See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/230588166

Anti-inflammatory activity of Mitraphylline isolated from Uncaria tomentosa

bark

Article  in  Journal of ethnopharmacology · July 2012

DOI: 10.1016/j.jep.2012.07.015 · Source: PubMed

CITATIONS READS

53 701

9 authors, including:

Victor Doroteo Joaquina Adelaida Albàn Castillo

Pontifical Catholic University of Peru National University of San Marcos
7 PUBLICATIONS   100 CITATIONS    267 PUBLICATIONS   1,105 CITATIONS   

SEE PROFILE SEE PROFILE

Guillaume Robert Patrick Auberger

French Institute of Health and Medical Research University of Nice Sophia Antipolis
95 PUBLICATIONS   2,501 CITATIONS    285 PUBLICATIONS   17,324 CITATIONS   

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Viral hepatitis in South-East Asia View project

Disentangling the SARS-CoV2 Origins : Emergence & Reservoir View project

All content following this page was uploaded by Eric Deharo on 11 December 2017.

The user has requested enhancement of the downloaded file.

 Journal of Ethnopharmacology 143 (2012) 801–804

Contents lists available at SciVerse ScienceDirect

Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jep

Anti-inflammatory activity of Mitraphylline isolated from

Uncaria tomentosa bark
R. Rojas-Duran a, G. González-Aspajo a, C. Ruiz-Martel a, G. Bourdy b,c, V.H. Doroteo-Ortega a,
J. Alban-Castillo d, G. Robert e, P. Auberger e, E. Deharo b,c,n
a
Unidad de Investigación en Productos Naturales, Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofı́a, Universidad Peruana Cayetano Heredia,
Av. Honorio Delgado 430, SMP, Lima, Peru
b
Université de Toulouse, Université Paul Sabatier, Pharma-Dev UMR 152, Faculté de Pharmacie, 35 Chemin des maraı̂chers, F-31062 Toulouse Cedex 9, France
c
Institut de Recherche pour le Développement (IRD), Pharma-Dev UMR 152, Faculté de Pharmacie, 35 Chemin des maraı̂chers, F-31062 Toulouse Cedex 9, France
d
Museo de Historia Natural, Universidad Nacional Mayor de San Marcos, Av. Arenales 1256, Jesus Maria, Lima, Peru
e
INSERM U1065 (C3M) Team 2 Cell Death, Differentiation, Inflammation and Cancer, 151 route de Saint Antoine de Ginestie re, 06204 Nice Cedex 3, France

a r t i c l e i n f o abstract

Article history: Ethnopharmacological relevance: Uncaria tomentosa (Willd. ex Roem. & Schult.) DC. (Rubiaceae) is
Received 4 April 2012 widely used by populations living in South America to treat many ailments associated with
Received in revised form inflammatory disorders. Mitraphylline was shown to be the major pentacyclic oxindolic alkaloid
8 July 2012
present in the bark chloroformic extract of this plant. Its activity against cytokines involved in
Accepted 18 July 2012
inflammation process was tested in a murine model in vivo.
Available online 27 July 2012
Materials and methods: Mice received mitraphylline once a day for 3 days at 30 mg/kg/day by oral
Keywords: route. Then, they were subjected to bacterial lipopolysaccharide (LPS) endotoxin (15 mg/kg) and the
Inflammation LPS-induced production of 16 different cytokines was determined by Elisa multiplex. Control group
Uncaria tomentosa
received dexamethasone orally at 2 mg/kg/day. Toxicity on K565 cells and murine peritoneal macro-
Pentacyclic oxindolic alkaloids
phages, in vitro, at doses up to 100 mM was monitored by XTT-colorimetric assay.
Traditional medicine
TNF-a Results and conclusions: For the first time mitraphylline was tested in vivo against a large range of
Mitraphylline cytokines that play a crucial role in inflammation. Mitraphylline inhibited around 50% of the release of
interleukins 1a, 1b, 17, and TNF-a. This activity was similar to dexamethasone. It also reduced almost
40% of the production of interleukin 4 (IL-4) while the corticoid did not. Lastly it did not show any
toxicity on K565 cells nor murine macrophages at doses up to 100 mM.
& 2012 Published by Elsevier Ireland Ltd.

1. Introduction in Latin America for the treatment of a wide-array of symptoms

(Obregón, 1997; Keplinger et al., 1999; Williams, 2001; Heitzman
Uncaria tomentosa (Willd. ex Roem. & Schult.) DC. (Rubiaceae) et al., 2005). For example, we have previously shown that in
is a woody vine growing up to 30 m, distributed from the Bolivia, the Tacanas administer U. tomentosa bark concentrated
Amazonian to Central American rain forests. It is popularly known decoction for the treatment of rheumatism, irregular menstrua-
as ‘‘Uña de Gato’’ (Cat’s claw) because of its claw-shaped thorns. In tion, and ailments of digestive tract, liver, and kidney (Bourdy
traditional medicine, people use it in the form of a decoction taken et al., 2000). The traditionally reported medicinal properties of U.
orally. Three bark strips of approximately 11 cm  3 cm are tomentosa have been validated by numerous experimental studies
placed in 1 l of cold water and boiled gently for at least 15–20 min demonstrating its antiviral, antioxidant, antiproliferative, immu-
to obtain a strong, dark dyed extract. Three cups (ca. 150 ml) of nostimulant, antimicrobial, and anti-inflammatory activities
this decoction are drunk for the treatment of various diseases (Aquino et al., 1989; Senatore et al., 1989; Desmarchelier et al.,
related to inflammatory processes (Aguilar et al., 2002; Bourdy 1997; Sheng et al., 1998, 2000, 2001; Wurm et al., 1998; Lemaire
com. pers). U. tomentosa is one of the most commonly used plants et al., 1999; Lamm et al., 2001; Riva et al., 2001; Aguilar et al.,
2002; Sandoval et al., 2002; Akesson et al., 2003; Deharo et al.,
2004; Winkler et al., 2004; Goncalves et al., 2005; Pilarski
Abbreviations: IL, Interleukin; LPS, Lipopolysaccharide; THP-1, monocytic cells et al., 2006; Allen-Hall et al., 2007; Hardin, 2007).
(ATCC TIB-202); TNF, tumor necrosis factor; XTT, sodium 30 -[1-(phenylaminocar- The anti-inflammatory activity of traditional extracts made
bonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro) benzene sulfonic acid hydrate. from U. tomentosa bark is well documented (Erowele and
n
Corresponding author at: Université de Toulouse, Université Paul Sabatier,
Kalejaiye, 2009). A water extract of micro-pulverised bark
Faculté de Pharmacie, Pharma-Dev UMR 152, 31062 Toulouse Cedex, France.
Tel.: þ33 05 62 25 65 68; fax: þ33 05 62 25 98 02. of U. tomentosa was able to inhibit the expression of tumour
E-mail address: [email protected] (E. Deharo). necrosis factor-a (TNF-a), which is known to stimulate the acute

0378-8741/$ - see front matter & 2012 Published by Elsevier Ireland Ltd.
http://dx.doi.org/10.1016/j.jep.2012.07.015
802 R. Rojas-Duran et al. / Journal of Ethnopharmacology 143 (2012) 801–804

phase reaction of the inflammation processes (Sandoval et al., 2.3. Biological tests
2000; Paul et al., 2006; Tincani et al., 2007). In addition, it
has been demonstrated that an ethanolic extract of U. tomentosa 2.3.1. In vitro cytotoxicity assays
bark was able to inhibit the liberation of TNF-a by lipopolysac- 20  103 cells K562 cells and 5  104 cells murine peritoneal
charide (LPS)-activated THP-1 monocytic cells (Allen-Hall et al., macrophages were incubated at 37 1C for 24 or 48 h in 96-wells
2010). microplates with increasing concentrations of mitraphylline
From a chemical standpoint, U. tomentosa has also been (1–100 mM; total volume: 100 ml). Afterwards, 50 ml of XTT were
extensively studied. The majority of alkaloids of Uncaria are of added to each well. Absorbance of the formazan dye produced by
the indole and oxindole families (Laus, 2004). Mitraphylline is the metabolically active cells was measured at 490 nm using a
most ubiquitous alkaloid being present in 20 of 34 Uncaria species Muktiskan FC Microplate Photometer (Thermo Scientific). Each
(Heitzman et al., 2005). Nevertheless, its activity on immunomo- assay was performed in triplicate.
dulatory markers has not been studied so far. Thus, we decided to
explore in a murine model the impact of mitraphylline on the 2.4. In vivo assays
production of 16 different cytokines involved in inflammation,
using an ELISA multiplex system. We also measured its cytotoxi- Eight-week-old Balb/c female mice were maintained on a 24 h
city on K565 cell line and murine macrophages. light/dark cycle, with food and water ad libitum. All experimental
animal procedures were conducted in accordance with the Guide-
lines of the National Legislation on Animal Care of the French
2. Materials and methods
statutory law (N12001-464). Batches of six mice were treated orally
with 30 mg/kg/day of mitraphylline, for 3 days. The dose was defined
2.1. Plant material
according to preliminary test on mice to assess tolerability, leading to
the highest cytokine signal. At that dose no apparent toxicity was
Bark from U. tomentosa was collected in Pucallpa (Ucayali
observed. The control group received 0.9% saline solution, while
region), Eastern Peru. Extraction with solvents of increasing
dexamethasone (2 mg/kg/day, oral route) was used as reference. Two
polarity was performed on dried milled material. A voucher
hours after the last dose, mice were injected intraperitoneally with
(BM 1500) was deposited at the National Herbarium of the San
saline-diluted LPS, which is an endotoxin of Gram-negative bacteria
Marcos University in Lima, Peru. Pr. Alban Castillo confirmed the
that causes massive release of cytokines. Two hours later, they were
botanical determination.
sacrificed and blood quickly collected. After coagulation, the serum
was recovered and centrifuged for 10 min at 2500 rpm. Sixteen
2.2. Bioguided fractionation studies different mouse cytokines [Interleukin (IL)-1a, IL-1b, IL-2, IL-3, IL-4,
IL-5, IL-6, IL-9, IL-10, IL-12, MCP-1, INF-g, TNF-a, MIP-1, GMCSF, and
Fifty grams of U. tomentosa bark was extracted with chloro- Rantes] were detected using the mouse cytokine Elisa multiplex
form (maceration, 5 days). Chloroform extract showed better Q-plex system, where distinct capture antibodies are spotted to each
anti-TNF-a activity than water extract (20% and 5% at 10 mg/ml, well of a 96-well plate in a defined array. A total of 30 ml of
respectively), then, the former was subjected to a bioguided supernatant was used following manufacturer’s instructions
fractionation process. Successive normal phase column chroma- (Quansys Biosciences, USA). Detection was performed using the
tography, using mixtures of chloroform and ethyl-acetate at Q-ViewTM Imager. The images were processed using Q-ViewTM
increasing polarities, led to the isolation of the pentacyclic Software. Sensitivity typically ranged between 30 pg/ml and less
oxindole alkaloid, the mitraphylline which was the major com- than 1 pg/ml. Statistical analysis was performed with GraphPad
pound in the extract (Fig. 1). Prism 5.01 (GraphPad Software, San Diego).
HPLC was performed using a VWR-Hitachi Elite Lachrom with
photodiode array detector. Samples were injected onto a Puro-
sphersSTAR RP-18e column (150  4.6 mm; 5 mm particle size) 3. Results and discussion
and eluted with 35% acetonitrile in phosphate buffer (pH 6.6) at a
flow rate of 1.8 ml/min. The volume injected was 20 ml and As previously described, our fractionation of a chloroformic
eluates were monitored at 245 nm. Authentic standards of oxi- extract of U. tomentosa revealed that mitraphylline was the
ndolic alkaloids were obtained from Chromadex (Laguna Hills, preponderant alkaloid of chloroformic Uncaria extract (Laus,
CA). 1H (300 MHz) and 13C (75 MHz) NMR experiments were run 2004). We evaluated the biological relevance of this molecule
on a Bruker AC-300, using CDCl3 as a solvent for mitraphylline (Fig. 2) and showed that it was able to impair the liberation of
and oxindolic alkaloid standards. TNF-a by 50% when administrated to mice orally at 30 mg/kg for
3 days. It also inhibited nearly 70% of the release of IL-1a and -1b.
This is comparable to dexamethasone, which is known to abolish
LPS-induced IL-1b and TNF-a productions (Teeling et al., 2010).
This result could have spectacular implications in the treatment
of some auto-immune diseases, such as rheumatoid and osteoar-
thritis, given the crucial roles of IL-1b and TNF-a in their
aggravation and progression (Dinarello, 2011).
Mitraphylline also reduced the production of IL-4 about 40% in
our murine model, while dexamethasone was inactive. IL-4 is a
pleiotropic cytokine produced by activated T cells, mast cells, and
basophils. This interleukin is particularly involved in allergies and
inflammation (Saggini et al., 2011). Impairing the production of
these pro-inflammatory cytokines might offer new therapeutic
tactics for the control of allergy and inflammation.
Mitraphylline also reduced IL-17 production by 50%. This
Fig. 1. Structure of mitraphylline. interleukin is known to play a protective role in host defence
 R. Rojas-Duran et al. / Journal of Ethnopharmacology 143 (2012) 801–804 803

Fig. 2. Percentage of inhibition of IL 1a,b, 4, 17 and TNF in mice receiving DEXA: dexamethasone (2 mg/kg/day) and MITRA: mitraphylline (30 mg/kg/day). The percentage
is related to control mice. P-value o0.001 for IL4 only.

especially in bacterial infections. Nevertheless, excessive activa- anti-inflammatory treatment. Further studies should be con-
tion contributes to autoimmunity. Reports from pharmaceutical ducted to determine the concentration of mitraphylline in
industries indicate that neutralizing members of this interleukin extracts and its exact role in the context of whole herbal
family have beneficial therapeutic impact in the treatment of remedies. In a recent review, Deharo and Ginsburg (2011) clearly
some auto-immune diseases (Pappu et al., 2011). Lastly, mitra- pointed out that for many plants used in traditional medicine, the
phylline displayed a focused immunological effect, as it did not isolated active molecules alone could not explain the activity of
show any in vivo impact on the levels of IL-2, IL-3, IL-5, IL-6, IL-9, the remedy because of their low concentration in the preparation.
IL-10, IL-12, MCP-1, INF-g, MIP-1, GMCSF, or Rantes. It would be interesting to search for other compounds, which
Mitraphylline did not show any toxicity against K562 cells nor contribute to the medicinal activity of U. tomentosa extracts in an
murine macrophages in vitro at doses up to 100 mM. This activity effort to optimize the traditional preparation.
seems to be cell specific, as some authors showed that it had a
cytotoxic effect on Human Ewing’s sarcoma and breast cancer cell
lines (Garcia Gimenez et al., 2010). It was also shown to be more Acknowledgments
cytotoxic than cyclophosphamide and vincristine on human
glioma cell lines (Garcia Prado et al., 2007). German Gonzalez was awarded a fellowship from the Coop-
For the first time, we showed herein that mitraphylline, the ération Technique Belge. The authors are grateful to CONCYTEC
major alkaloid of U. tomentosa, is able to modulate the immuno- (Project 334–2007-CONCYTEC-OAJ) for its financial support. The
logical status of mice subjected to LPS, and is probably, at least authors have written this article under the auspices of CaP
partially, responsible for the anti-inflammatory activity of Uncaria (Chemotherapy against Parasites/Consortium antiParasitaire).
bark extracts. Indeed, extracts have been shown to inhibit the We are indebt to Dr. Brian Gadd and Stéphane Bertani, from the
activation of nuclear factor-kB (NF-kB), which regulates host Cell, Molecular, and Developmental Biology Department of the
immune and anti-inflammatory responses (Aguilar et al., 2002). University of California Riverside for discussions and in-depth
It has also been demonstrated that extracts inhibit in vitro the reading of this manuscript.
expression of TNF-a, promote the liberation of lymphocyte-pro-
liferation-regulating factor by human endothelial cells, and
extends lymphocyte survival (Wurm et al., 1998; Akesson et al., References
2003). According to certain authors, the anti-inflammatory activity
of Uncaria extracts would not rely solely upon alkaloids (Sandoval Aguilar, J.L., Rojas, P., Marcelo, A., Plaza, A., Bauer, R., Reininger, E., Klaas, C.A.,
Merfort, I., 2002. Anti-inflammatory activity of two different extracts of
et al., 2002). Nevertheless, alkaloids per se are at least partially Uncaria tomentosa (Rubiaceae). Journal of Ethnopharmacology 81, 271–276.
responsible for the anti-inflammatory activity in traditional med- Akesson, C., Lindgren, H., Pero, R.W., Leanderson, T., Ivars, F., 2003. An extract of
icine. Indeed, a clinical trial carried out on patients affected with Uncaria tomentosa inhibiting cell division and NF-kappa B activity without
inducing cell death. International Immunopharmacology 3, 1889–1900.
rheumatoid arthritis reduced the pain in 50% of patients treated Allen-Hall, L., Arnason, J.T., Cano, P., Lafrenie, R.M., 2010. Uncaria tomentosa acts
with alkaloids-enriched extract of U. tomentosa (Mur et al., 2002). as a potent TNF-alpha inhibitor through NF-kappaB. Journal of Ethnopharma-
cology 127, 685–693.
Allen-Hall, L., Cano, P., Arnason, J.T., Rojas, R., Lock, O., Lafrenie, R.M., 2007.
Treatment of THP-1 cells with Uncaria tomentosa extracts differentially
4. Conclusion regulates the expression if IL-1beta and TNF-alpha. Journal of Ethnopharma-
cology 109, 312–317.
Mitraphylline could be used as a quality control marker for Aquino, R., De Simone, F., Pizza, C., Conti, C., Stein, M.L., 1989. Plant metabolites.
Structure and in vitro antiviral activity of quinovic acid glycosides from
herbal medicines based on the Uncaria extracts. It could also Uncaria tomentosa and Guettarda platypoda. Journal of Natural Products 52,
be considered as a new lead compound for the development of 679–685.
804 R. Rojas-Duran et al. / Journal of Ethnopharmacology 143 (2012) 801–804

Bourdy, G., DeWalt, S.J., Chavez de Michel, L.R., Roca, A., Deharo, E., Munoz, V., Paul, A.T., Gohil, V.M., Bhutani, K.K., 2006. Modulating TNF-alpha signaling with
Balderrama, L., Quenevo, C., Gimenez, A., 2000. Medicinal plants uses of the natural products. Drug Discovery Today 11, 725–732.
Tacana, an Amazonian Bolivian ethnic group. Journal of Ethnopharmacology Pilarski, R., Zielinski, H., Ciesiolka, D., Gulewicz, K., 2006. Antioxidant activity of
70, 87–109. ethanolic and aqueous extracts of Uncaria tomentosa (Willd.) DC. Journal of
Deharo, E., Baelmans, R., Gimenez, A., Quenevo, C., Bourdy, G., 2004. In vitro Ethnopharmacology 104, 18–23.
immunomodulatory activity of plants used by the Tacana ethnic group in Riva, L., Coradini, D., Di Fronzo, G., De Feo, V., De Tommasi, N., De Simone, F., Pizza,
Bolivia. Phytomedicine 11, 516–522. C., 2001. The antiproliferative effects of Uncaria tomentosa extracts and
Deharo, E., Ginsburg, H., 2011. Analysis of additivity and synergism in the fractions on the growth of breast cancer cell line. Anticancer Research 21,
antiplasmodial effect of purified compounds from plant extracts. Malaria 2457–2461.
Journal 10 (Suppl 1), S5. Saggini, A., Maccauro, G., Tripodi, D., De Lutiis, M.A., Conti, F., Felaco, P., Fulcheri,
Desmarchelier, C., Mongelli, E., Coussio, J., Ciccia, G., 1997. Evaluation of the in vitro M., Galzio, R., Caraffa, A., Antinolfi, P., Felaco, M., Pandolfi, F., Sabatino, G., Neri,
antioxidant activity in extracts of Uncaria tomentosa (Willd.) DC. Phytotherapy
G., Shaik-Dasthagirisaheb, Y.B., 2011. Allergic inflammation: role of cytokines
Research 2, 254–256.
with special emphasis on IL-4. International Journal of Immunopathology and
Dinarello, C.A., 2011. A clinical perspective of IL-1beta as the gatekeeper of
Pharmacology 24, 305–311.
inflammation. European Journal of Immunology 41, 1203–1217.
Sandoval, M., Charbonnet, R.M., Okuhama, N.N., Roberts, J., Krenova, Z.,
Erowele, G.I., Kalejaiye, A.O., 2009. Pharmacology and therapeutic uses of cat’s
Trentacosti, A.M., Miller, M.J., 2000. Cat’s claw inhibits TNFalpha production
claw. American Journal of Health-system Pharmacy 66, 992–995.
Garcia Prado, E., Garcia Gimenez, M.D., De la Puerta Vazquez, R., Espartero and scavenges free radicals: role in cytoprotection. Free Radical Biology &
Sanchez, J.L., Saenz Rodriguez, M.T., 2007. Antiproliferative effects of mitra- Medicine 29, 71–78.
phylline, a pentacyclic oxindole alkaloid of Uncaria tomentosa on human Sandoval, M., Okuhama, N.N., Zhang, X.J., Condezo, L.A., Lao, J., Angeles, F.M.,
glioma and neuroblastoma cell lines. Phytomedicine 14, 280–284. Musah, R.A., Bobrowski, P., Miller, M.J., 2002. Anti-inflammatory and antiox-
Garcia Gimenez, D., Garcia Prado, E., Saenz Rodriguez, T., Fernandez Arche, A., De la idant activities of cat’s claw (Uncaria tomentosa and Uncaria guianensis) are
Puerta, R., 2010. Cytotoxic effect of the pentacyclic oxindole alkaloid mitra- independent of their alkaloid content. Phytomedicine 9, 325–337.
phylline isolated from Uncaria tomentosa bark on human Ewing’s sarcoma and Senatore, A., Cataldo, A., Iaccarino, F.P., Elberti, M.G., 1989. Phytochemical and
breast cancer cell lines. Planta Medica 76, 133–136. biological study of Uncaria tomentosa. Bollettino della Societa italiana di
Goncalves, C., Dinis, T., Batista, M.T., 2005. Antioxidant properties of proantho- biologia sperimentale 65, 517–520.
cyanidins of Uncaria tomentosa bark decoction: a mechanism for anti- Sheng, Y., Bryngelsson, C., Pero, R.W., 2000. Enhanced DNA repair, immune
inflammatory activity. Phytochemistry 66, 89–98. function and reduced toxicity of C-MED-100, a novel aqueous extract from
Hardin, S.R., 2007. Cat’s claw: an Amazonian vine decreases inflammation in Uncaria tomentosa. Journal of Ethnopharmacology 69, 115–126.
osteoarthritis. Complementary Therapies in Clinical Practice 13, 25–28. Sheng, Y., Li, L., Holmgren, K., Pero, R.W., 2001. DNA repair enhancement of
Heitzman, M.E., Neto, C.C., Winiarz, E., Vaisberg, A.J., Hammond, G.B., 2005. aqueous extracts of Uncaria tomentosa in a human volunteer study. Phytome-
Ethnobotany, phytochemistry and pharmacology of Uncaria (Rubiaceae). dicine 8, 275–282.
Phytochemistry 66, 5–29. Sheng, Y., Pero, R.W., Amiri, A., Bryngelsson, C., 1998. Induction of apoptosis and
Keplinger, K., Laus, G., Wurm, M., Dierich, M.P., Teppner, H., 1999. Uncaria inhibition of proliferation in human tumor cells treated with extracts of
tomentosa (Willd.) DC. ethnomedicinal use and new pharmacological, toxico- Uncaria tomentosa. Anticancer Research 18, 3363–3368.
logical and botanical results. Journal of Ethnopharmacology 64, 23–34. Teeling, J.L., Cunningham, C., Newman, T.A., Perry, V.H., 2010. The effect of non-
Lamm, S., Sheng, Y., Pero, R.W., 2001. Persistent response to pneumococcal vaccine steroidal anti-inflammatory agents on behavioural changes and cytokine
in individuals supplemented with a novel water soluble extract of Uncaria
production following systemic inflammation: implications for a role of COX-
tomentosa, C-Med-100. Phytomedicine 8, 267–274.
1. Brain Behavior and Immunity 24, 409–419.
Laus, G., 2004. Advances in chemistry and bioactivity of the genus Uncaria.
Tincani, A., Andreoli, L., Bazzani, C., Bosiso, D., Sozzani, S., 2007. Inflammatory
Phytotherapy Research 18 (4), 259–274.
molecules: a target for treatment of systemic autoimmune diseases.
Lemaire, I., Assinewe, V., Cano, P., Awang, D.V., Arnason, J.T., 1999. Stimulation of
Autoimmunity Reviews 7, 1–7.
interleukin-1 and -6 production in alveolar macrophages by the neotropical
Williams, J.E., 2001. Review of antiviral and immunomodulating properties of
liana, Uncaria tomentosa (uña de gato). Journal of Ethnopharmacology 64,
109–115. plants of the Peruvian rainforest with a particular emphasis on Uña de Gato
Mur, E., Hartig, F., Eibl, G., Schirmer, M., 2002. Randomized double blind trial of an and Sangre de Grado. Alternative Medicine Review 6, 567–579.
extract from the pentacyclic alkaloid-chemotype of Uncaria tomentosa for the Winkler, C., Wirleitner, B., Schroecksnadel, K., Schennach, H., Mur, E., Fuchs, D.,
treatment of rheumatoid arthritis. The Journal of Rheumatology 29, 678–681. 2004. In vitro effects of two extracts and two pure alkaloid preparations of
Obregón, L., 1997. ‘‘Uña de gato’’. Género Uncaria. Estudios botánicos, quı́micos y Uncaria tomentosa on peripheral blood mononuclear cells. Planta Medica 70,
farmacológicos de Uncaria tomentosa, Uncaria guianensis., 3 ed. Instituto de 205–210.
Fitoterapia Americano, Lima, Peru. Wurm, M., Kacani, L., Laus, G., Keplinger, K., Dierich, M.P., 1998. Pentacyclic
Pappu, R., Ramirez-Carrozzi, V., Sambandam, A., 2011. The interleukin-17 cytokine oxindole alkaloids from Uncaria tomentosa induce human endothelial cells to
family: critical players in host defence and inflammatory diseases. Immuno- release a lymphocyte-proliferation-regulating factor. Planta Medica 64,
logy 134, 8–16. 701–704.

View publication stats