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Background and Purpose: Natural products are potential sources of anticancer components. Among various species, the lipophilic extract of the Viscum album subsp. austriacum (Wiesb.) Vollm. (VALE) has shown promising therapeutic potential. The present work aimed to qualify the plant source and characterize the extract's chemical profile. In addition, a self-nanoemulsifying drug delivery system (SNEDDS) containing VALE (SNEDDS-VALE) was developed. Methods: V. album subsp. austriacum histochemistry was performed, and the chemical profile of VALE was analyzed by GC-MS. After the SNEEDS-VALE development, its morphology was visualized by transmission electron microscopy (TEM), while its stability was evaluated by the average droplet size, polydispersity index (PdI) and pH. Lastly, SNEDDS-VALE chemical stability was evaluated by LC-DAD-MS. Results: The histochemical analysis showed the presence of lipophilic compounds in the leaves and stems. The major compound in the VALE was oleanolic acid, followed by lupeol acetate and ursolic acid. SNEDDS was composed of medium chain triglyceride and Kolliphor® RH 40 (PEG-40 hydrogenated castor oil). A homogeneous, isotropic and stable nanoemulsion was obtained, with an average size of 36.87 ± 1.04 nm and PdI of 0.14 ± 0.02, for 14 weeks. Conclusion: This is the first histochemistry analysis of V. album subsp. austriacum growing on Pinus sylvestris L. which provided detailed information regarding its lipophilic compounds. A homogeneous, isotropic and stable SNEDDS-VALE was obtained to improve the low water solubility of VALE. Further, in vitro and in vivo experiments should be performed, in order to evaluate the antitumoral potential of SNEDDS-VALE.

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The genus Viscum comprises a large number of semi-parasitic shrubs popularly known as Mistletoe. The Viscum species grow in many countries of Europe, Africa and Asia with different popular uses in ornamentation, foods and medicine. Many studies about Viscum have been done over the last years focusing on biological activities and chemical composition of the aqueous extracts, mainly related to anthroposophical medicines. However, it is known that non-aqueous preparations, as alcoholic extracts, have demonstrated different biological activities that are species-and host tree-dependent. Considering the potential of these alcoholic extracts, a scoping review was conducted using data from three online databases: PubMed, Scopus and Embase. Inclusion criteria consisted of the in vitro, in vivo, ex vivo, clinical and chemical studies of alcoholic extracts from Viscum species. The present review summarized 124 original publications about fourteen Viscum species. Viscum album, Viscum articulatum and Viscum coloratum were the main studied species. Alcoholic extracts demonstrated hypotensive, anticancer, antimicrobial, analgesic and anti-inflammatory capabilities, among other biological activities. Flavonoids, phenolic acids and terpenoids represented 48%, 24% and 11% of the total identified compounds, respectively. This review contributes to the knowledge of alcoholic preparations of the Viscum species and points out the lack of clinical studies concerning these different extracts.

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Viscum album is a semi-parasitic plant used for over one hundred years in complementary cancer therapy. The main commercial drugs used in cancer patients' treatment are derived from the aqueous V. album extracts, whose cytotoxic potential is mostly attributed to the aqueous soluble antitumoral metabolites. On the counterpart, ethanol solvents must be used to obtain V. album mother tinctures. This methodology permits better solubilization of phenolic compounds, among others, which present antitumoral bioactivity. Recently, the metabolomics approach revealed the influence of the host tree on the V. album subspecies differentiation. To increase the scientific information about the chemical differences related to the host trees and to clarify the seasonal influences, in this study, the metabolome of 50 V. album mother tinctures from three subspecies (abietis, album, austriacum) and five host trees (Malus domestica, Quercus sp., Ulmus carpinifolia, Pinus sylvestris, Abies alba) was evaluated using summer and winter plant harvests. The in vitro cytotoxic activities were investigated in breast cancer cells (MDA-MB-231) and immortalized normal human keratinocytes (HaCaT). The summer V. album mother tinctures presented higher cytotoxic activity than winter ones. Among the summer samples, those prepared with V. album subsp. album were more cytotoxic than V. album subsp. abietis and subsp. V. album subsp. austriacum. The V. album harvested from Quercus petraea and Abies alba inhibited the key-glycolytic enzymes: hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK). This activity was related to a reduction in glucose uptake and lactate production, which were host-tree-time-dose-dependent. The untargeted metabolomic approach was able to discriminate the mother tinctures according to respective botanical classes and harvest season. A total of 188 metabolites were annotated under positive and negative modes. Fourteen compounds were responsible for the samples differentiation, and, to the best of our knowledge, eight were described in the Viscum album species for the first time. Our study shows the interruption of the Warburg effect as a novel antitumoral mechanism triggered by V. album mother tinctures, which is related to their metabolite profile. These results bring scientific evidence that encourages the use of V. album mother tinctures as a natural product for cancer therapy.

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BACKGROUND: Viscum album L. (Santalaceae), commonly known as mistletoe, is a hemiparasitic plant traditionally used in complementary cancer treatment. Its antitumor potential is mostly attributed to the presence of aqueous soluble metabolites; however, the use of ethanol as solvent also permits the extraction of pharmacological compounds with antitumor potential. The clinical efficacy of mistletoe therapy inspired the present work, which focuses on ethanolic extracts (V. album "mother tinctures", MT) prepared from different host trees. METHODS: Samples from three European subspecies (album, austriacum, and abietis) were harvested, and five different V. album-MT strains were prepared. The following phytochemical analyses were performed: thin layer chromatography (TLC), high-performance liquid chromatography (HPLC) and liquid chromatography-high resolution mass spectrometry (LC-HRMS). The proliferation assay was performed with WST-1 after incubation of tumor (Yoshida and Molt-4) and fibroblast cell lines (NIH/3 T3) with different MT concentrations (0.5 to 0.05% v/v). The cell death mechanism was investigated by flow cytometry (FACS) using Annexin V-7AAD. RESULTS: Chemical analyses of MT showed the presence of phenolic acids, flavonoids and lignans. The MT flavonoid and viscotoxin contents (mg/g fresh weight) were highest in Quercus robur (9.67 ± 0.85 mg/g) and Malus domestica (3.95 ± 0.58 mg/mg), respectively. The viscotoxin isoform proportions (% total) were also different among the VA subspecies with a higher content of A3 in V. album growing on Abies alba (60.57 ± 2.13). The phytochemical compounds as well as the viscotoxin contents are probably related to the antitumor effects of MT. The cell death mechanisms evaluated by colorimetric and FACS methodologies involved necrotic damage, which was host tree-, time- and dose- dependent, with different selectivity to tumor cells. Mother tincture from V. album ssp. abietis was the most effective at inducing in vitro cellular effects, even when incubated at the smallest concentration tested, probably because of the higher content of VT A3. CONCLUSION: Our results indicate the promising antitumor potential of Viscum album ethanolic extracts and the importance of botanical and phytochemical characterization for in vitro anti-proliferative effects.

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O mapa apresenta uma visão geral das evidências sobre os efeitos das Plantas Medicinais e Fitoterapia para cicatrização e doenças agudas. A partir de uma ampla busca bibliográfica foram incluídos no mapa 16 estudos de revisão sistemática. Todos os estudos foram avaliados, caracterizados e categorizados por um grupo de pesquisadores do Laboratório de Pesquisa & Desenvolvimento de Práticas Integrativas e Complementares (LabPICs) da Faculdade de Farmácia da Universidade Federal do Rio de Janeiro.

El mapa presenta una visión general de la evidencia sobre los efectos de las plantas medicinales y la fitoterapia para cicatrización y las enfermedades agudas. A partir de una amplia búsqueda bibliográfica, se incluyeron 16 estudios de revisión sistemática en el mapa. Todos los estudios fueron evaluados, caracterizados y categorizados por un grupo de investigadores del Laboratorio de Investigación y Desarrollo para Prácticas Integrativas y Complementarias (LabPIC) en la Facultad de Farmacia de la Universidad Federal de Rio de Janeiro.

The map presents an overview of the evidence on the effects of Medicinal Plants and Phytotherapy for for wound healing and acute diseases. From a wide bibliographic search, 16 systematic review studies were included in the map. All studies were evaluated, characterized and categorized by a group of researchers from the Research & Development Laboratory for Integrative and Complementary Practices (LabPICs) at the Faculty of Pharmacy, Federal University of Rio de Janeiro.

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O mapa apresenta uma visão geral das evidências sobre os efeitos das Plantas Medicinais e Fitoterapia para Saúde Mental e Qualidade de Vida. A partir de uma ampla busca bibliográfica foram incluídos no mapa 37 estudos de revisão sistemática. Todos os estudos foram avaliados, caracterizados e categorizados por um grupo de pesquisadores do Laboratório de Pesquisa & Desenvolvimento de Práticas Integrativas e Complementares (LabPICs) da Faculdade de Farmácia da Universidade Federal do Rio de Janeiro.

El mapa presenta una visión general de la evidencia sobre los efectos de las plantas medicinales y la fitoterapia para ela salud mental y calidad de vida. A partir de una amplia búsqueda bibliográfica, se incluyeron 37 estudios de revisión sistemática en el mapa. Todos los estudios fueron evaluados, caracterizados y categorizados por un grupo de investigadores del Laboratorio de Investigación y Desarrollo para Prácticas Integrativas y Complementarias (LabPIC) en la Facultad de Farmacia de la Universidad Federal de Rio de Janeiro.

The map presents an overview of the evidence on the effects of Medicinal Plants and Phytotherapy for mental health and quality of life. From a wide bibliographic search, 37 systematic review studies were included in the map. All studies were evaluated, characterized and categorized by a group of researchers from the Research & Development Laboratory for Integrative and Complementary Practices (LabPICs) at the Faculty of Pharmacy, Federal University of Rio de Janeiro.

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O mapa apresenta uma visão geral das evidências sobre os efeitos das Plantas Medicinais e Fitoterapia para dor e doenças crônicas. A partir de uma ampla busca bibliográfica foram incluídos no mapa 49 estudos de revisão sistemática. Todos os estudos foram avaliados, caracterizados e categorizados por um grupo de pesquisadores do Laboratório de Pesquisa & Desenvolvimento de Práticas Integrativas e Complementares (LabPICs) da Faculdade de Farmácia da Universidade Federal do Rio de Janeiro.

El mapa presenta una visión general de la evidencia sobre los efectos de las plantas medicinales y la fitoterapia para el dolor y las enfermedades crónicas. A partir de una amplia búsqueda bibliográfica, se incluyeron 49 estudios de revisión sistemática en el mapa. Todos los estudios fueron evaluados, caracterizados y categorizados por un grupo de investigadores del Laboratorio de Investigación y Desarrollo para Prácticas Integrativas y Complementarias (LabPIC) en la Facultad de Farmacia de la Universidad Federal de Rio de Janeiro.

The map presents an overview of the evidence on the effects of Medicinal Plants and Phytotherapy for pain and chronic diseases. From a wide bibliographic search, 49 systematic review studies were included in the map. All studies were evaluated, characterized and categorized by a group of researchers from the Research & Development Laboratory for Integrative and Complementary Practices (LabPICs) at the Faculty of Pharmacy, Federal University of Rio de Janeiro.

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O mapa apresenta uma visão geral das evidências sobre os efeitos das Plantas Medicinais e Fitoterapia para Distúrbios Metabólicos e Fisiológicos. A partir de uma ampla busca bibliográfica foram incluídos no mapa 48 estudos de revisão sistemática. Todos os estudos foram avaliados, caracterizados e categorizados por um grupo de pesquisadores do Laboratório de Pesquisa & Desenvolvimento de Práticas Integrativas e Complementares (LabPICs) da Faculdade de Farmácia da Universidade Federal do Rio de Janeiro.

El mapa presenta una visión general de la evidencia sobre los efectos de las plantas medicinales y la fitoterapia para el trastornos metabólicos y fisiológicos. A partir de una amplia búsqueda bibliográfica, se incluyeron 48 estudios de revisión sistemática en el mapa. Todos los estudios fueron evaluados, caracterizados y categorizados por un grupo de investigadores del Laboratorio de Investigación y Desarrollo para Prácticas Integrativas y Complementarias (LabPIC) en la Facultad de Farmacia de la Universidad Federal de Rio de Janeiro.

The map presents an overview of the evidence on the effects of Medicinal Plants and Phytotherapy for Metabolic and Physiological Disorders. From a wide bibliographic search, 48 systematic review studies were included in the map. All studies were evaluated, characterized and categorized by a group of researchers from the Research & Development Laboratory for Integrative and Complementary Practices (LabPICs) at the Faculty of Pharmacy, Federal University of Rio de Janeiro.

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Cancer is one of the biggest problems in public health worldwide. Plants have been shown important role in anticancer research. Viscum album L. (Santalaceae), commonly known as mistletoe, is a semi-parasitic plant that grows on different host trees. In complementary medicine, extracts from European mistletoe (Viscum album L.) have been used in the treatment of cancer. The study was conducted to identify chemical composition and antitumor potential of Viscum album tinctures. Chemical analysis performed by high resolution chromatography equipped with high resolution mass spectrometer identified caffeic acid, chlorogenic acid, sakuranetin, isosakuranetin, syringenin 4-O-glucoside, syringenin 4-O-apiosyl-glucoside, alangilignoside C and ligalbumoside A compounds. Some of these compounds are probably responsible for the reduction of tumoral cellular growth in a dose-dependent manner. It was observed that melanoma murine cells (B16F10) were more sensitive to V. album tinctures than human leukaemic cells (K562), besides non-tumoral cells (MA-104) had a much lower cytotoxicity to them. Apoptotic-like cells were observed under light microscopy and were confirmed by a typical DNA fragmentation pattern. Additionally, flow cytometry results using Annexin-V/FITC permitted to quantify increased expression of early and late apoptotic markers on tumoral cells, confirming augmented Sub G0 population, which was probably associated with a consistent decrease in G1, and an increase in S or G2/M populations. Results indicate the chemical composition of V. album tinctures influences the mechanisms of in vitro tumoral cell death, suggesting a potential use in cancer pharmacotherapy research.