyl. = D-xylopyranosyl;; Api = β-D-Apiofuranosyl Galloyl = ; 3,4,5- Caffeoyl = 3-hydroxycoumaroyl.trihydroxybenzoyl; Api = −β-D-Apiofuranosyl; Caffeoyl = 3-hydroxycoumaroyl.− trihydroxybenzoyl; Api = −β-D-Apiofuranosyl; Caffeoyl = 3-hydroxycoumaroyl. The pharmacological potential of the compounds presented in Table 3 has not been evaluated The pharmacological potential of the compounds presented in Table 3 has not been evaluated so farThe by pharmacologicalthe researchers who potential have ofstudied the compounds Morella and presented Myrica species. in Table It 3should has not be been noted evaluated that the As an example,so farThe by the pharmacologicalthe only researchers structural who potential dihavefference studiedof the between compounds Morella myricanoland presented Myrica species. (4 in) andTable It myricananin should3 has not be been noted B evaluated ( 39that), the soisolation far by andthe researchersstructural elucidationwho have studiedare the Morellafirst steps and to Myrica describing species. the It metabolomicshould be noted profile that of the a isolationso far by andthe researchersstructural elucidation who have studiedare the Morellafirst steps and to Myrica describing species. the It metabolomic should be noted profile that of the a two compoundsisolationspecies isolated orand fromgenus, structural the helping roots elucidation of toMorella assess are nana thetheir (A.first potential Chev.) steps to J.as Herb.describing a source [21,28 the ],of ismetabolomic thatcommercially the latter profile hasvaluable of a speciesisolation or and genus, structural helping elucidation to assess are theirthe first potential steps toas describing a source the of metabolomiccommercially profile valuable of a an additional OHspeciesphytochemicals, group or atgenus, C-12. adding helping However, value to theassessto biologicalthe their species, potential activities as wellas of a myricanol assource finding of are alternativecommercially widely studied, sources valuable of phytochemicals,species or genus, adding helping value to assessto the theirspecies, potential as wellas aas source finding of alternativecommercially sources valuable of as reviewed inphytochemicals,pharmacologically the present work, adding active whereas metabolites.value the activitiesto the species, of myricananin as well Bas are finding not, which alternative is unfortunate, sources of pharmacologicallyphytochemicals, adding active metabolites.value to the species, as well as finding alternative sources of since such structuralpharmacologicallyThe similarity compounds indicates active listed metabolites. ain good Table pharmacological 3 belong to several potential families, for like myricananin chalcones, B.dihydrochalcones, A possible pharmacologicallyThe compounds active listed metabolites. in Table 3 belong to several families, like chalcones, dihydrochalcones, flavonoids,The compounds diterpenoids, listed triterpenoids, in Table 3 belong and diaryl to severalheptanoids, families, the likelatter chalcones, two being dihydrochalcones, the families with explanation isflavonoids, the factThe compounds that diterpenoids, myricananin listed triterpenoids, in B Table (39) is3 obtainedbelongand diaryl to several inheptanoids, low families, yields. the Inlikelatter fact, chalcones, two starting being dihydrochalcones, the with families 20 kg with flavonoids,the highest numberditerpenoids, of compounds triterpenoids, isolated. and Adiaryl similaheptanoids,r tendency the had latter already two beenbeing observed the families in Table with of dried Morellatheflavonoids, nanahighest(A. numberditerpenoids, Chev.) of J.compounds Herb., triterpenoids, Wang isolated. and et al. Adiaryl simila [28]heptanoids, onlyr tendency obtained the had latter 5already mg two of beenbeing myricananin observed the families in B, Table with the1, where highest it wasnumber observed of compounds that diarylheptanoids isolated. A simila werer tendencythe most representedhad already family,been observed which indicates in Table which according1,the where tohighest the it authors, wasnumber observed of represents compounds that diarylheptanoids a yieldisolated. of A 0.0000025%. simila werer thetendency most With representedhad such already a reduced family,been observed amountwhich indicates in of Table 1,that where Morella it was and observedMyrica genera that diarylheptanoidsare a good source were of this the family most ofrepresented compounds. family, which indicates compound, itthat is1, understandablewhere Morella it wasand observedMyrica that genera myricananinthat diarylheptanoidsare a good B source is so understudied, wereof this the family most of represented but compounds. the similarities family, which with indicates the that MorellaSince many and Myricaof the generaunstudied are acompounds good source compiled of this family in Table of compounds. 3 share many structural features bioactive myricanolthat MorellaSince point many and to a Myricaof high the pharmacological unstudiedgenera are compoundsa good potentialsource compiled of this of compound family in Table of compounds. 339 share, so strategiesmany structural to obtain features with Sincesome many of the of mostthe unstudied active compounds compounds that compiled have already in Table been 3 share assessed many for structural their biological features with Sincesome manyof the of most the unstudied active compounds compounds that compiled have already in Table been 3 share assessed many for structural their biological features higher amountswithactivities, of thissome compound,there of the is plenty most like ofactive totalpotential compounds or semi-synthesis for finding that new have shouldadded already value be employed.been compounds assessed tofor increase their biologicalthe value activities,with some there of theis plenty most ofactive potential compounds for finding that new have added already value been compounds assessed to for increase their biologicalthe value Another exampleactivities,of species is therefrom the group Morellais plenty of/Myrica unstudied of potential genera. pentacyclic for finding terpenesnew added57 –value70. A compounds compound to from increase the same the value ofactivities, species fromthere Morellais plenty/Myrica of potential genera. for finding new added value compounds to increase the value family, ursolic acid,of speciesAs was an from provenexample, Morella by thein/Myrica vivoonly structurandgenera. preclinical al difference studies between to possess myricanol multiple (4) and pharmacological myricananin B (39), of speciesAs an from example, Morella the/Myrica only structur genera. al difference between myricanol (4) and myricananin B (39), activities, liketwo anti-inflammatory, compoundsAs an example, isolated the antitumor, onlyfrom structur the cardioprotective,rootsal ofdifference Morella nanabetween and (A. antidiabetic, Chev.)myricanol J. Herb. (4) among and [21,28], myricananin others is that [the85 B ].latter (39), two compoundsAs an example, isolated the onlyfrom structurthe rootsal ofdifference Morella nanabetween (A. Chev.) myricanol J. Herb. (4) and[21,28], myricananin is that the B latter (39), twohas ancompounds additional isolated OH group from atthe C-12. roots However, of Morella th nanae biological (A. Chev.) activities J. Herb. of [21,28], myricanol is that are the widely latter However, the poorhastwo ancompounds water additional solubility isolated OH andgroup from low at the intestinalC-12. roots However, of absorption Morella th nanae biological of (A. ursolic Chev.) activities acid, J. Herb. which of [21,28], myricanol leads is to that a are rapid the widely latter hasstudied, an additional as reviewed OH in group the present at C-12. work, However, whereas th thee biological activities ofactivities myricananin of myricanol B are not, are which widely is elimination bystudied,has the an gut additional as wall reviewed/liver OH metabolism, in groupthe present at C-12. resulting work, However, whereas in low th bioavailabilitythee biological activities ofactivities [myricananin86,87], of hinder myricanol B are the not, clinical are which widely is studied,unfortunate, as reviewed since such in the structural present work, similarity whereas indicates the activities a good of myricananinpharmacological B are potentialnot, which for is applicability ofunfortunate,studied, ursolic as acid. reviewed since Some such in ofthe structural the present pentacyclic work,similarity whereas terpenes indicates the listed activities a ingoodTable of myricananinpharmacological3, like arjunglucoside B are potentialnot, which for is unfortunate,myricananin B.since A possible such structuralexplanatio nsimilarity is the fact thatindicates myricananin a good B (pharmacological39) is obtained in lowpotential yields. for In (68) and 3-O-(Emyricananinunfortunate,)-caffeoyl-ursolic B.since A possible acidsuch ( 70explanatiostructural), present nsimilarity is structural the fact thatindicates aspects myricananin thata good might B (pharmacological39) overcome is obtained some in lowpotential of yields. the forIn myricananinfact, starting withB. A possible20 kg of driedexplanatio Morellan is nana the fact (A. thatChev.) myricananin J. Herb., Wang B (39 et) is al. obtained [28] only in obtained low yields. 5 mg In fact,myricananin starting with B. A 20possible kg of driedexplanatio Morellan is nana the fact(A. Chev.)that myricananin J. Herb., Wang B (39 et) is al. obtained [28] only in obtained low yields. 5 mg In fact, starting with 20 kg of dried Morella nana (A. Chev.) J. Herb., Wang et al. [28] only obtained 5 mg fact, starting with 20 kg of dried Morella nana (A. Chev.) J. Herb., Wang et al. [28] only obtained 5 mg

Molecules 2020, 25, 6052 27 of 33 limitations of the clinical use of ursolic acid, namely by being less lipophilic, which could increase their intestinal absorption and improve bioavailability. These examples show that there are still many research opportunities in the study of Morella/Myrica and point out a great potential to increase the value of species belonging to these genera.

4. Conclusions Compounds isolated from Morella and Myrica genera show great potential to become important pharmacological agents. Both in vitro and in vivo studies showed that compounds isolated from these genera, like myricanol (4), myricitrin (10), and betulin (16), are already seen as important candidates for the treatment of several diseases, namely due to their antitumor and cardio-/neuro-/hepatoprotective activities. Interestingly, in most cases their activity is related to their capacity to modulate oxidative stress and inflammation pathways, which increases their value even further, because of the myriad of pathologies related with those processes. Although many of the studies presented their results with quality, there were some works where there was a lack of important information for a more correct interpretation of the validity of results. In some cases, authors present the IC50 without indicating the associated error, in others a positive control is not used, which hinders the perception of the true potency of the results. Future works should take these factors into consideration. There are still many compounds isolated from Morella and Myrica genera whose biological activities have not been evaluated. However, since these compounds belong to chemical families with a high number of reported biological activities, a great potential for the chemical valorization of Morella/Myrica species can be foreseen, opening the door for future studies.

Author Contributions: A.M.L.S., L.M.M. and M.C.B. conceptualized and revised the paper; G.P.R. and B.J.C.S. conducted the research and wrote the first draft. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by FCT—Fundação para a Ciência e a Tecnologia, supporting G.P.R.’s grant (SFRH/BD/144446/2019) as well by FCT—Fundação para a Ciência e Tecnologia, the European Union, QREN, FEDER, and COMPETE, through funding the cE3c center (UIDB/00329/2020) and the LAQV-REQUIMTE (UIDB/50006/2020). Funded by RTI2018-094356-B-C21 Spanish MINECO project, co-funded by European Regional Development Fund (FEDER). Acknowledgments: Thanks are due to the University of Azores and Universidad de La Laguna. Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations

6-OHDA 6-hydroxydopamine ACE-1 Angiotensin-converting-enzyme 1 AGE Advanced glycation end products AICAR 5-Aminoimidazole-4-carboxamide ribonucleotide Akt Protein kinase B ALT Alanine transaminase AMPK Adenosine monophosphate-activated protein kinase aP2 Adipocyte protein 2 AST Aspartate transaminase ATP Adenosine tri-phosphate α-SMA alpha smooth muscle actin Bax Bcl-2-associated X Bcl-2 B-cell lymphoma 2 C/EBPα CCAAT/enhancer-binding-protein-α COX-2 Cycloxygenase-2 CYP2E1 Cytochrome P450 2E1 DNP 2,4-dinitrophenol Molecules 2020, 25, 6052 28 of 33

EC50 Half maximal effective concentration ERK Extracellular-signal-regulated kinase FoxOs Forkhead box O3 γ-GCS Gamma-glutamylcysteine synthetase GSK-3β Glycogen synthase kinase 3 beta HDL High-density lipoprotein HFD High-fat diet HIF-1α Hypoxia-inducible factor 1-alpha HMGB1 High mobility group box 1 protein HO-1 Heme oxygenase 1 HUVECs Human umbilical vein endothelial cells IC50 Half maximal inhibitory concentration IL-1β Interleukin-1β IL-6 Interleukin-6 iNOS Nitric oxide synthase IRS-1 Insulin receptor substrate 1 IKK-β I-kappa-B-kinase beta JNK c-Jun NH2-terminal cinase LDH Lactate Dehydrogenase LDL Low-density lipoprotein LKB1 Tumor suppressor serine/threonine-protein kinase LPS Lipopolysaccharide MAPK Mitogen-activated protein kinase MCP-1 Monocyte chemoattractant protein-1 MIC Minimum inhibitory concentration mTOR mammalian target of rapamycin MuRF1 Muscle RING-finger protein-1 MyD88 Myeloid differentiation primary response 88 NA Neuraminidase NF-KB Nuclear factor kappa B NQO-1 NAD(P)H Quinone Dehydrogenase 1 Nrf2 Nuclear factor erythroid 2-related factor 2 Ox-LDL Oxidized low-density lipoprotein ROS Reactive oxygen species PGC-1α Peroxisome proliferator-activated receptor-gamma coactivator PI3-K Phosphoinositide 3-kinases PPARγ Peroxisome proliferator-activated receptor gamma PSD-45 Postsynaptic density protein-45 SIRT1 Sirtuin 1 SREB-1 Sterol regulatory element-binding transcription factor 1 STAT3 Signal transducer and activator of transcription 3 TGF-β1 Transforming growth factor beta 1 TH Tyrosine hydroxylase TG Triglycerides TLR4 Toll-like receptor 4 TNF-α Tumor necrosis factor α VEGF Vascular endothelial growth factor

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