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Activity of taraxasteryl acetate on inflammation and heat shock protein synthesis.


Pluchea sagittalis whole plant dichloromethane extract showed inhibitory activity in several inflammatory models: rat hind paw-edema, mice ear edema, and air-pouch rat granuloma. The extract inhibited the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in stimulated human neutrophils. It also showed inhibitory effect on heat shock protein 72 (hsp72) synthesis in stimulated neutrophils, while it had opposite effects on unstimulated cells. The triterpene taraxasteryl acetate was obtained from the dichloromethane extract by bioassay directed isolation, being active against induced ROS and RNS production in human neutrophils. In mice ear edema (induced by phorbol-12-mirystate-13-acetate, croton oil and arachidonic acid), taraxasteryl acetate showed a topical anti-inflammatory activity similar to the extract, but at 1/20 of the dose. The same ratio was observed for the inhibition of hsp72 production in stimulated human neutrophils. In unstimulated monocytes and neutrophils, taraxasteryl acetate showed a higher stimulating activity of hsp72 production than the extract, involving different mechanisms in each cell type. To our knowledge, taraxasteryl acetate is the first natural product for which a dual effect on the hsp response is reported.

[c] 2004 Elsevier GmbH. All rights reserved.

Keywords: Pluchea sagittalis; Taraxasteryl acetate; Anti-inflammatory activity; Oxidative stress; Heat shock proteins



Pluchea sagittalis (Lam.) Cabrera, known as "lucera", is widely used in the folk medicine of Argentina and Uruguay. It is taken before or after meals as a digestive tea, this use being confirmed by clinical observations (Soraru and Bandoni, 1979). It is also used as a poultice of leaves for headache. Regarding its phytochemical composition, some studies have been performed on the essential oil (Talenti, 1976), sesquiterpenes (Bohlmann et al., 1980), flavonoids (Martino et al., 1976) and caffeoylquinic derivatives (Martino et al., 1979).

Several studies have been reported on anti-inflammatory activity of different Pluchea sp., as P. lanceolata (Chawla et al., 1991) and P. indica (Sen et al., 1993). The aqueous and dichloromethane extracts of P. sagittalis have also shown anti-inflammatory activity in a previous screening (Perez et al., 1995; Perez-Garcia et al., 1996). In a screening for activity of 18 plant extracts on reactive oxygen species (ROS), reactive nitrogen species (RNS) and heat shock protein (hsp) production in human neutrophils, the dichloromethane extract of P. sagittalis presented the best activity (Perez Garcia et al., 2001). The main objective of this work was to search for new anti-inflammatory phytochemicals from P. sagittalis by anti-oxidant bioassay directed isolation and using oxidative stress and stress protein synthesis as targets, since it is well known that ROS and hsp are involved in inflammation as mediators (Polla and Cossarizza, 1996; van Eden, 2000).

Materials and methods

General experimental procedures

Hanks balanced salt solution (HBSS), croton oil, arachidonic acid, dextran, carrageenan, zymosan, plate-let-activating factor (PAF), indomethacin, phenylbutazone, methysergide, dexamethasone, phorbol-12-mirystate-13-acetate (PMA), N-formyl-methionyl-leucyl-phenylalanine (FMLP), sodium nitroprusside (SNP), W-13, H-7, genistein and propidium iodide were purchased from Sigma Chemical Co (USA). Hydrogen peroxide was obtained from Jansen (Belgium), 2',7'-dichlorofluorescin diacetate (DCFH-DA) from Serva (Germany), monoclonal antibody anti-hsp72 from Stressgen (Canada) and the components of the lysis solution were from Panreac (Spain).

Flow cytometry analyses were performed using an EPICS XL (Coulter, USA) flow cytometer. Leukocyte subpopulations were discriminated by forward and side scatter measurements, and the fluorescence of 10,000 viable neutrophils and above 1000 viable monocytes from each sample was measured.

CC stationary phases were silica gel 60 35-70 [micro]m (Chromagel, SDS, Peypin, France) and Sephadex LH-20 (Pharmacia Fine Chemicals, Uppsala, Sweden). MPLC (Buchi B-680) was over silica gel 60 25-40 [micro]m (Lichroprep Si 60, Merck, Darmstadt, Germany), and Flash Chromatography was performed over silica gel 60 35-70 [micro]m (Chromagel, SDS, Peypin, France). For preparative TLC, silica gel 60 [F.sub.254] plates (1 mm of layer thickness, Merck, Darmstadt, Germany) were used. Analytical TLC was performed on silica gel 60 [F.sub.254] aluminium sheets (Merck, Darmstadt, Germany). EI-MS and CI-MS spectra were obtained on a Hewlett Packard 5989A Mass Spectrometer. NMR measurements were performed at 300 K in CH[Cl.sub.3]-[d.sub.6], using TMS as internal standard, on a Brucker AC 400 spectrometer, operating at 400.16 and 100.62 MHz for proton and carbon, respectively, using an inverse prove.

Plant material

Whole plants of P. sagittalis (Lam.) Cabrera (Asteraceae) were collected at flowering stage in Cabracorral-Saladillo (Salta, Argentina). Plant material was authenticated by Prof. L. Novara (Universidad Nacional de Salta, Argentina) and a voucher specimen has been deposited in the BCF Herbarium (Faculty of Pharmacy, University of Barcelona) under the number 38322.

Extraction and isolation

Dichloromethane extract was prepared by Soxhlet extraction (12 h) of 1000 g of dried and powdered plant material with dichloromethane, then concentrated under reduced pressure, below 40[degrees]C, and the remaining dichloromethane was evaporated in an inert atmosphere of nitrogen. The yield was 5%. Taraxasteryl acetate was obtained from this extract by anti-oxidant activity guided isolation. Dichlorometane extract (50 g) was submitted to Flash Chromatography (using a gradient of dichloromethane to methanol), yielding 15 fractions. Fraction 1 (2.5 g) showed the highest anti-oxidant activity and was submitted to MPLC separation eluting with a gradient of hexane to dichlorometane. The activity was concentrated in the fraction 3 (580 mg), which was submitted to CC over silicagel eluted with a gradient of hexane to dichloromethane, giving 9 fractions. Preparative TLC of the fraction 6 (205 mg), eluted with a mixture of hexane:dichloromethane 1:1, followed by CC on Sephadex LH-20 eluted with the same mixture afforded 30 mg of the pure substance 1 (Fig. 1), which was identified as taraxasteryl acetate by a combination of standard spectroscopic methods (EI-MS, CI-MS, [.sup.1]H-NMR, [.sup.13]C-NMR, HMQC, HMBC, COSY and NOESY) and comparison with spectroscopic data from literature (Reynolds et al., 1984, 1985; Reynolds and Enriquez, 1996).


Topical anti-inflammatory tests

Male Swiss CD-1 albino mice (Interfauna, Sant Feliu de Codines, Spain) of 20-25 g were used for ear edema tests. Inflammation was evaluated measuring the weight of a plug of 7 mm diameter from the ear in a prescribed time after induction of inflammation (Young and de Young, 1989). Dichloromethane extract was tested at 100 [micro]g/ear. Indomethacin (0.2 [micro]mol/ear) was used as reference drug. Arachidonic acid, croton oil, and PMA were used as inflammatory agents as previously described (Perez-Garcia et al., 1996).

Hind paw edema tests

Female Wistar rats (Interfauna, Sant Feliu de Codines, Spain) of 130-160 g were used. The effect of dichloromethane extract (100 mg/kg i.p.) or the reference drug against the induced hind paw edema was recorded plethysmographically at 0, 15, 30, 45, 60 and 90 min after the induction of the inflammation (Young and de Young, 1989). Different inflammatory agents (dextran, zymosan, platelet activating factor, and arachidonic acid) were used according to Perez-Garcia et al. (1996).

Carrageenan air-pouch test

For semichronic evaluation of inflammation, male Sprague-Dawley rats of 130-160 g (Interfauna, Sant Feliu de Codines, Spain) were used in the carrageenan air-pouch test (Young and de Young, 1989). Dichloromethane extract or phenylbutazone, both at daily dose of 100 mg/kg were administered s.c. during 5 days. The anti-inflammatory effect was evaluated at the sixth day by measuring the exudate volume, the granulomatous tissue weigh and the number of cells present (Counter Coulter Multisizer II, cytometer, NJ, USA).

Preparation of human leukocytes

Leukocytes were isolated from buffy coat obtained from blood of healthy donors (Hospital de la Vall d'Hebron, Barcelona) as previously described (Perez-Garcia et al., 2001).

ROS and RNS measurements

Flow cytometry was used for evaluating ROS and RNS in human neutrophils, using 2',7'-dichlorofluorescin diacetate as fluorescence probe (Perez-Garcia et al., 2001). For measuring ROS production, [H.sub.2][O.sub.2], PMA or FMLP were used as stimulants, whereas SNP, or PMA with the calmodulin inhibitor W-13 were used as stimulants for measuring RNS production. Extract or 1 were tested at 0.3-100 [micro]g/ml or 0.3-100 [micro]M, respectively.

Hsp72 measurements

They were performed by flow cytometry according to Perez-Garcia et al. (2001). For measuring inhibitory activity, hsp production was induced using heat (42[degrees]C, 120 min.), PMA (10 [micro]M, 120 min), [H.sub.2][O.sub.2] (100 [micro]M, 120 min) or SNP (10 [micro]M, 120 min) and extract (1-100 [micro]g/ml) or 1 (1-100 [micro]M) were tested using HBSS as blank. To measure stimulant activity, cells were not previously stimulated and extract or 1 were tested at 100 [micro]g/ml or 100 [micro]M, respectively, towards the time (0-5 h). Additionally, stimulant activity was also studied with 1 (100 [micro]M) plus genistein (10 [micro]M), W-13 (10 [micro]M) or H-7 (10 [micro]M).


In the ROS, RNS and hsp experiments, viability was measured simultaneously by propidium iodide exclusion in the flow cytometer. It was above 95% in all experiments.

Statistical analysis

The results are presented as means [+ or -] standard deviation (s.d.). Statistics was performed using one-way analysis of variance (ANOVA) and Student's t test.

Results and discussion

The dichloromethane extract of P. sagittalis showed a broad spectrum of anti-inflammatory activity: on topical inflammation (Table 1), rat hind-paw edema induced by dextran, zymosan and arachidonic acid (Table 1), as well as in the semichronic model of carrageenan air-pouch granuloma, in which it reduced the volume of the inflammatory exudate, the wet weigh of granulomatous tissue and the cell concentration (Table 2). In the topical model of ear mice edema, the extract was active at 1000 [micro]g/ear against all the phlogogen agents tested (croton oil, PMA and arachidonic acid), whereas taraxasteryl acetate (Table 3) had the same level of activity at 46 [micro]g/ear (100 [micro]mol/ear), which is a 1/20 of the dose of the extract. This means that taraxasteryl acetate is an important active compound of the extract.

Nowadays, there is a well-established relationships between inflammation, free radicals and hsp. Inflammation results from the recruitment to a given tissue and activation of leukocytes, that induces oxidative stress. Also, it is observed that there is an influence on the expression of hsp72, which protects cells and tissues from the deleterious effects of free radicals. The primary action of several anti-inflammatory compounds has been attributed to the disruption of eicosanoid metabolism, but also an increase in hsp72 expression could contribute to the anti-inflammatory effect. It has been found that non-steroidal anti-inflammatory drugs induce hsp72 in monocytes (Housby et al., 1999). In addition, some findings underscore an inverse relationship between COX-2 expression and hsp72 induction (Ethridge et al., 1998), and the fact that the anti-inflammatory prostaglandin [A.sub.1] induces hsp72 synthesis (Elia et al., 1996).

The dichloromethane extract of P. sagittalis showed dose-dependent inhibitory activity against ROS and RNS (Table 4) production in stimulated neutrophils. At 100 [micro]g/ml, it inhibited hsp72 production induced by four agents in human neutrophils (Table 4), but, at the same concentration, it was also able to increase hsp72 in unstimulated cells (Fig. 2), showing a maximum (38% in neutrophils and 65% in monocytes) 1 h after starting the treatment. These activities can contribute to its anti-inflammatory action. It has been suggested that anti-oxidants can inhibit neutrophil influx contributing to the modulation of inflammation (McGilvray and Rotstein, 1999). This is in accordance with the reduction of cell number in the exudate caused by the extract in the granuloma experiments.



Taraxasteryl acetate showed a similar pattern of activity concerning ROS, RNS and hsp72 (Table 4, Figs. 3 and 4) as the dichloromethane extract of P. sagittalis. Nevertheless, it cannot be considered responsible of the inhibition of ROS and RNS production in the extract, since taraxasteryl acetate had the same level or less activity than the extract for ROS and RNS. For example, concerning results on ROS generation induced by PMA, the I[C.sub.50] of the extract and the taraxasteryl acetate were 10.0 [micro]g/ml and 43 [micro]M (= 20 [micro]g/ml), respectively. In the case of RNS induced by SNP, the I[C.sub.50] of the extract was 1.0 [micro]g/ml, whereas taraxasteryl acetate produced an inhibition of 50.4% at 46 [micro]g/ml (= 100 [micro]M).


In contrast, as it has been seen for the anti-inflammatory activity, taraxasteryl acetate appears as an important agent responsible for the activity of the extract on hsp. In this field, taraxasteryl acetate showed a dual effect, producing inhibition on stimulated cells (Table 4) and stimulation on unstimulated cells (Figs. 2 and 3). At 100 [micro]g/ml, the extract produced an inhibition of hsp72 production ranging from 30.8% to 45.7%, depending on the stimulant used, and taraxasteryl acetate produced similar inhibitions (35.4%-50.7%) at a dose of 4.6 [micro]g/ml (= 10 [micro]M), which is ca. 1/20 of the dose of the extract. When stimulant was not used, taraxasteryl acetate produced a stimulation of 95% (neutrophils) and 568% (monocytes) at 46 [micro]g/ml (= 100 [micro]M), whereas the stimulations caused by the extract at 100 [micro]g/ml were 65.6% and 38.8%, respectively. This stimulation of hsp synthesis could explain, at least in part, the inhibitory activity of taraxasteryl acetate on topical inflammation.

It is interesting to point out that, among natural products, only some flavonoids, such as quercetin, have been found to reduce hsp72 synthesis (Hosokawa et al., 1990) by a mechanism that seems not related to PKC inhibition (Katengwa and Polla, 1991) but to the inhibition of the transcription factor heat shock factor (HSF1) (Lee et al., 1994). Taraxasteryl acetate has a dual effect on hsp72 synthesis on human neutrophils. It acts as inhibitor on cells previously stimulated (Table 4), but as a stimulator on cells not stimulated (Fig. 2). This stimulation seems to be produced by a PKC dependent mechanism, since it is inhibited by H-7, which is a known PKC inhibitor, but not by W-13 and genistein, which are inhibitors of calcium-calmodulin and tyrosine kinase, respectively (Fig. 3). In human monocytes, taraxasteryl acetate stimulated hsp72 on not stimulated cells (Fig. 4), but no effect was observed on stimulated cells (results not shown). The monocyte stimulation of hsp72 was inhibited by W-13 but not by H-7 and genistein (Fig. 4), suggesting a calcium calmodulin dependent pathway.

In conclusion, P. sagittalis dichloromethane extract showed anti-inflammatory activity in rat hind paw-edema, as well as in subchronic and topical models. The extract inhibited ROS and RNS production in stimulated neutrophils. It also showed inhibitory effect on hsp72 synthesis on stimulated neutrophils, while it had opposite effect on unstimulated cells. The activity is, at least in part, due to the triterpene taraxasteryl acetate, that showed topical anti-inflammatory effect. The anti-inflammatory activity of taraxasteryl acetate can be related to its ability to reduce the induced ROS and RNS, as well as to modulate hsp72 production in human neutrophils. In unstimulated monocytes and neutrophils it was able to stimulate hsp72 production involving different mechanisms: results suggest a calcium-calmodulin-dependent one in the first case and a PKC-dependent one in the second case. To our knowledge, taraxasteryl acetate is the first natural product that has shown a dual effect on the hsp response.
Table 1. Anti-inflammatory activity of the dichloromethane extract of
Pluchea sagittalis at 1000 [micro]g/ear in mice ear edema test (topical
inflammation), and at 100 mg/kg i.p. in rat hind paw edema, both induced
by several inflammatory agents

 Inflammation (%)
Inflammatory agent Control Reference drug

Mouse ear edema (n = 10)
Arachidonic acid 107.6 [+ or -] 8.3 58.9 [+ or -] 8.5 (b)
Croton oil 99.3 [+ or -] 6.1 61.5 [+ or -] 6.2 (b)
PMA 105.4 [+ or -] 3.4 66.0 [+ or -] 3.1 (b)

Rat hind paw edema (n = 6) (c)
Dextran 45.8 [+ or -] 3.0 23.0 [+ or -] 3.1 (d)
Zymosan 82.9 [+ or -] 6.2 42.8 [+ or -] 4.6 (d)
PAF 36.2 [+ or -] 3.5 21.5 [+ or -] 3.4 (e)
Arachidonic acid 51.6 [+ or -] 2.7 30.2 [+ or -] 3.8 (e)

 Inflammation (%) Inhibition (%) (a)
Inflammatory agent Extract Reference drug Extract

Mouse ear edema (n = 10)
Arachidonic acid 40.1 [+ or -] 4.6 45.3* 62.7*
Croton oil 45.1 [+ or -] 4.2 38.1* 54.6*
PMA 60.3 [+ or -] 4.4 37.4* 42.8*

Rat hind paw edema (n = 6) (c)
Dextran 19.6 [+ or -] 3.3 56.9* 48.8*
Zymosan 44.1 [+ or -] 5.0 48.2* 46.6*
PAF 39.4 [+ or -] 4.0 42.3* -6.3
Arachidonic acid 8.7 [+ or -] 5.9 41.3* 82.5*

(a) Statistical significance: *p<0.05.
(b) Indomethacin (0.2 [micro]mol/ear).
(c) Data of inflammation corresponding to 45 min. (maximum
inflammation), and data of inhibition corresponding to AUC (area under
the curve).
(d) Methysergide (1 mg/kg i.p.).
(e) Dexamethasone (1 mg/kg i.p.).

Table 2. Effect of the dichloromethane extract of Pluchea sagittalis and
phenylbutazone (reference drug), both at 100 mg/kg s.c. daily, on
carrageenan air-pouch test (n = 8)

 Control Phenylbutazone

Weight (g) 15.8 [+ or -] 2.9 6.6 [+ or -] 2.1
Volume (ml) 22.1 [+ or -] 4.0 10.7 [+ or -] 2.8
Cells X [10.sup.6]/ml 36.5 [+ or -] 7.6 38.2 [+ or -] 5.0

 Inflammation Inhibition (%) (a)
 Extract Phenylbutazone Extract

Weight (g) 9.6 [+ or -] 1.2 58.2* 39.2*
Volume (ml) 7.6 [+ or -] 2.8 51.6* 65.6**
Cells X [10.sup.6]/ml 18.1 [+ or -] 3.2 -4.7 50.4*

Inflammation (mean [+ or -] s.d.) is represented as increment in weight
of the wet granulomatous tissue and volume of the inflammatory exudate.
Exudate cell number is also shown.
(a) Statistical significance: *p<0.05, **p<0.01.

Table 3. Topical anti-inflammatory activity of taraxasteryl acetate (100
[micro]mol/ear) in mice ear edema induced by several agents (n = 10)

 Inflammation (%)
Inflammatory agent Control Indomethacin

Arachidonic acid 95.1 [+ or -] 5.6 55.1 [+ or -] 5.4
Croton oil 111.3 [+ or -] 4.2 70.1 [+ or -] 4.0
PMA 99.5 [+ or -] 6.0 48.6 [+ or -] 4.9

 Inhibition (%) (a)
 Inflammation (%) Taraxasteryl
Inflammatory agent Taraxasteryl acetate Indomethacin acetate

Arachidonic acid 34.7 [+ or -] 3.2 42.1* 63.5*
Croton oil 58.9 [+ or -] 5.3 37.0* 47.1*
PMA 39.8 [+ or -] 5.1 51.2* 60.0*

Indomethacin (0.2 [micro]mol/ear) was used as reference drug.
(a) Statistical significance: *p<0.05.

Table 4. Effect of the dichloromethane extract of Pluchea sagittalis and
taraxasteryl acetate on production of ROS (induced by
[H.sub.2][O.sub.2], PMA and FMLP) RNS (induced by SNP and PMA + W - 13)
and hsp72 (induced by heat, [H.sub.2][O.sub.2], PMA and SNP) in human

 Inhibition (%) (a)
 Dichloromethane extract
Inducers 1 [micro]g/ml 10 [micro]g/ml

ROS production
[H.sub.2][O.sub.2] 10.3 [+ or -] 3.5 39.3 [+ or -] 4.0*
PMA 10.2 [+ or -] 4.8 31.0 [+ or -] 3.6*
FMLP -9.5 [+ or -] 6.9 17.1 [+ or -] 5.5

RNS production
SNP -6.1 [+ or -] 5.9 49.8 [+ or -] 4.3*
PMA + W13 10.0 [+ or -] 4.0 55.9 [+ or -] 3.9*

Hsp72 production
Heat 8.4 [+ or -] 3.9 6.8 [+ or -] 6.8
[H.sub.2]O 6.7 [+ or -] 5.6 17.5 [+ or -] 3.9
PMA 3.7 [+ or -] 4.7 20.0 [+ or -] 5.2
SNP 2.9 [+ or -] 5.7 21.3 [+ or -] 5.4

 Inhibition (%) (a)
 Dichloromethane extract Taraxasteryl acetate
Inducers 100 [micro]g/ml 1 [micro]M

ROS production
[H.sub.2][O.sub.2] 76.0 [+ or -] 3.9* -8.2 [+ or -] 4.3
PMA 79.8 [+ or -] 3.6* 5.2 [+ or -] 3.9
FMLP 51.1 [+ or -] 4.3* 0.5 [+ or -] 3.8

RNS production
SNP 83.5 [+ or -] 5.0* -5.1 [+ or -] 4.3
PMA + W13 85.0 [+ or -] 4.7* -0.2 [+ or -] 3.8

Hsp72 production
Heat 37.9 [+ or -] 4.7* 5.4 [+ or -] 6.0
[H.sub.2]O 30.1 [+ or -] 4.0* 10.0 [+ or -] 7.3
PMA 46.1 [+ or -] 3.8* 9.7 [+ or -] 4.3
SNP 40.0 [+ or -] 4.4* -5.4 [+ or -] 5.9

 Inhibition (%) (a)
 Taraxasteryl acetate
Inducers 10 [micro]M 100 [micro]M

ROS production
[H.sub.2][O.sub.2] 12.6 [+ or -] 5.1 40.0 [+ or -] 2.1*
PMA 31.6 [+ or -] 4.3* 87.6 [+ or -] 3.1*
FMLP 36.0 [+ or -] 3.6* 70.3 [+ or -] 5.8*

RNS production
SNP 45.3 [+ or -] 4.2* 58.8 [+ or -] 3.5*
PMA + W13 24.7 [+ or -] 4.8 49.7 [+ or -] 4.1*

Hsp72 production
Heat 44.3 [+ or -] 6.8* 55.8 [+ or -] 6.4*
[H.sub.2]O 38.9 [+ or -] 4.8* 64.5 [+ or -] 6.3*
PMA 48.9 [+ or -] 5.9* 67.8 [+ or -] 5.0*
SNP 30.4 [+ or -] 5.5* 48.0 [+ or -] 5.0*

Data are presented as percentage inhibition: mean [+ or -] s.d.
(n = 10).
(a) Statistical significance: *p<0.05.


The authors are grateful to the Hospital Vall d'Hebron (Barcelona) for providing the blood samples, and to the Flow Cytometry Unit of the Scientific-Technical Services of the University of Barcelona (Dr. Jaume Comas and Ms. Rosario Gonzalez).

Received 12 January 2004; accepted 31 March 2004


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F. Perez-Garcia (a), E. Marin (a), T. Parella (b), T. Adzet (a), S. Canigueral (a,*)

(a) Unitat de Farmacologia i Farmacognosia, Facultat de Farmacia, Universitat de Barcelona, Av. Diagonal, 643, E-08028 Barcelona, Spain

(b) Servei de Ressonancia Magnetica Nuclear, Departament de Quimica, Universitat Autonoma de Barcelona, E-08193 Bellaterra (Barcelona), Spain

*Corresponding author. Tel.: + 34 93 402 4531; fax: + 34 93 403 5982.

E-mail address: (S. Canigueral).
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Author:Perez-Garcia, F.; Marin, E.; Parella, T.; Adzet, T.; Canigueral, S.
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Geographic Code:1USA
Date:Apr 1, 2005
Previous Article:Extracts and constituents of Lavandula multifida with topical anti-inflammatory activity.
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