Future directions for the discovery of natural product-derived immunomodulating drugs: an IUPHAR positional review.

Drug discovery from natural sources is going through a renaissance, having spent many decades in the shadow of synthetic molecule drug discovery, despite the fact that natural product-derived compounds occupy a much greater chemical space than those created through synthetic chemistry methods. With this new era comes new possibilities, not least the novel targets that have emerged in recent times and the development of state-of-the-art technologies that can be applied to drug discovery from natural sources. Although progress has been made with some immunomodulating drugs, there remains a pressing need for new agents that can be used to treat the wide variety of conditions that arise from disruption, or over-activation, of the immune system; natural products may therefore be key in filling this gap. Recognising that, at present, there is no authoritative article that details the current state-of-the-art of the immunomodulatory activity of natural products, this in-depth review has arisen from a joint effort between the International Union of Basic and Clinical Pharmacology (IUPHAR) Natural Products and Immunopharmacology Sections, with contributions from a number of world-leading researchers in the field of natural product drug discovery, to provide a "position statement" on what natural products has to offer in the search for new immunomodulatory argents. To this end, we provide a historical look at previous discoveries of naturally occurring immunomodulators, present a picture of the current status of the field and provide insight into the future opportunities and challenges for the discovery of new drugs to treat immune-related diseases.

Differences in diterpenoid diversity reveal new evidence for separating the genus Coleus from Plectranthus.

Covering: up to 2019The large and medicinally important tropical plant genus Plectranthus (Lamiaceae) was recently split into three separate genera on the basis of molecular and morphological evidence; Plectranthus sensu stricto, Coleus and Equilabium. We found striking differences between the diterpenoids which strongly support this taxonomic split. Coleus is characterised by abietanes oxygenated at C-14 such as royleanones, spirocoleons and acylhydroquinones, which could be useful chemotaxonomic markers to distinguish this genus from Plectranthus s.s. In contrast, the abietanes in Plectranthus s.s. lack C-14 oxygenation, but are often acylated with unusual acids. Equilabium species do not seem to produce diterpenoids. The structures of the nearly 240 abietanes so far reported from Coleus and Plectranthus and their distribution are presented. The aim of this Highlight is to provide an overview of the differences in diterpenoid diversity between these newly defined genera, which are relevant to predict which previously understudied species could hold untapped potential for their medicinal and other economic uses, and to underpin future research on how these plants have evolved to synthesise distinct abietane types.

The Pathopharmacological Interplay between Vanadium and Iron in Parkinson's Disease Models.

Parkinson's disease (PD) pathology is characterised by distinct types of cellular defects, notably associated with oxidative damage and mitochondria dysfunction, leading to the selective loss of dopaminergic neurons in the brain's substantia nigra pars compacta (SNpc). Exposure to some environmental toxicants and heavy metals has been associated with PD pathogenesis. Raised iron levels have also been consistently observed in the nigrostriatal pathway of PD cases. This study explored, for the first time, the effects of an exogenous environmental heavy metal (vanadium) and its interaction with iron, focusing on the subtoxic effects of these metals on PD-like oxidative stress phenotypes in Catecholaminergic a-differentiated (CAD) cells and PTEN-induced kinase 1 (PINK-1)B9Drosophila melanogaster models of PD. We found that undifferentiated CAD cells were more susceptible to vanadium exposure than differentiated cells, and this susceptibility was modulated by iron. In PINK-1 flies, the exposure to chronic low doses of vanadium exacerbated the existing motor deficits, reduced survival, and increased the production of reactive oxygen species (ROS). Both Aloysia citrodora Paláu, a natural iron chelator, and Deferoxamine Mesylate (DFO), a synthetic iron chelator, significantly protected against the PD-like phenotypes in both models. These results favour the case for iron-chelation therapy as a viable option for the symptomatic treatment of PD.

A chemically characterized ethanolic extract of Thai Perilla frutescens (L.) Britton fruits (nutlets) reduces oxidative stress and lipid peroxidation in human hepatoma (HuH7) cells.

Perilla frutescens is cultivated in East Asian countries including Thailand, and the nutlets (single-seeded fruits) are used as traditional and medicinal food. Perilla nutlets extracted by ethyl acetate (EA), 80% ethanol (Eth), and hot water (HW) sequentially were chemically characterized using high-resolution accurate liquid chromatography-mass spectrometry with the main compounds detected assigned as rosmarinic acid and derivatives of the flavones apigenin and luteolin, with the more diverse chemical composition observed with the Eth extract. All extracts showed dose-dependent free-radical scavenging activity, with the Eth extract the most potent (IC50  = 3.43 mg/ml for ABTS• scavenging and 0.27 mg/ml for DPPH• scavenging). The Eth extract also inhibited AAPH-induced hemolysis (IC50  = 0.07 mg/ml) more potently than did the HW (IC50  = 0.38 mg/ml) and EA extracts (IC50  = 1.63 mg/ml). An MTT test revealed all the extracts were noncytotoxic at concentrations up to 200 µg/ml. Only the Eth and EA extracts showed protective effects against the generation of reactive oxygen species and lipid peroxidation in FeCl3 -induced HuH7 cells in a dose-dependent manner. Our findings suggest the Eth extract of Thai perilla nutlets, containing rosmarinic acid and flavones and their derivatives, may have potential to provide protection against oxidative stress in hepatic disorders.

The role of phytochemicals as micronutrients in health and disease.

PURPOSE OF REVIEW: Intake of dietary phytochemicals has frequently been associated with health benefits. Noninfectious diseases including cardiovascular disease (CVD), cancer and diabetes are major causes of death, whereas dementia cases are also increasing to 'epidemic' proportion. This review will focus on recent progress on mechanisms underlying the potential role of dietary phytochemicals in CVD, diabetes, cancer and dementia, with consideration of the latest clinical data. RECENT FINDINGS: The association of tea (Camellia sinensis), particularly catechins, with reported mechanistic effects for CVD, diabetes, cancer and cognition contributes to our understanding of the suggested benefits of tea consumption on health from limited and inconclusive clinical trial and epidemiological data. Resveratrol, which occurs in grapes (Vitis vinifera) and wine, and curcumin, a component of turmeric (Curcuma longa), are also emerging as potentially relevant to health, particularly for CVD and dementia, with some promising data also concluded for curcumin in cancer. Other phytochemicals mechanistically relevant for health include anthocyanins, isoflavones and glucosinolates, which are also discussed. SUMMARY: Evidence for the role of phytochemicals in health and disease is growing, but associations between phytochemicals and disease need to be more firmly understood and established from more robust clinical data using preparations that have been phytochemically characterized.

Evaluation of the anti-nociceptive profile of essential oil from Melissa officinalis L. (lemon balm) in acute and chronic pain models.

ETHNOPHARMACOLOGICAL RELEVANCE: Melissa officinalis L. (Lamiaceae) is a medicinal plant native to Mediterranean regions and found in other parts of the world. Extracts and essential oil from this widely cultivated culinary medicinal herb are used in traditional medicine to manage a variety of disorders that include epilepsy and pain. AIM OF THE STUDY: To assess the anti-nociceptive potentials of Melissa officinalis essential oil (MO) and probe the involvement of adrenergic, opioidergic, serotonergic and potassium adenosine triphosphate (KATP) mechanisms in its anti-nociceptive effects. MATERIAL AND METHODS: We employed formalin-, acetic acid and hot plate-induced nociception to study the acute anti-nociceptive effects of MO. The sciatic nerve injury (CCI) model of neuropathic pain was utilized to study the anti-nociceptive effects of MO on chronic pain. Effects of MO on anxiety, cognitive deficits, oxidative stress and inflammation in the CCI rats were evaluated on elevated plus maze, open field test, novel object recognition, oxidative stress parameters and pro-inflammatory cytokines, respectively. The possible mechanism(s) of MO's anti-nociceptive effects were elucidated using prazosin, yohimbine, propranolol, glibenclimide, naloxone and metergoline, which are acknowledged antagonists for α1-, α2- and ß-adrenergic, potassium adenosine triphosphate (KATP), opioidergic and serotonergic systems, respectively. RESULTS: MO significantly attenuated acetic acid- and formalin-induced nociception; prolonged the mean reaction time of rats on hot plate before and following sciatic nerve chronic injury (CCI). MO ameliorated anxiety, cognitive deficits and oxidative stress, reduced pro-inflammatory cytokine levels and produced a near total restoration of injured sciatic nerves in CCI rats. Naloxone, metergoline and glibenclimide significantly blocked, while prazosin, yohimbine and popranolol failed to block the anti-nociceptive effects of MO in formalin-induced nociception. CONCLUSIONS: MO contains biologically active compounds with potential anti-nociceptive properties that modulate KATP, opioidergic and serotonergic pathways. These support the development of bioactive compounds from MO as anti-nociceptive agents.

Wild edible yams from Madagascar: New insights into nutritional composition support their use for food security and conservation.

Yams (Dioscorea species) are an important food resource in Madagascar, where both cultivated winged yam (D. alata) and wild edible yams are consumed. However, there is limited knowledge on the nutrient composition of wild edible yams in Madagascar, and on how they compare with the cultivated winged yam. Therefore, in this study, nine wild edible yam species, one with two subspecies from Madagascar (D. bako, D. buckleyana, D. irodensis, D. maciba, D. orangeana, D. pteropoda, D. sambiranensis subsp. bardotiae and subsp. sambiranensis, D. seriflora, and Dioscorea species Ovy valiha), were analyzed for their nutrient composition, compared with cultivated D. alata. They include 6/6 of the most favored wild edible yam species in Madagascar. New nutrient composition data (protein, carbohydrate/starch, energy, lipid, ß-carotene, and minerals) are presented for these nine wild edible yam species. The results show that they contain comparable levels of lipids and starch to D. alata, but none are better sources of protein than D. alata. The results show that D. irodensis contains a significantly higher ß-carotene content when compared to all other edible yams analyzed, and that D. buckleyana, D. irodensis, and D. sambiranensis subsp. bardotiae have a higher calcium content than cultivated D. alata, while all nine wild edible yam species analyzed contain a higher iron content, compared to cultivated D. alata. The nutrient composition data presented could provide new incentives to conserve wild edible yams and inform on strategies to select Dioscorea species for sustainable cultivation and use, providing opportunities to enhance future food security in Madagascar.

Scutellaria incarnata Vent. root extract and isolated phenylethanoid glycosides are neuroprotective against C2-ceramide toxicity.

ETHNOPHARMACOLOGICAL RELEVANCE: Neuronal death is a central process in neurodegenerative diseases and represents a therapeutic challenge for their prevention and treatment. Scutellaria incarnata Vent. roots are used traditionally in Colombia for central nervous system conditions including those affecting cognitive functions, but their chemistry and neuroprotective action remain to be explored to understand the scientific basis for their medicinal uses. In this study, S. incarnata roots are investigated to assess whether they have neuroprotective effects that could provide some explanation for their traditional use in neurodegenerative diseases. AIM OF THE STUDY: To evaluate the neuroprotective effect of S. incarnata roots and its chemical constituents against C2-ceramide-induced cell death in Cath.-a-differentiated (CAD) cells. MATERIALS AND METHODS: S. incarnata root ethanol extract was fractionated and compounds were isolated by column chromatography; their structures were elucidated by nuclear magnetic resonance spectroscopy, mass spectrometry and infrared spectroscopy. The cytotoxic and neuroprotective effects against C2-ceramide of S. incarnata root extract, fractions and isolated compounds were assessed in CAD cells. RESULTS: S. incarnata root extract and its n-butanol fraction were not cytotoxic but showed neuroprotective effects against C2-ceramide toxicity in CAD cells. The phenylethanoid glycosides incarnatoside (isolated for the first time) and stachysoside C (12.5, 25 and 50 µg/mL) from S. incarnata roots also protected CAD cells against C2-ceramide without inducing cytotoxic effects. CONCLUSION: The observed neuroprotective effects of S. incarnata root extract and isolated phenylethanoid glycosides in CAD cells provide an ethnopharmacological basis for the traditional use of this species in Colombia for central nervous system disorders.

Machine learning enhances prediction of plants as potential sources of antimalarials.

Plants are a rich source of bioactive compounds and a number of plant-derived antiplasmodial compounds have been developed into pharmaceutical drugs for the prevention and treatment of malaria, a major public health challenge. However, identifying plants with antiplasmodial potential can be time-consuming and costly. One approach for selecting plants to investigate is based on ethnobotanical knowledge which, though having provided some major successes, is restricted to a relatively small group of plant species. Machine learning, incorporating ethnobotanical and plant trait data, provides a promising approach to improve the identification of antiplasmodial plants and accelerate the search for new plant-derived antiplasmodial compounds. In this paper we present a novel dataset on antiplasmodial activity for three flowering plant families - Apocynaceae, Loganiaceae and Rubiaceae (together comprising c. 21,100 species) - and demonstrate the ability of machine learning algorithms to predict the antiplasmodial potential of plant species. We evaluate the predictive capability of a variety of algorithms - Support Vector Machines, Logistic Regression, Gradient Boosted Trees and Bayesian Neural Networks - and compare these to two ethnobotanical selection approaches - based on usage as an antimalarial and general usage as a medicine. We evaluate the approaches using the given data and when the given samples are reweighted to correct for sampling biases. In both evaluation settings each of the machine learning models have a higher precision than the ethnobotanical approaches. In the bias-corrected scenario, the Support Vector classifier performs best - attaining a mean precision of 0.67 compared to the best performing ethnobotanical approach with a mean precision of 0.46. We also use the bias correction method and the Support Vector classifier to estimate the potential of plants to provide novel antiplasmodial compounds. We estimate that 7677 species in Apocynaceae, Loganiaceae and Rubiaceae warrant further investigation and that at least 1300 active antiplasmodial species are highly unlikely to be investigated by conventional approaches. While traditional and Indigenous knowledge remains vital to our understanding of people-plant relationships and an invaluable source of information, these results indicate a vast and relatively untapped source in the search for new plant-derived antiplasmodial compounds.

Cytotoxicity of Fenugreek Sprout and Seed Extracts and Their Bioactive Constituents on MCF-7 Breast Cancer Cells.

Trigonella foenum-graecum L. (fenugreek), a member of the legume family (Fabaceae), is a promising source of bioactive phytochemicals, which explains its traditional use for a variety of metabolic disorders including cancer. The current study aimed to evaluate extracts of fenugreek seeds and sprouts, and some of their constituents, to compare their cytotoxic and antiproliferative activities in MCF-7 breast cancer cells. The extracts were chemically characterised using high-resolution accurate mass liquid chromatography-mass spectrometry to reveal the detection of compounds assigned as flavone C-glycosides including those derived from apigenin and luteolin, in addition to isoflavones. Five different flavones or their glycosides (apigenin, vicenin-2, vitexin, luteolin and orientin) and two isoflavones (daidzein and formononetin) were quantified in the fenugreek extracts. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay using MCF-7 cells treated with fenugreek methanolic extracts showed dose- and time-dependent effects on cell viability. The MCF-7 cancer cells treated with the fenugreek methanolic extracts also displayed increased relative mitochondrial DNA damage as well as suppressed metastasis and proliferation. This study demonstrates the potential anti-cancer effects of fenugreek seeds and sprouts and reveals fenugreek sprouts as an untapped resource for bioactive compounds.

Global plant diversity as a reservoir of micronutrients for humanity.

With more than two billion people suffering from malnutrition and diets homogenizing globally, it is vital to identify and conserve nutrient-rich species that may contribute to improving food security and diversifying diets. Of the approximately 390,000 vascular plant species known to science, thousands have been reported to be edible, yet their nutritional content remains poorly characterized. Here we use phylogenetic information to identify plants with the greatest potential to support strategies alleviating B-vitamin deficiencies. We predict the B-vitamin profiles of >6,400 edible plants lacking nutritional data and identify 1,044 species as promising key sources of B vitamins. Several of these source species should become conservation priorities, as 63 (6%) are threatened in the wild and 272 (26%) are absent from seed banks. Moreover, many of these conservation-priority source species overlap with hotspots of malnutrition, highlighting the need for safeguarding strategies to ensure that edible plant diversity remains a reservoir of nutrition for future generations, particularly in countries needing it most. Although by no means a silver bullet to tackling malnutrition, conserving a diverse portfolio of edible plants, unravelling their nutritional potentials, and promoting their sustainable use are essential strategies to enhance global nutritional resilience.

Natural products as a source of Alzheimer's drug leads.

This review focuses on recent developments in the use of natural products as therapeutics for Alzheimer's disease. The compounds span a diverse array of structural classes and are organized according to their mechanism of action, with the focus primarily on the major hypotheses. Overall, the review discusses more than 180 compounds and summarizes 400 references.

A double-blind placebo-controlled randomized trial of Melissa officinalis oil and donepezil for the treatment of agitation in Alzheimer's disease.

BACKGROUND/AIMS: Behavioural and psychological symptoms (BPSD) are frequent in people with Alzheimer's disease and cause considerable stress to patients and their carers. Antipsychotics have been widely used as a first-line treatment, resulting in an estimated 1,800 excess strokes and 1,600 excess deaths in the UK alone. Safe and effective alternatives are urgently needed. Based upon preliminary evidence from clinical trials, aromatherapy with melissa oil may be such an alternative, but initial studies have been modest in size, and adequate blinding has been problematic. Our objective was to assess the efficacy of melissa aromatherapy in the treatment of agitation in people with Alzheimer's disease in an adequately powered and robustly blinded randomized controlled trial comparing it with donepezil, an anticholinesterase drug used with some benefit to treat BPSD. METHODS AND FINDINGS: The study was a double-blind parallel-group placebo-controlled randomized trial across 3 specialist old age psychiatry centres in England. Participants had probable or possible Alzheimer's disease, were resident in a care home, had clinically significant agitation (defined as a score of 39 or above on the Cohen Mansfield Agitation Inventory) and were free of antipsychotics and/or anticholinesterase for at least 2 weeks. Participants were allocated to 1 of 3 groups: placebo medication and active aromatherapy; active medication and placebo aromatherapy or placebo of both. MAIN OUTCOME: The primary outcome measure was reduction in agitation as assessed by the Pittsburgh Agitation Scale (PAS) at 4 weeks. This is an observational scale, and raters were required to wear nose clips to ensure that full blinding was maintained. The PAS, Neuropsychiatric Inventory (NPI; another measure of BPSD) and other outcome measures were completed at baseline, 4-week and 12-week follow-ups. 114 participants were randomized, of whom 94 completed the week 4 assessment and 81 completed the week 12 assessment. Aromatherapy and donepezil were well tolerated. There were no significant differences between aromatherapy, donepezil and placebo at week 4 and week 12, but importantly there were substantial improvements in all 3 groups with an 18% improvement in the PAS and a 37% improvement in the NPI over 12 weeks. CONCLUSION: When assessed using a rigorous design which ensures blinding of treatment arms, there is no evidence that melissa aromatherapy is superior to placebo or donepezil, in the treatment of agitation in people with Alzheimer's disease. However, the sizeable improvement in the placebo group emphasizes the potential non-specific benefits of touch and interaction in the treatment of agitation in people with Alzheimer's disease.

Glycosylated constituents of iris fulva and Iris brevicaulis.

The major constituents of leaf extracts of Iris fulva KER GAWL. comprised a known flavone C-glycoside, 5,4'-dihydroxy-7-methoxyflavone-6-C-(6‴-O-(E)-p-coumaroyl-ß-glucopyranosyl)(1‴→2″)-ß-glucopyranoside (1) and the new monoterpene glycoside, linalyl-6'-O-(3″-hydroxy-3″-methylglutaroyl)-ß-D-glucopyranoside (2), both of which were prominent components of Iris brevicaulis RAF. leaf extracts. The structure of a new polyacylated sucrose derivative (3a) obtained from the rhizomes of I. fulva was elucidated as 3-O-(E)-p-coumaroyl-ß-D-fructofuranosyl-(2↔1')-[2″,4″,6″-tri-O-acetyl-ß-D-glucopyranosyl-(1″→3')-(2',6'-di-O-acetyl-4'-O-(E)-p-coumaroyl-α-D-glucopyranoside)]. Selective hydrolysis of the 4″-O-acetyl moiety of the terminal ß-glucopyranosyl residue of 3a occurred after several hours in solution giving 3-O-(E)-p-coumaroyl-ß-D-fructofuranosyl-(2↔1')-[2″,6″-di-O-acetyl-ß-D-glucopyranosyl-(1″→3')-(2',6'-di-O-acetyl-4'-O-(E)-p-coumaroyl-α-D-glucopyranoside)] (3b), which subsequently underwent further deacetylation.

Plants used traditionally as antimalarials in Latin America: Mining the tree of life for potential new medicines.

ETHNOPHARMACOLOGICAL RELEVANCE: Malaria remains a serious and challenging disease. Traditional antimalarial medicines are largely based on plants, and ethnopharmacological research has inspired the development of antimalarial pharmaceuticals such as artemisinin. Antimalarial drug resistance is an increasing problem in Plasmodium species, and new therapeutic strategies to combat malaria are needed. Although the number of malaria cases has been decreasing in Latin America, malaria remains a significant threat in many regions. Local people in Latin America have been using numerous plant species to treat malaria, some of which have been scientifically studied, but many others have not. AIM OF THE STUDY: Our principal objective is to harness ethnobotanical data on species used traditionally to treat malaria, combined with phylogenetic approaches, to understand how ethnobotany could help identify plant genera as potential sources of new medicines. MATERIALS AND METHODS: Plants used to treat malaria in Latin America were compiled from published and grey literature, unpublished data, and herbarium specimens. Initial assessment of potentially important species/genera/families included compiling the number of species used within the genus, the number of use reports per genus and species, and the geographic distribution of their use. The analysis of taxonomic distribution of species reported as antimalarial in Latin America (excluding the Southern Cone) was conducted, to determine which genera and families with reputed antimalarial properties are over-represented, and phylogenetic analyses were performed to identify if there was evidence for antimalarial species being dispersed/clustered throughout the tree or at its tips. This approach enabled 'hot-nodes' in certain families to be identified, to predict new genera with potential antimalarial properties. RESULTS: Over 1000 plant species have been used to treat malaria in Latin America, of which over 600 species were cited only once. The genera with the highest number of antimalarial species were Aspidosperma, Solanum, Piper, Croton and Aristolochia. In terms of geographic distribution, the most widely used genera were Aspidosperma, Momordica, Cinchona, Senna and Stachytarpheta. Significant phylogenetic signal was detected in the distribution of native species used for malaria, analysed in a genus-level phylogenetic framework. The eudicot and magnoliidae lineages were over-represented, while monocots were not. CONCLUSION: Analysis of ethnobotanical use reports in a phylogenetic framework reveals the existence of hot nodes for malaria across the Latin American flora. We demonstrate how species and genera currently lacking such reports could be pinpointed as of potential interest based on their evolutionary history. Extending this approach to other regions of the world and other diseases could accelerate the discovery of novel medicines and enhance healthcare in areas where new therapeutic strategies are needed.

New Insights Into the Anticonvulsant Effects of Essential Oil From Melissa officinalis L. (Lemon Balm).

Melissa officinalis L. is used in traditional European and Iranian folk medicines to treat a plethora of neurological diseases including epilepsy. We utilized the in vitro and in vivo models of epilepsy to probe the anticonvulsant potentials of essential oil from M. officinalis (MO) to gain insight into the scientific basis for its applications in traditional medicine for the management of convulsive disorders. MO was evaluated for effects on maximal electroshock (MES) and pentylenetetrazole (PTZ) -induced seizures in mice, on 4-aminopyridine (4-AP)-brain slice model of epilepsy and sustained repetitive firing of current clamped neurons; and its ameliorative effects were examined on seizure severity, anxiety, depression, cognitive dysfunction, oxidative stress and neuronal cell loss in PTZ-kindled rats. MO reversibly blocked spontaneous ictal-like discharges in the 4-AP-brain slice model of epilepsy and secondary spikes from sustained repetitive firing, suggesting anticonvulsant effects and voltage-gated sodium channel blockade. MO protected mice from PTZ- and MES-induced seizures and mortality, and ameliorated seizure severity, fear-avoidance, depressive-like behavior, cognitive deficits, oxidative stress and neuronal cell loss in PTZ-kindled rats. The findings warrant further study for the potential use of MO and/or its constituent(s) as adjunctive therapy for epileptic patients.

Role of phytochemicals as nutraceuticals for cognitive functions affected in ageing.

Cognitive decline can occur with normal ageing and in age-related brain disorders, such as mild cognitive impairment and dementia, including Alzheimer's disease, with limited pharmacological therapies available. Other approaches to reduce cognitive decline are urgently needed, and so, the role of dietary interventions or nutraceuticals has received much attention in this respect. In this review, we examine the evidence for dietary plants and their chemical constituents as nutraceuticals, relevant to both cognitive decline in normal ageing and in dementia. Pharmacological (in vitro and in vivo), clinical and epidemiological evidence is assessed for both frequently consumed plants and their dietary forms, including tea, coffee, cocoa (chocolate), red wine, grapes, citrus and other fruits; in addition to plants used less frequently in certain diets and those that cross the blurred boundaries between foods, nutraceuticals and medicinal plants. For the latter, turmeric, saffron, sage, rosemary and lemon balm are examples of those discussed. LINKED ARTICLES: This article is part of a themed section on The Pharmacology of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.6/issuetoc.

Micronutrient composition and microbial community analysis across diverse landraces of the Ethiopian orphan crop enset.

Enset (Ensete ventricosum) is a major starch staple and food security crop for 20 million people. Despite substantial diversity in morphology, genetics, agronomy and utilization across its range, nutritional characteristics have only been reported in relatively few landraces. Here, we survey nutritional composition in 22 landraces from three enset growing regions. We present mineral characterization of enset corm tissue, free amino acid characterization of raw and processed (fermented) tissues and genomic analysis of the microbial community associated with fermentation. We show that compared to regionally important tubers and cereals, enset is high in calcium, iron, potassium and zinc and low in sodium. We report changes in free amino acid composition due to processing, and establish that the bacteria genera Acetobacter, Lactobacillus and Bifidobacterium, predominate during fermentation. Nutritional and microbial variation presents opportunities to select for improved composition, quality and safety with potentially significant impacts in food security and public health.