Smelling horses and finding Nemo
Not to be confused with Chinese lanterns, also sometimes known as winter cherries!
Here is Dr. Been’s Video: https://www.youtube.com/live/OrSmiZjNv_U?feature=share
Ashwagandha is an ayurvedic herb that has been in use in India and Africa for at least 3000 years. The Merck Manual describes Ashwagandha as a small evergreen shrub that grows in India, the Middle East, and Africa. Botanical name is Withania somnifera, and it is also known as Indian ginseng and winter cherry. The active chemical ingredients are known as withanolides. The root is the part that is used. And (wait for it…) “Ashwa” means “horse” and “gandha” means smell.
(Can’t wait to see what the CDC does with that one!)
Although ashwagandha is also known as an adaptogenic, the existing studies on lab mice have not been confirmed in people, so we will focus on the mechanism of action for its anti-inflammatory properties based on recent studies like this one from February 2023.
But first, we should look at …
Side Effects
- Probably unsafe for pregnant women because it might increase the risk of miscarriage;
- we do not know if it is safe for nursing mothers because there are no studies;
- It can irritate the digestive tract in some people;
Drug interactions (From Merck Index)
- Ashwagandha might lower blood sugar levels and thus make it unsafe to use with antihyperglycemic (glucose-lowering) drugs (by lowering blood sugar too much).
- Because of its potential to lower blood pressure, ashwagandha might not be safe in people who take drugs to treat high blood pressure.
- Ashwagandha, because it seems to make the immune system more active, could also interfere with drugs that suppress the immune system. Examples of these drugs include cyclosporine, mycophenolate, tacrolimus, prednisone, and corticosteroids.
- Ashwagandha might make people drowsy or sleepy. So combining sedative-hypnotic drugs (used to help with sleep) with ashwagandha might make people too sleepy. Examples of these sedatives are zolpidem, eszopiclone, clonazepam, quetiapine, and lorazepam.
- Ashwagandha may increase thyroid hormone levels, so doctors carefully monitor thyroid function by ordering blood tests for anyone who takes thyroid hormones and ashwagandha at the same time.
Dosing
- up to 1000 mg daily, for up to 12 weeks (There aren’t studies past 12 weeks, but millions of people and 3000 years of use can’t be so wrong…)
The aroma of Withania Somnifera comes from its flavonoids. Flavonoids are known to reduce stress and boost the immune system. Remember forest bathing? Ashwagandha is being studied for neural protective properties, sedative, adaptogenic, anti-inflammatory, antimicrobial, cardioprotective, anti-diabetic effects, and possible reproductive outcomes. Many phytochemicals …
“…that play a crucial role in pharmacological action are withanolides and alkaloids. Withanolides are compounds whose essential structure is that of ergostane, which has a six-membered lactone ring at the C-8 or C-9 position. The group of withanolides includes withaferin A, withanolides A-Y, withanone, withadomniferin A, and withasomniferols A-C. Figure 2 shows the main active compounds present. Alkaloids include withanin, somniferin, somnin, tropin, somniferinin, pseudowithanin, pseudotropine, choline, kuskohigrin, isopeletierin, and anaferon [5]. Also present in the raw material are flavonoids which include 3-O-rutinoside, 6,8-dihydroxycemferol, quercetin and its glycosidic derivative, 3-O-rutinoside-7-O-glucoside… Additionally, withanolide glycosides, which have a structure that contains a glucose moiety at position C-27, are also present in the raw material. This group of compounds includes sitoindoside IX and sitoindoside X. Ashwagandha also contains steroidal saponins that contain an acyl group–sitoindoside VII and VIII. Saponins, coumarins (scopoletin), sterols, chlorogenic acid, resins, lipids, carbohydrates and fatty acids have also been identified in the raw material [6].”
That’s quite a mouthful!
TC: 13:07 Anti-inflammatory Effect…(finding Nemo)
One of many pathways by which Ashwagandha influences inflammation is the nuclear factor Kappa-B pathway (NF-κB). This is the “cell survival” pathway. It is activated when stressors outside the cell ( eg. pathogens, bacteria, viruses, toxins) activate pathogen recognition receptors (PRR). An important one is the toll-like receptor or TLR4, that is connected inside the cell to nuclear factor Kappa-B, which produces an inflammatory response from the cell – a survival mechanism. When activated by offensive external factors, it is known as the canonical nuclear Kappa-B pathway.
Nuclear Factor Kappa B can also be activated in the absence of foreign material by other stressors like extraordinary stretching, or the pH is out of whack, or the oxygen levels are not correct. This is called the non-canonical nuclear Kappa-B pathway.
There are many pathways that can activate NF-κB as seen in this diagram, but we will focus only on the one which ashwagandha actually modulates and suppresses, reducing the inflammatory state. The brain responds to injury by gliosis (the overproduction of the brain’s tissue cells which respond with inflammation). Ashwagandha suppresses that too, and from a mechanism point of view reduces the brain’s inflammation, thereby reducing inflammation in the body.
TC 17:28 This is how it works:
On the cell membrane there is a toll-like receptor 4 (TLR4), that would identify a pathogen in the environment, and an interleukin receptor (IL1-R) that also activates the NF-kB.
Inside the cell, TLR4 is connected to a couple of proteins called TIRAP and TRAM.
We are going to follow the TIRAP pathway.
When a pathogen arrives at the cell, the TLR4 is activated and in turn activates TIRAP which wakes up another protein called MYD88. When that becomes activated it recruits another set of
Attached to the IRAKs is another protein called TRAF6. Once TRAF6 wakes up the cascade continues to another complex of three proteins made up of TAB 2/3 and TAK1. When these become activated they will activate another protein called NEMO (IKK-γ).
AHA! We found NEMO!
From here, the story isn’t so happy for NEMO, and the process gets quite a bit more complex.
When Nemo is activated, it will be destroyed by a process called ubiquitination.[1] Ubiquitination is a process where our cells destroy proteins in two ways. One is a normal function of the cell and does not trigger an alarm, the other is autophagy, which cleans up the damaged or dysfunctional parts of a cell and causes an alert.
NEMO gets ubiquitinated, meaning it gets marked to be destroyed. When it gets destroyed, then TAK1 sneaks past ill-fated NEMO and connects with two more proteins, IKK-B and
IkBa. TAK1 phosphorylates IkBa and IKK-b which in turn activate and phosphorylate the next protein complex in the chain called Ik beta Alpha(IkBa). IkBa sequesters or or binds with two more proteins called p50 and p65 this whole complex together is the nuclear Factor Kappa B complex.
In this complex one protein is the binding protein protecting the two active ones (p50 and P65). If P50 and P65 are set free, they will cause the cell to produce inflammatory mediators. The body won’t want that to happen, so IkBa acts to bind them. But when IKK-B is activated, it will attach a phosphate to IkBa and “poof” IkBa is destroyed, and releases its hold on those little brats, P50 and P65. And now all heck breaks loose.
P50 and P65 are active nuclear Factor Kappa B transcription proteins. They go to the nucleus and bind with the DNA and open up the DNA for transcription or gene expression and that produces messenger RNA. The messenger RNA then leaves the cell and attaches to the Golgi Apparatus and ribosomes that then produce various kinds of inflammatory proteins:
Interleukin-12, Interleukin-6, Interleukin- 8, tumor necrosis Factor Alpha, Interleukin-1 Beta, Interleukin-6, and nitro-oxidative stress enzymes.
Ashwagandha modulates the nuclear Factor Kappa B pathway which knocks down the inflammatory proteins. The result will be to reduce inflammation.
Not bad for a 3000-year-old plant from the old world!
To quote the researchers:
“Due to its properties, Withania somnifera is being studied for the treatment of many diseases associated with inflammation in the body, such as cardiovascular, pulmonary, and autoimmune diseases and diabetes, cancers, and neurodegenerative diseases. Preclinical studies have demonstrated the ability of this plant to regulate mitochondrial function and apoptosis and reduce inflammation by inhibiting inflammatory markers such as cytokines (including IL-6 and TNF-a), nitric oxide, and reactive oxygen species. Meanwhile, in a mouse model with lupus, a potential inhibitory effect of Ashwagandha root
powder was demonstrated in conditions such as proteinuria and nephritis [39]. Ashwagandha is also being investigated for its efficacy in rheumatoid diseases. In a study conducted in an animal model, Withania somnifera root powder was administered orally to rats for three days, one hour before inflammation was induced by an injection of CFA (complete Freund’s adjuvant). In the control group (positive control), rats were administered phenylbutazone. Changes in the concentrations of a number of serum proteins, such as α2 glycoprotein, acute phase protein α1 and prealbumin, were demonstrated, along with a significant reduction in inflammation [40]. In a study using the HaCaT human keratinocyte cell line, an aqueous solution from Ashwagandha root was found to inhibit the NF-κB and MAPK (mitogen-activated protein kinase) pathways by decreasing the expression of pro-inflammatory cytokines, including interleukin (IL)-8, IL-6, tumour necrosis factor (TNF-α), IL-1β, and IL-12, and increasing the expression of anti-inflammatory cytokines. Based on these results, it can be concluded that the anti-inflammatory effects of Ashwagandha could potentially be used in the prevention of skin inflammation [41]. In a preclinical study of the anti-neuroinflammatory effects of Ashwagandha water extract (ASH-WEX) against lipopolysaccharide-induced systemic neuroinflammation, animals treated with ASH-WEX showed an inhibition of reactive gliosis; production of inflammatory cytokines such as TNF-α, IL-1β, and IL-6; and expression of nitro-oxidative stress enzymes. The underlying molecular mechanisms for the anti-inflammatory potential of ASH-WEX appear to involve inhibition of lipopolysaccharide (LPS)-activated NFκB, P38 and JNK/SAPK MAPK pathways. The results of this study suggest the potential use of Withania somnifera in suppressing nervous system inflammation associated with various neurological disorders [42]. Evidence presented in a study by Kanjilal et al. [43] showed that Ashwagandha extract applied for a period of 8 to 12 weeks can be useful in managing arthritis symptoms in patients. The immunomodulatory effect was confirmed in a study on the effect of Withania somnifera root powder on the stimulation of immune activity in immunodeficient mice. Administration of Withania somnifera was found to increase the total number of white blood cells and bone marrow cells, as well as to increase the titre of circulating antibodies and antibody-producing cells and to stimulate the production of immune cells and the phagocytosis of macrophages [44]. A randomized, double-blind, placebo-controlled trial with an open-label extension was conducted to evaluate the effect of Ashwagandha extract on the immune system of healthy participants. The results of the study showed that Ashwagandha extract significantly increased natural killer cell activity and cytokine levels, compared to placebo [45].”