Photodynamic effect of meso-(aryl)porphyrins and meso-(1-methyl-4-pyridinium)porphyrins on HaCaT keratinocytes.

Sixteen porphyrins, including neutral, anionic and cationic meso-(aryl)porphyrins and meso-(1-methyl-4-pyridinium)porphyrins were herein evaluated in terms of their photosensitizing properties against HaCaT keratinocytes. After an initial screening, the cationic porphyrins were studied in more details, by both determining their log POW and performing PDT assays in lower porphyrin concentrations. Porphyrins presenting two or more adjacent positively charged groups, directly linked to the macrocycle meso positions, appeared to be the most effective photosensitizers. The present study also included the dicationic 5,10-diphenyl-15,20-di(1-methylpyridinium-4-yl)porphyrin (14b), which has previously shown promising results on a psoriasis-like in vivo model. Overall results indicated that the beneficial effect related to porphyrins on psoriasis can be related to the decreasing of keratinocyte viability. Furthermore, some of the cationic porphyrins studied appeared as candidates to be utilized as photosensitizers for psoriasis treatment.

Hspa8 and ICAM-1 as damage-induced mediators of γδ T cell activation.

Tissue-resident γδ T cells form the first line of defense at barrier surfaces where they survey host tissue for signs of stress or damage. Following recognition of injury, γδ T cells play a crucial role in the wound-healing response through the production of growth factors and cytokines that promote proliferation in surrounding epithelial cells. To initiate this response, γδ T cells require interactions with a variety of epithelial-expressed costimulatory molecules in addition to primary signaling through their TCR. In the epidermis these signals include the coxsackie and adenovirus receptor (CAR), histocompatibility antigen 60c (H60c), and plexin B2, which interact with γδ T cell-expressed junctional adhesion molecule-like protein (JAML), NKG2D, and CD100, respectively. Here we identify heat shock protein family A member 8 (Hspa8) and ICAM-1 as two additional keratinocyte-expressed costimulatory molecules for epidermal resident γδ T cells (termed DETC). These molecules were rapidly up-regulated in the epidermis following wounding in both mouse and human tissue. Both Hspa8 and ICAM-1 had a costimulatory effect on DETC, inducing proliferation, CD25 up-regulation, and IL-2 production. We also provide evidence that DETC can be activated through the potential ICAM-1 and Hspa8 receptors LFA-1 and CD316. Finally, knockdown of Hspa8 in keratinocytes reduced their ability to activate DETC in culture and ICAM-1-/- mice exhibited impaired rates of healing in skin-organ culture suggesting a role for these proteins in the DETC-mediated damage response. Together with previous work on CAR, H60c, and plexin B2, these results add to a picture of a complex keratinocyte wound signature that is required for efficient DETC activation.

Morinda citrifolia Linn (Noni): in vivo and in vitro reproductive toxicology.

UNLABELLED: Morinda citrifolia Linn (syn. Noni) is a plant widely used as food and medicine worldwide but there are no toxicological tests about this plant focused on reproduction. AIM OF THE STUDY: To investigate possible endocrine activity and toxic effect on the reproductive system of Wistar rats by exposure of aqueous extract of the Morinda citrifolia. MATERIALS AND METHODS: Two experimental protocols in vivo were developed, (a) uterotrophic assay and (b) in utero and lactational assay, and one test in vitro to investigate the effect on the contractility of pregnant uteri isolated from rats (doses of the extract: 7.5, 75 and 750 mg/kg). RESULTS: The uterotrophic assay indicates presence of in vivo antiestrogenic activity of extract at doses of 7.5 and 750 mg/kg. The in utero and lactation exposure showed that the treatment with extract at the dose of 7.5mg/kg induced a reduction of 50% in parturition index and an increase of 74% in postimplantation losses index. The in vitro test showed that uteri from rats treated with 7.5mg/kg of the extract presented a 50% reduction on contraction induced by arachidonic acid. CONCLUSION: The exposure of aqueous extract of Morinda citrifolia in Wistar rats induced reproductive toxicity in nonlinear dose-response.

Anti-inflammatory effects of hydroalcoholic extract and two biflavonoids from Garcinia gardneriana leaves in mouse paw oedema.

Garcinia gardneriana (Planch. & Triana) Zappi (Clusiaceae) is widely distributed in Brazil and used in folk medicine to treat inflammation, pain, and urinary tract and other infections. However, very few studies have analyzed these therapeutic effects. In this study, the anti-inflammatory effects of the hydroalcoholic extracts from Garcinia gardneriana (HEGG) and some of its isolated biflavonoids were evaluated. The results showed that HEGG from the leaves, bark and seeds reduced carrageenan-induced mouse paw inflammation, in addition to diminishing the myeloperoxidase activity in the stimulated tissues. The reduction of neutrophil infiltration by treatment with the HEGG from leaves was confirmed by histology. The leaf extract also reduced the paw oedema evoked by bradykinin, histamine, prostaglandin E2 and 12-O-tetradecanoylphorbol acetate. However, it partially decreased substance P and compound 48/80-caused paw oedema, without any influence on the arachidonic acid-induced oedema. Both of the isolated compounds, fukugetin and GB-2a, prevented the carrageenan-induced paw oedema. In conclusion, this study showed important anti-inflammatory effects of HEGG through its interaction with different intracellular signaling pathways, without interfering with the formation of arachidonic acid (AA) metabolites. These characteristics, in addition to the wide distribution and culturing ease of the plant, confirm its popular use and highlight its promise in the development of new anti-inflammatory drugs.

Mechanisms underlying the inhibitory actions of the pentacyclic triterpene alpha-amyrin in the mouse skin inflammation induced by phorbol ester 12-O-tetradecanoylphorbol-13-acetate.

The present study evaluated some of the mechanisms through which alpha-amyrin, a pentacyclic triterpene isolated from Protium Kleinii and other plants, exerts its effects against 12-O-tetradecanoylphorbol-acetate (TPA)-induced skin inflammation in mice. Topical application of alpha-amyrin (0.1-1 mg/ear) dose-dependently inhibited TPA-induced increase of prostaglandin E2 (PGE2) levels. In contrast with the selective cyclooxygenase (COX)-1 SC560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole] or COX-2 rofecoxib inhibitors, alpha-amyrin failed to alter either COX-1 or COX-2 activities in vitro. Western blot analysis revealed that alpha-amyrin dose-dependently inhibited TPA-induced COX-2 expression in the mouse skin. The evaluation of nuclear factor-kappaB (NF-kappaB) pathway revealed that topical treatment with alpha-amyrin is able to prevent IkappaB alpha degradation, p65/RelA phosphorylation and NF-kappaB activation. Moreover, alpha-amyrin given topically dose-dependently inhibited the activation of upstream protein kinases, namely extracellular signal-regulated protein kinase (ERK), p38 mitogen-activated protein kinase (MAPK) and protein kinase C (PKC)alpha, following topical TPA treatment. Collectively, present results suggest that topical skin application of alpha-amyrin exerts a strong and rapid onset inhibition of TPA-induced inflammation. These effects seem to be associated with the suppression of skin PGE2 levels by mechanisms involving the suppression of COX-2 expression, via inhibition of upstream protein kinases--namely ERK, p38 MAPK and PKCalpha--and blocking of NF-kappaB activation. These results indicate that alpha-amyrin-derivative could be potentially relevant for the development of a topical agent for the management of inflammatory diseases.

Pre-clinical efficacy assessment of Malva sylvestris on chronic skin inflammation.

In the search for improved quality of life, the treatment of skin diseases like psoriasis (hyperproliferative disease) is valid, since it causes huge social discomfort to the patient. In this context, earlier studies showed that Malva sylvestris L. has anti-inflammatory activity demonstrated by acute animal models of skin inflammation, becoming a promising target for further studies. The present investigation aimed to verify the effect of hydroalcoholic extract of M. sylvestris (HEMS) on the chronic inflammatory and hyperproliferative response caused by multiple applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) on mouse ears. Topical application of HEMS reduced oedema, leukocyte migration (mono- and polymorphonuclear cells) and keratinocyte hyperproliferation, confirmed by histology and proliferating cell nuclear antigen (PCNA) immunostaining. It was found that the anti-inflammatory effects of the extract did not involve the glucocorticoid system, and its incubation with HaCaT keratinocytes caused low toxicity and reduced cell proliferation by apoptosis. Thus, HEMS proved to be effective as an anti-psoriatic therapy, with the ability to prevent keratinocyte hyperproliferation and with low toxicity by topical application.

Topical antiinflammatory effects of the ether extract from Protium kleinii and alpha-amyrin pentacyclic triterpene.

Protium kleinii (Burseraceae), a native Brazilian medicinal plant is claimed to be useful to treat some inflammatory states. Now we reported that topical application of either the ether extract or the main active constituent from P. kleinii the pentacyclic triterpene alpha-amyrin, all caused a dose-related inhibition of both ear oedema (ID50 values are 0.55 and 0.31 mg/ear, respectively) and influx of polymorphonuclear cells (ID50 values are 0.72 and 0.45 mg/ear, respectively) in response to topical application of 12-O-tetradecanoylphorbol-acetate (TPA) in the of mice ear. In terms of the efficacy, the maximal obtained inhibition for both ear oedema and neutrophil influx was very similar to that produced by the topical application of the steroidal antiinflammatory drug dexamethasone (DE; with inhibition of 70+/-5%, 66+/-3%, and 87+/-4% for oedema and 83+/-6%, 73+/-5%, and 91+/-3% for neutrophil influx, for the ether extract, alpha-amyrin, and dexamethasone, respectively). Likewise, both the ether extract and alpha-amyrin given topically dose-dependently prevented the increase of the proinflammatory cytokine interleukin-1beta levels in response to topical application of TPA. The calculated mean ID50 values are 1.81 and 0.53 mg/ear, respectively. Again, the efficacy of the extract and alpha-amyrin was very similar to that produced by dexamethasone (63+/-6%, 61+/-5%, and 74+/-5%, respectively). In marked contrast to phenidone, a lipo and cyclooxygenase inhibitor, neither the ether extract nor the alpha-amyrin inhibited arachidonic acid-mediated ear oedema in mice. Collectively, these results indicate that the active constituents present in the ether extract of P. kleinii including the pentacyclic triterpene alpha-amyrin are good candidates to develop a skin permeable antiinflammatory drug.

The practice of OTC counseling by community pharmacists in Parana, Brazil.

BACKGROUND: In order to provide appropriate advice to the patient at the time of dispensing and over-the-counter (OTC) medication counseling, community pharmacists need access to current and reliable information about medicines. Brazilian pharmacists have assumed new functions such as prescribing medication, in a dependent model, based in protocols. OBJECTIVE: To examine the practice of community pharmacists in a Brazilian State, focusing on OTC recommendation. METHOD: A cross-sectional survey of community pharmacists in a state of Brazil was conducted from October 2013 to January 2014, with data collection through a pre-piloted self-administered anonymous survey via Survey Monkey(®) platform. Following ethical approval, the online instrument was sent to 8,885 pharmacists registered in Parana State, Brazil, focusing on professionals working in community pharmacies. The questionnaire assessed the community pharmacy setting, the search for information, the knowledge of the evidence-based practice, the important factors to consider when recommending an OTC medicine, and the pharmacist prescribing. Responses were imported into SPSS(®) (version 22.0) for analysis. Nonparametric tests were used to assess the association between responses and demographic information with a significance level less than 5% (p<0.05). RESULTS: Of the pharmacists, 97.4% dispensed medications and counseled patients for a median of six hours per day. Product's efficacy (97%) and adverse effects (62.3%) were the most important factors taken into account when counseling a nonprescription medicine. Few pharmacists knew the meaning of terms related to evidence-based health. Most respondents agreed that pharmacists have the necessary training to prescribe. CONCLUSION: Over-the-counter medication counseling is a daily practice among Brazilian pharmacists. Learning needs exist for community pharmacists in relation to evidence-based practice. Thus, sources of information with good evidence could be used daily by community pharmacists, especially as regards nonprescription medication counseling.

Topical anti-inflammatory activity of a monofloral honey of Mimosa scabrella provided by Melipona marginata during winter in southern Brazil.

Melipona marginata is an endangered species of stingless bee from Brazil that produces honey with particular physicochemical features and a remarkable exotic flavor. To the best of our knowledge, this is the first report devoted to exploring the medicinal potential of this honey. Thus, the aim of this paper was to investigate the potential anti-inflammatory activity of honey extract from M. marginata on skin inflammation. The honey sample was classified as a monofloral honey of Mimosa scabrella. The presence of 11 phenolic compounds as kaempferol and caffeic acid was detected using the high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-UV-ESI-MS) method. The anti-inflammatory activity was measured using a 12-O-tetradecanoylphorbol-13-acetate-induced ear edema model of inflammation in mice. The topical application of the M. marginata honey extract (1.0 mg/ear) was able to reduce ear edema with an inhibitory effect of 54 ± 5%. This extract decreased the myeloperoxidase activity in 75 ± 3%, which suggests a lower leucocyte infiltration that was confirmed by histological analysis. This extract also provided a reduction of 55 ± 14% in the production of reactive oxygen species. This anti-inflammatory activity could be due to a synergic effect of the phenolic compounds identified in the honey sample. Taken together, these results open up new possibilities for the use of M. marginata honey extract in skin disorders.

Efficacy of topical antifungals in the treatment of dermatophytosis: a mixed-treatment comparison meta-analysis involving 14 treatments.

IMPORTANCE: Considering that most randomized controlled trials compare antifungals with placebo instead of other antifungals, conventional meta-analysis is insufficient to define superiority between the evaluated strategies. To our knowledge, this is the first mixed-treatment comparison meta-analysis on antifungal treatments in the literature and shows all the evidence available at the time of the study. OBJECTIVE: To evaluate and compare the efficacy of topical antifungals used in dermatophytosis treatment, using mixed-treatment comparisons. EVIDENCE ACQUISITION: We performed a comprehensive search (up to July 31, 2012) for all entries in MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, Literatura Latino Americana e do Caribe em Ciências da Saúde, and International Pharmaceutical Abstracts. Randomized controlled trials that compared topical antifungals with one another or with placebo in dermatophytosis treatment were selected for analysis. Methodologic quality of the trials was assessed using the Jadad scale. We excluded studies that scored less than 3 points. The outcomes evaluated were mycologic cure at the end of treatment and sustained cure. A random-effects Bayesian mixed-treatment comparisons model was applied to combine placebo-controlled and direct topical antifungals comparison trials. RESULTS Pooled data of the 65 trials identified did not show any statistically significant differences among the antifungals concerning the outcome of mycologic cure at the end of treatment. Regarding the sustained cure outcome, butenafine hydrochloride and terbinafine hydrochloride were significantly more efficacious than were clotrimazole, oxiconazole nitrate, and sertaconazole nitrate. Terbinafine also demonstrated statistical superiority when compared with ciclopirox (ciclopiroxolamine), and naftifine hydrochloride showed better response compared with oxiconazole. No inconsistency was detected in the network of evidence for both outcomes, sustaining the validity of the mixed-treatment comparisons results. CONCLUSIONS AND RELEVANCE: With the outcome mycologic cure at the end of treatment, there was no significant difference among the antifungals. Butenafine, naftifine, and terbinafine might be the best strategies for maintaining cured status. Because of the different costs of the antifungals, pharmacoeconomic analysis is required to identify the most efficient strategy for dermatophytosis management.

Pre-clinical anti-inflammatory aspects of a cuisine and medicinal millennial herb: Malva sylvestris L.

Malva sylvestris has been used since ancient times for its emollient, laxative and anti-inflammatory properties, being extensively used as salads, soups and teas. The preset study evaluated the topical anti-inflammatory action of M. sylvestris hydroalcoholic extract (HE) and its compounds in mice ear inflammation caused by 12-O-tetradecanoylphorbol-acetate in mice. The LC-MS analysis of the HE confirmed the presence of scopoletin, quercetin and malvidin 3-glucoside compounds in the HE of M. sylvestris. Topical application of the HE reduced ear oedema, polymorphonuclear cells influx (myeloperoxydase activity and histological analysis) and interleukin-1ß levels in the tissue. The topical application of the compound present in the HE, malvidin 3-glucoside was also able to inhibit ear oedema and leukocytes migration. The other tested compounds, scopoletin, quercetin and malvidin 3,5-glucoside were able to prevent the formation of oedema and cell infiltration, but with less effectiveness when compared to HE and malvidin 3-glucoside. Therefore, these results consistently support the notion that M. sylvestris leaves possesses topical anti-inflammatory activity, the compound malvidin 3-glucoside seems to be major responsible for this effect, with the participation of other anti-inflammatory compounds in the extract. Thus, as recommended by population, M. sylvestris can be used as a future treatment to skin disorders.

Hyperpigmentant activity of leaves and flowers extracts of Pyrostegia venusta on murine B16F10 melanoma.

ETHNOPHARMACOLOGICAL RELEVANCE: Pyrostegia venusta is a native Brazilian plant which has a variety of uses in traditional folk medicine including the treatment of vitiligo. However, its effectiveness on melanogenesis is not yet elucidated. AIM OF THE STUDY: This study aimed to investigate the melanogenic activity of hydroalcoholic extracts from the leaves and flowers of P. venusta on murine B16F10 melanoma cells. MATERIALS AND METHODS: Different concentrations of the hydroalcoholic extracts of flowers and leaves of P. venusta were evaluated in trials of spontaneous melanin content (4 days), and cell viability by the MTT assay in murine B16F10 cells, and in the mushroom tyrosinase activity in vitro. RESULTS: Both extracts, leaves (0.1; 0.3; 1 and 3 µg/mL) and flowers (0.03 and 0.1 µg/mL) increased the melanin content in a concentration dependent manner after 4 days of incubation on melanoma cells. Leaves extract promoted enhancement of melanogenesis with maximum effect of 33.3±3% (3 µg/mL), and the flower extract increased in 23.4±3% (0.1 µg/mL). The cell viability test using MTT showed that in the same tested concentrations of both extracts no cell death was detected. Actually, either extract was not able to cause any change in the tyrosinase activity. HPLC analysis of P. venusta extracts found 0.09% and 1.08% of allantoin on leaves and flowers extracts, respectively. CONCLUSIONS: The leaves and flowers extracts of P. venusta stimulates B16F10 melanogenesis at very low concentrations. These findings support the folk medicinal use of P. venusta on the treatment of hypopigmentation diseases, such as vitiligo.

Garcinia gardneriana (Planchon & Triana) Zappi. (Clusiaceae) as a topical anti-inflammatory alternative for cutaneous inflammation.

Garcinia gardneriana is popularly used in skin disorders; therefore, this article investigated the effect of G. gardneriana extracts from leaves, bark and seeds and two isolated compounds in ear oedema and leucocytes migration caused by croton oil. The topical application of the extract of G. gardneriana leaves was able to reduce (70 ± 3%, and ID(50) 0.33 mg/ear) ear oedema, while the seeds (51 ± 5%) and the wood (60 ± 12%) extracts were less effective. In a time-course evaluation, the leaf extract (1 mg/ear) was effective when applied 2 hr before and until 3 hr after the stimulation, presenting a higher effectiveness when applied right after croton oil (83 ± 7% inhibition). In addition, the leaf extract was able to diminish the myeloperoxidase (MPO) activity in 64 ± 13%, which suggests the inhibition of leucocyte infiltration that was confirmed by histological analysis. Also, both biflavonoids isolated from the leaves of G. gardneriana, fukugetin (or morelloflavone) and 13-naringenin-II 8-eriodictyol (GB-2a), were able to reduce ear oedema, with ID(50) values of 0.18 (0.10-0.28) and 0.22 (0.15-0.31) mg/ear, respectively, besides the inhibition of MPO activity of 52 ± 6% and 64 ± 5%, respectively. Using the fluorescent probe 2',7'-dichlorodihydrofluorescein diacetate, the leaf extract, fukugetin and GB-2a topically applied to the ear treated with croton oil reduced 52 ± 15%, 63 ± 17% and 83 ± 4%, respectively, the production of reactive oxygen species of the skin. Thus, these results reveal the anti-inflammatory effect of G. gardneriana leaves for topical usage, and both biflavonoids are responsible for this effect.

Effectiveness of Vernonia scorpioides ethanolic extract against skin inflammatory processes.

ETHNOPHARMACOLOGICAL RELEVANCE: Vernonia scorpioides (Asteraceae) is a native Brazilian medicinal plant that is commonly used to treat skin disorders. Considering the traditional use of Vernonia scorpioides and the lack of information about its pharmacological properties, we investigated the topical anti-inflammatory effect of the ethanolic extract of Vernonia scorpioides (EEVS) on acute and chronic cutaneous inflammation models in mouse. MATERIALS AND METHODS: The topical anti-inflammatory effect of EEVS was evaluated against acute models (12-O-tetradecanoylphorbol acetate (TPA)- and arachidonic acid (AA)-induced mouse ear oedema) and chronic models (multiple applications of croton oil). RESULTS: The EEVS caused a dose-related inhibition of oedema in both the TPA- and AA-induced acute models (DI(50)=0.24 and 0.68 mg/ear with an inhibition of 80 ± 5% and 65 ± 5%, respectively, for 1mg/ear). In addition, the TPA-induced increase in myeloperoxidase activity (MPO) in the ear was reduced (77 ± 8%) by the topical application of EEVS. In the chronic model, the EEVS reduced all parameters evaluated: oedema formation (31 ± 2%), epidermal hyperproliferation (histology) and MPO (25 ± 10%). However, the topical treatment of EEVS had no effect on N-acetyl-ß-d-glucosaminidase activity. The EEVS effectively interfered in the ear oedema on the delayed-type hypersensitivity reaction induced by oxazolone. The topical treatment with EEVS performed on both phases or only on the elicitation phase caused the inhibition of the ear oedema-induced by oxazolone in 42.9% and 63.4%, respectively, when compared to control animals (sensitized and challenged). CONCLUSIONS: The results suggest that EEVS is effective as a topical anti-inflammatory agent in acute and chronic inflammatory processes and that its action is markedly influenced by the inhibition of neutrophil migration into inflamed tissue as well as by epidermal hyperproliferation.

Anti-inflammatory effect of crude extract and isolated compounds from Baccharis illinita DC in acute skin inflammation.

UNLABELLED: ETHNOPHARMACOLOGYCAL RELEVANCE: The tea from the leaves of Baccharis illinita DC (Asteraceae family) is commonly used by the population as anti-inflammatory (including topically), protective gastric and anti-infectious. However, no studies have been done with this species to confirm its topical anti-inflammatory action. AIM: This study evaluated he topical effects of crude extract of leaves (CE) and its active constituents in 12-O-tetradecanoylphorbol acetate (TPA)-induced ear oedema. METHODOLOGY: CE and compounds effects were tested in commonly used models of TPA-, arachidonic acid (AA)- and capsaicin-ear oedema. Polymorphonuclear (PMN) cell migration was evaluated by mieloperoxidase and analyzed histologically. RESULTS: CE (0.1-1 mg/ear) caused a dose-related inhibition of TPA-induced ear oedema and PMN influx similarly to that produced by topical application of the steroidal anti-inflammatory drug dexamethasone. The active constituents of the AcOEt fraction kaurenoic acid, alpha-spinasterol, oleanolic acid and baurenol also inhibited TPA-induced ear edema. Histological analysis of the ear of CE-treated animals confirmed the reduction of edema and of PMN infiltration. Both CE and the nosteroidal anti-inflammatory drug indomethacin inhibited the AA-induced ear oedema, but did not change capsaicin-induced oedema. CONCLUSION: These results indicate that the CE and the active constituents have a topical anti-inflammatory effect and the possible mechanisms for the pharmacological effects are discussed.

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Antinociceptive properties of mixture of alpha-amyrin and beta-amyrin triterpenes: evidence for participation of protein kinase C and protein kinase A pathways.

The mixture of the two pentacyclic triterpenes alpha-amyrin and beta-amyrin, isolated from the resin of Protium kleinii and given by intraperitoneal (i.p.) or oral (p.o.) routes, caused dose-related and significant antinociception against the visceral pain in mice produced by i.p. injection of acetic acid. Moreover, i.p., p.o., intracerebroventricular (i.c.v.), or intrathecal (i.t.) administration of alpha,beta-amyrin inhibited both neurogenic and inflammatory phases of the overt nociception caused by intraplantar (i.pl.) injection of formalin. Likewise, alpha,beta-amyrin given by i.p., p.o., i.t., or i.c.v. routes inhibits the neurogenic nociception induced by capsaicin. Moreover, i.p. treatment with alpha,beta-amyrin was able to reduce the nociception produced by 8-bromo-cAMP (8-Br-cAMP) and by 12-O-tetradecanoylphorbol-13-acetate (TPA) or the hyperalgesia caused by glutamate. On the other hand, in contrast to morphine, alpha,beta-amyrin failed to cause analgesia in thermal models of pain. The antinociception caused by the mixture of compounds seems to involve mechanisms independent of opioid, alpha-adrenergic, serotoninergic, and nitrergic system mediation, since it was not affected by naloxone, prazosin, yohimbine, DL-p-chlorophenylalanine methyl ester, or L-arginine. Interestingly, the i.p. administration of alpha,beta-amyrin reduced the mechanical hyperalgesia produced by i.pl. injection of carrageenan, capsaicin, bradykinin, substance P, prostaglandin E2, 8-Br-cAMP, and TPA in rats. However, the mixture of compounds failed to alter the binding sites of [3H]bradykinin, [3H]resiniferatoxin, or [3H]glutamate in vitro. It is concluded that the mixture of triterpene alpha-amyrin and beta-amyrin produced consistent peripheral, spinal, and supraspinal antinociception in rodents, especially when assessed in inflammatory models of pain. The mechanisms involved in their action are not completely understood but seem to involve the inhibition of protein kinase A- and protein kinase C-sensitive pathways.

Anti-inflammatory compounds of plant origin. Part I. Action on arachidonic acid pathway, nitric oxide and nuclear factor kappa B (NF-kappaB).

Over the last 10 years, a significant body of evidence has emerged indicating that chemically diverse classes of naturally-occurring substances derived from higher plants are of potential interest for therapeutic interventions in several inflammatory diseases. Part I of this review article focuses on our current knowledge of the mechanisms by which a large range of plant-derived constituents interfere with three relevant targets involved in the inflammatory process, namely arachidonic acid metabolite pathways, nitric oxide and NF-kappaB, and discusses their potential therapeutic use in the management of relevant inflammatory diseases.

Anti-inflammatory compounds of plant origin. Part II. modulation of pro-inflammatory cytokines, chemokines and adhesion molecules.

It has been widely shown that many plant-derived compounds present significant anti-inflammatory effects. For this reason, they represent potential molecules for the development of new drugs, especially designed for the treatment and/or control of chronic inflammatory states such as rheumatism, asthma, inflammatory bowel diseases, atherosclerosis, etc. This review focuses on the naturally-occurring compounds with anti-inflammatory properties and attempts to correlate their actions with the modulation of cytokines and associated intracellular signalling pathways; it continues the review published in the November, 2003 issue of Planta Medica. Abbreviations. AP-1:activator protein-1 CCR1:chemokine receptor 1 CINC-1:cytokine-induced neutrophil chemoattractant 1 COX:cyclooxygenase EGCG:(-)-epigallocatechin gallate ELAM-1:endothelial-leukocyte adhesion molecule-1 ERK:extracellular signal-regulated kinase GRO:growth-related oncogene HUVEC:human umbilical vein endothelial cells ICAM-1:intercellular adhesion molecule-1 IFN:interferon IL:interleukin iNOS:inducible nitric oxide synthase IRA:the natural interleukin receptor activation JAK:janus kinase JNK:c-Jun NH2-terminal kinase LPS:lipopolysaccharide MAPK:mitogen-activated protein kinases MCP:monocyte chemotactic protein MHC:major histocompatibility complex MIP:macrophage inflammatory protein MMP:matrix metalloproteinases MPO:myeloperoxidase NF-kappaBnuclear factor kappa B NO:nitric oxide PAF:platelet aggregation factor PGEE:prostaglandin PK:protein kinase PMA/TPA:phorbol myristate acetate RANTES:regulated upon activation normal T-cell expressed and secreted TGF-beta:transforming growth factor-beta TNFalpha:tumour necrosis factor VCAM-1:vascular cell adhesion molecule-1