The dose-limiting toxic effect of cyclophosphamide (CY) is cardiotoxicity. The pathogenesis of myocardial damage is poorly understood, and there is no established means of prevention. In previous ...studies, we suggested that for CY-induced cardiotoxicity, whereas acrolein is the key toxic metabolite, carboxyethylphosphoramide mustard (CEPM) is protective. We sought to verify that acrolein is the main cause of cardiotoxicity and to investigate whether aldehyde dehydrogenase (ALDH), which is associated with greater CEPM production, is involved in the protective effect for cardiotoxicity. We also evaluated the protective effect of N-acetylcysteine (NAC), an amino acid with antioxidant activity and a known acrolein scavenger.
H9c2 cells were exposed to CY metabolites HCY (4-hydroxy-cyclophosphamide), acrolein or CEPM. The degree of cytotoxicity was evaluated by MTT assay, lactate dehydrogenase (LDH) release, and the production of reactive oxygen species (ROS). We also investigated how the myocardial cellular protective effects of CY metabolites were modified by NAC. To quantify acrolein levels, we measured the culture supernatants using high performance liquid chromatography. We measured ALDH activity after exposure to HCY or acrolein and the same with pre-treatment with NAC.
Exposure of H9c2 cells to CEPM did not cause cytotoxicity. Increased ROS levels and myocardial cytotoxicity, however, were induced by HCY and acrolein. In cell cultures, HCY was metabolized to acrolein. Less ALDH activity was observed after exposure to HCY or acrolein. Treatment with NAC reduced acrolein concentrations.
Increased ROS generation and decreased ALDH activity confirmed that CY metabolites HCY and acrolein are strongly implicated in cardiotoxicity. By inhibiting ROS generation, increasing ALDH activity and decreasing the presence of acrolein, NAC has the potential to prevent CY-induced cardiotoxicity.
Innate immune activity plays an essential role in the development of Kawasaki disease (KD) vasculitis. Extracellular release of high mobility group box-1 (HMGB-1), an endogenous damage-associated ...molecular pattern protein that can activate the innate immune system and drive host inflammatory responses, may contribute to the development of coronary artery abnormalities in KD. Prednisolone (PSL) added to intravenous immunoglobulin treatment for acute KD may reduce such abnormalities. Here, we evaluate the dynamics of HMGB-1 and therapeutic effects of PSL on HMGB-1-mediated inflammatory pathways on KD vasculitis
in vitro
. Serum samples were collected prior to initial treatment from patients with KD, systemic juvenile idiopathic arthritis (sJIA), and from healthy controls (VH), then incubated with human coronary artery endothelial cells (HCAECs). Following treatment of KD serum-activated HCAECs with PSL or PBS as a control, effects on the HMGB-1 signaling pathway were evaluated. Compared to that from VH and sJIA, KD serum activation induced HCAEC cytotoxicity and triggered extracellular release of HMGB-1. KD serum-activated HCAECs up-regulated extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and, p38 phosphorylation in the cytoplasm and nuclear factor kappa B (NF-κB) phosphorylation in the nucleus and increased interleukin (IL)-1β and tumor necrosis factor (TNF)-α production. PSL treatment of KD serum-activated HCAECs inhibited extracellular release of HMGB-1, down-regulated ERK1/2, JNK, p38, and NF-κB signaling pathways, and decreased IL-1β and TNF-α production. Our findings suggest that extracellular HMGB-1 plays an important role in mediating KD pathogenesis and that PSL treatment during the acute phase of KD may ameliorate HMGB-1-mediated inflammatory responses in KD vasculitis.
Background
Acute kidney injury (AKI) after cardiac surgery (CS-AKI) in children with congenital heart disease is a serious complication closely associated with high morbidity and mortality. Kidney ...Disease: Improving Global Outcomes (KDIGO) AKI staging demonstrates high sensitivity for detecting AKI and predicting associated in-hospital mortality. However, neonatal-modified KDIGO criteria (n-KDIGO), recently introduced as a standard diagnostic tool, for CS-AKI have not been fully validated. Here, we evaluated the incidence of risk factors and postoperative outcomes of neonatal CS-AKI.
Methods
We retrospectively studied 114 consecutive neonates who underwent cardiac surgery at the Kagoshima University Hospital. CS-AKI was classified using the n-KDIGO criteria. Risk adjustment in congenital heart surgery (RACHS-1) score was used to predict the complexity-adjusted mortality and % fluid overload (%FO) was used to monitor fluid balance in pediatric cardiac surgery.
Results
Among 81 patients, neonatal CS
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AKI occurred in 57 (70.4%) patients according to n-KDIGO criteria. Of these, 28 (34.6%) patients reached n-KDIGO 1, 17 (21.0%) reached n-KDIGO 2, and 12 (14.8%) reached n-KDIGO 3. Patients with CS-AKI had significantly higher vasoactive-inotropic score levels, longer operative times, and higher %FO than patients without CS-AKI. Notably, increased duration of cardiopulmonary bypass times and %FO were risk factors for the development of neonatal CS-AKI. The n-KDIGO-based severe AKI grade had higher risk of in-hospital mortality; however, the n-KDIGO-based mild AKI grade was not associated with any postoperative outcomes.
Conclusions
CS-AKI based on n-KDIGO criteria is common in neonates and is closely associated with higher mortality, especially in patients with severe CS-AKI.
Drug resistance is a major problem in treatment with nelarabine, and its resolution requires elucidation of the underlying mechanisms. We established two nelarabine-resistant subclones of the human ...T-cell lymphoblastic leukemia cell line CCRF-CEM. The resistant subclones showed changes in the expression of several genes related to nelarabine intracellular activation and inhibition of apoptosis. Activation of the Akt protein upon nelarabine treatment was observed in both subclones. The combination treatment with nelarabine and PI3K/Akt inhibitors was shown to inhibit cell growth. Cross-resistance was observed with ara-C and not with vincristine, daunorubicin, or etoposide treatment. Thus, changes in the expression of cellular activation-related genes, inhibition of apoptosis, and induction of Akt may be involved in the development of nelarabine resistance in the CCRF-CEM cell model. The use of different classes of chemotherapeutic agents and combination therapy with PI3K/Akt pathway inhibitors may be used to overcome resistance to nelarabine.
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