A few days ago I began reading about genomic instability in people with ADPKD, but as so often happens, my interest jumped from one branch to another until I was several trees away from where I started. It included reading a whole book on epigenetics (see side panel) and I do want to talk about that soon. However it was the bright yellow spice, circumin, that finally pulled me down to detail. The result of my reading is that my husband is in the kitchen preparing a vegetable curry using far more turmeric than we have previously tried!
The detail has proved a challenging workout for my neurones. Since they say brain activity slows aging then I am not going to let you get away with a simplified version.
We shall start with signal transducers and STAT3.
The initials stand for “Signal Transducer and Activator of Transcription”
Going back to my impending lunch, the signal that it is almost ready is the smell, which I recognise and interpret before activating my lazy self to stand up and go into the kitchen to get my plate. Signal transduction is a bit like that, an environmental signal outside the cell is noticed, converted into another chemical form (transduced) which is carried across the cell to where it evokes a response. The response we are talking about here is transcription, the first step taken in reading the DNA recipe for the genes which code for protein manufacture.
A STAT is a protein inside the cells that acts as a signal to activate other genes.
STAT3 is one of a family of 7 proteins (1,2,3,4,5a,5b,6) (why 5b and not 7? No idea!)
STAT3 is important in PKD because activation of STAT3 is correlated with cyst progression. In both mouse models and ADPKD kidney tissues it has been found that STAT3 is aberrantly activated, that is, it does not behave as one would expect in health adult kidney cells.
The activation of STATs is triggered by binding to cytokines or growth factors in the cytoplasm of the cell.
The chemical detail of this is that it is turned on by phosphorylation of a single tyrosine residue within the trans-activation domain. This causes dimerisation and translocation to the nucleus.
In the nucleus the STATs bind to specific DNA sequences alongside cofactors and in this way they activate gene expression.
The cofactors are the elements which specify which gene is being targeted by the STAT.
STAT3 is one of the first STATs produced in an embryo, an embryo without STAT3 will die.
STAT3 confers resistance to apoptosis in any cell types. Apoptosis is where a cell self destructs, usually because it is old or damaged. Cells that don’t do this just go on forever, replicating themselves with all their faults – this is what cancers are.
It is this mechanism that makes it an oncogene (cancer inducing) as it stops the abnormal cancer cells from dying.
STAT3 has been found to be activated in several human cancers and inhibition of STAT3 can lead to inhibition of tumour growth. As of 2013, however, there were no drugs specifically to inhibit STAT3 that could be used in clinical practice.
In mice, at the point when the kidneys are growing, STAT3 is present and highly active. By the time the mouse is an adult the STAT3 activity has been down-regulated and is almost non-existant. This suggests that the importance of STAT3 is when the kidneys are developing and it shouldn’t be active when this process is over. Taking kidney cells and growing them outside the body has confirmed this so cultures of renal epithelial cells need STAT3 in order to grow into tubules. It is an overgrowth of tubular cells that forms the cysts in PKD.
So we have a healthy adult kidney that does contain plenty of the STAT3 protein but it is no longer active, it has effectively been switched off. It is, however, ready to be activated at a moments notice and if there is acute kidney damage this is what happens. One experiment that demonstrated this was by activating the STAT3 artificially before subjecting the mice to an insult that one would expect to damage the kidney (a Mercury compound). The activated STAT3 actually protected the mice kidneys from excessive damage and they all recovered.
It seems that STAT3 is the cell’s equivalent of a first responder emergency service to repair the damage and prevent things from getting worse. But just as a permanently on call paramedic will get tired and start making mistakes so, if the STAT3 remains in a hyperactive state, it starts repairing tissues that don’t initially have much wrong with them and inadvertently causes more harm than good, triggering a destructive process within the kidney, the formation of lots of new tubular cells that have nothing better to do than hang around in non-working groups: cysts.
Back in 2002 it was shown that polycystin 1 (PC1) has a role in regulating STAT1 activity. Four years later STAT6 was in focus and it was demonstrated that in a PKD mouse model, aberrant activation of STAT6 led to cyst growth which could be halted by inhibiting STAT6. Fast forward to 2011 and it was discovered that cells lining the cysts in ADPKD human kidneys had strongly activated STAT3. There were similar findings in four different mouse models of PKD.
PC1 is the protein affected in most cases of human PKD. It is a reasonable assumption that it may play a role in the unusual over-activity of STAT3. It isn’t a straightforward relationship though, with mutations known to both activate and inhibit the STAT3. Renal cyst growth can be caused by both reduced and increased expression of PC1. In the kidneys of ADPKD patients PC1 has been found to be consistently over expressed. This excess can amplify the activity of STAT3.
There are lots of other factors that have an effect on the STAT3, some also found to be high in the kidney cysts. Rather than looking at this as a single linear path it is better to envisage a network of inter-related molecules in a finely tuned balance – or imbalance in the case of a PKD patient.
Sprinkle on some circumin
The chemical name for circumin is diferuloylmethane. It is a compound which can affect several targets that we have heard mentioned in connection with PKD – such as mTOR, wnt signalling and, our current focus, STAT3.
Circumin is a yellow spice, maybe better known in the kitchen as turmeric. To be precise the root of the turmeric plant, Curcuma longa, contains the slightly bitter peppery spice called circumin in several formats, alongside some oil, sugar and proteins. It is used in Ayurvedic medicine for colds and indigestion but not for kidney ailments. There are many health studies involving circumin, so it is not surprising that PKD scientists would turn to it.
The turmeric plant needs high temperatures and high rainfall to grow and the spice comes from the root. Turmeric root looks like ginger might if your toddler had coloured the ends in with an orange felt tip. In food manufacture circumin has been used to add colour to foods as diverse as custard and popcorn. It even has an E number: E100.
Because turmeric powder contains relatively small concentrations of the active circumin several health-food companies market products claiming to have very high concentrations. It is easy to be drawn in by the hype and % figures. For example one company adds black pepper extract to “increase the bioavailability of our 95% circuminoids by as much as 2000%”
The potential benefits of circumin, according to fringe nutritionists, are endless – anti-inflammatory, anti-oxidant, anti-brain-aging, anti-cancer – such that after reading all of this over-enthusiastic praise, I could easily become anti-circumin as a stubborn reaction.
The academic papers prove more demanding reading but after a few days of random googling on the scholar pages I am growing more convinced that circumin does actually carry some benefit for kidney health, particularly in ADPKD.
Take the following as examples:
- 2011: Leonhard et al treated some PKD mice with high doses of circumin, observing that this stopped further cyst growth.
- 2012: Tapia et al showed circumin to protect against glomerular and systemic hypertension in rats after partial nephrectory
- 2013: Soetikno et al found that circumin could attenuate diabetic nephropathy
- 2013: Soetikno et al found that circumin reduced renal fibrosis in rat kidneys
- 2014: Gao et al showed that cysts in vitro became smaller when treated with circumin
- 2016: Muta et al demonstrated that circumin suppressed histone acetylation in rat kidneys fed on salt
This latest study takes steps into the very exciting field of epigenetics and deserves a post all of its own (work in progress). In a nutshell, adding acetyl molecules to histone will change the gene expression and so alter the clinical picture of the disease. It is one factor in the explanation of why people with the same genetic defect can have such variation in how it affects them.
Circumin acts on many different molecules including growth factors and cytokines and inflammatory enzymes. It also reacts with some transcription factors including STAT3.
Could the circumin effect on PKD be due to its inhibition of STAT3?
Are there any negatives about circumin?
I have been reminded to add in a rider that circumin/turmeric does interact with some common prescribed drugs so you should check this before starting to take it. Check with following website may help:
On the whole humans seem to be able to tolerate quite high doses of circumin without any ill effect. Trials on doses up to 2500mg daily have found it to be safe. Some trials have used 8g safely.
I came across one article entitled “The dark side of circumin” where the pharmacist authors suggest it’s use should be circumspect. They particularly mention the low bioavailability and extensive metabolism, so high and frequent dosing is needed to maintain therapeutic levels. This is addressed by adding enhancers such as the black pepper extract used in the neutraceutical industry. Also turmeric contains oxalate which is water soluble and so is excreted in the urine. In people prone to kidney stones this could be an undesirable effect.
It should be understood that one of the actions of circumin is to change epigenetic modifications, and to change the expression of genes. Though desirable in PKD, indiscriminate application of such changes could in fact lead to illness, including developing cancers. There have been no reports of cancer occurring in this situation as yet, it is a theoretical adverse event only to date.
The question of whether to supplement with circumin or turmeric is unanswered. A few studies suggest that reconstituting the circumin with some of the other chemicals found in turmeric might provide the best therapeutic agent. It is currently marketed in many formats from capsules to soap. These may contain other chemicals such as solvents, additives and synthetic circumin. Some methods of delivery include making emulsions, capsules, or nanoparticles. Unbiased advice is more or less impossible to find, just look at the bottom of the web page to find who sponsors the information!
In US the FDA approves circumin as GRAS (generally recognised as safe) but it does not have a drug license for use in specific illnesses outside of clinical trials.
Under clinical trials.gov there is a current study, currently recruiting, to look at use of circumin to treat vascular dysfunction in young people with ADPKD. Another is looking at the risk of kidney stones with several dietary supplements including turmeric.
There are several ongoing trials on circumin or turmeric in cancer, arthritis, Alzheimer’s and gut disorders and two on mental health disorders. Only one trial is looking at circumin and chronic kidney disease but sadly it is focuses on CKD with proteinuria, not a frequent feature of ADPKD, so it is doubtful the results will be applicable to us.
Another Google search tells me I can buy extracts of circumin or turmeric for anything from £6 to £37. The choices are actually overwhelming; words such as optimum, awesome (yes, seriously), potent, nutritionally-informed actually lose their ‘potency’ with repetition. I conclude that if they have some on the shelf in WaitTescBury’s then I shall pick some up and give it a try, it I am not going to become a passionate advocate just yet.
I enjoyed my curry by the way, all that turmeric and my STAT3 should be sleeping quietly!