Honokiol Protects against Anti-ß1-Adrenergic Receptor Autoantibody-Induced Myocardial Dysfunction via Activation of Autophagy.

Myocardial diseases are prevalent syndromes with high mortality rate. The exploration of effective interference is important. Anti-ß1-adrenergic receptor autoantibody (ß1-AAB) is highly correlated with myocardial dysfunction. The actions and underlying mechanisms of honokiol (HNK) in ß1-AAB-positive patients await to be unraveled. In this study, we established a rat model of ß1-AAB positive with myocardial dysfunction. Cardiac function following ß1-AR-ECII administration was analyzed using the VisualSonics Vevo 770 High-Resolution In Vivo Imaging System. The levels of autophagy-related proteins were detected by Western blotting. Our data revealed that HNK reversed ß1-AAB-induced effects and protected myocardial tissues from dysfunction. After HNK treatment, the cardiac contractile ability increased and the LDH activity decreased. HNK attenuated myocardial degeneration. In addition, HNK promoted the activation of the AMP-dependent protein kinase/Unc-51-like autophagy activating kinase (AMPK/ULK) pathway and activated autophagy. These results suggest that HNK protects against ß1-AAB-induced myocardial dysfunction via activation of autophagy and it may be a potentially therapeutic compound for ß1-AAB-positive myocardial diseases.

Astragaloside IV inhibits ventricular remodeling and improves fatty acid utilization in rats with chronic heart failure.

Chronic heart failure (CHF) is the end-stage of many cardiovascular diseases and severely affects the patients' lifespan. Inhibiting ventricular remodeling is thus a primary treatment target for CHF patients. Astragaloside IV (AS-IV) can improve cardiac function and protect myocardial cells. The study aims to investigate the effects of AS-IV on ventricular remodeling and explore its role in regulating energy metabolism using a rat CHF model. Sprague-Dawley rats were divided into five groups (n=20 per group): CHF + benazepril hydrochloride (Benazepril HCL), CHF + low-dose (30 mg.kg-1day-1) AS-IV, CHF + high-dose (60 mg.kg-1day-1) AS-IV, and a sham control group. After 8 weeks of treatment, the cardiac structure and functional parameters were measured. Morphological changes in the myocardial tissue in five groups were evaluated. Protein and mRNA expression of peroxisome proliferator-activated receptor α (PPARα), medium-chain acyl-CoA dehydrogenase (MCAD), and muscle carnitine palmitoyl transferase-1 (MCPT1) were also analyzed. Our results showed that the left ventricular mass index (LVMI), collagen volume fraction (CVF), and free fatty acid (FFA) concentration of CHF group rats increased when compared with sham control group, while the protein and mRNA expressions of PPARα, MCAD, and MCPT1 decreased in CHF. Importantly, treatment with AS-IV (CHF + AS-IV group) showed improved heart function and structure, increased expression of PPARα, MCAD, and MCPT1 and improved FFA utilization in comparison with CHF group. In conclusion, our study shows that AS-IV inhibits ventricular remodeling, improves cardiac function, and decreases FFA concentration of CHF model rats. Our findings suggest a therapeutic potential of using AS-IV in CHF.

Effects of ramipril on serum monocyte chemoattractant protein 1, interleukin-18, and interleukin-10 in elderly patients with acute coronary syndrome.

Acute coronary syndrome (ACS) is a clinical syndrome caused by acute myocardial ischemia and a severe stage of coronary atherosclerosis heart disease. The aim of this study was to clarify whether ramipril was a therapeutic agent against monocyte chemoattractant protein 1 (MCP-1), interleukin 18 (IL-18), and interleukin 10 (IL-10) in elderly patients with ACS. A total of 190 subjects including 72 elderly patients with ACS (78.1% male, mean age 67.12 +/- 5.06 years), 60 elderly patients with stable angina pectoris (76.9% male, mean age 68.00 +/- 4.52 years), and 58 healthy volunteers (77.8% male, mean age 65.96 +/- 4.18 years) were recruited into the study. Serum MCP-1, IL-10, and IL-18 were determined in 132 elderly patients by enzyme-linked immunosorbent assay (ELISA) before and after treatment with low doses of ramipril (2.5-5 mg/day), and were determined in 58 healthy volunteers. The levels of serum MCP-1 and IL-18 were much higher in elderly patients with ACS than those in elderly patients with SAP and healthy volunteers. After treating with ramipril, the levels of MCP-1 and IL-18 were decreased in elderly patients with ACS. Moreover, ramipril significantly increased serum IL-10 in elderly patients with ACS. Ramipril plays an important role in elderly patients with ACS. With decreasing MCP-1 and IL-18, it can ameliorate cytokine-associated cardiac damage. This study may provide a new recognition of angiotensin-converting enzyme inhibitor for the treatment of ACS.

Over-expression of metallothionein predicts chemoresistance in breast cancer.

Metallothionein (MT) plays a role in fundamental cellular processes such as proliferation, apoptosis and differentiation. We examined MT expression in women with invasive breast ductal carcinoma who underwent mastectomy/lumpectomy without neo-adjuvant treatment. We showed that MT was over-expressed in 87.9% of breast cancer tissues examined, with the mean percentage of positive cells at 30%. There were two patterns of MT expression: predominantly cytoplasmic in 75.9% and nuclear in 24.1% of MT-positive cases. Higher MT scores were associated with poorer histological grade (p = 0.009) but were independent of age, tumour size and oestrogen receptor status. For patients who were treated with adjuvant chemotherapy (cyclophosphamide/methotrexate/5 fluorouracil- or doxorubicin-based regimes), those with high MT expression had a significantly lower recurrence-free survival (p = 0.048), suggesting a role of MT in predicting disease recurrence. Down-regulation of MT in MCF-7 cells by silencing the MT-2A gene (the most abundantly expressed of the 10 known functional MT isoforms) increased chemosensitivity of the cells to doxorubicin. To examine the mechanisms underlying these clinical data, we used siRNAs to decrease MT-2A mRNA expression and protein expression. In MT down-regulated cells challenged with the IC(50) concentration of doxorubicin, we observed a significant reduction in cell viability. Cell cycle analysis also revealed a corresponding increase in apoptosis in the MT down-regulated cells following doxorubicin exposure, showing that down-regulation of MT increased susceptibility to doxorubicin cytotoxicity. The data suggest that MT could be a potential marker of chemoresistance and a molecular therapeutic target.