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It's not an apple a day after all -- it's strawberries: Flavonoids could

represent two-fisted assault on diabetes and nervous system disorders

A recent study from scientists at the Salk Institute for Biological Studies

suggests that a strawberry a day (or more accurately, 37 of them) could keep not

just one doctor away, but an entire fleet of them, including the neurologist,

the endocrinologist, and maybe even the oncologist.

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Investigations conducted in the Salk Institute's Cellular Neurobiology

Laboratory (CNL) will appear in the June 27, 2011, issue of PLoS ONE. The report

explains that fisetin, a naturally-occurring flavonoid found most abundantly in

strawberries and to a lesser extent in other fruits and vegetables, lessens

complications of diabetes. Previously, the lab showed that fisetin promoted

survival of neurons grown in culture and enhanced memory in healthy mice. That

fisetin can target multiple organs strongly suggests that a single drug could be

used to mitigate numerous medical complications.

" This manuscript describes for the first time a drug that prevents both kidney

and brain complications in a type 1 diabetes mouse model, " says Schubert,

Ph.D., professor and head of the Cellular Neurobiology Laboratory and one of the

manuscript's co-authors. " Moreover, it demonstrates the probable molecular basis

of how the therapeutic is working. "

Pam Maher, Ph.D., a senior staff scientist in the CNL, is the study's

corresponding author. Maher initially identified fisetin as a neuroprotective

flavonoid ten years ago. " In plants, flavonoids act as sunscreens and protect

leaves and fruit from insects, " she explains. " As foods they are implicated in

the protective effect of the 'Mediterranean Diet.' "

Other celebrity flavonoids include polyphenolic compounds in blueberries and red

wine.

Although her group's focus is neurobiology, Maher and colleagues reasoned that,

like other flavonoids, fisetin might ameliorate a spectrum of disorders seen in

diabetic patients. To test this, they evaluated effects of fisetin

supplementation in Akita mice, a very robust model of type 1 diabetes, also

called childhood onset diabetes.

Akita mice exhibit increased blood sugar typical of type 1 diabetes and display

pathologies seen in serious human complications of both type 1 and 2 diabetes.

Those include diabetic nephropathy or kidney disease, retinopathy, and

neuropathies in which patients lose touch or heat sensations.

Mice fed a fisetin-enriched diet remained diabetic, but acute kidney

enlargement-or hypertrophy-seen in untreated mice was reversed, and high urine

protein levels, a sure sign of kidney disease, fell. Moreover, fisetin ingestion

ameliorated anxiety-related behaviors seen in diabetic mice. " Most mice put in a

large area become exploratory, " says Maher. " But anxious mice tend not to move

around. Akita mice showed enhanced anxiety behavior, but fisetin feeding

restored their locomotion to more normal levels. "

The study also defines a likely molecular mechanism underlying these effects.

Researchers observed that blood and brain levels of sugars affixed to proteins

known as advanced glycation end-products-or AGEs-were reduced in fisetin-treated

compared to untreated Akita mice. These decreases were accompanied by increased

activity of the enzyme glyoxalase 1, which promotes removal of toxic AGE

precursors.

The discovery of an AGE-antagonizing enzyme upregulated by fisetin is very

intriguing, because substantial evidence implicates high blood AGE levels with

many if not most diabetic complications. " We know that fisetin increases

activity of the glyoxalase enzyme and may increase its expression, " says Maher.

" But what is important is that ours is the first report that any compound can

enhance glyoxalase 1 activity. "

Interestingly, excessively high AGE levels also correlate with inflammatory

activity thought to promote some cancers. In fact, studies published by others

confirm that fisetin decreases tumorigenicity of prostate cancer cells both in

culture and in animal models, which if supported would represent a major added

incentive to eat your strawberries.

To ingest fisetin levels equivalent to those fed Akita mice, Maher estimates

that humans would have to eat 37 strawberries a day, assuming that strawberry

fisetin is as readily metabolizable by humans as fisetin-spiked lab chow is by

mice. Rather than through diet, Maher envisions that fisetin-like drugs could be

taken as a supplement.

Schubert notes that fisetin is also effective in mouse models of Alzheimer's

disease. " We and others have shown that diabetes may be a risk factor for

Alzheimer's disease, making identification of a safe prophylactic like fisetin

highly significant, " he says.

Maher acknowledges that the public may be suffering from flavonoid-fatigue,

given media coverage of the promises of these compounds. " Polyphenolics like

fisetin and those in blueberry extracts are found in fruits and vegetables and

are related to each other chemically, " she says. " There is increasing evidence

that they all work in multiple diseases. Hopefully some combination of these

compounds will eventually get to the clinic. "

Schubert concurs that their findings only reinforce what common sense and our

mothers told us was a healthy lifestyle. " Eat a balanced diet and as much

freshly prepared organic food as possible, get some exercise, keep socially and

mentally active and avoid sodas with sugar and highly processed foods since they

can contain high levels of AGEs, " he advises.

But he also worries that hoops that must be jumped through to bring a natural

product like fisetin, as opposed to a totally synthetic drug, to clinical trials

are daunting because it is difficult to protect patents on natural products. " We

will never know if a compound like fisetin works in humans until someone is

willing to support a clinical trial. "

Also contributing to this study were Dargusch and L. Ehren,

Ph.D.,of the Cellular Neurobiology Laboratory, and Kumar Sharma, M.D., and

Shinichi Okada, M.D., Ph.D., of the Department of Medicine at University of

California, San Diego.

Funding for the study came from the Fritz B. Burns Foundation, the Juvenile

Diabetes Research Foundation, the Hewitt Foundation, and the National Institutes

of Health.