Valsartan Attenuates Atherosclerosis via Upregulating the Th2 Immune Response in Prolonged Angiotensin II-Treated ApoE(-/-) Mice.

Valsartan has a protective effect against hypertension and atherosclerosis in humans and experimental animal models. This study aimed to determine the effect of prolonged treatment with angiotensin II (Ang II) on atherosclerosis and the effect of valsartan on the activity of CD4(+) T lymphocyte subsets. The results showed that prolonged treatment (8 wks) with exogenous Ang II resulted in an increased atherosclerotic plaque size and a switch of stable-to-unstable plaque via modulating on CD4(+) T lymphocyte activity, including an increase in the T helper cell type 1 (Th1) and Th17 cells and a decrease in Th2 and regulatory T (Treg) cells. In contrast, valsartan treatment efficiently reversed the imbalance in CD4(+) T lymphocyte activity, ameliorated atherosclerosis and elicited a stable plaque phenotype in addition to controlling blood pressure. In addition, treatment with anti-interleukin (IL)-5 monoclonal antibodies weakened the antiatherosclerotic effects of valsartan without affecting blood pressure.

Correlations of SELE genetic polymorphisms with risk of coronary heart disease and myocardial infarction: a meta-analysis.

This meta-analysis of case-control studies was conducted to determine whether SELE genetic polymorphisms contribute to the pathogenesis of coronary heart disease (CHD) and myocardial infarction (MI). The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched for relevant articles published before November 1st, 2013 without any language restrictions. Meta-analysis was conducted using the STATA 12.0 software. Twenty case-control studies met the inclusion criteria, with a total of 2,292 CHD patients, 901 MI patients and 3,233 healthy controls. Six common polymorphisms in the SELE gene were evaluated, including 554L/F, 98G/T, 128S/R, 2692G/A, 1901C/T, and 1856A/G. The results of our meta-analysis suggest that SELE genetic polymorphisms might be strongly correlated with an increased risk of CHD (allele model: OR 2.08, 95% CI 1.67-2.58, P<0.001; dominant model: OR 2.12, 95% CI 1.68-2.68, P<0.001; respectively), especially the SELE 554L/F, 98G/T and 128S/R polymorphisms. Furthermore, our findings indicated that SELE genetic polymorphisms were closely linked to the risk of CHD in Asians but not Caucasians. However, our findings reveal no positive correlations between SELE genetic polymorphisms and MI risk (allele model: OR 1.39, 95% CI 1.00-1.94, P=0.054; dominant model: OR 1.40, 95% CI 0.96-2.04, P=0.081; respectively). The current meta-analysis suggests that SELE genetic polymorphisms may contribute to an increased risk of CHD, especially the SELE 554L/F, 98G/T and 128S/R polymorphisms in Asians. However, SELE genetic polymorphisms may not be important determinants of susceptibility to MI.

The role of cystatin C in vascular remodeling of balloon-injured abdominal aorta of rabbits.

This study aimed to evaluate the role of cystatin C (CysC) in the vascular remodeling of balloon-injured abdominal aorta of rabbits. Forty-eight New Zealand white rabbits were randomly divided into three groups: the balloon-injured injury group (n = 16), the CysC monoclonal antibody group (n = 16), and the sham-operative group (n = 16). Serum CysC levels were detected by enzyme linked immunosorbent assay. Changes in adventitial area, adventitial thickness, lumen area (LA), neointimal area (IA), internal elastic lamina area (IELA), external elastic lamina area (EELA), vascular remodeling index (VRI) and residual stenosis (RS) were measured by the Leica image analysis system. Immunohistochemical analysis of α-smooth muscle actin (α-SMA) and proliferating cell nuclear antigen (PCNA) were performed. Serum CysC levels of rabbits in the balloon-injured injury group were significantly higher than those in the CysC monoclonal antibody group and the sham-operative group (both P < 0.05). At 6 weeks after balloon injury, the adventitial area and thickness, LA, IA, IELA and EELA in the balloon-injured injury group were also higher than those in the CysC monoclonal antibody and sham-operative groups (all P < 0.05). In addition, the balloon-injured injury group showed higher VRI and RS than those of the CysC monoclonal antibody group (both P < 0.05). The positive expression of α-SMA in the vascular adventitia and media in the balloon-injured group were higher than that of the CysC monoclonal antibody and sham-operative groups. The balloon-injured group also showed a stronger expression of α-SMA in the neointima than that of the CysC monoclonal antibody group. There was a strong positive expression of PCNA in the vascular adventitia and neointima in the balloon-injured and CysC monoclonal antibody groups. However, the number of PCNA-positive cells in the balloon-injured group was higher than that of the CysC monoclonal antibody group (25.45 ± 4.21 vs. 6.75 ± 1.11, P = 0.003). Our findings provide empirical evidence that serum CysC levels may play an important role in the vascular remodeling of balloon-injured abdominal aorta of rabbits.

Acute myocardial infarction therapy using calycosin and tanshinone co-loaded mitochondria targeted lipid-polymer hybrid nano-system: Preparation, characterization, and anti myocardial infarction activity assessment.

BACKGROUND: Acute myocardial infarction (AMI) is one of the most common ischemic heart diseases. However, lack of sufficient drug concentrations in the ischemic heart may led to treatment failure. It is urgent for researchers to engineer novel drug delivery systems to enhance the targeted delivery of cardioprotective agents. OBJECTIVE: The aim of the present study was to investigate the anti-AMI ability of calycosin (CAL) and tanshinone (TAN) co-loaded mitochondria targeted lipid-polymer hybrid nano-system. METHODS: CAL and TAN combined lipid-polymer hybrid nano-systems were prepared and MTP-131 was conjugated with PEG and modified onto the nanoparticles to achieve MTP-CAL/TAN NS. The physicochemical properties of nano-systems were characterized, the AMI therapy ability of the systems was investigated in AMI rats' model. RESULTS: The size of MTP-CAL/TAN NS was 168.7 ±â€¯5.1 nm, with a surface charge of - 21.3 ±â€¯2.3 mV. The area under the curve (AUC) and blood circulation half-life (T1/2) of MTP-CAL/TAN NS was 178.86 ±â€¯6.62 µg·min/mL and 0.47 h, respectively. MTP-CAL/TAN NS exhibited the most significant infarct size reduction effect of 23.9 %. CONCLUSION: MTP-CAL/TAN NS exhibited the highest heart accumulation and best infarct size reduction effect, which could be used as a promising system for efficient treatment of cardiovascular diseases.

Prostate Cancer Therapy Using Docetaxel and Formononetin Combination: Hyaluronic Acid and Epidermal Growth Factor Receptor Targeted Peptide Dual Ligands Modified Binary Nanoparticles to Facilitate the in vivo Anti-Tumor Activity.

Objective: To evaluate the prostate cancer therapy efficiency of the synergistic combination docetaxel (DTX) and formononetin (FMN) in one nano-sized drug delivery system. Hyaluronic acid (HA) and epidermal growth factor receptor-targeted peptide (GE11) dual ligands were applied to modify the nano-systems. Methods: In this study, GE11-modified nanoparticles (GE-NPs) were applied for the loading of DTX, and HA-decorated NPs (HA-NPs) were used to encapsulate FMN. HA and GE11 dual ligand-modified binary nanoparticles (HAGE-DTX/FMN-NPs) were constructed by the self-assembling of GE-NPs and HA-NPs. The anti-PCa ability of the system was evaluated in vitro on PC-3 human prostate carcinoma cells (PC3 cells) and in vivo on PC3 tumor-bearing mice in comparison with single NPs and free drugs formulations. Results: HA/GE-DTX/FMN-NPs were nano-sized particles with smaller particles coating on the inner core and achieved a size of 189.5 nm. HA/GE-DTX/FMN-NPs showed a cellular uptake efficiency of 59.6%, and a more efficient inhibition effect on PC3 cells compared with single ligand-modified NPs and free drugs. HA/GE-DTX/FMN-NPs showed significantly higher tumor inhibition efficiency than their single drug-loaded counterparts and free drugs. Conclusion: HA/GE-DTX/FMN-NPs have a synergistic anti-tumor effect and also could the reduce unexpected side effects during the cancer therapy. It could be used as a promising anti-PCa system.

Acute myocardial infarction therapy using calycosin and tanshinone co-loaded; mitochondrion-targeted tetrapeptide and cyclic arginyl-glycyl-aspartic acid peptide co-modified lipid-polymer hybrid nano-system: preparation, characterization, and anti myocardial infarction activity assessment.

Acute myocardial infarction (AMI) is one of the most common ischemic heart diseases. However, lack of sufficient drug concentration (in the ischemic heart) is the major factor of treatment failure. It is urgent for researchers to engineer novel drug delivery systems to enhance the targeted delivery of cardioprotective agents. The aim of the present study was to investigate the anti-AMI ability of calycosin (CAL) and tanshinone (TAN) co-loaded; mitochondrion-targeted tetrapeptide (MTP) and cyclic arginyl-glycyl-aspartic acid (RGD) peptide co-modified nano-system.: We prepared CAL and TAN combined lipid-polymer hybrid nano-system, and RGD was modified to the system to achieve RGD-CAL/TAN NS. MTP-131 was conjugated with PEG and modified onto the nanoparticles to achieve dual ligands co-modified MTP/RGD-CAL/TAN NS. The physicochemical properties of nano-systems were characterized. The AMI therapy ability of the systems was investigated in AMI rats' model. The size of MTP/RGD-CAL/TAN NS was 170.2 ± 5.6 nm, with a surface charge of -18.9 ± 1.9 mV. The area under the curve (AUC) and blood circulation half-life (T1/2) of MTP/RGD-CAL/TAN NS was 178.86 ± 6.62 µg·min/mL and 0.47 h, respectively. MTP/RGD-CAL/TAN NS exhibited the most significant infarct size reduction effect of 22.9%. MTP/RGD-CAL/TAN NS exhibited the highest heart accumulation and best infarct size reduction effect, which could be used as a promising system for efficient treatment of cardiovascular diseases.

Plasma lipoprotein-associated phospholipase A2 in patients with metabolic syndrome and carotid atherosclerosis.

BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a recently identified and potentially useful plasma biomarker for cardiovascular and atherosclerotic diseases. However, the correlation between the Lp-PLA2 activity and carotid atherosclerosis remains poorly investigated in patients with metabolic syndrome (MetS). The present study aimed to evaluate the potential role of Lp-PLA2 as a comprehensive marker of metabolic syndrome in individuals with and without carotid atherosclerosis. METHODS: We documented 118 consecutive patients with MetS and 70 age- and sex-matched healthy subjects served as controls. The patients were further divided into two groups: 39 with carotid plaques and 79 without carotid plaques to elucidate the influence of Lp-PLA2 on carotid atherosclerosis. The plasma Lp-PLA2 activity was measured by using ELISA method and carotid intimal-media thickness (IMT) was performed by ultrasound in all participants. RESULTS: Lp-PLA2 activity was significantly increased in MetS subgroups when compared with controls, and was higher in patients with carotid plaques than those without plaques (P < 0.05). Furthermore, we found that significant difference in Lp-PLA2 was obtained between patients with three and four disorders of metabolic syndrome (P < 0.01). Age (ß = 0.183, P = 0.029), LDL-cholesterol (ß = 0.401, P = 0.000) and waist-hip ratio (ß = 0.410, P = 0.000) emerged as significant and independent determinants of Lp-PLA2 activity. Multiple stepwise regression analysis revealed that LDL-cholesterol (ß = 0.309, P = 0.000), systolic blood pressure (ß = 0.322, P = 0.002) and age (ß = 0.235, P = 0.007) significantly correlated with max IMT, and Lp-PLA2 was not an independent predictor for carotid IMT. CONCLUSIONS: Lp-PLA2 may be a modulating factor for carotid IMT via age and LDL-cholesterol, not independent predictor in the pathophysiological process of carotid atherosclerosis in patients with MetS.

Prognostic value of serum LP-PLA2 and hs-CRP in unstable atherosclerotic plaques.

To evaluate the prognostic value of LP-PLA2 and hs-CRP to the stability of atherosclerotic plaques. Forty-eight New Zealand White rabbits were randomly divided into control group, stable plaque group, P53 group, and P53 + drug group. Rabbits in the control group were fed a regular diet. Rabbits in stable plaque group, P53 group, and P53 + drug group underwent balloon-induced arterial wall injury and then were fed a diet of 1% cholesterol. Then the rabbits in the P53 group and P53 + drug group underwent Ad5-CMV P53 transfection in the 10th week; The P53 + drug group underwent pharmacologic triggering with Russell's viper venom (RVV) and histamine in 24 h and 48 h before euthanized. Intravascular ultrasound (IVUS) was used before sacrificing of the animal. In the 0 week and 12th week, rabbits underwent fast blood collection from the medium-sized artery of the ears, and the serum LP-PLA2 and hs-CRP level was determined. The animal altherosclerotic (AS) model was successfully gained and the rules of serum LP-PLA2 and hs-CRP level in instable plaque were discovered: serum LP-PLA2 in P53 group and P53 + drug group were significantly different from the control group and the stable group, while hs-CRP failed to differ between the control group and the stable group and succeeded in different degrees of unstable plague. The relationship analysis of serum and IVUS results revealed LP-PLA2 might predict an instability of plaque. Combining serum Lp-PLA2 and hs-CRP has higher specificity in predicting the vulnerability of the plaque.

Prevalence and genotype distribution of human papillomavirus infection among women aged 30-65 years in Xi'an, China: a population-based study of 14,655 women.

Cervical cancer is the fourth most common cancer among women worldwide in terms of both incidence and mortality. Persistent infection with high-risk human papillomavirus (HPV) has been identified as a cause of cervical intraepithelial neoplasia and invasive cervical cancer. The distribution of human papillomavirus genotypes varies regionally. To acquire baseline data on the population-based prevalence and genotype distribution of HPV infection, we investigated the molecular epidemiology of HPV infection among women in Xi'an, China. The study was conducted from September 2018 to December 2020. A total of 14,655 women aged 30-65 years were screened. The overall prevalence of HPV infection was 13.5% (95% confidence interval [CI]: 13.0-14.1%), with 10.4% of participants being positive for a single HPV type and 3.1% being positive for multiple HPV types. The prevalence of high-risk HPV (HR-HPV), low-risk HPV (LR-HPV) and mixed HPV infection was 10.1% (95% CI: 9.6-10.5%), 2.2% (95% CI: 2.0-2.4%), and 1.3% (95% CI: 1.1-1.5%), respectively. The five most frequently detected HR-HPV types were types 52 (2.6%), 16 (1.9%), 53 (1.8%), 58 (1.4%), and 51 (0.9%). The most frequently detected LR-HPV type was HPV-42 (1.1%). The prevalence and HPV genotype distribution varied by region and age. Age-specific HPV prevalence peaked in the over 60 years age group (18.8%), and Beilin District had the highest HPV prevalence (18.1%). The results of this first population-based study provide a reference for HPV-based cervical cancer screening and HPV vaccination programs in Xi'an.

[The correlation of human serum Lp-PLA2 and hs-CRP and stability of coronary atherosclerotic plaques].

OBJECTIVE: To explore the relationship of serum lipoprotein-associated phospholipase A2 and high sensitive C-reactive protein in vulnerable coronary atherosclerotic plaques. METHODS: Patients undergoing coronary angiography (CAG) were examined for CAD with intravascular ultrasound (IVUS). According to the findings of CAG and IVUS, all the patients were divided into three groups: a control group without plaque, stable plaque group and vulnerable plaque group. The total serum Lp-PLA2 and hs-CRP were measured before angiography and they were valued with T test and Pearson's correlation analysis. RESULTS: (1) Lp-PLA2 level in stable plaque group and vulnerable plaque group was higher than that in control group (P < 0.05). (2) Lp-PLA2 level in the vulnerable plaque group was higher than that in stable plaque group (P < 0.05). (3) hs-CRP level in the vulnerable plaque group is higher than that in the stable plaque group and control group (P < 0.05) and there was significant difference between them. (4) To discriminate vulnerable plaque, the specificity of serum Lp-PLA2 was stronger than that of hs-CRP. CONCLUSIONS: Serum Lp-PLA2 level has higher sensitivity in predicting the vulnerability of the coronary atherosclerotic plaque than hs-CRP. In combination with hs-CRP, we can use Lp-PLA2 as a new biomarker to predict the presence of vulnerable plaque.

Predictive value of fasting blood glucose for serious coronary atherosclerosis in non-diabetic patients.

OBJECTIVE: To determine if high fasting blood glucose (FBG) level is an independent predictor of serious coronary lesions in patients with coronary artery disease (CAD). METHODS: We enrolled 64 patients who had symptoms of chest discomfort and who underwent coronary angiography. FBG was determined from blood samples and the extent of coronary artery lesions was analyzed according to Gensini score. We examined the relationships among diabetes, FBG, and coronary artery severity. RESULTS: Diabetes and FBG were significantly and positively related to Gensini score. Diabetes, but not FBG, was independently correlated with the occurrence of a Gensini score >41. However, FBG was significantly associated with Gensini score >41 in non-diabetic patients. CONCLUSION: Hyperglycemia is an independent predictor of severe CAD in non-diabetic patients. Clinicians should be aware of this and should carry out appropriate early interventions.

Therapy for myocardial infarction: In vitro and in vivo evaluation of puerarin-prodrug and tanshinone co-loaded lipid nanoparticulate system.

Myocardial infarction (MI) is the leading cause of morbidity and mortality worldwide. Nanoparticle systems carrying drugs have already been developed to treat MI. To improve the efficiency of tanshinone (TAN), and to achieve the synergistic effect of TAN and puerarin (PUE), PUE-prodrug and TAN co-loaded solid lipid nanoparticles (SLN) was structured and utilized for MI treatment in the present research. PUE-prodrug was synthesized by an esterification reaction. PUE-prodrug and TAN co-loaded SLN (PUEp/TAN-SLN) were prepared by a single emulsification followed by a solvent evaporation method. The physicochemical properties of SLN were characterized and the in vivo infarct therapy effects were evaluated in MI rats. PUE-prodrug and TAN contained SLN showed a size of 112.6 ± 3.1 nm. The SLN encapsulation reduced the cytotoxicity of drugs and was a safer system. PUEp-SLN exhibited a 1.7-fold increase in comparison to PUE-SLN (21.2 ± 2.1 versus 12.5 ± 1.5 mg/L), in the mean time a 3.4-fold increase compared with free PUE in heart drug concentration (21.2 ± 2.1 versus 6.3 ± 0.9 mg/L). In vivo infarct therapy efficiency of double drugs loaded PUEp/TAN-SLN (17 ± 1.9%) was significantly better than the single drug loaded PUEp-SLN (31 ± 1.6%) and TAN-SLN (40 ± 2.2%). PUE-prodrug contained, double drugs co-loaded SLN can be utilized as promising candidate delivery system for cardioprotective drugs in treatment of myocardial infarction.

RGD modified and PEGylated lipid nanoparticles loaded with puerarin: Formulation, characterization and protective effects on acute myocardial ischemia model.

CONTEXT: Puerarin has been widely used as a therapeutic agent for the treatment of cardiovascular diseases. However, its rapid elimination half-life in plasma and poor water solubility limits its clinical efficacy. OBJECTIVE: RGD modified and PEGylated solid lipid nanoparticles loaded with puerarin (RGD/PEG-PUE-SLN) were developed to improve bioavailability of PUE, to prolong retention time in vivo and to enhance its protective effect on acute myocardial ischemia model. METHODS: In the present study, RGD-PEG-DSPE was synthesized. RGD/PEG-PUE-SLN were prepared by the solvent evaporation method with some modifications. The physicochemical properties of NPs were characterized, the pharmacokinetics, biodistribution, pharmacodynamic behavior of RGD/PEG-PUE-SLN were evaluated in acute MI rats. RESULTS: The mean diameter, zeta potential, entrapment efficiency and drug loading capacity for RGD/PEG-PUE-SLN were observed as 110.5nm, -26.2mV, 85.7% and 16.5% respectively. PUE from RGD/PEG-PUE-SLN exhibited sustained drug release with a burst release during the initial 12h and a followed sustained release. Pharmacokinetics results indicated that AUC increased from 52.93 (µg/mLh) for free PUE to 176.5 (µg/mLh) for RGD/PEG-PUE-SLN. Similarly, T1/2 increased from 0.73h for free PUE to 2.62h for RGD/PEG-PUE-SLN. RGD/PEG-PUE-SLN exhibited higher drug concentration in the heart and plasma compared with other PUE formulations. It can be clearly seen that the infarct size of RGD/PEG-PUE-SLN is the lowest among all the formulation. CONCLUSION: We conclude that RGD modified and PEGylated SLN are promising candidate delivery vehicles for cardioprotective drugs in treatment of myocardial infarction.

[Plasma activated coagulation factor VII and Msp I polymorphism in elderly patients with coronary heart disease].

OBJECTIVE: To investigate the association of activated coagulation factor VII(F7a) and its gene Msp I polymorphism with coronary heart disease in elderly patients. METHODS: This was a case-control study, and the method of candidate gene was adopted. F7 genotypes were identified with polymerase chain reaction amplified genomic deoxyribonulieic acid (DNA) and Msp I restriction fragment length polymorphism analysis, and the level of plasma F7a was detected with recombinant tissue factor method for 108 elderly patients with coronary heart disease and 120 sex- and age-matched healthy control subjects. RESULTS: (1) Plasma F7a levels was significantly higher in elderly patients with coronary heart disease than in healthy control subjects (2.88 +/- 0.62 vs 2.58 +/- 0.60 microg/L, P < 0.05), and was significantly higher in old myocardial infarction than in stable angina pectoris (3.12 +/- 0.62 vs 2.76 +/- 0.60, P < 0.05). F7a was shown to be a risk factor for coronary heart disease in elderly patients by Logistic regression analysis (OR=1.21 P < 0.05). (2) The allelic frequencies were in accordance with Hardy-Weinberg equilibrium. The results suggested that the distribution of genotype and allelic frequencies in the groups displayed no significant difference, and there was no difference between the subgroups of coronary heart disease in elderly patients, either (P > 0.05). (3) F7a level was significantly higher in RR genotype than in Q allele carriers (2.72 +/- 0.60 vs 1.98 +/- 0.59 microg/L, P < 0.05) and was associated with F7 gene polymorphism. CONCLUSION: Plasma F7a level may be an independent risk factor of coronary heart disease in elderly patients, and it may be influenced by the Msp I polymorphism of F7 gene.

Association of lipoprotein-associated phospholipase A2 with characteristics of vulnerable coronary atherosclerotic plaques.

PURPOSE: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory enzyme expressed in atherosclerotic plaques. We investigated the association of circulating Lp-PLA2 with characteristics of vulnerable coronary atherosclerotic plaques. MATERIALS AND METHODS: We recruited 113 patients with either unstable angina (UA, n=59) and stable angina (SA, n=54) by coronary angiography. Thirty-six healthy subjects served as controls. Intravascular ultrasound (IVUS) was used to evaluate the characteristics of coronary atherosclerotic plaque, and serum Lp-PLA2 concentration was measured as well. RESULTS: Lp-PLA2 concentration was significantly higher in both UA and SA patients [(396±36) µg/L and (321±39) µg/L, respectively] compared with the controls [(127 ± 49) µg/L, p<0.01], and higher in UA than SA group. IVUS findings showed that remodeling index (RI) (0.91 ± 0.15 vs. 0.85 ± 0.11, p=0.005) and eccentricity index (EI) (0.73 ± 0.16 vs. 0.65 ± 0.22, p=0.039) were larger in UA than in SA group, and fibrous caps were thicker in SA than UA group [(0.91 ± 0.23) mm vs. (0.63 ± 0.21) mm, p=0.032]. Moreover, Lp-PLA2 correlated positively with EI (r=0.439, p<0.01) and RI (r=0.592, p<0.05) in UA group. There was an inverse relationship between Lp-PLA2 and fibrous cap thickness in both UA (r=-0.587, p<0.001) and SA (r=-0.318, p<0.05) groups. The independent risk factors in UA group were Lp-PLA2 (OR=1.055, 95% CI: 1.03-1.08, p=0.013), LDL-cholesterol (OR=0.032, 95% CI: 0.00-0.05, p=0.041) and fibrous cap thickness (OR=0.008, 95% CI: 0.00-0.45, p=0.019). Lp-PLA2 was strongly associated with both EI and fibrous cap thickness in both groups. CONCLUSION: Serum level of Lp-PLA2 is associated with both eccentricity index and fibrous cap thickness in both UA and SA groups. Elevated levels of circulating Lp-PLA2 might to be a strong risk factor and more serious for unstable angina than stable angina.