Chemical analysis of the semipurified extract of Paullinia cupana and evaluation of in vitro inhibitory effects against Helicobacter pylori.

Paullinia cupana Kunth, commonly known as guarana, is a native Brazilian plant species from the Amazon area that presents various biological effects, including antimicrobial action. The aim of this study was to chemically analyse the semipurified aqueous extract (AqF) of the plant and to evaluate the activity of crude (CE), ethyl-acetate (EAF), and AqF extracts against Helicobacter pylori. The chemical profile of AqF was determined based on solid analysis 13C-NMR, direct infusion mass spectrometry (ESI-MS), and MALDI-TOF. The 13C-NMR spectrum showed characteristics of flavan-3-ol and oligomeric proanthocyanidins. ESI-MS revealed the presence of procyanidin, caffeic acid and its derivatives. MALDI-TOF analysis detected procyanidins of up to 6 units and profisetinidins of up to 5 units. Whereas CE and EAF showed inhibitory activity against H. pylori, CE, EAF, and AqF presented not high inhibitory activity against urease. The results demonstrate the potential of P. cupana to control and prevent H. pylori infection.

Rare complications of multikinase inhibitor treatment

ABSTRACT Objective: The advent of multikinase inhibitor (MKI) therapy has led to a radical change in the treatment of patients with advanced thyroid carcinoma. The aim of this manuscript is to communicate rare adverse events that occurred in less than 5% of patients in clinical trials in a subset of patients treated in our hospital. Subjects and methods: Out of 760 patients with thyroid cancer followed up with in our Division of Endocrinology, 29 (3.8%) received treatment with MKIs. The median age at diagnosis of these patients was 53 years (range 20-70), and 75.9% of them were women. Sorafenib was prescribed as first-line treatment to 23 patients with differentiated thyroid cancer and as second-line treatment to one patient with advanced medullary thyroid cancer (MTC). Vandetanib was indicated as first-line treatment in 6 patients with MTC and lenvatinib as second-line treatment in two patients with progressive disease under sorafenib treatment. Results: During the follow-up of treatment (mean 13.7 ± 7 months, median 12 months, range 6-32), 5/29 (17.2%) patients presented rare adverse events. These rare adverse effects were: heart failure, thrombocytopenia, and squamous cell carcinoma during sorafenib therapy and squamous cell carcinoma and oophoritis with intestinal perforation during vandetanib treatment. Conclusions: About 3 to 5 years after the approval of MKI therapy, we learned that MKIs usually lead to adverse effects in the majority of patients. Although most of them are manageable, we still need to be aware of potentially serious and rare or unreported adverse effects that can be life-threatening.

Maternal diet-induced obesity during suckling period programs offspring obese phenotype and hypothalamic leptin/insulin resistance.

During the early post-natal period, offspring are vulnerable to environmental insults, such as nutritional and hormonal changes, which increase risk to develop metabolic diseases later in life. Our aim was to understand whether maternal obesity during lactation programs offspring to metabolic syndrome and obese phenotype, in addition we aimed to assess the peripheral glucose metabolism and hypothalamic leptin/insulin signaling pathways. At delivery, female Wistar rats were randomly divided in two groups: Control group (CO), mothers fed a standard rodent chow (Nuvilab); and Diet-induced obesity group (DIO), mothers who had free access to a diet performed with 33% ground standard rodent chow, 33% sweetened condensed milk (Nestlé), 7% sucrose and 27% water. Maternal treatment was performed throughout suckling period. All offspring received standard rodent chow from weaning until 91-day-old. DIO dams presented increased total body fat and insulin resistance. Consequently, the breast milk from obese dams had altered composition. At 91-day-old, DIO offspring had overweight, hyperphagia and higher adiposity. Furthermore, DIO animals had hyperinsulinemia and insulin resistance, they also showed pancreatic islet hypertrophy and increased pancreatic ß-cell proliferation. Finally, DIO offspring showed low ObRb, JAK2, STAT-3, IRß, PI3K and Akt levels, suggesting leptin and insulin hypothalamic resistance, associated with increased of hypothalamic NPY level and decreased of POMC. Maternal obesity during lactation malprograms rat offspring to develop obesity that is associated with impairment of melanocortin system. Indeed, rat offspring displayed glucose dyshomeostasis and both peripheral and central insulin resistance.

Therapeutic Effects of Medicinal Plants on Cutaneous Wound Healing in Humans: A Systematic Review.

The pharmaceutical industry has made great strides in providing drugs that are able to stimulate the healing process, but only 1-3% of all drugs that are listed in Western pharmacopoeias are intended for use on the skin or cutaneous wounds. Of these, at least one-third are obtained from plants. We sought to review the therapeutic effects of medicinal plants on human skin lesions. For this systematic review, we searched the PubMed, Scopus, and Web of Science databases to identify clinical trials that were published from 1997 to 2017. We reviewed studies that described the use of medicinal plants for the treatment of skin lesions in humans. Ten studies were selected, eight of which were published from 2007 to 2016, with a total of 503 patients. Among the plant species that were used for the treatment of human skin lesions, 12 belonged to 11 families and were included in the analysis. All of the plant species that were studied presented high therapeutic potential for the treatment of cutaneous lesions.

Rare complications of multikinase inhibitor treatment.

OBJECTIVE: The advent of multikinase inhibitor (MKI) therapy has led to a radical change in the treatment of patients with advanced thyroid carcinoma. The aim of this manuscript is to communicate rare adverse events that occurred in less than 5% of patients in clinical trials in a subset of patients treated in our hospital. SUBJECTS AND METHODS: Out of 760 patients with thyroid cancer followed up with in our Division of Endocrinology, 29 (3.8%) received treatment with MKIs. The median age at diagnosis of these patients was 53 years (range 20-70), and 75.9% of them were women. Sorafenib was prescribed as first-line treatment to 23 patients with differentiated thyroid cancer and as second-line treatment to one patient with advanced medullary thyroid cancer (MTC). Vandetanib was indicated as first-line treatment in 6 patients with MTC and lenvatinib as second-line treatment in two patients with progressive disease under sorafenib treatment. RESULTS: During the follow-up of treatment (mean 13.7 ± 7 months, median 12 months, range 6-32), 5/29 (17.2%) patients presented rare adverse events. These rare adverse effects were: heart failure, thrombocytopenia, and squamous cell carcinoma during sorafenib therapy and squamous cell carcinoma and oophoritis with intestinal perforation during vandetanib treatment. CONCLUSIONS: About 3 to 5 years after the approval of MKI therapy, we learned that MKIs usually lead to adverse effects in the majority of patients. Although most of them are manageable, we still need to be aware of potentially serious and rare or unreported adverse effects that can be life-threatening.

Ação cicatrizante de plantas medicinais: um estudo de revisão / Healing action of medicinal plants: a review

Plantas Medicinais são utilizadas desde a antiguidade para tratar uma série de doenças desempenhando um papel fundamental na saúde mundial. O uso da fitoterapia é muitas vezes o único recurso terapêutico de algumas comunidades. A Organização Mundial da Saúde reconhece a fitoterapia como uma alternativa de tratamento viável com baixo custo e recomenda o levantamento, identificação, estímulo e orientação do uso das plantas medicinais que possuem eficácia e segurança terapêutica comprovada. Nos últimos anos, os fitoterápicos ganharam espaço importante na reparação de tecidos, obtendo a partir deles formulações que agem no tratamento das feridas. O presente estudo teve por objetivo analisar pesquisas envolvendo plantas medicinais e seu poder cicatrizante. Foram utilizados dados de bases online, dos últimos dez anos, utilizando como descritores: "feridas, cicatrização, plantas medicinais". Foram analisados os nomes científico e popular das plantas, a parte da planta que foi utilizada para os experimentos, tipo de extração e utilização, classes das substâncias e efeito na cicatrização. As plantas pesquisadas foram: Aloe vera (L.) Burm. f. (Babosa), Coronopu didymus (Mastruz), Tabebuia avellanedae (Ipê roxo), Arnica Montana L. (Arnica), Orbignya phalerata (Babaçu), Stryphnodendron adstringens Martius (Barbatimão), Caesalpinia ferrea Martius (Jucá), Chenopodium ambrosioides L. (Erva de Santa Maria), Triticum vulgare (Trigo), Tabernaemontana catharinensis (Jasmim), Calendula officinalis (Calêndula) e Helianthus annus (Girassol), Catharanthus roseus L. (Vinca Rosea) e Schinus terebinthifolius Raddi (Aroeira). Assim, pode-se observar que todas as plantas estudadas no artigo favoreceram o processo de cicatrização por meio de diferentes atividades, e que essas atividades estão relacionadas com as diversas classes de metabólitos

Medicinal plants have been used to treat a number of diseases since ancient times, and play a key role in human health. In recent decades, modern medicine has made great advances, but plants still contribute to the development of medicines. The use of herbal medicine is often the only therapeutic resource available in some communities. The World Health Organization recognizes herbal therapy as a viable treatment alternative at a low cost and recommends the collection, identification, stimulation and guidance of the use of medicinal plants that have presented efficacy and safety therapeutics. In recent years, herb therapy has gained important space in the repair of tissues through formulations that act in the treatment of wounds. The aim of this study was to analyze studies involving medicinal plants and their healing potential. Data from online databases from the past ten years were analyzed, using the descriptors: "wounds, healing, medicinal plants". The scientific and popular names of plants, the part of the plant used, type of extraction, therapeutic use, classes of substances and effect on wound healing were analyzed. The plants studied were: Aloe vera (L.) Burm. f. (Babosa), Coronopu didymus (lesser swine cress), Tabebuia avellanedae (pink ipe), Arnica Montana L. (wolf's bane), Orbignya phalerata (Babassu), Stryphnodendron adstringens Martius (Barbatimão), Caesalpinia ferrea Martius (Brazilian ironwood), Chenopodium ambrosioides L. (wormseed), Triticum vulgare (wheat), Tabernaemontana catharinensis (Jasmin), Calendula officinalis (Calendula) and Helianthus annus (sunflower), Catharanthus roseus L. (Madagascar periwinkle) and, Schinus terebinthifolius Raddi (Brazilian peppertree). Thus, the results showed that all the studied plants favored the wound healing process through different mechanism. These activities may be related to the different classes of substances

Enhanced Cutaneous Wound Healing In Vivo by Standardized Crude Extract of Poincianella pluviosa.

Wound healing is a complex process that involves several biological events, and a delay in this process may cause economic and social problems for the patient. The search continues for new alternative treatments to aid healing, including the use of herbal medicines. Members of the genus Caesalpinia are used in traditional medicine to treat wounds. The related species Poincianella pluviosa (DC.) L.P. Queiroz increases the cell viability of keratinocytes and fibroblasts and stimulates the proliferation of keratinocytes in vitro. The crude extract (CE) from bark of P. pluviosa was evaluated in the wound-healing process in vivo, to validate the traditional use and the in vitro activity. Standardized CE was incorporated into a gel and applied on cutaneous wounds (TCEG) and compared with the formulation without CE (Control) for 4, 7, 10, or 14 days of treatment. The effects of the CE on wound re-epithelialization; cell proliferation; permeation, using photoacoustic spectroscopy (PAS); and proteins, including vascular endothelial growth factor (VEGF), superoxide dismutase 2 (SOD-2) and cyclooxygenase 2 (COX-2) were evaluated. The TCEG stimulated the migration of keratinocytes at day 4 and proliferation on the following days, with a high concentration of cells in metaphase at 7 days. Type I collagen formed more rapidly in the TCEG. PAS showed that the CE had permeated through the skin. TCEG stimulated VEGF at day 4 and SOD-2 and COX-2 at day 7. The results suggest that the CE promoted the regulation of proteins and helped to accelerate the processes involved in healing, promoting early angiogenesis. This led to an increase in the re-epithelialized surface, with significant mitotic activity. Maturation of collagen fibers was also enhanced, which may affect the resistance of the extracellular matrix. PAS indicated a correlation between the rate of diffusion and biological events during the healing process. The CE from P. pluviosa appears promising as an aid in healing.

Stryphnodendron adstringens: Clarifying Wound Healing in Streptozotocin-Induced Diabetic Rats.

Diabetes mellitus is a serious public health problem in which a major complication is impaired wound healing. Among the strategies developed to foster tissue repair is the use of medicinal plants. The bark of Stryphnodendron adstringens, which is popularly used as an aid in wound healing, has a documented effect on wound repair in normal rats. This study evaluated the healing action of the crude extract of S. adstringens in diabetic rats, and its chemical content. Compounds present in the crude extract were characterized by mass spectrometry. In diabetic rats (streptozotocin 35 mg/kg), two wounds made in the skin were treated daily for 4, 7, 10, and 14 days with gel containing 1 % crude extract or with base gel. Histological analyses involved the measurement of the length and thickness of the re-epithelialized surface, quantification of the number of cells in mitosis, and types I and III collagen fibers. Also, cutaneous permeation by photoacoustic spectroscopy, and the expression of cyclooxygenase-2 and vascular endothelial growth factor by Western blot were assessed. The crude extract fingerprint showed masses indicating proanthocyanidins. The crude extract mainly stimulated cell migration and proliferation of keratinocytes at the beginning of the treatment in addition to stimulating the replacement of type III collagen fibers by type I collagen fibers at 10 and 14 days. The photoacoustic spectroscopy technique showed that the gel containing 1 % of crude extract permeated through the skin to the dermis, where the crude extract was found. Vascular endothelial growth factor was stimulated after 7 days of treatment with the crude extract and cyclooxygenase-2 at 4, 7, and 10 days. The crude extract of S. adstringens acted in tissue repair in wounds in diabetic rats by stimulating the production of collagen fibers at the wound site. The crude extract favored the formation of a more organized extracellular matrix and filled the entire extent of the wound, and also fostered the upregulation of cyclooxygenase-2 and vascular endothelial growth factor, which are essential to this process. These crude extract actions in diabetic wounds are probably due to the presence of proanthocyanidins.

Hydrolyzable tannins from hydroalcoholic extract from Poincianella pluviosa stem bark and its wound-healing properties: phytochemical investigations and influence on in vitro cell physiology of human keratinocytes and dermal fibroblasts.

Extracts from Poincianella pluviosa stem bark are used in traditional medicine of South America for its wound healing properties. For validation of this traditional use and for rationalizing a potential pharmaceutical development towards standardized preparations bioassay-guided fractionation of EtOH-water (1:1v/v) extract (crude extract, CE) of P. pluviosa bark was performed. HaCaT keratinocytes cell line and human primary dermal fibroblasts (pNHDF) were used as in vitro systems. Significant stimulation of mitochondrial activity was found for CE on both cell types, which caused a strong increase of cell proliferation of keratinocytes. Fractionation of CE over Sephadex LH20 revealed two inactive fractions (FA and FB) and an active fraction FC, which was further fractionated by MPLC into 4 subfractions. Subfraction FC1 increased mitochondrial activity and proliferation of keratinocytes and dermal fibroblasts in a dose dependent manner (10 to 100 µg/mL) and did not show necrotic cytotoxicity on keratinocytes (LDH release assay). FC1 was investigated by ESI-MS/MS and solid-state (13)C NMR which confirmed the presence of various polyphenols and hydrolyzable tannins. MS studies suggest the presence of pyrogallol (1), gallic acid (2), gallic acid methyl ester (3), ellagic acid (4), corilagin (5), 1,4,6-tri-O-galloyl-glucose (6), tellimagrandin I (7), 1,2,3,6-tetra-O-galloyl-glucose (8), mallotinic acid (9), tellimagrandin II (10), 1,2,3,4,6-penta-O-galloyl-glucose (11), geraniin (12), and mallotusinic acid (13).

Direct proof by (13)C-nuclear magnetic resonance of semi-purified extract and isolation of ent-Catechin from leaves of Eucalyptus cinerea.

BACKGROUND: Eucalyptus cinerea F. Muell. ex Benth. is native to Australia and acclimatized to Southern Brazil. Its aromatic leaves are used for ornamental purposes and have great potential for essential oil production, although reports of its use in folk medicine are few. OBJECTIVE: This study evaluated the composition of E. cinerea leaves using the solid state (13)C-nuclear magnetic resonance (NMR) and isolation of the compound from the semipurified extract (SE). MATERIALS AND METHODS: The SE of E. cinerea leaves was evaluated in the solid state by (13)C-NMR spectrum, and the SE was chromatographed on a Sephadex LH-20 column, followed by high-speed counter-current chromatography to isolate the compound. The SE was analyzed by (13)C-NMR and matrix-assisted laser desorption/ionization-time-of-flight spectra. RESULTS: Flavan-3-ol units were present, suggesting the presence of proanthocyanidins as well as a gallic acid unit. The uncommon ent-catechin was isolated. CONCLUSION: The presence of ent-catechin is reported for the first time in this genus and species.

In vitro and in vivo assessment of the anti-malarial activity of Caesalpinia pluviosa.

BACKGROUND: To overcome the problem of increasing drug resistance, traditional medicines are an important source for potential new anti-malarials. Caesalpinia pluviosa, commonly named "sibipiruna", originates from Brazil and possess multiple therapeutic properties, including anti-malarial activity. METHODS: Crude extract (CE) was obtained from stem bark by purification using different solvents, resulting in seven fractions. An MTT assay was performed to evaluate cytotoxicity in MCF-7 cells. The CE and its fractions were tested in vitro against chloroquine-sensitive (3D7) and -resistant (S20) strains of Plasmodium falciparum and in vivo in Plasmodium chabaudi-infected mice. In vitro interaction with artesunate and the active C. pluviosa fractions was assessed, and mass spectrometry analyses were conducted. RESULTS: At non-toxic concentrations, the 100% ethanolic (F4) and 50% methanolic (F5) fractions possessed significant anti-malarial activity against both 3D7 and S20 strains. Drug interaction assays with artesunate showed a synergistic interaction with the F4. Four days of treatment with this fraction significantly inhibited parasitaemia in mice in a dose-dependent manner. Mass spectrometry analyses revealed the presence of an ion corresponding to m/z 303.0450, suggesting the presence of quercetin. However, a second set of analyses, with a quercetin standard, showed distinct ions of m/z 137 and 153. CONCLUSIONS: The findings show that the F4 fraction of C. pluviosa exhibits anti-malarial activity in vitro at non-toxic concentrations, which was potentiated in the presence of artesunate. Moreover, this anti-malarial activity was also sustained in vivo after treatment of infected mice. Finally, mass spectrometry analyses suggest that a new compound, most likely an isomer of quercetin, is responsible for the anti-malarial activity of the F4.