In Alzheimer disease (AD), the microtubule-associated protein tau is found hyperphosphorylated in paired helical filaments. Among many phosphorylated sites in tau, Ser-262 is the major site for abnormal phosphorylation of tau in AD brain. The kinase known to phosphorylate this particular site is MARK2, whose activation mechanism is yet to be studied. Our first finding that treatment of cells with LiCl, a selective inhibitor of another major tau kinase, glycogen synthase kinase-3 (GSK-3), inhibits phosphorylation of Ser-262 of tau led us to investigate the possible involvement of GSK-3 in MARK2 activation. In vitro kinase reaction revealed that recombinant GSK-3 indeed phosphorylates MARK2, whereas it failed to phosphorylate Ser-262 of tau. Our further findings led us to conclude that GSK-3 phosphorylates MARK2 on Ser-212, one of the two reported phosphorylation sites (Thr-208 and Ser-212) found in the activation loop of MARK2. Down-regulation of either GSK-3 or MARK2 by small interfering RNAs suppressed the level of phosphorylation on Ser-262. These results, respectively, indicated that GSK-3 is responsible for phosphorylating Ser-262 of tau through phosphorylation and activation of MARK2 and that the phosphorylation of tau at this particular site is predominantly mediated by a GSK-3-MARK2 pathway. These findings are of interest in the context of the pathogenesis of AD.
Aims
AJM300 is an oral antagonist of α4‐integrin that reduces inflammation by blocking leucocyte trafficking. This study aimed to investigate safety, tolerability, pharmacokinetics and pharmacodynamics of AJM300 in healthy male subjects.
Methods
A total of 23 subjects were randomised to receive 240 mg (n = 6), 480 mg (n = 5), 960 mg (n = 6) of AJM300 or the corresponding placebo (n = 2 per group). The study drugs were taken orally 3 times daily after each meal on the first day followed by a 4‐day washout period. Thereafter, multiple‐dose administration was conducted for 6 consecutive days. The pharmacokinetic parameters of AJM300 and its active metabolite (HCA2969) were assessed, and total white blood cells and the differential cell count were used to determine the pharmacodynamic effects. Adverse events (AEs) were also monitored.
Results
The plasma AJM300 and HCA2969 concentration–time curves displayed a triphasic pattern on Day 1 (single‐day administration) and Day 10 (last day of multiple dosing), whereas the concentration of HCA2969 was much higher than that of AJM300. A significant but transient increase in lymphocyte count was observed after AJM300 dosing at all dosages tested compared with the placebo. The increase was sustained over a 24‐h period only at the 960‐mg dosage. In particular, a significant increase in the lymphocyte count compared to placebo (mean, 50.58%; 95% confidence intervals, 20.40–80.76) was observed at the first 960‐mg dose on Day 10. Six (26.1%) subjects reported ≥1 AEs, all of which were mild and resolved spontaneously.
Conclusion
The maximal and 24‐h sustained pharmacodynamic effects were demonstrated at the 960‐mg dosage after oral administration of AJM300 3 times daily for 6 days, which was also found to be safe and well tolerated.
The metabolic syndrome is strongly associated with insulin resistance and has been recognized as a cluster of risk factors for cardiovascular disease. Insulin resistance and/or impaired early-phase insulin secretion are major determinants of postprandial hyperglycemia. In this study, we investigated the potential utility of combination therapy with telmisartan, an angiotensin II receptor blocker and nateglinide, a rapid-onset/short-duration insulinotropic agent, for the treatment of postprandial hyperglycemia and metabolic derangements in Zucker Fatty (ZF) rats. ZF rats fed twice daily were given vehicle, 50 mg/kg of nateglinide, 5 mg/kg of telmisartan, or both for 6 weeks. Combination therapy with nateglinide and telmisartan for 2 weeks ameliorated postprandial hyperglycemia in ZF rats fed twice daily. Furthermore, 6-week treatment with nateglinide and telmisartan not only decreased fasting plasma insulin, triglycerides, and free fatty acid levels, but also improved the responses of blood glucose to insulin and subsequently reduced the decremental glucose areas under the curve in the ZF rats. Combination therapy also restored the decrease of plasma adiponectin levels in the ZF rats. Monotherapy with nateglinide or telmisartan alone didnot significantly improve these metabolic parameters. These observations demonstrate that combination therapy with nateglinide and telmisartan may improve the metabolic derangements by ameliorating early phase of insulin secretion as well as insulin resistance in ZF rats fed twice daily. Our present findings suggest that the combination therapy with nateglinide and telmisartan could be a promising therapeutic strategy for the treatment of the metabolic syndrome.
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