Cycloastragenol ameliorates experimental heart damage in rats by promoting myocardial autophagy via inhibition of AKT1-RPS6KB1 signaling.

Cycloastragenol, a naturally occurring compound in Astragali Radix, has been demonstrated to possess various pharmacological actions including anti-aging, anti-inflammation, anti-fibrosis, antibacterial, liver and endothelium protection. However, whether cycloastragenol ameliorates heart failure remains unclear. Isoproterenol administration to rats triggered classic cardiac damage, as demonstrated by objective parameters of cardiac dysfunction. The treatment of cycloastragenol improved deranged cardiac parameters in the isoproterenol-induced heart damage model in a dose-dependent manner. At the same time, cycloastragenol markedly ameliorated cardiac histological changes and down-regulated serum levels of various neuroendocrine factors including norepinephrine, aldosterone, brain natriuretic peptide, endothelin 1, angiotensin II and so on. Moreover, the expressions of matrix metalloproteinase-2 (MMP-2) and MMP-9 in rat heart were also inhibited by cycloastragenol. Mechanistically, augmenting autophagy of myocardial cells via the inhibition of AKT1-RPS6KB1 signaling contributed to the improvement of isoproterenol-induced rat heart failure by cycloastragenol. These results suggest that cycloastragenol ameliorates cardiac dysfunction and remodeling through promoting autophagy in myocardial cells and suppressing MMP-2 and MMP-9 expressions, indicating that it could be a drug candidate for patients with congestive heart failure.

Icariin attenuated oxidative stress induced-cardiac apoptosis by mitochondria protection and ERK activation.

Our previous study showed that Icariin (ICA) has anti-cardiac hypertrophy effect in rats with an unknown mechanism. In the present study, we aimed to clarify the cardiac protective effect and mechanism of ICA in vitro. H9C2 cardiac myocytes were incubated with H2O2 to build up the oxidative stress injury model. The results showed that pre-treatment of ICA protected cells against the toxicity induced by H2O2. H2O2 treatment significantly reduced H2O2-induced apoptosis, evidenced by lower Annexin V/PI stained cells and less PARP and caspase-3/9 activation. Mitochondria membrane potential (MMP) dissipation occurred following the exposure of H2O2, which could be prevented by ICA treatment. Moreover, Ca2+ homeostasis was preserved by ICA and ROS generation was significantly suppressed by ICA incubation. Interestingly, ICA treatment increased the phosphorylation of upstream ERK mitogen-activated protein kinase (MAPK) while ERK inhibitor U1026 could reverse the protective effect of ICA. Overall, ICA seems to protect the cardiac cells from oxidative stress injury through ROS scavenge and stimulation of ERK pathway which may explain its effects in vivo.

Icariin attenuates cardiac remodelling through down-regulating myocardial apoptosis and matrix metalloproteinase activity in rats with congestive heart failure.

OBJECTIVES: In this study, the anti-heart failure effect of icariin, a natural flavonol glycoside, and the underlying mechanisms were investigated. METHODS: Heart failure was induced by isoproterenol in male Sprague-Dawley rats. Matrix metalloproteinase activity was determined by gelatin zymography assay. The mRNA expression was determined by real-time PCR. The protein expression was determined by Western bolt. Mitochondria structure was examined by transmission electron microscopy. KEY FINDINGS: Isoproterenol administration resulted in a severe heart failure, as shown by the increased levels of left ventricular weight index, heart rate, left ventricular end diastolic pressure, maximal rate of left ventricular pressure decline (dp/dt(min) ), decreased levels of left ventricular systolic pressure and maximal rate of left ventricular pressure rise (dp/dt(max) ). Against these, icariin dose-dependently reversed the changes of these cardiac morphometric and haemodynamic parameters. In addition, icariin significantly inhibited serum levels of tumour necrosis factor-α, noradrenaline, angiotensin II and brain natriuretic peptide in rats with congestive hear failure and improved the histological changes, including cardiocyte hypertrophy, cardiocyte degeneration, inflammatory infiltration and cardiac desmoplasia. Furthermore, the expression and activity of matrix metalloproteinase (MMP)-2 and MMP-9, which regulate collagen production, were also blocked by icariin. Moreover, myocardial apoptosis was remarkably attenuated by icariin through regulating Bcl-2/Bax axle. CONCLUSIONS: Icariin ameliorates left ventricular dysfunction and cardiac remodelling through down-regulating matrix metalloproteinase-2 and 9 activity and myocardial apoptosis in rats with congestive heart failure.

Ethanol extract from Epimedium brevicornum attenuates left ventricular dysfunction and cardiac remodeling through down-regulating matrix metalloproteinase-2 and -9 activity and myocardial apoptosis in rats with congestive heart failure.

Epimedium, a traditional Chinese herb, has been used for the remedy of coronary heart disease, impotence and osteoporosis in traditional oriental medicine. However, despite extensive pharmacological studies, the molecular mechanism of the anti-heart failure effect of epimedium is little known. In the present study, we investigated the pharmacological action mechanism of ethanol extract of epimedium (EPI-ext) on isoproterenol-induced congestive heart failure (CHF) in rats. Isoproterenol administration resulted in severe heart failure, as shown by the increased levels of left ventricular (LV) weight index and heart rate, as well as LV end diastolic pressure, and by the decreased levels of LV systolic pressure, maximal rate of LV pressure rise, and maximal rate of LV pressure decline. EPI-ext dose-dependently reversed the changes of these cardiac morphometric and hemodynamic parameters. In addition, EPI-ext significantly inhibited the serum levels of tumor necrosis factor alpha, norepinephrine, angiotensin II and brain natriuretic peptide in rats with CHF and improved the histological changes including cadiocyte hypertrophy, cadiocyte degeneration, inflammatory infiltration, and cardiac desmoplasia. Furthermore, the expression and activities of matrix metalloproteinase-2 and -9, which regulate collagen production, were also blocked by EPI-ext. Moreover, myocardial apoptosis was remarkably attenuated by EPI-ext through the regulating Bcl-2/Bax axle. In conclusion, EPI-ext ameliorates LV dysfunction and cardiac remodeling through down-regulating matrix metalloproteinase-2 and -9 activity and myocardial apoptosis in rats with CHF.

Apolipoprotein B gene 3'VNTR polymorphism: association with plasma lipids and coronary heart disease in Han Chinese.

BACKGROUND: Studies that considered polymorphisms within the apolipoprotein B (APOB) gene as risk factors for coronary heart disease (CHD) have reported conflicting results. METHODS: The phenotypic effects of the 3'VNTR polymorphism of the APOB gene on the susceptibility to CHD were investigated in 120 unrelated healthy individuals and 137 CHD patients. The internal structure of APOB gene 3'VNTR alleles was also analyzed by the methods of SspI restriction mapping and DNA sequencing of the allele fragments. RESULTS: In total, 14 segregating alleles and 32 genotypes of APOB gene 3'VNTR were characterized in the pooled total of 257 subjects. The frequency of 3'VNTR-B alleles [hypervariable element (HVE) > or =38)] in the CHD cases was higher than that of the controls (10.95% vs. 5.00%, p<0.05). 3'VNTR-B allele was dependently related to total cholesterol levels (p<0.05). Compared with SS homozygotes, 3'VNTR-B allele carriers were associated with an increased risk of CHD (OR=2.137, 95% CI=1.055-4.328, p=0.0349). No significant differences in the internal structure and sequences of APOB gene 3'VNTR alleles were found between cases and controls. CONCLUSIONS: APOB gene 3'VNTR polymorphism exerts an impact on lipid metabolism and may contribute to the susceptibility to the development of CHD in Han Chinese.

Aqueous extract of Yin-Chen-Hao decoction, a traditional Chinese prescription, exerts protective effects on concanavalin A-induced hepatitis in mice through inhibition of NF-kappaB.

In traditional oriental medicine, Yin-Chen-Hao decoction is used for the remedy of liver diseases such as hepatitis, fatty liver, hepatocirrhosis and jaundice. However, despite extensive pharmacological study, the molecular mechanism of the anti-inflammatory effect of Yin-Chen-Hao decoction is poorly understood. In this study, we have investigated the pharmacological action on the mechanism of concanavalin A-induced T cell-dependent hepatitis in mice. Concanavalin A administration resulted in a severe liver injury. This was shown through increased levels of serum transaminase and lactic dehydrogenase, and increased liver DNA fragmentation and caspase-3 activity. Pretreatment with the aqueous extract from Yin-Chen-Hao decoction dose-dependently inhibited the elevation in transaminase and lactic dehydrogenase activity, and reduced liver DNA fragmentation and caspase-3 levels. There was an improvement in histological changes including inflammatory infiltration, hepatocyte necrosis and degeneration, and Kupffer cell hyperplasia. In addition, Yin-Chen-Hao decoction significantly inhibited tumour necrosis factor-alpha (TNF-alpha) production in-vitro and in-vivo. Moreover, the activation of nuclear factor kappa B (NF-kappaB), which regulates TNF-alpha production, was blocked by Yin-Chen-Hao decoction in-vitro and in-vivo. In conclusion, Yin-Chen-Hao decoction was capable of regulating T-cell-mediated liver injury in-vivo. This event may have depended on the decrease of TNF-alpha production through the inhibition of NF-kappaB activation.

Apolipoprotein A5 gene polymorphism -1131T-->C: association with plasma lipids and type 2 diabetes mellitus with coronary heart disease in Chinese.

Type 2 diabetes mellitus (DM) is associated with significant abnormalities of lipoprotein metabolism and coronary heart disease (CHD). The most commonly recognized lipid abnormality in type 2 DM is hypertriglyceridemia, which is known to be an independent risk factor for CHD in diabetics. The -1131T-->C polymorphism found in the newly identified apolipoprotein A5 ( APOA5 ) gene has been found to be associated with elevated plasma triglyceride (TG) concentrations in different racial groups. In this study, DNA samples from 155 control subjects, 172 type 2 diabetics and 113 type 2 DM patients with CHD were analyzed to examine the influence of APOA5 1131T-->C polymorphism on plasma lipids and the susceptibility to CHD in type 2 diabetics. The frequency of the APOA5 -1131C allele in the DM+CHD group was significantly higher than that of control subjects (37.2% vs. 27.7%, p=0.021). The distribution of the APOA5 -1131T-->C genotypes (TT, TC and CC) was 36.3%, 53.1% and 10.6% in type 2 DM patients with CHD, and 53.6%, 37.4% and 9.0% in controls, respectively (p=0.018). The frequencies of alleles and genotypes in type 2 diabetics were not significant compared to controls. In controls, plasma TG concentrations in subjects with the TT genotype were significantly lower than in those with TC/CC (0.92, 1.28 and 1.35 mmol/L for TT, TC and CC, respectively; p = 0.003 by ANOVA). These data suggest that the APOA5 -1131T-->C polymorphism might play a role in elevated plasma TG levels in type 2 diabetic patients in the Chinese population.

[Study on serum inhibin concentrations in women during menopausal transition].

OBJECTIVE: To investigate the changes of serum inhibin (Inh)-A, Inh-B concentrations during menopausal transition and the time relationship between changes of serum Inh-A, Inh-B and other reproductive hormone levels. METHODS: Serum Inh-A, Inh-B concentrations were measured by Serotec modified two-site enzyme immunoassay during different phases of normal menstrual cycle in 10 healthy reproductive women, any time of 10 postmenopausal women. So did the serum Inh-A on 5 - 9 days prior to next period (premenstrual phase) and Inh-B determinations on the 3rd day of menstrual cycle in 40 women of age 43 - 52 (menopausal transition group). In addition, serum follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E(2)), progesterone (P) levels were also determined when necessary for the purpose of analysis. RESULTS: The fluctuation patterns of serum Inh-A, Inh-B concentrations during normal menstrual cycle were completely different. About 48% of women during menopausal transition had normal luteal function as shown by the P levels during the premenstrual phase. The only significant change in these women as compared with the young was decrease of Inh-A concentration [(24.7 +/- 13.0) ng/L Vs (42.9 +/- 12.1) ng/L, P = 0.017] in the same phase. Further significant declines of serum Inh-A levels were seen in the luteal phase defect (LPD) and anovulatory (AOV) groups [(12.4 +/- 10.2) ng/L and (5.3 +/- 3.8) ng/L, P = 0.033, P < 0.000 1 respectively], until undetectable in the postmenopausal group. The day 3 Inh-B levels tended to decrease in the normal luteal and LPD groups, became undetectable in the AOV and postmenopausal groups (P = 0.001). Day 3 Inh-B levels was significantly lower in women with day 3 FSH > or = 10 IU/L than those with < 10 IU/L [(16.2 +/- 4.0) ng/L Vs (62.0 +/- 43.8) ng/L]. The elevation of day 3 FSH, LH levels was not significant until the AOV group (P = 0.009, P = 0.027 respectively), and the drop of E(2) levels until the postmenopausal group (P < 0.001). CONCLUSIONS: It is suggested that serum reproductive hormones should be measured in women of menopausal transition in order to know the stage of menopausal transition and to guide the clinical management. The decrease of serum Inh-A levels during the premenstrual phase is the earliest change of menopausal transition, and decrement of day 3 Inh-B levels a marker of decreased ovarian reserve.

[Hyperhomocysteinemia and deep-vein thrombosis].

OBJECTIVE: To study the relationship between plasma homocysteine (Hcy) level and deep-vein thrombosis (DVT), and analyze the interaction of Hcy, folate and methylenetetrahydrofolate reductase (MTHFR) gene polymorphism in patients with DVT. METHODS: Totally 69 patients with DVT and 111 healthy controls were included in our case-control study. We determined the MTHFR C677T genotypes by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP), measured the serum folate and vitamin B12 by radioimmunoassay (RIA), and measured the plasma homocysteine level by fluorescence polarization immunoassay (FPIA). RESULTS: The frequency of the MTHFR C677T TT genotype had no significant difference between DVT group and control group (P > 0.05). The plasma Hcy level was significantly higher in DVT group than in control group (13.03 +/- 8.74 mumol/L vs 10.14 +/- 4.30 mumol/L, P < 0.05). Both serum folate and VitB12 of patients with DVT were not significantly different from those of controls. The odds radios (OR) of hyperhomocysteinemia for DVT was 2.53 (95% CI 1.08-5.92). The interaction of low folate level and TT genotype increased the risk of DVT (OR = 3.12, 95% CI 1.17-8.38). CONCLUSION: Hyperhomocysteinemia may be an independent risk factor for DVT in Han nationality, while serum folate level and MTHRF C677T genotype are not. An interaction between serum folate level and MTHFR genotype that affect the Hcy level is an important risk factor for DVT.

[Clinical evaluation of two kinds homogenous assays for determination of high-density lipoprotein cholesterol].

OBJECTIVE: To evaluate the clinical efficacy of two kinds homogenous assays for direct determination of high-density lipoprotein cholesterol (HDL-C) based on the principle of polyanion polymer/detergent (PPD method) and polyethylene glycol-modified enzyme (PEGME) method. METHODS: The two homogenous methods were compared with the precipitation method (PTA-Mg2+ method), their precision, accuracy, specificity and interference were also analyzed. RESULTS: Both homogenous HDL-C assays were precise, having a within-run CV < 3%, day-to-day CV < 3% and total CV < 4%. The HDL-C values measured by the two homogenous methods correlated well with those by PTA-Mg2+ method (X): Y = 0.9316 X + 0.1063, r = 0.9762 for PPD method (Y); and Y = 0.9106 X + 0.1368, r = 0.9894 for PEGME method (Y). The linearity studies showed the two homogenous methods to be linear up to 4.14 mmol/L. The lowest detectable concentration of the two methods was apparently 0.08 mmol/L. Recoveries of the two methods were 94.1%-106.2%. Hemoglobin did not interfere with the HDL-C results in the two homogenous methods, whereas icteric samples with total bilirubin > 200 mg/L showed discrepancies. Lipemia up to triglyceride concentration of 17.0 mmol/L did not interfere with the two homogenous HDL-C assays. CONCLUSIONS: The two new homogenous HDL-C assays meet the requirements for accuracy, precision, ease of handling with massive sample, allow full automation, and are clinically useful.