Natural ingredients as Natural ingredients as Functional Foods vs. Functional Foods vs.

supplementssupplementsMarco Valussi

EHTPA

Reconciliation Reconciliation

2. Traditional insights on medicinal plants (MPs) and functional foods (FFs): polypharmacology

1. Classical pharmacology: mono-target

Classical Classical pharmacologypharmacology

Although a minor part of the MPs diversity (1%), heroic plants monopolized early research.

Digitalis spp., Strophanthus spp., Convallaria majalis, Papaver somniferum, Nicotiana spp., Amanita muscaria,

FFs and MPs are just vessels for diluted "drugs”.

Erlich’s “silver bullet”: one gene, one target, one molecule

ProblemsProblems

Health benefits of FFs decrease as we move towards isolated supplements: see antioxidants.

The attempt to isolate a single molecule/mechanism for MPs has often failed failed: see Hypericum, Ginkgo, Allium, Crataegus, etc.

ProblemsProblemsMany of modern drugs are promiscuous or pleiotropic

Polypharmacology: AIDS, infections, diabetes, cancer, asthma, depression, cholesterol, etc.

New “silver bullets”: high attrition rates (high toxicity, low efficacy) in phase II and III trials

Chronic diseases are better described as involving a complex network of molecules and interactions.

FFs act through mixtures of different compounds and modes of action: “herbal shotgun”

1. Evolutionary bases

2. Hormesis/xenohormesis

3. Synergy

4. Network pharmacology

A new positionA new position

Evolutionary basesEvolutionary basesPlants: many low activity compounds rather than few very active ones: this favors synergy.

Evolutionary continuity: conserved receptorial and signaling systems between Phyla

Adaptive advantage: plants' stress signals are clues to environmental trends and dangers.

Hormesis/Hormesis/XenohormesisXenohormesis

Toxic molecules detoxified and read by the organisms as triggers for defense reactions: hormesis.

Plants’ stress signals trigger a change: diverting metabolic energy from reproduction and growth to extended life-span and survival: xenohormesis

Joint action of two or more molecules.

Effect greater than that obtained with single molecules in equivalent quantity.

Effects that could not be obtained with any safe quantity of either molecule.

SynergySynergy

SynergySynergy1. Weakly targeting proteins in the same

network

2. Acting on targets in different networks

3. Pharmacokinetic synergy

4. Protection of active substance from degradation

5. Circumvention of MDR mechanisms

Some diseases are described as network of multiple interactions: gene-gene, gene-protein, and protein-protein.

Robust phenotype

Modeling: multiple weak ligands disrupt a network like or better than single strong ligands, with lesser undesirable effects.

Network Network pharmacologypharmacology

MoleculesMoleculesAlkaloids: toxic extreme, MPs. Activity based on similarities between insects and human CNS.

Terpenoids: middle ground, MPs and FFs. Effects depend on similarities between insects and humans and between plants and humans

Phenolics: benign extreme, MPs and FFs. Effects almost totally dependent on plant-human similarities.

Lipid-lowering effects

Anti-inflammatory effects

Antioxidant effects

Detoxifying effects

Anti microbial effects

Antiproliferative

FFs and phenolicsFFs and phenolics

Fruits and vegetables vs. Fruits and vegetables vs. antioxidant supplementsantioxidant supplements

Discrepancy between epidemiology, in vitro and RCTs

1.Synergy and stereoisomery

2.Bad kinetics

3.Bioavailability and intestinal flora

4.Xenohormesis

Plant Components Effects

Allium sativum Allicin, ajoene, diallyl trisulfide, 2-vinyl-4H-1,3-dithiin

Inhibition iNOS synthase and platelet aggregation, antioxidant, anti-inflammatory, ajoene apoptosis leukemia cells, hypocholesterolemic, anti microbial.

Aronia melanocarpa

Phenolic compounds Phenolic effects: antioxidant; anti-inflammatory; cancer; aging; diabetes; neurodegenerative disorders; renal diseases

Camellia sinensis Catechins, sesquiterpenes, indoles

Catechins: iron chelators, scavengers, anti-inflammatory, neuroprotectants, PKC and MAPK signaling; MDR inhibitors.

Curcuma longa Curcuminoids Cancer; liver cirrhosis; chronic renal disease; COPD; diabetes; AD; Chron’s Disease

Lactuca sativa Ascorbate, a-tocopherol, phenolic compounds

Common cold; phenolic effects

Plant Components Effects

Opuntia ficus-indica

Betalains Diabetes; dyslipidemia; gastritis; prostate hypertrophy

Punica granatum Polyphenols The juice shows evidence of anti proliferation activity compared to isolated polyphenols

Ribes nigrum Phenolic compounds Phenolic effects

Urtica dioica fol. Caffeic acids derivatives and oxylipin

Inhibition of COX and cytosine. Arthritis and RA

Vitis vinifera Phenolic compounds Phenolic effects

Zingiber officinale

A-zingiberene, b-sesquiphellandrene, bisabolene, curcumene

Very different effects of total extract compared to individual components. Antipyretic, anti-inflammatory, analgesic.

Thank you for your attention.