Tests

Urine 6-sulfatoxymelatonin levels are inversely associated with arterialstiffness in post-menopausal women.

OBJECT: The secretion of melatonin, a pleiotropic hormone mainly synthesized by the pineal gland, typically decreases with age and may be associated with the development of aging-related pathologici conditions such as cardiovascular disease. Atherosclerosis is an aging-related disease, the pathogenesis of which involves chronic inflammation and increased oxidative stress. Since melatonin has both anti-oxidant and anti-inflammatory properties, it may be associated with atherosclerosis. Therefore, we investigated the relationship between urine concentrations of 6-sulfatoxymelatonin (aMT6s) and arterial stiffness in post-menopausal women.

METHODS: A total of 66 post-menopausal women participated in the study. Melatonin secretion was estimated by measuring aMT6s levels in first morning urine samples. The cardio-ankle vascular index (CAVI) was used as an indicator of arterial stiffness.

RESULTS: Estimated mean CAVI decreased gradually with increasing aMT6s quartiles. The multivariate logistic regression analysis showed that the fourth aMT6s quartile was associated with a high CAVI with an adjusted odds ratio of 0.03 (95% confidence interval, 0.01-0.47).

CONCLUSION: Our study revealed an inverse relationship between urine aMT6s and arterial stiffness as determined by CAVI. Although it is impossible to determine causality, our results suggest that melatonin may have a beneficial role in the pathogenesis of atherosclerosis. Further prospective studies are required to establish the clinical significance of our study.

Subject	->	Object
Urine 6-sulfatoxymelatonin level	+	post-menopausal women arterial stiffness
pineal gland	+	melatonin
melatonin	-	age
age	+	cardivascular disease
age	+	atherosclerosis
atherosclerosis	+	chronic inflammation
atherosclerosis	+	oxidative stress
aMT6s quartiles	-	cardio-ankle vascular index
high urine AMT6	-	arterial stiffness
melatonin	-	atherosclerosis

A small-molecule oxocarbazate inhibitor of human cathepsin L blocks severe acute respiratory syndrome and ebola pseudotype virus infection into human embryonic kidney 293T cells.

A tetrahydroquinoline oxocarbazate (PubChem CID 23631927) was tested as an inhibitor of human cathepsin L (EC 3.4.22.15) and as an entry blocker of severe acute respiratory syndrome (SARS) coronavirus and Ebola pseudotype virus. In the cathepsin L inhibition assay, the oxocarbazate caused a time-dependent 17-fold drop in IC(50) from 6.9 nM (no preincubation) to 0.4 nM (4-h preincubation). Slowly reversible inhibition was demonstrated in a dilution assay. A transient kinetic analysis using a single-step competitive inhibition model provided rate constants of k(on) = 153,000 M(-1)s(-1) and k(off) = 4.40 x 10(-5) s(-1) (K(i) = 0.29 nM). The compound also displayed cathepsin L/B selectivity of >700-fold and was nontoxic to human aortic endothelial cells at 100 muM. The oxocarbazate and a related thiocarbazate (PubChem CID 16725315) were tested in a SARS coronavirus (CoV) and Ebola virus-pseudotype infection assay with the oxocarbazate but not the thiocarbazate, demonstrating activity in blocking both SARS-CoV (IC(50) = 273 +/- 49 nM) and Ebola virus (IC(50) = 193 +/- 39 nM) entry into human embryonic kidney 293T cells. To trace the intracellular action of the inhibitors with intracellular cathepsin L, the activity-based probe biotin-Lys-C5 alkyl linker-Tyr-Leu-epoxide (DCG-04) was used to label the active site of cysteine proteases in 293T lysates. The reduction in active cathepsin L in inhibitor-treated cells correlated well with the observed potency of inhibitors observed in the virus pseudotype infection assay. Overall, the oxocarbazate CID 23631927 was a subnanomolar, slow-binding, reversible inhibitor of human cathepsin L that blocked SARS-CoV and Ebola pseudotype virus entry in human cells.