Investigating the mechanisms of amylolysis of starch granules by solution-state NMR.

Starch is a prominent component of the human diet and is hydrolyzed by α-amylase post-ingestion. Probing the mechanism of this process has proven challenging, due to the intrinsic heterogeneity of individual starch granules. By means of solution-state NMR, we demonstrate that flexible polysaccharide chains protruding from the solvent-exposed surfaces of waxy rice starch granules are highly mobile and that during hydrothermal treatment, when the granules swell, the number of flexible residues on the exposed surfaces increases by a factor of 15. Moreover, we show that these flexible chains are the primary substrates for α-amylase, being cleaved in the initial stages of hydrolysis. These findings allow us to conclude that the quantity of flexible α-glucan chains protruding from the granule surface will greatly influence the rate of energy acquisition from digestion of starch.

The identification of beta-hydroxy carboxylic acids as selective MMP-12 inhibitors.

A new class of selective MMP-12 inhibitors have been identified via high throughput screening. Crystallization with MMP-12 confirmed the mode of binding and allowed initial optimization to be carried out using classical structure based design.

Ketamine elicits sustained antidepressant-like activity via a serotonin-dependent mechanism.

RATIONALE: Behavioural antidepressant-like effects of ketamine have been reported in the forced swimming test (FST). The mechanisms mediating such effects are unknown. OBJECTIVES: As serotonin (5-HT) is an important transmitter mediating antidepressant responsiveness in the FST, the influence of 5-HT depletion on the antidepressant-like effect of ketamine was assessed. METHODS: The effect of ketamine (25 mg/kg, i.p., 1 or 24 h prior to test) was assessed in the FST in naive rats or animals subjected to 5-HT depletion, repeated stress or following a combination of 5-HT depletion and stress. Endogenous 5-HT was depleted using the tryptophan hydroxylase inhibitor para-chlorophenylalanine (3 × 150 mg/kg, i.p.). Stress was induced by physical restraint (2 h/day for 10 days). RESULTS: In naive rats, ketamine administered 24 or 1 h prior to test produced a characteristic antidepressant-like reduction in immobility time in the FST. Depletion of 5-HT blocked this reduction in immobility when ketamine was administered 24 h prior FST, indicative of 5-HT dependency. The increase in immobility provoked by repeated restraint stress (2 h/day for 10 days) was blocked by ketamine when administered 24 h prior to FST, but this effect dissipated when animals were subjected to 5-HT depletion. CONCLUSIONS: These observations are consistent with a role for 5-HT in mediating sustained antidepressant activity of ketamine in the FST. Molecular and cellular changes induced by ketamine may produce a rapid adaptation of 5-HT transmission which underlies the antidepressant response.