I’m fascinated with the transcriptomic/proteomic effects of “health
food” supplements. The fascination doesn’t derive from being a “believer”, but
from being a skeptic. At least at the level of cell-culture and the
force-feeding of mice, however, some of these supplements really do alter gene
expression. Here, we’ll do a “shallow dive” on the topic of resveratrol, a
compound prominently found in wine and peanuts, and likely available in a local
health food shop (possibly in the form of “grape skin extract”).
There are 12 studies relating to the transcriptomic effects
of resveratrol in our database. Just type the keyword “resveratrol” into the “relevant
genes” app to see these studies. Two of the studies use CRISPR to find genes
that enhance sensitivity to resveratrol, while a third compares resveratrol and
pinosylvin. We tossed these 3 studies and created lists of “canonically”
upregulated and downregulated transcripts following resveratrol treatment in
the remaining 9 studies. You can play with these canonical datasets yourself
using the dbase IDs 122772121
and 122773121. On the upregulation side, the following genes were found
in 3 of the 9 studies:
RETSAT, PIK3IP1, PLA2G4C, ACTA2, ALDOC, GADD45A, CDKN1A, DDIT3,
JUN, SERTAD1
On the downregulation side, 2 genes were actually found in 4
of the 9 studies, with a large number (which we won’t list) found 3 times:
KIF20A and RRM2
If you plug KIF20A or RRM2 into the coregulation tool, you'll see that these two genes tend to be up/down-regulated hand in hand (log(P)=-200).
Let’s jump to the juiciest (but not most significant)
results. One of resveratrol’s myriad supposed positive effects would be life
extension. And, in fact, Fisher analysis of the upregulated genes (122772121) actually suggests
relevance. For example, these genes overlap well with those in a study
involving metformin treatment of MCF7 cells; for a taste of metformin’s
effects, see the review, Metformin as Anti-Aging Therapy: Is It for
Everyone? Metformin is an anti-diabetic drug; another anti-diabetic, troglitazone, also overlaps with the effects of the canonically upregulated set. Another overlapping study (SIRT1 activator SRT1720 extends
lifespan…) is obviously relevant. A final study leads us deeper into the
realm of health food supplements: Identification of Targets of a New
Nutritional Mixture for Osteoarthritis Management Composed by Curcuminoids
Extract, Hydrolyzed Collagen and Green Tea Extract.
Downregulated transcripts, as suggested above, are more
significantly relevant to resveratrol’s effects. These transcripts overlap
quite strongly with studies involving the cell cycle (e.g. studies involving
CDK4/6 inhibitors, segregation of G1 and S phases, and knockdown of cell-cycle
regulators such as DDX6, DHX9, and TRIM33).
Anti-cancer relevance is seen in the results. Most
powerfully, genes upregulated in cervical cancer are downregulated (log(P)
= -79 via our “Fisher” app) in the canonical downregulation list. Other
extremely significant overlaps relate to yet another cervical carcinoma study,
laryngeal carcinoma, and high-grade astrocytoma. Inserting both canonical
datasets into the “Match Studies” app suggests particular relevance to luminal
B (vs A) breast cancer, and myc (vs ras) –driven cancers.
Numerous other drugs in the database seem to offer similar
profiles to resveratrol: butylidenephthalide, ly101-4b (an e2f inhibitor), roscovotine,
and BET inhibitors, for example. These similarities may be important as
resveratrol’s optimal dosage and bioavailability to various organs may be
questioned. We do note, however, numerous studies suggesting an effect at
relatively low dosages (e.g. Low dose resveratrol improves cerebrovascular
function in type 2 diabetes mellitus, Low dose resveratrol ameliorates
mitochondrial respiratory dysfunction and enhances cellular reprogramming,
and more).
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