Aloe Emodin Reduces Cardiac Inflammation Induced by a High-Fat Diet through the TLR4 Signaling Pathway.

BACKGROUND: Aloe emodin (AE) is a lipid-lowering agent, which could be used to treat hyperlipidemia, thereby reducing the risk of cardiovascular disease. Recent evidence suggests that hyperlipidemia is associated with many cardiac pathological alterations and might worsen myocardial damages. PURPOSE: The purpose of this study is to evaluate the potential roles and mechanisms of AE in hyperlipidemia-induced oxidative stress and inflammation in the heart. Study Design. We established a hyperlipidemia-induced cardiac inflammation model in rats and cells then administered AE and observed its effect on hyperlipidemia-induced cardiac inflammation. METHODS: We used a mouse model of hyperlipidemia caused by a high-fat diet (HFD) for 10 weeks and cell culture experimental models of inflammation in the heart stimulated by PA for 14 h. Inflammatory markers were detected by qRT-PCR, WB, and immunofluorescence. RESULTS: We demonstrated that the expression levels of proinflammatory cytokines IL-1ß, IL-6, and TNF-α were increased in the HFD group compared to the normal diet (ND) group, whereas AE treatment significantly reduced their levels in the myocardium. In addition, vascular cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM-1) protein expressions were also inhibited by AE. Our in vitro study showed AE treatment dose-dependently decreased the expression of IL-1ß, IL-6, and TNF-α were increased in the HFD group compared to the normal diet (ND) group, whereas AE treatment significantly reduced their levels in the myocardium. In addition, vascular cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM-1) protein expressions were also inhibited by AE. Our κB, and p-P65l in vivo and in vitro study showed AE treatment dose-dependently decreased the expression of IL-1. CONCLUSION: Taken together, our findings disclose that AE could alleviate HFD/PA-induced cardiac inflammation via inhibition of the TLR4/NF-κB signaling pathway. Thus, AE may be a promising therapeutic strategy for preventing hyperlipidemia-induced myocardial injury.κB, and p-P65l.

Inhibition of miR-23a attenuates doxorubicin-induced mitochondria-dependent cardiomyocyte apoptosis by targeting the PGC-1α/Drp1 pathway.

BACKGROUND AND PURPOSE: Doxorubicin (Dox)-induced cardiotoxicity limits its clinical use. A number of microRNAs (miRs) have been found essential in Dox-induced cardiotoxicity. The aim of the present study was to elucidate the effects of miR-23a on Dox-induced cardiomyocyte apoptosis and underlying mechanisms. EXPERIMENTAL APPROACH: Dox-induced cardiotoxicity model was established in primary neonatal rat ventricular myocytes (NRVMs). MTT assay, Live/Dead staining was employed to examine the viability and cell death of NRVMs. Mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) were measured. Protein levels of mitochondria biogenesis and fission/fusion associated factors including peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), dynamin-related protein-1 (Drp1) and mitofusin 2 (Mfn2) were detected. Meanwhile, apoptosis-related cytochrome c (Cyt c) and caspase-3 expression were examined by western blot. PGC-1α siRNA was employed to validate the role of miR-23a in Dox-induced cardiotoxicity. KEY RESULTS: MiR-23a expression was significantly increased by Dox concentration-dependently. Inhibition of miR-23a markedly increased viability and MMP, reduced cell death and ROS production of NRVMs. MiR-23a mimic significantly inhibited expression of its target PGC-1α. MiR-23a inhibitor significantly diminished phosphorylation of Drp1 without affecting Mfn2 expression. Protein expression of Cyt c and cleaved caspase-3 were markedly inhibited by miR-23a inhibitor. The protective effects of miR-23a inhibitor were reversed by PGC-1α siRNA. CONCLUSIONS AND IMPLICATIONS: Increased miR-23a promoted mitochondrial injury in the Dox-induced cellular model. Inhibition of miR-23a attenuated cardiomyocyte damage by directly targeting PGC-1α/p-Drp1, thereby inhibiting mitochondria-dependent apoptosis. These findings may provide a new potential target for the treatment of Dox-induced cardiotoxicity.

Ethyl 2-Succinate-Anthraquinone Attenuates Inflammatory Response and Oxidative Stress via Regulating NLRP3 Signaling Pathway.

Aloe-emodin widely possesses antibacterial, anti-inflammatory, antioxidant, antiviral, and anti-infectious properties. This study investigated the effect of ethyl 2-succinate-anthraquinone (Luhui derivative, LHD) on inflammation. In vitro, a THP-1 macrophage inflammation model, made by 100 ng/ml phorbol-12-myristate-13-acetate (PMA) and 1 µg/ml LPS for 24 h, was constructed. The LHD group (6.25 µmol/L, 12.5 µmol/L, 25 µmol/L, 50 µmol/L) had no effect on THP-1 cell activity, and the expression of IL-6 mRNA was down-regulated in a concentration-dependent manner, of which the 25 µmol/L group had the best inhibitory effect. The migration of THP-1 macrophages induced by LPS was decreased by the LHD. Moreover, the LHD suppressed ROS fluorescence expression by inhibiting MDA expression and increasing SOD activity. In vivo, we revealed that the LHD, in different doses (6.25 mg/kg, 12.5 mg/kg, 25 mg/kg, 50 mg/kg), has a protective effect on stress physiological responses by assessing the body temperature of mice. Interestingly, acute lung injury (e.g., the structure of the alveoli disappeared and capillaries in the alveolar wall were dilated and congested) and liver damage (e.g., hepatocyte swelling, neutrophil infiltration, and hepatocyte apoptosis) were obviously improved at the same condition. Furthermore, we initially confirmed that the LHD can down-regulate the expression of NLRP3, IL-1ß, and caspase-1 proteins, thereby mediating the NLRP3 inflammasome signaling pathway to produce anti-inflammatory effects. In conclusion, our results indicate that the LHD exerts anti-inflammatory activity via regulating the NLRP3 signaling pathway, inhibition of oxidative stress, and THP-1 macrophage migration.

Aloe-emodin relieves zidovudine-induced injury in neonatal rat ventricular myocytes by regulating the p90rsk/p-bad/bcl-2 signaling pathway.

BACKGROUND/AIMS: Zidovudine (3'-azido-2',3'-deoxythymidine; AZT) is a first-line drug for treatment of human immunodeficiency virus infection (HIV). However, its application is limited by cardiotoxicity due to cardiomyocyte injury. This study investigated whether Aloe-emodin (AE), an anthraquinone compound, protects against AZT-induced cardiomyocyte toxicity. METHODS: MTT, JC-1 assays and TUNEL were examined to verify the protective effect of AE against AZT-induced cardiomyocyte injury. Western blotting was performed to explore the anti-apoptotic effect of AE using anti-apoptotic proteins p90rsk, p-bad, and bcl-2 and pro-apoptotic proteins apaf-1, cleaved-caspase-3, and cytochrome c. RESULTS: We observed a protective effect of AE against cell viability decrease and TUNEL positive cells increase induced by AZT, which was counteracted by BI-D1870. Western blot analysis found that AE significantly inhibited cardiomyocyte apoptosis by activating p90rsk/p-bad/bcl-2 signaling pathway. Furthermore, BI-D1870 counteracted the anti-apoptotic effect of AE. CONCLUSIONS: Taken together, these results indicate that AE attenuated AZT-induced cardiomyocyte apoptosis by activating p90rsk.