Long-acting PGE2 and Lisinopril Mitigate H-ARS.

Thrombocytopenia is a major complication in hematopoietic-acute radiation syndrome (H-ARS) that increases the risk of mortality from uncontrolled hemorrhage. There is a great demand for new therapies to improve survival and mitigate bleeding in H-ARS. Thrombopoiesis requires interactions between megakaryocytes (MKs) and endothelial cells. 16, 16-dimethyl prostaglandin E2 (dmPGE2), a longer-acting analogue of PGE2, promotes hematopoietic recovery after total-body irradiation (TBI), and various angiotensin-converting enzyme (ACE) inhibitors mitigate endothelial injury after radiation exposure. Here, we tested a combination therapy of dmPGE2 and lisinopril to mitigate thrombocytopenia in murine models of H-ARS following TBI. After 7.75 Gy TBI, dmPGE2 and lisinopril each increased survival relative to vehicle controls. Importantly, combined dmPGE2 and lisinopril therapy enhanced survival greater than either individual agent. Studies performed after 4 Gy TBI revealed reduced numbers of marrow MKs and circulating platelets. In addition, sublethal TBI induced abnormalities both in MK maturation and in in vitro and in vivo platelet function. dmPGE2, alone and in combination with lisinopril, improved recovery of marrow MKs and peripheral platelets. Finally, sublethal TBI transiently reduced the number of marrow Lin-CD45-CD31+Sca-1- sinusoidal endothelial cells, while combined dmPGE2 and lisinopril treatment, but not single-agent treatment, accelerated their recovery. Taken together, these data support the concept that combined dmPGE2 and lisinopril therapy improves thrombocytopenia and survival by promoting recovery of the MK lineage, as well as the MK niche, in the setting of H-ARS.

Direct Rivaroxaban-Induced Factor XA Inhibition Proves to be Cardioprotective in Rats.

BACKGROUND: Acute myocardial infarction is a leading cause of death worldwide. Though highly beneficial, reperfusion of myocardium is associated with reperfusion injury. While indirect inhibition of Factor Xa has been shown to attenuate myocardial ischemia-reperfusion (I/R) injury, the underlying mechanism remains unclear. Our study sought to evaluate the effect of rivaroxaban (RIV), a direct inhibitor of Factor Xa, on myocardial I/R injury and determine its cellular targets. EXPERIMENTAL APPROACH: We used a rat model of 40-min coronary ligation followed by reperfusion. RIV (3 mg/kg) was given per os 1 h before reperfusion. Infarct size and myocardial proteic expression of survival pathways were assessed at 120 and 30 min of reperfusion, respectively. Plasmatic levels of P-selectin and von Willebrand factor were measured at 60 min of reperfusion. Cellular RIV effects were assessed using hypoxia-reoxygenation (H/R) models on human umbilical vein endothelial cells and on rat cardiomyoblasts (H9c2 cell line). KEY RESULTS: RIV decreased infarct size by 21% (42.9% vs. 54.2% in RIV-treated rats and controls respectively, P < 0.05) at blood concentrations similar to human therapeutic (387.7 ±â€Š152.3 ng/mL) levels. RIV had no effect on H/R-induced modulation of endothelial phenotype, nor did it alter myocardial activation of reperfusion injury salvage kinase and survivor activating factor enhancement pathways at 30 min after reperfusion. However, RIV exerted a cytoprotective effect on H9c2 cells submitted to H/R. CONCLUSIONS: RIV decreased myocardial I/R injury in rats at concentrations similar to human therapeutic ones. This protection was not associated with endothelial phenotype modulation but rather with potential direct cytoprotection on cardiomyocytes.

[Effects of Danqi Capsule on Platelet Function in Healthy People].

OBJECTIVES: To study the effects of Danqi Capsule on platelet function in healthy people. METHODS: Sixteen healthy volunteer were divided into low dose (4 capsules/time, 3 times/d) and high dose group (6 capsules/time, 3 times/d), and received Danqi Capsule by orally administration for 2 weeks. The venous blood were collect at 3 time points: one week before taking Danqi Capsule (control), one week after taking Danqi Capsule (1 week), two week after taking Danqi Capsule (2 weeks). Blood samples were used for the measurements of conventional coagulation examination, complete blood count, liver and kidney function test, platelet aggregation test, the plasma levels of P-selectin and von Willebrand factor (vWF) , and maximum aggregation (MA). RESULTS: In both dosage group, Danqi capsule(1 week/2 weeks) administration showed no difference in conventional coagulation examination, complete blood count, liver and kidney function test, or the plasma level of vWF ( P>0.05), but showed difference (decreased) in platelet aggregation test and the plasma level of P-selectin (vs. control, P<0.05). CONCLUSIONS: Danqi Capsule inhibits platelet activation and platelet aggregation, but not affects the plasma level of vWF, the coagulation function or the hepatorenal function in normal subjects.

Mechanism of action of antiplatelet drugs on decompression sickness in rats: a protective effect of anti-GPIIbIIIa therapy.

Literature highlights the involvement of disseminated thrombosis in the pathophysiology of decompression sickness (DCS). We examined the effect of several antithrombotic treatments targeting various pathways on DCS outcome: acetyl salicylate, prasugrel, abciximab, and enoxaparin. Rats were randomly assigned to six groups. Groups 1 and 2 were a control nondiving group (C; n = 10) and a control diving group (CD; n = 30). Animals in Groups 3 to 6 were treated before hyperbaric exposure (HBE) with either prasugrel (n = 10), acetyl salicylate (n = 10), enoxaparin (n = 10), or abciximab (n = 10). Blood samples were taken for platelet factor 4 (PF4), thiobarbituric acid reactive substances (TBARS), and von Willebrand factor analysis. Onset of DCS symptoms and death were recorded during a 60-min observation period after HBE. Although we observed fewer outcomes of DCS in all treated groups compared with the CD, statistical significance was reached in abciximab only (20% vs. 73%, respectively, P = 0.007). We also observed significantly higher levels of plasmatic PF4 in abciximab (8.14 ± 1.40 ng/ml; P = 0.004) and enoxaparin groups (8.01 ± 0.80 ng/ml; P = 0.021) compared with the C group (6.45 ± 1.90 ng/ml) but not CD group (8.14 ± 1.40 ng/ml). Plasmatic levels of TBARS were significantly higher in the CD group than the C group (49.04 ± 11.20 µM vs. 34.44 ± 5.70 µM, P = 0.002). This effect was prevented by all treatments. Our results suggest that abciximab pretreatment, a powerful glycoprotein IIb/IIIa receptor antagonist, has a strong protective effect on decompression risk by significantly improving DCS outcome. Besides its powerful inhibitory action on platelet aggregation, we suggest that abciximab could also act through its effects on vascular function, oxidative stress, and/or inflammation.

The effects of folic acid on markers of endothelial function in patients with type 1 diabetes mellitus.

BACKGROUND: Endothelial dysfunction is considered as a fundamental and also preventable factor in the progression of vascular complications among type 1 diabetic patient. It occurs before the clinical manifestation of the mentioned complications. The aim of this study was to evaluate the effects of folic acid on endothelial function by measurements of adhesion molecules and von Willebrand factor (vWF) in patients with type 1 diabetes in Isfahan, Iran. METHODS: This double blind, placebo-controlled crossover trial included type 1 diabetic patients aged 5-20 years old. Selected patients were randomized into two groups of A and B to receive folic acid 5 mg daily or placebo for 8 weeks. After a 2-week washout period, patients in the two groups were swapped to receive placebo or folic acid, respectively, for another 8 weeks. Blood and urine samples were taken to evaluate glycosylated hemoglobin (HbAlc), folic acid, vWF, intracellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), and microalbuminuria levels. Results of these measurements were compared in the two groups before and after folic acid and placebo administrations. RESULTS: Fifty five type 1 diabetic patients aged 12.1 +/- 3.4 years with diabetes duration of 3.9 +/- 2.1 years were enrolled. Mean of folic acid level in the two studied groups was increased significantly (10.1 +/- 3.8 vs. 21.2 +/- 1.1 in group A and 15.5 +/- 1.9 vs. 19.9 +/- 2.8 in group B, p < 0.05). Mean of VCAM and microalbuminuria was decreased significantly after folic acid administration in the two groups (p < 0.05). Mean of HbA1c, ICAM and vWF did not significantly change after folic acid administration in the two groups (p > 0.05). CONCLUSION: Folic acid administration decreased the level of endothelial dysfunction measured by adhesion molecules, especially VCAM and microalbuminuria. However, it did not significantly affect vWF. Further studies with larger sample size and long-term administration of folic acid are necessary for making precise decisions in this field. Key words: endothelial function, Diabetes Mellitus, folic acid.

Effect of Salvia miltiorrhiza hydrophilic extract on the endothelial biomarkers in diabetic patients with chronic artery disease.

The aim of this pilot study was to investigate whether the administration of Salvia miltiorrhiza hydrophilic extract (SMHE) reduced the level of soluble vascular cell adhesion molecule-1 (sVCAM-1) and von Willebrand factor (vWF) in diabetic patients with coronary heart disease (CHD). Sixty-two diabetic patients with CHD were recruited and randomly assigned into placebo and treatment groups. Patients were given SMHE for 60 days. Levels of sVCAM-1, vWF and oxidative low density lipoprotein (oxLDL) were determined by using enzyme linked immunosorbent assay (ELISA). The results showed that the levels of VCAM-1 and vWF positively correlated with the level of oxLDL in diabetic patients with CHD. Levels of sVCAM-1 and vWF in serum were reduced significantly in patients receiving SMHE treatment at day 60 in comparison with the baseline. Administration of SMHE also led to a clear decrease in the levels of oxLDL in diabetic patients with CHD. In summary, this study suggests that SMHE has a potential protective effect on the development of diabetic cardiovascular disease.

A phase II randomized placebo-controlled trial of omega-3 fatty acids for the treatment of acute lung injury.

OBJECTIVES: Administration of eicosapentaenoic acid and docosahexanoic acid, omega-3 fatty acids in fish oil, has been associated with improved patient outcomes in acute lung injury when studied in a commercial enteral formula. However, fish oil has not been tested independently in acute lung injury. We therefore sought to determine whether enteral fish oil alone would reduce pulmonary and systemic inflammation in patients with acute lung injury. DESIGN: Phase II randomized controlled trial. SETTING: Five North American medical centers. PATIENTS: Mechanically ventilated patients with acute lung injury ≥18 yrs of age. INTERVENTIONS: Subjects were randomized to receive enteral fish oil (9.75 g eicosapentaenoic acid and 6.75 g docosahexanoic acid daily) or saline placebo for up to 14 days. MEASUREMENTS AND MAIN RESULTS: Bronchoalveolar lavage fluid and blood were collected at baseline (day 0), day 4 ± 1, and day 8 ± 1. The primary end point was bronchoalveolar lavage fluid interleukin-8 levels. Forty-one participants received fish oil and 49 received placebo. Enteral fish oil administration was associated with increased serum eicosapentaenoic acid concentration (p < .0001). However, there was no significant difference in the change in bronchoalveolar lavage fluid interleukin-8 from baseline to day 4 (p = .37) or day 8 (p = .55) between treatment arms. There were no appreciable improvements in other bronchoalveolar lavage fluid or plasma biomarkers in the fish oil group compared with the control group. Similarly, organ failure score, ventilator-free days, intensive care unit-free days, and 60-day mortality did not differ between the groups. CONCLUSIONS: Fish oil did not reduce biomarkers of pulmonary or systemic inflammation in patients with acute lung injury, and the results do not support the conduct of a larger clinical trial in this population with this agent. This experimental approach is feasible for proof-of-concept studies evaluating new treatments for acute lung injury.

[Effect of naoxintong capsule on the vascular endothelial function and the infarct size of patients with acute myocardial infarction].

OBJECTIVE: To observe the effect of Naoxintong Capsule (NC) on the vascular endothelial function and the infarct size of patients with acute myocardial infarction (AMI). METHODS: One hundred and four patients with AMI were randomly assigned to the NC group (Group A, 36 cases), the Tongguan Capsule group (Group B, 32 cases), and the conventional Western medicine group (Group C, 36 cases). The conventional Western medicine was given to the three groups. NC was additionally given to Group A, and Tongguan Capsule was additionally given to Group B. The therapeutic course for all was 4 weeks. The plasma nitric oxide (NO), endothelin (ET), von Willebrand factor (vWF) were detected in the 3 groups before and after treatment. The inner diameter of brachial artery was examined by ultrasonograph. The flow-mediated dilation (FMD) and the nitroglycerin-mediated dilation (NMD) were calculated. The ECG QRS integral and the infarct size were assessed. RESULTS: There was no significant difference in the vascular endothelial function, ECG QRS integral, or the infarct size among the three groups before treatment (P > 0.05). Compared with before treatment, NO and NMD obviously increased after treatment in Group A and Group B, while the vWF and the infarct size obviously decreased in Group A, all showing statistical difference (P < 0.05). Compared with those in Group C, the NO, FMD, NMD significantly increased and ET obviously decreased in Group A and B after treatment (P < 0.05). The ECG QRS integral and the infarct size also decreased, with statistically significant differences in Group A (P < 0.05). Better effects on improving NO, NMD, and vWF were obtained in Group A than in Group B (P < 0.05). CONCLUSION: NC could reduce the infarct size of AMI patients possibly through improving the vascular endothelial function.

Toward a new paradigm for the identification and functional characterization of von Willebrand disease.

The diagnosis and functional characterization of von Willebrand disease (VWD) is challenging. There are inherent difficulties in both its identification and classification because of clinical uncertainty, the limitations in the test processes and test panels typically used by laboratories, and because the classification scheme does not always allow unequivocal assignment of any subtype. This article reviews current thoughts and alternatives to the classic approach of the classification and functional characterization of VWD. Of particular interest to this author is the utility of an extended core test panel that includes additional functional VWF assays, such as the collagen binding assay, and the potential for desmopressin (DDAVP) challenge to not only provide therapeutic information but also assist in the better characterization of individuals with defects or deficiencies in von Willebrand factor (VWF). The potential use of supplementary assays such as the PFA-100 and the VWF propeptide assay after DDAVP challenge is also worth noting.

Early initiation of low-dose atorvastatin treatment after an acute ST-elevated myocardial infarction, decreases inflammatory process and prevents endothelial injury and activation.

BACKGROUND: High-dose statin treatment improves clinical outcome of ST-elevated myocardial infarction (STEMI). However, the effect of low-dose atorvastatin treatment on inflammatory and pro-thrombotic molecules during the post-STEMI period is unclear. We investigated the effect of low-dose atorvastatin treatment on the kinetics of cytokine IL-6, vascular cell adhesion molecule (sVCAM-1) and endothelium-derived markers of thrombosis/fibrinolysis such as von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA), post STEMI. METHODS: Twenty-four normocholesterolemic patients with STEMI were randomised to receive atorvastatin 10mg/day or no statin treatment for 6 weeks after the event. Blood samples were obtained by their admission to the hospital as well as at weeks 1 and 6. Circulating levels of IL-6, sVCAM-1, vWF, PAI-1 and tPA were determined by ELISA. RESULTS: Atorvastatin induced a decrease of IL-6 at 1 week, an effect which reached significance compared to baseline at 6 weeks post STEMI (p<0.05 vs baseline). Serum sVCAM-1 was increased in controls both at 1 and 6 weeks post-STEMI (p<0.05 vs baseline), an effect prevented by atorvastatin. Plasma vWF was increased 1 week post-STEMI in controls (p<0.05 vs baseline) and returned to baseline at 6 weeks, an effect prevented by atorvastatin. Plasma PAI-1, tPA and the PAI-1/tPA ratio remained unchanged in both groups. CONCLUSION: Early initiation of low-dose atorvastatin treatment decreases the expression of IL-6 and sVCAM-1 and the release of vWF in patients with STEMI. Therefore, low-dose atorvastatin, modulates inflammatory response and decreases endothelial injury and activation in patients with recent STEMI.

Supplementation with orange and blackcurrant juice, but not vitamin E, improves inflammatory markers in patients with peripheral arterial disease.

Inflammation and endothelial activation are associated with an increased risk of CVD and epidemiological evidence suggests an association between levels of markers of inflammation or endothelial activation and the intake of fruit. Also, vitamin E, a fat-soluble antioxidant, has anti-inflammatory properties. We performed a randomised 2 x 2 factorial, crossover trial to determine the effect of orange and blackcurrant juice (500 ml/d) and vitamin E (15 mg RRR-alpha-tocopherol/d) supplementation on markers of inflammation and endothelial activation in forty-eight patients with peripheral arterial disease. Patients were randomly allocated to two dietary supplements from the four possible combinations of juice and vitamin E: juice+vitamin E; juice+placebo; reference beverage (sugar drink)+vitamin E; and reference beverage+placebo. The supplementations were given for 28 d, separated by a 4-week wash-out period. Analysis of main effects showed that juice decreased C-reactive protein (CRP) by 11% and fibrinogen by 3% while the reference drink increased CRP by 13% and fibrinogen by 2% (P<0.008 and P<0.002, respectively). No significant differences were measured for IL-6 and the endothelial activation markers von Willebrand factor, tissue-plasminogen activator and plasmin activator inhibitor-1. Vitamin E supplementation had no significant effects on the various markers. We observed no significant interaction between juice and vitamin E. In this study, orange and blackcurrant juice reduced markers of inflammation, but not markers of endothelial activation, in patients with peripheral arterial disease, relative to sugar drinks.

Myristica malabarica heals stomach ulceration by increasing prostaglandin synthesis and angiogenesis.

Earlier we had shown that on the 3 (rd) day of its administration to mice, indomethacin (18 mg kg (-1), P. O.) produced maximum stomach ulceration with a damage score of 3.46, which was reduced by a 3-day treatment with the methanol extract of Myristica malabarica (40 mg kg (-1), P. O.) and omeprazole (3 mg kg (-1), P. O.) to 0.95 and 0.82, respectively. Presently, we investigated the possible role of the test samples in modulating PG synthesis and angiogenesis for their healing action. The ulceration was found to be associated with suppression of PGE (2), VEGF and vWF VIII, and an increase in EGF and endostatin levels. Treatment with the plant extract reversed all these parameters accounting for its healing activity. However, despite providing similar healing, omeprazole did not alter these parameters.

Prevalence of von Willebrand disease in women with iron deficiency anaemia and menorrhagia in Taiwan.

Iron deficiency anaemia (IDA) is a frequently encountered disease, which can be attributed to menorrhagia. Most female patients with von Willebrand disease (VWD) have menorrhagia. The aim of this study was to investigate the prevalence of VWD in women with both IDA and menorrhagia in Taiwan. From January to December 2005 and November 2006 to January 2007, 56 consecutive patients with both IDA and menorrhagia were enrolled in this study. Their median age was 41 years (range 18-53). IDA was diagnosed by anaemia plus either low ferritin or transferrin saturation. Menorrhagia was evaluated by patient's menses history. Both von Willebrand factor antigen (VWF:Ag) and ristocetin cofactor activity (VWF:RCo) were measured for each patient. Bleeding time (BT) and platelet function analyser (PFA)-100 assay were determined as ancillary tests. The VWD diagnosis was established if: (i) both VWF:Ag (<50%) and VWF:RCo (<50%) were low; (ii) either VWF:Ag or VWF:RCo was low plus prolonged BT or prolonged PFA closure times. VWF multimer analysis was performed for subtype confirmation of VWD. Nine of the 56 (16.1%) patients were identified to have VWD. VWD patients with menorrhagia might develop IDA at younger age (34.3 vs. 39.7, P = 0.09) and had more IDA recurrence (75% vs. 16%, P = 0.03) than those patients without VWD. Of the eight VWD patients with VWF multimer analyses, all were revealed to have type I VWD. Our study demonstrates that VWD was not uncommon in women with both IDA and menorrhagia in Taiwan.

Experimental renal preservation by normothermic resuscitation perfusion with autologous blood.

BACKGROUND: Normothermic perfusion (NP) has the potential to improve metabolic support and maintain the viability of ischaemically damaged organs. This study investigated the effects of NP compared with current methods of organ preservation in a model of controlled non-heart-beating donor (NHBD) kidneys. METHODS: Porcine kidneys (n = 6 in each group) were subjected to 10 min warm ischaemia and then preserved as follows: 2 h cold storage (CS) in ice (CS2 group), 18 h CS (CS18 group), 18 h cold machine perfusion (CP group) or 16 h CS + 2 h NP (NP group). Renal haemodynamics and function were measured during 3 h reperfusion with autologous blood using an isolated organ perfusion system. RESULTS: Increasing CS from 2 to 18 h reduced renal blood flow (mean(s.d.) area under the curve (AUC) 444(57) versus 325(70) ml per 100 g; P = 0.004), but this was restored by NP (563(119) ml per 100 g; P = 0.035 versus CS18). Renal function was also better in CS2, CP and NP groups than in the CS18 group (mean(s.d.) serum creatinine fall 92(6), 79(9) and 64(17) versus 44(13) per cent respectively; P = 0.001). The AUC for serum creatinine was significantly lower with CS for 2 h than for 18 h (mean(s.d.) 1102(2600) versus 2156(401) micromol/l.h; P = 0.001), although values in CP and NP groups were not significantly different from those in the CS2 group (1354(300) and 1756(280) micromol/l.h respectively). Two hours of NP increased the adenosine 3'-triphosphate : adenosine 3'-diphosphate ratio to a significantly higher level than the preperfusion values in all other groups (P = 0.046). CONCLUSION: NP with oxygenated blood was able to restore depleted ATP levels and reverse some of the deleterious effects of CS.

The effect of aggressive versus conventional lipid-lowering therapy on markers of inflammatory and oxidative stress.

PURPOSE: Recent trial results are in favor of aggressive lipid lowering using high dose statins in patients needing secondary prevention. It is unclear whether these effects are solely due to more extensive lipid lowering or the result of the potentially anti-inflammatory properties of statins. We aimed to determine whether aggressive compared with conventional statin therapy is more effective in reducing systemic markers of inflammation and oxidative stress. MATERIALS AND METHODS: This was a multi-centre, double-blind, placebo-controlled trial. Patients with previous cardiovascular disease, who did not achieve low density lipoprotein (LDL) cholesterol levels <2.6 mmol/l on conventional statin therapy (simvastatin 40 mg) were randomized to continue with simvastatin 40 mg or to receive atorvastatin 40 mg for 8 weeks and thereafter atorvastatin 80 mg for the final 8 weeks (aggressive treatment). Lipids, C-reactive protein, soluble cellular adhesion molecules, neopterin, von Willebrand Factor, and antibodies against oxidized LDL were measured at baseline and after 16 weeks. RESULTS: Lipid levels decreased significantly in the aggressive treatment group (LDL-C reduction 20.8%; P < 0.001), whereas a slight increase was observed in the conventional group (LDL-C increase 3.7%; P = 0.037). A significant reduction in antibodies against oxidized LDL was seen in the aggressive (13.4%; P < 0.001) and the conventional (26.8%; P < 0.001) group, but there was no difference between groups (P = 0.25). Furthermore, no significant differences in change in other biomarkers was observed between both groups. CONCLUSIONS: This study does not support the hypothesis that a more profound reduction in inflammatory and oxidative stress contributes to the benefits of aggressive statin therapy.

2-methoxycinnamaldehyde reduces IL-1beta-induced prostaglandin production in rat cerebral endothelial cells.

Prostaglandin E2 (PGE2) works as a common final mediator of the febrile. Guizhi-Tang, one of the most famous traditional Chinese medical formula used to treat influenza, common cold and other pyretic conditions, was previously reported to reduce the production of PGE 2 in rats. 2-Methoxycinnamaldehyde is a principle compound isolated from Guizhi-Tang. The aim of the present study was to investigate the effects of 2-methoxycinnamaldehyde on PGE2 production of rat cerebral endothelial cells (CECs). 2-Methoxycinnamaldehyde dose-dependently inhibited interleukin (IL)-1beta-induced PGE2 production in CECs with IC50 values of 174 microM. IL-1beta stimulation increased the protein, activity and mRNA expression of cyclooxygenase (COX)-2 but not COX-1. 2-Methoxycinnamaldehyde reduced IL-1beta-induced protein and activity of COX-2, but did not influence the COX-2 mRNA expression. Our results show that prostaglandin production in CECs during stimulated conditions is sensitive to inhibition by 2-methoxycinnamaldehyde and suggest that 2-methoxycinnamaldehyde may reduce COX-2 protein level and activity but not COX-2 mRNA.

Biomarkers and mechanisms of drug-induced vascular injury in non-rodents.

In preclinical safety studies, drug-induced vascular injury can negatively impact candidate-drug selection because there are no obvious diagnostic markers for monitoring this pathology preclinically or clinically. Furthermore, our current understanding of the pathogenesis of this lesion is limited. While vasodilatation and increased shear stress appear to play a role, the exact mechanism(s) of injury to the primary target cells, smooth muscle (SMC) and endothelial cell (EC), are unknown. Evaluation of potential novel markers for clinical monitoring with a mechanistic underpinning would add value in risk assessment and risk management. This mini review focuses on the efforts and progress to identify diagnostic markers as well as understanding the mechanism of action in nonrodent drug-induced vascular injury.

[Effect of electroacupuncture combined with medication on vascular endothelial cells in the compound hypertension and hyperlipemia rat].

OBJECTIVE: To explore the mechanism of electroacupuncture combined with medication for treatment of compound model of hypertension and hyperlipemia (CMHH). METHODS: CMHH rat model was made by the way of "2K1C" combined with intragastric perfusion of high fat diet, and a normal group and a pseudosurgery group were set up. After modeling for 4 weeks, the successful model rats who had synchronously increase of blood pressure (BP) and blood lipids were randomly divided into a model group, a medication group , an electroacupuncture group and an acupuncture plus medication group. After interference of 4 weeks, changes of BP, total cholesterol (TC) and thiglyceride (TG) and contents of serum vWF, tissue plasminogen activator (t-PA ) and plasminogen activator inhibitor-1 (PAl-1) were observed. RESULTS: After interference, the levels of BP, TC, TG, vWF, t-PA and PAl-1 significantly changed in all the treatment groups as compared with those in the model group (P < 0.05 or P < 0.01) with most significantly changed in the electroacupuncture plus medication group. CONCLUSION: Both electroacupunctore and electroacupuncture combined with medication can down-regulate levels of BP, TC, TG, and decrease plasma vWF and PAl-1 levels, increase t-PA content, so as to effectively prevent and treat CMHH and possibly induced cerebral diseases.

Influence of long-term intervention with dietary counseling, long-chain n-3 fatty acid supplements, or both on circulating markers of endothelial activation in men with long-standing hyperlipidemia.

BACKGROUND: Dietary factors and very-long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) may influence the atherothrombotic process. Elevated concentrations of circulating cell adhesion molecules, thrombomodulin (TM), von Willebrand factor (vWF), and tissue-type plasminogen activator antigen (tPAag) are related to atherothrombotic cardiovascular disease. OBJECTIVE: The randomized Diet and Omega-3 Intervention Trial (DOIT) targeted a comparison of the effect of 3-y dietary counseling, n-3 PUFA supplementation (2.4 g/d), or both on circulating markers of endothelial activation. DESIGN: The study included 563 elderly men with long-standing hyperlipidemia. The men were randomly assigned by factorial design into 4 groups: control (no dietary counseling and placebo capsules), dietary counseling (and placebo capsules), n-3 PUFA supplementation (no dietary counseling), and dietary counseling and n-3 PUFA supplementation. RESULTS: Serum concentrations of fatty acids reflected good compliance. Dietary counseling was followed by significantly reduced concentrations of soluble intercellular adhesion molecule 1 (sICAM-1; P < 0.001), sTM (P = 0.004), and tPAag (P < 0.001) than in subjects without dietary counseling. After n-3 PUFA supplementation, significantly reduced concentrations of sICAM-1 (P < 0.001) and sTM (P = 0.006) were observed when compared with subjects receiving placebo capsules. An increase in tPAag was not significantly different from that observed in subjects receiving placebo capsules. For sICAM-1, a significant effect was observed for both interventions combined. CONCLUSIONS: Each intervention (dietary counseling or n-3 PUFA supplements) reduced sTM and sICAM-1 concentrations, indicating decreased endothelial activation. The tPAag increase in the groups not receiving dietary counseling (pooled), which indicates progression of atherosclerosis, was significantly counteracted by dietary counseling.