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Objectives Hyperuricaemia is recognized as an independent risk marker for cardiovascular and renal diseases. However, uric acid is a powerful free-radical scavenger, and the optimal level of serum uric acid (SUA) determining outcomes is unknown. This study explored whether interventional treatments for excessive SUA reduction were harmful and what constituted the optimal lowering of SUA levels for the prevention of events in patients with asymptomatic hyperuricaemia. Methods This was a post hoc analysis of a randomized trial (Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy [FREED]) in which 1070 older patients with asymptomatic hyperuricaemia were enrolled and allocated to febuxostat (n  = 537) or non-febuxostat treatment group (n  = 533). We assessed the relationship between the endpoint (withdrawal or study completion) SUA levels and clinical outcomes. Primary endpoint was defined as a composite of all-cause mortality, cerebral and cardiorenovascular events. Results In the febuxostat group, patients achieving SUA levels ≤4 mg/dl (hazard ratio: 2.01 [95% CI: 1.05, 3.87]), >4 to ≤5 mg/dl (2.12 [1.07, 4.20], >6 to ≤7 mg/dl (2.42 [1.05, 5.60]), and >7 mg/dl (4.73 [2.13, 10.5]) had significantly higher risks for a primary composite event than those achieving SUA levels >5 to ≤6 mg/dl (P = 0.003 [log-rank test]). This J-shaped relationship applied to patients with renal impairment (P  = 0.007 [Gray's test]) and was not significant in the non-febuxostat treatment group (P  = 0.212 [log-rank test]). Conclusion Optimal SUA level by febuxostat treatment is 5–6 mg/dl for reducing all-cause mortality, cerebral, cardiovascular and renal events. Excessive SUA reduction may be harmful in older hyperuricaemic populations. Trial Registration ClinicalTrial.gov , https://clinicaltrials.gov , NCT01984749 [ABSTRACT FROM AUTHOR]

ZFP36L1 is an RNA-binding protein responsible for mRNA decay in the cytoplasm. ZFP36L1 has also been suggested as a nuclear-cytoplasmic shuttling protein because it contains a potential nuclear localization signal and a nuclear export signal. However, it remains unclear how the nuclear localization of ZFP36L1 is controlled. In this study, we provide evidence that the nuclear accumulation of ZFP36L1 protein is modulated in a cell cycle-dependent manner. ZFP36L1 protein accumulation in fractionated nuclei was particularly prominent in cells arrested at G1-/S-phase boundary, while it was downregulated in S-phase cells, and eventually disappeared in G2-phase nuclei. Moreover, forced nuclear targeting of ZFP36L1 revealed marked downregulation of this protein in S- and G2-phase cells, suggesting that ZFP36L1 can be eliminated in the nucleus. The C-terminal serine-rich cluster of ZFP36L1 is critical for the regulation of its nuclear accumulation because truncation of this probable disordered region enhanced the nuclear localization of ZFP36L1, increased its stability and abolished its cell cycle-dependent fluctuations. These findings provide the first hints to the question of how ZFP36L1 nuclear accumulation is controlled during the course of the cell cycle. [ABSTRACT FROM AUTHOR]

BAG6 (also known as BAT3/Scythe) is a ubiquitin-like protein that is thought to participate in a variety of seemingly unrelated physiological and pathological processes, such as apoptosis, antigen presentation and the T-cell response. Recent studies have shown that BAG6 is essential for the quality control of aggregation-prone polypeptide biogenesis. It forms part of a complex that determines the fate of newly synthesized client proteins for membrane insertion, ubiquitin-mediated degradation and/or aggregate formation. A biologically relevant transmembrane protein family has recently been shown to be a major client of BAG6, suggesting that many of the known diverse BAG6 functions can be interpreted by BAG6-mediated control of membrane protein biogenesis. In this review, we summarize the current understanding of the physiological roles of BAG6 with a particular focus on quality control for nascent chain polypeptides. [ABSTRACT FROM AUTHOR]

BackgroundEffects of dietary n-3 polyunsaturated fatty acids (n-3 PUFA) intake on the cardiovascular system have been reported, and thus we hypothesized that the prevalence of hypertensive cardiovascular remodeling would be lower in a fishing than a farming community.MethodsWe recruited 263 essential hypertensives from a fishing and 333 from a farming village; all subjects were ≥40 years (mean 73 years; 42% men). They were cross-sectionally examined for serum eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), asymmetric dimethylarginine (ADMA) levels, left ventricular mass index (LVMI), and common-carotid artery (CCA) and internal-carotid artery (ICA) intima-media thickness (IMT).ResultsCompared to the patients in the farming village, those in the fishing village had higher serum EPA and DHA levels (63.3 vs.70.9 µg/ml, 137.2 vs.157.8 µg/ml) and lower ADMA levels (0.49 vs.0.47 nmol/ml; all P < 0.05). LVMI and both CCA-IMT and ICA-IMT levels were lower in the fishing than the farming village (113.2 vs.121.6 g/m2, 0.88 vs.0.94 mm, 1.10 vs.1.17 mm: all P < 0.01) even after adjustment for age, sex, body mass index (BMI), duration of hypertensive medication, number of antihypertensive medications, and 24-h systolic blood pressure (SBP) level. The differences in LVMI and IMT levels between these communities also remained unchanged (all P < 0.01) after additional adjustment for the regional differences in EPA, DHA, and ADMA levels. A multivariable linear regression analysis showed that the difference in place of residence was independently associated with LVMI as well as with both CCA-IMT and ICA-IMT levels (all P < 0.01).ConclusionThe prevalence of cardiovascular remodeling was significantly lower in patients in the fishing community than in those in the farming community. Further investigations are required to explain the mechanisms underlying this association.American Journal of Hypertension (2011). doi:10.1038/ajh.2010.263 [ABSTRACT FROM AUTHOR]

Objective: This study was designed to investigate the modification of plasma and cardiac tissue brain natriuretic peptide concentrations in spontaneously hypertensive rats and Wistar-Kyoto rats in relation to those of atrial natriuretic peptide during the development of hypertension. Methods: Blood pressure, tissue weight, and plasma and cardiac tissue atrial natriuretic peptide and brain natriuretic peptide concentrations were measured in conscious 5, 10, and 18 week old, spontaneously hypertensive, and in corresponding normotensive rats. Pharmacokinetics of atrial natriuretic peptide and brain natriuretic peptide were also examined. Results: Plasma concentrations of both atrial natriuretic peptide and brain natriuretic peptide in hypertensive rats increased significantly with development of hypertension. The pattern was not in parallel, so that the brain natriuretic peptide/atrial natriuretic peptide ratio was high in spontaneously hypertensive rats. Concentrations of brain natriuretic peptide in the cardiac ventricle were already higher in hypertensive rats than in controls as early as 5 weeks of age, whereas atrial natriuretic peptide was comparable. Progression of hypertension led to an increase in both atrial natriuretic peptide and brain natriuretic peptide concentrations in the ventricle, predominantly in the left ventricles, and the highest brain natriuretic peptide/atrial natriuretic peptide ratio was in the left ventricles from 18 week old spontaneously hypertensive rats. Pharmacokinetics showed that the plasma half lives of atrial natriuretic peptide and brain natriuretic peptide were not different between the two strains. Conclusions: Although raised blood pressure stimulates both atrial natriuretic peptide and brain natriuretic peptide, production of brain natriuretic peptide in the ventricles is already increased in the prehypertensive stage, and in older hypertensive rats, it is more responsive to progression of hypertension than atrial natriuretic peptide. It is suggested that regulation of production and secretion of the two natriuretic peptides is not temporally coordinated during development of hypertension in this model.Cardiovascular Research 1993;27:1312-1315 [ABSTRACT FROM PUBLISHER]