An unusual chemical relative of vitamin A is the main culprit behind the most common form of blindness in the elderly: age-related macular degeneration (AMD). Now, US researchers have developed a total synthesis of the compound, which should help investigators figure out what causes the disease and may eventually lead to a drug-based treatment.
Several years
ago, opthalmologist Graig Eldred of the University of Missouri-Columbia
isolated a tiny amount of an orange pigment from more than 250 donor eyes of
patients over 40 years old. Collaborators, Koji Nakanishi, Rex Ren and Naomi
Sakai in the Department of Chemistry at Columbia University, New York,
figured out the exact structure of this pigment using spectroscopy.1
The compound in question, pyridinium bisretinoid, or A2-E,
is the fluorescent orange culprit. It accumulates in granules at the back of
the eye, damaging the retina and eventually causing partial loss of sight
and blindness in one percent of the over 70s. With an ageing population the
problem is likely to increase and there is no known remedy.
Rather ironically, A2-E turns out to be like two vitamin A type molecules joined by a pyridinium group. Vitamin A and its derivatives, the retinoids, are more commonly associated with good eyesight as they are the essential pigments for building the light- sensitive surface of the retina. A2-E, however, is a surfactant, or soap-like molecule, according to the researchers. This means it can burst holes in cell walls like a soap molecule penetrating a greasy layer in the washing-up bowl. The surfactant properties of A2-E also interfere with the removal of waste proteins from the retina causing a build up of unwanted material, which damages sight too. In addition, visible light trigger A2-E to produce damaging superoxide radicals – the more A2-E present the more likely superoxide radicals are to form on the retina and accelerate the degeneration to blindness.
Now, the team has worked out a way to make A2-E from off the shelf ingredients.2 Nakanishi says this offers some hope, "We think that A2-E could be used for in vitro testing of AMD inhibitors," he says. His team has now formed a multidisciplinary group including opthalmologists to look for a remedy for AMD.
Vaccines are usually produced with so-called adjuvants, tiny particles of a
metal salt such aluminium hydroxide that become coated with the protein (the
antigen) to trigger the immune response. The adjuvant effect was first
observed in 1926 and has been used deliberately since the 1930s to boost the
efficacy of vaccines. Theories to explain the effect were based on the
notion that once injected the adjuvant particles with their antigen payload
would "lodge" in muscular tissue providing a constant source of antigen for
the antibodies to be built on ready for infectious attack at any time in the
future.
While there have been numerous dissenters from the theory, researchers in the School of Pharmacy and Pharmaceutical Sciences at Purdue University in West Lafayette, Indiana have now proved the theory wrong using results from a super sensitive mass spectrometer.
Stan Hem and his team have used a huge mass spectrometer, which they converted from an old particle accelerator, to build a highly sensitive machine. The detection limits are effectively as low as the equivalent of one grain of sand in a football stadium, according to Hem.
The team vaccinated laboratory rabbits with adjuvants containing the isotope aluminium- 26. They then monitored the blood and urine of the animals for a month. Samples were fed into the accelerator mass spectrometer and they looked for the signal due to the aluminum-26. They found that the aluminium began to appear in the blood samples within just one hour of the intermuscular injection. This say the researchers indicates that the adjuvant was dissolving in interstitial fluid and not remaining in the muscle at all as was predicted by the adjuvant theory. The team is at a loss now to explain the adjuvant effect but suspects that it is more to do with the initial injection than lodging of particles in muscle.3
Hem and his colleagues have now moved on to study whether human armpits can absorb aluminium from deodorants using the same accelerator mass spectrometer.
Various reports on the effect of diet on cancer rates has pointed to green
tea as being one possible agent in keeping incidence of the disease down in
China and Japan and other oriental countries. Now researchers at the Medical
College of Ohio and the University of Toledo believe they have discovered
the chemical rationale behind the effects.
Jerzy Jankun and his colleagues were searching a massive database of 190 000 molecules using the screening programs BIOSYSM LUDI and DOCKING to see if any would fit into the active site of an enzyme called urokinase. Urokinase splits proteins such as collagens and in the hands of a cancer cell help the cancer spread around the body - an effect known as metastasis which makes certain cancers, such as breast and prostate, very difficult to treat if they are not caught early enough.
The computer models showed that numerous polyphenols were excellent fits
for the site. One of the best fits was found for epigallocathechin-3 gallate
()
a compound found perhaps not surprisingly in green tea. With this
theoretical result to hand the team set about measuring the ability of the
green tea compound to dock with urokinase in the laboratory and they found
that the enzyme was effectively inhibited.
A single cup of green tea (not the black stuff drunk in the UK) contains 150 milligrams of EGCG and some drinkers imbibe ten cups a day. The researchers suspect that the overall inhibitory effect of this amount of green tea could explain the very low incidence of cancers in China and Japan.4
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