基于网络毒理学探讨草乌心脏毒性

目的:通过建立草乌活性成分-作用靶点、蛋白相互作用、靶点相应的生物功能和通路网络,以及利用分子对接技术探讨草乌心脏毒性的作用机制。方法:通过中药系统药理学数据库和分析平台(Traditional Chinese Medicine Systems Pharmacology,TCMSP)和毒性与基因比较数据库(Comparative Toxicogenomics Database,CTD)筛选出草乌有毒候选成分。依据反向药效团匹配(Pharm Mapper)方法预测草乌毒性候选成分的作用靶点,与从人类基因数据库(Gene Cards)中寻找到的心脏相关基因蛋白进行比对,筛选出重合的蛋白作为草乌的潜在的心脏毒性靶点。采用Cytoscape软件构建草乌毒性候选成分-作用靶点网络。通过String数据库结合Cytoscape软件绘制蛋白相互作用网络,用DAVID平台对靶点生物功能及涉及的通路进行分析,最后用Discover Studio软件对关键蛋白与草乌毒性候选成分的结合进行验证。结果:草乌中筛选得到6种有毒候选成分,涉及27个心脏毒性作用靶点,网络分析结果表明靶点主要是通过参与心脏磷代谢,磷酸化的监管等磷相关的代谢和调节,以及通过FKBP1A,TGFB2,INSR等靶点对心脏的代谢,发育及形态产生重要的影响,进而产生心脏毒性。结论:利用中药多成分-多靶点-多通路的特点,探究了草乌心脏毒性作用机制,并预测了其可能存在的毒性,为进一步开展草乌心脏毒性作用机制研究提供了新思路和新方法。     

3种新型蛋白酶体抑制剂对斑马鱼心脏毒性的评价

为了观察3种新型蛋白酶体抑制剂对斑马鱼的心脏毒性并初步探讨其机制,将斑马鱼胚胎分别暴露于一系列浓度的化合物NNU395、NNU458和NNU459。于显微镜下观察并拍摄斑马鱼的心脏形态,统计死亡率及心率,并检测斑马鱼心脏发育相关基因的表达情况。结果显示,NNU395、NNU458和NNU459呈浓度依赖地增加了斑马鱼的死亡率,对斑马鱼胚胎的半数致死浓度分别为(179.7±12.2),(27.5±1.3)和(24.4±2.6)μmol/L,且较之各自改构前体,3种化合物对斑马鱼的毒性更低。120~200 μmol/L NNU395及30 μmol/L的NNU458或NNU459处理后的斑马鱼出现明显的心包水肿和心脏畸形。120~200 μmol/L的NNU395及0.1~30 μmol/L的NNU458或10~30 μmol/L的NNU459均显著降低斑马鱼的心率。3种化合物对斑马鱼心脏发育相关基因的表达都没有显著影响。本研究提示低浓度的NNU395、NNU458和NNU459对斑马鱼心脏无明显毒性,高浓度的3种化合物对斑马鱼可产生心血管毒性。     

基于CiteSpace对中医药治疗蒽环类所致心脏毒性的可视化分析

目的 通过文献计量学方法,评估中医药治疗蒽环类所致心脏毒性的研究趋势,并探讨机构合作、研究热点和前沿趋势。方法 计算机检索Web of Science、中国知网（CNKI）、万方、中国生物医学（CBM）和维普（VIP）数据库,检索2000年1月1日—2022年10月31日发表的关于中医药治疗蒽环类所致心脏毒性的中英文文献。运用文献计量学软件CiteSpace对国家、机构、期刊、作者、被引文献和关键词进行可视化分析。结果 检索到1134篇关于中医药治疗蒽环类所致心脏毒性的论文,其中英文文献237篇,中文文献897篇。该领域发文量逐年增加,发文量最多的国家是中国（117篇）;英文文献中发文量最多的机构是阿卜杜勒·阿齐兹国王大学（9篇）,中文文献发文量最多的机构是湖南中医药大学（45篇）。中医药治疗蒽环类心脏毒性主要以中成药研究为主,主要的治疗方向是蒽环类所致的心力衰竭和心肌病,心脏毒性早期更关注心肌损害,之后更关注心力衰竭。蒽环类心脏毒性研究分为临床研究和实验研究。该领域的早期研究主要集中在临床研究,近10年主要以分子机制研究为主;实验研究的早期主要以动物实验为主,近4年更关注细胞实验。氧化应激一直是该领域研究的主要趋势,氧化应激、凋亡和自噬分子机制及三者之间的关系研究将是该领域研究的主流趋势。结论 分子机制研究及氧化应激、凋亡和自噬机制之间的关系是中医药治疗蒽环类所致心脏毒性的研究热点和趋势,文献计量学分析结果为中医药研究人员提供了有价值信息,有助于研究者发现潜在的合作者和机构,发现该领域的热点问题和探索新的研究方向。     

Ultrasound tissue characterization by integrated backscatter for analyzing Fluorouracil induced myocardial damage

BACKGROUND: 5-Fluorouracil (5-FU) cardiotoxicity is a well-known clinical phenomenon whose pathophysiology remains controversial. Cyclic variation of integrated backscatter (CVIBS) assesses acoustic properties of myocardium that may reflect both contractility and structural changes. The aim of this study was to evaluate CVIBS alterations in cancer patients under high-dose leucovorin and infusional 5-FU (HDLV5FU) chemotherapy. METHOD: We prospectively evaluated 37 cancer patients under HDLV5FU treatment. Transthoracic echocardiography and CVIBS were performed at the 0th, 48th hours, and on day 15 of the first cycle. The parasternal long-axis view was preferred to obtain the image of integrated backscatter and mainly two regions of interest--interventricular septum (IVS) and posterior wall (PW)--were used. RESULTS: Clinical cardiotoxicity was observed in two patients. No significant differences were detected in pre- and posttreatment conventional echocardiography evaluations. However, both the IVS (9.3 +/- 1.0 to 8.1 +/- 1.2 dB, P < 0.001) and PW (9.1 +/- 0.7 to 7.8 +/- 0.9 dB, P < 0.001) CVIBS values significantly decreased in all patients. All values were returned to pretreatment levels (9.2 +/- 0.9 dB in the CVIBS-IVS and 8.9 +/- 0.6 dB in CVIBS-PW, respectively) on day 15 after the treatments. CONCLUSION: This study suggests that HDLV5FU may cause acute transient alterations in CVIBS values in the absence of clinical symptoms and signs of cardiotoxicity. The clinical value of CVIBS should be further studied in patients receiving 5-FU-based therapy.     

Cardiotoxicity and myocardial infarction‐associated DNA damage induced by thiamethoxam in vitro and in vivo: Protective role of Trigonella foenum‐graecum seed‐derived polysaccharide

The risk of pesticides on the human health and environment has drawn increasing attention. Today, new tools are developed to reduce pesticide adverse effects. This study aimed to evaluate the toxicity induced by, thiamethoxam (TMX), and the cytoprotective effect of a novel polysaccharide, named fenugreek seed water polysaccharide (FWEP) in vitro using H9c2 cardiomyoblastes and in vivo using Wistar rat model. Animals were assigned into four groups per eight rats each: group 1 served as a control group, group 2 received TMX, group 3, and group 4 received both FWEP and TMX tested at two doses (100 and 200 mg/kg, respectively). Regarding the in vitro study, our results demonstrated that TMX induced a decrease in H9c2 cell viability up to 70% with the highest concentration. In vivo, TMX injection induced marked heart damage noted by a significant increase in plasma lactate dehydrogenase, creatine phosphokinase, troponin‐T, aspartate amino transferase activities, cholesterol, and triglyceride levels. Concomitant alterations in cardiac antioxidant defense system revealed depletion in the levels of glutathione and non‐protein thiol and an increase in the activity of superoxide dismutase, catalase, and glutathione peroxidase. Similarly, a significant increase in heart lipid, malondialdehyde, advanced oxidation protein product and in protein carbonyls levels was also noted. In addition, heart tissues histo‐architecture displayed major presence of apoptosis and necrosis as confirmed by DNA degradation. However, supplementation with FWEP alleviated heart oxidative damage and genotoxicity. In this manner, ABTS radical‐scavenging activity, linoleic acid oxidation tests and heart genomic and DNA nicking assay had proved FWEP strong antioxidant potential. In conclusion, FWEP provided significant protection against TMX‐induced heart injury, and could be a useful and efficient agent against cardiotoxicity and atherosclerosis.     

Cardiotoxicity of Mitoxantrone Treatment in a German Cohort of 639 Multiple Sclerosis Patients

Background and Purpose

The aim of this study was to elucidate the role of therapy-related cardiotoxicity in multiple sclerosis (MS) patients treated with mitoxantrone and to identify potential predictors for individual risk assessment.

Methods

Within a multicenter retrospective cohort design, cardiac side effects attributed to mitoxantrone were analyzed in 639 MS patients at 2 MS centers in Germany. Demographic, disease, treatment, and follow-up data were collected from hospital records. Patients regularly received cardiac monitoring during the treatment phase.

Results

None of the patients developed symptomatic congestive heart failure. However, the frequency of patients experiencing cardiac dysfunction of milder forms after mitoxantrone therapy was 4.1% (26 patients) among all patients. Analyses of the risk for cardiotoxicity revealed that cumulative dose exposure was the only statistically relevant risk factor associated with cardiac dysfunction.

Conclusions

The number of patients developing subclinical cardiac dysfunction below the maximum recommended cumulative dose is higher than was initially assumed. Interestingly, a subgroup of patients was identified who experienced cardiac dysfunction shortly after initiation of mitoxantrone and who received a low cumulative dose. Therefore, each administration of mitoxantrone should include monitoring of cardiac function to enhance the treatment safety for patients and to allow for early detection of any side effects, especially in potential high-risk subgroups (as determined genetically).     

Protection against tacrolimus-induced cardiotoxicity in rats by olmesartan and aliskiren

Context: Tacrolimus (TAC), a calcineurin inhibitor, is commonly used as an immunosuppressive agent in organ transplantation, but its clinical use may be limited due to cardiotoxicity. Olmesartan (OLM; angiotensin receptor blocker) and aliskiren (ALK; renin inhibitor) may attenuate cardiotoxicity induced by TAC by inhibition of renin–angiotensin aldosterone system.

Objective: The aim of this study was to evaluate the effect of OLM and ALK on TAC-induced cardiotoxicity.

Materials and methods: Male Wistar albino rats weighing 200–250?g (10–12 weeks old) were used in this study. Animals were divided into four groups. Group 1 received normal saline, group 2 received TAC (2?mg/kg, intraperitoneally for 14?d), group 3 received OLM (2?mg/kg, p.o. for 28?d)?+?TAC and group 4 received ALK (50?mg/kg, p.o. for 28?d)?+?TAC. TAC-induced cardiotoxicity was assessed biochemically and histopathologically.

Results: Treatment with OLM or ALK decreased the TAC-induced changes in biochemical markers of cardiotoxicity such as serum aspartate transaminase, creatine kinase and lactate dehydrogenase. OLM or ALK also attenuated the effects of TAC on oxidant–antioxidant parameters such as malondialdehyde, reduced glutathione and catalase. Histopathological and ultrastructural studies showed that OLM or ALK also attenuated TAC-induced cardiotoxicity.

Discussion and conclusion: These results suggest that OLM as well as ALK has protective effects against TAC-induced cardiotoxicity; implying that angiotensin receptor blocker or renin inhibitor, respectively, may counteract cardiotoxicity associated with immunosuppressant use.     

The minipig as a new model for the evaluation of doxorubicin‐induced chronic toxicity

Doxorubicin can cause life‐threatening toxic effects in several organs, with cardiotoxicity being the major concern. Although a large number of animal models have been utilized to study doxorubicin toxicity, several restrictions limit their use. Since the Göttingen minipig is an accepted species for non‐clinical safety assessment and translation to man, we aimed at exploring its use as a non‐rodent animal model for safety assessment and regulatory toxicity studies using doxorubicin. Three groups of three males and three females adult Göttingen minipigs received 1.5 mg kg^?1, 3/2.3 mg kg^?1 or vehicle at intervals of 3 weeks for 7 cycles. Doxorubicin treatment resulted in a dose‐related decrease in the erythrocytes, hemoglobin and hematocrit count, accompanied by leukopenia and thrombocytopenia. Bone marrow smears revealed dose‐related hypocellularity. Urea and creatinine levels were elevated in treated animals, associated with proteinuria and hematuria. Histopathological evaluation detected nephropathy and atrophy of hematopoietic tissues/organs, mucosa of the intestinal tract and male genital tract. Cardiac lesions including chronic inflammation, endocardial hyperplasia, hemorrhage and myxomatous changes were evident in hematoxylin and eosin stains, and evaluation of semi‐thin sections showed the presence of dose‐related vacuolation in the atrial and ventricular cardiomyocytes. Cardiac troponin levels were increased in the high‐dose group, but there was no direct correlation to the severity of the histopathological lesions. This study confirms that the Göttingen minipig has a comparable toxicity profile to humans and considering its anatomical, physiological, genetic and biochemical resemblance to humans, it should be considered as the non‐rodent species of choice for studies on doxorubicin toxicity. Copyright © 2015 John Wiley & Sons, Ltd.     

炙甘草汤预防蒽环类药物心脏毒性的临床观察

目的：研究炙甘草汤改善含蒽环类方案化疗的乳腺癌患者心脏毒性的临床效果。方法：收集40例接受含蒽环类方案化疗的乳腺癌患者的病案资料,根据随机数字表法,将患者随机分为单纯组和联合治疗组,记录并比较两组患者化疗前和随后第2、4、6周期治疗后的 LVEF、BNP、CK - MB、cTnT、心电图等的变化。结果：所有患者均未出现充血性心力衰竭（ CHF）。两组患者,随着治疗周期的延长,LVEF 呈下降趋势（P ﹤0.05）,cTnT、BNP 及 CK - MB 呈上升趋势（P ﹤0.05）。结论：炙甘草汤能有效改善蒽环类药物化疗所致的心脏毒性,且未观察到毒副反应增加。     

Early cardiac toxicity following adjuvant radiotherapy of left-sided breast cancer with or without concurrent trastuzumab

Purpose

To evaluate the influence of concurrent trastuzumab on the cardiotoxicity in patients receiving left-sided adjuvant radiotherapy.

Materials and Methods

Medical records of stage I-III left-sided breast cancer patients, including 64 receiving concurrent trastuzumab with radiotherapy and 73 receiving radiotherapy alone were retrospectively reviewed. All of the patients had normal LVEF after adjuvant chemotherapy. Information of doses volume to cardiac structures was collected. Cardiac events were assessed according to CTC 2.0.

Results

Median follow-up of LVEF and clinical assessment of cardiac function from the initiation of radiotherapy was 6.7 months (range 3–60.9) and 26 months (range 6.4–60.9), respectively. Grade 1 LVEF dysfunction occurred in 5 (7.8%) and 3 (4.1%) patients of the concurrent-trastuzumab and radiotherapy alone cohort, respectively. Trastuzumab was the only significant factor influencing absolute LVEF decrease in univariate analysis. In multivariate analysis of concurrent-trastuzumab cohort, IMC radiotherapy and start trastuzumab during radiotherapy were independent risk factors. For concurrent cohort, mean heart dose, as well as D₁₀-D₃₀, D₅₀-D₅₅, V₅-V₂₀ of the heart and D₃₀-D₄₅, D₆₅-D₇₅, V₆-V₁₅ of the LV were significantly higher in patients developing LVEF dysfunction.

Conclusions

Concurrent trastuzumab and left-sided radiotherapy is well tolerated in terms of cardiotoxicity in patients with normal baseline cardiac function after adjuvant chemotherapy. However, increases in mean dose and low–dose volume of cardiac structures are associated with a higher risk of acute LVEF dysfunction.