[Show abstract][Hide abstract] ABSTRACT: Background: Approximately 25% of ischemic strokes occur during nocturnal sleep. It has been known as wake-up stroke (WUS) and has been reported to have more severe symptoms and worse clinical outcomes. However, the association between nocturnal blood pressure change and WUS has not been evaluated. Objective: The objective of our study is to investigate association between WUS and nocturnal blood pressure change by ambulatory blood pressure monitoring (ABPM). Method: From March 2011 to February 2014, a total 369ischemic stroke within one week were consecutively included. Patients with following characteristics were excluded: severe hypertension (systolic > 220 mmHg or diastolic >120 mmHg), secondary hypertension, life-threatening medical condition, night-shift working, bed-ridden status and inadequate ABPM data. ABPM was applied 1~2 weeks after the ictus and antihypertensive medications were suspended until ABPM monitoring. WUS was defined as stroke onset during nocturnal sleep. The subjects were classified into two groups by the presence of WUS and compared clinical characteristics including ABPM parameters. Results and conclusion: Sixty-seven(18%) subjects had WUS. In univariate analysis, patients with WUS had higher initial NIHSS score, discharge NIHSS score and discharge mRS score. There were no differences in age, gender, stroke subtype, risk factors and previous medications between two groups. In addition, ABPM parameters including nocturnal dipping pattern did not showed any association with the occurrence of WUS. In conclusion,patients with WUS had more severe clinical stroke symptoms and worse clinical outcomes. Nocturnal dipping pattern of blood pressure may not affect the occurrence of WUS. Copyright
No preview · Article · Jun 2015 · Journal of Hypertension
[Show abstract][Hide abstract] ABSTRACT: White matter lesions (WMLs) are a common finding in stroke patients, and the most important risk factors are old age and hypertension. Although many studies have described the association between WMLs and ambulatory blood pressure monitoring (ABPM) parameters in healthy subjects and hypertensive patients, little is known about the association in hypertensive ischemic stroke patients.
From July 2009 to June 2012, 169 consecutive hypertensive noncardioembolic ischemic stroke patients were recruited within 1 week of suffering a stroke, and ABPM was applied 1 or 2 weeks after stroke onset. The subjects were classified into 2 groups according to the presence of advanced WMLs, and their ABPM parameters were compared. Finally, multivariable logistic regression analyses were performed to investigate the independent relationships between WMLs and ABPM parameters.
Seventy (41%) patients had advanced WMLs. In univariable analysis, higher 24-hour, awake, and asleep systolic blood pressure (SBP)/diastolic blood pressure levels and 24-hour pulse pressure were associated with advanced WMLs. However, circadian blood pressure parameters such as 24-hour BP variability, morning surge, and nocturnal dipping pattern were not associated with advanced WMLs. After adjustments, old age (odds ratio (OR) = 1.063; 95% confidence interval (CI) = 1.024-1.104; P = 0.002), high 24-hour SBP levels (OR = 1.055; 95% CI = 1.028-1.082; P < 0.001), and high 24-hour heart rate (OR = 1.041; 95% CI = 1.006-1.078; P = 0.023) were independently associated with advanced WMLs.
In addition to old age and elevated 24-hour SBP, increased heart rate is associated with advanced WMLs in ischemic stroke patients. Heart rate deserves more attention in predicting advanced WMLs in those patients.
No preview · Article · Oct 2013 · American Journal of Hypertension
[Show abstract][Hide abstract] ABSTRACT: Hypoxia inducible factor-1α (HIF-1α) is a transcription factor found in mammalian cells under hypoxia. While HIF-1α in hypoxia translocates to the nucleus where it transcribes the target genes including vascular endothelial growth factor (VEGF) mRNA, HIF-1α is degraded under normoxia, which involves its proline hydroxylation and subsequent binding to the von Hippel-Lindau protein-Elongin B-Elogin C (VBC) complex. Previously, peptide inhibitors against this interaction between hydroxylated HIF-1α and VBC have been developed to stabilize the transcriptional activity of HIF-1α by preventing the degradation of the protein even under normoxia. Despite the specific inhibition by these peptides, their poor inhibition potency needs to be improved for further clinical application. In this work, we have designed and prepared a streptavidin-based multivalent peptide inhibitor against the HIF-1α-VBC complexation. We have evaluated the potency of the multivalent peptide in terms of stabilization of HIF-1α and the downstream effect. As the result, we have found that the inhibitor showed about 13-fold lowered IC value compared with that of the corresponding monovalent peptide, thereby activating HIF-1α and leading to up-regulation of VEGF protein at the cellular level.
No preview · Article · Mar 2013 · Bioorganic & medicinal chemistry letters
[Show abstract][Hide abstract] ABSTRACT: Vascular endothelial growth factor (VEGF) plays a pro-angiogenic role in tumor progression. Stabilization of a key regulator termed the hypoxia inducible factor (HIF)-1α under oxygen deficient environment around tumor is known to elicit expression of VEGF through binding to p300. Thus, inhibition of the HIF-1α-p300 interaction would lead to down-regulation of VEGF expression, thereby providing potential cancer therapeutics. Here, we have screened a chemical library against the interaction of the HIF-1α-derived peptide with p300 employing a fluorescence polarization-based assay. We have identified a compound as the most prominent inhibitor against the protein-protein interaction. Further, we have observed suppression of the mRNA level of VEGF upon treatment of HeLa cells with the compound, demonstrating its inhibitory effect at the cellular level.
No preview · Article · Jun 2012 · Bioorganic & medicinal chemistry letters
[Show abstract][Hide abstract] ABSTRACT: Oxygen dependent degradation of hypoxia-inducible factor (HIF)-1α is triggered with hydroxylation by proline hydroxylase domain 2 (PHD2) under normoxic conditions. Some of previously developed PHD2 inhibitors show a considerable potency against factor inhibiting HIF (FIH), the HIF asparagine hydroxylase. For specific inhibition of PHD2, we have synthesized peptides containing 556-575 residues of HIF-1α with modifications at the Pro-564 and examined their inhibitory effect against PHD2. Adopting fluorescence polarization-based assays, we evaluated inhibitory potency of the peptides and selected potent inhibitors. These PHD2 inhibitor peptides showed no significant potency against FIH, demonstrating their specific inhibitory effect on PHD2.
No preview · Article · May 2011 · Bioorganic & medicinal chemistry letters
[Show abstract][Hide abstract] ABSTRACT: Substrate analog peptides of CaMKII with varying degrees of the inhibitory potency were linked to ATPgammaS either by considering a phosphoryl transfer mechanism or simply by using a relatively long flexible linker. The latter bisubstrate inhibitors showed relatively little effects while the former ones improved inhibitory potency to different levels depending on the binding affinities of the peptide moieties. One of the mechanism-based bisubstrate inhibitors was then utilized to demonstrate an ATP-competitive but peptide substrate-uncompetitive inhibition, supporting an ordered binding mechanism for CaMKII.
No preview · Article · Feb 2007 · Bioorganic & Medicinal Chemistry Letters