Efficacy and safety of Tongxin formula after stent implantation for acute coronary syndrome: A multicenter, double-blind, placebo-controlled randomized trial.

OBJECTIVE: The aim of this study is to comprehensively evaluate both the efficacy and safety profile of integrating the Tongxin formula with optimal medical therapy (OMT) for patients experiencing acute coronary syndromes subsequent to coronary stenting, over the course of one year. METHODS: We enrolled 150 patients diagnosed with acute coronary syndromes who had received stent placement within one month and exhibited a TCM syndrome characterized by Qi deficiency and blood stasis. This group comprised patients with unstable angina, non-ST-segment elevation myocardial infarction, and ST-segment elevation myocardial infarction. The participants were divided equally, allocating 75 to the Tongxin formula group and 75 to a placebo-controlled group. After undergoing percutaneous coronary intervention (PCI) surgery, both groups received conventional Western medical care, including dual antiplatelet therapy and lipid-lowering medications. The placebo-controlled group received a placebo, while the Tongxin formula group were administered Tongxin formula granules orally. Both study cohorts were monitored for a duration of 6 months. The primary endpoints included the occurrence of major adverse cardiovascular events and the rate of lumen diameter reduction post-treatment in both groups, with the Seattle Angina Scale serving as a secondary assessment tool. Safety evaluations encompassed the measurement of liver and kidney function, coagulation parameters, and other relevant indicators. RESULTS: The rate of adverse cardiovascular events in the placebo-controlled group was 42.46 % within a year of surgery, whereas it was 16.90 % in the Tongxin formula group (P < 0.05). Comparing the Tongxin formula group to the placebo-controlled group, there was a decrease in the frequency of unstable angina and readmission due to cardiovascular events (P < 0.05). Coronary angiography performed 6 months after surgery revealed that the Tongxin formula group had considerably less lumen loss than the placebo-controlled group in a number of segments, including the entire segment, within the stent, at the proximal end, and at the distal end (P < 0.05). Six months after surgery, the Seattle angina score was higher in the Tongxin formula group than in the placebo-controlled group (P < 0.05). There were no significant changes in indicators such as liver and renal function as well as coagulation indexes in both groups within the first 12 months after surgery (P > 0.05). CONCLUSION: Tongxin formula has been shown to lower the occurrence of major adverse cardiovascular events, minimize narrowing of blood vessel lumen, enhance clinical symptoms, and enhance the quality of life of patients following PCI surgery, all while maintaining a good safety profile.

Pyrazole-Isoindoline-1,3-dione Hybrid: A Promising Scaffold for 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors.

The discovery of 4-hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) inhibitors has been an active area of research due to their great potential as herbicides for weed control. Starting from the binding mode of known inhibitors of HPPD, a series of HPPD inhibitors with new molecular scaffolds were designed and synthesized by hybridizing 2-benzoylethen-1-ol and isoindoline-1,3-dione fragments. The results of the in vitro tests indicated that the newly synthesized compounds showed good HPPD inhibitory activity with IC50 values against the recombinant Arabidopsis thaliana HPPD (AtHPPD) ranging from 0.0039 µM to over 1 µM. Most promisingly, compound 4ae, 2-benzyl-5-(5-hydroxy-1,3-dimethyl-1H-pyrazole-4- carbonyl)isoindoline-1,3-dione, showed the highest AtHPPD inhibitory activity with a Ki value of 3.92 nM, making it approximately 10 times more potent than pyrasulfotole (Ki = 44 nM) and slightly more potent than mesotrione (Ki = 4.56 nM). In addition, the cocrystal structure of the AtHPPD-4ae complex was successfully resolved at a resolution of 1.8 Å. The X-ray diffraction analysis indicated that the two carbonyl groups of 2-benzoylethen-1-ol formed a bidentate chelating interaction with the metal ion, while the isoindoline-1,3-dione moiety formed pronounced π-π stacking interactions with Phe381 and Phe424. Moreover, water-mediated hydrogen bonding interactions were observed between Asn282 and the nitrogen atoms of the pyrazole ring of 4ae. The above results showed that the pyrazole-isoindoline-1,3-dione hybrid is a promising scaffold for developing HPPD inhibitors.

[Peroxisome proliferator-activated receptor α/γ agonist tesaglitazar stabilizes atherosclerotic plaque in diabetic low density lipoprotein receptor knockout mice].

OBJECTIVE: To investigate the effects of peroxisome proliferator-activated receptor (PPAR) α/γ agonist on atherosclerotic plaque stabilization in diabetic LDL receptor knockout (LDLr-/-) mice. METHODS: Female 4-week-old LDLr-/- mice fed with high-glucose and high-fat diet for 4 weeks were randomly divided into three groups (n = 15 each): control group (only fed with high-glucose and high-fat diet), diabetic group [induced by high-glucose and high-fat diet combined with a low-dose of streptozotocin (STZ)] without tesaglitazar and with tesaglitazar (20 µg/kg oral treatment). After 6 weeks, the mice were sacrificed, body weight, fasting blood glucose (Glu), total cholesterol (TC), triglyceride (TG) levels were measured. The expression of ICAM-1, VCAM-1, MCP-1 in the brachiocephalic atherosclerotic lesions were determined by Western blot and immunohistochemistry, respectively. Brachiocephalic artery was prepared for morphologic study (HE, oil red O, Sirius red staining) and immunohistochemical analysis (macrophage surface molecule-3, α-smooth muscle actin), respectively. RESULTS: Serum TC [(32.34 ± 3.26) mmol/L vs. (16.17 ± 1.91) mmol/L], TG [(3.57 ± 0.99) mmol/L vs. (2.21 ± 0.11) mmol/L] and Glu [(15.21 ± 4.67) mmol/L vs. (6.89 ± 0.83) mmol/L] levels were significantly higher in diabetic group than in the control group (all P < 0.01). The expression of ICAM-1 (2.31 ± 0.35 vs.1.34 ± 0.21), VCAM-1 (1.65 ± 0.14 vs.0.82 ± 0.26), MCP-1 (2.27 ± 0.16 vs.1.56 ± 0.23) were significantly upregulated in diabetic group compared with control group (all P < 0.01). Brachiocephalic atherosclerotic plaque area [(4.597 ± 1.260)×10(3) µm(2) vs. (0.075 ± 0.030)×10(3) µm(2)], lipid deposition [(47.23 ± 2.64)% vs. (9.67 ± 1.75)%], Mac-3 positive area [(19.15 ± 3.51)% vs. (1.72 ± 0.16)%], α-smooth muscle actin [(5.54 ± 1.17)% vs. (2.13 ± 0.41)%] and collagen content [(4.27 ± 0.74)% vs. (0.43 ± 0.09)%] were all significantly larger/higher in diabetic LDLr-/- mice than in the control group (all P < 0.01). While tesaglitazar treatment significantly reduced serum TC [(30.47 ± 3.18) mmol/L], TG [(3.14 ± 0.71) mmol/L] and Glu [(7.92 ± 1.28) mmol/L] levels (all P < 0.01). Similarly, the expression of ICAM-1 [(1.84 ± 0.22)], VCAM-1 [(1.27 ± 0.11)], MCP-1 [(1.83 ± 0.24)], brachiocephalic atherosclerotic lesion area[(1.283 ± 0.410)×10(3) µm(2)], lipid deposition[(23.52 ± 1.39)%] were also significantly reduced by tesaglitazar (all P < 0.05). Moreover, tesaglitazar increased α-smooth muscle actin [(9.46 ± 1.47)%] and collagen content [(6.32 ± 1.15)%] in diabetic LDLr-/- mice (all P < 0.05). In addition, lipid deposition and Mac-3 positive areas [(10.67 ± 0.88)% vs. (15.83 ± 1.01)%] in the aortic root were also reduced in tesaglitazar treated diabetic LDLr-/- mice (P < 0.01). CONCLUSIONS: Tesaglitazar has anti-inflammatory effects in the diabetic LDLr-/- mice. Tesaglitazar could reduce lipid deposition, increase collagen and α-SMA content in the brachiocephalic atherosclerotic lesions, thus, stabilize atherosclerotic plaque in this model.

Tesaglitazar ameliorates non-alcoholic fatty liver disease and atherosclerosis development in diabetic low-density lipoprotein receptor-deficient mice.

Previous research has demonstrated that the dual PPARα/γ agonist tesaglitazar reduces atherosclerosis in a mouse model of hyperlipidemia by reducing both lipid content and inflammation in the aorta. However, much of the underlying mechanism of tesaglitazar in non-alcoholic fatty liver disease (NAFLD) remains less clear. The aim of the present study was to determine whether tesaglitazar attenuates NAFLD and atherosclerosis development in diabetic low-density lipoprotein receptor-deficient (LDLr(-/-)) mice. Female LDLr(-/-) mice (3 weeks old) were induced by a high-fat diet (HFD) combined with low-dose streptozotocin (STZ) injection to develop an animal model of type 2 diabetes (T2DM). The mice were randomly divided into two groups: diabetic group (untreated diabetic mice, n=15) and tesaglitazar therapeutic group (n=15, 20 µg/kg/day oral treatment for 6 weeks). Fifteen LDLr(-/-) mice were fed with an HFD as the control group. Tesaglitazar decreased serum glucose and lipid levels compared with the diabetic mice. Tesaglitazar significantly reduced atherosclerotic lesions, lipid accumulation in the liver, macrophage infiltration, and decreased total hepatic cholesterol and triglyceride content compared to the diabetic mice. In addition, tesaglitazar reduced inflammatory markers at both the serum and mRNA levels. Our data suggest that tesaglitazar may be effective in preventing NAFLD and atherosclerosis in a pre-existing diabetic condition by regulating glucose and lipid metabolism, and the inflammatory response.

Relationship of a low ankle-brachial index with all-cause mortality and cardiovascular mortality in Chinese patients with metabolic syndrome after a 6-year follow-up: a Chinese prospective cohort study.

OBJECTIVE: Peripheral arterial disease (PAD) is a common clinical manifestation of the systemic atherosclerotic process, and the ankle-brachial index (ABI) is an ideal tool to diagnose PAD. Currently, there have been few long-term follow-up studies focused on the associations of the ABI with all-cause mortality and cardiovascular disease (CVD) mortality in Chinese MetS patients. The aim of this study was to evaluate the usefulness of ABI to predict the prognosis of CVD in hospitalized Chinese patients with metabolic syndrome (MetS). METHODS: Participants from multi-center departments were followed up from November 2004 to January 2011. The study sample actually comprised 1,266 valid participants whose age was ≥35 years. Patients were separated into four groups, with an ABI ≤0.4, 0.41-0.7, 0.71-0.9 and 0.91-1.4. An ABI ≤0.9 was defined as PAD, and subjects with an ABI >1.4 were excluded because of the false negative rate. Factors related to all-cause and cardiovascular mortality were observed by Cox models and the log rank test. Potential confounding variables with values of p<0.10 were adjusted for the multivariate analysis. RESULTS: An abnormal ABI value was strongly, independently, and inversely correlated with the all-cause and cardiovascular mortality. After adjusting for age and other covariates, Cox models revealed that an abnormal ABI value was still correlated with the all-cause mortality (relative risk/RR/=1.82, 95% confidence interval/CI/=1.45-2.34 p<0.01), and CVD mortality (RR=1.88, 95% CI=1.51-2.90 p<0.01). CONCLUSION: An abnormal ABI value was not only a significant and independent risk factor for CVD, but also for the survival rate in Chinese MetS patients. Routine ABI evaluation could therefore be helpful for identifying high risk patients, especially MetS patients.

[The relationship between high-sensitivity C-reactive protein and peripheral artery disease].

OBJECTIVE: To investigate the association between high-sensitivity C-reactive protein and peripheral arterial disease. METHODS: The study population comprised 643 subjects aged at least 40 years in whom both CRP and ankle-brachial index were measured. The survey included information on demographic characteristics, clinical examinations and ankle-brachial index (ABI). Ankle-brachial index (ABI) < 0.9 was diagnostic of PAD. RESULTS: 64 subjects (10%) were diagnosed as PAD. The prevalence of current smoking, hypertension, diabetes, low HDL cholesterol and history of cardiovascular disease in the participants with PAD were higher than without (P < 0.05). The prevalence of hypertension, diabetes, and history of cardiovascular disease was higher in subjects with high CRP (P < 0.05). In logistic regression analyses, the moderate CRP group and high CRP group had a two-fold higher OR compared with the low CRP group. The P-trend across CRP groups was statistically significant (P = 0.036). High log-transformed hs-CRP level was significantly related to PAD after adjustment for the cardiovascular risk factors mentioned above (P = 0.007). CONCLUSION: hs-CRP is related to PAD and high level hs-CRP is an independent risk factor for PAD in Chinese adults aged 40 years and more.

[Relationship between low ankle-brachial index and mortality of men with several atherosclerotic risk factors: a cohort study of 1941 cases].

OBJECTIVE: To study the relationship between ankle-brachial index (ABI) and all cause mortality and cardiovascular disease mortality in men with several atherosclerotic risk factors. METHODS: 1941 male patients with no less than two atherosclerotic risk factors, aged 67 (36 approximately 96), from 20 hospitals in Shanghai and Beijing, underwent examination of ABI and were followed up for 13.6 +/- 1.3 months to record the all cause mortality and cardiovascular disease (CVD) mortality. RESULTS: The baseline examination showed that 467 patients were with the ABI 0.9 (7.7% and 1.8%, both P < 0.01). After adjusting other risk factors, the patients with 0.41 < ABI

[The relationship of ankle brachial index to all-cause and cardiovascular disease mortality in Chinese male patients with hypertension].

OBJECTIVE: To evaluate the risk factors for peripheral arterial disease (PAD) and the relationship of low ankle brachial index (ABI) to all-cause and cardiovascular disease (CVD) mortality in Chinese male patients with hypertension. METHODS: The data of 1606 male participants with hypertension from the eight hospitals in Beijing and Shanghai were analyzed. ABI was ascertained at baseline by measuring the systolic pressures on bilateral brachial and tibial arteries. ABI < or = 0.9 was used as the diagnostic criteria for PAD identification. The follow-up survey was conducted from November 2005 to January 2006. RESULTS: Of 1606 male participants with hypertension at baseline, 406 (25.3% ) were in low-ABI group and 1200 (74.7%) were in normal-ABI group. Older age, TC, history of diabetes, history of smoking and 2-grade hypertension were associated with low ABI in male patients with hypertension. During the (12.87 +/- 2.94) months follow-up, there were 153 deaths. Of which, 62 were attributable to CVD. Low ABI was associated with adjusted all-cause and CVD mortality risk of 1.728 (1.223-2.441) and 2.388 (1.409-4.046) respectively in Cox regression models. Rate of survival for the low-ABI group was significantly worse than for the normal-ABI group. The risk of all-cause and CVD mortality was increased with the decline of ABI. CONCLUSION: Low ABI is independently associated with the high risks of all-cause and CVD mortality in Chinese male patients with hypertension. The utility of ABI as a tool for predicting mortality in the patients with hypertension should be popularized.