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Hetrombopag, a Thrombopoietin Receptor Agonist, Protects Cardiomyocyte Survival from Oxidative Stress Damage as an Enhancer of Stem Cells
Zhou, NN;Wang, JC;Li, XD;Zhao, Y;Sun, YY;Zou, CW
CARDIOVASCULAR DRUGS AND THERAPY 2016年 30卷6期 页码:567-577
UMBILICAL-CORD BLOOD; ACUTE MYOCARDIAL-INFARCTION; MONONUCLEAR-CELLS; ADULT RECIPIENTS; AKR-501 YM477; TRANSPLANTATION; ELTROMBOPAG; HEMATOPOIESIS; AKT; EXPANSION
Current human umbilical cord blood stem cell therapy faces the great challenges, because the stem cells are scarce and cannot survive for a long time. Here we describe how hetrombopag, an orally-active TPO receptor agonists, enhanced ex vivo expansion of human UCB stem cells, and protected cardiac myocytes from the damage caused by oxidative stress.;-;Ex vivo expansion of stem cells were performed in serum-free medium supplemented with rhSCF and rhFL plus hetrombopag for 7 days. The percentage and number of stem cell subsets were determined by flow cytometry. Rat cardiac myocytes, ex vivo expanded stem cells, or cardiac myocytes plus ex vivo expanded stem cells were serum starved for 24 hours, and were then subjected to H2O2, hetrombopag or both for 12 hours at the indicated concentrations. Cell viability assays, protein microarrays and western blots were then performed in each group.;-;Our studies first revealed that the combination of hetrombopag and rhTPO manifested additive effect on ex vivo expansion of human UCB stem cells. Besides, hetrombopag dose-dependently enhanced the beneficial effects of ex vivo expanded human UCB MNCs in increasing the survival of injured cardiomyocytes during free oxygen radical stress.;-;These data, for the first time, uncovered a novel function of non-peptide small molecular TPO receptor agonists as enhancers of stem cells in protecting cardiac myocyte survival from oxidative stress damage, which might provide a new therapeutic avenue for the treatment of oxidative stress-related cardiovascular disease.
Effect of bedtime administration of blood-pressure lowering agents on ambulatory blood pressure monitoring results: A meta-analysis
Sun, YY;Yu, X;Liu, JN;Zhou, NN;Chen, LM;Zhao, Y;Li, XD;Wang, JC;Cui, LQ
CARDIOLOGY JOURNAL 2016年 23卷4期 页码:473-481
ESSENTIAL-HYPERTENSION; TIME; CHRONOTHERAPY; GUIDELINES; MANAGEMENT; THERAPY; SOCIETY; PATTERN; RISK
Background: Bedtime administration of antihypertensive drugs currently receives more attention, but no clear consensus has been reached on the blood pressure (BP)-lowering effect of this strategy.;-;Methods: We systematically searched literature for clinical trials of ingestion time of antihypertensive drugs evaluated by ambulatory blood pressure monitoring (ABPM) to perform a meta-analysis which aimed at determining the difference in diurnal, nocturnal, and 24-h mean of systolic BP (SBP) and diastolic BP (DBP), absolute BP reduction from baseline between bedtime administration group (experimental group) and morning (awaking) administration group (control group).;-;Results: The synthesis analysis showed that the level of BP in bedtime administration group was lower than the morning administration group, which reduced diurnal SBP/DBP by 1.67/1.13 mm Hg (p = 0.36/0.48), 24-h SBP/DBP by 2.78/0.36 mm Hg (p = 0.09/0.62), nocturnal SBP/DBP by 6.32/3.17 mm Hg (p = 0.03/0.007). Furthermore, there was lack of statistically significant differences in the diurnal mean of SBP/DBP reduction from baseline between the two groups (p = 0.94/0.85), but bedtime administration resulted in significant reduction from baseline in the nocturnal mean of SBP/DBP, by -4.72/-3.57 mm Hg (p = 0.01/0.05). Funnel plot demonstrated that there was no evidence of publication bias.;-;Conclusions: Administration of >= 1 antihypertensive drugs at bedtime or evening results in a greater reduction of nocturnal hypertension than dosing in the morning without loss of efficacy of diurnal and 24 h mean BP reduction.
Calpain-Calcineurin-Nuclear Factor Signaling and the Development of Atrial Fibrillation in Patients with Valvular Heart Disease and Diabetes
Zhao, Y;Cui, GM;Zhou, NN;Li, C;Zhang, Q;Sun, H;Han, B;Zou, CW;Wang, LJ;Li, XD;Wang, JC
JOURNAL OF DIABETES RESEARCH 2016年
ACTIVATION; HYPERTROPHY; FAILURE; PROTEOLYSIS; MYOCARDIUM; PROGNOSIS; PATHWAY
Calpain, calcineurin (CaN), and nuclear factor of activated T cell (NFAT) play a key role in the development of atrial fibrillation. Patients with valvular heart disease (VHD) are prone to develop atrial fibrillation (AF). Thus, our current study was aimed at investigating whether activation of calpain-CaN-NFAT pathway is associated with the incidence of AF in the patients with VHD and diabetes. The expressions of calpain 2 and alpha-and beta-isoforms of CaN catalytic subunit (CnA) as well as NFAT-c3 and NFAT-c4 were quantified by quantitative reverse transcription-polymerase chain reaction in atrial tissues from 77 hospitalized patients with VHD and diabetes. The relevant protein content was measured by Western blot and calpain 2 in human atrium was localized by immunohistochemistry. We found that the expressions of calpain 2, CnA alpha and CnA beta, and NFAT-c3 but not NFAT-c4 were significantly elevated in the samples from patients with AF compared to those with sinus rhythm (SR). Elevated protein levels of calpain 2 and CnA were observed in patients with AF, and so was the enhanced localization of calpain 2. We thereby concluded that CaN together with its upstream molecule, calpain 2, and its downstream effector, NFAT-c3, might contribute to the development of AF in patients with VHD and diabetes.
Ideal cardiovascular health behaviors and factors prevent the development of hypertension in prehypertensive subjects
Gao, JS;Sun, H;Liang, X;Gao, M;Zhao, HT;Qi, YH;Wang, YX;Liu, Y;Li, JF;Zhu, Y;Zhao, Y;Wang, W;Ma, LY;Wu, SL
CLINICAL AND EXPERIMENTAL HYPERTENSION 2015年 37卷8期 页码:650-655
LIAONING PROVINCE; PREVALENCE; PREDICTORS; RISK; ASSOCIATION; PROGRESSION; POPULATION; COHORT
Background: Seven ideal health metrics were defined by AHA to monitor cardiovascular health. This study aimed to investigate the impact of ideal cardiovascular health behaviors and factors on the development of hypertension in prehypertensive subjects. Methods: Thirty-two thousand eight-hundred and eighty-seven participants with prehypertension were included in the study after excluding for preexisting stroke, myocardial infarction or malignancy. Cox proportional hazards regression was used to calculate hazard ratios and 95% confidence intervals [CI] for the development of hypertension. Results: During a follow-up of 52.2 months, 15500 prehypertensive participants developed hypertension. The cumulative incidence of hypertension decreased with the number of ideal health metrics increased. It was 78.61%, 71.08%, 63.15%, 56.07% and 61.62% in prehypertensive individuals carrying 1, 2, 3, 4 and 5 ideal health behaviors or factors, respectively. After adjustment for age, gender, family history of hypertension, alcohol consumption, resting heart rate, plasma triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein, the risk ratios of incident hypertension in the subjects who carried 2, 3, 4, and 5 ideal health metrics were 0.833 (95%CI: 0.789-0.880), 0.710 (95%CI: 0.672-0.749), 0.604 (95%CI: 0.568-0.642), and 0.581 (95%CI: 0.524-0.643), respectively, in comparison to those with 1 ideal health metric. A similar trend was also observed in male and female populations. Poor health metrics, including body mass index, diet (salt intake), physical activity, total cholesterol, and smoking, were predictors for the development of hypertension in prehypertensive individuals. Conclusion: Ideal cardiovascular health behaviors and factors are protective factors to prevent the progression from prehypertension to hypertension.
Valsartan blocks thrombospondin/transforming growth factor/Smads to inhibit aortic remodeling in diabetic rats
Sun, H;Zhao, Y;Bi, XP;Li, SH;Su, GH;Miao, Y;Ma, X;Zhang, Y;Zhang, W;Zhong, M
DIAGNOSTIC PATHOLOGY 2015年 10卷
EXTRACELLULAR-MATRIX PRODUCTION; BLOOD-PRESSURE CONTROL; HUMAN MESANGIAL CELLS; TGF-BETA; ANGIOTENSIN-II; CARDIOVASCULAR OUTCOMES; MICROVASCULAR OUTCOMES; RANDOMIZED-TRIAL; VESSEL WALL; THROMBOSPONDIN-1
Background: Angiotensin II (Ang II) and transforming growth factor beta (TGF beta) are closely involved in the pathogenesis of diabetic complications. We aimed to determine whether an aberrant thrombospondin 1 (TSP1)-mediated TGF beta 1/Smads signaling pathway specifically affects vascular fibrosis in diabetic rats and whether valsartan, an Ang II subtype 1 receptor blocker, has an anti-fibrotic effect.;-;Methods: Age-matched male Wistar rats were randomly divided into 3 groups: control (n = 8), diabetes (n = 16) and valsartan (30 mg/kg/day) (n = 16). Type 2 diabetes mellitus (T2DM) was induced by a high-calorie diet and streptozotocin injection. Morphological and biomechanical properties of the thoracic aorta were assessed by echocardiography and cardiac catheterization. Masson staining was used for histological evaluation of extracellular matrix (ECM). The expression of components in the TSP1-mediated TGF beta 1/Smads signaling pathway was analyzed by immunohistochemistry and real-time quantitative reverse transcription polymerase chain reaction.;-;Results: As compared with controls, diabetic aortas showed reduced distensibility and compliance, with excess ECM deposition. Components in the TSP1-mediated TGF beta 1/Smads signaling pathway, including TSP1, TGF beta 1, TGF beta type II receptor (T beta RII), Smad2 and Smad3, were accumulated in vascular smooth muscle cytoplasm of diabetic aortas and their protein and mRNA levels were upregulated. All these abnormalities were attenuated by valsartan.;-;Conclusions: TSP1-mediated TGF beta 1/Smads pathway activation plays an important role in marcovascular remodeling in T2DM in rat. Valsartan can block the pathway and ameliorate vascular fibrosis.
Influence of diabetes on cardiac resynchronization therapy in heart failure patients: a meta-analysis
Sun, H;Guan, YQ;Wang, L;Zhao, Y;Lv, H;Bi, XP;Wang, HT;Zhang, XJ;Liu, L;Wei, M;Song, H;Su, GH
BMC CARDIOVASCULAR DISORDERS 2015年 15卷
MORTALITY; ETIOLOGY; MELLITUS; EPIDEMIOLOGY; IMPROVEMENT; PREDICTORS; ACTIVATION; MORBIDITY; MIRACLE; TRIAL
Background: Diabetes mellitus is an independent risk factor of increased morbidity and mortality in patients with heart failure. Cardiac resynchronization therapy (CRT), a pacemaker-based therapy for dyssynchronous heart failure, improves cardiac performance and quality of life, but its effect on mortality in patients with diabetes is uncertain.;-;Methods: We performed a meta-analysis of results from randomized controlled trials (RCTs) of the long-term outcome of cardiac resynchronization therapy for heart failure in diabetic and non-diabetic patients. Literature search of MEDLINE via Pubmed for reports of randomized controlled trials of Cardiac resynchronization for chronic symptomatic left-ventricular dysfunction in patients with and without diabetes mellitus, with death as the outcome. Relevant data were analyzed by use of a random-effects model. Reports published from 1994 to 2011 that described RCTs of CRT for treating chronic symptomatic left ventricular dysfunction in patients with and without diabetes, with all-cause mortality as an outcome.;-;Results: A total of 5 randomized controlled trials met the inclusion criteria, for 2,923 patients. The quality of studies was good to moderate. Cardiac resynchronization significantly reduced the mortality for heart failure patients with or without diabetes mellitus. Mortality was 24.3% for diabetic patients with heart failure and 20.4 % for non-diabetics (odds ratio 1.28, 95% confidence interval 1.06-1.55; P = 0.010).;-;Conclusions: Cardiac resynchronization therapy (CRT) may reduce mortality from progressive heart failure in patients with or without diabetes mellitus, but mortality may be higher for patients with than without diabetes after CRT for heart failure.
Association between Phosphatase Related Gene Variants and Coronary Artery Disease: Case-Control Study and Meta-Analysis
Han, X;Zhang, LJ;Zhang, ZQ;Zhang, ZT;Wang, JC;Yang, J;Niu, JM
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 2014年 15卷8期 页码:14058-14076
PROTEIN-TYROSINE PHOSPHATASES; GENOME-WIDE ASSOCIATION; HEART-DISEASE; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; CHINESE POPULATION; MUTATION ANALYSIS; NOONAN-SYNDROME; GASTRIC-CANCER; HAN CHINESE
Recent studies showed that the serum alkaline phosphatase is an independent predictor of the coronary artery disease (CAD). In this work, we aimed to summarize the association between three phosphatase related single nucleotide polymorphisms (rs12526453, rs11066301 and rs3828329) and the risk of CAD in Han Chinese. Our results showed that the rs3828329 of the ACP1 gene was closely related to the risk of CAD in Han Chinese (OR = 1.45, p = 0.0006). This significant association of rs3828329 with CAD was only found in the females (Additive model: OR = 1.80, p = 0.001; dominant model: OR = 1.69, p = 0.03; recessive model: OR = 1.96, p = 0.0008). Moreover, rs3828329 was likely to exert its effect in females aged 65 years and older (OR = 2.27, p = 0.001). Further meta-analyses showed that the rs12526453 of PHACTR11 gene (OR = 1.14, p < 0.0001, random-effect method) and the rs11066301 of PTPN11 gene (OR = 1.15, p < 0.0001, fixed-effects method) were associated with CAD risk in multiple populations. Our results showed that the polymorphisms rs12526453 and rs11066301 are significantly associated with the CAD risk in multiple populations. The rs3828329 of ACP1 gene is also a risk factor of CAD in Han Chinese females aged 65 years and older.
Adiponectin Receptor 1 (ADIPOR1) rs1342387 Polymorphism and Risk of Cancer: a Meta-analysis
Yu, LX;Zhou, NN;Liu, LY;Wang, F;Ma, ZB;Li, J;Yu, ZG
ASIAN PACIFIC JOURNAL OF CANCER PREVENTION 2014年 15卷18期 页码:7515-7520
COLORECTAL-CANCER; GENETIC-VARIATIONS; PROSTATE-CANCER; GASTRIC-CANCER; OBESITY; PATHWAY; ADIPOKINES; EXPRESSION; VARIANTS; BIAS
Many studies have indicated possible associations between a polymorphism of adiponectin receptor 1 (ADIPOR1) rs1342387 and risk of cancer, but contradictory results have been reported. The main aim of this study was to draw a reliable conclusion about the relationship between the rs1342387 polymorphism and cancer incidence, by conducting a literature search of Pubmed, Embase, Wanfang and Cochrane libraries. Eleven studies including 3, 738 cases and 4, 748 controls were identified in this meta-analysis. The ADIPOR1 rs1342387 polymorphism was associated with risk of colorectal cancer for all genetic comparison models (GG vs AA, OR: 1.44, 95% CI: 1.21 - 1.70; G carriers vs A carriers, OR: 1.23, 95% CI: 1.11 - 1.36; dominant model, OR: 1.28, 95% CI: 1.10 - 1.49 and recessive model, OR: 1.31, 95% CI: 1.12 - 1.55). Stratified by ethnicity, the rs1342387 polymorphism was significantly associated with risk of colorectal cancer in Asian ancestry for all genetic comparison models (GG vs AA, OR: 1.56, 95% CI: 1.26- 1.92; G carriers vs. A carriers OR: 1.30, 95% CI: 1.18 - 1.43; dominant model OR: 1.31, 95% CI: 1.08 - 1.60 and recessive model OR: 1.44, 95% CI: 1.26 - 1.64), but not in Caucasian or mixed (Caucasian mainly) groups. In summary, the ADIPOR1 rs1342387 polymorphism is significantly associated with risk of colorectal cancer among individuals of Asian ancestry.
Trends in Hypertension Prevalence, Awareness, Treatment, and Control Rates in Shandong Province of China
Zhao, Y;Lu, FH;Sun, H;Liu, ZD;Zhao, YX;Sun, SW;Wang, SJ;Diao, YT;Zhang, H
JOURNAL OF CLINICAL HYPERTENSION 2012年 14卷9期 页码:637-643
BLOOD-PRESSURE; CARDIOVASCULAR-DISEASE; GLOBAL BURDEN; HEALTH; POPULATION; RISK; PREVENTION; GUIDELINES; MANAGEMENT; TRIALS
J Clin Hypertens (Greenwich). 2012; 14:637643. (c) 2012 Wiley Periodicals, Inc. The authors retrospectively examined data from 3 surveys on hypertension according to the 2010 Chinese Guidelines for the Management of Hypertension. These surveys were conducted in 1991, 1999, and 2007, and included 85,371 individuals 18 years and older who were living in Shandong Province, China. Age-standardized prevalent hypertension increased from 15.6% in 1991 to 17.3% in 1999 and 32.7% in 2007 (both P<.0001). The ascending prevalence can be partially explained by increasing body weight. Among individuals with hypertension, awareness increased significantly from 27.8% in 1991 to 39.1% in 1999 and 49.2% in 2007. The proportion of pharmacologic treatment also considerably improved, with the estimate of 12.9%, 28.1%, and 43.3% in the 3 surveys, respectively. Hypertension control increased from 3.0% to 4.4% to 7.1% in the past 20 years. The upward trend in blood pressure control was mostly attributable to a rise among men and persons at middle age. This study suggests that the prevalence of hypertension increased in the Shandong population from 1991 to 2007. Although substantially improved, control rates were still unacceptably low. Comprehensive strategies are urgently required to put into practice for the management of hypertension in Shandong Province, China.
A 48-week study of amlodipine plus amiloride/hydrochlorothiazide vs. amlodipine plus telmisartan in the treatment of hypertension
Lu, F;Zhao, Y;Liu, Z;Sun, H;Zhao, Y;Sun, S;Wang, S
INTERNATIONAL JOURNAL OF CLINICAL PRACTICE 2012年 66卷8期 页码:792-799
BLOOD-PRESSURE CONTROL; SUBCUTANEOUS TISSUE PRESSURE; TYPE-2 DIABETES-MELLITUS; OLMESARTAN MEDOXOMIL; DOUBLE-BLIND; CARDIOVASCULAR OUTCOMES; PARALLEL-GROUP; ANKLE EDEMA; OPEN-LABEL; COMBINATION
Background: Chinese Hypertension Intervention Efficacy (CHIEF) study is a large-scale randomised clinical trial across China, which compares the efficacy of two combination regimens in reducing cardiovascular events associated with hypertension. Methods: We reported the 48-week efficacy and tolerability of the two antihypertensive regimens in participants from Shandong Province, China. Eligible patients aged 5079 years were randomised to receive amlodipine plus amiloride/hydrochlorothiazide (Group A) or amlodipine plus telmisartan (Group B). The doses of both regimens were titrated and other antihypertensive agents were added subsequently to achieve a blood pressure (BP) goal (<140/90 mmHg for general population, <130/80 mmHg for diabetics and <150/90 mmHg for elderly). Efficacy variables included the changes of BP, control rates (the proportion of patients achieving a BP goal), and response rates (the proportion of patients achieving a BP goal or a reduction of BP =20/10 mmHg). Safety was assessed by monitoring the incidence of adverse events (AEs). Results: Of the 349 patients enrolled, 314 were randomised and 291 completed the study (141 in Group A and 150 in Group B). At week 48, the BP was reduced by 28.77/15.55 mmHg in Group A and by 31.38/16.07 mmHg in Group B (p > 0.05 for comparisons between Group A and Group B). The control rates (71.79% vs. 77.22%; p = 0.270) and response rates (79.49% vs. 84.81%; p = 0.218) were also similar. For both regimens, the control rates in diabetic patients were relatively lower (31.91% and 32.50%), while those in elderly patients were pretty higher (90.74% and 97.62%). AEs were mild to moderate in severity (17.95% vs. 12.66%, p = 0.193). Conclusion: Both combination regimens, amlodipine plus amiloride/hydrochlorothiazide and amlodipine plus telmisartan, were effective and safe for the high-risk hypertensive patients.
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