OBJECTIVE: To investigate the effect of honokiol (HKL) for reducing doxorubicin (DOX)-induced cardiotoxicity in H9c2 cells and the underlying mechanisms. METHODS: H9c2 cells were divided into control group, DOX group, HKL + DOX group, and HKL+compound C+DOX group. After 24 h of corresponding treatment, the cells were examined for morphological changes and cell viability using CCK-8 assay. The mRNA expressions of the inflammatory factors including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) were detected by RT-PCR, and the protein levels of cleaved caspase-3, cytochrome c, NOD-like receptor pyrin domain containing 3 (NLRP3), caspase-1, apoptosis-associated speck-like protein containing a CARD (ASC), p-AMPK and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) were detected with Western blotting; the expressions of NLRP3 and p-AMPK also detected with immunofluorescence staining. RESULTS: DOX treatment caused swelling and significantly lowered the viability of H9c2 cells (P < 0.05), resulting also in increased mRNA expressions of TNF-α, IL-6 and IL-1β (P < 0.05) and protein expressions of cleaved caspase-3, cytochrome c, NLRP3, caspase-1 and ASC (P < 0.05) but reduced protein levels of p-AMPK and Nrf2 (P < 0.05); fluorescence staining showed significantly increased NLRP3 expression and decreased expression of p-AMPK in DOX-treated cells (P < 0.05). All these changes in COX-treated cells were significantly alleviated by HKL treatment (P < 0.05). The application of compound C obviously mitigated the protective effects of HKL against DOX-induced cardiotoxicity in H9c2 cells. CONCLUSIONS HKL can alleviate DOX-induced cardiotoxicity by inhibiting pyroptosis in H9c2 cells, and this effect is mediated by activation of AMPK to regulate Nrf2 signaling.
AMP-Activated Protein Kinases/metabolism* ; Allyl Compounds ; Biphenyl Compounds ; Cardiotoxicity/pathology* ; Caspase 3/metabolism* ; Cytochromes c ; Doxorubicin/adverse effects* ; Humans ; Interleukin-6/metabolism* ; Myocytes, Cardiac ; NF-E2-Related Factor 2/metabolism* ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Phenols ; Pyroptosis ; RNA, Messenger/metabolism* ; Tumor Necrosis Factor-alpha/metabolism*

BackgroundCardiotoxicity is one of the most serious chronic complications of anthracyclines therapy. Assessment of the left ventricular ejection fraction (LVEF) fails to detect subtle cardiac dysfunction of left ventricular (LV). This study aimed to detect and evaluate new parameters of subclinical anthracyclines' cardiotoxicity in children with solid tumor.

MethodsA detailed echocardiographic examination was performed in 36 children with hepatoblastoma or rhabdomyosarcoma after receiving anthracyclines' chemotherapy and 36 healthy controls from January 2015 to December 2016. The LVEF, ratio of early diastolic peak velocity of transmitral flow (E) and septal diastolic e' mitral annular peak velocity (e'), tricuspid annular plane systolic excursion (TAPSE), and LV global longitudinal strain (GLS) were evaluated using M-mode, tissue Doppler imaging (TDI), and two-dimensional speckle tracking echocardiography (2D-STE), respectively. Echocardiographic parameters were compared between patient group and healthy controls. All patients were divided into two subgroups based on their anthracyclines' cumulative dosage (<300 mg/m subgroup and ≥300 mg/m subgroup).

ResultsAll patients had no presentation of heart failure and LVEF within normal range (65.7 ± 5.1%). Compared with healthy controls, the mean E/e' increased significantly (7.9 ± 0.7 vs. 10.2 ± 3.5, t = 3.72, P < 0.01), mean TAPSE decreased significantly (17.2 ± 1.3 mm vs. 14.2 ± 3.0 mm, t = -4.03, P < 0.01), and mean LV GLS decreased significantly (-22.2% ± 1.9% vs. -17.9% ± 2.9%, t = -5.58, P < 0.01) in patient group. Compared with subgroup with anthracyclines' cumulative dosage < 300 mg/m, mean LV GLS decreased significantly (-18.7 ± 2.7% vs. -16.5 ± 2.1%, t = 2.15, P = 0.04), the mean E/e' increased significantly (9.1 ± 1.5 vs. 11.5 ± 4.9, t = -2.17, P = 0.04), and mean TAPSE decreased significantly (14.2 ± 2.1 mm vs. 12.5 ± 2.2 mm, t = -2.82, P = 0.02) in subgroup with anthracyclines' cumulative dosage ≥300 mg/m.

ConclusionsLV GLS is helpful in the early detection of subclinical LV dysfunction using 2D-STE. E/e' and TAPSE are other sensitive parameters in detecting subclinical cardiac dysfunction of both ventricles by TDI. These parameters show significant change with different anthracyclines' cumulative dosage, so cumulative dosage should be controlled in clinical treatment.

Anthracyclines ; therapeutic use ; Cardiotoxicity ; diagnosis ; Child, Preschool ; Echocardiography ; Female ; Heart Failure ; drug therapy ; pathology ; Humans ; Infant ; Male ; Ventricular Function, Left ; drug effects

OBJECTIVETo investigate the protect effects of sodium ferulate (SF) on the daunormbicin(DNR-induced cardiotoxicity in juvenile rats.

METHODSForty male juvenile SD rats were randomly divided into control group (Control), daunorubicin group (DNR), sodium ferudate treatment group (DNR + SF), sodium ferudate group (SF) (n = 10) . Juvenile rats were intraperitoneally treated with DNR (2.5 mg/kg every week for a cumulative dose of 10 mg/kg) preparation immature myocardial injury model in presence with SF (60 mg/kg) oral treat- ment for 25 days. The left ventricular pressure and its response to isoproterenol were measured using left ventricular catheter. Rat myocardium myocardial pathology specimens and ultrastructure changes were also observed. The expression of cardiac Troponin I (cTNI) was detected by Western blot and RT-PCR. Results: SF treatment could inhibit the decreasing of heart rates induced by DNR damage (P < 0.05); it could increase the left ventrivular end diastolic pressure(LVEDP), heart rate, the maximal left ventrivular systolic speed(LVP + dp/dtmax) and the maximal left ventrivular diastolic speed (LVP-dp/dtmax) responding to isoproterenol stimulation(P < 0.01); SF also could improve the myocardial ultrastructure injuries and inhibit the decreasing of cTNI expression caused by DNR damages (P < 0.05).

CONCLUSIONSF treatment could alleviate the decreasing of cardiac reservation induced by DNR damages in juvenile rats, which might be related to its reversing the effects on the cardiac systolic and diastolic function injuries and its inhibiting effects on the decreasing of cTNI expression caused by DNR. The mechanism of SF preventing daunorubicin-induced cardiotoxicity in juvenile rats is relevant to inhabited cardiac Troponin I expression.

Animals ; Blood Pressure ; Cardiotoxicity ; drug therapy ; Coumaric Acids ; pharmacology ; Daunorubicin ; toxicity ; Heart ; physiopathology ; Heart Rate ; Isoproterenol ; Male ; Myocardium ; pathology ; Protective Agents ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Troponin I ; metabolism