Evidences for the mechanism of Shenmai injection antagonizing doxorubicin-induced cardiotoxicity.

BACKGROUND: Doxorubicin (DOX) is a widely used antitumor drug. However, its clinical application is limited for its serious cardiotoxicity. The mechanism of DOX-induced cardiotoxicity is attributed to the increasing of cell stress in cardiomyocytes, then following autophagic and apoptotic responses. Our previous studies have demonstrated the protective effect of Shenmai injection (SMI) on DOX-induced cardiotoxicity via regulation of inflammatory mediators for releasing cell stress. PURPOSE: To further investigate whether SMI attenuates the DOX-induced cell stress in cardiomyocytes, we explored the mechanism underlying cell stress as related to Jun N-terminal kinase (JNK) activity and the regulation of autophagic flux to determine the mechanism by which SMI antagonizes DOX-induced cardiotoxicity. STUDY DESIGN: The DOX-induced cardiotoxicity model of autophagic cell death was established in vitro to disclose the protected effects of SMI on oxidative stress, autophagic flux and JNK signaling pathway. Then the autophagic mechanism of SMI antagonizing DOX cardiotoxicity was validated in vivo. RESULTS: SMI was able to reduce the DOX-induced cardiomyocyte apoptosis associated with inhibition of activation of the JNK pathway and the accumulation of reactive oxygen species (ROS). Besides, SMI antagonized DOX cardiotoxicity, regulated cardiomyocytes homeostasis by restoring DOX-induced cardiomyocytes autophagy. Under specific circumstances, SMI depressed autophagic process by reducing the Beclin 1-Bcl-2 complex dissociation which was activated by DOX via stimulating the JNK signaling pathway. At the same time, SMI regulated lysosomal pH to restore the autophagic flux which was blocked by DOX in cardiomyocytes. CONCLUSION: SMI regulates cardiomyocytes apoptosis and autophagy by controlling JNK signaling pathway, blocking DOX-induced apoptotic pathway and autophagy formation. SMI was also found to play a key role in restoring autophagic flux for counteracting DOX-damaged cardiomyocyte homeostasis.

Sleep deprivation aggravates brain injury after experimental subarachnoid hemorrhage via TLR4-MyD88 pathway.

Subarachnoid hemorrhage (SAH) is a life-threatening cerebrovascular disease, and most of the SAH patients experience sleep deprivation during their hospital stay. It is well-known that sleep deprivation is one of the key components of developing several neurological disorders, but its effect on brain damage after SAH has not been determined. Therefore, this study was designed to evaluate the effect of sleep deprivation using an experimental SAH model in rats. Induction of sleep deprivation for 24 h aggravated the SAH-induced brain damage, as evidenced by brain edema, neuronal apoptosis and activation of caspase-3. Sleep deprivation also worsened the neurological impairment and cognitive deficits after SAH. The results of immunostaining and western blot showed that sleep deprivation increased the activation of microglial cells. In addition, sleep deprivation differently regulated the expression of anti-inflammatory and pro-inflammatory cytokines. The results of immunofluorescence staining and western blot showed that sleep deprivation markedly increased the activation of Toll-like receptor 4 (TLR4) and myeloid differentiation primary response protein 88 (MyD88). Mechanically, treatment with the TLR4 inhibitor TAK-242 or the MyD88 inhibitor ST2825 significantly attenuated the brain damage and neuroinflammation induced by sleep deprivation after SAH. In conclusion, our results indicate that sleep deprivation aggravates brain damage and neurological dysfunction following experimental SAH in rats. These effects were mediated by the activation of the TLR4-MyD88 cascades and regulation of neuroinflammation.

The aging properties and phase morphology of silica filled silicone rubber/butadiene rubber composites.

Large amounts of antioxidants are used in unsaturated rubber composites, such as butadiene rubber (BR), which would inevitably cause surface discoloration. In this study, silicone rubber (VMQ) was blended with BR for improving its anti-aging properties. It was found that VMQ/BR exhibits better thermal oxidative aging and ozone aging resistance than BR, especially for 20/80 VMQ/BR. Atomic force microscopy (AFM) and transmission electron microscopy (TEM) were applied to characterize the phase morphology of VMQ-silica master-batch/BR, indicating that VMQ phases present island-dispersed domains of circular and elliptical shapes in the BR matrix, and silica particles mainly exist at the interface between BR and VMQ phases. These are two decisive factors for the improved aging properties of VMQ/BR.

Protective effect of Shenmai injection on doxorubicin-induced cardiotoxicity via regulation of inflammatory mediators.

BACKGROUND: Doxorubicin (DOX) is a chemotherapy drug for malignant tumors. The clinical application of DOX is limited due to its dosage relative cardiotoxicity. Oxidative damage and cardiac inflammation appear to be involved in DOX-related cardiotoxicity. Shenmai injection (SMI), which mainly consists of Panax ginsengC.A.Mey.and Ophiopogon japonicus (Thunb.) Ker Gawl, is widely used for the treatment of atherosclerotic coronary heart disease and viral myocarditis in China. In this study, we investigated the protective effect of Shenmai injection on doxorubicin-induced acute cardiac injury via the regulation of inflammatory mediators. METHODS: Male ICR mice were randomly divided into seven groups: control, DOX (10 mg/kg), SMI (5 g/kg), DOX with pretreatment with SMI (0.5 g/kg, 1.5 g/kg or 5 g/kg) and DOX with post-treatment with SMI (5 g/kg). Forty-eight hours after the last DOX administration, all mice were anesthetized for ultrasound echocardiography. Then, serum was collected for biochemical and inflammatory cytokine detection, and heart tissue was collected for histological and Western blot detection. RESULTS: A cumulative dose of DOX (10 mg/kg) induced acute cardiotoxicity in mice manifested by altered echocardiographic outcome, and increased tumor necrosis factor, interleukin 6 (IL-6), monocyte chemotactic protein 1, interferon-γ, and serum AST and LDH levels, as well as cardiac cytoplasmic vacuolation and myofibrillar disarrangement. DOX also caused the increase in the expression of IKK-α and iNOS and produced a large amount of NO, resulting in the accumulation of nitrotyrosine in the heart tissue. Pretreatment with SMI elicited a dose-dependent cardioprotective effect in DOX-dosed mice as evidenced by the normalization of serum inflammatory mediators, as well as improve dcardiac function and myofibril disarrangement. CONCLUSIONS: SMI could recover inflammatory cytokine levels and suppress the expression of IKK-α and iNOS in vivo, which was increased by DOX. Overall, there was evidence that SMI could ameliorate DOX-induced cardiotoxicity by inhibiting inflammation and recovering heart dysfunction.

[Effects of transforming growth factor-beta1 on rat cardiocyte hypertrophy].

AIM: To investigate the effects of transforming growth factor-beta1 (TGF-beta1) and signal protein Smad3 on rat myocardial hypertrophy. METHODS: The total protein was analysed by flow cytometer assay to judge the hypertrophy of myocardial cell incubated with different level of TGF-beta1 in cultured myocardial cells of neonatal rats. The models of rat cardiac hypertrophy were produced with constriction of the abdominal aorta. At the different time after the operation, the rats were killed, and the left ventricular mass indexes (LVMl) were investigated. The mRNA expressions of TGF-beta1 and Smad3 of cultured cells and hypertrophic left ventricles were assessed by RT-PCR, the protein expressions of Smad3 were assessed by Western blot. RESULTS: In cultured neonatal myocardial cells, different level TGF-beta1 could significantly increase the total protein, and TGF-beta1 (3 ng/ml) could increase the expression of mRNA and protein of Smad3 and continued for 8 h of cultured cardiomyocytes. The LVMI and the expression of TGF-beta1 mRNA and Smad3 mRNA/protein of hypertrophic left ventricle were increased at the 3rd day after the operation and continued for 4 weeks. The peak expression of them was in 2 weeks after operation. CONCLUSION: TGF-beta1 has the effects on rat myocardial hypertrophy, signal protein Smad3 is included in the pathologic progress of rat myocardial hypertrophy.