Over the centuries humans have discovered the amazing therapeutic potential of plants either serendipitously or intentionally.
Ancient healers and medicine men of time past knew that plants had a peculiar force, a Vital Force which bestowed plants with unique qualities and personalities that if harnessed could influence the body therapeutically (Herbal Medicine). This personification of plants is evidenced in various pharmacopeias of which the Mandrake plant has most commonly been depicted.
Recorded evidence on medicinal plants and their preparations date back to prehistoric times, particularly ancient Mesopotamia where the first written body of evidence was inscribed on Sumerian Cuneiform Tablets around 5,000 BC. While the Sumer civilization kept written records of their medicinal practices, other ancient cultures had rich oral traditions as with Ayurveda an Indian healing system that dates back to 3,000 BC (although written evidence was unearthed in 440 BC). Chinese Herbal Medicine, Pen Ts’ao Ching, also had an oral tradition that dates back to 2,700 BC and a written history from 500 BC. By 1,500 BC the Egyptian pharmacopoeia on medicinal therapies known as Ebers Papyrus, was consulted on all matters of healing. European plant medicine gained traction over the centuries (300 BC - 200 AD) as notable physicians and pharmacognosists such as Hippocrates (Father of Modern Medicine), Dioscorides and Galen, further advanced plant medicine. However, it was the greek physician Pedanius Dioscorides who is credited for assimilating vast assortments of Traditional Systems of Medicine (TSM) which he recorded in his pharmacopeia titled Materia Medica ("Medical Material"). [1-3]
Dioscorides is touted as the Father of Pharmacognosy, the study of the therapeutic potential of crude medicine obtained from natural sources. Today's field of Pharmacy is a prominent off-shoot.
By the 19th to mid 20th century advancement in disciplines like Organic Chemistry, Biochemistry and Molecular Biology popularized the reductionistic world view on therapeutics that:
"...biological activity of botanicals and crude extracts is mediated by specific interactions of Small Organic Compounds which target biological macromolecules." [4]
This paradigm shift catalysed Pharmacognosy with the isolation of bioactive plant compounds which were termed 'Natural Drugs'. Some of these natural drugs like Artemisinin from Artemesia annua, was historically used in its crude drug form for treating malaria (Antimalarial) and for fever suppression (Antipyretic); while Morphine from Papaver somniferum, opium poppy, was used for dulling pain (Analgesic). Overtime the challenge to satisfy global natural drug demand, led scientists and chemists to find rapid, cost-effective ways of synthesizing variants or analogs with identical therapeutic potential (Drug Discovery and Development). While about 50% of today's medicine particularly cancer drugs are nature-derived (semi-synthetic) there is still a large portion of fully synthetic or de novo drugs. Over the years many users of fully synthesized drugs have reported less than ideal outcomes which scientists correlate with poor pharmacophore or target specificity design. Poorly designed drugs commonly present clinically with Adverse Drug Reactions (ADR) and many Side Effects.
Modern medicine protocols limit the number of small organic compounds to one sometimes two compounds in a drug (Lipinski's Rule of 5) in contrast to the bio-complexity of crude botanical extracts. Scientific insights are being gleaned into the bioactivity of crude full spectrum extracts for therapy, where hundreds of organic compounds work synergistically to restore holistic balance in a unique kind of individualized therapy (Entourage Effect). [5-9] Today's wellness and sustainability-conscious population are valuing higher qualities of health and personalized therapies with promising outcomes. A return and rediscovery is unfolding in our eon as herbal therapeutics and other natural healing modalities are being sort after once more. Plants and their organic compounds (Phytochemicals) could be the heroes of today and the future quietly waiting to be rediscovered and leveraged for our Holistic Healing.
Bee Propolis
Honeybees (Apis mellifera) formulate a special concoction of plant exudate using tree sap, beeswax and their enzymatic secretions to produce a sticky compound beekeepers refer to as ‘bee glue’. Bee glue waterproofs the living space of a honeybee colony, sealing off cracks and crevices and allowing for regulated temperature and air flow. The term bee glue, however, falls short of its many other functional qualities. Prop·o·lisis is of Greek etiology, pro meaning "in defense of" and polis meaning "community”. Put together, Propolis translates to Hive Guardian. Classified as an oleoresin, with essential oil and waxy-resin components, bee propolis serves as a powerful antiseptic and first-line immunity against the infection and spread of harmful microbes and diseases.
Beyond the hive, Traditional Systems of Medicine (TSM) have utilized bee propolis therapeutically for coughs and common colds, other times for wound healing. Recent studies have uncovered more than 300 bioactive compounds found in bee propolis, suggesting the combined effect of these phytochemicals on various body systems. Its bioactive compounds are also region-specific, reflecting the biodiverse floral notes of a bee’s flight path. These organic compounds confer anti-oxidant, anti-inflammatory, anti-microbial, immunomodulatory and anti-cancer properties in the body. Recent research has revealed over 300 bioactive compounds present in bee propolis, indicating the collective impact of these phytochemicals on different bodily systems. Polyphenols and Terpenes are notable classes of plant chemicals known for their therapeutic benefits. In bee propolis, the polyphenol subclass known as Flavonoids are predominantly responsible for bestowing these benefits. Also present in propolis are trace minerals (magnesium, calcium, iodine, potassium, sodium, copper, zinc, manganese, iron) and vitamins (A, B1, B2, B6, C and E) all of which supplement daily nutritional needs and metabolic processes. [6.1, 6.2]
Propolis could be used as an adjunctive therapy for upper respiratory and oral care matters. Whether as a cough suppressant (Antitussive); or as an antimicrobial against opportunistic bacteria like Streptococcus; or as a natural antiviral against Adenoviruses, Rhinoviruses, Influenza viruses, SARS-COV2; or yet still preventing plaque deposition and dental caries (Cariostatic). These therapeutic benefits are attributed to secondary metabolites such as Chrysin, Pinocembrin, Galangin and others. The general mechanism of action is by down-regulating IgE antibody production commonly associated with Type 1 Hypersensitivities such as allergies and reducing histamine levels. In asthma-associated inflammatory cascades, propolis bio-molecules have been shown to act as immunomodulators, reducing air passage swelling, facilitating active breathing [6.3-6.5]
Plant Metabolites
Organic plant compounds better termed Plant Metabolites, come in two flavours: Primary and Secondary Metabolites. Primary Metabolites fulfill most of a plant's everyday function like Growth, Development and Reproduction; while Secondary Metabolites confer an ecological advantage to the plant and include Adaptability, Defence, Resource Competition and Fecundity. Scientists have determined that Secondary Metabolites are mostly responsible for a plant's therapeutic potential and have categorized these special compounds into four (4) broad groups namely: Terpenes, Phenolics, Alkaloids and Polyketides. These metabolites, as mentioned before fulfill ecological roles, specifically in 1. Signalling, chemo-attraction and visual attraction for pollination purposes; 2. Defence, against biotic stressors like pathogens and herbivores (Allelopathy); and 3. Adaptive Mechanisms, against abiotic stressors such as heat stress, UV radiation, drought and atmospheric salinity.
Terpenes
Terpenes, which are the largest and most diverse group of secondary metabolites are mainly made by plants but also biosynthesized in animals and microorganisms. Due to their high therapeutic potency and low adverse effects, this group of secondary metabolites stands out proudly from the rest. The structural motif of terpenes is comprised of linked and repeating Isoprene units— (C5H8)n. The number of linked isoprene units present in a given terpene determines the naming protocol (Hemiterpene, Monoterpene, Sesquiterpene, Diterpene, Sesterterpene, Triterpene, Sesquarterterpene, Tetraterpene, Polyterpene).
Oxidative variants of terpenes are termed Terpenoids or Isoprenoids and may include other functional groups beside oxygen. This group of secondary metabolites also has been attributed with organoleptic properties of fragrance, taste and colour which influence the brain’s Limbic System having unique effects on our mood and associative memories, a phenomenon that can be considered as ‘Sensory Fingerprinting’.
Terpenes present in the trichomes of the female Cannabis sativa L. are believed to be responsible for the plant's medicinal properties together with its Phytocannabinoids like CBD and THC.
Pinene
Pinene is a monoterpene that exists in nature as two different structural configurations or isomers: Alpha Pinene (α-pinene) or Beta Pinene (β-pinene). Found in cone-bearing plants and conifers α-pinene is at highest concentrations in Pine, Spruce and Cedar; while β-pinene is prominent in Rosemary, Basil, Parsley and Dill. Some plants boast both alpha and beta pinene isomers, as with Cannabis sativa L. Turpentine, the well known paint thinner and varnish also contains both isomers. But in nature, it is α-pinene that can be found in greater abundance and is prominently attributed with organoleptic properties. If one were to spend time under the forest canopy or (Forest Bathing) one would appreciate the fresh, piney aroma of aerosolized α-pinene molecules suspended in the forest air. [6]
Japanese culture place great value on forest bathing terming it 'Shinrin-yoku'. Alpha-pinene has the ability to lower our stress hormone Cortisol, lower blood pressure, relieve anxiety, uplift the spirit (Anxiolytic, Adaptogen); combat inflammation (Anti-inflammatory); fight respiratory infections (Antimicrobial) and resist oxidative stress (Anti-oxidant). Alpha pinene also increases airway intake by relaxing airway smooth musles much like the β₂ adrenergic agonist, Albuterol, the pharmaceutical used in asthmatic inhalers (Bronchodilator). These beneficial bioactive effects suggest α-pinene's therapeutic potential as a powerful terpene. [11]
In Pharmacology, for a drug or compound (Xenobiotic) to have an effect on the body (Pharmacodynamics) it must first demonstrate good Absorption, Distribution, Metabolism and Excretion (Pharmacokinetics). Studies have shown α-pinene's bioactivity throughout the body with uptake into systemic circulation highest at the lungs on inhalation (Bioavailability). [11]
Alpha-pinene's action on the body as an anti-inflammatory seems to be modulating inflammatory mediators and pathways like Tumor Necrosis Factor-α (TNF-α), Interleukins (IL-6, IL-1β), Nuclear Factor Kappa B (NF-κB), Nitric Oxide (NO), Mitogen-Activated Protein Kinases (MAPKs) and Prostaglandin E1 (PGE1). Promising anti-tumor properties of α-pinene have been demonstrated in skin and liver tumor cell lines that show cell cycle arrest (G2/M) and programmed cell death (Apoptosis); as well as promising anti-oxidative outcomes which result in the spawning of protective pathways against Reactive Oxygen Species (ROS). Alpha-pinene's potential to enhance cognition and memory is attributed not only to improved blood flow to the brain, but as an Acetylcholinesterase Inhibitor (AchEI) delaying enzymatic breakdown of the neurotranmistter Aceytlcholine responisble for attention, learning and memory. In the brain, α-pinene acts as an adaptogen capable of adapting to and relieving stress, reducing anxiety and improving overall mood by allosterically modulating GABA receptors thereby suppressing the excitability or neuronal tone of the nervous system. The physiological mechanisms which result in calming effects are similar to the short-acting pharmaceutical drug class known as Benzodiazepines: Alprazolam (Xanax), Diazepam (Valium), Lorazepam (Ativan) etcetera. [11-14]
On the other hand, β-pinene has been demonstrated to show anti-depressant properties similar to the long-acting and commonly prescribed drug class known as SSRIs (Selective Serotonin Reuptake Inhibitors). In the brain, Serotonin is a neurotransmitter associated with mood, emotion, cognition, memory and apetite. In the 1960s, it was hypothesized that depression was due to low Serotonin levels and that anti-depressant drugs were the sole means of boosting levels (The Serotonin Hypothesis) although this hypothesis has since been updated. SSRIs bind to presynaptic Serotonin 1A Receptors (5-HT1A) blocking the reuptake of the neurotransmitter by Serotonin Transporter (SERT) from the synaptic cleft, resulting in an accumulation of serotonin, thus 'increasing serotonin levels'. However, novel research is revealing β-pinene's similar potential as an SSRI-like acting compound exerting anti-depressant effects similar to well-known SSRIs such as Paroxetine (Paxil), Fluoxetine (Prozac), Sertraline (Zoloft) etcetera. [15,16]
Aromatherapy, which is a therapy where essential oils with chosen qualities are volatized to beneficially influence mood, could easily be employed to harness the mood enchancing benefits of α-pinene. To promote relaxation and recenter, essential oils of rosemary, juniper, cypress, french lavender, basil, orange peel, bergamot and eucalyptus can be use to garner a subtle relaxing mood therapy.
Limonene
Limonene is another monoterpene that comes in two flavours, D-Limonene and L-Limonene with both forms having more than identical chemical formulas but existing as 'right-handed' and 'left-handed' forms. These twin opposites are non-superimposable mirror images of each other (Enantiomers). D-Limonene is the more prominent form of the monoterpene and is known for its citrusy, zesty and fresh aroma. This form of limonene is found at highest concentrations in the peels and rinds of citrus fruits like orange, lime, lemon, mandarin, and grapefruit. By contrast, L-limonene which has more of a piny aroma is found in pine needle, bergamot, spearmint, dill, cumin and caraway. [17]
Limonene has been demonstrated in scientific literature to have anti-proliferative and chemotherapeutic properties by either inducing cell death (Pro-apoptotic) or removing the cellular checks that prevent cell death (Anti-apoptotic). This modulatory effect was observed with the pro-apoptotic regulator known as BAX from the Bcl-2 protein family as well as with Caspases 3 and 9. D-limonene notedly shows promising outcomes in thwarting breast cancer proliferation specifically mediated by Cyclin D1 via allosteric regulation of Cyclin Dependent Kinase 4 and 6 (CDK4, CDK6). [19-21]
Limonene also shows good promise as an anti-inflammatory, antioxidant, antiviral, anti-diabetic, antihyperalgesic, antinocicpetive among many others. This monoterpene has been demonstrated to tame inflammatory responses by down regulating pro-inflammatory players (TNF-α, COX, iNOS, PGE2). Limonene applied topically in a carrier emulsion cream or lotion shows good promise as an anti-inflammatory cosmeceutical. While limonene demonstrates cosmeceutic skin benefits, skin sensitization can develop at concentrations exceeding dermal limit standards. Our body's ability to combat reactive oxygen species (ROS) is crucial in slowing aging and preventing other mutagenic processes which can lead to disease. This is achieved through an inherent antioxidant defense system comprising of special enzymes like glutathione peroxidase, catalase and superoxide dismutase (SOD). As an antioxidant, Limonene has demonstrated supportive effects on these antioxidant players showing potential also to restore these enzymes once depleted. [20-22]
Citral
In nature the monoterpene aldehyde known as Citral, takes on two structural forms although sharing the same chemical formula. These variant forms or stereoisomers are known as alpha-citral (α-Citral) and beta citral (β-Citral) and also go by the names Geranial and Neral respectively. Together these twin compounds collectively called Citral comprises 95% of lemon myrtle and about 80% of lemongrass. Smaller fractions are present in lemon, lime, bergamot and basil. Citral has a notable lemon-like, fresh, zesty aroma that conjures ideals of optimism and new beginnings reminiscent of morning’s dawn. In industry, Citral is capitalized as a potent aromatic used in cosmetics, perfume and food. Its aromatic personality is utilized as a fresh sensory opener in beauty products meant for morning and daytime use.
In fragrances bright, opening scents like Citral are selected as top notes or headers after the first spray. In addition, Citral is used as a heart or middle note which carries the longevity of a perfume. In food Citral is used as a natural preservative thanks to its antibacterial, antifungal, antiseptic, antiparasitic, antibiofilm and overall antimicrobial properties by disrupting the lipopolysaccharide (LPS) cell membrane of microbes resulting in death. This versatile monoterpene also has insect repellent properties with research demonstrating Citral’s ability to disrupt olfactory mosquito receptors. It is therefore no surprise that citral makes up a notable fraction of Citronella oil, an essential oil known to offer reasonable repellence. [23,24]
The bioactive potential of Citral is being explored by scientists as this terpene displays influence a broad range of physiological systems. In Type 2 Diabetes (Diabetes Mellitus) pancreatic cells may have difficulty secreting a hormone known as Insulin which facilitates the entry of glucose into cells to be used as energy. Another instance of Type 2 could be due to a reduced sensitivity or responsiveness of special glucose entry gates (alpha and beta insulin receptors) to the hormone, drastically diminishing cells’ ability to take up and utilize glucose as energy (Insulin Resistance). Citral as a natural organic compound has been demonstrating its ability to re-sensitize these gates in a way that makes them recognizes the hormone and uptake glucose from the bloodstream, i.e. improved Glucose Tolerance. In addition, Citral’s ability to decrease fat accumulation (Antiadipogenic) is a positive effect especially for obese diabetics as obesity is a major determinant of acquired diabetes. Citral may be a promising natural compound drug scaffold for weight lost solutions which target Beta 3 adrenoreceptors inducing fat breakdown (Lypolysis); increasing energy expenditure while improving insulin action. [25]
High blood pressure is another comorbidity seen in Type 2 diabetic patients with studies revealing Citral’s ability to lower hypertension via fluid regulation at the level of the kidneys (Diuretic). In the respiratory airways, Citral exhibits expectorant properties inducing the expulsion of mucus or sputum from airways. Citral’s potential to reduce inflammation (Anti-inflammatory), lower sensitivity to pain (Antihyperalgesic) and regulate immunoinflammatory cascades and circuits (Immunomodulator) has been demonstrated in mice with bioactivity on COX2 expression, TRP channels, NF-κB. Citral has also been demonstrated to retard the progression of prostate cancer in rat models (Antitumorigenic), thwart the proliferation of colorectal and breast cancer cells (Antiproliferative), while also serving as a sentinel at the level of DNA to defend against mutagenesis. [24-28]
Samuel M.T Jones
Bsc. Biological Sciences (Hons.)
Dip. Organic Cosmetic Science
Cert. Biotechnology & Bioengineering
Cert. Medicinal & Pharmaceutical Chemistry (in progress)
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