1. Traditional pharmacology views medicinal plants and functional foods as containing diluted "drugs" that act through single targets, but they are now understood to act through mixtures and multiple modes of action. 2. Components in functional foods and medicinal plants like phenolics generally have low activity but act through synergistic effects on multiple targets rather than single strong ligands, disrupting networks associated with diseases more safely and robustly. 3. Evolutionary continuity between plants and humans means plants contain stress signals that trigger defense responses in humans through hormesis and xenohormesis, diverting energy from growth to survival and extending lifespan.

1. Natural ingredients as
Functional Foods vs.
supplements
Marco Valussi
EHTPA

2. Reconciliation
1. Classical pharmacology: mono-
target
2. Traditional insights on medicinal plants (MPs) and
functional foods (FFs): polypharmacology

3. Classical pharmacology
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

4. Problems
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.

5. Problems
Many 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.

6. A new position
FFs act through mixtures of different compounds and
modes of action: “herbal shotgun”
1. Evolutionary bases
2. Hormesis/xenohormesis
3. Synergy
4. Network pharmacology

7. Evolutionary bases
Plants: 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.

8. Hormesis/Xenohorm
esis
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

9. Synergy
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.

10. Synergy
1. 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

11. Network pharmacology
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.

12. Molecules
Alkaloids: 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.

13. FFs and phenolics
Lipid-lowering effects
Anti-inflammatory effects
Antioxidant effects
Detoxifying effects
Anti microbial effects
Antiproliferative

14. Fruits and vegetables vs.
antioxidant supplements
Discrepancy between epidemiology, in vitro and
RCTs
1.Synergy and stereoisomery
2.Bad kinetics
3.Bioavailability and intestinal flora
4.Xenohormesis

16. Plant Components Effects
Allium sativum Allicin, ajoene, diallyl Inhibition iNOS synthase and platelet aggregation,
trisulfide, 2-vinyl-4H-1,3- antioxidant, anti-inflammatory, ajoene apoptosis
dithiin leukemia cells, hypocholesterolemic, anti microbial.
Aronia Phenolic compounds Phenolic effects: antioxidant; anti-inflammatory;
melanocarpa cancer; aging; diabetes; neurodegenerative
disorders; renal diseases
Camellia sinensis Catechins, Catechins: iron chelators, scavengers, anti-
sesquiterpenes, indoles 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, Common cold; phenolic effects
phenolic compounds

17. Plant Components Effects
Opuntia ficus- Betalains Diabetes; dyslipidemia; gastritis; prostate
indica 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 Inhibition of COX and cytosine. Arthritis and RA
oxylipin
Vitis vinifera Phenolic compounds Phenolic effects
Zingiber A-zingiberene, b- Very different effects of total extract compared to
officinale sesquiphellandrene, individual components. Antipyretic, anti-
bisabolene, curcumene inflammatory, analgesic.

18. Thank you for
your attention.