Carotenoids from Marine Microalgae as Antimelanoma Agents.

Melanoma cells are highly invasive and metastatic tumor cells and commonly express molecular alterations that contribute to multidrug resistance (e.g., BRAFV600E mutation). Conventional treatment is not effective in a long term, requiring an exhaustive search for new alternatives. Recently, carotenoids from microalgae have been investigated as adjuvant in antimelanoma therapy due to their safety and acceptable clinical tolerability. Many of them are currently used as food supplements. In this review, we have compiled several studies that show microalgal carotenoids inhibit cell proliferation, cell migration and invasion, as well as induced cell cycle arrest and apoptosis in various melanoma cell lines. MAPK and NF-ĸB pathway, MMP and apoptotic factors are frequently affected after exposure to microalgal carotenoids. Fucoxanthin, astaxanthin and zeaxanthin are the main carotenoids investigated, in both in vitro and in vivo experimental models. Preclinical data indicate these compounds exhibit direct antimelanoma effect but are also capable of restoring melanoma cells sensitivity to conventional chemotherapy (e.g., vemurafenib and dacarbazine).

Complexation with ß-cyclodextrin enhances apoptosis-mediated cytotoxic effect of harman in chemoresistant BRAF-mutated melanoma cells.

Harman, a natural ß-carboline alkaloid, has recently gained considerable interest due to its anticancer properties. However, its physicochemical characteristics and poor oral bioavailability have been limiting factors for its pharmaceutical development. In this paper, we described the complexation of harman (HAR) with ß-cyclodextrin (ßCD) as a promising alternative to improve its solubility and consequently its cytotoxic effect in chemoresistant melanoma cells (A2058 cell line). Inclusion complexes (ßCD-HAR) were prepared using a simple method and then characterized by FTIR, NMR and SEM techniques. Through in silico studies, the mechanism of complexation of HAR with ßCD was elucidated in detail. Both HAR and ßCD-HAR promoted cytotoxicity, apoptosis, cell cycle arrest and inhibition of cell migration in melanoma cells. Interestingly, complexation of HAR with ßCD enhanced its pro-apoptotic effect by increasing of caspase-3 activity (p < 0.05), probably due to an improvement in HAR solubility. In addition, HAR and ßCD-HAR sensitized A2058 cells to vemurafenib, dacarbazine and 5FU treatments, potentializing their cytotoxic activity. These findings suggest that complexation of HAR with natural polymers such as ßCD can be useful to improve its bioavailability and antimelanoma activity.

Pre-clinical investigations of ß-carboline alkaloids as antidepressant agents: A systematic review.

Depressive disorders remain a current public health problem whose prevalence has increased in the past decades. In the constant search for new therapeutic alternatives, ß-carboline alkaloids have been identified as good candidates for new antidepressant drugs. In this systematic review, we summarized all pre-clinical investigations involving the use of natural or semisynthetic ß-carboline in depression models. A literature search was conducted in August 2018, using PubMed, Scopus and Science Direct databases. All reports were carefully analyzed, and data extraction was conducted through standardized forms. Methodological quality assessment of in vivo studies was also performed. The entire systematic review was performed according to PRISMA statement. From a total of 373 articles, 26 met all inclusion criteria. In vitro and in vivo studies have evaluated a wide variety of ß-carbolines through enzymatic and binding assays, and acute or chronic animal models. Most of the in vivo and in vitro studies is concentrated on two molecules: harman and harmine. They have been investigated in several animal models and some mechanisms of action have been proposed for their antidepressant activity. In general, ß-carbolines modulate 5-HT and GABA systems, promote neurogenesis, induce neuroendocrine response and restore astrocytic function, being effective when administrated acutely or chronically in different animal models, including chronic mild stress protocols. In short, ß-carbolines are multi-target antidepressant compounds and may be useful in the treatment of depressive disorders.

Bixin, an apocarotenoid isolated from Bixa orellana L., sensitizes human melanoma cells to dacarbazine-induced apoptosis through ROS-mediated cytotoxicity.

Cutaneous melanoma has a high capacity to metastasize and significant resistance to conventional therapeutic protocols, which makes its treatment difficult. The combination of conventional drugs with cytostatic molecules of low toxicity has been shown to be an interesting alternative for sensitization of tumor cells to chemotherapy. In this study, we evaluated the effect of bixin, an abundant apocarotenoid present in Bixa orellana, on the sensitization of human melanoma cells (A2058) to dacarbazine treatment, an anticancer agent clinically used for the therapy of metastatic melanoma. UPLC-DAD-MS/MS analyses of bioactive extracts from B. orellana seeds led to the identification of two new apocarotenoids: 6,8'-diapocarotene-6,8'-dioic acid and 6,7'-diapocarotene-6,7'-dioic acid. After being identified as its major compound, bixin (Z-bixin) was evaluated on A2058 cells expressing the oncogenic BRAF VE600 mutation and resistant to dacarbazine treatment. Bixin promoted growth inhibition, reduced cell migration, induced apoptosis and cell cycle arrest in the G2/M phase. When associated with dacarbazine, bixin restored the sensitivity of A2058 cells to chemotherapy, enhancing its antiproliferative, anti-migratory and pro-apoptotic effects. Combined treatment also induced higher ROS (reactive oxygen species) and MDA (malondialdehyde, a lipid peroxidation marker) generation than monotreatment, suggesting that the oxidative stress caused by bixin contributes significantly to its sensitizing effect. Taken together, these data suggest that bixin exerts intrinsic antimelanoma activity by mechanisms complementary to those of dacarbazine, encouraging its use in combined therapy for cutaneous melanoma treatment.

Phytochemical and pharmacological aspects of Cnidoscolus Pohl species: A systematic review.

BACKGROUND: Cnidoscolus is a genus belonging to the Euphorbiaceae family, distributed in South American countries, such as Mexico and Brazil, which includes several species widely used in folk medicine. However, the genus is not sufficiently exploited from a chemical and pharmacological point of view. HYPOTHESIS/PURPOSE: This paper aims to present a systematic review of known pharmacological and chemical aspects from Cnidoscolus, an important genus for South America research groups on medicinal plants. In this article, we highlight the importance of Cnidoscolus species in the search for new bioactive molecules. STUDY DESIGN: A systematic review was conducted in order to collect chemical and pharmacological information on species of this genus in the last 25 years. METHODS: Literature search was performed through specialized databases (PUBMED, LILACS, SCIELO, Science Direct and Web of Science) using different combinations of the following keywords: Cnidoscolus, phytochemistry, pharmacological activity. For the selection of the manuscripts, two independent investigators (RGOJ and CAAF) first selected the articles according to the title, then to the abstract and finally through an analysis of the full-text publication. All selected manuscripts were analyzed for year of publication, country where the research was performed, reported plant species, isolated chemical compounds and evaluated biological activities. RESULTS: Most of the studies involving Cnidoscolus were conducted by research groups located in Brazil, Nigeria and Mexico. Regarding the annual evolution of the publications, a larger number of articles published in 2014 were observed. Flavonoids, triterpenes and diterpenes represent the main classes of secondary metabolites that have been isolated from Cnidoscolus. In terms of the pharmacological investigations, C. aconitifolius, C. chayamansa and C. quercifolius are considered the most studied species, with different pharmacological activities. CONCLUSION: All findings indicate that Cnidoscolus is an important genus of the Euphorbiaceae family. However, considering its chemical and pharmacological importance, the studies developed with Cnidoscolus species are still limited, representing an opportunity to investigate new bioactive molecules.

Neuropharmacological effects of essential oil from the leaves of Croton conduplicatus Kunth and possible mechanisms of action involved.

ETHNOPHARMACOLOGICAL RELEVANCE: Croton conduplicatus Kunth (Euphorbiaceae) is a Brazilian aromatic medicinal plant, widely known as "quebra-faca". In folk medicine, its leaves and stem-barks are used as a natural analgesic for the treatment of headaches. AIM OF THE STUDY: In this study, we describe for the first time the neuropharmacological potential of the essential oil obtained from the leaves of Croton conduplicatus (EO) in experimental models of pain, anxiety and insomnia. The mechanisms of action involved in these activities were also investigated. MATERIAL AND METHODS: Different experimental models were used to evaluate the antinociceptive (acetic acid, formalin-induced nociception and hot plate tests), anxiolytic (elevated plus maze and hole board tests) and sedative (thiopental-induced sleeping time) effects of EO in mice. EO was evaluated in three different doses (25, 50 and 100 mg/kg, i.p.) and compared with positive and negative controls in all experimental protocols. When appropriate, animals were pretreated with pharmacological antagonists (naloxone, atropine and flumazenil) in order to evaluate the mechanisms of action involved. A docking study also was performed to identify possible targets involved. RESULTS: EO (25, 50 and 100 mg/kg, i.p.) demonstrated a significant antinociceptive activity in all experimental models. Pretreatment with naloxone or atropine reversed the antinociceptive response (p < 0.05), suggesting the involvement of opioid and muscarinic receptors, respectively. A docking study was performed with the major components identified in EO (1,8 cineole - 21.42%, spathulenol - 15.47%, p-cymene - 12.41% and caryophyllene oxide - 12.15%), demonstrating favorable interaction profile with different subtypes of muscarinic (M2, M3 and M4) and opioids (delta and mu) receptors. EO also showed anxiolytic (mainly at doses of 25 and 50 mg/kg, i.p.) and sedative (only at the dose of 100 mg/kg, i.p.) effects in mice. These pharmacological responses were reversed by flumazenil (p < 0.05), indicating possible involvement of GABAA receptors. CONCLUSION: Our findings support the traditional use of this plant as a natural analgesic and suggest that EO is a multi-target natural product, presenting not only antinociceptive effect but also anxiolytic and sedative activities depending on the dose used.

Development and Evaluation of Photoprotective O/W Emulsions Containing Hydroalcoholic Extract of Neoglaziovia variegata (Bromeliaceae).

Neoglaziovia variegata is a Bromeliaceae plant species widely found in Brazil with several pharmacological properties, including photoprotective activity. Although herbal-based active ingredients have been applied in cosmetic products, especially for skin treatment, its application in sunscreen formulations remains unexplored. The aim of this work is to evaluate the photoprotective effect of cosmetic formulations containing hydroalcoholic extract of N. variegata (Nv-HA). Initially, the phenolic and flavonoid total content of Nv-HA were determined. The photoprotective activity of Nv-HA was subsequently assessed using a spectrophotometric method. Nv-HA was incorporated in O/W emulsions in the presence or absence of synthetic filters and their photoprotective efficacy was evaluated by spectrophotometric SPF determination. Finally, the stability study of the formulations was performed through the freezing/defrosting method. Nv-HA showed significant phenolic and flavonoids content (61.66 ± 5.14 mg GAE/g and 90.27 ± 5.03 mg CE/g, resp.). Nv-HA showed SPF values of 5.43 ± 0.07 and 11.73 ± 0.04 for the concentrations of 0.5 and 1.0% (v/v), respectively. It was verified that Nv-HA potentiated the photoprotective effect of formulations containing only synthetic filters. Furthermore, the formulations have remained stable at the end of the preliminary stability study. According to the results, it was concluded that Nv-HA can be used as a chemical filter in cosmetic formulations.

Antinociceptive Effect of the Essential Oil from Croton conduplicatus Kunth (Euphorbiaceae).

Medicinal plants have been widely used in the treatment of chronic pain. In this study, we describe the antinociceptive effect of the essential oil from Croton conduplicatus (the EO 25, 50, and 100 mg/kg, i.p.), a medicinal plant native to Brazil. Antinociceptive activity was investigated by measuring the nociception induced by acetic acid, formalin, hot plate and carrageenan. A docking study was performed with the major constituents of the EO (E-caryophyllene, caryophyllene oxide, and camphor). The EO reduced nociceptive behavior at all doses tested in the acetic acid-induced nociception test (p < 0.05). The same was observed in both phases (neurogenic and inflammatory) of the formalin test. When the hot-plate test was conducted, the EO (50 mg/kg) extended the latency time after 60 min of treatment. The EO also reduced leukocyte migration at all doses, suggesting that its antinociceptive effect involves both central and peripheral mechanisms. Pretreatment with glibenclamide and atropine reversed the antinociceptive effect of the EO on the formalin test, suggesting the involvement of KATP channels and muscarinic receptors. The docking study revealed a satisfactory interaction profile between the major components of the EO and the different muscarinic receptor subtypes (M2, M3, and M4). These results corroborate the medicinal use of C. conduplicatus in folk medicine.

Condições de trabalho das Equipes de Saúdeda Família do município de Petrolina-PE:percepção dos profissionais de saúde / Working conditions of Family Health Teams of the municipalityof Petrolina-PE: perceptions of health care professionals

O estudo objetiva traçar o perfil das Equipes de Saúde da Família (ESF) do município de Petrolina-PE, Brasil, quanto àscondições físico-estruturais nas quais se encontram e quanto à qualidade dos serviços de saúde prestados à população,analisando os principais problemas a serem enfrentados pelos profissionais de saúde em seu processo de trabalho. Foirealizado um estudo de caráter observacional descritivo, baseado na aplicação de um questionário semiestruturado, destinadoaos profissionais de saúde das mais diversas categorias que trabalham nas ESF do município de Petrolina. Entre osserviços disponibilizados pelo município nas ESF citados pelos profissionais, os considerados mais eficientes foram: vacinação,serviço de enfermagem e pré-natal, enquanto que a farmácia e odontologia foram consideradas os mais precários.A estrutura das unidades foi relatada como o principal problema que dificulta a execução dos serviços nas unidades (43%)e 27% dos profissionais entrevistados afirmaram que as unidades em que trabalham não conseguem atender à demanda.A escassez de profissionais, aliada à falta de equipamentos, materiais e medicamentos, acaba inviabilizando as práticasde trabalho, tornando o sistema de saúde vigente no país defasado, sobrecarregando os macrocomponentes dos níveis demédia e alta complexidade em saúde.

The study aims to evaluate the profile of ESF (Family Health Teams) in the city of Petrolina (Pernambuco, Brazil), concerningphysical and structural conditions of the ESF and concerning the quality of health services rendered to the population, byanalyzing the main problems to be faced by health professionals at work. An observational descriptive study was conductedbased on a semi-structured questionnaire intended to health professionals from several categories working at Petrolina’s ESF.Among the services provided by the municipality in the ESF, mentioned by the professionals, the ones considered as moreeffective were vaccination, nursing services and prenatal care, while pharmacy and dentistry were considered the most precarious.The units’ structure was reported by 43% of the professional as the main problem that hinders the implementation ofservices in the units and 27% said that the units in which they work cannot meet the demand. The shortage of professionalscoupled with lack of equipment, supplies and medicines preclude the working practices, lagging the current health system inthe country, overloading macrocomponents of medium and high levels of complexity in health.