Active natural compounds perturb the melanoma risk-gene network.

Cutaneous melanoma is an aggressive type of skin cancer with a complex genetic landscape caused by the malignant transformation of melanocytes. This study aimed at providing an in silico network model based on the systematic profiling of the melanoma-associated genes considering germline mutations, somatic mutations, and genome-wide association study signals accounting for a total of 232 unique melanoma risk genes. A protein-protein interaction network was constructed using the melanoma risk genes as seeds and evaluated to describe the functional landscape in which the melanoma genes operate within the cellular milieu. Not only were the majority of the melanoma risk genes able to interact with each other at the protein level within the core of the network, but this showed significant enrichment for genes whose expression is altered in human melanoma specimens. Functional annotation showed the melanoma risk network to be significantly associated with processes related to DNA metabolism and telomeres, DNA damage and repair, cellular ageing, and response to radiation. We further explored whether the melanoma risk network could be used as an in silico tool to predict the efficacy of anti-melanoma phytochemicals, that are considered active molecules with potentially less systemic toxicity than classical cytotoxic drugs. A significant portion of the melanoma risk network showed differential expression when SK-MEL-28 human melanoma cells were exposed to the phytochemicals harmine and berberine chloride. This reinforced our hypothesis that the network modeling approach not only provides an alternative way to identify molecular pathways relevant to disease but it may also represent an alternative screening approach to prioritize potentially active compounds.

In Vitro Cytotoxic Effects of Ferruginol Analogues in Sk-MEL28 Human Melanoma Cells.

Ferruginol is a promising abietane-type antitumor diterpene able to induce apoptosis in SK-Mel-28 human malignant melanoma. We aim to increase this activity by testing the effect of a small library of ferruginol analogues. After a screening of their antiproliferative activity (SRB staining, 48 h) on SK-Mel-28 cells the analogue 18-aminoferruginol (GI50 ≈ 10 µM) was further selected for mechanistic studies including induction of apoptosis (DAPI staining, p < 0.001), changes in cell morphology associated with the treatment (cell shrinkage and membrane blebbing), induction of caspase-3/7 activity (2.5 at 48 h, 6.5 at 72 h; p < 0.0001), changes in the mitochondrial membrane potential (not significant) and in vitro effects on cell migration and cell invasion (Transwell assays, not significant). The results were compared to those of the parent molecule (ferruginol, GI50 ≈ 50 µM, depolarisation of mitochondrial membrane p < 0.01 at 72 h; no caspases 3/7 activation) and paclitaxel (GI50 ≈ 10 nM; caspases 3/7 activation p < 0.0001) as a reference drug. Computational studies of the antiproliferative activity of 18-aminoferruginol show a consistent improvement in the activity over ferruginol across a vast majority of cancer cells in the NCI60 panel. In conclusion, we demonstrate here that the derivatisation of ferruginol into 18-aminoferruginol increases its antiproliferative activity five times in SK-MEL-28 cells and changes the apoptotic mechanism of its parent molecule, ferruginol.

Potential Pharmacokinetic Interactions of Common Cardiovascular Drugs and Selected European and Latin American Herbal Medicines: A Scoping Review.

BACKGROUND: Herb-drug interactions are nowadays an important decision factor in many healthcare interventions. Patients with cardiovascular risk factors such as hyperlipidemia and hypertension are usually prescribed long-term treatments. We need more informed decision tools to direct future clinical research and decision making to avoid HDI occurrences in this group. METHODS: A scoping review was conducted using data from online databases such as PUBMED, the National Library of Medicine, and the electronic Medicines Compendium. Included studies consisted of the reported effects on Phase 1/2 and P-glycoprotein of herbal medicines listed in the medicines agencies of Latin America and Europe and drugs used for cardiovascular conditions (statins, diuretics, beta blockers, calcium channel blockers, and ACE inhibitors). The cross tabulation of the results allowed for finding potential HDI. RESULTS AND CONCLUSIONS: as per the preclinical data reviewed here, we encourage more clinical research on whether drugs with apparently very low interaction risk, such as pravastatin, nadolol, and nimodipine/nitrendipine, may help prevent HDI when statins, beta blockers, and calcium channel blockers, respectively, are prescribed for long-term treatments.

COVID-19: Is There Evidence for the Use of Herbal Medicines as Adjuvant Symptomatic Therapy?

BACKGROUND: Current recommendations for the self-management of SARS-Cov-2 disease (COVID-19) include self-isolation, rest, hydration, and the use of NSAID in case of high fever only. It is expected that many patients will add other symptomatic/adjuvant treatments, such as herbal medicines. AIMS: To provide a benefits/risks assessment of selected herbal medicines traditionally indicated for "respiratory diseases" within the current frame of the COVID-19 pandemic as an adjuvant treatment. METHOD: The plant selection was primarily based on species listed by the WHO and EMA, but some other herbal remedies were considered due to their widespread use in respiratory conditions. Preclinical and clinical data on their efficacy and safety were collected from authoritative sources. The target population were adults with early and mild flu symptoms without underlying conditions. These were evaluated according to a modified PrOACT-URL method with paracetamol, ibuprofen, and codeine as reference drugs. The benefits/risks balance of the treatments was classified as positive, promising, negative, and unknown. RESULTS: A total of 39 herbal medicines were identified as very likely to appeal to the COVID-19 patient. According to our method, the benefits/risks assessment of the herbal medicines was found to be positive in 5 cases (Althaea officinalis, Commiphora molmol, Glycyrrhiza glabra, Hedera helix, and Sambucus nigra), promising in 12 cases (Allium sativum, Andrographis paniculata, Echinacea angustifolia, Echinacea purpurea, Eucalyptus globulus essential oil, Justicia pectoralis, Magnolia officinalis, Mikania glomerata, Pelargonium sidoides, Pimpinella anisum, Salix sp, Zingiber officinale), and unknown for the rest. On the same grounds, only ibuprofen resulted promising, but we could not find compelling evidence to endorse the use of paracetamol and/or codeine. CONCLUSIONS: Our work suggests that several herbal medicines have safety margins superior to those of reference drugs and enough levels of evidence to start a clinical discussion about their potential use as adjuvants in the treatment of early/mild common flu in otherwise healthy adults within the context of COVID-19. While these herbal medicines will not cure or prevent the flu, they may both improve general patient well-being and offer them an opportunity to personalize the therapeutic approaches.

Resins and Gums in Historical Iatrosophia Texts from Cyprus - A Botanical and Medico-pharmacological Approach.

This study explores historical iatrosophia texts from Cyprus from a botanical and medico-pharmacological point of view focusing on remedies containing resins and gums. The iatrosophia are a genre of Greek medical literature of Byzantine origin and can be described as medicine handbooks which serve as therapeutic repositories containing recipes or advice. To extract and analyze information on plant usage in such sources - which are largely unedited texts and so far have not been translated - we investigate (i) the relationship of the iatrosophia to Dioscorides' De Materia Medica as well as historic pharmaceutical books or standard texts on modern phytotherapy and (ii) the validity of the remedies by comparing them to modern scientific data on reported biological activities. In the six texts investigated 27 substances incorporating plant exudates are mentioned. They are obtained from over 43 taxa of higher plants and in particular are used to treat dermatological, gastrointestinal, and respiratory tract conditions. The comparison to historic pharmaceutical books and phytotherapy texts reflects the gradual decline of the use of plant exudates in Western medicine. While remarkable parallels to Dioscorides' text exist, the non-Dioscoridean influence suggests a complex pattern of knowledge exchange. Overall, this resulted in an integration of knowledge from so far poorly understood sources. The comparison with bioscientific data reveals a fragmentary picture and highlights the potential of these unexplored substances and their uses. Where relevant bioscientific data are available, we generally found a confirmation. This points to a largely rational use of the associated remedies. Taken together, the iatrosophia are a valuable resource for ethnopharmacological and natural product research. Most importantly they contribute to the understanding of the development of herbal medicines in the (Eastern) Mediterranean and Europe.

Effect of free versus liposomal-complexed pentamidine isethionate on biological characteristics of Acanthamoeba castellanii in vitro.

Acanthamoeba is an opportunistic protozoan pathogen that can cause blinding keratitis and a rare but fatal encephalitis involving the central nervous system with a very poor prognosis. This is due to limited availability of effective anti-acanthamoebic drugs. Here, we tested whether the use of liposomes can improve the potency of pentamidine isethionate, an anti-amoebic compound. The liposomes consisted of l-alpha-phosphatidylcholine and cholesterol or ergosterol in a molar ratio of 1 : 5. Pentamidine isethionate was incorporated to achieve a final drug to lipid ratio of 1 : 5. At a drug concentration of 10 microg ml(-1), the liposomal drug was >12 times more effective than the free drug at preventing Acanthamoeba binding to human cells and significantly more effective in reducing parasite-mediated human cell cytopathogenicity, compared with the drug alone. Both the free and liposomal drug blocked Acanthamoeba encystation.