Natural products with therapeutic potential in melanoma metastasis

Malignant melanoma is the most aggressive form of skin cancer and accounts for about 3% of all cases of malignant tumour. Its incidence is increasing worldwide and it is becoming resistant to current therapeutic agents. Natural products continue to provide lead cytotoxic compounds for cancer treatment but less attention has been given to antimigratory compounds. This paper systematically and critically surveys all natural products with direct in vitro and in vivo pharmacological effects on migration and/or metastasis of melanoma cells and maps the mechanisms of action for these underexploited properties. As a result, over 30 natural active principles are described acting mainly through their antagonistic effects upon the TNF-α and EP2 receptors or the suppression of several protein kinases involved in metastatic pathways such as RAS, PI3K, ERK and FAK. Also, some were able to reduce the level of mesenchymal biomarkers such as N-cadherin and/or elevate the expression of other molecules such as E-cadherin. Consequently, downstream transcription factors namely NF-kB, AP-1, ATF-2, CREB, and HIF were inactivated leading to diminished production of MMPs, IL-1, IL-6, COX-2, VEGF and GM-CSF. This review also discusses the opportunity of combination therapies based on natural products and approved drugs, such as the combination of EGCG and dacarbazine, or the combination of two natural compounds such as quercetin and sulforaphane

Herbal medicines in Brazil: pharmacokinetic profile and potential herb-drug interactions

A plethora of active compounds found in herbal medicines can serve as substrate for enzymes involved in the metabolism of xenobiotics. When a medicinal plant is co-administered with a conventional drug and little or no information is known about the pharmacokinetics of the plant metabolites, there is an increased risk of potential herb-drug interactions. Moreover, genetic polymorphisms in a population may act to predispose individuals to adverse reactions. The use of herbal medicines is rapidly increasing in many countries, particularly Brazil where the vast biodiversity is a potential source of new and more affordable treatments for numerous conditions. Accordingly, the Brazilian Unified Public Health System (SUS) produced a list of 71 plant species of interest, which could be made available to the population in the near future. Physicians at SUS prescribe a number of essential drugs and should herbal medicines be added to this system the chance of herb-drug interactions further increases. A review of the effects of these medicinal plants on Phase 1 and Phase 2 metabolic mechanisms and the transporter P-glycoprotein was conducted. The results have shown that approximately half of these medicinal plants lack any pharmacokinetic data. Moreover, most of the studies carried out are in vitro. Only a few reports on herb-drug interactions with essential drugs prescribed by SUS were found, suggesting that very little attention is being given to the safety of herbal medicines. Here we have taken this information to discuss the potential interactions between herbal medicines and essential drugs prescribed to Brazilian patients whilst taking into account the most common polymorphisms present in the Brazilian population. A number of theoretical interactions are pinpointed but more pharmacokinetic studies and pharmacovigilance data are needed to ascertain their clinical significance

Bioactive properties of commercialised pomegranate (Punica granatum) juice: antioxidant, antiproliferative and enzyme inhibiting activities

Pomegranate juice and related products have long been used either in traditional medicine or as nutritional supplements claiming beneficial effects. Although there are several studies on this food plant, only a few studies have been performed with pomegranate juice or marketed products. The aim of this work is to evaluate the antioxidant effects of pomegranate juice on cellular models using hydrogen peroxide as an oxidizing agent or DPPH and superoxide radicals in cell free systems. The antiproliferative effects of the juice were measured on HeLa and PC-3 cells by the MTT assay and pharmacologically relevant enzymes (cyclooxygenases, xanthine oxidase, acetylcholinesterase and monoamine oxidase A) were selected for enzymatic inhibition assays. Pomegranate juice showed significant protective effects against hydrogen peroxide induced toxicity in the Artemia salina and HepG2 models; these effects may be attributed to radical scavenging properties of pomegranate as the juice was able to reduce DPPH and superoxide radicals. Moderate antiproliferative activities in HeLa and PC-3 cancer cells were observed. However, pomegranate juice was also able to inhibit COX-2 and MAO-A enzymes. This study reveals some mechanisms by which pomegranate juice may have interesting and beneficial effects in human health

Application of Artificial Intelligence to the Prediction of the Antimicrobial Activity of Essential Oils

Essential oils (EOs) are vastly used as natural antibiotics in Complementary and Alternative Medicine (CAM). Their intrinsic chemical variability and synergisms/antagonisms between its components make difficult to ensure consistent effects through different batches. Our aim is to evaluate the use of artificial neural networks (ANNs) for the prediction of their antimicrobial activity. Methods. The chemical composition and antimicrobial activity of 49 EOs, extracts, and/or fractions was extracted from NCCLS compliant works. The fast artificial neural networks (FANN) software was used and the output data reflected the antimicrobial activity of these EOs against four common pathogens: Staphylococcus aureus, Escherichia coli, Candida albicans, and Clostridium perfringens as measured by standardised disk diffusion assays. Results. ANNs were able to predict >70% of the antimicrobial activities within a 10 mm maximum error range. Similarly, ANNs were able to predict 2 or 3 different bioactivities at the same time. The accuracy of the prediction was only limited by the inherent errors of the popular antimicrobial disk susceptibility test and the nature of the pathogens. Conclusions. ANNs can be reliable, fast, and cheap tools for the prediction of the antimicrobial activity of EOs thus improving their use in CAM

In Vitro Modulation of Glibenclamide Transport by P-glycoprotein Inhibitory Antidiabetic African Plant Extracts (1)

The rise of diabetes incidence in Nigeria enhances the use of popular remedies that may interact with conventional therapies. The aqueous extracts of 27 popular Nigerian “antidiabetic” plants were tested for their in vitro effects on glutathione levels within HepG2 cells, P-glycoprotein (P-gp)-mediated Rh-123 efflux activity in Caco-2 vincristine-resistant cells, and modulation of glibenclamide transport in Caco-2 monolayers. The extract from Ximenia americana significantly depleted intracellular glutathione at 100 µg/mL similarly to the reference buthionine sulphoximine (p < 0.05). Other 10 extracts raised glutathione levels. Eight extracts inhibiting P-gp efflux in a concentration-dependent manner (p < 0.01) were selected for further evaluation in a bi-directional transport model across Caco-2 monolayers: Annona senegalensis, Bridellia ferruginea, Cassytha filiformis, Daniellia ogea, Khaya ivorensis, Syzygium guineense, Terminalia avicennioides, and X. americana. When interferences in paracellular transport were discarded, only 3 of them may be modulating the efflux ratio of glibenclamide (efflux ratio: 2.65 ± 0.13) in the same manner the reference drug verapamil (efflux ratio: 1.14 ± 0.25, p < 0.01) does: Syzygium guineense (efflux ratio: 1.70 ± 0.23, p < 0.01), Terminalia avicennioides (efflux ratio: 1.80 ± 0.25, p < 0.05), and X. americana (efflux ratio: 1.66 ± 0.10, p < 0.01). HPLC-UV analyses for P-gp inhibitors in these extracts revealed several phenolic compounds such as rutin, gallic acid, and ellagic acid reported to decrease P-gp expression and/or directly modify its function. In conclusion, some popular herbal medicines used by Nigerian diabetic patients are here shown to potentially affect glibenclamide absorption at concentrations that could be reached in the intestinal tract

Herbal medicines in Brazil: pharmacokinetic profile and potential herb-drug interactions

A plethora of active compounds found in herbal medicines can serve as substrate for enzymes involved in the metabolism of xenobiotics. When a medicinal plant is co-administered with a conventional drug and little or no information is known about the pharmacokinetics of the plant metabolites, there is an increased risk of potential herb-drug interactions. Moreover, genetic polymorphisms in a population may act to predispose individuals to adverse reactions. The use of herbal medicines is rapidly increasing in many countries, particularly Brazil where the vast biodiversity is a potential source of new and more affordable treatments for numerous conditions. Accordingly, the Brazilian Unified Public Health System (SUS) produced a list of 71 plant species of interest, which could be made available to the population in the near future. Physicians at SUS prescribe a number of essential drugs and should herbal medicines be added to this system the chance of herb-drug interactions further increases. A review of the effects of these medicinal plants on Phase 1 and Phase 2 metabolic mechanisms and the transporter P-glycoprotein was conducted. The results have shown that approximately half of these medicinal plants lack any pharmacokinetic data. Moreover, most of the studies carried out are in vitro. Only a few reports on herb-drug interactions with essential drugs prescribed by SUS were found, suggesting that very little attention is being given to the safety of herbal medicines. Here we have taken this information to discuss the potential interactions between herbal medicines and essential drugs prescribed to Brazilian patients whilst taking into account the most common polymorphisms present in the Brazilian population. A number of theoretical interactions are pinpointed but more pharmacokinetic studies and pharmacovigilance data are needed to ascertain their clinical significance