Excerpts from Carmina Gadelica

Around the turn of the 20th century, Alexander Carmichael collected poems, hymns and incantations from the Scottish highlands into a six-volume compendium that includes both (extensive) Christian and Pagan verses. The digitized edition of Volume II includes a number of gems, with facing text in the original Gaelic. Here are some excerpts:

I will pluck the yarrow fair
That more benign shall be my face
That more warm shall be my lips
That more chaste shall be my speech
Be my speech the beams of the sun
Be my lips the sap of the strawberry

May I be an isle in the sea
May I be a hill on the shore
May I be a star in the dark time
May I be a staff to the weak

Wound can I every man
Wound can no man me

Saint John's wort Saint John's wort
My envy whosoever has thee
I will pluck thee with my right hand
I will preserve thee with my left hand
Whoso findeth thee in the cattle fold
Shall never be without kine

The club moss is on my person
No harm nor mishap can me befall
No sprite shall slay me no arrow shall wound me
No fay nor dun water nymph shall tear me

Thou shamrock of good omens
Beneath the bank growing
Whereon stood the gracious Mary.
The seven joys are,
Without evil trace,
On thee peerless one
Of the sunbeams:
  Joy of health
  Joy of friends
  Joy of kine
  Joy of sheep
  Joy of sons and Daughters fair
  Joy of peace
  Joy of God

The four leaves of the straight stem
Of the straight stem from the root of the hundred rootlets
Thou shamrock of promise on Mary's Day,
Bounty and blessing thou art at all times.


Kevin Spelman - molecular bio of immunomodulators

From the AHG symposium

Immunomodulators: botanical medicines that through the dynamical regulation of informational molecules alter the activity of the immune systems.

Cytokines and the cytokine theory of disease (Czura, CJ 2005): overproduction of cytokines can cause the clinical manifestations of disease. But it can begin on an emotional level (anger/shame as opposed to medidative states) - then as cytokines levels increase, disease manifests: first depression, pain, anorexia. Then, psoriasis, colitis. Then, tissue damage and arthritis. Finally, shock and organ failure.

Tumor necrosis factor (TNF) and other cytokines like Epidermal Growth Factor stimulate a series of intracellular changes that ultimately have effects in the nucleus - on genetic expression. When, in researching botanicals, we look at the nucleus, we're getting somewhere.

Paul Ridker MD 2002: "It may be possible that having a high cytokine response in our evolutionary past served us well, when our lifespan was 35-40 years. Insulin resistance might have been useful (to prevent starvation). Not so anymore."

The effect of cytokines depends on the cell secreting it (lymphocytes, monocytes, etc) and the physiological context in which they are secreted. They are "immune hormones". Subtypes:
-interleukins, which have profound effects on inflammation, immunity, central nervous systems, hormone secretions (esp. ACTH, corticoids), they drive antibody response.
-interferons, which are the first line of defense against viruses. They are also cytotoxic, disrupt sleep and HPA axis, stimulate fever-like response.
-colony stimulation factors, which affect cell motility and proliferation, wound healing, inflammation, and hematopoiesis
-chemokines, which stimulate chemotaxis, immune function, inflammation.

Cytokines are versatile. They have different roles, redundancy, synergy and antagonism, and can be autocrine, paracrine, or systemic in their actions. Cytokine receptors are membrane bound, though some are freely floating and act as an activating complex. They are secreted and produced for short periods of time, with little storage and tight regulation of production, and super-short half-lives - "like fireflies".
Normal physiologic functions that induce cytokine production are sleep (to repair/renew) and ovulation. Production in healthy tissue is minimal. Microbial infection, other cytokines, stress, corticoids, histamine all stimulate cytokines as well. "This is why hayfever can actually make you feel really sick".

We are attempting to exploit cytokines pharmacologically. Stimulate, inhibit, block, activate. Herbal medicines have been doing this for a long time. For example, now we use interferon for hepatitis, melanoma, lymphoma. TNF-alpha inhibitors are used for rheumatoid arthritis. Interleukins and interleukin inhibitors are used for asthma modulation, to reduce the risk of Alzheimers.

What about further, bigger thinking on cytokine use? They're implicated in all chronic, age-related, inflammatory diseases. They travel broadly throughout the body. They may also have huge behavioral effects (if we buy in to the psycho-neuro-immunology - PNI - model). Why do we get grumpy when we have the flu? Cytokines. But the behavior also isolates us, separating us from the herd, to protect our peers from infection.
Liver, heart, vessel walls, and adipose tissue all produce cytokines, and may contribute to the etiology of cardiovascular disease. The liver is dear to herbalists - for so many good reasons.
Diseases such as anorexia, schizophrenia, depression, Alzheimer's all show high plasma levels of cytokines. These can be directly measured (though the tests are expensive right now). What we still need clarity on is defining the normal range (which right now is super-wide). Maybe we can get there through genetic medicine, by refining the "normal" depending on genome. Herbalists, however, have always had a good differentiating tool: the constitution. Perhaps pitta people, for instance, exhibit higher "normal" ranges of cytokines.

Adhesion molecules (cellular adhesion molecules - CAMs) are immunoglobulin superfamily CAMs (IgSF - CD-x cell surface receptors), integrins, cadherins, selectins. They are involved in embryonic development, neuro development, tissue adhesion, and expressed by leukocytes, platelets, epithelial and endothelial cells. They maintain tissue integrity, and recruit cells to tissues. They have a critical role to play in pathology, cancer. There are higher levels in those at risk for heart attacks. They may also be involved in behavior - though the research is preliminary (Walzog, B 2000).
The conformation of adhesion molecules - extended versus bent - has an important role to play in the ability of adhesion molecules to function.
Adhesion molecules are important in inflammation - for example, p-selectins expressed on the endothelium sticks to sugars on white blood cell membranes and get snagged there. Then, integrins on white blood cells actually cause the WBC to stop, so it can engage in diapedesis (move across the vessel wall). In the wrong conditions, with too much inflammation, this leads to plaque formation in the vessel wall - atherosclerosis. It may also be important in perpetuating inflammation in autoimmune disease.

Next, nitric oxide (NO) starts to be produced. It is a free radical, second messenger, paracrine, vasodilative, neurotransmitter, and hormone. Signal molecule in the vasculature, neurons and immune system. It can act within the cell, moves through water and fat, and readily diffuses. It's synthesized from arginine (sister amino acid to lysine - they are in counterbalance to each other) using nitric-oxide-synthases. Interestingly, arginine levels are high in veg protein (peanuts, e.g.) and lysine high in animal protein.
The enzyme nitric-oxide-synthase is the key intervention point. It needs cofactors: NADPH, FAD, FMN (all based on B-vits) all linked by a calmodulin binding site [note from Guido: calmodulin found in, and stimulated by, milky oats]. Eventually, NO activates smooth muscle cAMP which relaxes the muscle.
Another important NO stimulating factor (through eNOS activation) is shear stress on the endothelium: often caused by high blood pressure.
NO not only leads to vasorelaxation, but also decreases platelet aggregation.
iNOS, which is created on an as-needed basis, often comes from macrophages when they are activated. So extra NO is produced when needed by immune cells! This vasodilates, sure, but NO is also a free radical that the immune players "shoot out" to damage invaders. Unfortunately, though, it can also damage us. Interferon is often the cytokine that gets iNOS going by activating iNOS gene expression.
nNOS (neuronal-nitric-oxide-synthase) is stimulated through a glutamate-sensitive NMDA receptor. The nitric oxide produced as a result enhances memory and learning. It's crucial for this purpose.

When NO is broken down, it produces superoxide ions, nitrates, and perhaps also peroxinitrites (ONOO-) which has been implicated as a cause of chronic fatigue syndrome (cf. Pall). It's extremely toxic, and will uncouple oxydative phosphorylation in the mitochondria - you can't make ATP anymore! If we remember that, because inflammation can come from infection, inflammation, or emotion, NO can come from a variety of causes, chronically elevated levels can lead to profound fatigue.
"We should be looking at the common molecular basis for disease, rather that all these different disease labels. This is part of the future of medicine".

Angelica sinensis: inhibits adhesion molecules, reduces iNOS
Curcuma spp.: modulates adhesion molecules, reduces iNOS. Very pleiotropic. A variety of constituents with multiple countervalent effects - depending on cell type and physiological context.
Echinacea purpurea: countervalent effects on cytokines (TNF), interleukins, selectins and iNOS. It has a lot to do with the dose and research model (in vitro) presenting different conditions. Also, extraction has a huge role to play: European products, for instance, often have low alkylamide content.
Ginkgo biloba: inhibits adhesion molecules, reduces iNOS.

Spelman - 2008: Modulation of Cytokine Expression by Traditional Medicines

Lisa Ganora - synergy in botanical medicines

From the AHG Symposium
The scientific research process makes it difficult to research more than a small handful of chemicals at a time. Considering that, by some estimates, botanicals contain up to 10,000 active constituents, scientific research runs up against a limit very quickly. Fortunately, we have a practical use history to turn to: we've been eating these plants for a long time with no harm.

Polymolecular approaches, which rely on synergy, have a unique ability to interface with the complex biological system of the human being. Plants provide this. Huge difference compared to pharmaceutical agents. Additionally, pharmaceuticals are very new on the scene. And most aren't cheap (whereas plants...)

Vitalism: boiled down by Paul Bergner, "Nature is Smarter". Case in point: digoxin in foxglove. When consumed alongside other foxglove chemicals, overdoses cause nausea and vomiting. When digoxin is purified, it loses that "warning sign". Molecules are like people: we behave differently in different situations. You're not going to behave in the same way at church with grandma as you do at the corner bar. Another example: "when embedded in a phytochemical matrix with companion molecules, ascorbic acid can behave differently ... this is antioxidant synergy". Ascorbic acid + Iron, on the other hand, is a strong oxidative agent.

Plants are chemistry's dynamic matrix. Dynamic is key. Always changing, always adapting, always efficient! This variability can seem to be a source of difficulty, of confusion. But herbalists can get a handle on the overall balance of botanical chemistry through organoleptic (sense-based) assays. [Guido's note: I really feel that human intuition is an expression of an interaction between complex living systems. That is to say, when we intuit that a plant is ready to harvest and will be useful, we are drawing on the sum total of our organoleptic assay, environmental awareness, memory, and need and coming up with a synthesis that determines usefulness. Our physiology (brain included) is a great pattern-recognition system that can be drawn upon to do complex, "fuzzy" calculations in near-real time... but only if we let the rational side go].

Co-evolutionary theory underlies the development of complex phytochemical matrices - and extends to humans as well. As people develop relationships with plants, we select for each other.

Types of synergy: potentiating (enhanced activity), stabilization (protect certain constituents), modification (attenuation of toxicity). Side note - "just because there's a known toxic constituent in a plant doesn't mean that plant will be toxic. I ate comfrey as a vegetable when I was pregnant. Modification synergy at work".

St. Johnswort is a great example of a plant that only works through potentiating synergy. Isolation of an active ingredient has consistently failed. Hyperforin, hypericin, xanthones, hyperoside, melationin and more all work together [Guido's note: Ginseng is another great example. We still can't point out an active constituent].
Clinical note: consider mixing your concentrated extract (St. Johnswort, Ginkgo, Milk Thistle, Turmeric, etc...) with a little powdered whole herb, tea, tincture or other crude prep. Take advatage of synergy.

Potentiating synergy types: affecting stability / reactivity of different constituents; increasing bioavailability; chemicals can be co-ligands of a receptor; one compound might inhibit enzymatic breakdown of another chemical.

An example of stabilizing synergy is the process of "redox cycling": botanical antioxidants re-activate one another and prevent pro-oxidant activity. Way more effective than eating isolated, single antioxidants (vitamin c, or quercetin, e.g.). There are well over 60 types of citrus bioflavonoids in a fruit, along with carotenoids or vitamin c.
This might underlie an interesting observation about carotenoids: 20mg/day trans-beta-carotene over 5-8 years to 29K smokers / drinkers actually led to 18% more lung cancer. When taken with Vit. E, no change in lung cancer rates. If they simply ate a high-carotenoid diet, there was less lung cancer (NEJM 1994; 330:1029-35).

Dandelion flowers are a great example of phytochemical synergy. They contain a cocktail of carotenes (beta and other). Also xanthophylls (lutein, cryptoxanthin). Flavonoids (luteolin, quercetin and their glycosides). Phenylpropanoids  - simple plant acids such as caffeic and chlorogenic acids. Triterpenes such as taraxasterol. Bitter sesquiterpene lactones. Some are oily, some watery. Taken together, they are anti-cancer, antioxidant, anti-inflammatory, and neuroprotective - but only when eaten as WHOLE dandelion flowers.

Black pepper (and its alkaloid piperine) is another example of synergy, but one where synergy relies on affecting endogenous (inside us) processes and thereby potentiating the activity of other phytochemicals. Piperine increases absorption and delays breakdown of many oil-based plant constituents. This has long been known in Ayurveda, where Trikatu is added to lots of formulas.

Oregon grape root is a great story of synergy. Its root contains lots of berberine, which is antibacterial and strongly inhibits Staph aureus. However, Staph uses a multi-drug-resistance pump (P-glycoprotein) that ejects the berberine to try to counteract its toxicity. But in the leaf of Oregon grape has 5'-MHC-D and pheophorbide-A which inhibit the multi-drug-resistance pump. Moral of the story: great synergy, but take a whole-plant preparation! (Stermitz, 1999)

Attenuation of toxicity is often seen in traditional polyherbal preparations. For example, Licorice markedly buffers the toxicity of prepared Aconite (monkshood) root.