It has been postulated that reactive oxygen species (ROS) may act as second messengers leading to nuclear factor (NF)-kB activation. This hypothesis is mainly based on the ®ndings that N-acetyl-L-cysteine (NAC) and pyrrolidine dithiocarbamate (PDTC), compounds recognized as potential antioxidants, can inhibit NF-kB activation in a wide variety of cell types. Here we reveal that both NAC and PDTC inhibit NF-kB activation independently of antioxidative function. NAC selectively blocks tumor necrosis factor (TNF)-induced signaling by lowering the af®nity of receptor to TNF. PDTC inhibits the IkB± ubiquitin ligase activity in the cell-free system where extracellular stimuli-regulated ROS production does not occur. Furthermore, we present evidence that endogenous ROS produced through Rac/NADPH oxidase do not mediate NF-kB signaling, but instead lower the magnitude of its activation.

A kaiABC clock gene cluster was previously identified from cyanobacterium Synechococcus elongatus PCC 7942, and the feedback regulation of kai genes was proposed as the core mechanism generating circadian oscillation. In this study, we confirmed that the Kai-based oscillator is the dominant circadian oscillator functioning in cyanobacteria. We probed the nature of this regulation and found that excess KaiC represses not only kaiBC but also the rhythmic components of all genes in the genome. This result strongly suggests that the KaiC protein primarily coordinates genomewide gene expression, including its own expression. We also found that a promoter derived from E. coli is feedback controlled by KaiC and restores the complete circadian rhythm in kaiBC-inactivated arrhythmic mutants, provided it can express kaiB and kaiC genes at an appropriate level. Unlike eukaryotic models, specific regulation of the kaiBC promoter is not essential for cyanobacterial circadian oscillations.

Abstract-The aim of this study was to compare the effects between calcium channel blockers and diuretics when used in combination with angiotensin II receptor blocker on aortic systolic blood pressure (BP) and brachial ambulatory systolic BP. We conducted a prospective, randomized, open-label, blinded end point study in 207 hypertensive patients (mean age: 68.4 years). Patients received olmesartan monotherapy for 12 weeks, followed by additional use of azelnidipine (nϭ103) or hydrochlorothiazide (nϭ104) for 24 weeks after randomization. The central BP by radial artery tonometry, aortic pulse wave velocity, and ambulatory BP were assessed at baseline and 24 weeks later. After adjustment for baseline covariates, the extent of the reduction in central systolic BP in the olmesartan/azelnidipine group was significantly greater than that in the olmesartan/hydrochlorothiazide group (the between-group difference was 5.2 mm Hg; 95% CI: 0.3 to 10.2 mm Hg; Pϭ0.039), whereas the difference in the reduction in brachial systolic BP between the groups was not significant (2.6 mm Hg; 95% CI: Ϫ2.2 to 7.5 mm Hg; Pϭ0.29). The aortic pulse wave velocity showed a significantly greater reduction for the olmesartan/azelnidipine combination than for the olmesartan/ hydrochlorothiazide combination (0.8 m/s; 95% CI: 0.5 to 1.1 m/s; PϽ0.001) after adjustment for covariates. The extent of the reduction in brachial ambulatory systolic BP was similar between the groups. These data showed that the combination of olmesartan ( Key Words: angiotensin II receptor blocker Ⅲ calcium channel blocker Ⅲ thiazide diuretic Ⅲ central blood pressure Ⅲ pulse wave velocity Ⅲ ambulatory blood pressure R ecent clinical trials have demonstrated that strict control of blood pressure (BP) is essential to prevent target organ damage and to reduce cardiovascular mortality in hypertensive patients. 1-3 The angiotensin II receptor blocker (ARB) is one of the first-line antihypertensive drugs for most patients with hypertension, but monotherapy achieves the target BP recommended by the treatment guidelines 4,5 in only a limited number of patients, and, thus, combination therapy is required in a majority of patients. 5 A thiazide diuretic is commonly used in combination with an ARB or angiotensinconverting enzyme inhibitor (ACE-I) because it has an additive effect on BP reduction because of the complementary mechanisms of action of the components, 5 and the efficacy of these combinations has been demonstrated in clinical trials. 1,2,6 On the other hand, the combination of a dihydropyridine calcium channel blocker (CCB) with an ARB or ACE-I has also become widely used because this regimen is effective in BP control and is well tolerated. 7 Recently, the combination of an ACE-I and a CCB has been reported to be more effective than the combination of an ACE-I and a thiazide diuretic for decreasing cardiovascular events in high-risk hypertensive patients. 8 In the Anglo-Scandinavian Cardiac Outcomes Trial, 3 the CCB/ACE-I combination was more effective than a combination ...