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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.

It has been demonstrated that periodontitis, a chronic oral disease, can induce systemic inflammation which is associated with systemic diseases, including rheumatoid arthritis. Here, we evaluated whether periodontitis can modulate the inflammatory response at a site distant to the oral cavity. Wistar rats were subjected to ligature-induced experimental periodontitis. Fourteen days after the procedure, paw edema was induced by carrageenan or by different receptor-specific inflammatory mediators. Blood and the tissue of the paws were obtained for TNF-α and IL-1β measurement. It was observed that carrageenan-induced paw edema and leukocyte migration was potentiated in periodontitis animals. The edema induced by carrageenan, bradykinin and des-Arg9-BK (B1 agonist) was also potentiated in periodontitis animals and blocked by a B1 antagonist. Ligature-induced periodontitis increased plasma levels of TNF-α and tissue IL-1β. Periodontitis also up-regulated kinin B1 receptor expression in paw tissue. Additionally, the treatment of ligature animals with anti-TNF-α, etanercept, completely abolished the potentiation of edema induced by des-Arg9-BK. Taken together, these results show that experimental periodontitis in rats can induce systemic inflammation through the up-regulation of kinin B1 receptors at a site distant from the oral cavity, modifying the inflammatory response.

Ethnopharmacological relevance 3β,6β,16β-Trihydroxylup-20(29)-ene (TTHL) is a triterpene isolated from the flowers of Combretum leprosum, a plant used in folk medicine in the north of Brazil for the treatment of skin disorders. Aim of the study In the present study, TTHL was evaluated as a potential topical anti-inflammatory and anti-proliferative agent through in vivo and in vitro models. Material and methods Anti-inflammmatory and anti-proliferative effects of TTHL were assessed using Swiss mice in acute and chronic models of skin inflammation induced by 12- O -tetradecanoylphorbol-acetate (TPA) application. Anti-proliferative activity was proved through in vitro experiments with the HaCaT human keratinocyte cell line. Results Treatment with TTHL inhibited inflammatory parameters such as oedema formation and cellular infiltration in acute and chronic models. In the chronic model, TTHL also inhibited epidermal hyperproliferation, as evidenced by reduction of epidermis thickness and proliferating cell nuclear antigen expression. The anti-proliferative effect was confirmed by the capability of TTHL in reducing the proliferation and inducing cell apoptosis of HaCaT cells. Suggesting a mechanism of action, TTHL showed activation of corticosteroid receptors, but without the induction of corticosteroid-related cutaneous side effects. Conclusion Our results demonstrate consistent anti-inflammatory and anti-proliferative activity and assign TTHL as a valuable tool in the development of a new treatment for skin inflammatory and proliferative diseases, such as psoriasis.

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.

Angiotensin-converting enzyme inhibitors (ACEIs) are widely used in the treatment of hypertension, congestive heart failure and renal disease, and are considered relatively safe and generally well-tolerated drugs. However, adverse effects of ACEIs have been reported, including non-productive cough and angioedema, which can lead to poor adherence to therapy. The mechanisms by which ACEIs promote adverse effects are not fully elucidated, although increased bradykinin plasma levels following ACEI therapy seem to play an important role. Since bradykinin can sensitise the transient potential vanilloid receptor 1 (TRPV1), we investigated the role of TRPV1 in plasma extravasation in the trachea and bronchi of rats treated with the ACEI captopril. We observed that intravenous (i.v.) administration of captopril did not cause plasma extravasation in the trachea or bronchi of spontaneously breathing rats, but induced plasma extravasation in the trachea and bronchi of artificially ventilated rats. The intratracheal (i.t.) instillation of capsaicin or bradykinin also induced an increase in plasma extravasation in the trachea and bronchi of artificially ventilated rats. As expected, capsaicin-induced plasma extravasation was inhibited by i.t. pretreatment with the TRPV1 selective antagonist capsazepine (CPZ) while bradykinin-induced plasma extravasation was reduced by i.t. pretreatment with the selective B2 receptor antagonist Icatibant, originally known as HOE 140 (HOE). Interestingly, bradykinin-induced plasma extravasation was also inhibited by CPZ. The pretreatment with HOE and CPZ, singly or in combination and at doses which do not cause inhibitory effects per se, significantly inhibited the plasma extravasation induced by captopril treatment in artificially ventilated rats. In addition, treatment with a high dose of capsaicin in newborn rats, which induces degeneration of TRPV1-expressing sensory neurons, abolished both capsaicin and captopril-induced plasma extravasation in artificially ventilated rats. In conclusion, our study identified that captopril treatment promoted sensitisation of TRPV1, via B2 receptor activation, inducing plasma extravasation in the airways of mechanically ventilated rats. The present findings add a new view about the role of TRPV1 in the plasma extravasation induced by captopril and could to contribute to the elucidation of mechanisms by which ACEI induces adverse effects on airways.

Multiple myeloma (MM) is a B cell bone marrow neoplasia characterized by inflammation with an intense secretion of growth factors that promote tumor growth, cell survival, migration and invasion. The aim of this study was to evaluate the effects of pravastatin, a drug used to reduce cholesterol, in a MM cell line.Cell cycle and viability were determinate by Trypan Blue and Propidium Iodide. IL6, VEGF, bFGF and TGFβ were quantified by ELISA and qRT-PCR including here de HMG CoA reductase. It was observed reduction of cell viability, increase of cells in G0/G1 phase of the cell cycle and reducing the factors VEGF and bFGF without influence on 3-Methyl-Glutaryl Coenzyme A reductase expression.The results demonstrated that pravastatin induces cell cycle arrest in G0/G1 and decreased production of growth factors in Multiple Myeloma cell line.

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.

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-1β 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.

The marine snail peptide ziconotide (ω-conotoxin MVIIA) is used as an analgesic in cancer patients refractory to opioids, but may induce severe adverse effects. Animal venoms represent a rich source of novel drugs, so we investigated the analgesic effects and the side-effects of spider peptide Phα1β in a model of cancer pain in mice with or without tolerance to morphine analgesia. Cancer pain was induced by the inoculation of melanoma B16-F10 cells into the hind paw of C57BL/6 mice. After 14 days, painful hypersensitivity was detected and Phα1β or ω-conotoxin MVIIA (10-100 pmol/site) was intrathecally injected to evaluate the development of antinociception and side-effects in control and morphine-tolerant mice. The treatment with Phα1β or ω-conotoxin MVIIA fully reversed cancer-related painful hypersensitivity, with long-lasting results, at effective doses 50% of 48 (32-72) or 33 (21-53) pmol/site, respectively. Phα1β produced only mild adverse effects, whereas ω-conotoxin MVIIA induced dose-related side-effects in mice at analgesic doses (estimated toxic dose 50% of 30 pmol/site). In addition, we observed that Phα1β was capable of controlling cancer-related pain even in mice tolerant to morphine antinociception (100% of inhibition) and was able to partially restore morphine analgesia in such animals (56 ± 5% of inhibition). In this study, Phα1β was as efficacious as ω-conotoxin MVIIA in inducing analgesia in a model of cancer pain without producing severe adverse effects or losing efficacy in opioid-tolerant mice, indicating that Phα1β has a good profile for the treatment of cancer pain in patients.

Ethnopharmacological relevance Combretum leprosum is a species that is popularly used in Brazil as a healing agent to treat skin problems and lesions. In this study we investigated the possible potential of this extract to treat inflammatory and hyperproliferative skin conditions. Materials and methods Classical models of skin inflammation such as TPA- and croton oil-induced mouse ear oedema were applied in order to verify the potential topical anti-inflammatory activity of the ethanolic extract from flowers of Combretum leprosum . Results Topical application of ethanolic extract promoted a dose-dependent inhibition of phorbol ester-induced ear oedema, reduced myeloperoxidase activity and IL-6 tissue levels with inhibition comparable to dexamethasone (positive control). Histological and immunohistochemical analysis revealed that ethanolic extract also suppressed cell infiltration. Ethanolic extract altered inflammatory parameters on a chronic skin inflammation model induced by repeated applications of croton oil, decreasing ear oedema, epidermal hyperproliferation and cell infiltration. In addition, immunohistochemical analysis showed that the extract decreased PCNA expression on the epidermis. Conclusion Taken together, these results suggest that the extract from flowers of Combretum leprosum could be considered as a new potential tool for the treatment of several skin inflammatory diseases since it reversed the skin inflammatory and hyperproliferative process in a very significant manner. Further investigations are needed in order to verify the cellular mechanism and safety of Combretum leprosum extract.

Background Statins represent a class of drugs that effectively lowers cholesterol, however they also possess pleiotropic effects, like promotion of angiogenesis, prevention of bone loss, immunomodulatory and anti-inflammatory effects. Objectives Thus, the aim of this study was to investigate the activity of simvastatin topically applied in mice in acute and chronic skin inflammation models. Methods Skin inflammation was induced in mice ears by topical application of 12-O-tetradecanoylphorbol acetate (TPA). In the acute model, ear oedema was measured by the increase of ear thickness 6h after TPA (2.5μg/ear). The chronic inflammatory process was induced by multiple applications of TPA (2.0μg/ear) for nine alternate days, and the oedema was measured daily as the increase in ear thickness. Results Topical treatment was applied immediately after TPA in acute model or started at 5th day of chronic experiment. For acute model treatment was simvastatin (0.24, 0.71 and 2.40μM), dexamethasone (0.13μM), both in acetone or vehicle alone (acetone). In chronic model simvastatin (1% and 3%) and dexamethasone (0.5%) were incorporated in ointment preparations, and a group received ointment alone (vehicle). Samples of ear tissue (6mm) were taken from acute and chronic models, weighted and prepared for histological analysis and myeloperoxidase (MPO) enzymatic activity evaluation. Application of simvastatin in acetone reduced the ear oedema after a single TPA application in a dose dependent manner [ID 50 of 0.47 (0.22–1.13) μM], and the MPO enzymatic activity up to 61±10%. Also, both simvastatin ointment preparations 1% and 3% reduced acute TPA-induced ear oedema in 55±7% and 65±8%, respectively. In the chronic model, simvastatin ointment 1% was able to reduce ear oedema (25±3%) and ear weight (10±1%), though 3% formulation augmented both parameters. Histological analysis revealed a reduction of swelling and leukocyte migration in the acute model for both the formulations of simvastatin (1% and 3%), while in chronic model simvastatin 1% decreased ear swelling and epidermal thickness, but simvastatin 3% increased both parameters. Conclusion The results confirm the anti-inflammatory activity of simvastatin when applied topically in both acute and chronic models of skin inflammation. Besides, the formulation of simvastatin ointment 1% shows to be a very effective formulation for a chronic usage.

The analysis of comparative efficacy and safety of topical antifungals in the literature is restricted to the treatment of tinea pedis and onychomycosis. Therefore our objective was to evaluate and compare the efficacy and safety of topical antifungals used in the treatment of dermatomycosis, we performed a comprehensive search for randomized controlled trials (RCTs) in the following databases: Medline, Cochrane Central Register of Controlled Trials, EMBASE, Lilacs and International Pharmaceutical Abstracts, we identified studies that compared the use of topical antifungals with other antifungals or with placebo published up to July 2010 in English, Spanish or Portuguese. The quality of reporting was assessed according to the Jadad scale; only studies with a score of 3 or more were included. The outcomes evaluated were mycological cure at the end of treatment, sustained cure, occurrence of adverse events and tolerability, including withdrawals due to adverse events. A total of 104 RCTs satisfied the inclusion criteria, containing a total of 135 comparisons, with 55 out of 120 possible comparisons among the 16 drugs evaluated. Pooled data on efficacy showed that all the antifungals were better than placebo. There were no significant differences among antifungal classes. No differences were found in safety or tolerability in any direct comparison. Sensitivity analysis indicated the robustness of the findings. Our results indicate the clear superiority of topical antifungals over placebo but that there is no consistent difference among classes. Mixed treatment comparisons are necessary to rank antifungals, as direct comparisons among many of them are lacking.

The aim of this study was to evaluate efficacy and safety of amfepramone, fenproporex and mazindol as a monotherapy for the treatment of obese or overweight patients. A systematic review of primary studies was conducted, followed by a direct meta-analysis (random effect) and mixed treatment comparison. Medline and other databases were searched. Heterogeneity was explored through I2 associated with a p-value. Of 739 identified publications, 25 were included in the meta-analysis. The global evaluation of Cochrane resulted in 19 studies with a high level of bias and six with unclear risk. Due to the lack of information in primary studies, direct meta-analyses were conducted only for amfepramone and mazindol. Compared to placebo, amfepramone resulted in higher weight loss in the short-term (

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 ID50 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 ID50 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.

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-tetradecanoilforbol 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, α-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.

Study Objective. To evaluate the efficacy and safety of using the anti-tumor necrosis factor-α (anti-TNF-α) drugs adalimumab, etanercept, and infliximab for the treatment of rheumatoid arthritis. Design. Systematic review and meta-analysis of 21 randomized, placebo-controlled trials (eight adalimumab, seven infliximab, six etanercept). Patients. Adults with rheumatoid arthritis who received adalimumab (1524 patients), infliximab (1116 patients), etanercept (1029 patients), or placebo (2834 patients) with or without concomitant methotrexate in all groups. Measurements and Main Results. A literature search of several databases from January 1995-December 2008 was performed. There were no restrictions based on language or date of publication, and low-quality studies (based on Jadad score) were excluded. American College of Rheumatology (ACR) 20% improvement criteria (ACR20), 50% improvement criteria (ACR50), and 70% improvement criteria (ACR70) were used to compare treatment efficacy. Safety was compared based on frequency of serious adverse events, serious infections, malignancy, and death. Withdrawals due to adverse events and lack of efficacy were also evaluated. With short-term treatment (12–30 wks), etanercept demonstrated the highest risk ratios (RRs) for reaching ACR20 and ACR50: 2.94 (95% confidence interval [CI] 2.27–3.81) and 5.28 (95% CI 3.12–8.92), respectively. Adalimumab demonstrated the highest RR for achieving ACR70 (5.36, 95% CI 3.76– 7.64). Over a long-term treatment course (1–3 yrs), adalimumab demonstrated the highest RRs (95% CIs) for these parameters: 1.85 (1.07–3.19), 2.80 (1.16–6.77), and 3.23 (1.37–7.61) for ACR20, ACR50, and ACR70, respectively. No statistically significant differences were noted in the safety of any of the three drugs compared with placebo. Infliximab had the highest RRs for withdrawing from the study due to lack of efficacy (2.05, 95% CI 1.33–3.16) and adverse events (0.41, 95% CI 0.18–0.95). Conclusion. With short-term treatment, etanercept and adalimumab had higher efficacy results; with long-term treatment, adalimumab appeared to be the most effective. Clinicians should be aware that each of the three drugs has different rates of efficacy and different safety considerations that must be taken into account when selecting the best treatment for an individual with rheumatoid arthritis.

Infliximab is a chimeric monoclonal antibody. Published studies indicate that its use in patients with rheumatoid arthritis can be efficient in providing long-term benefits. The aim of this study is to evaluate the efficacy and safety of using infliximab for the treatment of rheumatoid arthritis. A systematic review was performed to search for randomized clinical trials that compared intravenous administration of 3 mg/kg body weight infliximab or placebo in patients concomitantly using methotrexate. Only studies of moderate or high quality were included. A meta-analysis was conducted to assess the efficacy (based on changes of American College of Rheumatology (ACR) criteria) and the safety (based on serious adverse events, serious infections, malignancy, and deaths) of infliximab use. Withdrawals due to adverse events or lack of efficacy were also evaluated in both infliximab-treated and control groups. Seven trials met the inclusion criteria, comprising 2,129 patients. In the efficacy meta-analysis, a greater number of infliximab-treated patients relative to those in the placebo group achieved ACR20, ACR50, and ACR70 values from 14 weeks to 2 years of treatment. For safety analysis, there were no statistically significant differences between the groups. Withdrawals due to adverse events were higher in the infliximab group relative to the placebo group, and withdrawals due to lack of efficacy were higher in the placebo group relative to the infliximab-treated group. This meta-analysis shows a higher efficacy of infliximab relative to placebo without significant safety differences between the infliximab-treated and control groups.

Eugenia brasiliensis Lam., a plant from the south of Brazil, is used in the popular medicine for rheumatism treatment. This study reports that topical application of hydroalcoholic extract, fractions and isolated compounds from E. brasiliensis caused an inhibition of ear oedema in response to topical application of croton oil on the mouse ear. For oedema inhibition, the estimated ID50 values (dose reducing the inflammatory response by 50% relative to the control value) for hydroalcoholic extract and fractions (hexane, ethyl acetate and dichloromethane) were 0.17, 0.29, 0.13 and 0.14 mg/ear, respectively, with inhibition of 79 ± 7%, 87 ± 6%, 88 ± 5% and 96 ± 2%, respectively. Isolated phenolic compounds (quercetin, catechin and gallocatechin) were also effective in inhibiting the oedema (inhibition of 61 ± 5%, 66 ± 2% and 37 ± 9%, respectively). Moreover, both extract and isolated compounds caused inhibition of polymorphonuclear cells influx (inhibition of 85 ± 6%, 81 ± 5%, 73 ± 6% and 76 ± 6%, respectively). The histological analysis of the ear tissue clearly confirmed that the extract and compounds of E. brasiliensis inhibited the influx of polymorphonuclear cells to mouse ear skin after application of croton oil. Furthermore, hydroalcoholic extract was also effective in inhibiting the arachidonic acid-mediated mouse ear oedema (ID50 value was 1.94 mg/ear and inhibition of 60 ± 7%). Therefore, these results consistently support the notion that E. brasiliensis possesses topical anti-inflammatory activity.

An efficient micropropagation protocol was developed for the medicinal plant Phyllanthus caroliniensis (Euphorbiaceae) using nodal segments for axillary shoot proliferation. Maximum multiplication (21–23 shoots per explant) was achieved on MS or AR media supplemented with either 5.0 μM BA, 1.25–5.0 μM kinetin or 2.5–5.0 μM 2iP. Rooting was achieved with 80–100% of the microshoots on MS medium without growth regulators, although 1.25 μM NAA and 1.25–5.0 μM IAA promoted significant increases in the number of roots per explant. Regenerated plants were successfully acclimatized and about 88% of plantlets survived under ex vitro conditions. Flowering was observed on in vitro grown plantlets and after 3–4 weeks of acclimatization. High frequency callus initiation and growth was achieved when nodal segment explants were inoculated in the vertical position on MS medium supplemented with 5.0 μM 2,4-D. Root cultures were successfully established on MS medium containing 1.1 μM NAA. The optimized micropropagation, callus and root culture protocols offer the possibility to use cell/root culture techniques for vegetative propagation and secondary metabolism studies.

Topical application of acetylenic acetogenins (AAG) from avocado (0.01-1.0mg/ear), was effective in inhibiting both 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema, and in decreasing tissue myeloperoxidase activity (indicative of polymorphonuclear leukocyte influx). Maximum edema inhibition of 72% was achieved by AAG at lower concentration (0.6 mg/ear) than that of the anti-inflammatory drug indomethacin (2mg/ear). The maximum myeloperoxidase inhibition of 60% was obtained at AAG concentration 0.1mg/ear. Chemical reduction of unsaturated bonds in aliphatic chain of AAG molecules almost abrogated inhibition effect of AAG at high concentration. In vitro AAG administration reduced secretion of PGE(2) in TPA-induced keratinocytes, and inhibited total PLA(2) and sPLA(2) activities in HaCaT cells. The results indicate a topical anti-inflammatory effect of acetylenic acetogenins which is associated with inhibition of PLA(2) activity in skin.

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 Ciencias da Saude, 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.

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.

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 1 mg/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-β- 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.

Background Statins induces cell cycle arrest, apoptosis, reduction of angiogenic factors, inhibition of the endothelial growth factor, impairing tissue adhesion and attenuation of the resistance mechanisms. The aim of this study was evaluate the anti-tumoral activity of simvastatin in a B16F10 melanoma-mouse model. Methods Melanoma cells were treated with different concentrations of simvastatin and assessed by viability methods. Melanoma cells (5 × 104) were implanted in two month old C57Bl6/J mice. Around 7 days after cells injection, the oral treatments were started with simvastatin (5 mg/kg/day, p.o.). Tumor size, hematological and biochemical analyses were evaluated. Results Simvastatin at a concentration of 0.8 μM, 1.2 μM and 1.6 μM had toxic effect. Concentration of 1.6 μM induced a massive death in the first 24 h of incubation. Simvastatin at 0.8 μM induces early cell cycle arrest in G0/G1, followed by increase of hypodiploidy. Tumor size were evaluated and the difference of treated group and control, after ten days, demonstrates that simvastatin inhibited the tumor expansion in 68%. Conclusion Simvastatin at 1.6 μM, presented cytototoxicity after 72 h of treatment, with an intense death. In vivo, simvastatin being potentially useful as an antiproliferative drug, with an impairment of growth after ten days.