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Zhang Y.,Shandong University | Zhang Y.,Baoshan Hospital of Integrated Traditional Chinese and Western Medicine | Zhang B.-C.,Shandong University | Xu J.,Shandong University | And 7 more authors.
Acta pharmacologica Sinica | Year: 2016

AIM: The eicosanoids derived from phospholipids play key roles in inflammation. However, the profiles of serum eicosanoids in subclinical hypothyroidism (SH) patients and the effects of thyroxine replacement therapy (TRT) on these eicosanoids remain unclear. Many studies show that TSH regulates lipid metabolism. As eicosanoids derived from phospholipids play key roles in oxidative stress and immune function and inflammatory process, it was necessary to explore the profiles of serum eicosanoids in SH patients and the effects of thyroxine replacement therapy (TRT) on the eicosanoids.METHODS: A total of 50 Chinese SH patients and 22 healthy volunteers were recruited. SH patients received TRT (L-T4, 25 and 50 mcg/d for patients with TSH≤10.0 mIU/L and TSH>10.0 mIU/L, respectively) for 3 months. Serum levels of major eicosanoids and cPLA2 were analyzed using LC-MS and clinical biochemical assays.RESULTS: The serum levels of cPLA2, eicosanoids (8-isoPGF2a, 11-dehydroTXB2 and 12-HETE) and 11-dehydroTXB2/6-Keto-PGF1a were significantly elevated in SH patients. The serum TSH levels were significantly correlated with the levels of cPLA2 (r=+0.65), 11-dehydroTXB2 (r=+0.32) and 11-dehydroTXB2/6-Keto-PGF1a (r=+0.37). After 3-month TRT, the serum levels of TSH, cPLA2 and the above-mentioned eicosanoids in SH patients were significantly decreased.CONCLUSION: The metabolism of eicosanoids is significantly altered in Chinese SH patients, and TRT can ameliorate the abnormalities of serum eicosanoid levels.


PubMed | Henan Province Peoples Hospital, The Key Laboratory of Cardiovascular Remodeling and Function Research and Luoyang Orthopedic Traumatological Hospital
Type: Journal Article | Journal: International journal of environmental research and public health | Year: 2015

In this study, a multiple linear regression model to evaluate the risk of morbidity and mortality of ischemic cardiovascular disease is demonstrated. In this model, predictor variables are selected from physiological chemicals in a blood test of the subjects. Meanwhile, the calculated risk score is selected as a response variable. Four major latent variables including hepatic, nephric, metabolic, and BMI (Body Mass Index) are revealed by performing statistical and principal component analysis for the collected survey data. The analyzed result also shows that the cardiac disorder is correlated with symptoms of abnormal BMI, hepatic disorder, nephric disorder, and metabolic disorder. Thus, the risk of morbidity and mortality of ischemic cardiovascular disease can be assessed from the proposed multiple regression model.


Xing Y.,The Key Laboratory of Cardiovascular Remodeling and Function Research | Yan F.,The Key Laboratory of Cardiovascular Remodeling and Function Research | Liu Y.,The Key Laboratory of Cardiovascular Remodeling and Function Research | Liu Y.,Shandong University | Zhao Y.,The Key Laboratory of Cardiovascular Remodeling and Function Research
Biochemical and Biophysical Research Communications | Year: 2010

In this study, we examined whether matrine could inhibit the differentiation of 3T3-L1 preadipocytes and further explored the possible inhibitory mechanisms. Evidenced by Oil Red O staining and AdipoRed assay, matrine dose-dependently inhibited lipid accumulation at concentrations of 125, 250 and 500 μg/ml. At molecular level, the expression of transcription factors, PPARγ and C/EBPα, was reduced by matrine during adipogenesis. After treatment for 6 days, the mRNA levels of adipocyte-specific genes, such as aP2, LPL, adiponectin and leptin, were also down-regulated by matrine in a dose-dependent manner. Moreover, 500 μg/ml matrine inhibited the phosphorylation of ERK1/2 at the early stage of differentiation. Our results indicate that inhibition of 3T3-L1 preadipocyte differentiation by matrine is associated with the suppression of ERK1/2 phosphorylation. Thus, matrine has the potential to be an alternative natural product for the treatment of obesity. © 2010 Elsevier Inc. All rights reserved.


Chen Y.-Q.,The Key Laboratory of Cardiovascular Remodeling and Function Research | Zhao J.,The Key Laboratory of Cardiovascular Remodeling and Function Research | Jin C.-W.,The Key Laboratory of Cardiovascular Remodeling and Function Research | Li Y.-H.,The Key Laboratory of Cardiovascular Remodeling and Function Research | And 6 more authors.
Age | Year: 2016

Testosterone deficiency is associated with a higher incidence of cardiovascular diseases in men. However, its effect on cell senescence, which plays a causal role in vascular aging, remains unclear. Here, we tested the hypothesis that testosterone alleviated vascular smooth muscle cell (VSMC) senescence and collagen synthesis via growth arrest-specific protein 6 (Gas6)/Axl- and Akt/FoxO1a-dependent pathways. Testosterone significantly ameliorated angiotensin II-induced VSMC senescence and collagen overexpression. In addition, testosterone inhibited angiotensin II-induced matrix metalloproteinase-2 (MMP-2) activity, which played a pivotal role in facilitating age-related collagen deposition. Testosterone increased the expression of tissue inhibitor of metalloproteinase-2 but decreased the expression of MMP-2 and membrane type-1 metalloproteinase which contributed to increase MMP-2 activity. The effects on VSMCs senescence and collagen synthesis were mediated by restoration of angiotensin II-induced downregulation of Gas6 and Axl expression and a subsequent reduction of Akt and FoxO1a phosphorylation. The effects of testosterone were reversed by a Gas6 blocker, Axl-Fc, and a specific inhibitor of Axl, R428. Treatment of VSMCs with PI3K inhibitor LY294002 abrogated the downregulating effect of testosterone on MMP-2 activity. Furthermore, when FoxO1a expression was silenced by using a specific siRNA, the inhibitory effect of testosterone on MMP-2 activity was revered as well, that indicated this process was Akt/FoxO1a dependence. Taken together, Gas6/Axl and Akt/FoxO1a were involved in protective effects of testosterone on VSMCs senescence and collagen synthesis. Our results provide a novel mechanism underlying the protective effect of testosterone on vascular aging and may serve as a theoretical basis for testosterone replacement therapy. © 2016, American Aging Association.


Xu F.,The Key Laboratory of Cardiovascular Remodeling and Function Research | Xu F.,Shandong University | Chen Y.G.,The Key Laboratory of Cardiovascular Remodeling and Function Research | Chen Y.G.,Shandong University | And 16 more authors.
Journal of Cellular and Molecular Medicine | Year: 2011

This study aimed to investigate the association of the aldehyde dehydrogenase 2 (ALDH2) Glu504Lys polymorphism, which exists in 30-50% of East Asians, and risk of acute coronary syndrome (ACS). We enrolled 1092 unrelated Han Chinese, including 546 with ACS and 546 age- and sex-matched controls. Subjects with ALDH2 mutant genotypes showed significantly higher ACS than did controls (46.7%versus31.9%,P< 0.001). Logistic regression analysis revealed the ALDH2 mutant independently associated with ACS (odds ratio [OR] 1.95, 95% confidence interval [CI]: 1.31-2.92,P= 0.001), but the association was weaker on adjusting for alcohol consumption (OR 1.82, 95% CI: 1.23-2.70,P= 0.003). Similar results were found in a subgroup analysis of patients with primary ST-segment elevation myocardial infarction (STEMI). The ALDH2 mutant was significantly associated with level of high-sensitivity C-reactive protein (hs-CRP) in patients with ACS (P= 0.002) and in controls (P= 0.009) and number of circulating endothelial progenitor cells (EPCs) (P= 0.032); furthermore, inclusion of hs-CRP level and EPCs number as independent variables in regression analysis reduced the importance of ALDH2 polymorphism in ACS or primary STEMI. However, ALDH2 polymorphism was not associated with number of coronary arteries with significant stenosis, Gensini score or flow-mediated dilation of the brachial artery. Our results suggest that ALDH2 mutation is a genetic risk marker for ACS, which is explained in part by alcohol consumption, inflammation and number of circulating EPCs. © 2011 The Authors Journal compilation © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.


Yang J.,Shandong University | Yang J.,The Key Laboratory of Cardiovascular Remodeling and Function Research | Yu Y.,Shandong University | Yu H.,Shandong University | And 5 more authors.
European Journal of Pain | Year: 2010

Previous studies suggested that brain-derived neurotrophic factor (BDNF) might act as an important modulator in chronic pain states. However, no systematic study has used knock-out mice to clarify its effect on visceral sensitivity. In the present study, 2,4,6-trinitrobenzene sulfonic acid (TNBS) was administered to heterozygous (BDNF+/-) knock-out and wild-type (BDNF+/+) mice to induce colitis. Visceral response to colorectal distension (CRD) and bladder reactivity were recorded. Results demonstrated that in normal state, BDNF+/- and BDNF+/+ mice did not differ in the visceral response to CRD at <60 mm Hg pressure and the bladder reactivity; however, with ≥60 mm Hg pressure, BDNF+/- mice showed a weaker visceral response to CRD. In inflammatory state of colitis, TNBS induced upregulation of BDNF in dorsal root ganglia of both genotypes while BDNF+/- mice showing significantly lower sensitivity in the colon at ≥30 mm Hg and lower sensitivity in bladder than BDNF+/+ mice. The two genotypes showed no significant difference in inflammatory severity. Thus, BDNF deficiency results in developmental changes in colonic nociception in both control and inflammatory states, which are more significant in inflammatory state. For bladder reactivity, BDNF deficiency leads to lower sensitization in inflammatory state but has no effect in control state. Perspective: This article highlights the role of BDNF in colonic and referred bladder hyperalgesia in mice. The findings might help in determining novel pharmaceutical interventions targeted at BDNF to relieve abdominal pain. © 2009 European Federation of International Association for the Study of Pain Chapters.


Li T.,The Key Laboratory of Cardiovascular Remodeling and Function Research | Chen W.,The Key Laboratory of Cardiovascular Remodeling and Function Research | An F.,The Key Laboratory of Cardiovascular Remodeling and Function Research | Tian H.,Shandong University | And 4 more authors.
Tohoku Journal of Experimental Medicine | Year: 2011

Probucol, a lipid-lowering agent with anti-oxidant properties, has been implicated in protection against atherogenesis, whereas its effect on plaques stability remains to be fully elucidated. The present study was aimed to test the hypothesis that probucol may attenuate inflammation and increase stability of vulnerable atherosclerotic plaques using a rabbit model. After abdominal aortic balloon injury, 45 rabbits were fed a 1% cholesterol diet for 24 weeks. From week 12 to week 24, the animals were treated with probucol (1% by weight in the diet), simvastatin (5 mg·kg -1, positive control) or no drugs (control), respectively. At the end of week 22, recombinant-p53 adenovirus was injected into the abdominal aortic plaques. Two weeks later, plaque disruption was induced by injection of Chinese Russell's viper venom and histamine. The results showed that the incidence of plaque disruption in probucol or simvastatin groups was significantly lower than that in the control group (7.15% or 14.29% vs. 71.43% respectively, both P < 0.01). Probucol significantly increased the thickness of fibrous caps and decreased plaque vulnerability index. Serum concentrations of inflammatory cytokines and matrix metalloproteinases, and expression levels of Toll-like receptor (TLR)-2, TLR-4, monocyte chemoattractant protein-1, intercellular adhesion molecule 1, scavenger receptor A, CD36 and oxidized low-density lipoprotein receptor 1 within the lesions were markedly lower in both treatment groups than in the control group. We conclude that probucol increases the stability of vulnerable plaques, possibly through its lipid lowering, anti-inflammation and scavenger receptors suppression effects, suggesting probucol as a promising pharmacologic approach to stabilize vulnerable plaques. © 2011 Tohoku University Medical Press.


PubMed | Shandong University and The Key Laboratory of Cardiovascular Remodeling and Function Research
Type: Journal Article | Journal: Journal of translational medicine | Year: 2016

Trimetazidine, as an anti-ischemic and antioxidant agent, has been demonstrated to have many cardioprotective effects. However, whether early administration of trimetazidine has an effect on diabetic cardiomyopathy and the mechanisms underlying the effect have not yet been elucidated.We established a type 2 DCM rat model by high-fat diet and low-dose streptozotocin. Rats were separated into different groups: control, diabetes, and diabetes+trimetazidine (n=6, each). Cardiac autophagy, cardiac functions, and cardiomyocyte apoptosis were monitored.Rats with type 2 DCM showed severe insulin resistance, left ventricular dysfunction, increased cardiomyocyte apoptosis, and reduced cardiac autophagy. Collagen volume fraction (CVF) and perivascular collagen area/luminal area (PVCA/LA) ratio were significantly higher in the diabetic group than the control group. We found that trimetazidine treatment ameliorated metabolic disturbance and insulin resistance, reduced cardiomyocyte apoptosis, and restored cardiac autophagy. CVF and PVCA/LA ratio were also lower in the diabetes+trimetazidine group than the diabetic group (CVF, 4.750.52% vs. 11.041.67%, p<0.05; PVCA/LA, 8.370.51 vs. 17.972.66, p<0.05). Furthermore, trimetazidine inhibited phosphorylation of ERK and P38 MAPK to reduce myocardial fibrosis. Inhibited phosphorylation of AMPK was restored and the interaction between Bcl-2 and Beclin1 was enhanced in diabetes+trimetazidine group, resulting in the initiation of autophagy and alleviation of apoptosis.Early administration of trimetazidine could ameliorate diabetic cardiomyopathy by inhibiting myocardial fibrosis and cardiomyocyte apoptosis and enhancing autophagy. Therefore, trimetazidine may be a good choice in the prevention of diabetic cardiomyopathy if applied at the early stage of diabetes.

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