# Medicinal Plants from Mexico, Central America, and the Caribbean Used as Immunostimulants

Authors: Angel Josabad Alonso-Castro; María del Carmen Juárez-Vázquez; Nimsi Campos-Xolalpa
Journal: Evidence-Based Complementary and Alternative Medicine
 (2016)

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## Abstract

A literature review was undertaken by analyzing distinguished books, undergraduate and postgraduate theses, and peer-reviewed scientific articles and by consulting worldwide accepted scientific databases, such as SCOPUS, Web of Science, SCIELO, Medline, and Google Scholar. Medicinal plants used as immunostimulants were classified into two categories: (1) plants with pharmacological studies and (2) plants without pharmacological research. Medicinal plants with pharmacological studies of their immunostimulatory properties were subclassified into four groups as follows: (a) plant extracts evaluated forin vitro effects, (b) plant extracts with documentedin vivo effects, (c) active compounds tested onin vitro studies, and (d) active compounds assayed in animal models. Pharmacological studies have been conducted on 29 of the plants, including extracts and compounds, whereas 75 plants lack pharmacological studies regarding their immunostimulatory activity. Medicinal plants were experimentally studiedin vitro (19 plants) andin vivo (8 plants). A total of 12 compounds isolated from medicinal plants used as immunostimulants have been tested usingin vitro (11 compounds) andin vivo (2 compounds) assays. This review clearly indicates the need to perform scientific studies with medicinal flora from Mexico, Central America, and the Caribbean, to obtain new immunostimulatory agents.


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## Body

## 1. Introduction

The immune system is a complex organization of leukocytes, antibodies, and blood factors that protect the body against pathogens [1]. Innate immunity consists of cells such as lymphocytes, macrophages, and natural killer (NK) cells, which are the first line of host defence [2, 3]. The NK cells lyse pathogens and tumor cells without prior sensitization [4]. Activated macrophages defend the host by phagocytosis, releasing the enzyme lysosomal acid phosphatase, and through the synthesis and release of nitrous oxide (NO) and hydrogen peroxide (H2O2) [5, 6]. These two components inhibit the mitochondrial respiration and the DNA replication of pathogens and cancer cells [7]. When an infection occurs, macrophages and mast cells immediately release interleukins [2]. The interleukins link the communication between cells of the immune system, facilitating innate immune reactions. Among these cytokines, IL-2 and IL-6 induce the stimulation of cytotoxic T cells and enhance the cytolytic activity of NK cells [8, 9]. Interferon gamma (IFN-γ), mainly produced by NK cells, exerts antitumor and antiviral effects, increases antigen presentation and lysosomal activity of macrophages, and promotes the cytotoxic effect of NK cells [10].Immunodeficiency occurs when there is a loss in the number or function of the immune cells, which might lead to infections and diseases such as cancer [11, 12]. Therefore, the discovery of agents which enhance the immune system represents an attractive alternative to the inhibition of tumor growth and the prevention and treatment of some infections. An immunostimulatory agent is responsible for strengthening the resistance of the body against pathogens. In preclinical and clinical studies, some immunostimulatory medicinal plants (e.g.,Viscum album andEchinacea purpurea) have increased the immune responsiveness by activating immune cells [3, 11].In ancient traditional medicine, the term immunostimulant was unknown. In some cases, medicinal plants species that “purify the blood,” “strengthen the body,” and “increase the body’s defences” have been used as immunostimulant agents [13, 14].Some of thein vitro andin vivo tests used to evaluate the immunostimulatory effects of plant extracts and compounds include the following: (a) proliferation of splenocytes, macrophages, and lymphocytes, (b) phagocytosis, (c) pinocytosis, (d) production of NO and/or H2O2, (e) NK cell activity, (f) release of IFN-γ, IL-2, IL-6, and other interleukins, and (g) lysosomal enzyme activity.In vivo studies mainly consist in the induction of an immunosuppressed state in the animals by using (a) chemical agents such as 5-fluorouracil, cyclophosphamide, and methotrexate or (b) biological agents such as tumorigenic cells. All the above-mentioned agents have been extensively studied on inducing immunosuppression [15, 16].This review provides ethnomedicinal, phytochemical, and pharmacological information about plants and their active compounds used as immunostimulants in Mexico, Central America, and the Caribbean. This information will be useful for developing preclinical and clinical studies with the plants cited in this review.


## 2. Methodology

A literature search was conducted from December 2014 to July 2015 by analyzing the published scientific material on native medicinal flora from Mexico, Central America, and the Caribbean. Academic information from the last five decades that describes the ethnobotanical, pharmacological, and chemical characterization of medicinal plants used as immunostimulants was gathered. The following keywords were used to search for the academic information: plant extract, plant compound, immune system, immunostimulant, immunostimulatory, Mexico, Central America, and the Caribbean. No restrictions regarding the language of publication were imposed, but the most relevant studies were published in Spanish and English. The criteria for the selection of reports in this review were as follows: (i) plants native to Mexico, Central America, and the Caribbean, (ii) plants used in traditional medicine as immunostimulants with or without pharmacological evidence, and (iii) plants and their active compounds with information obtained from a clear source. The immunostimulatory activity of plant extracts or compounds in combination with a known immunostimulant agent (such as lipopolysaccharide, CD3) was omitted in this review.Medicinal plants used as immunostimulants were classified into two categories: (1) plants with pharmacological studies and (2) plants without pharmacological research. The information on medicinal plants with pharmacological studies was obtained from peer-reviewed articles by consulting the academic databases SCOPUS, Web of Science, SCIELO, Medline, and Google Scholar. Medicinal plants with pharmacological studies of their immunostimulatory properties were subclassified into four groups: (a) plant extracts that have been evaluated forin vitro effects, (b) plant extracts with documentedin vivo effects, (c) active compounds tested usingin vitro studies, and (d) active compounds that have been assayed in animal models. The information for medicinal plants without pharmacological research was obtained from both undergraduate and postgraduate theses, in addition to peer-reviewed articles, and scientific books.


## 3. Medicinal Plants from Mexico, Central America, and the Caribbean Used as Immunostimulants

We documented 104 plant species belonging to 55 families that have been used as immunostimulants. Of these plants, 28 have pharmacological studies (Table1), and 76 plants lacked pharmacological research regarding their immunostimulatory activity (Table 6). All plant names and their distributions were confirmed by consulting the Missouri botanical garden (http://www.tropicos.org/). Asteraceae (11 plant species), Fabaceae (8 plant species), and Euphorbiaceae (7 plant species) are the plant families most often used as immunostimulants, including plants with and without pharmacological studies (Tables 1 and 6). We found that 46% of plants used as immunostimulants, with or without pharmacological studies, are also used for the empirical treatment of cancer. This was confirmed, for many plant species, by consulting our previous work [94]. Therefore, we highly recommend evaluating the immunostimulatory effects of medicinal plants used for cancer treatment. Medicinal plants used as immunostimulants are also used for the treatment of diarrhea (23%), cough (18%), and inflammation (18%). Diarrhea and cough are two symptoms associated with gastrointestinal and respiratory infections, respectively. We may therefore infer that immunostimulatory plants may also be used for the treatment and prevention of infections. Medicinal plants used as an antiparasitic agent may treat diseases such as malaria, whereas plants used as antivirals may treat diseases such as measles, smallpox, and others (Tables 1 and 6).Table 1
Medicinal plants with pharmacological evidence of their immunostimulant effects.
Family
Scientific name
Common name
Plant part
Other popular uses
Reference
Acanthaceae
Carlowrightia cordifoliaA. Gray
Arnica
Lv
AI
[17]
Justicia spicigeraSchltdl.
Muicle
Lv
DB, CA
[18]
Anacardiaceae
Amphipterygium adstringens (Schltdl.) Standl.
Cuachalalate
Bk
SA, DG, CA
[19]
Asteraceae
Bidens pilosaL.
Aceitilla
Wp
DB, DI, SA, CA
[20]
Psacalium peltatum(Kunth) Cass.
Matarique
Rt
WH, BP, CA
[21]
Tridax procumbensL.
Ghamra
Ap
WH
[22]
Xanthium strumariumL.
Guizazo de caballo
Rt
DU, CA
[23]
Bignoniaceae
Tabebuia chrysantha (Jacq.) G. Nicholson
Guayacan
Bk
AI, DB, SA
[24]
Cactaceae
Lophocereus schottii(Engelm.) Britton & Rose
Garambullo
Sm
CO, DB, SA, CA
[25]
Lophophora williamsii (Lem. ex Salm-Dyck) J. M. Coult.
Peyote
Tb
BP, CA
[26]
Caricaceae
Carica papaya L.
Papaya
Fr
SA, DG, DI, CA
[27]
Euphorbiaceae
Euphorbia cotinifoliaL.
Palito lechero
Latex
AI
[28]
Euphorbia hirtaL.
Tártago de jardín
Ap
AV
[29]
Euphorbia pulcherrimaWilld. ex Klotzsch
Nochebuena
Ap
AI, CO, FL, CA
[28]
Hura crepitansL.
Ceiba
Lv
AI
[28]
Fabaceae
Hymenaea courbarilL.
Guapinol
Bk
DU, AP
[30]
Mucuna urens(L.) Medik.
Tortera
Bk
DU
[31]
Phaseolus vulgarisL.
Frijol
Sd
DI, BP
[32]
Hypericaceae
Hypericum perforatum L.
Hierba de San Juan
Wp
DP, WH
[33]
Lauraceae
Persea americana Mill.
Aguacate
Lv
AH, BP, WH, CA
[34]
Molluginaceae
Mollugo verticillataL.
Hierba de la arena
Ap
AI
[35]
Nyctaginaceae
Bougainvillea × buttiana Holttum & Standl.
Bugambilia
Fw
SA, CO
[36]
Phyllanthaceae
Phyllanthus niruriL.
Chancapiedra
Ap
AI, DU, CA
[37]
Phytolaccaceae
Petiveria alliaceaL.
Anamú
Ap
AI, SA, BP, CA
[38]
Plantaginaceae
Plantago virginica L.
Platano
Lv
AI
[39]
Rubiaceae
Uncaria tomentosa(Willd.) DC.
Uña de gato
Bk
AV, CA
[40]
Santalaceae
Phoradendron serotinum(Raf.) M. C. Johnst.
Muerdago
Lv
DB, CA
[41]
Talinaceae
Talinum triangulare(Jacq.) Willd.
Espinaca
Lv
CA, AV, DB
[42]
Urticaceae
Phenax rugosus (Poir.) Wedd.
Parietaria
Wp
WH, AV
[43]
Other popular uses: AP: antiparasitic; AI: anti-inflammatory; AV: antiviral; BP: body pain; CA: cancer; CO: cough; DG: digestive; DI: diarrhea; DU: diuretic; DP: depression; FL: flu; SA: stomachache; TB: tuberculosis; WH: wound healing. Plant part: Ap: aerial parts; Bk: bark; Br: branches; Fr: fruit; Lv: leaves; Fw: flower; Rb: root bark; Rt: root; Sd: seeds; Sm: stem; Tb: tubercle; Wp: whole plant.A total of 20 plants, belonging to 15 botanical families, havein vitro studies regarding their immunostimulatory effects (Table 2). Furthermore, 8 plant species from 8 botanical families were assessed usingin vivo assays (Table 3). A total of 11 compounds, isolated from 7 plants, have been tested usingin vitro assays (Table 4). Only two compounds, isolated from two plants, were studied usingin vivo models (Table 5).Table 2
Plant extracts with immunostimulatory effects tested usingin vitro assays.
Family
Scientific name
Plant part
Extract
Range of concentration testedμg/mL
Immunostimulatory effects, compared to untreated control [duration of the experiment]
Reference
Acanthaceae
Carlowrightia cordifoliaA. Gray
Lv
Hex
13.3 (mg/mL)
NO production (2.5-fold) at 13.3 mg/mL [48 h] in human primary peritoneal macrophage
[17]
Justicia spicigeraSchltdl.
Lv
EtOH
10–200
Induction of phagocytosis (0.4-fold) at 200μg/mL [48 h] by human primary lymphocytes against Saccharomyces cerevisiae NO production (6.4-fold) in murine primary macrophages and  H2O2 release (8.5-fold)  at  200 μg/mL with  murine monocyte–macrophages cocultured with Saccharomyces cerevisiae [48 h]Proliferation of human primary lymphocytes (0.4-fold) at 200 µg/mL [48 h]
[14]
Asteraceae
Bidens pilosaL.
Wp
H2O
500
Increased on IFN-γ promoter (1.9-fold) in Jurkat T cells at 500 µg/mL [72 h]
[44]
Xanthium strumariumL.
Wp
H2O
10–100
Proliferation of murine primary lymphocytes (13-fold) at 100µg/mL [44 h]
[45]
Cactaceae
Lophophora williamsii (Lem. ex Salm-Dyck) J. M. Coult.
Tb
MeOH
0.18–18
Proliferation of murine primary lymphocytes (2.5-fold) at 0.18–1.8μg/mL [72 h]NO production (3-fold) at 18 μg/mL using murine peritoneal macrophages [72 h]
[26]
Caricaceae
Carica papayaL.
Lv
H2O
1.25–5 (mg/mL)
Production of IFN-γ (2.0-fold), IL-12 p40 (2.0-fold) in human primary lymphocytes at 1.25 mg/mL [24 h]
[46]
Euphorbiaceae
Euphorbia cotinifoliaL.
Latex
—
25
Proliferation of human primary lymphocytes (1.6-fold) at 25μg/mL [66 h]
[47]
Euphorbia hirtaL.
Ap
EtOH
0.06–500 (mg/mL)
Induction of phagocytosis ofCandida albicans(2.0-fold) by primary murine macrophages at 500 mg/mL [1 h]
[29]
Euphorbia pulcherrimaWilld. ex Klotzsch
Lv
Hex : DCM : MeOH (2 : 1 : 1)
25
Proliferation of human primary lymphocytes (6.5-fold) at 25μg/mL [66 h]
[47]
Hura crepitansL.
Lv
Hex : DCM : MeOH (2 : 1 : 1)
25
Proliferation of human primary lymphocytes (0.85-fold) at 25μg/mL [66 h]
[47]
Hypericaceae
Hypericum perforatum L.
Wp
H2O
750
Proliferation of murine primary lymphocytes (1.6-fold) at 750μg/mL [18 h]
[48]
Lauraceae
Persea americana Mill.
Lv
MeOH
3.91–250
Proliferation of murine primary lymphocytes (1.6-fold) at 250μg/mL [48 h]
[39]
Molluginaceae
Mollugo verticillataL.
Ap
EtOH
25
NO production (1.6-fold) at 25μg/mL using murine peritoneal primary macrophages cocultures with Mycobacterium tuberculosis [48 h]
[44]
Nyctaginaceae
Bougainvillea × buttiana Holttum & Standl.
Fw
EtOH
2.9–290
H2O2 production (0.4-fold) at 2.9 μg/mL with  murine primary peritoneal macrophages [24 h]Proliferation of murine primary peritoneal macrophages (0.6-fold) at 29 μg/mL [48 h]NO production (2.4-fold) at 290 μg/mL with  murine primary peritoneal macrophages  [48 h]
[36]
Phyllanthaceae
Phyllanthus niruriL.
Lv
Hex : DCM : MeOH (2 : 1 : 1)
25
Proliferation of  human primary lymphocytes (1.3-fold) at 25μg/mL [66 h]
[47]
Phytolaccaceae
Petiveria alliaceaL.
Ap
H2O
25
Production of IL-6 (100-fold), IL-10 (14-fold), and IL-8 (12-fold) in dendritic cells at 25μg/mL [48 h]
[49]
Plantaginaceae
Plantago virginica L.
Lv
MeOH
3.91–250
Proliferation of murine primary lymphocytes at 250μg/mL (1.6-fold) [48 h]
[39]
Rubiaceae
Uncaria tomentosa(Willd.) DC.
Rb
H2O
0.32–320
NO production (1.5-fold) at 320μg/mL using murine primary peritoneal macrophages [48 h]Production of IL-6 (7.2-fold) at 320 μg/mL in  murine primary peritoneal macrophages [24 h]
[50]
Santalaceae
Phoradendron serotinum(Raf.) M. C. Johnst.
Lv
EtOH
1–50
Proliferation of RAW 264.7 macrophages (0.2-fold) and murine primary splenocytes (0.3-fold)  at 50μg/mL [48 h]Lysosomal enzyme activity (0.2-fold)  at 50 μg/mL using  RAW 264.7 macrophages [48 h]Stimulation of NK cell activity (7.1-fold)  at 50 μg/mL using murine primary splenocytes cocultured with K562 cells [48 h]Production of IFN-γ (1.6-fold), IL-2 (1.4-fold), and IL-6 (1.3-fold)  at 50 μg/mL  using murine primary splenocytes cocultured with K562 cells [48 h]
[41]
Talinaceae
Talinum triangulare(Jacq.) Willd.
Sm
EtOH
100–1000
Proliferation of human primary lymphocytes (2-fold) at 1000μg/mL [72 h]NO production (4-fold) at 1000 μg/mL [72 h]Production of IFN-γ (16-fold) at 500 μg/mL in human primary lymphocytes [72 h]
[42]
Solvent used for the extract:  Hex: hexane; DCM: dichloromethane; MeOH: methanol; EtOH: ethanol; H2O: aqueous. Plant part:  Rb: root bark; Tb: tubercle; Lv: leaves; Wp: whole plant.Table 3
Plant extracts with immunostimulatory effects tested usingin vivo assays.
Family
Scientific name
Plant part
Extract
Model of immunosuppression and duration of the experiment [range of dose tested]
Immunostimulatory effects (compared to immunosuppressed mice)
Reference
Anacardiaceae
Amphipterygium adstringens (Schltdl.) Standl.
Bk
H2O
BALB/c mice bearing lymphoma L5178Y for 10 days [10 mg/kg p.o.]
Proliferation of splenocytes (2.0-fold) at 10 mg/kg
[51]
Asteraceae
Tridax procumbensL.
Ap
H2O
Immunocompetent Swiss mice for 6 days [250 and 500 mg/kg i.p.]
Increase of leukocyte number (1.4-fold) at 500 mg/kgIncrease in phagocytic index (0.3-fold) at 500 mg/kg
[22]
Bignoniaceae
Tabebuia chrysantha (Jacq.) G. Nicholson
Lv
H2O : EtOH (1 : 1)
Wistar rats immunized with sheep red blood cells for 17 days [1000 mg/kg p.o.]
Increase of leucocyte number (1.2-fold) at 1000 mg/kg
[24]
Cactaceae
Lophocereus schottii(Engelm.) Britton & Rose
Sm
EtOH
BALB/c mice bearing lymphoma L5178Y for 22 days [10 mg/kg p.o.]
Proliferation of lymphocytes (0.2-fold) at 10 mg/kg
[25]
Molluginaceae
Mollugo verticillataL.
Ap
EtOH
Mice inoculated with 0.1 mg Bacillus Calmette–Guérin for 7 days [500 mg/kg p.o.]
NO production (3.1-fold) at 500 mg/kg
[52]
Phytolaccaceae
Petiveria alliaceaL.
Ap
H2O
BALB/c mice treated with 5-fluorouracil for 4 days [400 and 1200 mg/kg p.o.]
Increase of leukocyte number (1.4-fold) at 1200 mg/kg
[53]
Santalaceae
Phoradendron serotinum(Raf.) M. C. Johnst.
Lv
EtOH
C57BL/6 mice bearing TC-1 tumor for 25 days [1–10 mg/kg i.p.]
Production of IFN-γ (1.3-fold), IL-2 (2.1-fold), and IL-6 (2.1-fold) at 10 mg/kg
[41]
Urticaceae
Phenax rugosus (Poir.) Wedd.
Lv
H2O : EtOH (1 : 1)
Wistar rats immunized with sheep red blood cells for 17 days [1000 mg/kg p.o.]
Increase of leucocyte number (1.5-fold) at 1000 mg/kg
[24]
Solvent used for the extract: EtOH: ethanol; H2O: aqueous. Plant part: Rb: root bark; Tb: tubercle; Lv: leaves; Wp: whole plant; Ap: aerial parts; Sm: stem; Bk: bark.Table 4
In vitro immunostimulatory effects of plant compounds.
Family
Scientific name
Compound
Group
Range of concentration testedµM
Immunostimulatory effects, compared to untreated control [duration of the experiment]
Reference
Acanthaceae
Justicia spicigera Schtdl.
Kaempferitrin
Flavonoid
1–25
Induction of phagocytosis (0.4-fold) at 200µg/mL using RAW 264.7 macrophages [48 h]Induction of lysosomal enzyme activity (0.5-fold) at 25 µM with RAW 264.7 macrophages [48 h]Increase of NK cell activity (10-fold) at 25 µM with RAW 264.7 macrophages cocultured with K562 cells [48 h]
[54]
Anacardiaceae
Amphipterygium
adstringens (Schltdl.) Standl.
Masticadienonic acid
Triterpenoid
0.001–10
NO production (1.8-fold) [72 h] at 0.001µM in murine primary peritoneal macrophages
[55]
3α-Hydroxymasticadienolic acid
Triterpenoid
0.001–10
NO production (1.7-fold) [72 h] at 1µM in murine primary peritoneal macrophages
24,25S-dihydromasticadienonic acid
Triterpenoid
0.001–10
NO production (1.3-fold) [72 h] at 0.01µM in murine primary peritoneal macrophages
Masticadienolic acid
Triterpenoid
0.001–10
NO production (1.6-fold) [72 h] at 0.1µM in murine primary peritoneal macrophages
Asteraceae
Bidens pilosa L.
CentaureinCentaureidin
FlavonoidFlavonoid
EC50 = 0.14 µMEC50 = 2.5 µM
Increase on IFN-γ promoter in Jurkat T cells [72 h]
[44]
Psacalium peltatum(Kunth) Cass.
Maturin acetate
Sesquiterpene
1–25
Increase of NK cell activity (7-fold) at 25µM using murine primary splenocytes cocultured with K562 cells [48 h]Induction of lysosomal enzyme activity (0.2-fold) at 25 µM using RAW 264.7 macrophages [48 h]Proliferation of RAW 264.7 macrophages and murine primary splenocytes (0.2-fold, each) at 25 µM [48 h]
[56]
Fabaceae
Hymenaea courbaril L.
Xyloglucan
Polysaccharide
0.1–50
NO production (2.1-fold) at 0.25µM with murine primary peritoneal macrophages [48 h]
[57]
Mucuna urens(L.) Medik.
Xyloglucan
Polysaccharide
0.06–3.2
NO production (1.4-fold) at 0.16µM  with murine primary peritoneal macrophages [48 h]
Phaseolus vulgaris
Pectic polysaccharide
Polysaccharide
0.07–1.12
Murine primary splenocytes proliferation (2.5-fold) at 1.12µM [72 h]Murine primary thymocyte proliferation (2.1-fold) at 0.14 µM [72 h]
[58]Table 5
In vivo immunostimulatory effects of plant compounds.
Family
Scientific name
Compound
Group
Model of immunosuppression and duration of the experiment [range of dose tested]
Immunostimulatory effects (compared to immunosuppressed mice)
Reference
Asteraceae
Psacalium peltatum(Kunth) Cass.
Maturin acetate
Sesquiterpene
BALB/c mice treated with 100 mg/kg cyclophosphamide for 14 days [10–50 mg/kg i.p.]
Production of IFN-γ (1.4-fold) and IL-2 (1.8-fold)
[56]
Rubiaceae
Uncaria tomentosa(Willd.) DC.
Pteropodine
Alkaloid
Immunocompetent mice for 4 days [100–600 mg/kg i.p.]
Lymphocyte proliferation (1.6-fold) at 600 mg/kg
[59]Table 6
Medicinal plants used as immunostimulants with no pharmacological studies.
Family
Scientific name
Common name
Plant part
Other popular uses
Reference
Adoxaceae
Sambucus mexicanaC. Presl ex DC.
Sauco
Lv
AI, CO, DU
[60]
Agavaceae
Agave americanaL.
Maguey
Ap
DU, CA
[61]
Agave salmianaOtto ex Salm-Dyck
Agave
Ap
DU, CA
[19]
Agave tequilana F. A. C. Weber
Agave
Ap
DG
[62]
Furcraea tuberosa (Mill.) W. T. Aiton
Maguey
Rt
AI
[31]
Amaranthaceae
Chenopodium ambrosioidesL.
Epazote
Lv
AP, DI, CA
[63]
Chenopodium berlandieriMoq.
Epazote
Lv
BR,  AP
[63]
Chenopodium incisum Poir.
Epazote zorrillo
Lv
AP, DU
[63]
Iresine ajuscana Suess. & Beyerle
Iresine
Lv
AI
[13]
Anacardiaceae
Spondias mombinL.
Jobo
Fr
WH, DI
[64]
Asteraceae
Austroeupatorium inulifolium (Kunth) R. M. King & H. Rob.
Salvia amarga
Wp
CO
[65]
Bidens aurea(Aiton) Sherff
Aceitilla
Wp
DB, DI, SA
[66]
Mikania cordifolia(L. f.) Willd.
Trepadora
Lv
AI, CO, BP
[67]
Neurolaena lobata (L.) Cass.
Burrito
Rt
BP, DB, CA, AP
[67]
Pterocaulon alopecuroides (Lam.) DC.
Varita pienegro
Wp
AV, CA
[68]
Sanvitalia ocymoidesDC.
Ojo de gallo
Wp
DI, SA
[69]
Tagetes lucida Cav.
Pericón
Ap
SA, DP, CA
[33]
Bignoniaceae
Crescentia alataKunth
Huaje
Fr
TB, CA, DI
[70]
Parmentiera aculeata(Kunth) Seem.
Cuajilote
Ap
DB, BP, DU, CO, DI
[60]
Tecoma stans(L.) Juss. ex Kunth
Tronadora
Ap
DB, DU, CA
[71]
Bixaceae
Bixa orellanaL.
Achiote
Sd
CA, WH, DU
[68]
Bromeliaceae
Ananas comosus(L.) Merr.
Pineapple
Fr
DB, AH, CA
[72]
Burseraceae
Bursera copallifera(DC.) Bullock
Copal
Ap
AI, CA
[73]
Bursera fagaroides (Kunth) Engl.
Palo xixote
Bk
SA, CA
[74]
Bursera simaruba (L.) Sarg.
Palo mulato
Lv
CO, SA, CA
[67]
Commelinaceae
Zebrina pendulaSchnizl.
Hierba de pollo
Lv
BP, WH, DB, CA
[43]
Cordiaceae
Cordia alliodora (Ruiz & Pav.) Oken
Aguardientillo
Lv
TB, WH
[67]
Varronia globosaJacq.
Yerba de la sangre
Ap
DU
[23]
Costaceae
Costus arabicusL.
Caña Guinea
Ap
AI
[75]
Cupressaceae
Taxodium mucronatumTen.
Ahuehuete
Br
DI
[76]
Gesneriaceae
Moussonia deppeana (Schltdl. & Cham.) Hanst.
Tlalchichinole
Ap
WH, DI
[19]
Euphorbiaceae
Acalypha phleoidesCav.
Hierba del cáncer
Ap
CA, DI
[76]
Cnidoscolus aconitifolius(Mill.) I. M. Johnst.
Chaya
Lv
DB, CA
[28]
Codiaeum variegatum(L.) Rumph. ex A. Juss.
Croton
Lv
DI
[28]
Equisetaceae
Equisetum laevigatum A. Braun
Cola de caballo
Ap
DU
[77]
Fabaceae
Desmodium molliculum(Kunth) DC.
Manayupa
Ap
DU, WH
[40]
Eysenhardtia polystachya(Ortega) Sarg.
Palo dulce
Lv
DU, DB, WH, CA
[78]
Haematoxylum brasiletto H. Karst.
Palo de Brasil
Bk
CO, DI
[19]
Senna reticulata(Willd.) H. S. Irwin & Barneby
Barajo
Ap
DB, WH
[43]
Zornia thymifoliaKunth
Hierba de la vibora
Wp
DI, BP
[66]
Juglandaceae
Juglans jamaicensisC. DC.
Palo de nuez
Bk
WH, AP
[31]
Juglans major(Torr.) A. Heller
Nogal
Lv
DU, AP, WH, CA
[76]
Juglans mollisEngelm.
Nuez de caballo
Ap
WH, BP
[79]
Krameriaceae
Krameria grayiRose & J. H. Painter
Zarzaparrilla
Wp
DU
[20]
Lamiaceae
Salvia reglaCav.
Salvia
Lv
WH
[63]
Satureja macrostema(Moc. & Sessé ex Benth.) Briq.
Té de monte
Lv
CO
[80]
Lauraceae
Cinnamomum pachypodum (Nees) Kosterm.
Laurel
Ap
AP
[63]
Loranthaceae
Psittacanthus calyculatus(DC.) G. Don
Muerdago
Ap
CA, WH
[76]
Meliaceae
Cedrela odorataL.
Cedro
Bk
TB, DI
[37]
Myrtaceae
Psidium guajavaL.
Guayaba
Ap
AI, DI, CA
[81]
Moraceae
Brosimum alicastrumSw.
Ojite
Lv
TB, FL
[82]
Musaceae
Musa sapientum L.
Banana
Fr
DI, DG
[83]
Onagraceae
Ludwigia peploides(Kunth) P. H. Raven
Clavo de la laguna
Ap
CO
[43]
Orobanchaceae
Castilleja tenuifloraBenth.
Cola de borrego
Ap
WH, CO, DI, CA
[84]
Papaveraceae
Bocconia frutescensL.
Gordolobo
Lv
CO, SA, CA
[35]
Passifloraceae
Turnera diffusaWilld.
Damiana
Lv
CO, DI, CA
[79]
Piperaceae
Piper auritumKunth
Acoyo
Lv
SA, CO, DI
[85]
Polemoniaceae
Loeselia mexicana(Lam.) Brand
Espinosilla
Ap
DI, DU
[86]
Polygonaceae
Polygonum aviculare L.
Sanguinaria
Ap
DI, BR, DU, CA
[76]
Polypodiaceae
Polypodium polypodioides (L.) Watt
Helecho de resurrección
Lv
AP
[31]
Serpocaulon triseriale (Sw.) A. R. Sm.
Calaguala
Rt
WH, AH
[87]
Rhizophoraceae
Rhizophora mangleL.
Mangle rojo
Bk
DI, DB, CA
[23]
Rubiaceae
Hamelia patensJacq.
Escobetilla
Lv
AI, BP, CA
[67]
Salicaceae
Salix humboldtianaWilld.
Sauce criollo
Rt
AI, TB
[88]
Zuelania guidonia(Sw.) Britton & Millsp.
Guaguasí
Bk
WH, CA
[23]
Selaginellaceae
Selaginella lepidophylla (Hook. & Grev.) Spring
Doradilla
Wp
DU, CO, CA
[86]
Smilacaceae
Smilax domingensis Willd.
Zarzaparrilla
Rt
DI, SA
[89]
Smilax moranensisM. Martens & Galeotti
Zarzaparrilla
Wp
DU, CO
[66]
Smilax spinosaMill.
Zarzaparrilla
Wp
BP, CA
[90]
Solanaceae
Lycopersicon esculentum Mill.
Jitomate
Fr
CO, CA
[13]
Solanum americanumMill.
Hierba mora
Lv
BP, WH, CA
[91]
Urticaceae
Urera baccifera(L.) Gaudich. ex Wedd.
Chichicate
Rt
DU, AI, BP
[23]
Verbenaceae
Verbena litoralis Kunth
Verbena negra
Lv
SA, CO, AH
[92]
Viscaceae
Phoradendron brachystachyum(DC.) Nutt.
Muerdago
Ap
DB, CA
[93]
Vitaceae
Cissus sicyoidesL.
Tripa de Judas
Lv
BP, WH, AI, CA
[85]
AP: antiparasitic; AI: anti-inflammatory; AV: antiviral; BP: body pain; CA: cancer; CO: cough; DG: digestive; DI: diarrhea; DU: diuretic; DP: depression; FL: flu; SA: stomachache; TB: tuberculosis; WH: wound healing. Plant part: Ap: aerial parts; Bk: bark; Br: branches; Fr: fruit; Lv: leaves; Fw: flower; Rb: root bark; Rt: root; Sd: seeds; Sm: stem; Tb: tubercle; Wp: whole plant.Among thein vitro studies,Lophophora williamsii was one of the plant species that showed good immunostimulatory effects. This plant tested at 0.18 μg/mL showed a similar activity (2.4-fold, compared to untreated cells) on the proliferation of human primary lymphocytes, compared to the positive control 0.6 μg/mL concanavalin A [26]. Further studies withLophophora williamsii, as well as the isolation and purification of its active compounds, are highly recommended. Among thein vivo studies, an ethanol extract fromPhoradendron serotinum leaves, tested from 1 to 10 mg/kg i.p., showed immunostimulatory effects, in a dose-dependent manner, by increasing the levels of IFN-γ, IL-2, and IL-6 in serum from C57BL/6 mice bearing TC-1 tumor [41]. The immunostimulatory effects obtained usingin vitro studies were confirmed inin vivo studies for some plant species such asMollugo verticillata,Phoradendron serotinum, andPetiveria alliacea and compounds such as maturin acetate (Figure 1). This indicates that these plants and the compound can be metabolized, and their immunostimulatory effects are also shown in animals.Figure 1
Chemical structures of some compounds with immunostimulatory effects isolated from medicinal plants.On the other hand, in many works cited in this review, only one concentration or dose was tested. Further studies will be required to obtain the EC50 or ED50 values, if possible, and analyze whether the plant extracts or compounds induce a concentration/dose-dependent effect. In many studies, a single immunostimulant test is used (e.g., the NO production). Authors are encouraged to perform more than one immunostimulatory test in further studies to provide more information on the immunostimulant effects of plant extracts or compounds. In some cases, the initial screening of thein vivo immunostimulatory effects is carried out using immunocompetent mice. Further studies are necessary to be performed on plant extracts and compounds using models of immunosuppressed mice, induced with chemical or biological agents.


## 4. Medicinal Plants Used as Immunostimulants without Pharmacological Studies

We documented 75 medicinal plants used as immunostimulants that lack pharmacological studies (Table6). Plants from theSmilax genus (S. domingensis,S. moranensis, andS. spinosa) and theJuglans genus (J. major,J. mollis, andJ. jamaicensis) could be an excellent option for the isolation and identification of immunostimulatory agents because compounds isolated from their related species have shown immunostimulatory activity. Smilaxin (1.56 μM), a 30 kDa protein obtained fromSmilax glabra, increased the proliferation of splenocytes and bone marrow cells with similar activity to the positive control 0.52 μM concanavalin A [95]. A water-soluble polysaccharide, called JRP1, isolated fromJuglans mandshurica showedin vivo immunostimulatory effects by increasing the release of IFN-γ and IL-2 in an immunosuppressed model of mice bearing S-180 tumor [96]. Taking this into consideration, further studies with plants from theSmilax andJuglans genera should be carried out. Furthermore, mistletoe species such asPhoradendron brachystachyum andPsittacanthus calyculathus could be a good option for discovering immunostimulatory agents since the related speciesPhoradendron serotinum showed good immunostimulatory activity [41]. However, the toxicity of the mistletoe species should be assessed.


## 5. Further Considerations

More ethnobotanical studies are necessary to provide information on medicinal plants used as immunostimulants in Mexico, Central America, and the Caribbean. The ethnomedicinal information of plant species will be updated with these studies.The toxicity of plant species cited in this review should also be assessed. For instance,Xanthium strumarium is considered a toxic plant. Recently, it was described that this plant induces hepatotoxicity [97]. On the contrary,Hymenaea courbaril was shown to lack genotoxic and mutagenic effects [98]. Toxicological studies are necessary to provide safety in the use of plant extracts and their compounds in clinical trials.To our knowledge, there are no pharmacokinetic studies carried out with plant compounds cited in this review. This might be due to (a) the lack of established methodologies for their quantitation, (b) the quantity of the obtained compound being not enough to carry out a pharmacokinetic study, and (c) many plants extracts not being chemically characterized, and there is no main metabolite for its quantification using HPLC. Further pharmacokinetic studies will provide additional pharmacological information prior to carrying out clinical trials. The isolation and elucidation of the structure of bioactive principles should also be encouraged.Eight percent of medicinal plants listed in this review are classified as endangered. In the order of most endangered,Juglans jamaicensis,Cedrela odorata, andLophophora williamsii are cataloged as vulnerable, whereasTaxodium mucronatum,Rhizophora mangle,Eysenhardtia polystachya,Cordia alliodora, andHymenaea courbaril are cataloged as of least concern [99]. For instance,Lophophora williamsii (peyote) is a species that has been overexploited because of its high content of hallucinogenic alkaloids. The conservation of these species, as well as their habitats, should be encouraged by national and international programs to preserve biodiversity.There is null or limited information regarding the trade of medicinal plants used as immunostimulants. Therefore, we performed direct interviews (n=45) with local sellers of medicinal plants in Mexico, called “hierberos” or “yerbateros” in 7 different markets (Portales, Sonora, Xochimilco, Milpa Alta, Tlahuac, and Ozumba) located in Mexico City and the metropolitan area (Figure 2). Two of the markets are located in Xochimilco. In order of importance, the most recommended plant species used as immunostimulants areJusticia spicigera,Polygonum aviculare,Carlowrightia cordifolia, Amphipterygium adstringens, Uncaria tomentosa, and others. It was interesting to find that 85% of yerbateros recommended the use ofJusticia spicigera as immunostimulant (Figure 2(a)). Its way of preparation consists of the following: four or five branches and leaves are boiled with 1 L of water during 30 min. The recommended administration is 3 times daily. The rest of plant species were cited by less than 10% of yerbateros.Figure 2
Trade of medicinal plants used as immunostimulants in Mexico City. (a)Justicia spicigera was the most cited plant species used as immunostimulatory agent. (b and c) Traditional markets in Mexico City, showing the sellers of medicinal plants called hierberos or yerbateros.
(a)
(b)
(c)The demand for medicinal plants used as immunostimulants clearly indicates that these plant species are a current topic of interest. This indicates that ethnobotanical knowledge is a valuable tool, which supports the selection of plants to carry out pharmacological studies. Some of the medicinal plants cited in our survey have been pharmacologically investigated.Carlowrightia cordifolia showed poor immunostimulatory effects [17].Amphipterygium adstringens showedin vivo immunostimulatory effects [51], whereas masticadienonic acid (Figure 1), its active compound at 0.001 μM, increased the NO production (1.8 fold) with higher activity compared to 0.001 μM ursolic acid (1.4 fold) [55].Uncaria tomentosa showedin vitro immunostimulatory effects [50], whereas pteridine (Figure 1), its active compound, tested at 600 mg/kg i.p., increased the lymphocyte proliferation in immunocompetent mice [59].Justicia spicigera and kaempferitrin (Figure 1), its active compound, showedin vitro immunostimulatory effects [14, 54]. Nevertheless, thein vivo immunostimulatory effects remain to be performed withJusticia spicigera, kaempferitrin, and masticadienonic acid. The molecular mechanism by which this plant and the compounds exert their immunostimulatory effects should also be assessed.Finally, this review highlights the need to perform pharmacological, phytochemical, toxicological, and ethnobotanical studies with medicinal flora, from Mexico, Central America, and the Caribbean, to obtain new immunostimulatory agents.



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*Source: 4017676-2016-03-03.xml*