Mitoxantrone: Propensity for free radical formation and lipid peroxidation — implications for cardiotoxicity

Summary Results of comparative studies on stimulation of the rates of cofactor consumption, superoxide generation and hydrogen peroxide production by mitoxantrone (Novantrone®; dihydroxyanthracenedione; MXN), ametantrone (AM), doxorubicin (DOX) and daunorubicin (DNR) in the presence of NADPH-cytochrome P-450 reductase, NADH dehydrogenase, or rabbit hepatic microsomes have been reported. MXN and AM were substantially less effective in stimulating the rate of cofactor oxidation, superoxide formation or hydrogen peroxide production relative to the anthracyclines. In the presence of P-450 reductase, the rate of NADPH oxidation or superoxide generation produced by 100 M MXN or AM was only 15% and 2% respectively of that produced by 100 M anthracycline.The effects of MXN and AM on lipid peroxidation in hepatic microsomes, cardiac sarcosomes and cardiac mitochondria were determined and compared with those produced by ADM. MXN and AM at 50 M inhibited the basal rate of NADPH-dependent rabbit liver microsomal lipid peroxidation by 50%; in contrast, DOX enhanced the rate of hepatic microsomal lipid peroxidation by 2-and 2.5-fold at 100 and 200 M, respectively. Rabbit cardiac sarcosomal NADPH-dependent lipid peroxidation was inhibited completely at 100 M anthracenedione. NADH-dependent lipid peroxidation in cardiac mitochondria was diminished by 50 M MXN and AM, whereas 50 M DOX produced a 2-fold stimulation in lipid peroxidation. The anthracenediones also effectively inhibited DOX-stimulated lipid peroxidation with 50% inhibition occurring at 4 M (MXN) and 6 M (AM). Moreover, both MXN and AM potently inhibited iron (100 M)-stimulated lipid peroxidation in rabbit hepatic microsomes with 80% inhibition produced by 15 M anthracenedione.These results are consistent with the diminished cardiotoxicity of mitoxantrone and ametantrone relative to DOX or DNR and may require a reassessment of the role of lipid peroxidation in the mechanism(s) of quinone antineoplastic agent-mediated cardiotoxicity.     

Intravenous Lipid Emulsions in the Prevention and Treatment of Liver Disease in Intestinal Failure

The development of intestinal failure-associated liver disease (IFALD) in pediatric and adult patients on parenteral nutrition is usually multifactorial in nature due to nutritional and non-nutritional causes. The role of lipid therapy as a contributing cause is well-established with the pathophysiological pathways now better understood. The review focuses on risk factors for IFALD development, biological effects of lipids, lipid emulsions and the mechanisms of lipid toxicity observed in laboratory animals followed by a synopsis of clinical studies in pediatric and adult patients. The introduction of fish oil-based lipid emulsions that provide partial or complete lipid replacement therapy has resulted in resolution of IFALD that had been associated with soybean oil-based therapy. Based on case reports and cohort studies in pediatric and adult patients who were at risk or developed overt liver disease, we now have more evidence that an early switch to partial or complete fish oil–based lipid therapy should be implemented in order to successfully halt and reverse IFALD.     

Matcha Green Tea Alleviates Non-Alcoholic Fatty Liver Disease in High-Fat Diet-Induced Obese Mice by Regulating Lipid Metabolism and Inflammatory Responses

Lately, matcha green tea has gained popularity as a beverage and food additive. It has proved to be effective in preventing obesity and related metabolic syndromes. However, the underlying mechanisms of its control effects against non-alcoholic fatty liver disease (NAFLD) are complicated and remain elusive. In the present study, we performed an in vivo experiment using male C57BL/6 mice fed with a high-fat diet and simultaneously treated with matcha for six weeks. Serum biochemical parameters, histological changes, lipid accumulation, inflammatory cytokines, and relevant indicators were examined. Dietary supplementation of matcha effectively prevented excessive accumulation of visceral and hepatic lipid, elevated blood glucose, dyslipidemia, abnormal liver function, and steatosis hepatitis. RNA sequencing analyses of differentially expressed genes in liver samples indicated that matcha treatment decreased the activity of lipid droplet-associated proteins and increased the activity of cytochrome P450 enzymes, suggesting improved metabolic capacity and liver function. The current study provided evidence for new dietary strategies based on matcha supplementation to ameliorate lipotoxicity-induced obesity and NALFD.     

血脂水平与缺血性脑卒中认知预后的关系研究

目的 探讨血脂水平与缺血性脑卒中认知预后的关系。方法 对序贯收集的首次发病急性缺血性脑卒中患者做血脂全套分析,用MMSE进行认知功能随访。对发病后三个月MMSE评分与血脂指标进行单因素及多因素分析。结果 认知评分较低组TG、TC、ApoB、LDL－C显著较高。TG、TC、APOb、LDL－C机遇比分别为4．37（95％CI0．08－0．64）、3．35（2．25－4．99）、3．95（0．05－1．41）、6．68（0．05－0．45）。多元逐步回归方程：三个月的MMSE评分＝37．655－0．075年龄＝2．015ApoB-0.930LDL-C-2.014梗塞个数。结论 血脂水平与缺血性脑卒中认知预后密切相关,LDL－C及ApoB是预测缺血性脑卒中认知预后的独立变量。     

活性氧对红细胞膜流动性影响的研究

目的 :研究活性氧诱导红细胞发生氧化溶血的机制。方法 :用不同浓度的 H2 O2 作用于离体正常红细胞 ,分别用比色法、硫代巴比妥酸荧光法、荧光偏振法测定红细胞溶血度、红细胞膜脂质过氧化物 (L PO)、红细胞膜微粘度。结果 :5 0 ,10 0 ,12 0 mm ol/ L 浓度的 H2 O2 作用于红细胞后 ,均引起红细胞发生氧化溶血 ,红细胞溶血度、红细胞膜 L PO、红细胞膜微粘度均明显增加 ;H2 O2 在 5 0～ 12 0 mm ol· L- 1浓度范围内 ,红细胞溶血度、红细胞膜 L PO、红细胞膜微粘度的增加与 H2 O2 有明显的量效关系 ;红细胞膜微粘度与红细胞溶血度呈明显正相关 ,红细胞膜 L PO与红细胞膜微粘度呈明显正关。结论 :活性氧引发红细胞膜脂质过氧化导致红细胞膜流动性降低在活性氧诱导红细胞发生氧化溶血的机制中起一定的作用     

中华眼镜蛇毒F组分对沙鼠脑缺血再灌注损伤的保护作用

目的：研究中华眼镜它毒F组分脑缺血再灌注损伤的保护作用,方法：结扎沙鼠双侧颈总动脉1h,造成前脑缺血模型,用比色法测定脑匀浆过氧化脂质的最终产物丙二醛（MDA）的含量及超氧化物歧化酶（SOD）的活性,结果：F组分0．9,0．3,0．1mg/kg可显著抑制脑内脂质过氧化,降低MDA的含量,并提高超化物歧化酶的活,性且呈一定的量效关系,同缺血再灌组比较P＜0．05,同阳性对照药尼莫通比较,P＞0．05,结论：中华眼镜蛇毒F组分对脑缺血再灌注损伤有保护作用,可能与抑制自由基的生成和促进自由基的清除有关。     

化湿汤对冠心病患者血浆心钠素、内皮素及 血脂的影响及临床观察

应用化湿汤治疗50例痰浊型冠心病（CHD）患,并与冠心Ⅱ号方治疗血瘀型冠心病患50例作对照。结果表明：两组皆取得较好的疗效。用药后不仅心绞痛等症状明显缓解,而且能改善心电图,降低血浆心钠素（ANP）,内皮素（ET）和血脂（TC、TG）等临床客观指标。其作用机制可能与阻滞细胞Ca^ 内流有关。     

低铅染毒大鼠体内脂质过氧化及抗氧化水平改变

目的：观察低剂量铅染毒后大鼠体内脂质过氧化水平改变,为铅的毒作用机制研究提供依据。方法：以醋酸铅为受试物,雄性Wistar大鼠为受试对象,分别观察其脏器脂质过氧化水平改变。结果：低铅染毒后,大鼠各脏器超氧化物歧化酶（SOD）、谷胱苷肽过氧化物酶（GSH－Px）及过氧化脂质（LPO）均有不同程度改变（P＜0.05,P＜0.01）,而巯基（－SH）含量仅肝脏变化较明显。结论：较低剂量的铅即可引起体内脂质过氧化水平的改变,而这种变化可能是铅的毒作用途径之一。     

葡萄籽提取物对四氯化碳诱导大鼠脂质过氧化反应的影响

目的 :研究葡萄籽提取物对四氯化碳 (CCl4 )引起的脂质过氧化反应和抗氧化能力的影响。方法 :通过对大鼠的体内实验 ,测定大鼠肝和脑组织中由 CCl4 诱导产生的过氧化脂质生成物丙二醛(MDA) (TBA法 )的含量、血清中的超氧化物歧化酶 (SOD) (比色法 )活性和血清中总抗氧化能力(T- AOC) (比色法 )。结果 :葡萄籽提取物可明显降低大鼠肝和脑组织中 MDA的生成量 ,明显升高血清中 SOD活性和 T- AOC。结论 :葡萄籽提取物具有明显的抗氧化作用。