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Sample records for radiation induced cardiotoxicity

  1. UVRAG Deficiency Exacerbates Doxorubicin-Induced Cardiotoxicity

    PubMed Central

    An, Lin; Hu, Xiao-wen; Zhang, Shasha; Hu, Xiaowen; Song, Zongpei; Naz, Amber; Zi, Zhenguo; Wu, Jian; Li, Can; Zou, Yunzeng; He, Lin; Zhu, Hongxin

    2017-01-01

    Doxorubicin (DOX) is an effective chemotherapeutic drug in the treatment of various types of cancers. However, its clinical application has been largely limited by potential development of cardiotoxicity. Previously we have shown that ultra-violet radiation resistance-associated gene (UVRAG), an autophagy-related protein, is essential for the maintenance of autophagic flux in the heart under physiological conditions. Here, we sought to determine the role of UVRAG-mediated autophagy in DOX-induced cardiotoxicity. Mouse models of acute or chronic DOX-induced cardiotoxicity were established. UVRAG deficiency exacerbated DOX-induced mortality and cardiotoxicity manifested by increased cytoplasmic vacuolization, enhanced collagen accumulation, elevated serum activities of lactate dehydrogenase and myocardial muscle creatine kinase, higher ROS levels, aggravated apoptosis and more depressed cardiac function. Autophagic flux was impaired in DOX-induced cardiotoxicity. UVRAG deficiency aggravated impaired autophagic flux in DOX-induced cardiotoxicity. Intermittent fasting restored autophagy and ameliorated pathological alterations of DOX-induced cardiotoxicity. Collectively, our data suggest that UVRAG deficiency exacerbates DOX-induced cardiotoxicity, at least in part, through aggravation of DOX-induced impaired autophagic flux. Intermittent fasting, which restores blunted autophagic flux and ameliorates pathology in the mouse models of DOX-induced cardiotoxicity, may be used as a potential preventive or therapeutic approach for DOX cardiotoxicity. PMID:28225086

  2. UVRAG Deficiency Exacerbates Doxorubicin-Induced Cardiotoxicity.

    PubMed

    An, Lin; Hu, Xiao-Wen; Zhang, Shasha; Hu, Xiaowen; Song, Zongpei; Naz, Amber; Zi, Zhenguo; Wu, Jian; Li, Can; Zou, Yunzeng; He, Lin; Zhu, Hongxin

    2017-02-22

    Doxorubicin (DOX) is an effective chemotherapeutic drug in the treatment of various types of cancers. However, its clinical application has been largely limited by potential development of cardiotoxicity. Previously we have shown that ultra-violet radiation resistance-associated gene (UVRAG), an autophagy-related protein, is essential for the maintenance of autophagic flux in the heart under physiological conditions. Here, we sought to determine the role of UVRAG-mediated autophagy in DOX-induced cardiotoxicity. Mouse models of acute or chronic DOX-induced cardiotoxicity were established. UVRAG deficiency exacerbated DOX-induced mortality and cardiotoxicity manifested by increased cytoplasmic vacuolization, enhanced collagen accumulation, elevated serum activities of lactate dehydrogenase and myocardial muscle creatine kinase, higher ROS levels, aggravated apoptosis and more depressed cardiac function. Autophagic flux was impaired in DOX-induced cardiotoxicity. UVRAG deficiency aggravated impaired autophagic flux in DOX-induced cardiotoxicity. Intermittent fasting restored autophagy and ameliorated pathological alterations of DOX-induced cardiotoxicity. Collectively, our data suggest that UVRAG deficiency exacerbates DOX-induced cardiotoxicity, at least in part, through aggravation of DOX-induced impaired autophagic flux. Intermittent fasting, which restores blunted autophagic flux and ameliorates pathology in the mouse models of DOX-induced cardiotoxicity, may be used as a potential preventive or therapeutic approach for DOX cardiotoxicity.

  3. Polyphenols, autophagy and doxorubicin-induced cardiotoxicity.

    PubMed

    Shabalala, S; Muller, C J F; Louw, J; Johnson, R

    2017-07-01

    Doxorubicin is a highly effective, first line chemotherapeutic agent used in the management of hematological and solid tumors. The effective use of doxorubicin in cancer therapy has been severely limited owing to its well-documented cardiotoxic side effect. Oxidative stress, lipid peroxidation, apoptosis as well as dysregulation of autophagy, has been implicated as a major contributor associated with doxorubicin-induced cardiotoxicity. Increased oxidative stress and lipid peroxidation are known to enhance the production of reactive oxygen species, while autophagy has been reported to protect the cell from stress stimuli or, alternatively, contribute to cell death. Nonetheless, to date, no single chemical synthesized drug is available to prevent the harmful action of doxorubicin without reducing its anti-cancer efficacy. Therefore, the search for an effective and safe antagonist of doxorubicin-induced cardiotoxicity remains a challenge. In recent years, there has been much interest in the role plant-derived polyphenols play in the regulation of oxidative stress and autophagy. Therefore, the present review renders a concise overview of the mechanism associated with doxorubicin-induced cardiotoxicity as well as giving insight into the role plant-derived phytochemical play as a possible adjunctive therapy against the development of doxorubicin-induced cardiotoxicity. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Cardiomyocyte death in doxorubicin-induced cardiotoxicity

    PubMed Central

    Zhang, Yi-Wei; Shi, Jianjian; Li, Yuan-Jian; Wei, Lei

    2009-01-01

    SUMMARY Doxorubicin (DOX) is one of the most widely used and successful antitumor drugs, but its cumulative and dose-dependent cardiac toxicity has been the major concern of oncologists in cancer therapeutic practice for decades. With the increasing population of cancer survivals, there is a growing need to develop preventive strategies and effective therapies against DOX-induced cardiotoxicity, in particular, the late onset cardiomyopathy. Although intensive investigations on the DOX-induced cardiotoxicity have been continued for decades, the underlying mechanisms responsible for DOX-induced cardiotoxicity have not been completely elucidated. A rapidly expanding body of evidence supports that cardiomyocyte death by apoptosis and necrosis is a primary mechanism of DOX-induced cardiomyopathy and other types of cell death, such as autophagy and senescence/aging, may participate in this process. In this review, we will focus on the current understanding of molecular mechanisms underlying DOX-induced cardiomyocyte death, including the major primary mechanism of excess production of reactive oxygen species (ROS) and other recently discovered ROS-independent mechanisms. Different sensitivity to DOX-induced cell death signals between adult and young cardiomyocytes will also be discussed. PMID:19866340

  5. Drug-induced mitochondrial dysfunction and cardiotoxicity

    PubMed Central

    Varga, Zoltán V; Ferdinandy, Peter; Liaudet, Lucas

    2015-01-01

    Mitochondria has an essential role in myocardial tissue homeostasis; thus deterioration in mitochondrial function eventually leads to cardiomyocyte and endothelial cell death and consequent cardiovascular dysfunction. Several chemical compounds and drugs have been known to directly or indirectly modulate cardiac mitochondrial function, which can account both for the toxicological and pharmacological properties of these substances. In many cases, toxicity problems appear only in the presence of additional cardiovascular disease conditions or develop months/years following the exposure, making the diagnosis difficult. Cardiotoxic agents affecting mitochondria include several widely used anticancer drugs [anthracyclines (Doxorubicin/Adriamycin), cisplatin, trastuzumab (Herceptin), arsenic trioxide (Trisenox), mitoxantrone (Novantrone), imatinib (Gleevec), bevacizumab (Avastin), sunitinib (Sutent), and sorafenib (Nevaxar)], antiviral compound azidothymidine (AZT, Zidovudine) and several oral antidiabetics [e.g., rosiglitazone (Avandia)]. Illicit drugs such as alcohol, cocaine, methamphetamine, ecstasy, and synthetic cannabinoids (spice, K2) may also induce mitochondria-related cardiotoxicity. Mitochondrial toxicity develops due to various mechanisms involving interference with the mitochondrial respiratory chain (e.g., uncoupling) or inhibition of the important mitochondrial enzymes (oxidative phosphorylation, Szent-Györgyi-Krebs cycle, mitochondrial DNA replication, ADP/ATP translocator). The final phase of mitochondrial dysfunction induces loss of mitochondrial membrane potential and an increase in mitochondrial oxidative/nitrative stress, eventually culminating into cell death. This review aims to discuss the mechanisms of mitochondrion-mediated cardiotoxicity of commonly used drugs and some potential cardioprotective strategies to prevent these toxicities. PMID:26386112

  6. Cellular mechanisms for trazodone-induced cardiotoxicity.

    PubMed

    Lee, S; Lee, H-A; Kim, S J; Kim, K-S

    2016-05-01

    The second-generation selective 5-HT2 receptor antagonists and reuptake inhibitors (SARIs) class antidepressants are known to have fewer cardiovascular side effects than the older ones. However, several case reports showed that trazodone, one of the second-generation SARIs, induces QT prolongation, cardiac arrhythmia, and ventricular tachycardia. Although these clinical cases suggested trazodone-induced cardiotoxicity, the toxicological actions of trazodone on cardiac action potentials (APs) beyond the human ether-a-go-go related gene (hERG) remain unclear. To elucidate the cellular mechanism for the adverse cardiac effects of trazodone, we investigated its effects on cardiac APs and ion channels using whole-cell patch clamp techniques in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and transiently transfected human embryonic kidney cells (HEK293) with cardiac ion channel complementary DNA. Trazodone dose-dependently decreased the maximum upstroke velocity (Vmax) and prolonged the AP duration, inducing early after depolarizations at 3 and 10 μM that triggered ventricular arrhythmias in hiPSC-CMs. Trazodone also inhibited all of the major ion channels (IKr, IKs, INa, and ICa), with an especially high inhibitory potency on hERG. These data indicate that the prolonged AP duration and decreased Vmax due to trazodone are mainly the result of hERG and sodium ion inhibition, and its inhibitory effects on cardiac ion channels can be exhibited in hiPSC-CMs.

  7. Resveratrol, a polyphenol phytoalexin, protects against doxorubicin-induced cardiotoxicity.

    PubMed

    Gu, Jun; Hu, Wei; Zhang, Da-dong

    2015-10-01

    Doxorubicin is the mainstay of treatment for various haematological malignancies and solid tumours. However, its clinical application may be hampered by dose-dependent cardiotoxicity. The mechanism of doxorubicin-induced cardiotoxicity may involve various signalling pathways including free radical generation, peroxynitrite formation, calcium overloading, mitochondrial dysfunction and alteration in apoptosis and autophagy. Interestingly, the use of resveratrol in combination with doxorubicin has been reported to prevent cardiac toxicity as well as to exert a synergistic effect against tumour cells both in vivo and in vitro. Thus, the aim of this review is to summarize current knowledge and to elucidate the protective effect of resveratrol in doxorubicin-induced cardiotoxicity. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  8. Resveratrol, a polyphenol phytoalexin, protects against doxorubicin-induced cardiotoxicity

    PubMed Central

    Gu, Jun; Hu, Wei; Zhang, Da-dong

    2015-01-01

    Doxorubicin is the mainstay of treatment for various haematological malignancies and solid tumours. However, its clinical application may be hampered by dose-dependent cardiotoxicity. The mechanism of doxorubicin-induced cardiotoxicity may involve various signalling pathways including free radical generation, peroxynitrite formation, calcium overloading, mitochondrial dysfunction and alteration in apoptosis and autophagy. Interestingly, the use of resveratrol in combination with doxorubicin has been reported to prevent cardiac toxicity as well as to exert a synergistic effect against tumour cells both in vivo and in vitro. Thus, the aim of this review is to summarize current knowledge and to elucidate the protective effect of resveratrol in doxorubicin-induced cardiotoxicity. PMID:26177159

  9. Breast cancer treatment-induced cardiotoxicity.

    PubMed

    Martel, Samuel; Maurer, Christian; Lambertini, Matteo; Pondé, Noam; De Azambuja, Evandro

    2017-09-01

    Breast cancer is the most frequent cancer affecting women worldwide. In every setting, the majority of women are treated with an evergrowing arsenal of therapeutic agents that have greatly improved their outcomes. However, these therapies can also be associated with significant adverse events. Areas covered: This review aims to thoroughly describe the current state of the evidence regarding the potential cardiotoxicity of agents commonly used in the treatment of breast cancer. These include chemotherapeutic agents, anti-HER2 therapies and CDK4/6 and mTOR inhibitors. Furthermore, issues related to the risk stratification and monitoring tools are explored. Expert opinion: Anthracycline- and trastuzumab-related cardiac toxicities have been extensively studied. Substantial evidence is now available concerning additional anti-HER2 agents such as pertuzumab, T-DM1 and tyrosine kinase inhibitors; overall, the cardiotoxicity profile is reassuring. Cardiac events due to endocrine therapy are mostly ischemic and, in the context of prolonged therapy, need specific attention. Novel agents implicated in the treatment of hormone receptor-positive disease are potentially arrhythmogenic and the exact risk will need to be further refined. As for today, assessment of baseline risk factors prior to treatment initiation and cardiac imaging before and during treatment remains the optimal way to prevent cardiac dysfunction. Cardioprotective therapy in primary prevention is still a matter of debate.

  10. Effect of disulfiram on ketamine-induced cardiotoxicity in rats

    PubMed Central

    Cetin, Nihal; Suleyman, Bahadir; Altuner, Durdu; Kuyrukluyildiz, Ufuk; Ozcicek, Fatih; Coskun, Resit; Kurt, Nazahat; Suleyman, Halis

    2015-01-01

    It is known that ketamine increases the production of catecholamines, causing oxidative damage to the heart. Suppression of the production of catecholamines by disulfiram, a drug with antioxidant properties, indicates that disulfiram may decrease ketamine-induced cardiotoxicity. The objective of the present study was to investigate the effect of disulfiram on ketamine-induced cardiotoxicity in rats. Disulfiram was administered by oral gavage in doses of 25 mg/kg to rats in the DK-25 group and 50 mg/kg to rats in the DK-50 group. Distilled water was applied in the ketamine control (KC) and healthy (HG) rat groups. At one hour after drug administration and subsequently at ten-minute intervals, a 60 mg/kg dose of ketamine was intraperitoneally injected in the rats in all groups other than HG, and anesthesia was maintained for three hours. Disulfiram prevented both increase in the levels of parameters indicating oxidative and myocardial damage and decrease of antioxidant levels in the heart tissue with ketamine in a dose-dependent manner. Disulfiram better prevented occurrence of cardiotoxicity with ketamine in the 50 mg/kg dose than in the 25 mg/kg dose. It is concluded that disulfiram may usefully be applied in clinical practice in the prevention of cardiotoxicity as observed during anesthesia with ketamine. PMID:26550292

  11. Febuxostat ameliorates doxorubicin-induced cardiotoxicity in rats.

    PubMed

    Krishnamurthy, Bhaskar; Rani, Neha; Bharti, Saurabh; Golechha, Mahaveer; Bhatia, Jagriti; Nag, Tapas Chandra; Ray, Ruma; Arava, Sudheer; Arya, Dharamvir Singh

    2015-07-25

    The clinical use of doxorubicin is associated with dose limiting cardiotoxicity. This is a manifestation of free radical production triggered by doxorubicin. Therefore, we evaluated the efficacy of febuxostat, a xanthine oxidase inhibitor and antioxidant, in blocking cardiotoxicity associated with doxorubicin in rats. Male albino Wistar rats were divided into four groups: control (normal saline 2.5mL/kg/dayi.p. on alternate days, a total of 6 doses); Doxorubicin (2.5mg/kg/dayi.p. on alternate days, a total of 6 doses), Doxorubicin+Febuxostat (10mg/kg/day oral) and Doxorubicin+Carvedilol (30mg/kg/day oral) for 14days. Febuxostat significantly ameliorated the doxorubicin-induced deranged cardiac functions as there was significant improvement in arterial pressures, left ventricular end diastolic pressure and inotropic and lusitropic states of the myocardium. These changes were well substantiated with biochemical findings, wherein febuxostat prevented the depletion of non-protein sulfhydryls level, with increased manganese superoxide dismutase level and reduced cardiac injury markers (creatine kinase-MB and B-type natriuretic peptide levels) and thiobarbituric acid reactive substances level. Febuxostat also exhibited significant anti-inflammatory (decreased expression of NF-κBp65, IKK-β and TNF-α) and anti-apoptotic effect (increased Bcl-2 expression and decreased Bax and caspase-3 expression and TUNEL positivity). Hematoxylin and Eosin, Masson Trichome, Picro Sirius Red and ultrastructural studies further corroborated with hemodynamic and biochemical findings showing that febuxostat mitigated doxorubicin-induced increases in inflammatory cells, edema, collagen deposition, interstitial fibrosis, perivascular fibrosis and mitochondrial damage and better preservation of myocardial architecture. In addition, all these changes were comparable to those produced by carvedilol. Thus, our results suggest that the antioxidant and anti-apoptotic effect of febuxostat

  12. Extracorporeal life support for severe drug-induced cardiotoxicity: a promising therapeutic choice.

    PubMed

    Ashrafian, Hutan; Athanasiou, Thanos

    2009-01-01

    Drug-induced cardiovascular failure is an acute condition that is associated with significant healthcare consequences. Antidotes and supportive treatments are the initial measures to manage cardiotoxicity, but if severe drug-induced cardiotoxicity develops, usually as cardiovascular shock or cardiac arrest, then circulatory assistance may have an important role in the therapeutic algorithm. A number of circulatory assistance techniques have been increasingly employed to treat severe drug-induced cardiotoxicity. These include extracorporeal membrane oxygenation, intra-aortic balloon pumping and standard cardiopulmonary bypass. Recently, extracorporeal life support (ECLS) has been developed to provide percutaneous cardiopulmonary support peripherally without the need for sternotomy. ECLS can provide successful treatment of severe drug-induced cardiotoxicity in selected cases. This technique may be associated with complications of limb ischaemia, haemorrhage and embolism. An increased consideration of ECLS within the context of rigorous clinical studies and strong evidence can add to its future use for severe drug-induced cardiotoxicity.

  13. Halogenated carbazoles induce cardiotoxicity in developing zebrafish (Danio rerio) embryos.

    PubMed

    Fang, Mingliang; Guo, Jiehong; Chen, Da; Li, An; Hinton, David E; Dong, Wu

    2016-10-01

    Halogenated carbazoles are increasingly identified as a novel class of environmental contaminants. However, no in vivo acute toxicity information on those compounds was available. In the present study, an in vivo zebrafish embryonic model (Danio rerio) was used to investigate the developmental toxicity of those halogenated carbazoles. The results suggested that acute toxicity was structure-dependent. Two of the 6 tested carbazoles, 2,7-dibromocarbazole (27-DBCZ) and 2,3,6,7-tetrachlorocarbazole, showed obvious developmental toxicity at nanomolar levels. The typical phenotypes were similar to dioxin-induced cardiotoxicity, including swollen yolk sac, pericardial sac edema, elongated and unlooped heart, and lower jaw shortening. During embryonic development 27-DBCZ also induced a unique pigmentation decrease. Gene expression and protein staining of cytochrome P4501A (CYP1A) showed that both halogenated carbazoles could induce CYP1A expression at the micromolar level and primarily in the heart area, which was similar to dioxin activity. Further, aryl hydrocarbon receptor-(AhR)2 gene knockdown with morpholino confirmed that the acute cardiotoxicity is AhR-dependent. In conclusion, the results demonstrate that halogenated carbazoles represent yet another class of persistent organic pollutants with dioxin-like activity in an in vivo animal model. Environ Toxicol Chem 2016;35:2523-2529. © 2016 SETAC.

  14. Perflurooctanoic Acid Induces Developmental Cardiotoxicity in ...

    EPA Pesticide Factsheets

    Perfluorooctanoic acid (PFOA) is a widespread environmental contaminant that is detectable in serum of the general U.S. population. PFOA is a known developmental toxicant that induces mortality in mammalian embryos and is thought to induce toxicity via interaction with the peroxisome proliferator activated receptor alpha (PPAR_). As the cardiovascular system is crucial for embryonic survival, PFOA-induced effects on the heart may partially explain embryonic mortality. To assess impacts of PFOA exposure on the developing heart in an avian model, we used histopathology and immunohistochemical staining for myosin to assess morphological alterations in 19-day-old chicken embryo hearts after PFOA exposure. Additionally, echocardiography and cardiac myofibril ATPase activity assays were used to assess functional alterations in 1-day-old hatchling chickens following developmental PFOA exposure. Overall thinning and thinning of a dense layer of myosin in the right ventricular wall were observed in PFOA-exposed chicken embryo hearts. Alteration of multiple cardiac structural and functional parameters, including left ventricular wall thickness, left ventricular volume, heart rate, stroke volume, and ejection fraction were detected with echocardiography in the exposed hatchling chickens. Assessment of ATPase activity indicated that the ratio of cardiac myofibril calcium-independent ATPase activity to calcium-dependent ATPase activity was not affected, which suggests that d

  15. Berberine attenuates doxorubicin-induced cardiotoxicity in mice.

    PubMed

    Zhao, X; Zhang, J; Tong, N; Liao, X; Wang, E; Li, Z; Luo, Y; Zuo, H

    2011-01-01

    This study investigated the effects of berberine, a natural alkaloid, on doxorubicin-induced cardiotoxicity in mice. Mice were injected intraperitoneally with saline 10 ml/kg (n = 10), doxorubicin 2.5 mg/kg (n = 10), 60 mg/kg berberine 1 h before doxorubicin 2.5 mg/kg (n = 10), or 60 mg/kg berberine alone (n = 10) every other day for 14 days. Body weight, general condition and mortality were recorded over the 14-day study period. Electro cardiography was performed before the start of treatment and after 14 days and plasma lactate dehydrogenase (LDH) activity was measured after 14 days. At the end of the study period the heart was excised and examined histologically. An increase in mortality, an initial decrease in body weight, increased LDH activity, prolongation of QRS duration and increased myocardial injury were seen in the doxorubicin-treated group compared with the saline control group. These changes were significantly attenuated by pretreatment with berberine. The study suggests that berberine may have a potential protective role against doxorubicin-induced cardiotoxicity in mice.

  16. Erdosteine prevents doxorubicin-induced cardiotoxicity in rats.

    PubMed

    Yagmurca, Murat; Fadillioglu, Ersin; Erdogan, Hasan; Ucar, Muharrem; Sogut, Sadik; Irmak, M Kemal

    2003-10-01

    The clinical use of doxorubicin (Dxr) is limited by its cardiotoxic effects which are mediated by oxygen radicals. The purpose of this study was to investigate in vivo protective effects of erdosteine, an antioxidant agent because of its secondary active metabolites in vivo, against the cardiotoxicity induced by Dxr in rats. Three groups of male Sprague-Dawley rats (60 days old) were used. Group 1 was untreated group used as control; the other groups were treated with Dxr (single i.p. dosage of 20 mg kg(-1) b.wt.) or Dxr plus erdosteine (10 mg kg(-1) day(-1), orally), respectively. Erdosteine or oral saline treatment was done starting 2 days before Dxr for 12 days. The analyses were done at the 10th day of Dxr treatment. The protein carbonyl content, the activities of myeloperoxidase, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and creatine kinase (CK) as well as heart rate and blood pressures were significantly increased in Dxr group in comparison with the other groups. However, pulse pressure was decreased in Dxr group. The body and heart weights were decreased in both Dxr administered groups in comparison with control group. Disorganization of myocardial histology, picnotic nuclei, edema, and increase in collagen content around vessels were seen in the slides of Dxr group, whereas normal myocardial microscopy was preserved in Dxr plus erdosteine group. Collectively, these in vivo hemodynamic, enzymatic and morphologic studies provide an evidence for a possible prevention of cardiac toxicity in Dxr-treated patients.

  17. High frequency resonant waveguide grating imager for assessing drug-induced cardiotoxicity

    NASA Astrophysics Data System (ADS)

    Ferrie, Ann M.; Wu, Qi; Deichmann, Oberon D.; Fang, Ye

    2014-05-01

    We report a high-frequency resonant waveguide grating imager for assessing compound-induced cardiotoxicity. The imager sweeps the wavelength range from 823 nm to 838 nm every 3 s to identify and monitor compound-induced shifts in resonance wavelength and then switch to the intensity-imaging mode to detect the beating rhythm and proarrhythmic effects of compounds on induced pluripotent stem cell-derived cardiomyocytes. This opens possibility to study cardiovascular biology and compound-induced cardiotoxicity.

  18. Protective effects of Terminalia arjuna against Doxorubicin-induced cardiotoxicity.

    PubMed

    Singh, Gurvinder; Singh, Anu T; Abraham, Aji; Bhat, Beena; Mukherjee, Ashok; Verma, Ritu; Agarwal, Shiv K; Jha, Shivesh; Mukherjee, Rama; Burman, Anand C

    2008-04-17

    Terminalia arjuna has been marked as a potential cardioprotective agent since vedic period. The present study was aimed to investigate the effects of butanolic fraction of Terminalia arjuna bark (TA-05) on Doxorubicin (Dox)-induced cardiotoxicity. Male wistar rats were used as in vivo model for the study. TA-05 was administered orally to Wistar rats at different doses (0.42 mg/kg, 0.85 mg/kg, 1.7 mg/kg, 3.4 mg/kg and 6.8 mg/kg) for 6 days/week for 4 weeks. Thereafter, all the animals except saline and TA-05-treated controls were administered 20 mg/kg Dox intraperitonially. There was a significant decrease in myocardial superoxide dismutase (38.94%) and reduced glutathione (23.84%) in animals treated with Dox. Concurrently marked increase in serum creatine kinase-MB (CKMB) activity (48.11%) as well as increase in extent of lipid peroxidation (2.55-fold) was reported. Co-treatment of TA-05 and Dox resulted in an increase in the cardiac antioxidant enzymes, decrease in serum CKMB levels and reduction in lipid peroxidation as compared to Dox-treated animals. Electron microscopic studies in Dox-treated animals revealed mitochondrial swelling, Z-band disarray, focal dilatation of smooth endoplasmic reticulum (SER) and lipid inclusions, whereas the concurrent administration of TA-05 led to a lesser degree of Dox-induced histological alterations. These findings suggest that butanolic fraction of Terminalia arjuna bark has protective effects against Dox-induced cardiotoxicity and may have potential as a cardioprotective agent.

  19. Amelioration of doxorubicin‑induced cardiotoxicity by resveratrol.

    PubMed

    Al-Harthi, Sameer E; Alarabi, Ohoud M; Ramadan, Wafaa S; Alaama, Mohamed N; Al-Kreathy, Huda M; Damanhouri, Zoheir A; Khan, Lateef M; Osman, Abdel-Moneim M

    2014-09-01

    Doxorubicin (DOX), is a highly active anticancer agent, but its clinical use is limited by its severe cardiotoxic side‑effects associated with increased oxidative stress and apoptosis. Resveratrol (RSVL) is a naturally occurring polyphenolic compound (trans-3,5,4'-trihydroxystilbene) found primarily in root extracts of the oriental plant Polygonum cuspidatum and of numerous additional plant species. It has recently been shown that RSVL has a number of beneficial effects in different biological systems, which include anti-oxidant, antineoplastic, anticarcinogenic, cardioprotective and antiviral effects. In this study, we examined whether RSVL has protective effects against DOX‑induced free radical production and cardiotoxicity in male rats. The tested dose of DOX (20 mg/kg) caused a significant increase in the serum activities of the cardiac enzymes lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) and the level of malondialdehyde (MDA) in the heart tissue. However, there was a significant decrease in the glutathione level in the heart tissue. Simultaneous treatment of rats with RSVL [10 mg/kg, intraperitoneal (i.p.) injection] reduced the activity of LDH and CPK and significantly reduced MDA production in the heart. The total antioxidant capacity was increased following RSVL administration. Electron microscopy examination of the heart tissue showed that DOX treatment results in massive fragmentation and lysis of the myofibrils, and that mitochondria show either vacuolization or complete loss of the cristae. Simultaneous treatment with RSVL ameliorated the effect of DOX administration on cardiac tissue, with cardiomyocytes appearing normal compared to the control samples, and mitochondria retaining their normal structure.

  20. Protective effect of silymarin against chemical-induced cardiotoxicity

    PubMed Central

    Razavi, Bibi Marjan; Karimi, Gholamreza

    2016-01-01

    Cardiac disorders remain one of the most important causes of death in the world. Oxidative stress has been suggested as one of the molecular mechanisms involved in drug-induced cardiac toxicity. Recently, several natural products have been utilized in different studies with the aim to protect the progression of oxidative stress-induced cardiac disorders. There is a large body of evidence that administration of antioxidants may be useful in ameliorating cardiac toxicity. Silymarin, a polyphenolic flavonoid has been shown to have utility in several cardiovascular disorders. In this review, various studies in scientific databases regarding the preventive effects of silymarin against cardiotoxicity induced by chemicals were introduced. Although there are many studies representing the valuable effects of silymarin in different diseases, the number of researches relating to the possible cardiac protective effects of silymarin against drugs induced toxicity is rather limited. Results of these studies show that silymarin has a broad spectrum of cardiac protective activity against toxicity induced by some chemicals including metals, environmental pollutants, oxidative agents and anticancer drugs. Further studies are needed to establish the utility of silymarin in protection against cardiac toxicity. PMID:27803777

  1. Gemcitabine induced cardiomyopathy: a case of multiple hit cardiotoxicity.

    PubMed

    Mohebali, Donya; Matos, Jason; Chang, James Ducksoon

    2017-02-01

    Gemcitabine is a commonly used antineoplastic agent used to treat a variety of cancers with rarely reported cardiac side effects. We describe a case of a 67-year-old woman with follicular lymphoma who experienced a rarely reported side effect of gemcitabine: cardiomyopathy. This case highlights a multiple hit mechanism of myocyte damage that may occur following the use of multiple cardio-toxic agents despite their administration in doses not associated with cardiotoxicity.

  2. A systematic review of the pathophysiology of 5-fluorouracil-induced cardiotoxicity

    PubMed Central

    2014-01-01

    Background Cardiotoxicity is a serious side effect to treatment with 5-fluorouracil (5-FU), but the underlying mechanisms are not fully understood. The objective of this systematic review was to evaluate the pathophysiology of 5-FU- induced cardiotoxicity. Methods We systematically searched PubMed for articles in English using the search terms: 5-FU OR 5-fluorouracil OR capecitabine AND cardiotoxicity. Papers evaluating the pathophysiology of this cardiotoxicity were included. Results We identified 27 articles of 26 studies concerning the pathophysiology of 5-FU-induced cardiotoxicity. The studies demonstrated 5-FU-induced: hemorrhagic infarction, interstitial fibrosis and inflammatory reaction in the myocardium; damage of the arterial endothelium followed by platelet aggregation; increased myocardial energy metabolism and depletion of high energy phosphate compounds; increased superoxide anion levels and a reduced antioxidant capacity; vasoconstriction of arteries; changes in red blood cell (RBC) structure, function and metabolism; alterations in plasma levels of substances involved in coagulation and fibrinolysis and increased endothelin-1 levels and N-terminal-pro brain natriuretic peptide levels. Based on these findings the proposed mechanisms are: endothelial injury followed by thrombosis, increased metabolism leading to energy depletion and ischemia, oxidative stress causing cellular damage, coronary artery spasm leading to myocardial ischemia and diminished ability of RBCs to transfer oxygen resulting in myocardial ischemia. Conclusions There is no evidence for a single mechanism responsible for 5-FU-induced cardiotoxicity, and the underlying mechanisms might be multifactorial. Further research is needed to elucidate the pathogenesis of this side effect. PMID:25186061

  3. Cardioprotective Effects of Carvedilol in Inhibiting Doxorubicin-induced Cardiotoxicity.

    PubMed

    Nabati, Maryam; Janbabai, Ghasem; Baghyari, Saideh; Esmaili, Khadige; Yazdani, Jamshid

    2017-05-01

    Anthracyclines (ANTs) are a class of active antineoplastic agents with topoisomerase-interacting activity that are considered the most active agents for the treatment of breast cancer. We investigated the efficacy of carvedilol in the inhibition of ANT-induced cardiotoxicity. In this randomized, single-blind, placebo-controlled study, 91 women with recently diagnosed breast cancer undergoing ANT therapy were randomly assigned to groups treated with either carvedilol (n = 46) or placebo (n = 45). Echocardiography was performed before and at 6 months after randomization, and absolute changes in the mean left ventricular ejection fraction, left ventricular end diastolic volume, and left ventricular end systolic volume were determined. Furthermore, the percentage change in the left atrial (LA) diameter and other variables of left ventricular (LV) diastolic function, such as transmitral Doppler parameters, including early (E wave) and late (A wave) diastolic velocities, E/A ratio and E wave deceleration time, pulmonary venous Doppler signals, including forward systolic (S wave) and diastolic (D wave) velocities into LA, late diastolic atrial reversal velocity, and early diastolic tissue Doppler mitral annular velocity (e') were measured. In addition, tissue Doppler mitral annular systolic (s') velocity, as a marker of early stage of LV systolic dysfunction, E/e' ratio, as a determinant of LV filling pressure, and troponin I level, as a marker of myocardial necrosis were measured. At the end of follow-up period, left ventricular ejection fraction did not change in the carvedilol group. However, this parameter was significantly reduced in the control group (P < 0.001). Echocardiography showed that both left ventricular end systolic volume and LA diameter were significantly increased compared with the baseline measures in the control group. In pulse Doppler studies, pulmonary venous peak atrial reversal flow velocity was significantly increased in the control group

  4. New signal transduction paradigms in anthracycline-induced cardiotoxicity.

    PubMed

    Ghigo, Alessandra; Li, Mingchuan; Hirsch, Emilio

    2016-07-01

    Anthracyclines, such as doxorubicin, are the most potent and widely used chemotherapeutic agents for the treatment of a variety of human cancers, including solid tumors and hematological malignancies. However, their clinical use is hampered by severe cardiotoxic side effects and cancer therapy-related heart disease has become a leading cause of morbidity and mortality among cancer survivors. The identification of therapeutic strategies limiting anthracycline cardiotoxicity with preserved antitumor efficacy thus represents the current challenge of cardio-oncologists. Anthracycline cardiotoxicity has been originally ascribed to the ability of this class of drugs to disrupt iron metabolism and generate excess of reactive oxygen species (ROS). However, small clinical trials with iron chelators and anti-oxidants failed to provide any benefit and suggested that doxorubicin cardiotoxicity is not solely due to redox cycling. New emerging explanations include anthracycline-dependent regulation of major signaling pathways controlling DNA damage response, cardiomyocyte survival, cardiac inflammation, energetic stress and gene expression modulation. This review will summarize recent studies unraveling the complex web of mechanisms of doxorubicin-mediated cardiotoxicity, and identifying new druggable players for the prevention of heart disease in cancer patients. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.

  5. Protective effect of Syzygium cumini against pesticide-induced cardiotoxicity.

    PubMed

    Atale, Neha; Gupta, Khushboo; Rani, Vibha

    2014-01-01

    Pesticide-induced toxicity is a serious issue which has resulted in plethora of diseases all over the world. The organophosphate pesticide malathion has caused many incidents of poisoning such as cardiac manifestations. The present study was designed to evaluate the effect of Syzygium cumini on malathion-induced cardiotoxicity. Dose optimization of malathion and polyphenols such as curcumin, (−)-epicatechin, gallic acid, butylated hydroxyl toluene, etc. was done by MTT cell proliferation assay. Nuclear deformities, ROS production, and integrity of extra cellular matrix components were analyzed by different techniques. S. cumini methanolic pulp extract (MPE), a naturally derived gallic acid-enriched antioxidant was taken to study its effect on malathion-induced toxicity. Nuclear deformities, ROS production, and integrity of extra cellular matrix components were also analyzed. Twenty micrograms per milliliter LD50 dose of malathion was found to cause stress-mediated responses in H9C2 cell line. Among all the polyphenols, gallic acid showed the most significant protection against stress. Gallic acid-enriched methanolic S. cumini pulp extract (MPE) showed 59.76 % ± 0.05, 81.61 % ± 1.37, 73.33 % ± 1.33, 77.19 % ± 2.38 and 64.19 % ± 1.43 maximum inhibition for DPPH, ABTS, NO, H2O2 and superoxide ion, respectively, as compared to ethanolic pulp extract and aqueous pulp extract. Our study suggests that S. cumini MPE has the ability to protect against the malathion-mediated oxidative stress in cardiac myocytes.

  6. Doxorubicin induces cardiotoxicity through upregulation of death receptors mediated apoptosis in cardiomyocytes

    PubMed Central

    Zhao, Liqun; Zhang, Baolin

    2017-01-01

    Doxorubicin is a highly effective anticancer agent but causes cardiotoxicity in many patients. The mechanisms of doxorubicin-induced cardiotoxicity remain incompletely understood. Here we investigated doxorubicin-induced cytotoxicity in human induced pluripotent stem cells-derived cardiomyocytes (iPS-CMs). We found that doxorubicin and related anthracycline agents (e.g., daunorubicin, idarubicin, and epirubicin) significantly upregulated the expression of death receptors (DRs) (TNFR1, Fas, DR4 and DR5) in iPS-derived cardiomyocytes at both protein and mRNA levels. The resulting iPS-CMs cells underwent spontaneous apoptosis which was further enhanced by physiologically relevant death ligands including TNF-related apoptosis inducing ligand (TRAIL). Furthermore, TRAIL potentiated doxorubicin-induced decrease in beating rate and amplitude of iPS-derived cardiomyocytes. These data demonstrate that the induction of death receptors in cardiomyocytes is likely a critical mechanism by which doxorubicin causes cardiotoxicity. PMID:28300219

  7. Herb-induced cardiotoxicity from accidental aconitine overdose

    PubMed Central

    Sheth, Sujata; Tan, Elaine Ching Ching; Tan, Hock Heng; Tay, Leslie

    2015-01-01

    Patients who overdose on aconite can present with life-threatening ventricular arrhythmia. Aconite must be prepared and used with caution to avoid cardiotoxic effects that can be fatal. We herein describe a case of a patient who had an accidental aconite overdose but survived with no lasting effects. The patient had prepared Chinese herbal medication to treat his pain, which resulted in an accidental overdose of aconite with cardiotoxic and neurotoxic effects. The patient had ventricular tachycardia, bidirectional ventricular tachycardia and ventricular fibrillation. Following treatment with anti-arrhythmic medications, defibrillation and cardiopulmonary resuscitation, he made an uneventful recovery, with no further cardiac arrhythmias reported. PMID:26243980

  8. Mitochondrial catastrophe during doxorubicin-induced cardiotoxicity: a review of the protective role of melatonin.

    PubMed

    Govender, Jenelle; Loos, Ben; Marais, Erna; Engelbrecht, Anna-Mart

    2014-11-01

    Anthracyclines, such as doxorubicin, are among the most valuable treatments for various cancers, but their clinical use is limited due to detrimental side effects such as cardiotoxicity. Doxorubicin-induced cardiotoxicity is emerging as a critical issue among cancer survivors and is an area of much significance to the field of cardio-oncology. Abnormalities in mitochondrial functions such as defects in the respiratory chain, decreased adenosine triphosphate production, mitochondrial DNA damage, modulation of mitochondrial sirtuin activity and free radical formation have all been suggested as the primary causative factors in the pathogenesis of doxorubicin-induced cardiotoxicity. Melatonin is a potent antioxidant, is nontoxic, and has been shown to influence mitochondrial homeostasis and function. Although a number of studies support the mitochondrial protective role of melatonin, the exact mechanisms by which melatonin confers mitochondrial protection in the context of doxorubicin-induced cardiotoxicity remain to be elucidated. This review focuses on the role of melatonin on doxorubicin-induced bioenergetic failure, free radical generation, and cell death. A further aim is to highlight other mitochondrial parameters such as mitophagy, autophagy, mitochondrial fission and fusion, and mitochondrial sirtuin activity, which lack evidence to support the role of melatonin in the context of cardiotoxicity.

  9. Validating the pharmacogenomics of chemotherapy-induced cardiotoxicity: What is missing?

    PubMed

    Magdy, Tarek; Burmeister, Brian T; Burridge, Paul W

    2016-12-01

    The cardiotoxicity of certain chemotherapeutic agents is now well-established, and has led to the development of the field of cardio-oncology, increased cardiac screening of cancer patients, and limitation of patients' maximum cumulative chemotherapeutic dose. The effect of chemotherapeutic regimes on the heart largely involves cardiomyocyte death, leading to cardiomyopathy and heart failure, or the induction of arrhythmias. Of these cardiotoxic drugs, those resulting in clinical cardiotoxicity can range from 8 to 26% for doxorubicin, 7-28% for trastuzumab, or 5-30% for paclitaxel. For tyrosine kinase inhibitors, QT prolongation and arrhythmia, ischemia and hypertension have been reported in 2-35% of patients. Furthermore, newly introduced chemotherapeutic agents are commonly used as part of changed combinational regimens with significantly increased incidence of cardiotoxicity. It is widely believed that the mechanism of action of these drugs is often independent of their cardiotoxicity, and the basis for why these drugs specifically affect the heart has yet to be established. The genetic rationale for why certain patients experience cardiotoxicity whilst other patients can tolerate high chemotherapy doses has proven highly illusive. This has led to significant genomic efforts using targeted and genome-wide association studies (GWAS) to divine the pharmacogenomic cause of this predilection. With the advent of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), the putative risk and protective role of single nucleotide polymorphisms (SNPs) can now be validated in a human model. Here we review the state of the art knowledge of the genetic predilection to chemotherapy-induced cardiotoxicity and discuss the future for establishing and validating the role of the genome in this disease.

  10. Mitochondria death/survival signaling pathways in cardiotoxicity induced by anthracyclines and anticancer-targeted therapies.

    PubMed

    Montaigne, David; Hurt, Christopher; Neviere, Remi

    2012-01-01

    Anthracyclines remain the cornerstone of treatment in many malignancies but these agents have a cumulative dose relationship with cardiotoxicity. Development of cardiomyopathy and congestive heart failure induced by anthracyclines are typically dose-dependent, irreversible, and cumulative. Although past studies of cardiotoxicity have focused on anthracyclines, more recently interest has turned to anticancer drugs that target many proteins kinases, such as tyrosine kinases. An attractive model to explain the mechanism of this cardiotoxicity could be myocyte loss through cell death pathways. Inhibition of mitochondrial transition permeability is a valuable tool to prevent doxorubicin-induced cardiotoxicity. In response to anthracycline treatment, activation of several protein kinases, neuregulin/ErbB2 signaling, and transcriptional factors modify mitochondrial functions that determine cell death or survival through the modulation of mitochondrial membrane permeability. Cellular response to anthracyclines is also modulated by a myriad of transcriptional factors that influence cell fate. Several novel targeted chemotherapeutic agents have been associated with a small but worrying risk of left ventricular dysfunction. Agents such as trastuzumab and tyrosine kinase inhibitors can lead to cardiotoxicity that is fundamentally different from that caused by anthracyclines, whereas biological effects converge to the mitochondria as a critical target.

  11. Mitochondria Death/Survival Signaling Pathways in Cardiotoxicity Induced by Anthracyclines and Anticancer-Targeted Therapies

    PubMed Central

    Montaigne, David; Hurt, Christopher; Neviere, Remi

    2012-01-01

    Anthracyclines remain the cornerstone of treatment in many malignancies but these agents have a cumulative dose relationship with cardiotoxicity. Development of cardiomyopathy and congestive heart failure induced by anthracyclines are typically dose-dependent, irreversible, and cumulative. Although past studies of cardiotoxicity have focused on anthracyclines, more recently interest has turned to anticancer drugs that target many proteins kinases, such as tyrosine kinases. An attractive model to explain the mechanism of this cardiotoxicity could be myocyte loss through cell death pathways. Inhibition of mitochondrial transition permeability is a valuable tool to prevent doxorubicin-induced cardiotoxicity. In response to anthracycline treatment, activation of several protein kinases, neuregulin/ErbB2 signaling, and transcriptional factors modify mitochondrial functions that determine cell death or survival through the modulation of mitochondrial membrane permeability. Cellular response to anthracyclines is also modulated by a myriad of transcriptional factors that influence cell fate. Several novel targeted chemotherapeutic agents have been associated with a small but worrying risk of left ventricular dysfunction. Agents such as trastuzumab and tyrosine kinase inhibitors can lead to cardiotoxicity that is fundamentally different from that caused by anthracyclines, whereas biological effects converge to the mitochondria as a critical target. PMID:22482055

  12. Biomarkers for Presymptomatic Doxorubicin-Induced Cardiotoxicity in Breast Cancer Patients

    PubMed Central

    Todorova, Valentina K.; Makhoul, Issam; Siegel, Eric R.; Wei, Jeanne; Stone, Annjanette; Carter, Weleetka; Beggs, Marjorie L.; Owen, Aaron; Klimberg, V. Suzanne

    2016-01-01

    Cardiotoxicity of doxorubicin (DOX) remains an important health concern. DOX cardiotoxicity is cumulative-dose-dependent and begins with the first dose of chemotherapy. No biomarker for presymptomatic detection of DOX cardiotoxicity has been validated. Our hypothesis is that peripheral blood cells (PBC) gene expression induced by the early doses of DOX-based chemotherapy could identify potential biomarkers for presymptomatic cardiotoxicity in cancer patients. PBC gene expression of 33 breast cancer patients was conducted before and after the first cycle of DOX-based chemotherapy. Cardiac function was evaluated before the start of chemotherapy and at its completion. Differentially expressed genes (DEG) of patients who developed DOX-associated cardiotoxicity after the completion of chemotherapy were compared with DEG of patients who did not. Ingenuity database was used for functional analysis of DEG. Sixty-sevens DEG (P<0.05) were identified in PBC of patients with DOX-cardiotoxicity. Most of DEG encode proteins secreted by activated neutrophils. The functional analysis of the DEG showed enrichment for immune- and inflammatory response. This is the first study to identify the PBC transcriptome signature associated with a single dose of DOX-based chemotherapy in cancer patients. We have shown that PBC transcriptome signature associated with one dose of DOX chemotherapy in breast cancer can predict later impairment of cardiac function. This finding may be of value in identifying patients at high or low risk for the development of DOX cardiotoxicity during the initial doses of chemotherapy and thus to avoid the accumulating toxic effects from the subsequent doses during treatment. PMID:27490685

  13. Mechanism of protection of moderately diet restricted rats against doxorubicin-induced acute cardiotoxicity

    SciTech Connect

    Mitra, Mayurranjan S.; Donthamsetty, Shashikiran; White, Brent; Latendresse, John R.; Mehendale, Harihara M.

    2007-11-15

    Clinical use of doxorubicin (Adriamycin (registered) ), an antitumor agent, is limited by its oxyradical-mediated cardiotoxicity. We tested the hypothesis that moderate diet restriction protects against doxorubicin-induced cardiotoxicity by decreasing oxidative stress and inducing cardioprotective mechanisms. Male Sprague-Dawley rats (250-275 g) were maintained on diet restriction [35% less food than ad libitum]. Cardiotoxicity was estimated by measuring biomarkers of cardiotoxicity, cardiac function, lipid peroxidation, and histopathology. A LD{sub 100} dose of doxorubicin (12 mg/kg, ip) administered on day 43 led to 100% mortality in ad libitum rats between 7 and 13 days due to higher cardiotoxicity and cardiac dysfunction, whereas all the diet restricted rats exhibited normal cardiac function and survived. Toxicokinetic analysis revealed equal accumulation of doxorubicin and doxorubicinol (toxic metabolite) in the ad libitum and diet restricted hearts. Mechanistic studies revealed that diet restricted rats were protected due to (1) lower oxyradical stress from increased cardiac antioxidants leading to downregulation of uncoupling proteins 2 and 3, (2) induction of cardiac peroxisome proliferators activated receptor-{alpha} and plasma adiponectin increased cardiac fatty acid oxidation (666.9 {+-}14.0 nmol/min/g heart in ad libitum versus 1035.6 {+-} 32.3 nmol/min/g heart in diet restriction) and mitochondrial AMP{alpha}2 protein kinase. The changes led to 51% higher cardiac ATP levels (17.7 {+-} 2.1 {mu}mol/g heart in ad libitum versus 26.7 {+-} 1.9 {mu}mol/g heart in diet restriction), higher ATP/ADP ratio, and (3) increased cardiac erythropoietin and decreased suppressor of cytokine signaling 3, which upregulates cardioprotective JAK/STAT3 pathway. These findings collectively show that moderate diet restriction renders resiliency against doxorubicin cardiotoxicity by lowering oxidative stress, enhancing ATP synthesis, and inducing the JAK/STAT3 pathway.

  14. The chemopreventive potential of lycopene against atrazine-induced cardiotoxicity: modulation of ionic homeostasis

    PubMed Central

    Lin, Jia; Li, Hui-Xin; Xia, Jun; Li, Xue-Nan; Jiang, Xiu-Qing; Zhu, Shi-Yong; Ge, Jing; Li, Jin-Long

    2016-01-01

    People who drink water contaminated with atrazine (ATR) over many years can experience problems with their cardiovascular system. Lycopene (LYC) has been shown to exhibit cardiovascular disease preventive effects. However, chemopreventive potential of LYC against ATR-induced cardiotoxicity remains unclear. To determine the effects of ATR and/or LYC on heart, mice were treated with ATR (50 mg/kg or 200 mg/kg) and/or LYC (5 mg/kg) by intragastric administration for 21 days. Histopathological and biochemical analyses, including analysis of ion concentrations (Na+, K+, Ca2+ and Mg2+), ATPases (Na+-K+-ATPase, Ca2+-ATPase, Mg2+-ATPase and Ca2+-Mg2+-ATPase) activities and the transcription of their subunits, were performed on heart. The results revealed that ATR led to decreased Creative Kinase (CK) activity and increased histological alterations. Furthermore, a significant change in Na+, K+ and Ca2+ content and the down-regulation of Na+-K+-ATPase and Ca2+-ATPase activities and the mRNA expression of their subunits were observed in ATR-exposed mice. Notably, supplementary LYC significantly protected the heart against ATR-induced damage. In conclusion, ATR induced cardiotoxicity by modulating cardiac ATPase activity and the transcription of its subunits, thereby triggering ionic disturbances. However, supplementary LYC significantly combated ATR-induced cardiotoxicity via the regulation of ATPase activity and subunit transcription. Thus, LYC exhibited a significant chemopreventive potential against ATR-induced cardiotoxicity. PMID:27112537

  15. Protective effects of agmatine on doxorubicin-induced chronic cardiotoxicity in rat.

    PubMed

    Yarmohmmadi, Fatemeh; Rahimi, Nastaran; Faghir-Ghanesefat, Hedyeh; Javadian, Nina; Abdollahi, Alireza; Pasalar, Parvin; Jazayeri, Farahnaz; Ejtemaeemehr, Shahram; Dehpour, Ahmad Reza

    2017-02-05

    The detrimental cardio-toxic effect of doxorubicin, an effective chemotherapeutic agent, limited its clinical use. It has been claimed that doxorubicin cardio-toxicity occurs through calcium ions (Ca(2+)) overload and reactive oxygen species production. Agmatine, an endogenous imidazoline receptor agonist, induce uptake of cytosolic Ca(2+) and cause an increase in activity of calcium pumps, including Ca(2+)-ATPase. Also it shows self-scavenging effect against reactive oxygen species production. Therefore, present study was designed to investigate the effects of agmatine against chronic cardio-toxicity of doxorubicin in rats. Male wistar rats were intraperitoneally injected with doxorubicin and agmatine four times a week for a month. Agmatine significantly alleviate the adverse effect of doxorubicin on left ventricular papillary muscle stimulation threshold and contractibility. Chronic co-administration of agmatine with doxorubicin blocked electrocardiographic changes induced by doxorubicin. In addition, agmatine improved body weight and decreased the mortality rate of animals by doxorubicin. Moreover, reversing the doxorubicin induced myocardial lesions was observed in animals treated by agmatine. A significant rise in the total antioxidant capacity of rat plasma was achieved in agmatine-treated animals in comparison to doxorubicin. To conclude, agmatine may improve therapeutic outcomes of doxorubicin since it exerts protective effects against doxorubicin-induced chronic cardiotoxicity in rats. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Sab mediates mitochondrial dysfunction involved in imatinib mesylate-induced cardiotoxicity.

    PubMed

    Chambers, Tara P; Santiesteban, Luis; Gomez, David; Chambers, Jeremy W

    2017-03-16

    Imatinib mesylate is an effective treatment for chronic myelogenous leukemia and gastrointestinal stromal tumors. Although imatinib mesylate is highly tolerable, it has been implicated in severe congestive heart failure in mouse models and patients. A hallmark of imatinib mesylate-induced cardiotoxicity is mitochondrial dysfunction. The mitochondrial scaffold Sab has been implicated in facilitating signaling responsible for mitochondrial dysfunction in a c-Jun N-terminal Kinase (JNK)-dependent manner. We examined the impact of Sab-mediated signaling on imatinib mesylate cardiotoxicity in H9c2 rat cardiomyocyte-like cells. Silencing Sab increased the LD50 of imatinib mesylate 4-fold in H9c2 cells. Disrupting Sab-mediated signaling prevented imatinib mesylate-induced apoptosis as well. Knockdown of Sab or inhibition with a small peptide prevented oxidative stress, which was indicated by decreased reactive oxygen species production, lipid peroxidation, and protein carbonylation. Further, inhibition of Sab-related signaling partially rescued deficits in mitochondrial respiration, ATP production, and membrane potential in imatinib mesylate-treated H9c2 cells. Conversely, over-expression of Sab in H9c2 cells increased the cardiotoxicity of imatinib mesylate in vitro decreasing the LD50 over 4-fold. Sab expression was induced in H9c2 cells following cardiovascular-like stress in an AP-1 dependent manner. These data demonstrate that imatinib mesylate influences mitochondrial signaling leading to mitochondrial dysfunction and cardiotoxicity.

  17. High fat diet-fed obese rats are highly sensitive to doxorubicin-induced cardiotoxicity

    SciTech Connect

    Mitra, Mayurranjan S.; Donthamsetty, Shashikiran; White, Brent; Mehendale, Harihara M.

    2008-09-15

    Often, chemotherapy by doxorubicin (Adriamycin) is limited due to life threatening cardiotoxicity in patients during and posttherapy. Recently, we have shown that moderate diet restriction remarkably protects against doxorubicin-induced cardiotoxicity. This cardioprotection is accompanied by decreased cardiac oxidative stress and triglycerides and increased cardiac fatty-acid oxidation, ATP synthesis, and upregulated JAK/STAT3 pathway. In the current study, we investigated whether a physiological intervention by feeding 40% high fat diet (HFD), which induces obesity in male Sprague-Dawley rats (250-275 g), sensitizes to doxorubicin-induced cardiotoxicity. A LD{sub 10} dose (8 mg doxorubicin/kg, ip) administered on day 43 of the HFD feeding regimen led to higher cardiotoxicity, cardiac dysfunction, lipid peroxidation, and 80% mortality in the obese (OB) rats in the absence of any significant renal or hepatic toxicity. Doxorubicin toxicokinetics studies revealed no change in accumulation of doxorubicin and doxorubicinol (toxic metabolite) in the normal diet-fed (ND) and OB hearts. Mechanistic studies revealed that OB rats are sensitized due to: (1) higher oxyradical stress leading to upregulation of uncoupling proteins 2 and 3, (2) downregulation of cardiac peroxisome proliferators activated receptor-{alpha}, (3) decreased plasma adiponectin levels, (4) decreased cardiac fatty-acid oxidation (666.9 {+-} 14.0 nmol/min/g heart in ND versus 400.2 {+-} 11.8 nmol/min/g heart in OB), (5) decreased mitochondrial AMP-{alpha}2 protein kinase, and (6) 86% drop in cardiac ATP levels accompanied by decreased ATP/ADP ratio after doxorubicin administration. Decreased cardiac erythropoietin and increased SOCS3 further downregulated the cardioprotective JAK/STAT3 pathway. In conclusion, HFD-induced obese rats are highly sensitized to doxorubicin-induced cardiotoxicity by substantially downregulating cardiac mitochondrial ATP generation, increasing oxidative stress and downregulating

  18. Overweight in mice, induced by perinatal programming, exacerbates doxorubicin and trastuzumab cardiotoxicity.

    PubMed

    Guenancia, Charles; Hachet, Olivier; Aboutabl, Mona; Li, Na; Rigal, Eve; Cottin, Yves; Rochette, Luc; Vergely, Catherine

    2016-04-01

    Trastuzumab (TRZ) is believed to potentiate doxorubicin (DOX) cardiotoxicity, resulting in left ventricular dysfunction. There is some evidence that overweight could influence anticancer drug-induced cardiotoxicity, though no study has evaluated the impact of moderate overweight, induced by postnatal nutritional programming, on the cardiotoxic effects of DOX alone or in combination with TRZ. Immediately after birth, litters of C57BL/6 mice were either maintained at 9 pups (normal litter, NL) or reduced to 3 (small litter, SL) in order to induce programming of ~15 % overweight through postnatal overfeeding. At 4 months, NL and SL mice received a single intra-peritoneal injection of either saline, DOX (6 mg/kg), TRZ (10 mg/kg) or both (DOX-TRZ). Transthoracic echocardiography was performed 24 h before as well as 10 and 20 days after treatments. Twenty days after DOX administration, systolic dysfunction was observed only in the overweight SL group, while NL mice group had a normal left ventricular ejection fraction. However, in the NL group, functional impairment appeared when TRZ was co-administered. Forty-eight hours after drug administration, gene expression of natriuretic peptides (ANP, BNP) appeared to be potentiated in DOX-TRZ mice of both the NL and SL group, whereas the expression of β-MHC increased significantly in overweight SL mice only. In an acute model of DOX cardiotoxicity, moderately overweight adult mice were more sensitive to cardiac systolic impairment. Moreover, our results confirm the potentiating action of TRZ on DOX-induced cardiotoxicity in lean mice.

  19. MicroRNAs as potential biomarkers for doxorubicin-induced cardiotoxicity.

    PubMed

    Holmgren, Gustav; Synnergren, Jane; Andersson, Christian X; Lindahl, Anders; Sartipy, Peter

    2016-08-01

    Anthracyclines, such as doxorubicin, are well-established, highly efficient anti-neoplastic drugs used for treatment of a variety of cancers, including solid tumors, leukemia, lymphomas, and breast cancer. The successful use of doxorubicin has, however, been hampered by severe cardiotoxic side-effects. In order to prevent or reverse negative side-effects of doxorubicin, it is important to find early biomarkers of heart injury and drug-induced cardiotoxicity. The high stability under extreme conditions, presence in various body fluids, and tissue-specificity, makes microRNAs very suitable as clinical biomarkers. The present study aimed towards evaluating the early and late effects of doxorubicin on the microRNA expression in cardiomyocytes derived from human pluripotent stem cells. We report on several microRNAs, including miR-34a, miR-34b, miR-187, miR-199a, miR-199b, miR-146a, miR-15b, miR-130a, miR-214, and miR-424, that are differentially expressed upon, and after, treatment with doxorubicin. Investigation of the biological relevance of the identified microRNAs revealed connections to cardiomyocyte function and cardiotoxicity, thus supporting the findings of these microRNAs as potential biomarkers for drug-induced cardiotoxicity. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Ethanolic extract of Boswellia ovalifoliolata bark and leaf attenuates doxorubicin-induced cardiotoxicity in mice.

    PubMed

    Uma Mahesh, Bandari; Shrivastava, Shweta; Kuncha, Madhusudhana; Sahu, Bidya Dhar; Swamy, Challa Veerabhadra; Pragada, Rajeswara Rao; Naidu, V G M; Sistla, Ramakrishna

    2013-11-01

    The aim of the study was to investigate the potential protective effect of ethanolic extract of Boswellia ovalifoliolata (BO) bark and leaf against doxorubicin (DOX)-induced cardiotoxicity in mice. Ethanolic extracts of BO bark (400 mg/kg) and leaves (250 mg/kg) were given orally to mice for 9 consecutive days and DOX (15 mg/kg; i.p.) was administered on the seventh day. Extract protected against DOX-induced ECG changes. It significantly inhibited DOX-provoked glutathione depletion and accumulation of malondialdehyde. The decrease in antioxidant enzyme activities of catalase, superoxide dismutase, glutathione peroxidase in cardiac tissue were significantly (p<0.05) mitigated after treatment with BO bark and leaf extracts. Pretreatment with BO significantly (p<0.05) restored the levels of DOX-induced rise of SGPT, SGOT, serum lactate dehydrogenase and creatine kinase-MB levels. These findings suggest that ethanolic extract of BO has protective effects against DOX-induced cardiotoxicity.

  1. Rituximab-induced Takotsubo syndrome: more cardiotoxic than it appears?

    PubMed Central

    Ng, Kien Hoe; Dearden, Claire; Gruber, Pascale

    2015-01-01

    Rituximab is used for treatment of multiple haematological cancers. Caution for use is advised in patients with significant cardiorespiratory disease due to known cases of exacerbations of angina and arrhythmias. However, its cardiotoxicity profile is not as well recognised as other monoclonal antibodies such as transtuzumab. We report a case of a 66-year-old man who developed Takotsubo's cardiomyopathy (TC) after an elective infusion of rituximab. This case is exceptional in that rituximab has not been linked to TC, and the vast majority of chemotherapy-linked and immunotherapy-linked TC reactions have occurred during initial infusions. We also discuss the different mechanisms which link TC to immunotherapy and chemotherapy, and propose that there may be a potential for risk-stratifying recipients of this frequently used immunotherapy prior to administering treatment. PMID:25733089

  2. Subclinical Cardiotoxicity Detected by Strain Rate Imaging up to 14 months After Breast Radiation Therapy

    SciTech Connect

    Erven, Katrien; Florian, Anca; Slagmolen, Pieter; Sweldens, Caroline; Jurcut, Ruxandra; Wildiers, Hans; Voigt, Jens-Uwe; Weltens, Caroline

    2013-04-01

    Purpose: Strain rate imaging (SRI) is a new echocardiographic modality that enables accurate measurement of regional myocardial function. We investigated the role of SRI and troponin I (TnI) in the detection of subclinical radiation therapy (RT)-induced cardiotoxicity in breast cancer patients. Methods and Materials: This study prospectively included 75 women (51 left-sided and 24 right-sided) receiving adjuvant RT to the breast/chest wall and regional lymph nodes. Sequential echocardiographs with SRI were obtained before RT, immediately after RT, and 8 and 14 months after RT. TnI levels were measured on the first and last day of RT. Results: Mean heart and left ventricle (LV) doses were both 9 ± 4 Gy for the left-sided patients and 4 ± 4 Gy and 1 ± 0.4 Gy, respectively, for the right-sided patients. A decrease in strain was observed at all post-RT time points for left-sided patients (−17.5% ± 1.9% immediately after RT, −16.6% ± 1.4% at 8 months, and −17.7% ± 1.9% at 14 months vs −19.4% ± 2.4% before RT, P<.01) but not for right-sided patients. When we considered left-sided patients only, the highest mean dose was given to the anterior left ventricular (LV) wall (25 ± 14 Gy) and the lowest to the inferior LV wall (3 ± 3 Gy). Strain of the anterior wall was reduced after RT (−16.6% ± 2.3% immediately after RT, −16% ± 2.6% at 8 months, and −16.8% ± 3% at 14 months vs −19% ± 3.5% before RT, P<.05), whereas strain of the inferior wall showed no significant change. No changes were observed with conventional echocardiography. Furthermore, mean TnI levels for the left-sided patients were significantly elevated after RT compared with before RT, whereas TnI levels of the right-sided patients remained unaffected. Conclusions: In contrast to conventional echocardiography, SRI detected a regional, subclinical decline in cardiac function up to 14 months after breast RT. It remains to be determined whether these changes are related to clinical

  3. Sesamin ameliorates doxorubicin-induced cardiotoxicity: involvement of Sirt1 and Mn-SOD pathway.

    PubMed

    Su, Suwen; Li, Qian; Liu, Yi; Xiong, Chen; Li, Junxia; Zhang, Rong; Niu, Yujie; Zhao, Lijuan; Wang, Yongli; Guo, Huicai

    2014-01-13

    Oxidative stress caused by doxorubicin (DOX) is believed to be a major underlying molecular mechanism of DOX-induced cardiotoxicity. Sesamin (Ses), an active component extracted from sesame seeds, exhibits antioxidative and anti-inflammatory effects. In the present study, possible protective mechanisms of Ses on DOX-induced cardiotoxicity were investigated in rats and cultured H9C2 cells. We demonstrated that Ses exhibits a significant protective effect on cardiac tissue in animal and cell models of DOX-induced cardiac injury. Moreover, Ses can ameliorate DOX-induced oxidative stress and mitochondrial damage. Further studies suggested that Ses is able to up-regulate the protein expression of Mn-SOD in normal rats and to restore the decreased expression of Mn-SOD in DOX-induced cardiac injury rats. Exposure to Ses or DOX alone slightly increased the protein expression of Sirt1; however, a more remarkable increase in Sirt1 protein level was detected in the Ses+DOX group. Treatment with a pan-sirtuin inhibitor (nicotinamide) or a Sirt1-specific inhibitor (EX-527) partially antagonised the effect of Ses on DOX-induced mitochondrial damage and completely abolished the effect of Ses on Mn-SOD expression. These findings indicate that the protective mechanisms of Ses on DOX-induced cardiotoxicity are involved in the alleviation of oxidative stress injury and Mn-SOD dysfunction, partially via the activation of Sirt1.

  4. Astragalus polysaccharide restores autophagic flux and improves cardiomyocyte function in doxorubicin-induced cardiotoxicity

    PubMed Central

    Cao, Yuan; Shen, Tao; Huang, Xiuqing; Lin, Yajun; Chen, Beidong; Pang, Jing; Li, Guoping; Wang, Que; Zohrabian, Sylvia; Duan, Chao; Ruan, Yang; Man, Yong; Wang, Shu; Li, Jian

    2017-01-01

    Doxorubicin (adriamycin), an anthracycline antibiotic, is commonly used to treat many types of solid and hematological malignancies. Unfortunately, clinical usage of doxorubicin is limited due to the associated acute and chronic cardiotoxicity. Previous studies demonstrated that Astragalus polysaccharide (APS), the extracts of Astragalus membranaceus, had strong anti-tumor activities and anti-inflammatory effects. However, whether APS could mitigate chemotherapy-induced cardiotoxicity is unclear thus far. We used a doxorubicin-induced neonatal rat cardiomyocyte injury model and a mouse heart failure model to explore the function of APS. GFP-LC3 adenovirus-mediated autophagic vesicle assays, GFP and RFP tandemly tagged LC3 (tfLC3) assays and Western blot analyses were performed to analyze the cell function and cell signaling changes following APS treatment in cardiomyocytes. First, doxorubicin treatment led to C57BL/6J mouse heart failure and increased cardiomyocyte apoptosis, with a disturbed cell autophagic flux. Second, APS restored autophagy in doxorubicin-treated primary neonatal rat ventricular myocytes and in the doxorubicin-induced heart failure mouse model. Third, APS attenuated doxorubicin-induced heart injury by regulating the AMPK/mTOR pathway. The mTOR inhibitor rapamycin significantly abrogated the protective effect of APS. These results suggest that doxorubicin could induce heart failure by disturbing cardiomyocyte autophagic flux, which may cause excessive cell apoptosis. APS could restore normal autophagic flux, ameliorating doxorubicin-induced cardiotoxicity by regulating the AMPK/mTOR pathway. PMID:27902477

  5. (-)-Epigallocatechin-3-gallate (EGCG) attenuates arsenic-induced cardiotoxicity in rats.

    PubMed

    Sun, Tao-Li; Liu, Zhi; Qi, Zheng-Jun; Huang, Yong-Pan; Gao, Xiao-Qin; Zhang, Yan-Yan

    2016-07-01

    Chronic arsenic exposure in drinking water is associated with the abnormalities of cardiac tissue. Excessive generation of ROS induced by arsenic has a central role in arsenic-induced cardiotoxicity. (-)-Epigallocatechin-3-gallate (EGCG), the most abundant polyphenol in green tea, possesses a potent antioxidant capacity and exhibits extensive pharmacological activities. This study was aim to evaluate the effect of EGCG on arsenic-induced cardiotoxicity in vivo and in vitro. Treatment with NaAsO2 seriously affected the morphology and ultrastructure of myocardium, and induced cardiac injuries, oxidative stress, intracellular calcium accumulation and apoptosis in rats. In consistent with in vivo study, the injuries, oxidative stress and apoptosis were also observed in NaAsO2-treated H9c2 cells. All of these effects induced by NaAsO2 were attenuated by EGCG. These results suggest EGCG could attenuate NaAsO2-induced cardiotoxicity, and the mechanism may involve its potent antioxidant capacity. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Isorhamnetin protects against doxorubicin-induced cardiotoxicity in vivo and in vitro.

    PubMed

    Sun, Jing; Sun, Guibo; Meng, Xiangbao; Wang, Hongwei; Luo, Yun; Qin, Meng; Ma, Bo; Wang, Min; Cai, Dayong; Guo, Peng; Sun, Xiaobo

    2013-01-01

    Doxorubicin (Dox) is an anthracycline antibiotic for cancer therapy with limited usage due to cardiotoxicity. Isorhamnetin is a nature antioxidant with obvious cardiac protective effect. The aim of this study is going to investigate the possible protective effect of isorhamnetin against Dox-induced cardiotoxicity and its underlying mechanisms. In an in vivo investigation, rats were intraperitoneally (i.p.) administered with Dox to duplicate the model of Dox-induced chronic cardiotoxicity. Daily pretreatment with isorhamnetin (5 mg/kg, i.p.) for 7 days was found to reduce Dox-induced myocardial damage significantly, including the decline of cardiac index, decrease in the release of serum cardiac enzymes and amelioration of heart vacuolation. In vitro studies on H9c2 cardiomyocytes, isorhamnetin was effective to reduce Dox-induced cell toxicity. A further mechanism study indicated that isorhamnetin pretreatment can counteract Dox-induced oxidative stress and suppress the activation of mitochondrion apoptotic pathway and mitogen-activated protein kinase pathway. Isorhamnetin also potentiated the anti-cancer activity of Dox in MCF-7, HepG2 and Hep2 cells. These findings indicated that isorhamnetin can be used as an adjuvant therapy for the long-term clinical use of Dox.

  7. Isorhamnetin Protects against Doxorubicin-Induced Cardiotoxicity In Vivo and In Vitro

    PubMed Central

    Sun, Jing; Sun, Guibo; Meng, Xiangbao; Wang, Hongwei; Luo, Yun; Qin, Meng; Ma, Bo; Wang, Min; Cai, Dayong; Guo, Peng; Sun, Xiaobo

    2013-01-01

    Doxorubicin (Dox) is an anthracycline antibiotic for cancer therapy with limited usage due to cardiotoxicity. Isorhamnetin is a nature antioxidant with obvious cardiac protective effect. The aim of this study is going to investigate the possible protective effect of isorhamnetin against Dox-induced cardiotoxicity and its underlying mechanisms. In an in vivo investigation, rats were intraperitoneally (i.p.) administered with Dox to duplicate the model of Dox-induced chronic cardiotoxicity. Daily pretreatment with isorhamnetin (5 mg/kg, i.p.) for 7 days was found to reduce Dox-induced myocardial damage significantly, including the decline of cardiac index, decrease in the release of serum cardiac enzymes and amelioration of heart vacuolation. In vitro studies on H9c2 cardiomyocytes, isorhamnetin was effective to reduce Dox-induced cell toxicity. A further mechanism study indicated that isorhamnetin pretreatment can counteract Dox-induced oxidative stress and suppress the activation of mitochondrion apoptotic pathway and mitogen-activated protein kinase pathway. Isorhamnetin also potentiated the anti-cancer activity of Dox in MCF-7, HepG2 and Hep2 cells. These findings indicated that isorhamnetin can be used as an adjuvant therapy for the long-term clinical use of Dox. PMID:23724057

  8. Glutathione S-transferase P protects against cyclophosphamide-induced cardiotoxicity in mice

    SciTech Connect

    Conklin, Daniel J.; Haberzettl, Petra; Jagatheesan, Ganapathy; Baba, Shahid; Merchant, Michael L.; Prough, Russell A.; Williams, Jessica D.; Prabhu, Sumanth D.; Bhatnagar, Aruni

    2015-06-01

    High-dose chemotherapy regimens using cyclophosphamide (CY) are frequently associated with cardiotoxicity that could lead to myocyte damage and congestive heart failure. However, the mechanisms regulating the cardiotoxic effects of CY remain unclear. Because CY is converted to an unsaturated aldehyde acrolein, a toxic, reactive CY metabolite that induces extensive protein modification and myocardial injury, we examined the role of glutathione S-transferase P (GSTP), an acrolein-metabolizing enzyme, in CY cardiotoxicity in wild-type (WT) and GSTP-null mice. Treatment with CY (100–300 mg/kg) increased plasma levels of creatine kinase-MB isoform (CK·MB) and heart-to-body weight ratio to a significantly greater extent in GSTP-null than WT mice. In addition to modest yet significant echocardiographic changes following acute CY-treatment, GSTP insufficiency was associated with greater phosphorylation of c-Jun and p38 as well as greater accumulation of albumin and protein–acrolein adducts in the heart. Mass spectrometric analysis revealed likely prominent modification of albumin, kallikrein-1-related peptidase, myoglobin and transgelin-2 by acrolein in the hearts of CY-treated mice. Treatment with acrolein (low dose, 1–5 mg/kg) also led to increased heart-to-body weight ratio and myocardial contractility changes. Acrolein induced similar hypotension in GSTP-null and WT mice. GSTP-null mice also were more susceptible than WT mice to mortality associated with high-dose acrolein (10–20 mg/kg). Collectively, these results suggest that CY cardiotoxicity is regulated, in part, by GSTP, which prevents CY toxicity by detoxifying acrolein. Thus, humans with low cardiac GSTP levels or polymorphic forms of GSTP with low acrolein-metabolizing capacity may be more sensitive to CY toxicity. - Graphical abstract: Cyclophosphamide (CY) treatment results in P450-mediated metabolic formation of phosphoramide mustard and acrolein (3-propenal). Acrolein is either metabolized and

  9. Protective effects of berberine against doxorubicin-induced cardiotoxicity in rats by inhibiting metabolism of doxorubicin.

    PubMed

    Hao, Gang; Yu, Yunli; Gu, Bingren; Xing, Yiwen; Xue, Man

    2015-01-01

    1. The clinical use of doxorubicin, an effective anticancer drug, is severely hampered by its cardiotoxicity. Berberine, a botanical alkaloid, has been reported to possess cardioprotective and antitumor effects. In this study, we investigated the cardioprotective effect of berberine on doxorubicin-induced cardiotoxicity and the effect of berberine on the metabolism of doxorubicin. 2. Adult male Sprague-Dawley rats were administered doxorubicin in the presence or absence of berberine for 2 weeks. Administration of berberine effectively prevented doxorubicin-induced body weight reduction and mortality in rats. 3. Berberine reduced the activity of myocardial enzymes, including aspartate aminotransferase (AST), creatine kinase (CK), CK isoenzyme (CK-MB) and lactate dehydrogenase (LDH). Echocardiographic examination further demonstrated that berberine effectively ameliorated cardiac dysfunction induced by doxorubicin. 4. Berberine inhibited the metabolism of doxorubicin in the cytoplasm of rat heart and reduced the accumulation of doxorubicinol (a secondary alcohol metabolite of doxorubicin) in heart. 5. These data showed that berberine alleviated the doxorubicin-induced cardiotoxicity in rats via inhibition of the metabolism of doxorubicin and reduced accumulation of doxorubicinol selectively in hearts.

  10. Cranberry (Vaccinium macrocarpon) protects against doxorubicin-induced cardiotoxicity in rats.

    PubMed

    Elberry, Ahmed A; Abdel-Naim, Ashraf B; Abdel-Sattar, Essam A; Nagy, Ayman A; Mosli, Hisham A; Mohamadin, Ahmed M; Ashour, Osama M

    2010-05-01

    Doxorubicin (DOX) is a widely used cancer chemotherapeutic agent. However, it generates free oxygen radicals that result in serious dose-limiting cardiotoxicity. Supplementations with berries were proven effective in reducing oxidative stress associated with several ailments. The aim of the current study was to investigate the potential protective effect of cranberry extract (CRAN) against DOX-induced cardiotoxicity in rats. CRAN was given orally to rats (100mg/kg/day for 10 consecutive days) and DOX (15mg/kg; i.p.) was administered on the seventh day. CRAN protected against DOX-induced increased mortality and ECG changes. It significantly inhibited DOX-provoked glutathione (GSH) depletion and accumulation of oxidized glutathione (GSSG), malondialdehyde (MDA), and protein carbonyls in cardiac tissues. The reductions of cardiac activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and glutathione reductase (GR) were significantly mitigated. Elevation of cardiac myeloperoxidase (MPO) activity in response to DOX treatment was significantly hampered. Pretreatment of CRAN significantly guarded against DOX-induced rise of serum lactate dehydrogenase (LDH), creatine phosphokinase (CK), creatine kinase-MB (CK-MB) as well as troponin I level. CRAN alleviated histopathological changes in rats' hearts treated with DOX. In conclusion, CRAN protects against DOX-induced cardiotoxicity in rats. This can be attributed, at least in part, to CRAN's antioxidant activity. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  11. Dihydromyricetin prevents cardiotoxicity and enhances anticancer activity induced by adriamycin

    PubMed Central

    Fu, Yingying; Wang, Jincheng; Dai, Jiabin; Shao, Jinjin; Yang, Xiaochun; Chang, Linlin; Weng, Qinjie; Yang, Bo; He, Qiaojun

    2015-01-01

    Adriamycin, a widely used anthracycline antibiotic in multiple chemotherapy regimens, has been challenged by the cardiotoxicity leading to fatal congestive heart failure in the worst condition. The present study demonstrated that Dihydromyricetin, a natural product extracted from ampelopsis grossedentat, exerted cardioprotective effect against the injury in Adriamycin-administrated ICR mice. Dihydromyricetin decreased ALT, LDH and CKMB levels in mice serum, causing a significant reduction in the toxic death triggered by Adriamycin. The protective effects were also indicated by the alleviation of abnormal electrocardiographic changes, the abrogation of proliferation arrest and apoptotic cell death in primary myocardial cells. Further study revealed that Dihydromyricetin-rescued loss of anti-apoptosis protein ARC provoked by Adriamycin was involved in the cardioprotection. Intriguingly, the anticancer activity of Adriamycin was not compromised upon the combination with Dihydromyricetin, as demonstrated by the enhanced anticancer effect achieved by Adriamycin plus Dihydromyricetin in human leukemia U937 cells and xenograft models, in a p53-dependent manner. These results collectively promised the potential value of Dihydromyricetin as a rational cardioprotective agent of Adriamycin, by protecting myocardial cells from apoptosis, while potentiating anticancer activities of Adriamycin, thus further increasing the therapeutic window of the latter one. PMID:25226612

  12. VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection

    PubMed Central

    Räsänen, Markus; Degerman, Joni; Nissinen, Tuuli A.; Miinalainen, Ilkka; Kerkelä, Risto; Siltanen, Antti; Backman, Janne T.; Mervaala, Eero; Hulmi, Juha J.; Kivelä, Riikka; Alitalo, Kari

    2016-01-01

    Congestive heart failure is one of the leading causes of disability in long-term survivors of cancer. The anthracycline antibiotic doxorubicin (DOX) is used to treat a variety of cancers, but its utility is limited by its cumulative cardiotoxicity. As advances in cancer treatment have decreased cancer mortality, DOX-induced cardiomyopathy has become an increasing problem. However, the current means to alleviate the cardiotoxicity of DOX are limited. We considered that vascular endothelial growth factor-B (VEGF-B), which promotes coronary arteriogenesis, physiological cardiac hypertrophy, and ischemia resistance, could be an interesting candidate for prevention of DOX-induced cardiotoxicity and congestive heart failure. To study this, we administered an adeno-associated viral vector expressing VEGF-B or control vector to normal and tumor-bearing mice 1 wk before DOX treatment, using doses mimicking the concentrations used in the clinics. VEGF-B treatment completely inhibited the DOX-induced cardiac atrophy and whole-body wasting. VEGF-B also prevented capillary rarefaction in the heart and improved endothelial function in DOX-treated mice. VEGF-B also protected cultured endothelial cells from apoptosis and restored their tube formation. VEGF-B increased left ventricular volume without compromising cardiac function, reduced the expression of genes associated with pathological remodeling, and improved cardiac mitochondrial respiration. Importantly, VEGF-B did not affect serum or tissue concentrations of DOX or augment tumor growth. By inhibiting DOX-induced endothelial damage, VEGF-B could provide a novel therapeutic possibility for the prevention of chemotherapy-associated cardiotoxicity in cancer patients. PMID:27799559

  13. Protective effect of bilberry (Vaccinium myrtillus) against doxorubicin-induced oxidative cardiotoxicity in rats

    PubMed Central

    Ashour, Osama M.; Elberry, Ahmed A.; Alahdal, Abdulrahman M.; Al Mohamadi, Ameen M.; Nagy, Ayman A.; Abdel-Naim, Ashraf B.; Abdel-Sattar, Essam A.; Mohamadin, Ahmed M.

    2011-01-01

    Summary Background Doxorubicin (DOX) is a commonly used chemotherapeutic agent. It is associated with serious dose-limiting cardiotoxicity, which is at least partly caused by generation of reactive oxygen species (ROS). Supplementations with bilberries were effective in reducing oxidative stress in many tissue injuries due their high content of antioxidants. The present study investigated the potential protective effect of bilberry extract against DOX-induced cardiotoxicity in rats. Material/Methods Rats were treated orally with a methanolic extract of bilberry for 10 days. DOX was injected intraperitoneally on day 7. Twenty-four hours after the last bilberry administration, rats were subjected to ECG study. Blood was then withdrawn and cardiac tissues were dissected for assessment of oxidative stress and cardiac tissue injury. Cardiac tissues were also subjected to histopathological examination. Results Bilberry extract significantly inhibited DOX-provoked reduced glutathione depletion and accumulation of oxidized glutathione, malondialdehyde and protein carbonyls in cardiac tissues. This was accompanied by significant amelioration of reduced cardiac catalase, superoxide dismutase, and glutathione peroxidase activities; and increased cardiac myeloperoxidase activity in response to DOX challenge. Pretreatment with bilberry significantly guarded against DOX-induced increase in serum activities of lactate dehydrogenase, creatine phosphokinase and creatine kinase-MB, as well as the level of troponin I. Bilberry alleviated ECG changes in rats treated with DOX and attenuated its pathological changes. Conclusions Bilberry protects against DOX-induced cardiotoxicity in rats. This can be attributed, at least in part, to its antioxidant activity. PMID:21455099

  14. Cardioprotective effect of green tea extract on doxorubicin-induced cardiotoxicity in rats.

    PubMed

    Khan, Gyas; Haque, Syed Ehtaishamul; Anwer, Tarique; Ahsan, Mohd Neyaz; Safhi, Mohammad M; Alam, M F

    2014-01-01

    The in vivo antioxidant properties of green tea extract (GTE) were investigated against doxorubicin (DOX) induced cardiotoxicity in rats. In this experiment, 48 Wistar albino rats (200-250 g) were divided into eight groups (n = 6). Control group received normal saline for 30 days. Cardiotoxicity was induced by DOX (20 mg/kg ip.), once on 29th day of study and were treated with GTE (100, 200 and 400 mg/kg, p.o.) for 30 days. Aspartate aminotransferase (AST), creatinine kinase (CK), lactate dehydrogenase (LDH), lipid peroxidation (LPO), cytochrome P450 (CYP), blood glutathione, tissue glutathione, enzymatic and non-enzymatic antioxidants were evaluated along with histopathological studies. DOX treated rats showed a significant increased levels of AST, CK, LDH, LPO and CYP, which were restored by oral administration of GTE at doses 100, 200 and 400 mg/kg for 30 days. Moreover, GTE administration significantly increased the activities of glutathione peroxidase (GPX), glutathione reductase (GR), glutathione s-transferase (GST), superoxide dismutase (SOD) and catalase (CAT), in heart, which were reduced by DOX treatment. In this study, we have found that oral administration of GTE prevented DOX-induced cardiotoxicity by accelerating heart antioxidant defense mechanisms and down regulating the LPO levels to the normal levels.

  15. Dietary cyanidin 3-glucoside from purple corn ameliorates doxorubicin-induced cardiotoxicity in mice.

    PubMed

    Petroni, K; Trinei, M; Fornari, M; Calvenzani, V; Marinelli, A; Micheli, L A; Pilu, R; Matros, A; Mock, H-P; Tonelli, C; Giorgio, M

    2017-05-01

    Anthracyclines are effective anticancer drugs that have improved prognosis of hundred thousand cancer patients worldwide and are currently the most common chemotherapeutic agents used for the treatment of blood, breast, ovarian and lung cancers. However, their use is limited because of a cumulative dose-dependent and irreversible cardiotoxicity that can cause progressive cardiomyopathy and congestive heart failure. Aim of the present study was to determine the cardioprotective activity of a dietary source of cyanidin 3-glucoside (C3G), such as purple corn, against doxorubicin (DOX)-induced cardiotoxicity in mice. In vitro studies on murine HL-1 cardiomyocytes showed that pretreatment with both pure C3G and purple corn extract improved survival upon DOX treatment. However, C3G and purple corn extract did not affect the cytotoxic effect of DOX on human cancer cell lines. We then validated in vivo the protective role of a C3G-enriched diet against DOX-induced cardiotoxicity by comparing the effect of dietary consumption of corn isogenic lines with high levels of anthocyanins (purple corn - Red diet - RD) or without anthocyanins (yellow corn - Yellow diet - YD) incorporated in standard rodent diets. Results showed that mice fed RD survived longer than mice fed YD upon injection of a toxic amount of DOX. In addition, ultrastructural analysis of hearts from mice fed RD showed reduced histopathological alterations. Dietary intake of C3G from purple corn protects mice against DOX-induced cardiotoxicity. Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

  16. Taurine protects cisplatin induced cardiotoxicity by modulating inflammatory and endoplasmic reticulum stress responses.

    PubMed

    Chowdhury, Sayantani; Sinha, Krishnendu; Banerjee, Sharmistha; Sil, Parames C

    2016-11-12

    Oxidative stress, ER stress, inflammation, and apoptosis results in the pathogenesis of cisplatin-induced cardiotoxicity. The present study was designed to investigate the signaling mechanisms involved in the ameliorating effect of taurine, a conditionally essential amino acid, against cisplatin-mediated cardiac ER stress dependent apoptotic death and inflammation. Mice were simultaneously treated with taurine (150 mg kg(-1) body wt, i.p.) and cisplatin (10 mg kg(-1) body wt, i.p.) for a week. Cisplatin exposure significantly altered serum creatine kinase and troponin T levels. In addition, histological studies revealed disintegration in the normal radiation pattern of cardiac muscle fibers. However, taurine administration could abate such adverse effects of cisplatin. Taurine administration significantly mitigated the reactive oxygen species production, alleviated the overexpression of nuclear factor-κB (NF-κB), and inhibited the elevation of proinflammatoy cytokines, adhesion molecules, and chemokines. Cisplatin exposure resulted in the unfolded protein response (UPR)-regulated CCAAT/enhancer binding protein (CHOP) up-regulation, induction of GRP78: a marker of ER stress and eIF2α signaling. Increase in calpain-1 expression level, activation of caspase-12 and caspase-3, cleavage of the PARP protein as well as the inhibition of antiapoptotic protein Bcl-2 were reflected on cisplatin-triggered apoptosis. Taurine could, however, combat against such cisplatin induced cardiac-abnormalities. The above mentioned findings suggest that taurine plays a beneficial role in providing protection against cisplatin-induced cardiac damage by modulating inflammatory responses and ER stress. © 2016 BioFactors, 42(6):647-664, 2016.

  17. Protective Effects of Dexrazoxane against Doxorubicin-Induced Cardiotoxicity: A Metabolomic Study

    PubMed Central

    LiLi, Wan; YongLong, Han; Yan, Huo; Jie, Li; JinLu, Huang; Jin, Lu; Run, Gan; Cheng, Guo

    2017-01-01

    Cardioprotection of dexrazoxane (DZR) against doxorubicin (DOX)-induced cardiotoxicity is contentious and the indicator is controversial. A pairwise comparative metabolomics approach was used to delineate the potential metabolic processes in the present study. Ninety-six BALB/c mice were randomly divided into two supergroups: tumor and control groups. Each supergroup was divided into control, DOX, DZR, and DOX plus DZR treatment groups. DOX treatment resulted in a steady increase in 5-hydroxylysine, 2-hydroxybutyrate, 2-oxoglutarate, 3-hydroxybutyrate, and decrease in glucose, glutamate, cysteine, acetone, methionine, asparate, isoleucine, and glycylproline.DZR treatment led to increase in lactate, 3-hydroxybutyrate, glutamate, alanine, and decrease in glucose, trimethylamine N-oxide and carnosine levels. These metabolites represent potential biomarkers for early prediction of cardiotoxicity of DOX and the cardioprotective evaluation of DZR. PMID:28072830

  18. NLRP3 Deficiency Reduces Macrophage Interleukin-10 Production and Enhances the Susceptibility to Doxorubicin-induced Cardiotoxicity

    PubMed Central

    Kobayashi, Motoi; Usui, Fumitake; Karasawa, Tadayoshi; Kawashima, Akira; Kimura, Hiroaki; Mizushina, Yoshiko; Shirasuna, Koumei; Mizukami, Hiroaki; Kasahara, Tadashi; Hasebe, Naoyuki; Takahashi, Masafumi

    2016-01-01

    NLRP3 inflammasomes recognize non-microbial danger signals and induce release of proinflammatory cytokine interleukin (IL)-1β, leading to sterile inflammation in cardiovascular disease. Because sterile inflammation is involved in doxorubicin (Dox)-induced cardiotoxicity, we investigated the role of NLRP3 inflammasomes in Dox-induced cardiotoxicity. Cardiac dysfunction and injury were induced by low-dose Dox (15 mg/kg) administration in NLRP3-deficient (NLRP3−/−) mice but not in wild-type (WT) and IL-1β−/− mice, indicating that NLRP3 deficiency enhanced the susceptibility to Dox-induced cardiotoxicity independent of IL-1β. Although the hearts of WT and NLRP3−/− mice showed no significant difference in inflammatory cell infiltration, macrophages were the predominant inflammatory cells in the hearts, and cardiac IL-10 production was decreased in Dox-treated NLRP3−/− mice. Bone marrow transplantation experiments showed that bone marrow-derived cells contributed to the exacerbation of Dox-induced cardiotoxicity in NLRP3−/− mice. In vitro experiments revealed that NLRP3 deficiency decreased IL-10 production in macrophages. Furthermore, adeno-associated virus-mediated IL-10 overexpression restored the exacerbation of cardiotoxicity in the NLRP3−/− mice. These results demonstrated that NLRP3 regulates macrophage IL-10 production and contributes to the pathophysiology of Dox-induced cardiotoxicity, which is independent of IL-1β. Our findings identify a novel role of NLRP3 and provided new insights into the mechanisms underlying Dox-induced cardiotoxicity. PMID:27225830

  19. Essential role of GATA-4 in cell survival and drug-induced cardiotoxicity

    PubMed Central

    Aries, Anne; Paradis, Pierre; Lefebvre, Chantal; Schwartz, Robert J.; Nemer, Mona

    2004-01-01

    In recent years, significant progress has been made in understanding cardiomyocyte differentiation. However, little is known about the regulation of myocyte survival despite the fact that myocyte apoptosis is a leading cause of heart failure. Here we report that transcription factor GATA-4 is a survival factor for differentiated, postnatal cardiomyocytes and an upstream activator of the antiapoptotic gene Bcl-X. An early event in the cardiotoxic effect of the antitumor drug doxorubicin is GATA-4 depletion, which in turn causes cardiomyocyte apoptosis. Mouse heterozygotes for a null Gata4 allele have enhanced susceptibility to doxorubicin cardiotoxicity. Genetic or pharmacologic enhancement of GATA-4 prevents cardiomyocyte apoptosis and drug-induced cardiotoxicity. The results indicate that GATA-4 is an antiapoptotic factor required for the adaptive stress response of the adult heart. Modulation of survival/apoptosis genes by tissue-specific transcription factors may be a general paradigm that can be exploited effectively for cell-specific regulation of apoptosis in disease states. PMID:15100413

  20. Potential Effects of Pomegranate on Lipid Peroxidation and Pro-inflammatory Changes in Daunorubicin-induced Cardiotoxicity in Rats

    PubMed Central

    Al-Kuraishy, Hayder M.; Al-Gareeb, Ali I.

    2016-01-01

    Background: Daunorubicin-induced acute cardiotoxicity caused by oxidative stress and free radical formation. Pomegranate possessed a significant in vitro free radical scavenging activity. Therefore, the aim of this study was estimations of the role of pomegranate effects in daunorubicin-induced cardiotoxicity. Methods: A total of 21 Sprague male rats were allocated into three groups, seven animals in each group. Group A: Control group received distilled water. Group B: Treated group with daunorubicin 20 mg/kg via intraperitoneal injection daily for the 12th day for total cumulative dose of 240 mg/kg. Group C: Pretreatment group with pomegranate 25 mg/kg for 6 days orally, then daunorubicin 20 mg/kg administrated concomitantly for the next 6 days with a cumulative dose of 120 mg/kg. Cardiac troponin I([cTn I] pg/ml), malondialdehyde (MDA) (ng/ml), interleukin 17 (IL-17 pg/ml), and cardiac lactate dehydrogenase (LDH) (pm/ml), all these biomarkers were used to measure the severity of cardiotoxicity. Results: Daunorubicin at a dose of 20 mg/kg lead to pronounced cardiac damage that reflected on through elevations of serum cTn and serum LDH levels significantly P < 0.01, it induced lipid peroxidation during cardiotoxicity that reflected through an elevation in the serum MDA significantly P < 0.01, moreover, daunorubicin induces pro-inflammatory changes in cardiotoxicity; it raises the IL-17 serum level significantly P < 0.01 as compared with control. Pomegranate pretreatment demonstrated a significant cardioprotection from daunorubicin-induced cardiotoxicity; it attenuated the cardiac damage through reduction of cTn, LDH, MDA, and serum IL-17 level significantly P < 0.01 as compared with daunorubicin-treated group. Conclusions: Pomegranate demonstrated significant cardioprotection in daunorubicin-induced cardiotoxicity through reduction of oxidative stress, lipid peroxidation, pro-inflammatory, and cardiac injury biomarkers. PMID:27413516

  1. Baicalein alleviates doxorubicin-induced cardiotoxicity via suppression of myocardial oxidative stress and apoptosis in mice.

    PubMed

    Sahu, Bidya Dhar; Kumar, Jerald Mahesh; Kuncha, Madhusudana; Borkar, Roshan M; Srinivas, R; Sistla, Ramakrishna

    2016-01-01

    Doxorubicin is a widely used anthracycline derivative anticancer drug. Unfortunately, the clinical use of doxorubicin has the serious drawback of cardiotoxicity. In this study, we investigated whether baicalein, a bioflavonoid, can prevent doxorubicin-induced cardiotoxicity in vivo and we delineated the possible underlying mechanisms. Male BALB/c mice were treated with either intraperitoneal doxorubicin (15 mg/kg divided into three equal doses for 15 days) and/or oral baicalein (25 and 50 mg/kg for 15 days). Serum markers of cardiac injury, histology of heart, parameters related to myocardial oxidative stress, apoptosis and inflammation were investigated. Treatment with baicalein reduced doxorubicin-induced elevation of serum creatine kinase-MB isoenzyme (CK-MB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and ameliorated the histopathological damage. Baicalein restored the doxorubicin-induced decrease in both enzymatic and non-enzymatic myocardial antioxidants and increased the myocardial expression of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1). Further studies showed that baicalein could inverse the Bax/Bcl-2 ratio, suppress doxorubicin-induced p53, cleaved caspase-3 and PARP expression and prevented doxorubicin-induced DNA damage. Baicalein treatment also interferes with doxorubicin-induced myocardial NF-κB signaling through inhibition of IκBα phosphorylation and nuclear translocation of p65 subunit. Doxorubicin elevated iNOS and nitrites levels were also significantly decreased in baicalein treated mice. However, we did not find any significant change (p>0.05) in the myocardial TNF-α and IL-6 levels in control and treated animals. Our finding suggests that baicalein might be a promising molecule for the prevention of doxorubicin-induced cardiotoxicity. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Resveratrol protects against arsenic trioxide-induced cardiotoxicity in vitro and in vivo

    PubMed Central

    Zhao, X-Y; Li, G-Y; Liu, Y; Chai, L-M; Chen, J-X; Zhang, Y; Du, Z-M; Lu, Y-J; Yang, B-F

    2008-01-01

    Background and purpose The clinical use of arsenic trioxide (As2O3), a potent antineoplastic agent, is limited by its severe cardiotoxic effects. QT interval prolongation and apoptosis have been implicated in the cardiotoxicity of As2O3. The present study was designed to evaluate the effects of resveratrol on As2O3-induced apoptosis and cardiac injury. Experimental approach In a mouse model of As2O3-induced cardiomyopathy in vivo, QT intervals and plasma enzyme activities were measured; cardiac tissues were examined histologically and apoptosis assessed. In H9c2 cardiomyocyte cells, viability, apoptosis, generation of reactive oxygen species (ROS) and cellular calcium levels were measured. Key results In the mouse model, resveratrol reduced As2O3-induced QT interval prolongation and cardiomyocyte injury (apoptosis, myofibrillar loss and vacuolization). In addition, increased lactate dehydrogenase activity and decreased activities of glutathione peroxidase, catalase and superoxide dismutase were observed in the plasma of As2O3-treated mice; these changes were prevented by pretreatment with resveratrol. In As2O3-treated H9c2 cardiomyocytes, resveratrol significantly increased cardiomyocyte viability and attenuated cell apoptosis as measured by acridine orange/ethidium bromide staining, TdT-mediated dUTP nick end labelling assay and caspase-3 activity. As2O3-induced generation of ROS and intracellular calcium mobilization in H9c2 cells was also suppressed by pretreatment with resveratrol. Conclusions and implications Our results showed that resveratrol significantly attenuated As2O3-induced QT prolongation, structural abnormalities and oxidative damage in the heart. In H9c2 cardiomyocytes, resveratrol also decreased apoptosis, production of ROS and intracellular calcium mobilization induced by treatment with As2O3. These observations suggested that resveratrol has the potential to protect against cardiotoxicity in As2O3-exposed patients. PMID:18332854

  3. Resveratrol protects against arsenic trioxide-induced cardiotoxicity in vitro and in vivo.

    PubMed

    Zhao, X-Y; Li, G-Y; Liu, Y; Chai, L-M; Chen, J-X; Zhang, Y; Du, Z-M; Lu, Y-J; Yang, B-F

    2008-05-01

    The clinical use of arsenic trioxide (As(2)O(3)), a potent antineoplastic agent, is limited by its severe cardiotoxic effects. QT interval prolongation and apoptosis have been implicated in the cardiotoxicity of As(2)O(3). The present study was designed to evaluate the effects of resveratrol on As(2)O(3)-induced apoptosis and cardiac injury. In a mouse model of As(2)O(3)-induced cardiomyopathy in vivo, QT intervals and plasma enzyme activities were measured; cardiac tissues were examined histologically and apoptosis assessed. In H9c2 cardiomyocyte cells, viability, apoptosis, generation of reactive oxygen species (ROS) and cellular calcium levels were measured. In the mouse model, resveratrol reduced As(2)O(3)-induced QT interval prolongation and cardiomyocyte injury (apoptosis, myofibrillar loss and vacuolization). In addition, increased lactate dehydrogenase activity and decreased activities of glutathione peroxidase, catalase and superoxide dismutase were observed in the plasma of As(2)O(3)-treated mice; these changes were prevented by pretreatment with resveratrol. In As(2)O(3)-treated H9c2 cardiomyocytes, resveratrol significantly increased cardiomyocyte viability and attenuated cell apoptosis as measured by acridine orange/ethidium bromide staining, TdT-mediated dUTP nick end labelling assay and caspase-3 activity. As(2)O(3)-induced generation of ROS and intracellular calcium mobilization in H9c2 cells was also suppressed by pretreatment with resveratrol. Our results showed that resveratrol significantly attenuated As(2)O(3)-induced QT prolongation, structural abnormalities and oxidative damage in the heart. In H9c2 cardiomyocytes, resveratrol also decreased apoptosis, production of ROS and intracellular calcium mobilization induced by treatment with As(2)O(3). These observations suggested that resveratrol has the potential to protect against cardiotoxicity in As(2)O(3)-exposed patients.

  4. Development of In Vitro Drug-Induced Cardiotoxicity Assay by Using Three-Dimensional Cardiac Tissues.

    PubMed

    Takeda, Maki; Miyagawa, Shigeru; Fukushima, Satsuki; Saito, Atsuhiro; Ito, Emiko; Harada, Akima; Matsuura, Ryohei; Iseoka, Hiroko; Sougawa, Nagako; Mochizuki-Oda, Noriko; Matsusaki, Michiya; Akashi, Mitsuru; Sawa, Yoshiki

    2017-10-01

    An in vitro drug-induced cardiotoxicity assay is a critical step in drug discovery for clinical use. The use of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is promising for this purpose. However, single hiPSC-CMs are limited in their ability to mimic native cardiac tissue structurally and functionally, and the generation of artificial cardiac tissue using hiPSC-CMs is an ongoing challenging. We therefore developed a new method of constructing three-dimensional (3D) artificial tissues in a short time by coating extracellular matrix components on cell surfaces. We hypothesized that 3D cardiac tissues derived from hiPSC-CMs (3D-hiPSC-CT) could be used for an in vitro drug-induced cardiotoxicity assay. 3D-hiPSC-CT were generated by fibronectin and gelatin nanofilm coated single hiPSC-CMs. Histologically, the 3D-hiPSC-CT exhibited a sarcomere structure in the myocytes and extracellular matrix proteins, such as fibronectin, collagen type I/III, and laminin. The administration of cytotoxic doxorubicin at 5.0 μM induced the release of lactate dehydrogenase (LDH), while that at 2.0 μM reduced the cell viability. E-4031, hERG-type potassium channel blocker, and isoproterenol induced significant changes both in the Ca transient parameters and contractile parameters in a dose-dependent manner. The 3D-hiPSC-CT exhibited doxorubicin-sensitive cytotoxicity and hERG channel blocker/isoproterenol-sensitive electrical activity in vitro, indicating its usefulness for drug-induced cardiotoxicity assays or drug screening systems for drug discovery.

  5. Foxo3a inhibits mitochondrial fission and protects against doxorubicin-induced cardiotoxicity by suppressing MIEF2.

    PubMed

    Zhou, Luyu; Li, Ruibei; Liu, Cuiyun; Sun, Teng; Htet Aung, Lynn Htet; Chen, Chao; Gao, Jinning; Zhao, Yanfang; Wang, Kun

    2017-03-01

    Doxorubicin (DOX) as a chemotherapeutic drug is widely used to treat a variety of human tumors. However, a major factor limiting its clinical use is its cardiotoxicity. The molecular components and detailed mechanisms regulating DOX-induced cardiotoxicity remain largely unidentified. Here we report that Foxo3a is downregulated in the cardiomyocyte and mouse heart in response to DOX treatment. Foxo3a attenuates DOX-induced mitochondrial fission and apoptosis in cardiomyocytes. Cardiac specific Foxo3a transgenic mice show reduced mitochondrial fission, apoptosis and cardiotoxicity upon DOX administration. Furthermore, Foxo3a directly targets mitochondrial dynamics protein of 49kDa (MIEF2) and suppresses its expression at transcriptional level. Knockdown of MIEF2 reduces DOX-induced mitochondrial fission and apoptosis in cardiomyocytes and in vivo. Also, knockdown of MIEF2 protects heart from DOX-induced cardiotoxicity. Our study identifies a novel pathway composed of Foxo3a and MIEF2 that mediates DOX cardiotoxicity. This discovery provides a promising therapeutic strategy for the treatment of cancer therapy and cardioprotection.

  6. The protective effect of erdosteine against cyclosporine A-induced cardiotoxicity in rats.

    PubMed

    Selcoki, Yusuf; Uz, Ebru; Bayrak, Reyhan; Sahin, Semsettin; Kaya, Arif; Uz, Burak; Karanfil, Aydin; Ozkara, Adem; Akcay, Ali

    2007-09-24

    Cyclosporine A (CsA) is a frequently used immunosuppressive agent in transplant medicine to prevent rejection and in the treatment of autoimmune diseases. However, CsA generates reactive oxygen species, which causes nephrotoxicity, hepatotoxicity and cardiotoxicity. The use of antioxidants reduces the adverse effects of CsA. The aim of this study is to determine the protective effects of erdosteine on CsA-induced heart injury through tissue oxidant/antioxidant parameters and light microscopic evaluation in rats. CsA cardiotoxicity was induced by administrating an oral dose of 15mg/kg CsA daily for 21 days. The rats were divided into four groups: control group (n=4), CsA administrated group (15mg/kg, n=5), CsA+erdosteine administrated group (10mg/kg day orally erdosteine, n=4) and only erdosteine administrated group (10mg/kg day orally n=5). CsA treated rats showed increase in the number of infiltrated cells and disorganization of myocardial fibers with interstitial fibrosis. The number of infiltrated cells, disorganization of myocardial fibers and interstitial fibrosis was diminished in the hearts of CsA-treated rats given erdosteine. The malondialdehyde, the protein carbonyl content and nitric oxide levels were increased in the cyclosporine A group in comparison with the control and CsA plus erdosteine groups. The activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were higher in CsA plus erdosteine group than CsA group. However, the CAT, GSH-Px and SOD activities were significantly lower in CsA group than in control group and erdosteine group. These results suggest that erdosteine has protective effect against CsA-induced cardiotoxicity.

  7. Perflurooctanoic Acid Induces Developmental Cardiotoxicity in Chicken Embryos and Hatchlings

    EPA Science Inventory

    Perfluorooctanoic acid (PFOA) is a widespread environmental contaminant that is detectable in serum of the general U.S. population. PFOA is a known developmental toxicant that induces mortality in mammalian embryos and is thought to induce toxicity via interaction with the peroxi...

  8. Perflurooctanoic Acid Induces Developmental Cardiotoxicity in Chicken Embryos and Hatchlings

    EPA Science Inventory

    Perfluorooctanoic acid (PFOA) is a widespread environmental contaminant that is detectable in serum of the general U.S. population. PFOA is a known developmental toxicant that induces mortality in mammalian embryos and is thought to induce toxicity via interaction with the peroxi...

  9. Pyruvate attenuates cardiac dysfunction and oxidative stress in isoproterenol-induced cardiotoxicity.

    PubMed

    Ojha, Shreesh; Goyal, Sameer; Kumari, Santosh; Arya, Dharamvir Singh

    2012-05-01

    Pyruvate, a potent endogenous antioxidant and an important metabolic fuel is essential for the cardiac function and tissue defense mechanism. The present study was evaluated to investigate whether pyruvate attenuates the development of cardiotoxicity in isoproterenol (ISO)-induced myocardial infarction by assessing hemodynamic, biochemical and histopathological parameters. Subcutaneous injection of ISO (85 mg/kg) administered for 2 days at an interval of 24h was used for induction of cardiotoxicity. ISO administration significantly decreased arterial pressure indices, heart rate, contractility {(+)LVdP/dt} and relaxation {(-)LVdP/dt} and increased left ventricular end-diastolic pressure. In addition, a significant reduction in activities of myocardial creatine phosphokinase-MB, lactate dehydrogenase, superoxide dismutase, catalase, glutathione peroxidase and reduced glutathione levels along with increase in thiobarbituric acid reactive substances were also observed following ISO administration. However, pretreatment with pyruvate (0.25, 0.5 and 1.0 g/kg, p.o.) favorably modulated all most every studied parameters in ISO-induced myocardial injury. Furthermore, protective effect of pyruvate was confirmed by histopathological studies. Rats pretreated only with pyruvate did not produce significant change in hemodynamic, biochemical and histopathological parameters. Pyruvate at 0.50 and 1.0 g/kg doses was found to exert optimal cardioprotective effect against ISO-induced myocardial infarction. The results of our study suggest that pyruvate possessing antioxidant activity has a significant cardioprotective effect against ISO-induced myocardial injury.

  10. ALDH2 attenuates Dox-induced cardiotoxicity by inhibiting cardiac apoptosis and oxidative stress.

    PubMed

    Gao, Yawen; Xu, Yan; Hua, Songwen; Zhou, Shenghua; Wang, Kangkai

    2015-01-01

    The anthracycline chemotherapy drug doxorubicin (DOX) is cardiotoxic. This study aimed to explore the effect of acetaldehyde dehydrogenase 2 (ALDH2), a detoxifying protein, on DOX-induced cardiotoxicity and unveil the underlying mechanisms. BALB/c mice were randomly divided in four groups: control group (no treatment), DOX group (DOX administration for myocardial damage induction), DOX + Daidzin group (DOX administration + Daidzin, an ALDH2 antagonist) and DOX + Alda-1 group (DOX administration + Alda-1, an ALDH2 agonist). Then, survival, haemodynamic parameters, expression of pro- and anti-apoptosis markers, reactive oxygen species (ROS) and 4-Hydroxynonenal (4-HNE) levels, expression and localization of NADPH oxidase 2 (NOX2) and its cytoplasmic subunit p47(PHOX), and ALDH2 expression and activity were assessed. Mortality rates of 0, 35, 5, and 70% were obtained in the control, DOX, DOX + Alda-1, and DOX + Daidzin groups, respectively, at the ninth weekend. Compared with control animals, DOX treatment resulted in significantly reduced left ventricular systolic pressure (LVSP) and ± dp/dt, and overtly increased left ventricular end-diastolic pressure (LVEDP); increased Bax expression and caspase-3/7 activity, and reduced Bcl-2 expression in the myocardium; increased ROS (about 2 fold) and 4-HNE adduct (3 fold) levels in the myocardium; increased NOX2 protein expression and membrane translocation of P47(PHOX). These effects were aggravated in the DOX + Daidzin group, DOX + Alda-1 treated animals showed partial or complete alleviation. Finally, Daidzin further reduced the DOX-repressed ALDH2 activity, which was partially rescued by Alda-1. These results indicated that ALDH2 attenuates DOX-induced cardiotoxicity by inhibiting oxidative stress, NOX2 expression and activity, and reducing myocardial apoptosis.

  11. Antioxidant and antiapoptotic effects of sea cucumber and valsartan against doxorubicin-induced cardiotoxicity in rats: The role of low dose gamma irradiation.

    PubMed

    Ibrahim, Doaa M; Radwan, Rasha R; Abdel Fattah, Salma M

    2017-03-31

    Doxorubicin (DOX) is a highly effective antineoplastic drug; however, the clinical use of DOX is limited by its dose dependent cardiotoxicity. This study was conducted to evaluate the cardioprotective effect of sea cucumber and valsartan against DOX-induced cardiotoxicity in rats. Also, the role of exposure to low dose γ radiation (LDR) on each of them was investigated, since LDR could suppress various reactive oxygen species-related diseases. Rats received DOX (2.5mg/kg, ip) in six equal injections over a period of 2weeks, sea cucumber (14.4mg/kg, p.o) and valsartan (30mg/kg, p.o) for 8 successive weeks. Exposure to LDR (0.5Gy) was performed one day prior to DOX. Results revealed that DOX administration elevated serum levels of aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase (CK-MB) and troponin-I as well as increased cardiac lipid peroxide content and myeloperoxidase (MPO) activity. Additionally, it increased cardiac expressions of iNOS and caspase-3, accompanied by reduction in cardiac total protein and glutathione (GSH) contents. Treatment with sea cucumber or valsartan improved the cardiotoxicity of DOX. Their adjuvant therapy with LDR offers an additional benefit to the cardioprotection of the therapeutic drugs. These results confirmed by histopathological examination. In conclusion, sea cucumber and valsartan alone or combined with LDR attenuated DOX-induced cardiotoxicity via their antioxidant and anti-apoptotic activities and thus might be useful in the treatment of human patients under doxorubicin chemotherapy.

  12. Cardioprotective effects of sitagliptin against doxorubicin-induced cardiotoxicity in rats.

    PubMed

    El-Agamy, Dina S; Abo-Haded, Hany M; Elkablawy, Mohamed A

    2016-08-01

    There is a large body of evidence suggesting that inhibitors of dipeptidyl peptidase-4, such as sitagliptin, may exhibit beneficial effects against different inflammatory disorders. This investigation was conducted to elucidate the potential ability of sitagliptin to counteract the injurious effects of doxorubicin in cardiac tissue. Male Wistar rats were pretreated with sitagliptin for 10 days then treated with a single dose of doxorubicin (20 mg/kg, i.p). Electrocardiography, biochemical estimation of serum and tissue markers, and histo- and immunopathological examinations were done. Results have shown that supplementation with sitagliptin resulted in significant improvement of cardiac function with contaminant decrease in serum markers of doxorubicin-induced cardiotoxicity. These results were supported by the histopathological results. Furthermore, a marked protection against oxidative stress was evident through reduction of lipid peroxidation and prevention of reduced glutathione content depletion and superoxide dismutase activity reduction in cardiac tissue of rats pretreated with sitagliptin in combination with doxorubicin. Moreover, sitagliptin ameliorated the activation of nuclear factor kappa-B and the release of inflammatory cytokines, tumour necrosis factor-alpha and nitric oxide. Finally, sitagliptin attenuated doxorubicin-induced increase in the expression of pro-apoptotic protein Bax and in the apoptotic marker, caspase-3. Collectively, these data indicate that sitagliptin pretreatment could alleviate doxorubicin-induced cardiotoxicity via reducing oxidative damage and its subsequent inflammation and apoptosis. © 2016 by the Society for Experimental Biology and Medicine.

  13. Are cardiac magnetic resonance imaging and radionuclide ventriculography good options against echocardiography for evaluation of anthracycline induced chronic cardiotoxicity in childhood cancer survivors?

    PubMed

    Basar, Evic Zeynep; Corapcioglu, Funda; Babaoglu, Kadir; Anik, Yonca; Gorur Daglioz, Gozde; Dedeoglu, Reyhan

    2014-04-01

    Anthracyclines are widely used for the treatment of solid tumors in pediatric oncology. However, their uses may be limited by progressive chronic cardiotoxicity related to the cumulative dosage. The aims of this study are to compare diagnostic techniques and prepare an algorithm for diagnosis of anthracycline induced chronic cardiotoxicity. The patients were evaluated according to age, sex, time elapsed since the last dose of anthracycline treatment, presence of cardiovascular symptoms, follow-up duration, type of anthracycline, cumulative anthracycline dose, and concomitant mediastinal radiation therapy. Late subclinical cardiotoxicity was detected by history, physical examination, electrocardiography (ECG), Holter monitor, echocardiography (ECHO), radionuclide ventriculography (MUGA), and cardiac magnetic resonance imaging (MRI). Thirty-seven male and 19 female patients with a median age of 11.2 ± 4.6 (range, 3.5-22.0) years were included in the study. Patients were grouped according to cumulative anthracycline doses. Subclinical cardiac dysfunction was detected in 20 patients by at least one of ECHO, MRI or MUGA after anthracycline chemotherapy. We revealed that other than ECHO, MRI and MUGA have high clinical importance for evaluating subclinical late cardiac complications in children treated with anthracyclines.

  14. All‐trans retinoic acid protects against doxorubicin‐induced cardiotoxicity by activating the ERK2 signalling pathway

    PubMed Central

    Yang, Liang; Luo, Cheng; Chen, Cong; Wang, Xun; Shi, Wen

    2016-01-01

    Background and Purpose Doxorubicin is a powerful antineoplastic agent for treating a wide range of cancers. However, doxorubicin cardiotoxicity of the heart has largely limited its clinical use. All‐trans retinoic acid (ATRA) plays an important role in many cardiac biological processes, but its protective effects on doxorubicin‐induced cardiotoxicity remain unknown. Here, we studied the effect of ATRA on doxorubicin cardiotoxicity and the underlying mechanisms. Experimental Approaches Cellular viability assays, Western blotting and mitochondrial respiration analyses were employed to evaluate the cellular response to ATRA in H9c2 cells and primary cardiomyocytes. Quantitative PCR and gene knockdown were performed to investigate the underlying molecular mechanisms of ATRA's effects on doxorubicin cardiotoxicity. Key Results ATRA significantly inhibited doxorubicin‐induced apoptosis in H9c2 cells and primary cardiomyocytes. ATRA was more effective against doxorubicin cardiotoxicity than resveratrol and dexrazoxane. ATRA also suppressed reactive oxygen species generation and restored expression levels of mRNA and proteins in the phase II detoxifying enzyme system: nuclear factor‐E2‐related factor 2, manganese superoxide dismutase, haem oxygenase‐1, and mitochondrial function (mitochondrial membrane integrity, mitochondrial DNA copy numbers and mitochondrial respiration capacity, biogenesis and dynamics). Both a ERK1/2 inhibitor (U0126) and ERK2 siRNA, but not ERK1 siRNA, abolished the protective effect of ATRA against doxorubicin‐induced toxicity in H9c2 cells. Remarkably, ATRA did not compromise the anticancer efficacy of doxorubicin in gastric carcinoma cells. Conclusions and Implications ATRA protected cardiomyocytes against doxorubicin‐induced toxicity, by activating the ERK2 pathway, without compromising its anticancer efficacy. Therefore, ATRA is a promising candidate as a cardioprotective agent against doxorubicin cardiotoxicity. PMID:26507774

  15. Protective Effect of Silymarin against Acrolein-Induced Cardiotoxicity in Mice

    PubMed Central

    Taghiabadi, Elahe; Imenshahidi, Mohsen; Abnous, Khalil; Mosafa, Fatemeh; Sankian, Mojtaba; Memar, Bahram; Karimi, Gholamreza

    2012-01-01

    Reactive α,β-unsaturated aldehydes such as acrolein (ACR) are major components of environmental pollutants and have been implicated in the neurodegenerative and cardiac diseases. In this study, the protective effect of silymarin (SN) against cardiotoxicity induced by ACR in mice was evaluated. Studies were performed on seven groups of six animals each, including vehicle-control (normal saline + 0.5% w/v methylcellulose), ACR (7.5 mg/kg/day, gavage) for 3 weeks, SN (25, 50 and 100 mg/kg/day, i.p.) plus ACR, vitamin E (Vit E, 100 IU/kg, i.p.) plus ACR, and SN (100 mg/kg, i.p.) groups. Mice received SN 7 days before ACR and daily thereafter throughout the study. Pretreatment with SN attenuated ACR-induced increased levels of malondialdehyde (MDA), serum cardiac troponin I (cTnI), and creatine kinase-MB (CK-MB), as well as histopathological changes in cardiac tissues. Moreover, SN improved glutathione (GSH) content, superoxide dismutase (SOD), and catalase (CAT) activities in heart of ACR-treated mice. Western blot analysis showed that SN pretreatment inhibited apoptosis provoked by ACR through decreasing Bax/Bcl-2 ratio, cytosolic cytochrome c content, and cleaved caspase-3 level in heart. In conclusion, SN may have protective effects against cardiotoxicity of ACR by reducing lipid peroxidation, renewing the activities of antioxidant enzymes, and preventing apoptosis. PMID:23320028

  16. Modeling Doxorubicin-Induced Cardiotoxicity in Human Pluripotent Stem Cell Derived-Cardiomyocytes

    PubMed Central

    Maillet, Agnes; Tan, Kim; Chai, Xiaoran; Sadananda, Singh N.; Mehta, Ashish; Ooi, Jolene; Hayden, Michael R.; Pouladi, Mahmoud A.; Ghosh, Sujoy; Shim, Winston; Brunham, Liam R.

    2016-01-01

    Doxorubicin is a highly efficacious anti-cancer drug but causes cardiotoxicity in many patients. The mechanisms of doxorubicin-induced cardiotoxicity (DIC) remain incompletely understood. We investigated the characteristics and molecular mechanisms of DIC in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). We found that doxorubicin causes dose-dependent increases in apoptotic and necrotic cell death, reactive oxygen species production, mitochondrial dysfunction and increased intracellular calcium concentration. We characterized genome-wide changes in gene expression caused by doxorubicin using RNA-seq, as well as electrophysiological abnormalities caused by doxorubicin with multi-electrode array technology. Finally, we show that CRISPR-Cas9-mediated disruption of TOP2B, a gene implicated in DIC in mouse studies, significantly reduces the sensitivity of hPSC-CMs to doxorubicin-induced double stranded DNA breaks and cell death. These data establish a human cellular model of DIC that recapitulates many of the cardinal features of this adverse drug reaction and could enable screening for protective agents against DIC as well as assessment of genetic variants involved in doxorubicin response. PMID:27142468

  17. Astragalus Polysaccharide Suppresses Doxorubicin-Induced Cardiotoxicity by Regulating the PI3k/Akt and p38MAPK Pathways

    PubMed Central

    Cao, Yuan; Ruan, Yang; Shen, Tao; Huang, Xiuqing; Li, Meng; Yu, Weiwei; Zhu, Yuping; Man, Yong; Wang, Shu; Li, Jian

    2014-01-01

    Background. Doxorubicin, a potent chemotherapeutic agent, is associated with acute and chronic cardiotoxicity, which is cumulatively dose-dependent. Astragalus polysaccharide (APS), the extract of Astragalus membranaceus with strong antitumor and antiglomerulonephritis activity, can effectively alleviate inflammation. However, whether APS could ameliorate chemotherapy-induced cardiotoxicity is not understood. Here, we investigated the protective effects of APS on doxorubicin-induced cardiotoxicity and elucidated the underlying mechanisms of the protective effects of APS. Methods. We analyzed myocardial injury in cancer patients who underwent doxorubicin chemotherapy and generated a doxorubicin-induced neonatal rat cardiomyocyte injury model and a mouse heart failure model. Echocardiography, reactive oxygen species (ROS) production, TUNEL, DNA laddering, and Western blotting were performed to observe cell survival, oxidative stress, and inflammatory signal pathways in cardiomyocytes. Results. Treatment of patients with the chemotherapeutic drug doxorubicin led to heart dysfunction. Doxorubicin reduced cardiomyocyte viability and induced C57BL/6J mouse heart failure with concurrent elevated ROS generation and apoptosis, which, however, was attenuated by APS treatment. In addition, there was profound inhibition of p38MAPK and activation of Akt after APS treatment. Conclusions. These results demonstrate that APS could suppress oxidative stress and apoptosis, ameliorating doxorubicin-mediated cardiotoxicity by regulating the PI3k/Akt and p38MAPK pathways. PMID:25386226

  18. Peroxisome Proliferator-Activated Receptor-α Inhibition Protects Against Doxorubicin-Induced Cardiotoxicity in Mice.

    PubMed

    Rahmatollahi, Mahdieh; Baram, Somayeh Mahmoodi; Rahimian, Reza; Saeedi Saravi, Seyed Soheil; Dehpour, Ahmad Reza

    2016-07-01

    Doxorubicin is an effective chemotherapeutic drug against a considerable number of malignancies. However, its toxic effects on myocardium are confirmed as major limit of utilization. PPAR-α is highly expressed in the heart, and its activation leads to an increased cardiac fatty acid oxidation and cardiomyocyte necrosis. This study was performed to adjust the hypothesis that PPAR-α receptor inhibition protects against doxorubicin-induced cardiac dysfunction in mice. Male Balb/c mice were used in this study. Left atria were isolated, and their contractility was measured in response to electrical field stimulation in a standard organ bath. PPAR-α activity was measured using specific PPAR-α antibody in an ELISA-based system coated with double-strand DNA containing PPAR-α response element sequence. Moreover, cardiac MDA and TNF-α levels were measured by ELISA method. Following incubation with doxorubicin (35 µM), a significant reduction in atrial contractility was observed (P < 0.001). Pretreatment of animals with a selective PPAR-α antagonist, GW6471, significantly improved doxorubicin-induced atrial dysfunction (P < 0.001). Furthermore, pretreatment of the mice with a non-selective cannabinoid agonist, WIN55212-2, significantly decreased PPAR-α activity in cardiac tissue, subsequently leading to significant improvement in doxorubicin-induced atrial dysfunction (P < 0.001). Also, GW6471 and WIN significantly reduced cardiac MDA and TNF-α levels compared with animals receiving doxorubicin (P < 0.001). The study showed that inhibition of PPAR-α is associated with protection against doxorubicin-induced cardiotoxicity in mice, and cannabinoids can potentiate the protection by PPAR-α blockade. Moreover, PPAR-α may be considered as a target to prevent cardiotoxicity induced by doxorubicin in patients undergoing chemotherapy.

  19. An Engineered Bivalent Neuregulin Protects Against Doxorubicin-Induced Cardiotoxicity with Reduced Pro-Neoplastic Potential

    PubMed Central

    Jay, Steven M.; Murthy, Ashwin C.; Hawkins, Jessica F.; Wortzel, Joshua R.; Steinhauser, Matthew L.; Alvarez, Luis M.; Gannon, Joseph; Macrae, Calum A.; Griffith, Linda G.; Lee, Richard T.

    2013-01-01

    Background Doxorubicin (DOXO) is an effective anthracycline chemotherapeutic, but its use is limited by cumulative dose-dependent cardiotoxicity. Neuregulin-1β (NRG1B) is an ErbB receptor family ligand that is effective against DOXO-induced cardiomyopathy in experimental models but is also pro-neoplastic. We previously showed that an engineered bivalent neuregulin-1β (NN) has reduced pro-neoplastic potential compared to the epidermal growth factor (EGF)-like domain of NRG1B (NRG), an effect mediated by receptor biasing towards ErbB3 homotypic interactions uncommonly formed by native NRG1B. Here, we hypothesized that a newly formulated, covalent NN would be cardioprotective with reduced pro-neoplastic effects compared to NRG. Methods and Results NN was expressed as a maltose-binding protein fusion in E. coli. As established previously, NN stimulated anti-neoplastic or cytostatic signaling and phenotype in cancer cells, whereas NRG stimulated pro-neoplastic signaling and phenotype. In neonatal rat cardiomyocytes (NRCM), NN and NRG induced similar downstream signaling. NN, like NRG, attenuated the double-stranded DNA breaks associated with DOXO exposure in NRCM and human cardiomyocytes derived from induced pluripotent stem cells. NN treatment significantly attenuated DOXO-induced decrease in fractional shortening as measured by blinded echocardiography in mice in a chronic cardiomyopathy model (57.7% ± 0.6% vs. 50.9% ± 2.6%, P=0.004), whereas native NRG had no significant effect (49.4% ± 3.7% vs. 50.9% ± 2.6%, P=0.813). Conclusions NN is a cardioprotective agent that promotes cardiomyocyte survival and improves cardiac function in DOXO-induced cardiotoxicity. Given the reduced pro-neoplastic potential of NN versus NRG, NN has translational potential for cardioprotection in cancer patients receiving anthracyclines. PMID:23757312

  20. Stabilization of mitochondrial membrane potential prevents doxorubicin-induced cardiotoxicity in isolated rat heart

    SciTech Connect

    Montaigne, David; Marechal, Xavier; Baccouch, Riadh; Modine, Thomas; Preau, Sebastien; Zannis, Konstantinos; Marchetti, Philippe; Lancel, Steve; Neviere, Remi

    2010-05-01

    The present study was undertaken to examine the effects of doxorubicin on left ventricular function and cellular energy state in intact isolated hearts, and, to test whether inhibition of mitochondrial membrane potential dissipation would prevent doxorubicin-induced mitochondrial and myocardial dysfunction. Myocardial contractile performance and mitochondrial respiration were evaluated by left ventricular tension and its first derivatives and cardiac fiber respirometry, respectively. NADH levels, mitochondrial membrane potential and glucose uptake were monitored non-invasively via epicardial imaging of the left ventricular wall of Langendorff-perfused rat hearts. Heart performance was reduced in a time-dependent manner in isolated rat hearts perfused with Krebs-Henseleit solution containing 1 muM doxorubicin. Compared with controls, doxorubicin induced acute myocardial dysfunction (dF/dt{sub max} of 105 +- 8 mN/s in control hearts vs. 49 +- 7 mN/s in doxorubicin-treated hearts; *p < 0.05). In cardiac fibers prepared from perfused hearts, doxorubicin induced depression of mitochondrial respiration (respiratory control ratio of 4.0 +- 0.2 in control hearts vs. 2.2 +- 0.2 in doxorubicin-treated hearts; *p < 0.05) and cytochrome c oxidase kinetic activity (24 +- 1 muM cytochrome c/min/mg in control hearts vs. 14 +- 3 muM cytochrome c/min/mg in doxorubicin-treated hearts; *p < 0.05). Acute cardiotoxicity induced by doxorubicin was accompanied by NADH redox state, mitochondrial membrane potential, and glucose uptake reduction. Inhibition of mitochondrial permeability transition pore opening by cyclosporine A largely prevented mitochondrial membrane potential dissipation, cardiac energy state and dysfunction. These results suggest that in intact hearts an impairment of mitochondrial metabolism is involved in the development of doxorubicin cardiotoxicity.

  1. Stabilization of mitochondrial membrane potential prevents doxorubicin-induced cardiotoxicity in isolated rat heart.

    PubMed

    Montaigne, David; Marechal, Xavier; Baccouch, Riadh; Modine, Thomas; Preau, Sebastien; Zannis, Konstantinos; Marchetti, Philippe; Lancel, Steve; Neviere, Remi

    2010-05-01

    The present study was undertaken to examine the effects of doxorubicin on left ventricular function and cellular energy state in intact isolated hearts, and, to test whether inhibition of mitochondrial membrane potential dissipation would prevent doxorubicin-induced mitochondrial and myocardial dysfunction. Myocardial contractile performance and mitochondrial respiration were evaluated by left ventricular tension and its first derivatives and cardiac fiber respirometry, respectively. NADH levels, mitochondrial membrane potential and glucose uptake were monitored non-invasively via epicardial imaging of the left ventricular wall of Langendorff-perfused rat hearts. Heart performance was reduced in a time-dependent manner in isolated rat hearts perfused with Krebs-Henseleit solution containing 1 microM doxorubicin. Compared with controls, doxorubicin induced acute myocardial dysfunction (dF/dt(max) of 105+/-8 mN/s in control hearts vs. 49+/-7 mN/s in doxorubicin-treated hearts; p<0.05). In cardiac fibers prepared from perfused hearts, doxorubicin induced depression of mitochondrial respiration (respiratory control ratio of 4.0+/-0.2 in control hearts vs. 2.2+/-0.2 in doxorubicin-treated hearts; p<0.05) and cytochrome c oxidase kinetic activity (24+/-1 microM cytochrome c/min/mg in control hearts vs. 14+/-3 microM cytochrome c/min/mg in doxorubicin-treated hearts; p<0.05). Acute cardiotoxicity induced by doxorubicin was accompanied by NADH redox state, mitochondrial membrane potential, and glucose uptake reduction. Inhibition of mitochondrial permeability transition pore opening by cyclosporine A largely prevented mitochondrial membrane potential dissipation, cardiac energy state and dysfunction. These results suggest that in intact hearts an impairment of mitochondrial metabolism is involved in the development of doxorubicin cardiotoxicity. Copyright 2010 Elsevier Inc. All rights reserved.

  2. Paradoxically, iron overload does not potentiate doxorubicin-induced cardiotoxicity in vitro in cardiomyocytes and in vivo in mice

    SciTech Connect

    Guenancia, Charles; Li, Na; Hachet, Olivier; Rigal, Eve; Cottin, Yves; Dutartre, Patrick; Rochette, Luc; Vergely, Catherine

    2015-04-15

    Doxorubicin (DOX) is known to induce serious cardiotoxicity, which is believed to be mediated by oxidative stress and complex interactions with iron. However, the relationship between iron and DOX-induced cardiotoxicity remains controversial and the role of iron chelation therapy to prevent cardiotoxicity is called into question. Firstly, we evaluated in vitro the effects of DOX in combination with dextran–iron on cell viability in cultured H9c2 cardiomyocytes and EMT-6 cancer cells. Secondly, we used an in vivo murine model of iron overloading (IO) in which male C57BL/6 mice received a daily intra-peritoneal injection of dextran–iron (15 mg/kg) for 3 weeks (D0–D20) and then (D21) a single sub-lethal intra-peritoneal injection of 6 mg/kg of DOX. While DOX significantly decreased cell viability in EMT-6 and H9c2, pretreatment with dextran–iron (125–1000 μg/mL) in combination with DOX, paradoxically limited cytotoxicity in H9c2 and increased it in EMT-6. In mice, IO alone resulted in cardiac hypertrophy (+ 22%) and up-regulation of brain natriuretic peptide and β-myosin heavy-chain (β-MHC) expression, as well as an increase in cardiac nitro-oxidative stress revealed by electron spin resonance spectroscopy. In DOX-treated mice, there was a significant decrease in left-ventricular ejection fraction (LVEF) and an up-regulation of cardiac β-MHC and atrial natriuretic peptide (ANP) expression. However, prior IO did not exacerbate the DOX-induced fall in LVEF and there was no increase in ANP expression. IO did not impair the capacity of DOX to decrease cancer cell viability and could even prevent some aspects of DOX cardiotoxicity in cardiomyocytes and in mice. - Highlights: • The effects of iron on cardiomyocytes were opposite to those on cancer cell lines. • In our model, iron overload did not potentiate anthracycline cardiotoxicity. • Chronic oxidative stress induced by iron could mitigate doxorubicin cardiotoxicity. • The role of iron in

  3. Omega-3 Fatty Acid Protects Against Arsenic Trioxide-Induced Cardiotoxicity In Vitro and In Vivo.

    PubMed

    Varghese, Mathews V; Abhilash, M; Paul, M V Sauganth; Alex, Manju; Nair, R Harikumaran

    2017-04-01

    Arsenic trioxide (As2O3) is a highly effective therapeutic against acute promyelocytic leukaemia, but its clinical efficacy is burdened by serious cardiac toxicity. The present study was performed to evaluate the effect of omega (ω)-3 fatty acid on As2O3-induced cardiac toxicity in in vivo and in vitro settings. In in vivo experiments, male Wistar rats were orally administered with As2O3 4 mg/kg body weight for a period of 45 days and cardiotoxicity was assessed. As2O3 significantly increased the tissue arsenic deposition, micronuclei frequency and creatine kinase (CK)-MB activity. There were a rise in lipid peroxidation and a decline in reduced glutathione, glutathione peroxidase, glutathione-S-transferase, superoxide dismutase and catalase in heart tissue of arsenic-administered rats. The cardioprotective role of ω-3 fatty acid was assessed by combination treatment with As2O3. ω-3 fatty acid co-administration with As2O3 significantly alleviated these changes. In in vitro study using H9c2 cardiomyocytes, As2O3 treatment induced alterations in cell viability, lactate dehydrogenase (LDH) release, lipid peroxidation, cellular calcium levels and mitochondrial membrane potential (∆Ψm). ω-3 fatty acid co-treatment significantly increased cardiomyocyte viability, reduced LDH release, lipid peroxidation and intracellular calcium concentration and improved the ∆Ψm. These findings suggested that the ω-3 fatty acid has the potential to protect against As2O3-induced cardiotoxicity.

  4. Rutin Attenuates Carfilzomib-Induced Cardiotoxicity Through Inhibition of NF-κB, Hypertrophic Gene Expression and Oxidative Stress.

    PubMed

    Imam, Faisal; Al-Harbi, Naif O; Al-Harbia, Mohammed M; Korashy, Hesham M; Ansari, Mushtaq Ahmad; Sayed-Ahmed, Mohamed M; Nagi, Mahmoud N; Iqbal, Muzaffar; Khalid Anwer, Md; Kazmi, Imran; Afzal, Muhammad; Bahashwan, Saleh

    2017-01-01

    Carfilzomib is a proteasome inhibitor, commonly used in multiple myeloma, but its clinical use may be limited due to cardiotoxicity. This study was aimed to evaluate the influence of rutin in carfilzomib-induced cardiotoxicity in rats. Wistar albino male rats weighing 200-250 g (approximately 10 weeks old) were taken for this study. Animals were divided into four groups of six animals each. Group 1 served as normal control (NC), received normal saline; group 2 animals received carfilzomib (dissolved in 1 % DMSO) alone; group 3 animals received rutin (20 mg/kg) + carfilzomib; and group 4 animals received rutin (40 mg/kg) + carfilzomib. Hematological changes, biochemical changes, oxidative stress, hypertrophic gene expression, apoptotic gene expression, NFκB and IκB-α protein expression and histopathological evaluation were done to confirm the finding of carfilzomib-induced cardiotoxicity. Treatment with rutin decreased the carfilzomib-induced changes in cardiac enzymes such as lactate dehydrogenase, creatine kinase (CK) and CK-MB. For the assessment of cardiotoxicity, we further evaluated cardiac hypertrophic gene and apoptotic gene expression such as α-MHC, β-MHC and BNP and NF-κB and p53 gene expression, respectively, using RT-PCR. Western blot analysis showed that rutin treatment prevented the activation of NF-κB by increasing the expression of IκB-α. Rutin also attenuated the effects of carfilzomib on oxidant-antioxidant including malondialdehyde and reduced glutathione. Histopathological study clearly confirmed that rutin attenuated carfilzomib-induced cardiotoxicity in rats.

  5. [Biochemical predictors of anthracyclin and trastuzumab induced cardiotoxicity in early diagnostics of cardiomyopathy].

    PubMed

    Słowik, Agnieszka; Lelakowska-Pieła, Maria; Konduracka, Ewa

    2016-01-01

    The treatment based on athracyclines and trastuzumab may lead to heart failure in oncological setting. Assessment of the heart function is conducted using radiological examinations, especially echocardiography. Biochemical diagnostics enables to depict clinically silent cardiac dysfunction at an earlier stage. Biomarkers that showed to be the most promising in predicting the development of deterioration of systolic and/or diastolic function in course of chemotherapy are troponins and NT-pro-BNP. However, no cut-off point had been yet determined, especially in terms of cardiotoxicity induced by oncological therapy. Biomarkers serum level may be dependent on many conditions, mostly comorbidities, what makes the interpretation of the results difficult. Trials involving mikro RNA particles, which depict the molecular level of the pathological changes, also those involved in the development of cardiomyopathy, are underway. © 2016 MEDPRESS.

  6. Cardioprotective Effect of Selenium Against Cyclophosphamide-Induced Cardiotoxicity in Rats.

    PubMed

    Gunes, Sibel; Sahinturk, Varol; Karasati, Pinar; Sahin, Ilknur Kulcanay; Ayhanci, Adnan

    2017-05-01

    The objective of this study is to evaluate the possible protective effects of selenium (Se) against cyclophosphamide (CP)-induced acute cardiotoxicity in rats. A total of 42 male Spraque-Dawley rats were divided into six groups (n = 7). Rats in the first group were served as control. Rats in the second group received CP (150 mg/kg) at the sixth day of experiment. Animals in the third and fourth groups were treated with only 0.5 and 1 mg/kg Se respectively for six consecutive days. Rats in the fifth and sixth groups received respective Se doses (0.5 or 1 mg/kg) for 6 days and then a single dose of CP administered on the sixth day. On day 7, the animals were sacrificed; blood samples were collected to measure malondialdehyde (MDA), glutathione (GSH), lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), and ischemia-modified albumin (IMA) levels. Heart tissues were processed routinely and tissue sections were stained with H + E for light microscopic examination. In the CP-treated rats MDA, LDH, CK-MB, and IMA serum levels increased, while GSH levels decreased. Microscopic evaluation showed that tissue damage was conspicuously lower in CP plus Se groups. Moreover, 1 mg/kg Se was more protective than 0.5 mg/kg Se as indicated by histopathological and biochemical values. In conclusion, Se is suggested to be a potential candidate to ameliorate CP-induced cardiotoxicity which may be related to its antioxidant activity.

  7. Combinatorial resveratrol and quercetin polymeric micelles mitigate doxorubicin induced cardiotoxicity in vitro and in vivo.

    PubMed

    Cote, Brianna; Carlson, Lisa Janssen; Rao, Deepa A; Alani, Adam W G

    2015-09-10

    Doxorubicin hydrochloride (ADR) is an anthracycline antibiotic used to treat various cancers. However, due to its extensive cardiotoxic side effects a lifetime cumulative dose limit of 450-550 mg/m2 exists. The postulated mechanism of the cardiotoxicity is generation of reactive oxygen and nitrogen species. Natural products like resveratrol (RES), and quercetin (QUE) are known free radical scavengers and have shown cardioprotective effects. However, concurrent dosing of these natural products with ADR is limited due to their low solubility, and low oral bioavailability. We hypothesize that the combination of RES and QUE in Pluronic® F127 micelles (mRQ) when co-administered with ADR, will be cardioprotective in vitro and in vivo, while maintaining or increasing the efficacy of ADR against cancer cell lines in vitro. We prepared mRQ micelles capable of retaining 1.1mg/mL and 1.42 mg/mL of RES and QUE respectively. The in vitro release of RES and QUE from the micelles followed first order kinetics over 48h. In vitro cell viability and combination index analysis studies in human ovarian cancer cells (SKOV-3) and rat cardiomyocytes (H9C2) showed that RES:QUE: ADR at 10:10:1 ratio was synergistic in SKOV-3 cells and antagonistic in H9C2 cells. Caspase 3/7 activity studies indicated that mRQ did not interfere with ADR caspase activity in SKOV-3 cells but significantly decreased it in H9C2 cells. The generation of reactive oxygen species (ROS) in SKOV-3 and H9C2 cells in the presence of mRQ also indicated no changes in ROS activity in SKOV-3 cells but significant scavenging in H9C2 cells. Healthy mice were exposed to acute doses of ADR and ADR with mRQ. Based on biochemical estimations the presence of mRQ with ADR conferred full cardioprotection in these mice. Concurrent administration of mRQ with ADR at 10:10:1 ratio provides a viable strategy to mitigate acute ADR induced cardiotoxicity. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Circulating miR-1 as a potential biomarker of doxorubicin-induced cardiotoxicity in breast cancer patients

    PubMed Central

    Oliveira-Carvalho Vagner, Rigaud; Ferreira, Ludmila R.P; Ayub-Ferreira, Silvia M; Ávila, Mônica S; Brandão, Sara M.G; Cruz, Fátima D; Santos, Marília H.H; Cruz, Cecilia B.B.V; Alves, Marco S.L; Issa, Victor S; Guimarães, Guilherme V; Cunha-Neto, Edécio; Bocchi, Edimar A

    2017-01-01

    Cardiotoxicity is associated with the chronic use of doxorubicin leading to cardiomyopathy and heart failure. Identification of cardiotoxicity-specific miRNA biomarkers could provide clinicians with a valuable prognostic tool. The aim of the study was to evaluate circulating levels of miRNAs in breast cancer patients receiving doxorubicin treatment and to correlate with cardiac function. This is an ancillary study from “Carvedilol Effect on Chemotherapy-induced Cardiotoxicity” (CECCY trial), which included 56 female patients (49.9±3.3 years of age) from the placebo arm. Enrolled patients were treated with doxorubicin followed by taxanes. cTnI, LVEF, and miRNAs were measured periodically. Circulating levels of miR-1, -133b, -146a, and -423-5p increased during the treatment whereas miR-208a and -208b were undetectable. cTnI increased from 6.6±0.3 to 46.7±5.5 pg/mL (p<0.001), while overall LVEF tended to decrease from 65.3±0.5 to 63.8±0.9 (p=0.053) over 12 months. Ten patients (17.9%) developed cardiotoxicity showing a decrease in LVEF from 67.2±1.0 to 58.8±2.7 (p=0.005). miR-1 was associated with changes in LVEF (r=-0.531, p<0.001). In a ROC curve analysis miR-1 showed an AUC greater than cTnI to discriminate between patients who did and did not develop cardiotoxicity (AUC = 0.851 and 0.544, p= 0.0016). Our data suggest that circulating miR-1 might be a potential new biomarker of doxorubicin-induced cardiotoxicity in breast cancer patients. PMID:28052002

  9. MicroRNA-34a regulates doxorubicin-induced cardiotoxicity in rat

    PubMed Central

    Cappetta, Donato; Esposito, Grazia; Urbanek, Konrad; Dell'Aversana, Carmela; Altucci, Lucia; Berrino, Liberato; Rossi, Francesco; De Angelis, Antonella

    2016-01-01

    New strategies to prevent and early detect the cardiotoxic effects of the anticancer drug doxorubicin (DOXO) are required. MicroRNAs emerged as potential diagnostic, therapeutic and prognostic approaches in cardiovascular diseases. MiR-34a has a role in cardiac dysfunction and ageing and is involved in several cellular processes associated with DOXO cardiotoxicity. Our in vitro and in vivo results indicated that after DOXO exposure the levels of miR-34a are enhanced in cardiac cells, including Cardiac Progenitor Cells (CPCs). Since one of the determining event responsible for the initiation and evolution of the DOXO toxicity arises at the level of the CPC compartment, we evaluated if miR-34a pharmacological inhibition in these cells ameliorates the detrimental aftermath of the drug. AntimiR-34a has beneficial consequences on vitality, proliferation, apoptosis and senescence of DOXO-treated rat CPC. These effects are mediated by an increase of prosurvival miR-34a targets Bcl-2 and SIRT1, accompanied by a decrease of acetylated-p53 and p16INK4a. Importantly, miR-34a silencing also reduces the release of this miRNA from DOXO-exposed rCPCs, decreasing its negative paracrine effects on other rat cardiac cells. In conclusion, the silencing of miR-34a could represent a future therapeutic option for cardioprotection in DOXO toxicity and at the same time, it could be considered as a circulating biomarker for anthracycline-induced cardiac damage. PMID:27694688

  10. The role of nitric oxide in Doxorubicin-induced cardiotoxicity: experimental study.

    PubMed

    Bahadır, Ayşenur; Kurucu, Nilgün; Kadıoğlu, Mine; Yenilme, Engin

    2014-03-01

    We evaluated the myocardial damage in rats treated with doxorubicin (DOX) alone and in combination with nitric oxide synthase (NOS) inhibitors. Twenty-four male Sprague Dawley rats (12 weeks old, weighing 262±18 g) were randomly assigned into 4 groups (n=6). Group I was the control group. In Group II, rats were treated with intraperitoneal (ip) injections of 3 mg/kg DOX once a week for 5 weeks. In Group III, rats received weekly ip injections of 30 mg/kg L-NAME (nonspecific NOS inhibitor) 30 min before DOX injections for 5 weeks. In Group IV, rats received weekly ip injections of 3 mg/kg L-NIL (inducible NOS inhibitor) 30 min before DOX injections for 5 weeks. Rats were weighed 2 times a week. At the end of 6 weeks, hearts were excised and then fixed for light and electron microscopy evaluation and tissue lipid peroxidation (malondialdehyde). Blood samples were also obtained for measuring plasma lipid peroxidation. Weight loss was observed in Group II, Group III, and Group IV. Weight loss was statistically significant in the DOX group. Findings of myocardial damage were significantly higher in animals treated with DOX only than in the control group. Histopathological findings of cardiotoxicity in rats treated with DOX in combination with L-NAME and L-NIL were not significantly different compared with the control group. The level of plasma malondialdehyde in the DOX group (9.3±3.4 µmol/L) was higher than those of all other groups. Our results showed that DOX cardiotoxicity was significantly decreased when DOX was given with NO synthase inhibitors.

  11. The Role of Nitric Oxide in Doxorubicin-Induced Cardiotoxicity: Experimental Study

    PubMed Central

    Bahadır, Ayşenur; Kurucu, Nilgün; Kadıoğlu, Mine; Yenilme, Engin

    2014-01-01

    Objective: We evaluated the myocardial damage in rats treated with doxorubicin (DOX) alone and in combination with nitric oxide synthase (NOS) inhibitors. Materials and Methods: Twenty-four male Sprague Dawley rats (12 weeks old, weighing 262±18 g) were randomly assigned into 4 groups (n=6). Group I was the control group. In Group II, rats were treated with intraperitoneal (ip) injections of 3 mg/kg DOX once a week for 5 weeks. In Group III, rats received weekly ip injections of 30 mg/kg L-NAME (nonspecific NOS inhibitor) 30 min before DOX injections for 5 weeks. In Group IV, rats received weekly ip injections of 3 mg/kg L-NIL (inducible NOS inhibitor) 30 min before DOX injections for 5 weeks. Rats were weighed 2 times a week. At the end of 6 weeks, hearts were excised and then fixed for light and electron microscopy evaluation and tissue lipid peroxidation (malondialdehyde). Blood samples were also obtained for measuring plasma lipid peroxidation. Results: Weight loss was observed in Group II, Group III, and Group IV. Weight loss was statistically significant in the DOX group. Findings of myocardial damage were significantly higher in animals treated with DOX only than in the control group. Histopathological findings of cardiotoxicity in rats treated with DOX in combination with L-NAME and L-NIL were not significantly different compared with the control group. The level of plasma malondialdehyde in the DOX group (9.3±3.4 µmol/L) was higher than those of all other groups. Conclusion: Our results showed that DOX cardiotoxicity was significantly decreased when DOX was given with NO synthase inhibitors. PMID:24764732

  12. Carnitine deficiency and oxidative stress provoke cardiotoxicity in an ifosfamide-induced Fanconi Syndrome rat model

    PubMed Central

    Darweesh, Amal Q; Fatani, Amal J

    2010-01-01

    -depleted rats, IFO induced dramatic increase in serum creatinine, BUN, CK-MB, LDH, carnitine clearance and intramitochondrial acetyl-CoA/CoA-SH, as well as progressive reduction in total carnitine and ATP in cardiac tissues. Interestingly, PLC supplementation completely reversed the biochemical changes-induced by IFO to the control values. In conclusion, data from the present study suggest that: Carnitine deficiency and oxidative stress, secondary to Fanconi Syndrome, constitute risk factors and should be viewed as mechanisms during development of IFO-induced cardiotoxicity. Carnitine supplementation, using PLC, prevents the development of IFO-induced cardiotoxicity through antioxidant signalling and improving mitochondrial function. PMID:20972373

  13. Resveratrol inhibits doxorubicin-induced cardiotoxicity via sirtuin 1 activation in H9c2 cardiomyocytes.

    PubMed

    Liu, Mi-Hua; Shan, Jian; Li, Jian; Zhang, Yuan; Lin, Xiao-Long

    2016-08-01

    Doxorubicin (DOX) is an efficient drug used in cancer therapy; however, it can induce severe cytotoxicity, which limits its clinical application. In the present study, the effects of resveratrol (RES) on sirtuin 1 (SIRT1) activation in mediating DOX-induced cytotoxicity in H9c2 cardiac cells was investigated. H9c2 cells were exposed to 5 µM DOX for 24 h to establish a model of DOX cardiotoxicity. Apoptosis of H9c2 cardiomyocytes was assessed using the MTT assay and Hoechst nuclear staining. The results demonstrated that pretreating H9c2 cells with RES prior to the exposure of DOX resulted in increased cell viability and a decreased quantity of apoptotic cells. Western blot analysis demonstrated that DOX decreased the expression level of SIRT1. These effects were significantly alleviated by co-treatment with RES. In addition, the results demonstrated that DOX administration amplified forkhead box O1 (FoxO1) and P53 expression levels in H9c2 cells. RES was also found to protect against DOX-induced increases of FoxO1 and P53 expression levels in H9c2 cells. Furthermore, the protective effects of RES were arrested by the SIRT1 inhibitor nicotinamide. In conclusion, the results demonstrated that RES protected H9c2 cells against DOX-induced injuries via SIRT1 activation.

  14. Apelin-13 attenuates cisplatin-induced cardiotoxicity through inhibition of ROS-mediated DNA damage and regulation of MAPKs and AKT pathways.

    PubMed

    Zhang, Pu; Yi, Lu-Hua; Meng, Guang-Yuan; Zhang, Huan-Yi; Sun, Hai-Hui; Cui, Lian-Qun

    2017-05-01

    Platinum-based chemotherapy represents one of the most effective ways in combating human cancers. However, the cardiotoxicity subsequent severely limited its clinical application. Increased evidences indicate that oxidative stress plays a crucial role in the pathological process of platinum-induced cardiotoxicity. It is reported that apelin-13 a bioactive peptide has the scavenging capacity of free radical, and it has the potential to regulate the cardiovascular system. Hence, the potential of apelin-13 to antagonize cisplatin-induced cardiotoxicity was evaluated in H9c2 rat myocardial cells in vitro and in C57 mice in vivo. The results showed that cisplatin indeed caused DNA damage in H9c2 cells by promoting the accumulation of intracellular reactive oxygen species (ROS) and superoxide anion, which led to cell apoptosis and resulted in overt cardiotoxicity. However, apelin-13 pre-treatment effectively attenuated the cisplatin-induced ROS and superoxide anion generation, inhibited DNA damage, and suppressed the PARP cleavage and caspases activation. Further investigation revealed that apelin-13 blocked cisplatin-induced H9c2 cells apoptosis involving the regulation of MAPKs and PI3K/Akt signaling pathway. Importantly, apelin-13 co-treatment also significantly attenuated cisplatin-induced cardiotoxicity in vivo by inhibiting myocardial cells apoptosis and improving angiogenesis in mice heart. Taken together, our results suggest that the use of apelin-13 may be an effective strategy for antagonizing the cardiotoxicity-induced by platinum-based chemotherapy.

  15. Antioxidants and tumor necrosis factor alpha-inhibiting activity of sesame oil against doxorubicin-induced cardiotoxicity.

    PubMed

    Saleem, Mohamed T S; Chetty, Madhusudhana C; Kavimani, S

    2014-02-01

    Oxidative stress is currently considered to be the key factor in doxorubicin-induced cardiotoxicity. Comparatively small quantity of the endogenous antioxidant content of the heart is assumed to be the predisposing factor for doxorubicin-induced cardiotoxicity. The present research was designed to evaluate the antioxidant potential and tumor necrosis factor alpha-(TNF-α) inhibiting activity of sesame oil against acute doxorubicin-induced cardiotoxicity. Male Wistar albino rats (180-200 g) were administered sesame oil in two dissimilar doses (5 and 10 ml/kg body weight, orally) for 30 days, followed by a single dose of doxorubicin (30 mg/kg s.c.). In the doxorubicin-treated group, increased oxidative stress was proven by a significant rise of thiobarbituric acid reactive substances level and a decrease of myocardial superoxide dismutase, catalase and reduced glutathione content. Histopathological studies showed myocardial necrosis with accumulation of inflammatory cells, vacuolization and overall enlargement of the myocardium. Western blot analysis showed marked expression of TNF-α in the myocardium. Alteration in biochemical parameters by doxorubicin administration was prevented significantly (p < 0.0001) in the 5 and 10 ml/kg sesame oil treated rat hearts. Treatment with 5 and 10 ml/kg of sesame oil reduced the doxorubicin-induced TNF-α expression in the myocardium, which was associated with reduced myocyte injury. The overall effect of sesame oil was comparable with probucol, which shows similar protection. The chronic oral administration of sesame oil prevents acute doxorubicin-induced cardiotoxicity by enhancing cardiac endogenous antioxidants and decreasing myocardial TNF-α expression.

  16. Ferric Carboxymaltose-Mediated Attenuation of Doxorubicin-Induced Cardiotoxicity in an Iron Deficiency Rat Model

    PubMed Central

    Toblli, Jorge Eduardo; Rivas, Carlos; Cao, Gabriel; Giani, Jorge Fernando; Dominici, Fernando Pablo

    2014-01-01

    Since anthracycline-induced cardiotoxicity (AIC), a complication of anthracycline-based chemotherapies, is thought to involve iron, concerns exist about using iron for anaemia treatment in anthracycline-receiving cancer patients. This study evaluated how intravenous ferric carboxymaltose (FCM) modulates the influence of iron deficiency anaemia (IDA) and doxorubicin (3–5 mg per kg body weight [BW]) on oxidative/nitrosative stress, inflammation, and cardiorenal function in spontaneously hypertensive stroke-prone (SHR-SP) rats. FCM was given as repeated small or single total dose (15 mg iron per kg BW), either concurrent with or three days after doxorubicin. IDA (after dietary iron restriction) induced cardiac and renal oxidative stress (markers included malondialdehyde, catalase, Cu,Zn-superoxide dismutase, and glutathione peroxidase), nitrosative stress (inducible nitric oxide synthase and nitrotyrosine), inflammation (tumour necrosis factor-alpha and interleukin-6), and functional/morphological abnormalities (left ventricle end-diastolic and end-systolic diameter, fractional shortening, density of cardiomyocytes and capillaries, caveolin-1 expression, creatinine clearance, and urine neutrophil gelatinase-associated lipocalin) that were aggravated by doxorubicin. Notably, iron treatment with FCM did not exacerbate but attenuated the cardiorenal effects of IDA and doxorubicin independent of the iron dosing regimen. The results of this model suggest that intravenous FCM can be used concomitantly with an anthracycline-based chemotherapy without increasing signs of AIC. PMID:24876963

  17. Modulating Effects of Spirulina platensis against Tilmicosin-Induced Cardiotoxicity in Mice

    PubMed Central

    Ibrahim, Abdelaziz E.; Abdel-Daim, Mohamed Mohamed

    2015-01-01

    Objective Tilmicosin (TIL) is a long-acting macrolide antibiotic used to treat cattle for pathogens that cause bovine respiratory disease. However, overdoses of this medication have been reported to induce cardiac damage. Our experimental objective was to evaluate the protective effects of Spirulina platensis (SP) administration against TIL-induced cardiotoxicity in mice. Materials and Methods Our experimental in vivo animal study used 40 male albino mice that were divided into five groups of eight mice per group. The first group served as a control group and was injected with saline. The second group received SP at dose of 1000 mg/kg body weight for five days. The third group received a single dose of TIL (75 mg/kg, subcutaneously). Groups 4 and 5 were given SP at doses of 500 and 1000 mg/kg body weight for five consecutive days just before administration of TIL at the same dose and regimen used for group 3. Results TIL treated animals showed a significant increase in serum cardiac injury biomarkers as well as cardiac lipid peroxidation, however they had evidence of an inhibition in antioxidant biomarkers. SP normalized elevated serum levels of lactate dehydrogenase (LDH), creatine kinase (CK), and CK-MB. Furthermore, SP reduced TIL-induced lipid peroxidation and oxidative stress in a dose-dependent manner. Conclusion Administration of SP minimized the toxic effects of TIL by its free radicalscavenging and potent antioxidant activity. PMID:25870843

  18. Sodium Thiosulfate Versus Hydroxocobalamin in the Treatment of Acute, Severe Cyanide Induced Cardiotoxicity in a Swine (Sus Scrofa) Model

    DTIC Science & Technology

    2011-09-22

    intoxicated by cyanide develop cardiac-ar.rest or severely low blood pressure. Currently several antidotes exist, but many have severe adverse effects...machine. They were intoxicated with cyanide (infused through the vein) until the blood pressure was low. The animals were assigned to-one of three...IUIVIJ:lt:M Sodium thiosulfate versus hydroxocoba~amin in the treatment of acute, severe cyanide induced cardiotoxicity in a swine (Sus Scrofa)model on

  19. High-content screening of drug-induced cardiotoxicity using quantitative single cell imaging cytometry on microfluidic device.

    PubMed

    Kim, Min Jung; Lee, Su Chul; Pal, Sukdeb; Han, Eunyoung; Song, Joon Myong

    2011-01-07

    Drug-induced cardiotoxicity or cytotoxicity followed by cell death in cardiac muscle is one of the major concerns in drug development. Herein, we report a high-content quantitative multicolor single cell imaging tool for automatic screening of drug-induced cardiotoxicity in an intact cell. A tunable multicolor imaging system coupled with a miniaturized sample platform was destined to elucidate drug-induced cardiotoxicity via simultaneous quantitative monitoring of intracellular sodium ion concentration, potassium ion channel permeability and apoptosis/necrosis in H9c2(2-1) cell line. Cells were treated with cisapride (a human ether-à-go-go-related gene (hERG) channel blocker), digoxin (Na(+)/K(+)-pump blocker), camptothecin (anticancer agent) and a newly synthesized anti-cancer drug candidate (SH-03). Decrease in potassium channel permeability in cisapride-treated cells indicated that it can also inhibit the trafficking of the hERG channel. Digoxin treatment resulted in an increase of intracellular [Na(+)]. However, it did not affect potassium channel permeability. Camptothecin and SH-03 did not show any cytotoxic effect at normal use (≤300 nM and 10 μM, respectively). This result clearly indicates the potential of SH-03 as a new anticancer drug candidate. The developed method was also used to correlate the cell death pathway with alterations in intracellular [Na(+)]. The developed protocol can directly depict and quantitate targeted cellular responses, subsequently enabling an automated, easy to operate tool that is applicable to drug-induced cytotoxicity monitoring with special reference to next generation drug discovery screening. This multicolor imaging based system has great potential as a complementary system to the conventional patch clamp technique and flow cytometric measurement for the screening of drug cardiotoxicity.

  20. Assessment of beating parameters in human induced pluripotent stem cells enables quantitative in vitro screening for cardiotoxicity

    SciTech Connect

    Sirenko, Oksana; Cromwell, Evan F.; Crittenden, Carole; Wignall, Jessica A.; Wright, Fred A.; Rusyn, Ivan

    2013-12-15

    Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes show promise for screening during early drug development. Here, we tested a hypothesis that in vitro assessment of multiple cardiomyocyte physiological parameters enables predictive and mechanistically-interpretable evaluation of cardiotoxicity in a high-throughput format. Human iPSC-derived cardiomyocytes were exposed for 30 min or 24 h to 131 drugs, positive (107) and negative (24) for in vivo cardiotoxicity, in up to 6 concentrations (3 nM to 30 uM) in 384-well plates. Fast kinetic imaging was used to monitor changes in cardiomyocyte function using intracellular Ca{sup 2+} flux readouts synchronous with beating, and cell viability. A number of physiological parameters of cardiomyocyte beating, such as beat rate, peak shape (amplitude, width, raise, decay, etc.) and regularity were collected using automated data analysis. Concentration–response profiles were evaluated using logistic modeling to derive a benchmark concentration (BMC) point-of-departure value, based on one standard deviation departure from the estimated baseline in vehicle (0.3% dimethyl sulfoxide)-treated cells. BMC values were used for cardiotoxicity classification and ranking of compounds. Beat rate and several peak shape parameters were found to be good predictors, while cell viability had poor classification accuracy. In addition, we applied the Toxicological Prioritization Index (ToxPi) approach to integrate and display data across many collected parameters, to derive “cardiosafety” ranking of tested compounds. Multi-parameter screening of beating profiles allows for cardiotoxicity risk assessment and identification of specific patterns defining mechanism-specific effects. These data and analysis methods may be used widely for compound screening and early safety evaluation in drug development. - Highlights: • Induced pluripotent stem cell-derived cardiomyocytes are promising in vitro models. • We tested if evaluation

  1. Paradoxically, iron overload does not potentiate doxorubicin-induced cardiotoxicity in vitro in cardiomyocytes and in vivo in mice.

    PubMed

    Guenancia, Charles; Li, Na; Hachet, Olivier; Rigal, Eve; Cottin, Yves; Dutartre, Patrick; Rochette, Luc; Vergely, Catherine

    2015-04-15

    Doxorubicin (DOX) is known to induce serious cardiotoxicity, which is believed to be mediated by oxidative stress and complex interactions with iron. However, the relationship between iron and DOX-induced cardiotoxicity remains controversial and the role of iron chelation therapy to prevent cardiotoxicity is called into question. Firstly, we evaluated in vitro the effects of DOX in combination with dextran-iron on cell viability in cultured H9c2 cardiomyocytes and EMT-6 cancer cells. Secondly, we used an in vivo murine model of iron overloading (IO) in which male C57BL/6 mice received a daily intra-peritoneal injection of dextran-iron (15mg/kg) for 3weeks (D0-D20) and then (D21) a single sub-lethal intra-peritoneal injection of 6mg/kg of DOX. While DOX significantly decreased cell viability in EMT-6 and H9c2, pretreatment with dextran-iron (125-1000μg/mL) in combination with DOX, paradoxically limited cytotoxicity in H9c2 and increased it in EMT-6. In mice, IO alone resulted in cardiac hypertrophy (+22%) and up-regulation of brain natriuretic peptide and β-myosin heavy-chain (β-MHC) expression, as well as an increase in cardiac nitro-oxidative stress revealed by electron spin resonance spectroscopy. In DOX-treated mice, there was a significant decrease in left-ventricular ejection fraction (LVEF) and an up-regulation of cardiac β-MHC and atrial natriuretic peptide (ANP) expression. However, prior IO did not exacerbate the DOX-induced fall in LVEF and there was no increase in ANP expression. IO did not impair the capacity of DOX to decrease cancer cell viability and could even prevent some aspects of DOX cardiotoxicity in cardiomyocytes and in mice.

  2. Sodium arsenite-induced cardiotoxicity in rats: protective role of p-coumaric acid, a common dietary polyphenol.

    PubMed

    Prasanna, Nagalakshmi; Krishnan, Dhanalakshmi Navaneethan; Rasool, Mahaboobkhan

    2013-05-01

    This study was performed to investigate the ameliorative role of p-coumaric acid against sodium arsenite-induced cardiotoxicity in rats. Sodium arsenite (5 mg/kg/b.wt) was orally administered once a day for 30 days to the animals to induce cardiotoxicity. After the experimental period, cardiotoxicity was assessed by estimating the levels of lipid peroxidation, anti-oxidant status (superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase, glutathione reductase, total reduced glutathione, protein sulfyhydryl and non-protein sulfhydryl groups) and DNA fragmentation in the cardiac tissue of control and experimental rats. In addition, cardiac tissue specific serum markers (triacylglycerides, total cholesterol, low-density lipoprotein cholesterol and high density lipoprotein cholesterol) in serum and histopathological changes in the cardiac tissue were also evaluated. From the results obtained in our study, sodium arsenite administration to the rats increased lipid peroxidation, DNA fragmentation, triacylglycerides, total cholesterol and low-density lipoprotein cholesterol, whereas antioxidant status and high-density lipoprotein cholesterol were found to be reduced. However, p-coumaric acid (75 and100 mg/kg/b.wt) treatment orally once per day for 30 days, immediately before a daily administration of sodium arsenite protected the abnormal biochemical abnormalities observed in the cardiac tissue of sodium arsenite treated rats as evidenced by the cardiac histopathology. For comparison purpose, a standard antioxidant vitamin C (100 mg/kg/b.wt) was used. In conclusion, this study concluded that p-coumaric acid could be a promising candidate for protecting the sodium arsenite-induced cardiotoxicity in rats through its antioxidant character.

  3. Beneficial effects of mycophenolate mofetil on cardiotoxicity induced by tacrolimus in wistar rats

    PubMed Central

    Ferjani, Hanen; Timoumi, Rim; Amara, Ines; Abid, Salwa; Achour, Abedellatif; Boussema-Ayed, Imen

    2016-01-01

    The immunosuppressive drug tacrolimus (TAC) is used clinically to reduce the rejection rate in transplant patients. TAC has contributed to an increased prevalence of cardiovascular disease in patients receiving solid organ transplantation. Mycophenolate mofetil (MMF), a potent inhibitor of de novo purine synthesis, is known to prevent ongoing rejection in combination with TAC. In the present study, we investigated the antioxidant and antigenotoxic effect of MMF on TAC-induced cardiotoxicity in rats. Oral administration of TAC at 2.4, 24, and 60 mg/kg b.w. corresponding, respectively, to 1, 10, and 25% of LD50 for 24 h caused cardiac toxicity in a dose-dependant manner. TAC increased significantly DNA damage level in hearts of treated rats. Furthermore, it increased malondialdehyde (MDA) and protein carbonyl (PC) levels and decreased catalase (CAT) and superoxide dismutase (SOD) activities. The oral administration of MMF at 50 mg/kg b.w. simultaneously with TAC at 60 mg/kg b.w. proved a significant cardiac protection by decreasing DNA damage, MDA, and PC levels, and by increasing the antioxidant activities of CAT and SOD. Thus, our study showed, for the first time, the protective effect of MMF against cardiac toxicity induced by TAC. This protective effect was mediated via an antioxidant process. PMID:26582055

  4. Clinical review: Aggressive management and extracorporeal support for drug-induced cardiotoxicity

    PubMed Central

    Baud, Frédéric J; Megarbane, Bruno; Deye, Nicolas; Leprince, Pascal

    2007-01-01

    Poisoning may induce failure in multiple organs, leading to death. Supportive treatments and supplementation of failing organs are usually efficient. In contrast, the usefulness of cardiopulmonary bypass in drug-induced shock remains a matter of debate. The majority of deaths results from poisoning with membrane stabilising agents and calcium channel blockers. There is a need for more aggressive treatment in patients not responding to conventional treatments. The development of new antidotes is limited. In contrast, experimental studies support the hypothesis that cardiopulmonary bypass is life-saving. A review of the literature shows that cardiopulmonary bypass of the poisoned heart is feasible. The largest experience has resulted from the use of peripheral cardiopulmonary bypass. However, a literature review does not allow any conclusions regarding the efficiency and indications for this invasive method. Indeed, the majority of reports are single cases, with only one series of seven patients. Appealing results suggest that further studies are needed. Determination of prognostic factors predictive of refractoriness to conventional treatment for cardiotoxic poisonings is mandatory. These prognostic factors are specific for a toxicant or a class of toxicants. Knowledge of them will result in clarification of the indications for cardiopulmonary bypass in poisonings. PMID:17367544

  5. Silica nanoparticles induce cardiotoxicity interfering with energetic status and Ca(2+) handling in adult rat cardiomyocytes.

    PubMed

    Guerrero-Beltrán, Carlos Enrique; Bernal-Ramírez, Judith; Lozano, Omar; Oropeza-Almazán, Yuriana; Castillo, Elena Cristina; Garza, Jesús Roberto; García, Noemí; Vela, Jorge; García-García, Alejandra; Ortega, Eduardo; Torre-Amione, Guillermo; Ornelas-Soto, Nancy; García-Rivas, Gerardo

    2017-04-01

    Recent evidence has shown that nanoparticles that have been used to improve or create new functional properties for common products may pose potential risks to human health. Silicon dioxide (SiO2) has emerged as a promising therapy vector for the heart. However, its potential toxicity and mechanisms of damage remain poorly understood. This study provides the first exploration of SiO2-induced toxicity in cultured cardiomyocytes exposed to 7- or 670-nm SiO2 particles. We evaluated the mechanism of cell death in isolated adult cardiomyocytes exposed to 24-h incubation. The SiO2 cell membrane association and internalization were analyzed. SiO2 showed a dose-dependent cytotoxic effect with a half-maximal inhibitory concentration for the 7 nm (99.5 ± 12.4 µg/ml) and 670 nm (>1,500 µg/ml) particles, which indicates size-dependent toxicity. We evaluated cardiomyocyte shortening and intracellular Ca(2+) handling, which showed impaired contractility and intracellular Ca(2+) transient amplitude during β-adrenergic stimulation in SiO2 treatment. The time to 50% Ca(2+) decay increased 39%, and the Ca(2+) spark frequency and amplitude decreased by 35 and 21%, respectively, which suggest a reduction in sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) activity. Moreover, SiO2 treatment depolarized the mitochondrial membrane potential and decreased ATP production by 55%. Notable glutathione depletion and H2O2 generation were also observed. These data indicate that SiO2 increases oxidative stress, which leads to mitochondrial dysfunction and low energy status; these underlie reduced SERCA activity, shortened Ca(2+) release, and reduced cell shortening. This mechanism of SiO2 cardiotoxicity potentially plays an important role in the pathophysiology mechanism of heart failure, arrhythmias, and sudden death.NEW & NOTEWORTHY Silica particles are used as novel nanotechnology-based vehicles for diagnostics and therapeutics for the heart. However, their potential hazardous effects remain

  6. Resveratrol attenuates azidothymidine-induced cardiotoxicity by decreasing mitochondrial reactive oxygen species generation in human cardiomyocytes

    PubMed Central

    GAO, RACHEL YUE; MUKHOPADHYAY, PARTHA; MOHANRAJ, RAJESH; WANG, HUA; HORVÁTH, BÉLA; YIN, SHI; PACHER, PÁL

    2011-01-01

    Nucleotide reverse transcriptase inhibitors, such as zidovudine (azidothymidine, AZT) and stavudine, represent a class of approved antiretroviral agents for highly active antiretroviral therapy, which prolongs the life expectancy of patients infected with human-immunodeficiency virus. Unfortunately, the use of these drugs is associated with known toxicities in the liver, skeletal muscle, heart and other organs, which may involve increased reactive oxygen species (ROS) generation, among other mechanisms. Resveratrol is a polyphenolic plant-derived antioxidant abundantly found in certain grapes, roots, berries, peanuts and red wine. This study, using primary human cardiomyocytes, evaluated the effects of AZT and pre-treatment with resveratrol on mitochondrial ROS generation and the cell death pathways. AZT induced concentration-dependent cell death, involving both caspase-3 and -7 and poly(ADP-ribose) polymerase activation, coupled with increased mitochondrial ROS generation in human cardiomyocytes. These effects of AZT on mitochondrial ROS generation and cell death may be attenuated by resveratrol pre-treatment. The results demonstrate that mitochondrial ROS generation plays a pivotal role in the cardiotoxicity of AZT in human cardiomyocytes, and resveratrol may provide a potential strategy to attenuate these pathological alterations, which are associated with widely used antiretroviral therapy. PMID:21461578

  7. Resveratrol attenuates azidothymidine-induced cardiotoxicity by decreasing mitochondrial reactive oxygen species generation in human cardiomyocytes.

    PubMed

    Gao, Rachel Yue; Mukhopadhyay, Partha; Mohanraj, Rajesh; Wang, Hua; Horváth, Béla; Yin, Shi; Pacher, Pál

    2011-01-01

    Nucleotide reverse transcriptase inhibitors, such as zidovudine (azidothymidine, AZT) and stavudine, represent a class of approved antiretroviral agents for highly active antiretroviral therapy, which prolongs the life expectancy of patients infected with human-immunodeficiency virus. Unfortunately, the use of these drugs is associated with known toxicities in the liver, skeletal muscle, heart and other organs, which may involve increased reactive oxygen species (ROS) generation, among other mechanisms. Resveratrol is a polyphenolic plant-derived antioxidant abundantly found in certain grapes, roots, berries, peanuts and red wine. This study, using primary human cardiomyocytes, evaluated the effects of AZT and pre-treatment with resveratrol on mitochondrial ROS generation and the cell death pathways. AZT induced concentration-dependent cell death, involving both caspase-3 and -7 and poly(ADP-ribose) polymerase activation, coupled with increased mitochondrial ROS generation in human cardiomyocytes. These effects of AZT on mitochondrial ROS generation and cell death may be attenuated by resveratrol pre-treatment. The results demonstrate that mitochondrial ROS generation plays a pivotal role in the cardiotoxicity of AZT in human cardiomyocytes, and resveratrol may provide a potential strategy to attenuate these pathological alterations, which are associated with widely used antiretroviral therapy.

  8. A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer.

    PubMed

    Aminkeng, Folefac; Bhavsar, Amit P; Visscher, Henk; Rassekh, Shahrad R; Li, Yuling; Lee, Jong W; Brunham, Liam R; Caron, Huib N; van Dalen, Elvira C; Kremer, Leontien C; van der Pal, Helena J; Amstutz, Ursula; Rieder, Michael J; Bernstein, Daniel; Carleton, Bruce C; Hayden, Michael R; Ross, Colin J D

    2015-09-01

    Anthracyclines are used in over 50% of childhood cancer treatment protocols, but their clinical usefulness is limited by anthracycline-induced cardiotoxicity (ACT) manifesting as asymptomatic cardiac dysfunction and congestive heart failure in up to 57% and 16% of patients, respectively. Candidate gene studies have reported genetic associations with ACT, but these studies have in general lacked robust patient numbers, independent replication or functional validation. Thus, the individual variability in ACT susceptibility remains largely unexplained. We performed a genome-wide association study in 280 patients of European ancestry treated for childhood cancer, with independent replication in similarly treated cohorts of 96 European and 80 non-European patients. We identified a nonsynonymous variant (rs2229774, p.Ser427Leu) in RARG highly associated with ACT (P = 5.9 × 10(-8), odds ratio (95% confidence interval) = 4.7 (2.7-8.3)). This variant alters RARG function, leading to derepression of the key ACT genetic determinant Top2b, and provides new insight into the pathophysiology of this severe adverse drug reaction.

  9. Role of xanthine oxidase in the potentiation of doxorubicin-induced cardiotoxicity by mitomycin C.

    PubMed

    Gustafson, D L; Swanson, J D; Pritsos, C A

    1991-09-01

    Clinical evidence has suggested that mitomycin C (MMC) potentiates doxorubicin (DOX) induced cardiotoxicity. In this study a mouse model was used to examine the effect of DOX on the ability of cardiac tissue to bioactivate MMC to generate oxygen radicals. Cardiac damage was assessed by measuring serum CPK-MB isoenzyme levels and thiobarbituric acid reactive substances (TBARS) in the cardiac tissue. The exposure of animals to DOX or DOX and MMC over a three week period led to an increase in serum CPK-MB isoenzyme levels as well as TBARS. Treatment with DOX led to an increase in MMC-dependent, NADH-dependent, cyanide insensitive oxygen consumption, compared to control animals, thereby suggesting increased MMC-dependent oxygen radical generation. Levels of xanthine oxidase (XO; EC 1.1.3.22) and NADPH:cytochrome C reductase, two enzymes known to bioactivate MMC with subsequent oxygen radical generation, were measured in cardiac tissue with a 4.5 x increase in XO activity seen in DOX treated animals vs controls and no change in NADPH:cytochrome C reductase activity. Cardiac levels of xanthine dehydrogenase (XDH; EC 1.1.1.204) activity in DOX treated animals decreased while the XO/XDH ratio increased, suggesting a conversion of XDH to XO following DOX treatment.

  10. Candidate Gene Association Studies of Anthracycline-induced Cardiotoxicity: A Systematic Review and Meta-analysis.

    PubMed

    Leong, Siew Lian; Chaiyakunapruk, Nathorn; Lee, Shaun Wen Huey

    2017-12-01

    Anthracyclines play an important role in the management of patients with cancer but the development of anthracycline-induced cardiotoxicity (ACT) remains a significant concern for most clinicians. Recently, genetic approach has been used to identify patients at increased risk of ACT. This systematic review assessed the association between genomic markers and ACT. A systematic literature search was performed in Medline, PubMed, Cochrane Central Register of Controlled Studies, CINAHL Plus, AMED, EMBASE and HuGE Navigator from inception until May 2016. Twenty-eight studies examining the association of genetic variants and ACT were identified. These studies examined 84 different genes and 147 single nucleotide polymorphisms. Meta-analyses showed 3 risk variants significantly increased the risk for ACT; namely ABCC2 rs8187710 (pooled odds ratio: 2.20; 95% CI: 1.36-3.54), CYBA rs4673 (1.55; 1.05-2.30) and RAC2 rs13058338 (1.79; 1.27-2.52). The current evidence remains unclear on the potential role of pharmacogenomic screening prior to anthracycline therapy. Further research is needed to improve the diagnostic and prognostic role in predicting ACT.

  11. Prevention of Trastuzumab and Anthracycline-induced Cardiotoxicity Using Angiotensin-converting Enzyme Inhibitors or β-blockers in Older Adults With Breast Cancer.

    PubMed

    Wittayanukorn, Saranrat; Qian, Jingjing; Westrick, Salisa C; Billor, Nedret; Johnson, Brandon; Hansen, Richard A

    2017-05-23

    Although clinical trials have provided some data on the benefit of angiotensin-converting enzyme inhibitors (ACEIs) or β-blockers (BBs) in patients with chemotherapy-induced cardiotoxicity, evidence of ACEIs/BBs on prevention of trastuzumab and/or anthracycline-induced cardiotoxicity outside trials is limited. A cohort study of 142,990 women (66 y and above) newly diagnosed with breast cancer from 2001 to 2009 was conducted using the Surveillance, Epidemiology, and End Results-Medicare-linked database. The ACEI/BB exposure was defined as filled prescription(s) before or after the initiation of trastuzumab/anthracyclines. The nonexposed group was defined as those who had never been prescribed ACEIs/BBs. Cumulative rates of cardiotoxicity and all-cause mortality were estimated and marginal structural Cox models were used to determine factors associated with cardiotoxicity and all-cause mortality adjusting for baseline covariates and use of chemotherapy. All statistical tests were 2 sided. The final sample included 6542 women. Adjusted hazard ratio for cardiotoxicity and all-cause mortality for the ACEI/BB exposed group were 0.77 (95% confidence interval, 0.62-0.95) and 0.79 (95% confidence interval, 0.70-0.90) compared with the nonexposed group, respectively. Starting ACEIs/BBs≤6 months after the initiation of trastuzumab/anthracyclines and having exposed duration≥6 months were also associated with decreased risk of cardiotoxicity and all-cause mortality. Baseline characteristics, including age, non-Hispanic black, advanced cancer, region, comorbidity, preexisting cardiovascular conditions, lower socioeconomic status, and concomitant treatment were significantly associated with an elevated risk of all-cause mortality and/or cardiotoxicity (all P<0.05). ACEIs/BBs show favorable effects on preventing cardiotoxicity and improving survival in female breast cancer patients undergoing trastuzumab/anthracycline treatment.

  12. Cardiotoxicity of anthracycline therapy: current perspectives

    PubMed Central

    Valcovici, Mihaela; Serban, Corina; Dragan, Simona

    2016-01-01

    Anthracyclines, especially doxorubicin and daunorubicin, are the drugs of first choice in the treatment of patients with hematologic malignancies, soft-tissue sarcomas, and solid tumors. Unfortunately, the use of anthracyclines is limited by their dose-dependent and cumulative cardiotoxicity. The molecular mechanism responsible for anthracycline-induced cardiotoxicity remains poorly understood, although experimental and clinical studies have shown that oxidative stress plays the main role. Hence, antioxidant agents, especially dexrazoxane, and also other drug classes (statins, β-blockers) proved to have a beneficial effect in protecting against anthracycline-induced cardiotoxicity. According to previous clinical trials, the major high-risk factors for anthracycline-induced cardiotoxicity are age, body weight, female gender, radiotherapy, and other diseases such as Down syndrome, familial dilated cardiomyopathy, diabetes and hypertension. Consequently, further studies are needed to elucidate the molecular pathogenesis of anthracycline-induced cardiotoxicity and also to discover new cardioprotective agents against anthracycline-induced cardiotoxicity. PMID:27186191

  13. Assessment of Beating Parameters in Human Induced Pluripotent Stem Cells Enables Quantitative In Vitro Screening for Cardiotoxicity

    PubMed Central

    Sirenko, Oksana; Cromwell, Evan F.; Crittenden, Carole; Wignall, Jessica A.; Wright, Fred A.; Rusyn, Ivan

    2014-01-01

    Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes show promise for screening during early drug development. Here, we tested a hypothesis that in vitro assessment of multiple cardiomyocyte physiological parameters enables predictive and mechanistically-interpretable evaluation of cardiotoxicity in a high-throughput format. Human iPSC-derived cardiomyocytes were exposed for 30 minutes or 24 hours to 131 drugs, positive (107) and negative (24) for in vivo cardiotoxicity, in up to 6 concentrations (3 nM to 30 μM) in 384-well plates. Fast kinetic imaging was used to monitor changes in cardiomyocyte function using intracellular Ca2+ flux readouts synchronous with beating, and cell viability. A number of physiological parameters of cardiomyocyte beating, such as beat rate, peak shape (amplitude, width, raise, decay, etc.) and regularity were collected using automated data analysis. Concentration-response profiles were evaluated using logistic modeling to derive a benchmark concentration (BMC) point-of-departure value, based on one standard deviation departure from the estimated baseline in vehicle (0.3% dimethylsulfoxide)-treated cells. BMC values were used for cardiotoxicity classification and ranking of compounds. Beat rate and several peak shape parameters were found to be good predictors, while cell viability had poor classification accuracy. In addition, we applied the Toxicological Prioritization Index approach to integrate and display data across many collected parameters, to derive “cardiosafety” ranking of tested compounds. Multi-parameter screening of beating profiles allows for cardiotoxicity risk assessment and identification of specific patterns defining mechanism-specific effects. The data and analysis methods may be used widely for compound screening and early safety evaluation in the drug development process. PMID:24095675

  14. Attenuation of Doxorubicin-Induced Cardiotoxicity by mdivi-1: A Mitochondrial Division/Mitophagy Inhibitor

    PubMed Central

    Gharanei, Mayel; Hussain, Afthab; Janneh, Omar; Maddock, Helen

    2013-01-01

    Doxorubicin is one of the most effective anti-cancer agents. However, its use is associated with adverse cardiac effects, including cardiomyopathy and progressive heart failure. Given the multiple beneficial effects of the mitochondrial division inhibitor (mdivi-1) in a variety of pathological conditions including heart failure and ischaemia and reperfusion injury, we investigated the effects of mdivi-1 on doxorubicin-induced cardiac dysfunction in naïve and stressed conditions using Langendorff perfused heart models and a model of oxidative stress was used to assess the effects of drug treatments on the mitochondrial depolarisation and hypercontracture of cardiac myocytes. Western blot analysis was used to measure the levels of p-Akt and p-Erk 1/2 and flow cytometry analysis was used to measure the levels p-Drp1 and p-p53 upon drug treatment. The HL60 leukaemia cell line was used to evaluate the effects of pharmacological inhibition of mitochondrial division on the cytotoxicity of doxorubicin in a cancer cell line. Doxorubicin caused a significant impairment of cardiac function and increased the infarct size to risk ratio in both naïve conditions and during ischaemia/reperfusion injury. Interestingly, co-treatment of doxorubicin with mdivi-1 attenuated these detrimental effects of doxorubicin. Doxorubicin also caused a reduction in the time taken to depolarisation and hypercontracture of cardiac myocytes, which were reversed with mdivi-1. Finally, doxorubicin caused a significant elevation in the levels of signalling proteins p-Akt, p-Erk 1/2, p-Drp1 and p-p53. Co-incubation of mdivi-1 with doxorubicin did not reduce the cytotoxicity of doxorubicin against HL-60 cells. These data suggest that the inhibition of mitochondrial fission protects the heart against doxorubicin-induced cardiac injury and identify mitochondrial fission as a new therapeutic target in ameliorating doxorubicin-induced cardiotoxicity without affecting its anti-cancer properties. PMID

  15. The Effects of Mangiferin (Mangifera indica L) in Doxorubicin-induced Cardiotoxicity in Rats.

    PubMed

    Arozal, W; Suyatna, F D; Juniantito, V; Rosdiana, D S; Amurugam, S; Aulia, R; Monayo, E R; Siswandi, R

    2015-11-01

    The cardiotoxicity effect of doxorubicin (DOX), a widely used antitumor agent has restricted its clinical application. The aim of the current study was to explore the potential protective effect of mangiferin, a naturally occurring glucosylxanthone, that have antioxidant activity by its iron-complexing ability in mitochondria, against DOX-induced cardiac toxicity in rats in comparison with other antioxidants namely Sylimarin (SYL) and Vitamin E (VitE). Mangiferin was given orally to rats at a dose of 50, and 100 mg/kg for 5 weeks, and DOX was injected at a total dose of 15 mg/kg. Cardiac toxicity was evaluated by lactate dehydrogenase and creatine kinase in the serum, malondialdehyde (MDA) level in plasma and cardiac tissue, and antioxidant enzyme superoxide dismutase (SOD) in cardiac tissue. Mangiferin protected against DOX-induced increased mortality and electrocardiogram abnormality and decreased biochemical markers of cardiac toxicity i. e., lactate dehydrogenase and creatine phosphokinase isoenzyme. In addition, elevation of plasma and cardiac tissue levels of MDA in response to DOX treatment were significantly attenuated. The reduction of cardiac activity of SOD was significantly reduced in contrast with the other antioxidant SYL and Vit E. Histopathologically, mangiferin treatment showed significant reduction in inflammatory cell number, fibrotic area, and necrotic foci as compared with DOX only-treated rats. These results suggested that mangiferin had better protective effect against DOX-induced cardiac toxicity in comparison with SYL and VitE, thus besides the antioxidant activity, different mechanism may be involved in the action of mangiferin and need to be clarified in the future studies. © Georg Thieme Verlag KG Stuttgart · New York.

  16. Protective effect of Emblica officinalis (amla) on isoproterenol-induced cardiotoxicity in rats.

    PubMed

    Ojha, Shreesh; Golechha, Mahaveer; Kumari, Santosh; Arya, Dharamvir Singh

    2012-06-01

    Emblica officinalis, commonly known as amla, is an important medicinal plant reputed for its dietary and therapeutic uses. The aim of the present study was to investigate the protective role of E. officinalis against isoproterenol (ISP)-induced cardiotoxicity in rats and elucidate the possible mechanism involved. Rats were administered E. officinalis (100, 250 and 500 mg/kg, p.o.) or vehicle (normal saline) for 30 days, with concurrent subcutaneous injections of ISP (85 mg/kg, at 24 h interval) on 29th and 30th day. ISP-induced cardiac dysfunction as evidenced by decreased mean arterial pressure, heart rate, contractility (+LVdP/dt) and relaxation (-LVdP/dt) along with increased left ventricular end diastolic pressure. ISP significantly (p < 0.05) decreased antioxidant enzymes, superoxide dismutase, catalase and glutathione peroxidase and myocyte-injury-specific marker enzymes, creatine phosphokinase-MB and lactate dehydrogenase in heart. A significant (p < 0.05) depletion of reduced glutathione and increase in thiobarbituric acid reactive substances along with histopathological alteration has further indicated the oxidative damage of myocardium. However, pretreatment with E. officinalis exhibited restoration of hemodynamic and left ventricular function along with significant preservation of antioxidants, myocytes-injury-specific marker enzymes and significant inhibition of lipid peroxidation. Furthermore, histopathological salvage of myocardium reconfirmed the protective effects of E. officinalis. Results of the present study demonstrate cardioprotective potential of E. officinalis attributed to its potent antioxidant and free radical scavenging activity as evidenced by favorable improvement in hemodynamic, contractile function and tissue antioxidant status.

  17. Anti-inflammatory agents and monoHER protect against DOX-induced cardiotoxicity and accumulation of CML in mice

    PubMed Central

    Bruynzeel, A M E; Abou El Hassan, M A; Schalkwijk, C; Berkhof, J; Bast, A; Niessen, H W M; van der Vijgh, W J F

    2007-01-01

    Cardiac damage is the major limiting factor for the clinical use of doxorubicin (DOX). Preclinical studies indicate that inflammatory effects may be involved in DOX-induced cardiotoxicity. Nɛ-(carboxymethyl) lysine (CML) is suggested to be generated subsequent to oxidative stress, including inflammation. Therefore, the aim of this study was to investigate whether CML increased in the heart after DOX and whether anti-inflammatory agents reduced this effect in addition to their possible protection on DOX-induced cardiotoxicity. These effects were compared with those of the potential cardioprotector 7-monohydroxyethylrutoside (monoHER). BALB/c mice were treated with saline, DOX alone or DOX preceded by ketoprofen (KP), dexamethasone (DEX) or monoHER. Cardiac damage was evaluated according to Billingham. Nɛ-(carboxymethyl) lysine was quantified immunohistochemically. Compared to saline, a 21.6-fold increase of damaged cardiomyocytes was observed in mice treated with DOX (P<0.001). Addition of KP, DEX or monoHER before DOX significantly reduced the mean ratio of abnormal cardiomyocytes in comparison to mice treated with DOX alone (P⩽0.02). In addition, DOX induced a significant increase in the number of CML-stained intramyocardial vessels per mm2 (P=0.001) and also in the intensity of CML staining (P=0.001) compared with the saline-treated group. Nɛ-(carboxymethyl) lysine positivity was significantly reduced (P⩽0.01) by DOX-DEX, DOX-KP and DOX-monoHER. These results confirm that inflammation plays a role in DOX-induced cardiotoxicity, which is strengthened by the observed DOX-induced accumulation of CML, which can be reduced by anti-inflammatory agents and monoHER. PMID:17325706

  18. Protective effect of curcumin on experimentally induced inflammation, hepatotoxicity and cardiotoxicity in rats: evidence of its antioxidant property.

    PubMed

    Naik, Suresh R; Thakare, Vishnu N; Patil, Snehal R

    2011-07-01

    The present study investigates the protective effects of curcumin on experimentally induced inflammation, hepatotoxicity, and cardiotoxicity using various animal models with biochemical parameters like serum marker enzymes and antioxidants in target tissues. In addition, liver and cardiac histoarchitecture changes were also studied. Curcumin treatment inhibited carrageenin and albumin induced edema, cotton pellet granuloma formation. The increased relative weight of liver and heart in CCl(4) induced liver injury and isoproterenol induced cardiac necrosis were also reduced by curcumin treatment. Elevated serum marker enzymes, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) increased lipid peroxidation, decreased gluthione (GSH), glutathione peroxidase (GPx) and superoxide dismutase (SOD) in edematous, granulomatus, liver and heart tissues during inflammation, liver injury and cardiac necrosis, respectively. Curcumin treatment reversed all these above mentioned biochemical changes significantly in all animal models studied. Even histoarchitecture alterations observed in liver injury and cardiac necrosis observed were partially reversed (improved) by curcumin treatments. In in vitro experiments too curcumin inhibited iron catalyzed lipid peroxidation in liver homogenates, scavenged nitric oxide spontaneously generated from nitroprusside and inhibited heat induced hemolysis of rat erythrocytes. The present in vitro and in vivo experimental findings suggest the protective effect of curcumin on experimentally induced inflammation, hepatotoxicity, and cardiotoxicity in rats.

  19. Assessment of Subclinical Doxorubicin-induced Cardiotoxicity in a Rat Model by Speckle-Tracking Imaging.

    PubMed

    Kang, Yu; Wang, Wei; Zhao, Hang; Qiao, Zhiqing; Shen, Xuedong; He, Ben

    2017-07-10

    Despite their clear therapeutic benefits, anthracycline-induced cardiotoxicity is a major concern limiting the ability to reduce morbidity and mortality associated with cancers. The early identification of anthracycline-induced cardiotoxicity is of vital importance to assess the cardiac risk against the potential cancer treatment. To investigate whether speckle-tracking analysis can provide a sensitive and accurate measurement when detecting doxorubicin-induced left ventricular injury. Wistar rats were divided into 4 groups with 8 rats each, given doxorubicin intraperitoneally at weekly intervals for up to 4 weeks. Group 1: 2.5 mg/kg/week; group 2: 3 mg/kg/week; group 3: 3.5mg/kg/week; group 4: 4mg/kg/week. An additional 5 rats were used as controls. Echocardiographic images were obtained at baseline and 1 week after the last dose of treatment. Radial (Srad) and circumferential (Scirc) strains, radial (SRrad) and circumferential (SRcirc) strain rates were analyzed. After the experiment, cardiac troponin I (cTnI) was analyzed and the heart samples were histologically evaluated. After doxorubicin exposure, LVEF was significantly reduced in group 4 (p = 0.006), but remained stable in the other groups. However, after treatment, Srads were reduced in groups 2, 3 and 4 (p all < 0.05). The decrease in Srads was correlated with cTnI (rho = -0.736, p = 0.000) and cardiomyopathy scores (rho = -0.797, p = 0.000). Radial strain could provide a sensitive and noninvasive index in early detection of doxorubicin-induced myocardial injury. The changes in radial strain had a significant correlation with myocardial lesions and serum cardiac troponin I levels, indicating that this parameter could accurately evaluate cardiotoxicity severity. Apesar dos seus claros benefícios terapêuticos, a cardiotoxicidade induzida pela antraciclina é uma grande preocupação que limita a capacidade de reduzir a morbidade e mortalidade associadas com cânceres. A identificação precoce da

  20. Pharmacological dose of {alpha}-tocopherol induces cardiotoxicity in Wistar rats determined by echocardiography and histology.

    PubMed

    Nascimento, Maria Carolina M O; Matsubara, Beatriz B; Matsubara, Luiz S; Correa, Camila R; Pereira, Elenize J; Moreira, Priscila L; Carvalho, Flavio A; Burini, Caio H; Padovani, Carlos R; Yeum, Kyung-Jin; Ferreira, Ana Lucia A

    2011-10-01

    The effect of pharmacological dose of α-tocopherol on heart health was determined in Wistar rats. Animals were randomly assigned to either C (control, n = 11) or E (α-tocopherol, n = 11) group. Animals received corn oil (C) or α-tocopherol dissolved in corn oil (250 mg α-tocopherol/[kg body wt/day]) (E) by gavage for a 7-week period. Rats underwent echocardiogram and were analyzed for cardiomyocyte histology and cardiac α-tocopherol absorption at the end of the study period. As compared to the C group, α-tocopherol-supplemented group showed significantly (p < 0.05) lower body weight (E, 412.8 g vs C, 480.3 g) and total cardiac weight (E, 0.94 g vs C, 1.08 g); cardiomyocyte histological impairment; smaller left ventricle (LV) (LV end-diastolic diameter (E, 7.22 mm vs C, 7.37 mm), lower LV systolic [left ventricle fractional shortening (E, 47.6% vs C, 53.6%) and ejection fraction ratio (E, 85.4 vs C, 89.9)] and diastolic [early peak velocities of diastolic transmitral flow (E, 64.6 cm/sec vs C, 75.1 cm/sec)] function. The α-tocopherol uptake in target tissue was confirmed by determination of α-tocopherol concentration medians in cardiac tissue (E, 109.91 nmol/kg vs C, 52.09 nmol/kg). The current study indicates that pharmacological dose of α-tocopherol supplementation can induce cardiotoxicity in healthy rats.

  1. Rutin Protects against Pirarubicin-Induced Cardiotoxicity through TGF-β1-p38 MAPK Signaling Pathway

    PubMed Central

    Wang, Yadi; Zhang, Yang; Sun, Bo; Tong, Qing

    2017-01-01

    We investigated the potential protective effect of rutinum (RUT) against pirarubicin- (THP-) induced cardiotoxicity. THP was used to induce toxicity in rat H9c2 cardiomyoblasts. Positive control cells were pretreated with a cardioprotective agent dexrazoxane (DZR) prior to treatment with THP. Some of the cells were preincubated with RUT and a p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, both individually and in combination, prior to THP exposure. At a dose range of 30–70 μM, RUT significantly prevented THP-induced reduction in cell viability; the best cardioprotective effect was observed at a dose of 50 μM. Administration of RUT and SB203580, both individually as well as in combination, suppressed the elevation of intracellular ROS, inhibited cell apoptosis, and reversed the THP-induced upregulation of TGF-β1, p-p38 MAPK, cleaved Caspase-9, Caspase-7, and Caspase-3. A synergistic effect was observed on coadministration of RUT and SB203580. RUT protected against THP-induced cardiotoxicity by inhibition of ROS generation and suppression of cell apoptosis. The cardioprotective effect of RUT appears to be associated with the modulation of the TGF-β1-p38 MAPK signaling pathway. PMID:28367221

  2. Plasma metabolic profiling analysis of cyclophosphamide-induced cardiotoxicity using metabolomics coupled with UPLC/Q-TOF-MS and ROC curve.

    PubMed

    Yin, Jia; Xie, Jiabin; Guo, Xuejun; Ju, Liang; Li, Yubo; Zhang, Yanjun

    2016-10-15

    Cyclophosphamide (CY) is a commonly-used nitrogen mustard alkylating agent, but its clinical application is severely limited by its cardiotoxicity. Since the development of metabolomics, the change of metabolite profiles caused by cyclophosphamide has been studied by metabolomics and has gained much attention. In this study, we analyzed rat plasma samples collected one, three and five days after cyclophosphamide administration using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS). Multiple statistical analyses, such as principal component analysis (PCA) and partial least squares - discriminant analysis (PLS-DA), were used to examine metabolite profile changes in plasma samples in order to screen for potential cardiotoxicity biomarkers and metabolic pathways. Levels of a dozen of metabolites changed significantly in plasma from the CY-treated group after one, three, and five days compared with the control group treated with normal saline (NS). Receiver operator characteristic (ROC) curve analysis suggested that the total 16 metabolites play important roles in different times of CY-induced cardiotoxicity respectively. Our results suggest that these metabolites in linoleic acid metabolism and glycerol phospholipid metabolism may be related to CY-induced cardiotoxicity. These metabolites could act as sensitive biomarkers for CY-induced cardiotoxicity and be useful for investigating toxic mechanisms. They may also lay a foundation for clinical use of cyclophosphamide. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Synergistic protective role of mirazid (Commiphora molmol) and ascorbic acid against tilmicosin-induced cardiotoxicity in mice.

    PubMed

    Abdel-Daim, Mohamed M; Ghazy, Emad W; Fayez, Mostafa

    2015-01-01

    Tilmicosin (TIL) is a long-acting macrolide antibiotic approved for the treatment of cattle with Bovine Respiratory Disease. However, overdose of TIL has been reported to induce cardiotoxicity. The purpose of our experiment was to evaluate the protective effects of Commiphora molmol (mirazid (MRZ); myrrh) and (or) ascorbic acid (AA) against TIL-induced cardiotoxicity in mice. MRZ and AA were orally administered using stomach gavage, either alone or in combination for 5 consecutive days, followed with a single TIL overdose. TIL overdose induced a significant increase in serum levels of cardiac damage biomarkers (AST, LDH, CK, CK-MB, and cTnT), as well as cardiac lipid peroxidation, but cardiac levels of antioxidant biomarkers (GSH, SOD, CAT, and TAC) were decreased. Both MRZ and AA tended to normalize the elevated serum levels of cardiac injury biomarkers. Furthermore, MRZ and AA reduced TIL-induced lipid peroxidation and oxidative stress parameters. MRZ and AA combined produced a synergistic cardioprotective effect. We conclude that myrrh and (or) vitamin C administration minimizes the toxic effects of TIL through their free-radical-scavenging and potent antioxidant activities.

  4. Salvianolic Acid B Prevents Arsenic Trioxide-Induced Cardiotoxicity In Vivo and Enhances Its Anticancer Activity In Vitro

    PubMed Central

    Wang, Min; Sun, Guibo; Wu, Ping; Chen, Rongchang; Yao, Fan; Qin, Meng; Luo, Yun; Sun, Hong; Zhang, Qiang; Dong, Xi; Sun, Xiaobo

    2013-01-01

    Clinical attempts to reduce the cardiotoxicity of arsenic trioxide (ATO) without compromising its anticancer activities remain to be an unresolved issue. In this study, we determined whether Sal B can protect against ATO-induced cardiac toxicity in vivo and increase the toxicity of ATO toward cancer cells. Combination treatment of Sal B and ATO was investigated using BALB/c mice and human hepatoma (HepG2) cells and human cervical cancer (HeLa) cells. The results showed that the combination treatment significantly improved the ATO-induced loss of cardiac function, attenuated damage of cardiomyocytic structure, and suppressed the ATO-induced release of cardiac enzymes into serum in BALB/c mouse models. The expression levels of Bcl-2 and p-Akt in the mice treated with ATO alone were reduced, whereas those in the mice given the combination treatment were similar to those in the control mice. Moreover, the combination treatment significantly enhanced the ATO-induced cytotoxicity and apoptosis of HepG2 cells and HeLa cells. Increases in apoptotic marker cleaved poly (ADP-ribose) polymerase and decreases in procaspase-3 expressions were observed through western blot. Taken together, these observations indicate that the combination treatment of Sal B and ATO is potentially applicable for treating cancer with reduced cardiotoxic side effects. PMID:23662152

  5. Melissa officinalis Protects against Doxorubicin-Induced Cardiotoxicity in Rats and Potentiates Its Anticancer Activity on MCF-7 Cells

    PubMed Central

    Hamza, Alaaeldin Ahmed; Ahmed, Mahguob Mohamed; Elwey, Hanan Mohamed; Amin, Amr

    2016-01-01

    Cardiotoxicity is a limiting factor of doxorubicin (DOX)-based anticancer therapy. Due to its beneficial effects, we investigated whether standardized extract of Melissa officinalis (MO) can attenuate doxorubicin-induced cardiotoxicity and can potentiate the efficacy of DOX against human breast cancer cells. MO was administered orally to male albino rats once daily for 10 consecutive days at doses of 250, 500 and 750 mg/kg b.wt. DOX (15 mg/kg b.wt. i.p.) was administered on the 8th day. MO protected against DOX-induced leakage of cardiac enzymes and histopathological changes. MO ameliorated DOX-induced oxidative stress as evidenced by decreasing lipid peroxidation, protein oxidation and total oxidant capacity depletion and by increasing antioxidant capacity. Additionally, MO pretreatment inhibited inflammatory responses to DOX by decreasing the expressions of nuclear factor kappa-B, tumor necrosis factor-alpha and cyclooxygenase-2 and the activity of myeloperoxidase. MO ameliorated DOX-induced apoptotic tissue damage in heart of rats. In vitro study showed that MO augmented the anticancer efficacy of DOX in human breast cancer cells (MCF-7) and potentiated oxidative damage and apoptosis. Thus, combination of DOX and MO may prove future cancer treatment protocols safer and more efficient. PMID:27880817

  6. Cardioprotective Activity of Methanol Extract of fruit of Trichosanthes cucumerina on Doxorubicin-induced Cardiotoxicity in Wistar Rats

    PubMed Central

    Shah, Sagar L.; Mali, Vishal R.; Zambare, Girish N.; Bodhankar, Subhash L.

    2012-01-01

    Aim and Objective: The objective was to determine the activity of methanol extract of fruit of Trichosanthes cucumerina in doxorubicin-induced cardiotoxicity in rats. Materials and Methods: The methanol extract of fruit of T. cucumerina was prepared. Male Wistar rats were divided in four groups. Group I was vehicle control. Group II animals received doxorubicin 4 mg/kg i.p. on days 21, 28, 35, and 42. Group III and IV animals were treated with methanol extract of T. cucumerina (500 and 1000 mg/kg, respectively) for 49 days. Doxorubicin was administered on days 21, 28, 35, and 42 days. The parameters of study were body weight, serum biomarkers, ECG, blood pressure, and left ventricular function. At the end of the study, the histology of heart, liver, and kidney was carried out. Results: Cardiac toxicity by doxorubicin was manifested as body weight loss, elevated serum LDH and CK-MB, increased ST, QT and QRS complex, reduced blood pressure, and left ventricular function. The methanol extract of T. cucumerina significantly decreased LDH and CK-MB, reduced ST, QT interval and QRS complex, increased heart rate, restored blood pressure, and left ventricular function. Doxorubicin caused liver and kidney necrosis, cellular infiltration, and vascular changes that indicated injury. Conclusion: T. cucumerina (1000 mg/kg) reduced the severity of doxorubicin-induced cardiac damage especially in heart. It is concluded that doxorubicin-induced cardiotoxicity is reduced by pretreatment with methanol extract of fruit of T. cucumerina. PMID:22778516

  7. Protective effects of vitamin E and selenium against dimethoate-induced cardiotoxicity in vivo: biochemical and histological studies.

    PubMed

    Amara, Ibtissem Ben; Soudani, Nejla; Hakim, Ahmed; Troudi, Afef; Zeghal, Khaled Mounir; Boudawara, Tahia; Zeghal, Najiba

    2013-11-01

    There is considerable interest in the study of free radical-mediated damage to biological systems due to pesticide exposure. However, there is a lack of consensus as to which determinations are best used to quantify future risks arising from xenobiotic exposure and natural antioxidant interventions. Our study investigated the potential ability of selenium and/or vitamin E, used as nutritional supplements, to alleviate cardiotoxicity induced by dimethoate. Female Wistar rats were exposed for 30 days either to dimethoate (0.2 g L⁻¹ of drinking water), dimethoate+selenium (0.5 mg kg⁻¹ of diet), dimethoate+vitamin E (100 mg kg⁻¹ of diet), or dimethoate+selenium+vitamin E. The exposure of rats to dimethoate promoted oxidative stress with a rise in malondialdehyde, advanced protein oxidation, and protein carbonyl levels. An increase of glutathione peroxidase, superoxide dismutase, and catalase activities was also noted. A fall in acetylcholinesterase and Na⁺ K⁺-ATPase activities, glutathione, nonprotein thiols, vitamins C and E levels was observed. Plasma levels of cholesterol, triglycerides, and low density lipoprotein-cholesterol increased and those of high density lipoprotein-cholesterol decreased. Coadministration of selenium or vitamin E to the diet of dimethoate-treated rats ameliorated the biochemical parameters cited above. The histopathological findings confirmed the biochemical results and the potential protective effects of selenium and vitamin E against cardiotoxicity induced by dimethoate.

  8. Effects of Lagenaria sicessaria fruit juice on lipid profile and glycoprotein contents in cardiotoxicity induced by isoproterenol in rats.

    PubMed

    Upaganlawar, Aman; Balaraman, R

    2012-01-01

    This study investigated antihyperlipidemic effects of Lagenaria siceraria fruit juice (LSFJ) in isoproterenol (ISO)induced cardiotoxicity in rats. Rats treated with ISO (200 mg/kg, s.c.) showed a significant increase in the levels of triglycerides, cholesterol, and free fatty acids, in both serum and heart tissue. An increase in the levels of phospholipids, low-density lipoprotein, and very low-density lipoprotein-cholesterol, and decrease in high-density lipoprotein-cholesterol in serum and phospholipid levels in the heart were observed. ISO intoxicated rats also showed a significant decrease in the activities of lecithin: cholesterol acyl transferase, whereas lipoprotein lipase was found to be increased. Administration of LSFJ (400 mg/kg, p.o.) for 30 consecutive days and challenged with ISO on day 29th and 30th significantly attenuated these alterations and restored the levels of serum and heart lipids along with lipid metabolizing enzymes. Histopathological observations were also in correlation with the biochemical parameters. These findings indicate the protective effect of LSFJ during ISO-induced cardiotoxicity in rats.

  9. Xinfuli improves cardiac function, histopathological changes and attenuate cardiomyocyte apoptosis in rats with doxorubicin-induced cardiotoxicity

    PubMed Central

    Lu, Pei-Pei; Ma, Jie; Liang, Xiao-Peng; Guo, Cai-Xia; Yang, Yan-Kun; Yang, Kun-Qi; Shen, Qi-Ming; Ma, Li-Hong; Zhou, Xian-Liang

    2016-01-01

    Background Xinfuli Granule (XG), a compound Chinese herbal medicine, has been effectively used in China for the treatment of heart failure for more than fifty years. This study aimed to investigate the effects and the underlying mechanisms of Xinfuli in rats with doxorubicin-induced cardiotoxicity. Methods Sprague–Dawley rats were treated with intraperitoneal injection of Doxorubicin (DOX, 2.5 mg/kg per week) for six weeks, and then randomly divided into four groups which received intragastrically administration of normal saline (control group) or different dosage of XG (0.675 g/kg per day, 1.35 g/kg per day, and 2.7g/kg per day, respectively) for six weeks. Transthoracic echocardiography was performed to evaluate the left ventricular fractional shortening (LVFS) and left ventricular ejection fraction (LVEF) before and after the XG treatment and histopathologic changes were also examined. Myocardial cell apoptosis was detected by TUNEL staining. The expression of related genes and proteins were analyzed using immunohistochemical staining. Results Compared to those in the control group, rats in XG treated groups showed significantly improved cardiac function and milder cardiac histopathological changes, lower cardiomyocyte apoptosis index, higher expression of Bcl-2 and lower expression of Bax. Conclusions Administration of XG improves cardiac function and histopathological changes in rats with doxorubicin-induced cardiotoxicity. These effects are associated with inhibition of cardiomyocyte apoptosis, perhaps via regulation of Bcl-2 and Bax protein expression. PMID:28321239

  10. Novel insights in pathophysiology of antiblastic drugs-induced cardiotoxicity and cardioprotection.

    PubMed

    Deidda, Martino; Madonna, Rosalinda; Mango, Ruggiero; Pagliaro, Pasquale; Bassareo, Pier P; Cugusi, Lucia; Romano, Silvio; Penco, Maria; Romeo, Francesco; Mercuro, Giuseppe

    2016-05-01

    Despite advances in supportive and protective therapy for myocardial function, heart failure caused by various clinical conditions, including cardiomyopathy due to antineoplastic therapy, remains a major cause of morbidity and mortality. Because of the limitations associated with current therapies, investigators have been searching for alternative treatments that can effectively repair the damaged heart and permanently restore its function. Damage to the heart can result from both traditional chemotherapeutic agents, such as anthracyclines, and new targeted therapies, such as trastuzumab. Because of this unresolved issue, investigators are searching for alternative therapeutic strategies. In this article, we present state-of-the-art technology with regard to the genomic and epigenetic mechanisms underlying cardiotoxicity and cardioprotection, the role of anticancer in influencing the redox (reduction/oxidation) balance and the function of stem cells in the repair/regeneration of the adult heart. These findings, although not immediately transferable to clinical applications, form the basis for the development of personalized medicine based on the prevention of cardiotoxicity with the use of genetic testing. Proteomics, metabolomics and investigations on reactive oxygen species-dependent pathways, particularly those that interact with the production of NO and energy metabolism, appear to be promising for the identification of early markers of cardiotoxicity and for the development of cardioprotective agents. Finally, autologous cardiac stem and progenitor cells may represent future contributions in the field of myocardial protection and recovery in the context of antiblastic therapy.

  11. Medical interventions for treating anthracycline-induced symptomatic and asymptomatic cardiotoxicity during and after treatment for childhood cancer.

    PubMed

    Cheuk, Daniel K L; Sieswerda, Elske; van Dalen, Elvira C; Postma, Aleida; Kremer, Leontien C M

    2016-08-23

    Anthracyclines are frequently used chemotherapeutic agents for childhood cancer that can cause cardiotoxicity during and after treatment. Although several medical interventions in adults with symptomatic or asymptomatic cardiac dysfunction due to other causes are beneficial, it is not known if the same treatments are effective for childhood cancer patients and survivors with anthracycline-induced cardiotoxicity. This review is an update of a previously published Cochrane review. To compare the effect of medical interventions on anthracycline-induced cardiotoxicity in childhood cancer patients or survivors with the effect of placebo, other medical interventions, or no treatment. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2015, Issue 8), MEDLINE/PubMed (1949 to September 2015), and EMBASE/Ovid (1980 to September 2015) for potentially relevant articles. In addition, we searched reference lists of relevant articles, conference proceedings of the International Society for Paediatric Oncology (SIOP), the American Society of Clinical Oncology (ASCO), the American Society of Hematology (ASH), the International Conference on Long-Term Complications of Treatment of Children & Adolescents for Cancer, and the European Symposium on Late Complications from Childhood Cancer (from 2005 to 2015), and ongoing trial databases (the ISRCTN Register, the National Institutes of Health (NIH) Register, and the trials register of the World Health Organization (WHO); all searched in September 2015). Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing the effectiveness of medical interventions to treat anthracycline-induced cardiotoxicity with either placebo, other medical interventions, or no treatment. Two review authors independently performed the study selection. One review author performed the data extraction and 'Risk of bias' assessments, which another review author checked. We performed analyses

  12. Arsenic cardiotoxicity: An overview.

    PubMed

    Alamolhodaei, Nafiseh Sadat; Shirani, Kobra; Karimi, Gholamreza

    2015-11-01

    Arsenic, a naturally ubiquitous element, is found in foods and environment. Cardiac dysfunction is one of the major causes of morbidity and mortality in the world. Arsenic exposure is associated with various cardiopathologic effects including ischemia, arrhythmia and heart failure. Possible mechanisms of arsenic cardiotoxicity include oxidative stress, DNA fragmentation, apoptosis and functional changes of ion channels. Several evidences have shown that mitochondrial disruption, caspase activation, MAPK signaling and p53 are the pathways for arsenic induced apoptosis. Arsenic trioxide is an effective and potent antitumor agent used in patients with acute promyelocytic leukemia and produces dramatic remissions. As2O3 administration has major limitations such as T wave changes, QT prolongation and sudden death in humans. In this review, we discuss the underlying pathobiology of arsenic cardiotoxicity and provide information about cardiac health effects associated with some medicinal plants in arsenic toxicity. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. [Herbs and cardiotoxic effects].

    PubMed

    Maffè, Stefano; Paffoni, Paola; Laura Colombo, Maria; Davanzo, Franca; Dellavesa, Pierfranco; Cucchi, Lorenzo; Zenone, Franco; Paino, Anna Maria; Franchetti Pardo, Nicolò; Bergamasco, Luca; Signorotti, Fabiana; Parravicini, Umberto

    2013-06-01

    Accidental or deliberate ingestion of poisonous herbs has become an increasingly common phenomenon over the last years. From existing literature data and case reports from emergency room visits or poison control centers, an overview is presented of the potential cardiotoxic manifestations following intoxication by wild herbal plants of the territory. The effects of the consumption of cardiac glycoside-containing plants (e.g., digitalis) are discussed along with tachyarrhythmias induced by Aconitum napellus L., Atropa belladonna L., Mandragora officinarum L. or Ephedra distachya L. herbs, and hypertensive crises associated with licorice abuse. For each plant, a brief historical and botanical background is provided, focusing on pathophysiology of intoxication and cardiotoxic effects on the basis of the most recent literature. Finally, medical management of intoxication, from both a general and cardiological viewpoint, is reviewed.

  14. Tannic acid ameliorates doxorubicin-induced cardiotoxicity and potentiates its anti-cancer activity: Potential role of tannins in cancer chemotherapy

    SciTech Connect

    Tikoo, Kulbhushan Sane, Mukta Subhash; Gupta, Chanchal

    2011-03-15

    Doxorubicin, an anthracycline antibiotic, is widely used in the treatment of various solid tumors including breast cancer. However, its use is limited due to a variety of toxicities including cardiotoxicity. The present study aimed to evaluate the effect of tannic acid, a PARG/PARP inhibitor and an antioxidant, on doxorubicin-induced cardiotoxicity in H9c2 embryonic rat heart myoblasts and its anti-cancer activity in MDA-MB-231 human breast cancer cells as well as in DMBA-induced mammary tumor animals. Doxorubicin-induced cardiotoxicity was assessed by measurement of heart weight, plasma LDH level and histopathology. Bcl-2, Bax, PARP-1 and p53 expression were examined by western blotting. Our results show that tannic acid prevents activation of PARP-1, reduces Bax and increases Bcl-2 expression in H9c2 cells, thus, preventing doxorubicin-induced cell death. Further, it reduces the cell viability of MDA-MB-231 breast cancer cells, increases p53 expression in mammary tumors and shows maximum tumor volume reduction, suggesting that tannic acid potentiates the anti-cancer activity of doxorubicin. To the best of our knowledge, this is the first report which shows that tannic acid ameliorates doxorubicin-induced cardiotoxicity and potentiates its anti-cancer activity both in vitro (H9c2 and MDA-MB-231 cells) as well as in in vivo model of DMBA-induced mammary tumor animals.

  15. TCDD‑induced chick cardiotoxicity is abolished by a selective cyclooxygenase‑2 (COX‑2) inhibitor NS398.

    PubMed

    Fujisawa, Nozomi; Nakayama, Shouta M M; Ikenaka, Yoshinori; Ishizuka, Mayumi

    2014-09-01

    Halogenated aromatic hydrocarbons, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are known to cause severe heart defects in avian species. However, the mechanism of TCDD-induced chick cardiovascular toxicity is unclear. In this study, we investigated cyclooxygenase-2 (COX-2) as a possible mechanism of TCDD-induced cardiotoxicity. Fertile chicken eggs were injected with TCDD and a COX-2 selective inhibitor, NS398, and we investigated chick heart failure on day 10. We found that the chick heart to body weight ratio and atrial natriuretic factor mRNA expression were increased, but this increase was abolished with treatment of NS398. In addition, the morphological abnormality of an enlarged ventricle resulting from TCDD exposure was also abolished with co-treatment of TCDD and NS398. Our results suggested that TCDD-induced chick heart defects are mediated via the nongenomic pathway and that they do not require the genomic pathway.

  16. Ameliorative effect of parsley oil on cisplatin-induced hepato-cardiotoxicity: A biochemical, histopathological, and immunohistochemical study.

    PubMed

    Abdellatief, Suhair A; Galal, Azza A A; Farouk, Sameh M; Abdel-Daim, Mohamed M

    2017-02-01

    Cisplatin (cis-diamminedichloroplatinum, CDDP) is an effective DNA alkylating agent used in the treatment of different types of tumors; however, its clinical use is associated with hepato-cardiotoxicity. The current study was designed to assess the potential protective effect of parsley oil (PO) against CDDP-induced hepato-cardiotoxicity. For this purpose, 25 adult male rats were assigned into five groups, each containing five animals. Group I (control) was administered saline solution. Group II was administered PO at a dosage of 0.42ml/kg BW. Group III were administered CDDP at a dosage of 5mg/kg BW. Group IV was administered PO in addition to CDDP. Group V was administered saline solution in addition to CDDP, after which they were administered PO for five days. Oral administration of either saline solution or PO was performed each day for 10days, while administration of CDDP was via a single intraperitoneal injection five days following the commencement of the experiment. The recorded results revealed that CDDP induced obvious hepatic and cardiac injuries that were indicated by biochemical, histopathological, and immunohistochemical alterations, including elevation of serum hepatic and cardiac injury markers as well as proinflammatory cytokines. Moreover, CDDP induced an increase in the level of hepatic and cardiac injury biomarkers, decreases in the activities of antioxidant enzymes, a decrease in GSH concentration, and an increase in MDA concentration. CDDP also induced histopathological hepatocellular and myocardial changes, and overexpression of p53 and COX-2 in hepatic and cardiac tissues. Administration of PO either as a preventative medicine or as treatment significantly improved all the observed deleterious effects induced by CDDP in rat liver and heart. Thus, it may be concluded that PO, with its antioxidant, anti-inflammatory, and antiapoptotic activities, can potentially be used in the treatment of CDDP-induced hepatic and cardiac injuries. Copyright

  17. Development of doxorubicin-induced chronic cardiotoxicity in the B6C3F{sub 1} mouse model

    SciTech Connect

    Desai, Varsha G.; Herman, Eugene H.; Moland, Carrie L.; Branham, William S.; Lewis, Sherry M.; Davis, Kelly J.; George, Nysia I.; Lee, Taewon; Kerr, Susan; Fuscoe, James C.

    2013-01-01

    Serum levels of cardiac troponins serve as biomarkers of myocardial injury. However, troponins are released into the serum only after damage to cardiac tissue has occurred. Here, we report development of a mouse model of doxorubicin (DOX)-induced chronic cardiotoxicity to aid in the identification of predictive biomarkers of early events of cardiac tissue injury. Male B6C3F{sub 1} mice were administered intravenous DOX at 3 mg/kg body weight, or an equivalent volume of saline, once a week for 4, 6, 8, 10, 12, and 14 weeks, resulting in cumulative DOX doses of 12, 18, 24, 30, 36, and 42 mg/kg, respectively. Mice were sacrificed a week following the last dose. A significant reduction in body weight gain was observed in mice following exposure to a weekly DOX dose for 1 week and longer compared to saline-treated controls. DOX treatment also resulted in declines in red blood cell count, hemoglobin level, and hematocrit compared to saline-treated controls after the 2nd weekly dose until the 8th and 9th doses, followed by a modest recovery. All DOX-treated mice had significant elevations in cardiac troponin T concentrations in plasma compared to saline-treated controls, indicating cardiac tissue injury. Also, a dose-related increase in the severity of cardiac lesions was seen in mice exposed to 24 mg/kg DOX and higher cumulative doses. Mice treated with cumulative DOX doses of 30 mg/kg and higher showed a significant decline in heart rate, suggesting drug-induced cardiac dysfunction. Altogether, these findings demonstrate the development of DOX-induced chronic cardiotoxicity in B6C3F{sub 1} mice. -- Highlights: ► 24 mg/kg was a cumulative cardiotoxic dose of doxorubicin in male B6C3F{sub 1} mice. ► Doxorubicin-induced hematological toxicity was in association with splenomegaly. ► Doxorubicin induced severe testicular toxicity in B6C3F{sub 1} male mice.

  18. Anthracycline Cardiotoxicity: Prevalence, Pathogenesis and Treatment

    PubMed Central

    Volkova, Maria; Russell, Raymond

    2011-01-01

    Anthracyclines, such as doxorubicin and idarubicin, remain an important class of chemotherapeutic agents. Unfortunately, their efficacy in treating cancer is limited by a cumulative dose-dependent cardiotoxicity, which can cause irreversible heart failure. In this review, we discuss the pathogenesis and incidence of anthracycline-induced cardiotoxicity as well as methods to detect, prevent and treat the condition. PMID:22758622

  19. Resveratrol protects against doxorubicin-induced cardiotoxicity in aged hearts through the SIRT1-USP7 axis

    PubMed Central

    Sin, Thomas K; Tam, Bjorn T; Yung, Benjamin Y; Yip, Shea P; Chan, Lawrence W; Wong, Cesar S; Ying, Michael; Rudd, John A; Siu, Parco M

    2015-01-01

    A compromised cardiac function is often seen in elderly cancer patients receiving doxorubicin therapy. The present study tested the hypothesis that acute intervention with resveratrol, a natural anti-oxidant found in grapes and red wine, reduces the cardiotoxicity of doxorubicin through restoration of sirtuin 1 (SIRT1) deacetylase activity, and attenuation of the catabolic/apoptotic pathways orchestrated by USP7, a p53 deubiquitinating protein, using young (aged 2 months) and old (aged 10 months) senescence-accelerated mice prone 8 (SAMP8). Animals were randomised to receive saline, doxorubicin, and doxorubicin in combination with resveratrol, in the presence or absence of SIRT1 inhibitors, sirtinol or EX527. Resveratrol alone, but not in combination with either of the SIRT1 inhibitors, suppressed the doxorubicin-induced impairment of cardiac systolic function in aged animals. Doxorubicin reduced SIRT1 deacetylase activity, and elevated proteasomal activity and USP7; it also increased the protein level of p300 and ubiquitinated proteins in hearts from aged SAMP8. These doxorubicin-induced alterations were prevented by resveratrol, whereas the protective action of resveratrol was antagonised by sirtinol and EX527. In young SAMP8 hearts, resveratrol attenuated the doxorubicin-induced increases in acetylation of Foxo1 and transactivation of MuRF-1, whereas these mitigations were not found after treatment with SIRT1 inhibitors. However, the protein contents of acetylated Foxo1 and MuRF-1 were not affected by any of the drugs studied in aged SAMP8 hearts. Resveratrol also ameliorated the augmentation of pro-apoptotic markers including p53, Bax, caspase 3 activity and apoptotic DNA fragmentation induced by doxorubicin in hearts from aged animals, whereas these reductions were diminished by combined treatment with SIRT1 inhibitors. These data demonstrate that resveratrol ameliorates doxorubicin-induced cardiotoxicity in aged hearts through the restoration of SIRT1

  20. Monitoring Ionizing Radiation Exposure for Cardiotoxic Effects of Breast Cancer Treatment.

    PubMed

    Murtagh, Gillian; Yu, Zoe; Harrold, Emily; Cooke, Jennie; Keegan, Niamh; Fukuda, Shota; Addetia, Karima; Kim, Jeong Hwan; Spencer, Kirk T; Takeuchi, Masaaki; Kennedy, John; Ward, R Parker; Patel, Amit R; Lang, Roberto M; DeCara, Jeanne M

    2016-05-15

    Serial assessments of left ventricular ejection fraction (LVEF) are customary in patients with breast cancer receiving trastuzumab. Radionuclide angiography (RNA) is often used; however, a typical monitoring schedule could include 5 scans in a year. We evaluated the proportion of imaging-related ionizing radiation attributable to RNA in 115 patients with breast cancer, from 3 medical centers in the United States, Ireland, and Japan, who completed 12 months of trastuzumab treatment. Estimated radiation dose (ERD) was used to calculate exposure associated with imaging procedures spanning the 18 months before and after trastuzumab therapy. In addition, 20 cardiologists and oncologists from participating centers were surveyed for their opinions regarding the contribution of RNA to overall radiation exposure during trastuzumab treatment. When RNA was used to monitor LVEF, the mean ERD from imaging was substantial (34 ± 24.3 mSv), with the majority attributable solely to RNA (24.7 ± 14.8 mSv, 72.6%). Actual ERD associated with RNA in this population differed significantly from the perception in surveyed cardiologists and oncologists; 70% of respondents believed that RNA typically accounted for 0% to 20% of overall radiation exposure from imaging; RNA actually accounted for more than 70% of ERD. In conclusion, RNA was used to monitor LVEF in most patients in this cohort during and after trastuzumab therapy. This significantly increased ERD and accounted for a greater proportion of radiation than that perceived by surveyed physicians. ERD should be taken into account when choosing a method of LVEF surveillance. Alternative techniques that do not use radiation should be strongly considered. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Terminalia arjuna (Roxb.) Wight & Arn. augments cardioprotection via antioxidant and antiapoptotic cascade in isoproterenol induced cardiotoxicity in rats.

    PubMed

    Shukla, Santosh K; Sharma, Suman B; Singh, Usha R; Ahmad, Sayeed; Dwivedi, Shridhar

    2015-12-01

    Worldwide, Ischemic heart disease (IHD) affects a large population. Implication of myocardial infarction (MI) and its multiple pathophysiology in cardiac function is well known. Further, isoproterenol (ISP) is known to induce MI. Today, there is an urgent need for effective drug that could limit the myocardial injury. Therapeutic intervention with antioxidants has been shown useful in preventing the deleterious changes produced by ISP. Here, we investigated the protective effects of oral pre-treatment of hydroalcoholic extract of bark of Terminalia arjuna (HETA) on biochemical and apoptotic changes during cardiotoxicity induced by isoproterenol (ISP) in rats. HETA was orally administered at a dose of 100, 200 and 400 mg/kg body wt., for 30 days with concurrent administration of ISP (85 mg/kg body wt.) on days 28th and 29th at an interval of 24 h. ISP caused deleterious changes in the myocardium and significantly increased (P < 0.05) malondialdehyde, serum glutamate oxaloacitate transaminase, creatine kinase-MB, lactate dehydrogenase and troponin-I. However, it significantly decreased (P < 0.05) glutathione and superoxide dismutase compared to healthy control. Oral pre-treatment of HETA for 30 days significantly decreased (P < 0.05) the biochemical parameters of oxidative stress and cardiac markers as compared to ISP control. Histopathological findings also revealed that architecture of the myocardium was restored towards normal in HETA pre-treated group. Overall, the present study has shown that the hydroalcoholic extract of bark of T. arjuna (HETA) attenuates oxidative stress, apoptosis and improves antioxidant status in ISP-induced cardiotoxicity in rats.

  2. Scientific validation of cardioprotective attribute by standardized extract of Bombyx mori against doxorubicin-induced cardiotoxicity in murine model

    PubMed Central

    Khan, Masood S.; Singh, Mhaveer; Khan, Mohammad A.; Arya, D. S.; Ahmad, Sayeed

    2014-01-01

    Doxorubicin (DOX) is an excellent antineoplastic agent used for the treatment of hematological and solid malignancies. The aqueous extract of Bombyx mori (BMAE) contains amino acids and some flavonoids with obvious cardioprotective effect. The aim of this study was to investigate the possible protective effect of BMAE against DOX-induced cardiotoxicity and its underlying mechanisms on murine model. The metabolic profiling of BMAE was carried out by Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS) and the amino acid profiling by HPLC method using fluorescence detector (HPLC-FLD). The biochemical parameter like caspase-3, tumor necrosis factor–alpha (TNF-α), interleukin -6 (IL-6), creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH) and malondialdehyde (MDA) were studied. Tissue damage was further evaluated by histopathological studies. The metabolic profiling of BMAE exhibited presence of quercetin 7-O-ß-D-glucoside, kaempferol 7-O-ß-D-glucopyranoside, coumaric acid glucoside, 2-hydroxy-nonadecanoic acid and 9,12-dihydroxy stearic acid as important constituents. The amino acid profile by HPLC-FLD showed presence of 17 amino acids. The BMAE showed prominent free radical scavenging activity when assessed by the H2O2 and super-oxide method. The results of present investigation showed protection against DOX-induced oxidative stress (lipid peroxidation), by reverting activities of apoptotic markers (caspase-3 and TNF-α), cardiac markers (CK-MB and LDH activities) as well as pro-inflammatory marker IL-6 followed by oral administration of BMAE. In addition, results of histopathology also supported well the above results. It was observed that BMAE protects DOX-induced cardiotoxicity by virtue of its antioxidants possibly by flavonoids and amino acids. PMID:26417320

  3. Molecular Mechanisms of Cardiotoxicity Induced by ErbB Receptor Inhibitor Cancer Therapeutics

    PubMed Central

    Hervent, Anne-Sophie; De Keulenaer, Gilles W.

    2012-01-01

    The introduction of the so-called “targeted therapies”, particularly those drugs that inhibit the activity of tyrosine kinases, has represented a remarkable progress in the treatment of cancer. Although these drugs improve survival rates in cancer, significant cardiotoxicity, manifesting as left vertricular dysfunction and/or heart failure, has emerged. The ErbB receptor tyrosine kinases are being pursued as therapeutic targets because of their important roles in normal physiology and in cancer. Besides the fact that the ErbB receptors are indispensable during development and in normal adult physiology, epidermal growth factor (EGFR) and ErbB2 in particular have been implicated in the development of many human cancers. This review focuses on the rationale for targeting members of ErbB receptor family and numerous agents that are in use for inhibiting the pathway. We summarize the current knowledge on the physiological role of ErbB signaling in the ventricle and on structural aspects of ErbB receptor activation in cancer and cardiac cells. We examine the underlying mechanisms that result in on-target or off-target cardiotoxicities of ErbB inhibitors, which can influence the design of future anticancer therapies. PMID:23202898

  4. Gp130-mediated STAT3 activation by S-propargyl-cysteine, an endogenous hydrogen sulfide initiator, prevents doxorubicin-induced cardiotoxicity

    PubMed Central

    Wu, J; Guo, W; Lin, S-Z; Wang, Z-J; Kan, J-T; Chen, S-Y; Zhu, Y-Z

    2016-01-01

    Doxorubicin (Dox) could trigger a large amount of apoptotic cells in the myocardium, which leads to dilated cardiomyopathy and heart failure. S-propargyl-cysteine (SPRC), a producing agent of endogenous hydrogen sulfide (H2S), possesses cardioprotective efficacy. However, the specific effect and mechanism of SPRC in Dox-induced cardiotoxicity remain elusive. Given gp130 with its main downstream signaling molecule, signal transducer and activator of transcription 3 (STAT3), is involved in cardiac myocyte survival and growth; the present study was performed to elucidate whether SPRC counteracts Dox-induced cardiotoxicity, and if so, whether the gp130/STAT3 pathway is involved in this cardioprotective activity. SPRC stimulated the activation of STAT3 via gp130-mediated transduction tunnel in vitro and in vivo. In Dox-stimulated cardiotoxicity, SPRC enhanced cell viability, restored expression of gp130/STAT3-regulated downstream genes, inhibited apoptosis and oxidative stress, and antagonized mitochondrial dysfunction and intracellular Ca2+ overload. Intriguingly, blockade of gp130/STAT3 signaling abrogated all these beneficial capacities of SPRC. Our findings present the first piece of evidence for the therapeutic properties of SPRC in alleviating Dox cardiotoxicity, which could be attributed to the activation of gp130-mediated STAT3 signaling. This will offer a novel molecular basis and therapeutic strategy of H2S donor for the treatment of heart failure. PMID:27537522

  5. Comparison of various iron chelators used in clinical practice as protecting agents against catecholamine-induced oxidative injury and cardiotoxicity.

    PubMed

    Hašková, Pavlína; Koubková, Lucie; Vávrová, Anna; Macková, Eliška; Hrušková, Kateřina; Kovaříková, Petra; Vávrová, Kateřina; Simůnek, Tomáš

    2011-11-18

    Catecholamines are stress hormones and sympathetic neurotransmitters essential for control of cardiac function and metabolism. However, pathologically increased catecholamine levels may be cardiotoxic by mechanism that includes iron-catalyzed formation of reactive oxygen species. In this study, five iron chelators used in clinical practice were examined for their potential to protect cardiomyoblast-derived cell line H9c2 from the oxidative stress and toxicity induced by catecholamines epinephrine and isoprenaline and their oxidation products. Hydroxamate iron chelator desferrioxamine (DFO) significantly reduced oxidation of catecholamines to more toxic products and abolished redox activity of the catecholamine-iron complex at pH 7.4. However, due to its hydrophilicity and large molecule, DFO was able to protects cells only at very high and clinically unachievable concentrations. Two newer chelators, deferiprone (L1) and deferasirox (ICL670A), showed much better protective potential and were effective at one or two orders of magnitude lower concentrations as compared to DFO that were within their clinically relevant plasma levels. Ethylenediaminetetraacetic acid (EDTA), dexrazoxane (ICRF-187, clinically approved cardioprotective agent against anthracycline-induced cardiotoxicity) as well as selected beta adrenoreceptor antagonists and calcium channel blockers exerted no effect. Hence, results of the present study indicate that small, lipophilic and iron-specific chelators L1 and ICL670A can provide significant protection against the oxidative stress and cardiomyocyte damage exerted by catecholamines and/or their reactive oxidation intermediates. This potential new application of the clinically approved drugs L1 and ICL670A warrants further investigation, preferably using more complex in vivo animal models. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  6. Ginkgolide B Exerts Cardioprotective Properties against Doxorubicin-Induced Cardiotoxicity by Regulating Reactive Oxygen Species, Akt and Calcium Signaling Pathways In Vitro and In Vivo

    PubMed Central

    Zhao, Deqiang; Zheng, Jianpu; Liu, Zongjun

    2016-01-01

    The aim of this study was to evaluate the effect of Ginkgolide B (GB) on doxorubicin (DOX) induced cardiotoxicity in vitro and in vivo. Rat cardiomyocyte cell line H9c2 was pretreated with GB and subsequently subjected to doxorubicin treatment. Cell viability and cell apoptosis were assessed by MTT assay and Hoechst staining, respectively. Reactive oxygen species (ROS), Akt phosphorylation and intracellular calcium were equally determined in order to explore the underlying molecular mechanism. To verify the in vivo therapeutic effect of GB, we established a mouse model of cardiotoxicity and determined left ventricle ejection fraction (LVEF) and left ventricular mass (LVM). The in vitro experimental results indicated that pretreatment with GB significantly decreases the viability and apoptosis of H9c2 cells by decreasing ROS and intracellular calcium levels and activating Akt phosphorylation. In the in vivo study, we recorded an improved LVEF and a decreased LVM in the group of cardiotoxic rats treated with GB. Altogether, our findings anticipate that GB exerts a cardioprotective effect through possible regulation of the ROS, Akt and calcium pathways. The findings suggest that combination of GB with DOX in chemotherapy could help avoid the cardiotoxic side effects of GB. PMID:27973574

  7. The protective effect of thiamine pyrophosphate, but not thiamine, against cardiotoxicity induced with cisplatin in rats.

    PubMed

    Coskun, Resit; Turan, Mehmet Ibrahim; Turan, Isil Siltelioglu; Gulapoglu, Mine

    2014-07-01

    This study investigated the effect of thiamine pyrophosphate on oxidative damage associated with cardiotoxicity caused by cisplatin (CIS), an antineoplastic agent, in rats, and compared this with thiamine. Animals used in the study were divided into four groups of 6 rats each. These represented a control group receiving 5 mg/kg of CIS, study groups receiving 20 mg/kg of thiamine pyrophosphate plus 5 mg/kg of cisplatin (CTPG) or 20 mg/kg of thiamine plus 5 mg/kg of cisplatin and a healthy (H) group. All doses were administered intraperitoneally once a day for 14 days. Malondialdehyde, total glutathione and products of DNA injury results were similar in the CTPG and H groups (p > 0.05). Creatinine kinase, creatine kinase MB and troponin 1 levels were similar in the CTPG and H groups (p > 0.05). Thiamine pyrophosphate prevented CIS-associated oxidative stress and heart injury, whereas thiamine did not prevent these.

  8. Early Diagnosis and Prediction of Anticancer Drug-induced Cardiotoxicity: From Cardiac Imaging to "Omics" Technologies.

    PubMed

    Madonna, Rosalinda

    2017-07-01

    Heart failure due to antineoplastic therapy remains a major cause of morbidity and mortality in oncological patients. These patients often have no prior manifestation of disease. There is therefore a need for accurate identification of individuals at risk of such events before the appearance of clinical manifestations. The present article aims to provide an overview of cardiac imaging as well as new "-omics" technologies, especially with regard to genomics and proteomics as promising tools for the early detection and prediction of cardiotoxicity and individual responses to antineoplastic drugs. Copyright © 2017 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

  9. Polymeric micellar co-delivery of resveratrol and curcumin to mitigate in vitro doxorubicin-induced cardiotoxicity.

    PubMed

    Carlson, Lisa Janssen; Cote, Brianna; Alani, Adam Wg; Rao, Deepa A

    2014-08-01

    Resveratrol (RES) and curcumin (CUR) have free radical scavenging ability and potential chemosensitizing effects. Doxorubicin hydrochloride (DH) is a potent chemotherapeutic with severe cardiotoxicity. We hypothesize that RES and CUR co-loaded in Pluronic(®) micelles and co-administered with DH will result in cardioprotective effects while maintaining/improving DH anti-proliferative effect in vitro. RES-CUR at a molar ratio of 5:1 in F127 micelles (mRC) were prepared and characterized for size, drug loading, and release. In vitro cell viability and apoptosis assays in ovarian cancer cells (SKOV-3) and cardiomyocytes (H9C2) with either individual drugs or RES-CUR or mRC in combination with DH were conducted. Combination index (CI) analysis was performed to determine combination effects. Reactive oxygen species (ROS) were quantified in H9C2 for DH, and combinations. The mRC solubilized 2.96 and 0.97 mg/mL of RES and CUR, respectively. Cell viability and CI studies indicated that the combinations were synergistic in SKOV-3 and antagonistic in H9C2 cells. Caspase 3/7 activity in combination treatments was lower than with DH alone in both cell lines. ROS activity was restored to baseline in H9C2 cells in the micelle combination groups. Co-administration of mRC with DH in vitro mitigates DH-induced cardiotoxicity through reduction in apoptosis and ROS while improving DH potency in ovarian cancer cells. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

  10. Heart fatty acid-binding protein may not be an early biomarker for anthracycline-induced cardiotoxicity in rabbits.

    PubMed

    Lai, Ren-chun; Wang, Xu-dong; Zhang, Xu; Lin, Wen-qian; Rong, Tie-hua

    2012-09-01

    The objective of this study was to investigate the feasibility of using serum heart fatty acid-binding protein (H-FABP) concentrations as an early biomarker for doxorubicin-induced myocardial damage. Forty-four male rabbits were randomly divided into a control (8 rabbits) or one of four doxorubicin groups (8 rabbits in each group). Rabbits in the control group received saline, whereas rabbits in the doxorubicin group received 2 mg/kg doxorubicin weekly for 1-8 weeks. Rabbits in the doxorubicin groups received doxorubicin 2 mg/kg for one (Group 1, 8 rabbits), two (Group 2, 8 rabbits), four (Group 3, 9 rabbits), or eight (Group 4, 11 rabbits) weeks. Echocardiography was performed to measure left ventricular ejection fraction (LVEF), shortening fraction (FS), and E/A ratio. Cardiotoxicity scores were assessed by light microscopy using Billingham's method and also by electron microscopy. Serum H-FABP concentrations were quantified by a rabbit-specific enzyme-linked immunosorbent assay. Decreased LVEF, FS, and E/A ratio were detected in Group 4 (P < 0.05). Billingham cardiomyopathy scores of the rabbits in Group 3 were significantly higher (P < 0.05) than those of rabbits in the control group or Groups 1 or 2. Billingham cardiomyopathy scores in Group 4 were the highest of all groups (P < 0.05). Myocardial injury was demonstrable by electron microscopy in rabbits in Groups 2, 3, and 4. Compared with the control group, serum H-FABP concentrations increased only in Group 4 (P < 0.05). Serum H-FABP concentrations may not be a sensitive method for assessing early cardiotoxicity of doxorubicin.

  11. Resveratrol protects against doxorubicin-induced cardiotoxicity in aged hearts through the SIRT1-USP7 axis.

    PubMed

    Sin, Thomas K; Tam, Bjorn T; Yung, Benjamin Y; Yip, Shea P; Chan, Lawrence W; Wong, Cesar S; Ying, Michael; Rudd, John A; Siu, Parco M

    2015-04-15

    Doxorubicin induced functional deteriorations and elevations of USP7-related apoptotic/catabolic signalling in the senescent heart Resveratrol protects against doxorubicin-induced alterations through the restoration of SIRT1 deacetylase activity A compromised cardiac function is often seen in elderly cancer patients receiving doxorubicin therapy. The present study tested the hypothesis that acute intervention with resveratrol, a natural anti-oxidant found in grapes and red wine, reduces the cardiotoxicity of doxorubicin through restoration of sirtuin 1 (SIRT1) deacetylase activity, and attenuation of the catabolic/apoptotic pathways orchestrated by USP7, a p53 deubiquitinating protein, using young (aged 2 months) and old (aged 10 months) senescence-accelerated mice prone 8 (SAMP8). Animals were randomised to receive saline, doxorubicin, and doxorubicin in combination with resveratrol, in the presence or absence of SIRT1 inhibitors, sirtinol or EX527. Resveratrol alone, but not in combination with either of the SIRT1 inhibitors, suppressed the doxorubicin-induced impairment of cardiac systolic function in aged animals. Doxorubicin reduced SIRT1 deacetylase activity, and elevated proteasomal activity and USP7; it also increased the protein level of p300 and ubiquitinated proteins in hearts from aged SAMP8. These doxorubicin-induced alterations were prevented by resveratrol, whereas the protective action of resveratrol was antagonised by sirtinol and EX527. In young SAMP8 hearts, resveratrol attenuated the doxorubicin-induced increases in acetylation of Foxo1 and transactivation of MuRF-1, whereas these mitigations were not found after treatment with SIRT1 inhibitors. However, the protein contents of acetylated Foxo1 and MuRF-1 were not affected by any of the drugs studied in aged SAMP8 hearts. Resveratrol also ameliorated the augmentation of pro-apoptotic markers including p53, Bax, caspase 3 activity and apoptotic DNA fragmentation induced by doxorubicin in

  12. Resveratrol protects against doxorubicin-induced cardiotoxicity in aged hearts through the SIRT1-USP7 axis.

    PubMed

    Sin, Thomas K; Tam, Bjorn T; Yung, Benjamin Y; Yip, Shea P; Chan, Lawrence W; Wong, Cesar S; Ying, Michael; Rudd, John A; Siu, Parco M

    2015-01-13

    A compromised cardiac function is often seen in elderly cancer patients receiving doxorubicin therapy. The present study tested the hypothesis that acute intervention with resveratrol, a natural antioxidant found in grapes and red wine, reduces the cardiotoxicity of doxorubicin through restoration of SIRT1 deacetylase activity, and attenuation of catabolic/apoptotic pathways orchestrated by USP7, a p53 deubiquitinating protein, using young (2 month-old) and old (10 month-old) senescence-accelerated mice (prone 8; SAMP8). Animals were randomised to receive saline, doxorubicin, and doxorubicin in combination with resveratrol, in the presence or absence of SIRT1 inhibitors, sirtinol or EX527. Resveratrol alone, but not in combination with either SIRT1 inhibitors, suppressed the doxorubicin-induced impairment of cardiac systolic function in aged animals. Doxorubicin reduced SIRT1 deacetylase activity, and elevated proteasomal activity and USP7; it also increased the protein level of p300 and ubiquitinated proteins in hearts from aged SAMP8 mice. These doxorubicin-induced alterations were prevented by resveratrol, but the protective action of resveratrol was antagonised by sirtinol and EX527. In young SAMP8 hearts, resveratrol attenuated the doxorubicin-induced increase in acetylation of Foxo1 and transactivation of MuRF-1 whereas these mitigations were not found with the treatment of SIRT1 inhibitors. However, the protein content of acetylated Foxo1 and MuRF-1 were not affected by any of the drugs studied in aged SAMP8 hearts. Resveratrol also ameliorated the augmentations of pro-apoptotic markers including p53, Bax, caspase 3 activity and apoptotic DNA fragmentation induced by doxorubicin in hearts from aged animals, whereas these reductions were diminished by combined treatment with SIRT1 inhibitors. These data demonstrate that resveratrol ameliorates doxorubicin-induced cardiotoxicity in the aged hearts through the restoration of SIRT1 activity to attenuate USP7

  13. Fatty Acid Oxidation and Calcium Homeostasis are Involved in the Rescue of Bupivacaine Induced Cardiotoxicity by Lipid Emulsion in Rats

    PubMed Central

    Partownavid, Parisa; Umar, Soban; Li, Jingyuan; Rahman, Siamak; Eghbali, Mansoureh

    2012-01-01

    OBJECTIVES Lipid Emulsion (LE) has been shown to be effective in resuscitating bupivacaine-induced cardiac arrest but its mechanism of action is not clear. Here we investigated whether fatty acid oxidation is required for rescue of bupivacaine induced cardiotoxicity by LE in rats. We also compared the mitochondrial function and calcium threshold for triggering of mitochondrial permeability transition pore (mPTP) opening in bupivacaine-induced cardiac arrest before and after resuscitation with LE. DESIGN Prospective, randomized, animal study. SETTING University Research Laboratory. SUBJECTS Adult male Sprague-Dawley rats. INTERVENTIONS Asystole was achieved with a single dose of bupivacaine (10mg/kg over 20seconds, i.v.) and 20% LE infusion (5ml/kg bolus, and 0.5ml/kg/min maintenance) with cardiac massage started immediately. The rats in CVT group were pretreated with a single dose of fatty acid oxidation inhibitor CVT (0.5, 0.25, 0.125 or 0.0625mg/kg bolus i.v.) 5min prior to inducing asystole by bupivacaine overdose. Heart rate (HR), ejection fraction (EF), fractional shortening (FS), the threshold for opening of mPTP, oxygen consumption and membrane potential were measured. The values are Mean±SEM. MEASUREMENTS AND MAIN RESULTS Administration of bupivacaine resulted in asystole. ILP infusion improved the cardiac function gradually as the EF was fully recovered within 5min (EF=64±4% and FS=36±3%, n=6) and heart rate increased to 239±9 beats/min (71% recovery, n=6) within 10min. LE was only able to rescue rats pretreated with low dose of CVT (0.0625mg/kg) (HR=~181±11 beats/min at 10 min, recovery of 56%; EF=50±1%; FS=26±0.6% at 5min, n=3) but was unable to resuscitate rats pretreated with higher doses of CVT (0.5, 0.25 or 0.125mg/kg). The calcium retention capacity in response to Ca2+ overload was significantly higher in cardiac mitochondria isolated from rats resuscitated with 20% LE compared to the group that did not receive ILP after bupivacaine

  14. Use of Anionic Liposomes for the Reduction of Chronic Doxorubicin-Induced Cardiotoxicity

    NASA Astrophysics Data System (ADS)

    Forssen, Eric A.; Tokes, Zoltan A.

    1981-03-01

    Anionic liposomes containing doxorubicin were evaluated in mice for therapeutic potential in reducing the risks of chronic cardiotoxicity characteristic of long-term high-dose anthracycline therapy. Doxorubicin first was complexed to phosphatidylcholine and then entrapped in anionic vesicles. Quantitation of myocardial injury was accomplished through examination of thin sections of cardiac tissue by light microscopy. At treatment levels of either 20 or 40 mg/kg (total dose), mice receiving liposomal doxorubicin had toxicity scores indistinguishable from or only slightly greater than those of saline-treated controls. Similar total doses of free drug produced moderate to severe myocardial damage and yielded much higher toxicity scores. Mixture of free doxorubicin with empty liposomes did not alleviate cardiac toxicity, indicating that the drug must be entrapped within phospholipid vesicles for reduction in toxicity. The inhibition of body growth produced by free doxorubicin at both dose levels was also completely eliminated by encapsulation in liposomes. Doxorubicin liposomes were also tested for chemotherapeutic potential against L-1210 and P-388 murine leukemias. In all cases, treatment with liposomal doxorubicin produced increases in life-span greater than that observed for free drug. We conclude that anionic liposomes can function as efficacious carriers of doxorubicin. These vesicles possess improved therapeutic action as reflected by their ability to reduce cardiac toxicity, overcome growth inhibition, and increase antileukemic activity.

  15. BGP-15, a PARP-inhibitor, prevents imatinib-induced cardiotoxicity by activating Akt and suppressing JNK and p38 MAP kinases.

    PubMed

    Sarszegi, Zsolt; Bognar, Eszter; Gaszner, Balazs; Kónyi, Attila; Gallyas, Ferenc; Sumegi, Balazs; Berente, Zoltan

    2012-06-01

    In this study, we investigate the cardiotoxic effects of the well-known cytostatic agent imatinib mesylate (Gleevec), and presented evidence for the cardioprotective effect of BGP-15 which is a novel insulin sensitizer. The cardiotoxic effect of imatinib mesylate was assessed in Langendorff rat heart perfusion system. The cardiac high-energy phosphate levels (creatine phosphate (PCr) and ATP) were monitored in situ by (31)P NMR spectroscopy. The protein oxidation, lipid peroxidation, and the activation of signaling pathways were determined from the freeze-clamped hearts. Prolonged treatment of the heart with imatinib mesylate (20 mg/kg) resulted in cardiotoxicity, which were characterized by the depletion of high-energy phosphates (PCr and ATP), and significantly increased protein oxidation and lipid peroxidation. Imatinib mesylate treatment-induced activation of MAP kinases (including ERK1/2, p38, and JNK) and the phosphorylation of Akt and GSK-3beta. BGP-15 (200 μM) prevented the imatinib mesylate-induced oxidative damages, attenuated the depletion of high-energy phosphates, altered the signaling effect of imatinib mesylate by preventing p38 MAP kinase and JNK activation, and induced the phosphorylation of Akt and GSK-3beta. The suppressive effect of BGP-15 on p38 and JNK activation could be significant because these kinases contribute to the cell death and inflammation in the isolated perfused heart.

  16. Dendrimer-doxorubicin conjugates exhibit improved anticancer activity and reduce doxorubicin-induced cardiotoxicity in a murine hepatocellular carcinoma model

    PubMed Central

    Tiruchinapally, Gopinath; Crouch, A. Colleen; ElSayed, Mohamed E. H.; Greve, Joan M.

    2017-01-01

    Hepatocellular carcinoma (HCC) is the 2nd leading cause of cancer-related deaths every year globally. The most common form of treatment, hepatic arterial infusion (HAI), involves the direct injection of doxorubicin (DOX) into the hepatic artery. It is plagued with limited therapeutic efficacy and the occurrence of severe toxicities (e.g. cardiotoxicity). We aim to improve the therapeutic index of DOX delivered via HAI by loading the drug onto generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers targeted to hepatic cancer cells via N-acetylgalactosamine (NAcGal) ligands. DOX is attached to the surface of G5 molecules via two different enzyme-sensitive linkages, L3 or L4, to achieve controllable drug release inside hepatic cancer cells. We previously reported on P1 and P2 particles that resulted from the combination of NAcGal-targeting with L3- or L4-DOX linkages, respectively, and showed controllable DOX release and toxicity towards hepatic cancer cells comparable to free DOX. In this study, we demonstrate that while the intratumoral delivery of free DOX (1 mg/kg) into HCC-bearing nod scid gamma (NSG) mice achieves a 2.5-fold inhibition of tumor growth compared to the saline group over 30 days, P1 and P2 particles delivered at the same DOX dosage achieve a 5.1- and 4.4-fold inhibition, respectively. Incubation of the particles with human induced pluripotent stem cell derived cardiomyocytes (hiPSC CMs) showed no effect on monolayer viability, apoptosis induction, or CM electrophysiology, contrary to the effect of free DOX. Moreover, magnetic resonance imaging revealed that P1- and P2-treated mice maintained cardiac function after intraperitoneal administration of DOX at 1 mg/kg for 21 days, unlike the free DOX group at an equivalent dosage, confirming that P1/P2 can avoid DOX-induced cardiotoxicity. Taken together, these results highlight the ability of P1/P2 particles to improve the therapeutic index of DOX and offer a replacement therapy for clinical HCC treatment

  17. Dendrimer-doxorubicin conjugates exhibit improved anticancer activity and reduce doxorubicin-induced cardiotoxicity in a murine hepatocellular carcinoma model.

    PubMed

    Kuruvilla, Sibu P; Tiruchinapally, Gopinath; Crouch, A Colleen; ElSayed, Mohamed E H; Greve, Joan M

    2017-01-01

    Hepatocellular carcinoma (HCC) is the 2nd leading cause of cancer-related deaths every year globally. The most common form of treatment, hepatic arterial infusion (HAI), involves the direct injection of doxorubicin (DOX) into the hepatic artery. It is plagued with limited therapeutic efficacy and the occurrence of severe toxicities (e.g. cardiotoxicity). We aim to improve the therapeutic index of DOX delivered via HAI by loading the drug onto generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers targeted to hepatic cancer cells via N-acetylgalactosamine (NAcGal) ligands. DOX is attached to the surface of G5 molecules via two different enzyme-sensitive linkages, L3 or L4, to achieve controllable drug release inside hepatic cancer cells. We previously reported on P1 and P2 particles that resulted from the combination of NAcGal-targeting with L3- or L4-DOX linkages, respectively, and showed controllable DOX release and toxicity towards hepatic cancer cells comparable to free DOX. In this study, we demonstrate that while the intratumoral delivery of free DOX (1 mg/kg) into HCC-bearing nod scid gamma (NSG) mice achieves a 2.5-fold inhibition of tumor growth compared to the saline group over 30 days, P1 and P2 particles delivered at the same DOX dosage achieve a 5.1- and 4.4-fold inhibition, respectively. Incubation of the particles with human induced pluripotent stem cell derived cardiomyocytes (hiPSC CMs) showed no effect on monolayer viability, apoptosis induction, or CM electrophysiology, contrary to the effect of free DOX. Moreover, magnetic resonance imaging revealed that P1- and P2-treated mice maintained cardiac function after intraperitoneal administration of DOX at 1 mg/kg for 21 days, unlike the free DOX group at an equivalent dosage, confirming that P1/P2 can avoid DOX-induced cardiotoxicity. Taken together, these results highlight the ability of P1/P2 particles to improve the therapeutic index of DOX and offer a replacement therapy for clinical HCC treatment.

  18. TXNIP/TRX/NF-κB and MAPK/NF-κB pathways involved in the cardiotoxicity induced by Venenum Bufonis in rats.

    PubMed

    Bi, Qi-Rui; Hou, Jin-Jun; Qi, Peng; Ma, Chun-Hua; Feng, Rui-Hong; Yan, Bing-Peng; Wang, Jian-Wei; Shi, Xiao-Jian; Zheng, Yuan-Yuan; Wu, Wan-Ying; Guo, De-An

    2016-03-10

    Venenum Bufonis (VB) is a widely used traditional medicine with serious cardiotoxic effects. The inflammatory response has been studied to clarify the mechanism of the cardiotoxicity induced by VB for the first time. In the present study, Sprague Dawley (SD) rats, were administered VB (100, 200, and 400 mg/kg) intragastrically, experienced disturbed ECGs (lowered heart rate and elevated ST-segment), increased levels of serum indicators (creatine kinase (CK), creatine kinase isoenzyme-MB (CK-MB), alanine aminotransferase (ALT), aspartate aminotransferase (AST)) and serum interleukin (IL-6, IL-1β, TNF-α) at 2 h, 4 h, 6 h, 8 h, 24 h, and 48 h, which reflected that an inflammatory response, together with cardiotoxicity, were involved in VB-treated rats. In addition, the elevated serum level of MDA and the down-regulated SOD, CAT, GSH, and GPx levels indicated the appearance of oxidative stress in the VB-treated group. Furthermore, based on the enhanced expression levels of TXNIP, p-NF-κBp65, p-IκBα, p-IKKα, p-IKKβ, p-ERK, p-JNK, and p-P38 and the obvious myocardial degeneration, it is proposed that VB-induced cardiotoxicity may promote an inflammatory response through the TXNIP/TRX/NF-κB and MAPK/NF-κB pathways. The observed inflammatory mechanism induced by VB may provide a theoretical reference for the toxic effects and clinical application of VB.

  19. TXNIP/TRX/NF-κB and MAPK/NF-κB pathways involved in the cardiotoxicity induced by Venenum Bufonis in rats

    PubMed Central

    Bi, Qi-rui; Hou, Jin-jun; Qi, Peng; Ma, Chun-hua; Feng, Rui-hong; Yan, Bing-peng; Wang, Jian-wei; Shi, Xiao-jian; Zheng, Yuan-yuan; Wu, Wan-ying; Guo, De-an

    2016-01-01

    Venenum Bufonis (VB) is a widely used traditional medicine with serious cardiotoxic effects. The inflammatory response has been studied to clarify the mechanism of the cardiotoxicity induced by VB for the first time. In the present study, Sprague Dawley (SD) rats, were administered VB (100, 200, and 400 mg/kg) intragastrically, experienced disturbed ECGs (lowered heart rate and elevated ST-segment), increased levels of serum indicators (creatine kinase (CK), creatine kinase isoenzyme-MB (CK-MB), alanine aminotransferase (ALT), aspartate aminotransferase (AST)) and serum interleukin (IL-6, IL-1β, TNF-α) at 2 h, 4 h, 6 h, 8 h, 24 h, and 48 h, which reflected that an inflammatory response, together with cardiotoxicity, were involved in VB-treated rats. In addition, the elevated serum level of MDA and the down-regulated SOD, CAT, GSH, and GPx levels indicated the appearance of oxidative stress in the VB-treated group. Furthermore, based on the enhanced expression levels of TXNIP, p-NF-κBp65, p-IκBα, p-IKKα, p-IKKβ, p-ERK, p-JNK, and p-P38 and the obvious myocardial degeneration, it is proposed that VB-induced cardiotoxicity may promote an inflammatory response through the TXNIP/TRX/NF-κB and MAPK/NF-κB pathways. The observed inflammatory mechanism induced by VB may provide a theoretical reference for the toxic effects and clinical application of VB. PMID:26961717

  20. Changes in the levels of l-carnitine, acetyl-l-carnitine and propionyl-l-carnitine are involved in perfluorooctanoic acid induced developmental cardiotoxicity in chicken embryo.

    PubMed

    Jiang, Qixiao; Wang, Chunbo; Xue, Chan; Xue, Lingfang; Wang, Meiting; Li, Changhao; Deng, Ziwen; Wang, Qian

    2016-12-01

    Perfluorooctanoic acid (PFOA), a persistent organic pollutant, is associated with developmental toxicity. This study investigated the mechanism of PFOA-induced developmental cardiotoxicity in chicken embryo, focusing on the interactions between developmental exposure to PFOA and the levels of l-carnitine (LC), acetyl-l-carnitine (ALC) and propionyl-l-carnitine (PLC) in the heart. To evaluate the developmental cardiotoxicity, fertile chicken eggs were exposed to 0.1, 0.5, 1, 2 or 5mg/kg PFOA via air cell injection. Furthermore, exposure to 2mg/kg PFOA, with or without 100mg/kg LC were applied to investigate the effects of LC supplement. The results of functional and morphological assessments confirmed PFOA induced developmental cardiotoxicity in chicken embryo, which could be alleviated by co-exposure to LC. LC-MS/MS results also revealed remarkable decrease in LC, ALC and PLC levels in embryonic day six (ED6) chicken embryo hearts as well as LC level in embryonic day fifteen (ED15) chicken embryo hearts following developmental exposure to 2mg/kg PFOA. Meanwhile, co-exposure to 100mg/kg LC significantly elevated the levels of LC, ALC and PLC in chicken embryo hearts. Significantly elevated expression level of carnitine acetyltransferase (CRAT) in PFOA-exposed ED6 chicken embryo hearts was observed via western blotting, while LC co-exposure counteracted such changes. In conclusion, changes in the levels of LC, ALC and PLC in early embryonic stages are associated with PFOA induced developmental cardiotoxicity in chicken embryos. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Protective effect of quercetin and/or l-arginine against nano-zinc oxide-induced cardiotoxicity in rats

    NASA Astrophysics Data System (ADS)

    Faddah, L. M.; Baky, Nayira A. Abdel; Mohamed, Azza M.; Al-Rasheed, Nouf M.; Al-Rasheed, Nawal M.

    2013-04-01

    The aim of this study was to investigate the protective role of quercetin and/or l-arginine against the cardiotoxic potency of zinc oxide nanoparticle (ZnO-NP)-induced cardiac infarction. ZnO-NPs (50 nm) were administered orally at either 600 mg or 1 g/kg body weight for 5 consecutive days. The results revealed that co-administration of quercetin and/or l-arginine (each 200 mg/kg body weight) daily for 3 weeks to rats intoxicated by either of the two doses markedly ameliorated increases in serum markers of cardiac infarction, including troponin T, creatine kinase-MB, and myoglobin, as well as increases in proinflammatory biomarkers, including tumor necrosis factor-α, interleukin-6, and C-reactive protein, compared with intoxicated, untreated rats. Each agent alone or in combination also successfully modulated the alterations in serum vascular endothelial growth factor, cardiac calcium concentration, and oxidative DNA damage as well as the increase in the apoptosis marker caspase 3 of cardiac tissue in response to ZnO-NP toxicity. In conclusion, early treatment with quercetin and l-arginine may protect cardiac tissue from infarction induced by the toxic effects of ZnO-NPs.

  2. Hydroxytyrosol ameliorates oxidative stress and mitochondrial dysfunction in doxorubicin-induced cardiotoxicity in rats with breast cancer.

    PubMed

    Granados-Principal, Sergio; El-Azem, Nuri; Pamplona, Reinald; Ramirez-Tortosa, Cesar; Pulido-Moran, Mario; Vera-Ramirez, Laura; Quiles, Jose L; Sanchez-Rovira, Pedro; Naudí, Alba; Portero-Otin, Manuel; Perez-Lopez, Patricia; Ramirez-Tortosa, Mcarmen

    2014-07-01

    Oxidative stress is involved in several processes including cancer, aging and cardiovascular disease, and has been shown to potentiate the therapeutic effect of drugs such as doxorubicin. Doxorubicin causes significant cardiotoxicity characterized by marked increases in oxidative stress and mitochondrial dysfunction. Herein, we investigate whether doxorubicin-associated chronic cardiac toxicity can be ameliorated with the antioxidant hydroxytyrosol in rats with breast cancer. Thirty-six rats bearing breast tumors induced chemically were divided into 4 groups: control, hydroxytyrosol (0.5mg/kg, 5days/week), doxorubicin (1mg/kg/week), and doxorubicin plus hydroxytyrosol. Cardiac disturbances at the cellular and mitochondrial level, mitochondrial electron transport chain complexes I-IV and apoptosis-inducing factor, and oxidative stress markers have been analyzed. Hydroxytyrosol improved the cardiac disturbances enhanced by doxorubicin by significantly reducing the percentage of altered mitochondria and oxidative damage. These results suggest that hydroxytyrosol improve the mitochondrial electron transport chain. This study demonstrates that hydroxytyrosol protect rat heart damage provoked by doxorubicin decreasing oxidative damage and mitochondrial alterations.

  3. Exome array analysis identifies GPR35 as a novel susceptibility gene for anthracycline-induced cardiotoxicity in childhood cancer.

    PubMed

    Ruiz-Pinto, Sara; Pita, Guillermo; Patiño-García, Ana; Alonso, Javier; Pérez-Martínez, Antonio; Cartón, Antonio J; Gutiérrez-Larraya, Federico; Alonso, María R; Barnes, Daniel R; Dennis, Joe; Michailidou, Kyriaki; Gómez-Santos, Carmen; Thompson, Deborah J; Easton, Douglas F; Benítez, Javier; González-Neira, Anna

    2017-09-27

    Pediatric cancer survivors are a steadily growing population; however, chronic anthracycline-induced cardiotoxicity (AIC) is a serious long-term complication leading to considerable morbidity. We aimed to identify new genes and low-frequency variants influencing the susceptibility to AIC for pediatric cancer patients. We studied the association of variants on the Illumina HumanExome BeadChip array in 83 anthracycline-treated pediatric cancer patients. In addition to single-variant association tests, we carried out a gene-based analysis to investigate the combined effects of common and low-frequency variants to chronic AIC. Although no single-variant showed an association with chronic AIC that was statistically significant after correction for multiple testing, we identified a novel significant association for G protein-coupled receptor 35 (GPR35) by gene-based testing, a gene with potential roles in cardiac physiology and pathology (P=7.0×10), which remained statistically significant after correction for multiple testing (PFDR=0.03). The greatest contribution to this observed association was made by rs12468485, a missense variant (p.Thr253Met, c.758C>T, minor allele frequency=0.04), with the T allele associated with an increased risk of chronic AIC and more severe symptomatic cardiac manifestations at low anthracycline doses. Using exome array data, we identified GPR35 as a novel susceptibility gene associated with chronic AIC in pediatric cancer patients.

  4. Radiation-induced gliomas

    PubMed Central

    Prasad, Gautam; Haas-Kogan, Daphne A.

    2013-01-01

    Radiation-induced gliomas represent a relatively rare but well-characterized entity in the neuro-oncologic literature. Extensive retrospective cohort data in pediatric populations after therapeutic intracranial radiation show a clearly increased risk in glioma incidence that is both patient age- and radiation dose/volume-dependent. Data in adults are more limited but show heightened risk in certain groups exposed to radiation. In both populations, there is no evidence linking increased risk associated with routine exposure to diagnostic radiation. At the molecular level, recent studies have found distinct genetic differences between radiation-induced gliomas and their spontaneously-occurring counterparts. Clinically, there is understandable reluctance on the part of clinicians to re-treat patients due to concern for cumulative neurotoxicity. However, available data suggest that aggressive intervention can lead to improved outcomes in patients with radiation-induced gliomas. PMID:19831840

  5. Values of using QTc and N-terminal fragment of B-type natriuretic peptide as markers for early detection of acute antipsychotic drugs-induced cardiotoxicity.

    PubMed

    Khalaf, Mohamed A M; Abdelrahman, Tarek M; Abbas, Mohamed F

    2011-03-01

    We aimed at studying the acute cardiotoxicity of the most commonly used antipsychotics in Egypt using QTc interval and NT-proBNP as markers for the early detection of such cases. Eighty-two admitted patients, at El-Minia PCC (period from 1-7-2005 to 30-6-2010), were classified into 3 groups: I: acute thioridazine overdose (n = 28), II: acute pimozide overdose (n = 23), and III: acute clozapine overdose (n = 31). Patients were investigated for NT-proBNP level and QTc on admission (day 0) and after 24 h (day 1). All the studied drugs had the ability to induce cardiotoxicity in the form of hypotension and dysrhythmias. Thioridazine and pimozide had potentially serious cardiotoxic effects than clozapine. NT-proBNP levels were elevated significantly in all groups on days 0 and 1 when compared with the reference value and a significant decrease in the same parameter on day 1 when compared with that of day 0 within the same group. QTc showed a significant prolongation in all studied groups on days 0 and 1, and there was a significant shortening of QTc on day 1 when compared with that of day 0 within the same group. A significant positive correlation of NT-proBNP level elevation with QTc prolongation was reported in all groups on days 0 and 1. Serious dysrhythmias were associated with QTc prolongation greater than 500 ms. And it was concluded that NT-proBNP, in adjunction with QTc measurement, may be a valuable and sensitive laboratory biomarker to predict cardiotoxicity of antipsychotic overdose. Larger multicenter studies are still needed to verify this possible relationship.

  6. Evaluation of the Cardiotoxicity of Mitragynine and Its Analogues Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

    PubMed Central

    Wu, Jianjun; Jamil, Mohd Fadzly Amar; Tan, Mei Lan; Adenan, Mohd Ilham; Wong, Philip; Shim, Winston

    2014-01-01

    Introduction Mitragynine is a major bioactive compound of Kratom, which is derived from the leave extracts of Mitragyna speciosa Korth or Mitragyna speciosa (M. speciosa), a medicinal plant from South East Asia used legally in many countries as stimulant with opioid-like effects for the treatment of chronic pain and opioid-withdrawal symptoms. Fatal incidents with Mitragynine have been associated with cardiac arrest. In this study, we determined the cardiotoxicity of Mitragynine and other chemical constituents isolated using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Methods and Results The rapid delayed rectifier potassium current (IKr), L-type Ca2+ current (ICa,L) and action potential duration (APD) were measured by whole cell patch-clamp. The expression of KCNH2 and cytotoxicity was determined by real-time PCR and Caspase activity measurements. After significant IKr suppression by Mitragynine (10 µM) was confirmed in hERG-HEK cells, we systematically examined the effects of Mitragynine and other chemical constituents in hiPSC-CMs. Mitragynine, Paynantheine, Speciogynine and Speciociliatine, dosage-dependently (0.1∼100 µM) suppressed IKr in hiPSC-CMs by 67% ∼84% with IC50 ranged from 0.91 to 2.47 µM. Moreover, Mitragynine (10 µM) significantly prolonged APD at 50 and 90% repolarization (APD50 and APD90) (439.0±11.6 vs. 585.2±45.5 ms and 536.0±22.6 vs. 705.9±46.1 ms, respectively) and induced arrhythmia, without altering the L-type Ca2+ current. Neither the expression,and intracellular distribution of KCNH2/Kv11.1, nor the Caspase 3 activity were significantly affected by Mitragynine. Conclusions Our study indicates that Mitragynine and its analogues may potentiate Torsade de Pointes through inhibition of IKr in human cardiomyocytes. PMID:25535742

  7. Effect of pretreatment with coenzyme Q10 on isoproterenol-induced cardiotoxicity and cardiac hypertrophy in rats

    PubMed Central

    Ghule, Arvindkumar E.; Kulkarni, Chetan P.; Bodhankar, Subhash L.; Pandit, Vijaya A.

    2009-01-01

    Background: Coenzyme Q10 (CoQ10) is a lipid-soluble, vitamin-like substance found in the hydrophobic interior of the phospholipid bilayer of most cellular membranes. It appears to be involved in the coordinated regulation between oxidative stress and antioxidant capacity of heart tissue when the heart is subjected to oxidative stress in various pathogenic conditions. Objective: The objective of the present study was to investigate the effect of pretreatment with CoQ10 (100 mg/kg) on isoproterenol (ISO)-induced cardiotoxicity and cardiac hypertrophy in rats. Methods: Albino male Wistar rats (250–300 g) were evenly divided by lottery method into 1 of the following 3 groups: the ISO group (olive oil 2 mL/kg orally for 18 days and ISO 1 mg/kg IP from days 9–18); the CoQ10 + ISO group (CoQ10 100 mg/kg orally for 18 days and ISO 1 mg/kg IP from days 9–18); and the control group (olive oil 2 mL/kg orally for 18 days and water IP from days 9–18). Twenty-four hours after the last dose of water or ISO, the rats were anesthetized and an ECG was recorded. Blood was withdrawn by retro-orbital puncture for estimation of serum creatine kinase-MB (CK-MB) isoenzyme levels, lactate dehydrogenase (LDH) levels, and aspartate aminotransferase activities. The animals were euthanized using an overdose of ether. The hearts of 6 animals from each group were used for estimation of superoxide dismutase (SOD) activity, reduced glutathione (GSH) concentration, lipid peroxidation (LPO), malondialdehyde (MDA), and total protein concentration. Histopathology of the 2 remaining hearts in each group was carried out by a blinded technician. Results: A total of 24 rats (8 in each group) were used in this study; all rats survived to study end. Compared with the control group, the ISO-treated rats had a significant change in heart to body weight ratio (P < 0.001); significant changes in the endogenous antioxidants (ie, significantly higher myocardial MDA concentration [P < 0.001]; significantly

  8. The Early Predictive Value of Right Ventricular Strain in Epirubicin-Induced Cardiotoxicity in Patients with Breast Cancer

    PubMed Central

    Chang, Wei-Ting; Shih, Jhih-Yuan; Feng, Yin-Hsun; Chiang, Chun-Yen; Kuo, Yu Hsuan; Chen, Wei-Yu; Wu, Hong-Chang; Cheng, Juei-Tang; Wang, Jhi-Joung; Chen, Zhih-Cherng

    2016-01-01

    Background As cancer therapies have improved, patient life spans have been extended but quality of life has been threatened by chemotherapy induced cardiotoxicity. Most cardiac complications remain unobserved until specific symptoms develop. Speckle-tracking echocardiography is a sensitive imaging modality in detecting early occult myocardial dysfunction. Methods A total number of 35 patients newly diagnosed with breast cancer and preparing for epirubicin therapy were prospectively recruited. Echocardiography, including speckle-tracking echocardiography, was performed sequentially at baseline (T1), after the first cycle (T2) and after the third cycle (T3) of epirubicin. At each visit, the severity of dyspnea was evaluated by the assessment scale. Results Compared with the baseline, right ventricular longitudinal strain (RVLS_FW) at T2 significantly declined (-22.49 ± 4.97 vs. -18.48 ± 4.46, p = 0.001), which was also positively associated with the development of dyspnea (R2 = 0.8, p = 0.01). At T3, both the left ventricular global longitudinal strain and RVLS_FW were significantly impaired (-21.4 ± 4.12 vs. -16.94 ± 6.81%; -22.49 ± 4.97 vs. -16.86 ± 7.27%, p = 0.01; 0.001, respectively). Also, the accumulating dose of epirubicin positively correlated with the development of dyspnea (R2 = 0.38, p = 0.04) and the decline of RVLS_FW (R2 = 0.53, p = 0.02). Notably, compared with the other echocardiographic parameters only RVLS_FW at the early stage (T2) significantly correlated with the development of dyspnea (odds ratio: 1.84, 95% confidence interval: 1.22-2.78, p = 0.04). Conclusions RVLS_FW sensitively predicts dyspnea development in breast cancer patients receiving epirubicin therapy. However, larger scale studies are required to validate its role in long-term patient survival. PMID:27713603

  9. In vitro cardiotoxicity assessment of environmental chemicals using an organotypic human induced pluripotent stem cell-derived model.

    PubMed

    Sirenko, Oksana; Grimm, Fabian A; Ryan, Kristen R; Iwata, Yasuhiro; Chiu, Weihsueh A; Parham, Frederick; Wignall, Jessica A; Anson, Blake; Cromwell, Evan F; Behl, Mamta; Rusyn, Ivan; Tice, Raymond R

    2017-03-01

    An important target area for addressing data gaps through in vitro screening is the detection of potential cardiotoxicants. Despite the fact that current conservative estimates relate at least 23% of all cardiovascular disease cases to environmental exposures, the identities of the causative agents remain largely uncharacterized. Here, we evaluate the feasibility of a combinatorial in vitro/in silico screening approach for functional and mechanistic cardiotoxicity profiling of environmental hazards using a library of 69 representative environmental chemicals and drugs. Human induced pluripotent stem cell-derived cardiomyocytes were exposed in concentration-response for 30min or 24h and effects on cardiomyocyte beating and cellular and mitochondrial toxicity were assessed by kinetic measurements of intracellular Ca(2+) flux and high-content imaging using the nuclear dye Hoechst 33342, the cell viability marker Calcein AM, and the mitochondrial depolarization probe JC-10. More than half of the tested chemicals exhibited effects on cardiomyocyte beating after 30min of exposure. In contrast, after 24h, effects on cell beating without concomitant cytotoxicity were observed in about one third of the compounds. Concentration-response data for in vitro bioactivity phenotypes visualized using the Toxicological Prioritization Index (ToxPi) showed chemical class-specific clustering of environmental chemicals, including pesticides, flame retardants, and polycyclic aromatic hydrocarbons. For environmental chemicals with human exposure predictions, the activity-to-exposure ratios between modeled blood concentrations and in vitro bioactivity were between one and five orders of magnitude. These findings not only demonstrate that some ubiquitous environmental pollutants might have the potential at high exposure levels to alter cardiomyocyte function, but also indicate similarities in the mechanism of these effects both within and among chemicals and classes.

  10. Exome array analysis identifies ETFB as a novel susceptibility gene for anthracycline-induced cardiotoxicity in cancer patients.

    PubMed

    Ruiz-Pinto, Sara; Pita, Guillermo; Martín, Miguel; Alonso-Gordoa, Teresa; Barnes, Daniel R; Alonso, María R; Herraez, Belén; García-Miguel, Purificación; Alonso, Javier; Pérez-Martínez, Antonio; Cartón, Antonio J; Gutiérrez-Larraya, Federico; García-Sáenz, José A; Benítez, Javier; Easton, Douglas F; Patiño-García, Ana; González-Neira, Anna

    2017-09-14

    Anthracyclines are widely used chemotherapeutic drugs that can cause progressive and irreversible cardiac damage and fatal heart failure. Several genetic variants associated with anthracycline-induced cardiotoxicity (AIC) have been identified, but they explain only a small proportion of the interindividual differences in AIC susceptibility. In this study, we evaluated the association of low-frequency variants with risk of chronic AIC using the Illumina HumanExome BeadChip array in a discovery cohort of 61 anthracycline-treated breast cancer patients with replication in a second independent cohort of 83 anthracycline-treated pediatric cancer patients, using gene-based tests (SKAT-O). The most significant associated gene in the discovery cohort was ETFB (electron transfer flavoprotein beta subunit) involved in mitochondrial β-oxidation and ATP production (P = 4.16 × 10(-4)) and this association was replicated in an independent set of anthracycline-treated cancer patients (P = 2.81 × 10(-3)). Within ETFB, we found that the missense variant rs79338777 (p.Pro52Leu; c.155C > T) made the greatest contribution to the observed gene association and it was associated with increased risk of chronic AIC in the two cohorts separately and when combined (OR 9.00, P = 1.95 × 10(-4), 95% CI 2.83-28.6). We identified and replicated a novel gene, ETFB, strongly associated with chronic AIC independently of age at tumor onset and related to anthracycline-mediated mitochondrial dysfunction. Although experimental verification and further studies in larger patient cohorts are required to confirm our finding, we demonstrated that exome array data analysis represents a valuable strategy to identify novel genes contributing to the susceptibility to chronic AIC.

  11. Distinct influence of atypical 1,4-dihydropyridine compounds in azidothymidine-induced neuro- and cardiotoxicity in mice ex vivo.

    PubMed

    Pupure, Jolanta; Isajevs, Sergejs; Gordjushina, Valentina; Taivans, Immanuels; Rumaks, Juris; Svirskis, Simons; Kratovska, Aina; Dzirkale, Zane; Pilipenko, Jelena; Duburs, Gunars; Klusa, Vija

    2008-11-01

    This study demonstrates the effective protection by compounds of atypical 1,4-dihydropyridine (DHP) series cerebrocrast, glutapyrone and tauropyrone against neuro- and cardiotoxicity caused by the model compound azidothymidine, a well-known mitochondria-compromising anti-HIV drug. In previous in vitro experiments, we have demonstrated distinct effects of these DHP compounds to influence mitochondrial functioning. In the present in vivo experiments, DHP compounds were administered intraperitoneally in mice daily for 2 weeks, per se and in combinations with azidothymidine at doses: azidothymidine 50 mg/kg; cerebrocrast 0.1 mg/kg; glutapyrone 1 mg/kg; and tauropyrone 1 mg/kg. At the end of the experiment, mice were killed, heart and brain tissues were removed and examined ex vivo histopathologically and immunohistochemically. NF-kappaBp65 and caspase-3 were used as the markers indicating inflammatory and apoptotic events, respectively. Cerebrocrast (dicyclic structure) was the most potent DHP, which effectively reduced azidothymidine-induced overexpression of NF-kappaBp65 and caspase-3 in mouse myocardium and brain cortex. Glutapyrone per se increased the number of caspase-3-positive cells in the brain, whereas it reduced NF-kappaBp65 and caspase-3 expression in cardiac tissue caused by azidothymidine. Tauropyrone showed dual action: per se it increased caspase-3 in the brain and NF-kappaBp65 expression in the heart, but it considerably reduced these activations in azidothymidine-treated mice. This study provides the first demonstration of a distinct pharmacological action for atypical DHP compounds in cardiac and brain tissues. The dicyclic structure of cerebrocrast is considered beneficial for neuro- and cardioprotection at least in part via mitochondrial targeting and consequent regulation of inflammatory and apoptotic processes.

  12. Radiation-induced pneumothorax

    SciTech Connect

    Epstein, D.M.; Littman, P.; Gefter, W.B.; Miller, W.T.; Raney, R.B. Jr.

    1983-01-01

    Pneumothorax is an uncommon complication of radiation therapy to the chest. The proposed pathogenesis is radiation-induced fibrosis promoting subpleural bleb formation that ruptures resulting in pneumothorax. We report on two young patients with primary sarcomas without pulmonary metastases who developed spontaneous pneumothorax after irradiation. Neither patient had antecedent radiographic evidence of pulmonary fibrosis.

  13. Mung bean (Phaseolus radiatus L.) polyphenol extract attenuates aluminum-induced cardiotoxicity through an ROS-triggered Ca(2+)/JNK/NF-κB signaling pathway in rats.

    PubMed

    Cheng, Dai; Wang, Ruhua; Wang, Chunling; Hou, Lihua

    2017-02-22

    Aluminum (Al) has been linked to the development of some cardiovascular diseases and mung bean is a functional food with the ability to detoxify. We aimed to evaluate the preventive effect and possible underlying mechanisms of the mung bean polyphenol extract (MPE) on Al-induced cardiotoxicity. Control, AlCl3 (171.8 mg Al per kg body weight), MPE + AlCl3 (Al-treatment plus 200 mg MPE per kg body weight), and a group of MPE per se were used. Al intake induced a significant increase of serum CK and LDH activity and the level of Na(+), Ca(2+), malondialdehyde and advanced oxidation protein products in the AlCl3-treated rats' heart tissue. Administration of MPE significantly improved the integrity and normal ion levels of heart tissue, and attenuated oxidative damage and the accumulation of Al in Al-treated rats. MPE significantly inhibited Al-induced increase of myocardial p-JNK, cytoplasmic NF-κB, cytochrome C, and caspase-9 protein expressions. Therefore, these results showed that MPE has a cardiac protective effect against Al-induced biotoxicity through ROS-JNK and NF-κB-mediated caspase pathways. Furthermore, the stability constant for the vitexin-Al complex was analyzed (log K = log K1 + log K2 = 4.91 + 4.85 = 9.76). We found that MPE-mediated protection against Al-cardiotoxicity is connected both with MPE antioxidant and chelation properties.

  14. The role of PPAR alpha in perfluorooctanoic acid induced developmental cardiotoxicity and l-carnitine mediated protection-Results of in ovo gene silencing.

    PubMed

    Zhao, Meng; Jiang, Qixiao; Geng, Min; Zhu, Li; Xia, Yunqiu; Khanal, Aashish; Wang, Chunbo

    2017-09-14

    Perfluorooctanoic acid (PFOA) is a persistent organic pollutant. This study established an in ovo peroxisome proliferator-activated receptor alpha (PPAR alpha) silencing model in chicken embryo heart, and investigated the role of PPAR alpha in PFOA induced developmental cardiotoxicity. The in ovo silencing was achieved by introducing lentivirus expressing PPAR alpha siRNA into ED2 chicken embryo via microinjection (0.05ul/g egg weight). Transfection efficacy was confirmed by fluorescent microscopy and western blotting. To assess the developmental cardiotoxicity, cardiac function (heart rate) and morphology (right ventricular wall thickness) were measured in D1 hatchling chickens. 2mg/kg (egg weight) PFOA exposure at ED0 induced significant elevation of heart rate and thinning of right ventricular wall thickness in D1 hatchling chickens. PPAR alpha silencing did not prevent PFOA-induced elevation of heart rate; however, it did significantly increase the right ventricular wall thickness as compared to PFOA exposed animals. Meanwhile, PPAR alpha silencing did not abolish the protective effects exerted by exposure to 100mg/kg (egg weight) l-carnitine. In conclusion, PFOA-induced heart rate elevation is likely PPAR alpha independent, while the right ventricular wall thinning seems to be PPAR alpha dependent. The protective effects of l-carnitine do not require PPAR alpha. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Radiation-Induced Bioradicals

    NASA Astrophysics Data System (ADS)

    Mondelaers, Win; Lahorte, Philippe

    This chapter is part one of a review in which the production and application of radiation-induced bioradicals is discussed. Bioradicals play a pivotal role in the complex chain of processes starting with the absorption of radiation in biological materials and ending with the radiation-induced biological after-effects. The general aspects of the four consecutive stages (physical, physicochemical, chemical and biological) are discussed from an interdisciplinary point of view. The close relationship between radiation dose and track structure, induced DNA damage and cell survival or killing is treated in detail. The repair mechanisms that cells employ, to insure DNA stability following irradiation, are described. Because of their great biomedical importance tumour suppressor genes involved in radiation-induced DNA repair and in checkpoint activation will be treated briefly, together with the molecular genetics of radiosensitivity. Part two of this review will deal with modern theoretical methods and experimental instrumentation for quantitative studies in this research field. Also an extensive overview of the applications of radiation-induced bioradicals will be given. A comprehensive list of references allows further exploration of this research field, characterised in the last decade by a substantial advance, both in fundamental knowledge and in range of applications.

  16. Structural and functional screening in human induced-pluripotent stem cell-derived cardiomyocytes accurately identifies cardiotoxicity of multiple drug types

    SciTech Connect

    Doherty, Kimberly R. Talbert, Dominique R.; Trusk, Patricia B.; Moran, Diarmuid M.; Shell, Scott A.; Bacus, Sarah

    2015-05-15

    Safety pharmacology studies that evaluate new drug entities for potential cardiac liability remain a critical component of drug development. Current studies have shown that in vitro tests utilizing human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CM) may be beneficial for preclinical risk evaluation. We recently demonstrated that an in vitro multi-parameter test panel assessing overall cardiac health and function could accurately reflect the associated clinical cardiotoxicity of 4 FDA-approved targeted oncology agents using hiPS-CM. The present studies expand upon this initial observation to assess whether this in vitro screen could detect cardiotoxicity across multiple drug classes with known clinical cardiac risks. Thus, 24 drugs were examined for their effect on both structural (viability, reactive oxygen species generation, lipid formation, troponin secretion) and functional (beating activity) endpoints in hiPS-CM. Using this screen, the cardiac-safe drugs showed no effects on any of the tests in our panel. However, 16 of 18 compounds with known clinical cardiac risk showed drug-induced changes in hiPS-CM by at least one method. Moreover, when taking into account the Cmax values, these 16 compounds could be further classified depending on whether the effects were structural, functional, or both. Overall, the most sensitive test assessed cardiac beating using the xCELLigence platform (88.9%) while the structural endpoints provided additional insight into the mechanism of cardiotoxicity for several drugs. These studies show that a multi-parameter approach examining both cardiac cell health and function in hiPS-CM provides a comprehensive and robust assessment that can aid in the determination of potential cardiac liability. - Highlights: • 24 drugs were tested for cardiac liability using an in vitro multi-parameter screen. • Changes in beating activity were the most sensitive in predicting cardiac risk. • Structural effects add in

  17. Preventive Effect of Phytic Acid on Isoproterenol-Induced Cardiotoxicity in Wistar Rats

    PubMed Central

    Brindha, E.; Rajasekapandiyan, M.

    2015-01-01

    This study was aimed to evaluate the preventive role of phytic acid on membrane bound enzymes such as sodium potassium- dependent adenosine triphosphatase (Na+ /K+ ATPase), calcium-dependent adenosine triphosphatase (Ca2+ ATPase) and magnesium- dependent adenosine triphosphatase (Mg2+ ATPase) and glycoproteins such as hexose, hexosamine, fucose and sialic acid in isoproterenol (ISO)-induced myocardial infarction (MI) in rats. Male albino Wistar rats were pretreated with phytic acid (25 and 50 mg/kg, respectively) for a period of 56 days. After the treatment period, ISO (85 mg/kg) was subcutaneously injected to rats at an interval of 24 h for 2 days. ISO-induced rats showed a significant decrease in the activity of Na+ /K+ ATPase and increase in the activities of Ca2+ and Mg2+ ATPase in the heart and a significant (P<0.05) increase in the levels of glycoproteins in serum and the heart were also observed in ISO-induced rats. Pretreatment with phytic acid for a period of 56 days exhibited a significant (P<0.05) effect and altered these biochemical parameters positively in ISO-induced rats. Thus, our study shows that phytic acid has cardioprotective role in ISO-induced MI in rats.

  18. Capparis spinosa reduces Doxorubicin-induced cardio-toxicity in cardiomyoblast cells

    PubMed Central

    Mousavi, Seyed Hadi; Hosseini, Azar; Bakhtiari, Elham; Rakhshandeh, Hassan

    2016-01-01

    Objective: Doxorubicin (DOX) is an effective anticancer drug but its clinical application is limited because it induces apoptosis in cardiomyocytes and leads to permanent degenerative cardiomyopathy and heart failure possibly due to oxidative stress. Recent studies showed that Capparis spinosa (C. spinose) exhibits potent antioxidant activity. So, in this study, we explored the protective effect of hydro-alcoholic extract of C. spinosa against DOX-induced cytotoxicity in H9c2 cells. Materials and Methods: Cell viability was quantified by MTT assay. Apoptotic cells were determined using flow cytometry (sub-G1 peak) evaluation of DNA fragmentation following PI staining. Cells were cultured with 5 μM DOX for 24 hr to induce cell damage. H9c2 cells were pretreated with different concentrations (6-200 μg/ml) of C. spinosa extract for 4 hr before DOX treatment in all trials. Results: Pretreatment with 25, 50, 100 and 200 µg/ml of C. spinosa could increase the viability of H9C2 cells to 72.63±2.8% (p<0.05), 77.37±1.8% (p<0.05), 83.56±2.6% (p<0.001) and 90.9±0.5% (p<0.001) of control, respectively. Also, C. spinosa decreased apoptotic induction significantly, at the doses of 50 µg/ml (p<0.05), 100 µg/ml (p<0.01) and 200 µg/ml (p<0.001) Conclusion: Our results showed that C. spinosa could exert cardioprotective effects against DOX-induced toxicity that might be mediated via its antioxidant activity. PMID:27761417

  19. Cardioprotective effect of royal jelly on paclitaxel-induced cardio-toxicity in rats

    PubMed Central

    Malekinejad, Hassan; Ahsan, Sima; Delkhosh-Kasmaie, Fatemeh; Cheraghi, Hadi; Rezaei-Golmisheh, Ali; Janbaz-Acyabar, Hamed

    2016-01-01

    Objective(s): Paclitaxel is a potent chemotherapy agent with severe side effects, including allergic reactions, cardiovascular problems, complete hair loss, joint and muscle pain, which may limit its use and lower its efficiency. The cardioprotective effect of royal jelly was investigated on paclitaxel-induced damages. Materials and Methods: Adult male Wistar rats were divided into control and test groups (n=8). The test group was assigned into five subgroups; 4 groups, along with paclitaxel administration (7.5 mg/kg BW, weekly), received various doses of royal jelly (50, 100, and 150 mg/kg BW) for 28 consecutive days. The last group received only royal jelly at 100 mg/kg. In addition to oxidative and nitrosative stress biomarkers, the creatine kinase (CK-BM) level was also determined. To show the cardioprotective effect of royal jelly on paclitaxel-induced damages, histopathological examinations were conducted. Results: Royal jelly lowered the paclitaxel-elevated malondialdehyde and nitric oxide levels in the heart. Royal jelly could also remarkably reduce the paclitaxel-induced cardiac biomarker of creatine kinase (CK-BM) level and pathological injuries such as diffused edema, hemorrhage, congestion, hyaline exudates, and necrosis. Moreover, royal jelly administration in a dose-dependent manner resulted in a significant (P<0.05) increase in the paclitaxel-reduced total antioxidant capacity. Conclusion: Our data suggest that the paclitaxel-induced histopathological and biochemical alterations could be protected by the royal jelly administration. The cardioprotective effect of royal jelly may be related to the suppression of oxidative and nitrosative stress. PMID:27081469

  20. Sarcoendoplasmic Reticulum Ca2+ ATPase. A Critical Target in Chlorine Inhalation–Induced Cardiotoxicity

    PubMed Central

    Ahmad, Aftab; Hendry-Hofer, Tara B.; Loader, Joan E.; Claycomb, William C.; Mozziconacci, Olivier; Schöneich, Christian; Reisdorph, Nichole; Powell, Roger L.; Chandler, Joshua D.; Day, Brian J.; Veress, Livia A.; White, Carl W.

    2015-01-01

    Autopsy specimens from human victims or experimental animals that die due to acute chlorine gas exposure present features of cardiovascular pathology. We demonstrate acute chlorine inhalation–induced reduction in heart rate and oxygen saturation in rats. Chlorine inhalation elevated chlorine reactants, such as chlorotyrosine and chloramine, in blood plasma. Using heart tissue and primary cardiomyocytes, we demonstrated that acute high-concentration chlorine exposure in vivo (500 ppm for 30 min) caused decreased total ATP content and loss of sarcoendoplasmic reticulum calcium ATPase (SERCA) activity. Loss of SERCA activity was attributed to chlorination of tyrosine residues and oxidation of an important cysteine residue, cysteine-674, in SERCA, as demonstrated by immunoblots and mass spectrometry. Using cardiomyocytes, we found that chlorine-induced cell death and damage to SERCA could be decreased by thiocyanate, an important biological antioxidant, and by genetic SERCA2 overexpression. We also investigated a U.S. Food and Drug Administration–approved drug, ranolazine, used in treatment of cardiac diseases, and previously shown to stabilize SERCA in animal models of ischemia–reperfusion. Pretreatment with ranolazine or istaroxime, another SERCA activator, prevented chlorine-induced cardiomyocyte death. Further investigation of responsible mechanisms showed that ranolazine- and istaroxime-treated cells preserved mitochondrial membrane potential and ATP after chlorine exposure. Thus, these studies demonstrate a novel critical target for chlorine in the heart and identify potentially useful therapies to mitigate toxicity of acute chlorine exposure. PMID:25188881

  1. Sarcoendoplasmic reticulum Ca(2+) ATPase. A critical target in chlorine inhalation-induced cardiotoxicity.

    PubMed

    Ahmad, Shama; Ahmad, Aftab; Hendry-Hofer, Tara B; Loader, Joan E; Claycomb, William C; Mozziconacci, Olivier; Schöneich, Christian; Reisdorph, Nichole; Powell, Roger L; Chandler, Joshua D; Day, Brian J; Veress, Livia A; White, Carl W

    2015-04-01

    Autopsy specimens from human victims or experimental animals that die due to acute chlorine gas exposure present features of cardiovascular pathology. We demonstrate acute chlorine inhalation-induced reduction in heart rate and oxygen saturation in rats. Chlorine inhalation elevated chlorine reactants, such as chlorotyrosine and chloramine, in blood plasma. Using heart tissue and primary cardiomyocytes, we demonstrated that acute high-concentration chlorine exposure in vivo (500 ppm for 30 min) caused decreased total ATP content and loss of sarcoendoplasmic reticulum calcium ATPase (SERCA) activity. Loss of SERCA activity was attributed to chlorination of tyrosine residues and oxidation of an important cysteine residue, cysteine-674, in SERCA, as demonstrated by immunoblots and mass spectrometry. Using cardiomyocytes, we found that chlorine-induced cell death and damage to SERCA could be decreased by thiocyanate, an important biological antioxidant, and by genetic SERCA2 overexpression. We also investigated a U.S. Food and Drug Administration-approved drug, ranolazine, used in treatment of cardiac diseases, and previously shown to stabilize SERCA in animal models of ischemia-reperfusion. Pretreatment with ranolazine or istaroxime, another SERCA activator, prevented chlorine-induced cardiomyocyte death. Further investigation of responsible mechanisms showed that ranolazine- and istaroxime-treated cells preserved mitochondrial membrane potential and ATP after chlorine exposure. Thus, these studies demonstrate a novel critical target for chlorine in the heart and identify potentially useful therapies to mitigate toxicity of acute chlorine exposure.

  2. Noninvasive early detection of anthracycline-induced cardiotoxicity in patients with hematologic malignancies using the phased tracking method.

    PubMed

    Saito, Yoshiko; Susukida, Ikuko; Uzuka, Yoshiro; Kanai, Hiroshi

    2016-09-01

    Anthracyclines are among the most effective and widely used anticancer drugs; however, their use is limited by serious cardiotoxicity. Early detection is necessary to prevent the high mortality rate associated with heart failure (HF). We evaluated cardiac function in 142 patients using conventional echocardiography and the phased tracking method (PTM), which was measured using the minute vibration and the rapid motion components, neither of which is recognized in standard M-mode nor in tissue Doppler imaging. For systolic function comparison, we compared left ventricular ejection fraction (LVEF) in conventional echocardiography with the average velocity of ventricular septum myocytes (Vave ) in the PTM. The Vave of 12 healthy volunteers was 1.5 (m/s)/m or more. At baseline of 99 patients, there was a positive correlation between LVEF and Vave in all patients. There were no significant differences in baseline cardiac function between patients with and without HF. There was a negative correlation between the cumulative anthracycline dose and LVEF or Vave among all patients. We determined that Vave 1.5 (m/s)/m was equivalent to LVEF 60%, 1.25 (m/s)/m to 55%, and 1.0 (m/s)/m to 50%. During the follow-up period, there was a pathological decrease in LVEF (<55%) and Vave (<1.25 m/s/m) in patients with HF; decreases in Vave were detected significantly earlier than those in LVEF (P < 0.001). When Vave declined to 1.5 (m/s)/m or less, careful continuous observation and cardiac examination was required. When Vave further declined to 1.0 (m/s)/m or lower, chemotherapy was postponed or discontinued; thus, serious drug-induced cardiomyopathy was avoided in patients who did not relapse. The PTM was superior to echocardiography for early, noninvasive detection and intermediate-term monitoring of left ventricle systolic function associated with anthracycline chemotherapy, among patients with hematologic malignancies. The PTM was an effective laboratory procedure to avoid the

  3. Overexpression of CYP2J2 provides protection against doxorubicin-induced cardiotoxicity

    PubMed Central

    Zhang, Yunfang; El-Sikhry, Haitham; Chaudhary, Ketul R.; Batchu, Sri Nagarjun; Shayeganpour, Anooshirvan; Jukar, Taibeh Orujy; Bradbury, J. Alyce; Graves, Joan P.; DeGraff, Laura M.; Myers, Page; Rouse, Douglas C.; Foley, Julie; Nyska, Abraham; Zeldin, Darryl C.; Seubert, John M.

    2009-01-01

    Human cytochrome P-450 (CYP)2J2 is abundant in heart and active in biosynthesis of epoxyeicosatrienoic acids (EETs). Recently, we demonstrated that these eicosanoid products protect myocardium from ischemia-reperfusion injury. The present study utilized transgenic (Tr) mice with cardiomyocyte-specific overexpression of human CYP2J2 to investigate protection toward toxicity resulting from acute (0, 5, or 15 mg/kg daily for 3 days, followed by 24-h recovery) or chronic (0, 1.5, or 3.0 mg/kg biweekly for 5 wk, followed by 2-wk recovery) doxorubicin (Dox) administration. Acute treatment resulted in marked elevations of serum lactate dehydrogenase and creatine kinase levels that were significantly greater in wild-type (WT) than CYP2J2 Tr mice. Acute treatment also resulted in less activation of stress response enzymes in CYP2J2 Tr mice (catalase 750% vs. 300% of baseline, caspase-3 235% vs. 165% of baseline in WT vs. CYP2J2 Tr mice). Moreover, CYP2J2 Tr hearts exhibited less Dox-induced cardiomyocytes apoptosis (measured by TUNEL) compared with WT hearts. After chronic treatment, comparable decreases in body weight were observed in WT and CYP2J2 Tr mice. However, cardiac function, assessed by measurement of fractional shortening with M-mode transthoracic echocardiography, was significantly higher in CYP2J2 Tr than WT hearts after chronic Dox treatment (WT 37 ± 2%, CYP2J2 Tr 47 ± 1%). WT mice also had larger increases in β-myosin heavy chain and cardiac ankryin repeat protein compared with CYP2J2 Tr mice. CYP2J2 Tr hearts had a significantly higher rate of Dox metabolism than WT hearts (2.2 ± 0.25 vs. 1.6 ± 0.50 ng·min−1·100 μg protein−1). In vitro data from H9c2 cells demonstrated that EETs attenuated Dox-induced mitochondrial damage. Together, these data suggest that cardiac-specific overexpression of CYP2J2 limited Dox-induced toxicity. PMID:19429816

  4. Taurine zinc solid dispersions attenuate doxorubicin-induced hepatotoxicity and cardiotoxicity in rats.

    PubMed

    Wang, Yu; Mei, Xueting; Yuan, Jingquan; Lu, Wenping; Li, Binglong; Xu, Donghui

    2015-11-15

    The clinical efficacy of anthracycline anti-neoplastic agents is limited by cardiac and hepatic toxicities. The aim of this study was to assess the hepatoprotective and cardioprotective effects of taurine zinc solid dispersions, which is a newly-synthesized taurine zinc compound, against doxorubicin-induced toxicity in Sprague-Dawley rats intraperitoneally injected with doxorubicin hydrochloride (3mg/kg) three times a week (seven injections) over 28 days. Hemodynamic parameters, levels of liver toxicity markers and oxidative stress were assessed. Taurine zinc significantly attenuated the reductions in blood pressure, left ventricular pressure and ± dp/dtmax, increases in serum alanine aminotransferase and aspartate aminotransferase activities, and reductions in serum Zn(2+) and albumin levels (P<0.05 or 0.01) induced by doxorubicin. In rats treated with doxorubicin, taurine zinc dose-dependently increased liver superoxide dismutase activity and glutathione concentration, and decreased malondialdehyde level (P<0.01). qBase(+) was used to evaluate the stability of eight candidate reference genes for real-time quantitative reverse-transcription PCR. Taurine zinc dose-dependently increased liver heme oxygenase-1 and UDP-glucuronyl transferase mRNA and protein expression (P<0.01). Western blotting demonstrated that taurine zinc inhibited c-Jun N-terminal kinase phosphorylation by upregulating dual-specificity phosphoprotein phosphatase-1. Additionally, taurine zinc inhibited cardiomyocyte apoptosis as there was decreased TUNEL/DAPI positivity and protein expression of caspase-3. These results indicate that taurine zinc solid dispersions prevent the side-effects of anthracycline-based anticancer therapy. The mechanisms might be associated with the enhancement of antioxidant defense system partly through activating transcription to synthesize endogenous phase II medicine enzymes and anti-apoptosis through inhibiting JNK phosphorylation. Copyright © 2015 Elsevier Inc

  5. Identification of protein targets underlying dietary nitrate-induced protection against doxorubicin cardiotoxicity.

    PubMed

    Xi, Lei; Zhu, Shu-Guang; Hobbs, Daniel C; Kukreja, Rakesh C

    2011-11-01

    We recently demonstrated protective effect of chronic oral nitrate supplementation against cardiomyopathy caused by doxorubicin (DOX), a highly effective anticancer drug. The present study was designed to identify novel protein targets related to nitrate-induced cardioprotection. Adult male CF-1 mice received cardioprotective regimen of nitrate (1 g NaNO(3) per litre of drinking water) for 7 days before DOX injection (15 mg/kg, i.p.) and continued for 5 days after DOX treatment. Subsequently the heart samples were collected for proteomic analysis with two-dimensional differential in-gel electrophoresis with 3 CyDye labelling. Using 1.5 cut-off ratio, we identified 36 proteins that were up-regulated by DOX in which 32 were completely reversed by nitrate supplementation (89%). Among 19 proteins down-regulated by DOX, 9 were fully normalized by nitrate (47%). The protein spots were further identified with Matrix Assisted Laser Desorption/Ionization-Time-of-Flight (MALDI-TOF)/TOF tandem mass spectrometry. Three mitochondrial antioxidant enzymes were altered by DOX, i.e. up-regulation of manganese superoxide dismutase and peroxiredoxin 3 (Prx3), and down-regulation of Prx5, which were reversed by nitrate. These results were further confirmed by Western blots. Nitrate supplementation also significantly improved animal survival rate from 80% in DOX alone group to 93% in Nitrate + DOX group 5 days after the DOX treatment. In conclusion, the proteomic analysis has identified novel protein targets underlying nitrate-induced cardioprotection. Up-regulation of Prx5 by nitrate may explain the observed enhancement of cardiac antioxidant defence by nitrate supplementation.

  6. A Novel Angiotensin Type I Receptor Antagonist, Fimasartan, Prevents Doxorubicin-induced Cardiotoxicity in Rats.

    PubMed

    Chang, Sung-A; Lim, Byung-Kwan; Lee, You Jung; Hong, Mi-Kyung; Choi, Jin-Oh; Jeon, Eun-Seok

    2015-05-01

    Angiotensin receptor blockers (ARBs) have organ-protective effects in heart failure and may be also effective in doxorubicin-induced cardiomyopathy (DOX-CMP); however, the efficacy of ARBs on the prevention of DOX-CMP have not been investigated. We performed a preclinical experiment to evaluate the preventive effect of a novel ARB, fimasartan, in DOX-CMP. All animals underwent echocardiography and were randomly assigned into three groups: treated daily with vehicle (DOX-only group, n=22), 5 mg/kg of fimasartan (Low-fima group, n=22), and 10 mg/kg of fimasartan (High-fima group, n=19). DOX was injected once a week for six weeks. Echocardiography and hemodynamic assessment was performed at the 8th week using a miniaturized conductance catheter. Survival rate of the High-fima group was greater (100%) than that of the Low-fima (75%) and DOX-only groups (50%). Echocardiography showed preserved left ventricular (LV) ejection fraction in the High-fima group, but not in the DOX-only group (P=0.002). LV dimensions increased in the DOX-only group; however, remodeling was attenuated in the Low-fima and High-fima groups. Hemodynamic assessment showed higher dP/dt in the High-fima group compared with the DOX-only group. A novel ARB, fimasartan, may prevent DOX-CMP and improve survival rate in a dose-dependent manner in a rat model of DOX-CMP and could be a treatment option for the prevention of DOX-CMP.

  7. Radiation-Induced Bioradicals

    NASA Astrophysics Data System (ADS)

    Lahorte, Philippe; Mondelaers, Wim

    This chapter represents the second part of a review in which the production and application of radiation-induced radicals in biological matter are discussed. In part one the general aspects of the four stages (physical, physicochemical, chemical and biological) of interaction of radiation with matter in general and biological matter in particular, were discussed. Here an overview is presented of modem technologies and theoretical methods available for studying these radiation effects. The relevance is highlighted of electron paramagnetic resonance spectroscopy and quantum chemical calculations with respect to obtaining structural information on bioradicals, and a survey is given of the research studies in this field. We also discuss some basic aspects of modem accelerator technologies which can be used for creating radicals and we conclude with an overview of applications of radiation processing in biology and related fields such as biomedical and environmental engineering, food technology, medicine and pharmacy.

  8. A novel pre-clinical strategy for identifying cardiotoxic kinase inhibitors and mechanisms of cardiotoxicity

    PubMed Central

    Cheng, Hui; Kari, Gabor; Dicker, Adam P; Rodeck, Ulrich; Koch, Walter J; Force, Thomas

    2011-01-01

    Rationale 1) Despite intense interest in strategies to predict which kinase inhibitor (KI) cancer therapeutics may be associated with cardiotoxicity, current approaches are inadequate. 2) Sorafenib is a KI of concern since it inhibits growth factor receptors and Raf-1/B-Raf, kinases that are upstream of ERKs and signal cardiomyocyte survival in the setting of stress. Objectives 1) Explore the potential use of zebrafish as a pre-clinical model to predict cardiotoxicity. 2) Determine whether sorafenib has associated cardiotoxicity and, if so, define the mechanisms. Methods and Results We find that the zebrafish model is readily able to discriminate a KI with little or no cardiotoxicity (gefitinib) from one with demonstrated cardiotoxicity (sunitinib). Sorafenib, like sunitinib, leads to cardiomyocyte apoptosis, a reduction in total myocyte number per heart, contractile dysfunction and ventricular dilatation in zebrafish. In cultured rat cardiomyocytes, sorafenib induces cell death. This can be rescued by adenovirus-mediated gene transfer of constitutively active MEK1 which restores ERK activity even in the presence of sorafenib. While growth factor-induced activation of ERKs requires Raf, α-adrenergic agonist-induced activation of ERKs does not. Consequently, activation of α-adrenergic signaling markedly decreases sorafenib-induced cell death. Consistent with these in vitro data, inhibition of α-adrenergic signaling with the receptor antagonist prazosin worsens sorafenib-induced cardiomyopathy in zebrafish. Conclusions 1) Zebrafish may be a valuable pre-clinical tool to predict cardiotoxicity. 2) The α-adrenergic signaling pathway is an important modulator of sorafenib cardiotoxicity in vitro and in vivo and appears to act via a here-to-fore unrecognized signaling pathway downstream of α-adrenergic activation that bypasses Raf to activate ERKs. PMID:21998323

  9. Comparison of cardiac troponin I and T, including the evaluation of an ultrasensitive assay, as indicators of doxorubicin-induced cardiotoxicity.

    PubMed

    Reagan, William J; York, Malcolm; Berridge, Brian; Schultze, Eric; Walker, Dana; Pettit, Syril

    2013-01-01

    Cardiac troponin (cTn) has been utilized to assess acute myocardial injury, but the cTn response in active/ongoing chronic injury is not well documented. The purpose of this study was to characterize the cardiac troponin I (cTnI), cardiac troponin T (cTnT), high-sensitivity cTnI, hematology, and clinical chemistry responses in rats treated with doxorubicin. Rats treated with 1, 2, or 3 mg/kg/week (wk) of doxorubicin for 2, 4, or 6 wks were sacrificed after 0, 2, or 4 wks of recovery and compared to untreated controls and animals treated with doxorubicin/dexrazoxane (50 mg/kg/wk) or etoposide (1 and 3 mg/kg/wk). The incidence and mean magnitude of cTn response increased with increasing dose and/or duration of doxorubicin treatment. Conversely, dexrazoxane/doxorubicin was partially protective for cardiotoxicity, and minimal cardiotoxicity occurred with etoposide treatment. Both cTnI and cTnT effectively identified doxorubicin-induced injury as indicated by vacuolation of cardiomyocytes of the atria/ventricles. The association between the cTn responses and histological changes was greater at the higher total exposures, but the magnitude of cTn response did not match closely with histologic grade. The high-sensitivity cTnI assay was also effective in identifying cardiac injury. Alterations occurred in the hematology and clinical chemistry parameters and reflected both dose and duration of doxorubicin treatment.

  10. Resveratrol prevents doxorubicin-induced cardiotoxicity in H9c2 cells through the inhibition of endoplasmic reticulum stress and the activation of the Sirt1 pathway.

    PubMed

    Lou, Yu; Wang, Zhen; Xu, Yi; Zhou, Ping; Cao, Junxian; Li, Yuanshi; Chen, Yeping; Sun, Junfeng; Fu, Lu

    2015-09-01

    Treatment with doxorubicin (DOX) is one of the major causes of chemotherapy-induced cardiotoxicity and is therefore, the principal limiting factor in the effectiveness of chemotherapy for cancer patients. DOX‑induced heart failure is thought to result from endoplasmic reticulum (ER) stress and cardiomyocyte apoptosis. Resveratrol (RV), a polyphenol antioxidant found in red wine, has been shown to play a cardioprotective role. The aim of the present study was to examine the effects of RV on DOX‑induced cardiotoxicity in H9c2 cells. We hypothesized that RV would protect H9c2 cells against DOX‑induced ER stress and subsequent cell death through the activation of the Sirt1 pathway. Our results demonstrated that the decrease observed in the viability of the H9c2 cells following exposure to DOX was accompanied by a significant increase in the expression of the ER stress‑related proteins, glucose‑regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP). However, we found that RV downregulated the expression of ER stress marker protein in the presence of DOX and restored the viability of the H9c2 cells. Exposure to RV or DOX alone only slightly increased the protein expression of Sirt1, whereas a significant increase in Sirt1 protein levels was observed in the cells treated with both RV and DOX. The Sirt1 inhibitor, nicotinamide (NIC), partially neutralized the effects of RV on the expression of Sirt1 in the DOX‑treated cells and completely abolished the effects of RV on the expression of GRP78 and CHOP. The findings of our study suggest that RV protects H9c2 cells against DOX‑induced ER stress through ER stabilization, and more specifically through the activation of the Sirt1 pathway, thereby leading to cardiac cell survival.

  11. The Roles of Reactive Oxygen Species and Nitric Oxide in Perfluorooctanoic Acid-Induced Developmental Cardiotoxicity and l-Carnitine Mediated Protection

    PubMed Central

    Zhao, Meng; Jiang, Qixiao; Wang, Wencheng; Geng, Min; Wang, Meng; Han, Yantao; Wang, Chunbo

    2017-01-01

    Perfluorooctanoic acid (PFOA) is an environmental contaminant that could induce developmental cardiotoxicity in a chicken embryo, which may be alleviated by l-carnitine. To explore the roles of reactive oxygen species (ROS) and nitric oxide (NO) in such changes and the potential effects of l-carnitine, fertile chicken eggs were exposed to PFOA via an air cell injection, with or without l-carnitine co-treatment. The ROS and NO levels in chicken embryo hearts were determined with electron spin resonance (ESR), and the protein levels of the nuclear factor κ-light chain-enhancer of activated B cells (NF-κB) p65 and inducible nitric oxide synthase (iNOS) in chicken embryo hearts were assessed with western blotting. The results of ESR indicated that PFOA exposure induced an elevation in the ROS levels in ED19 chicken embryo hearts and hatchling chicken hearts, while l-carnitine could alleviate such changes. Meanwhile, increased NO levels were observed in ED19 embryo hearts and hatchling hearts following PFOA exposure, while l-carnitine co-treatment exerted modulatory effects. Western blotting revealed that p65 translocation in ED19 embryo hearts and hatchling hearts was enhanced by PFOA, while l-carnitine co-treatment alleviated such changes. iNOS expression levels in ED19 embryo hearts followed the same pattern as NO levels, while a suppression of expression was observed in hatchling hearts exposed to PFOA. ROS/NF-κB p65 and iNOS/NO seem to be involved in the late stage (ED19 and post hatch) of PFOA-induced developmental cardiotoxicity in a chicken embryo. l-carnitine could exert anti-oxidant and NO modulatory effects in the developing chicken embryo hearts, which likely contribute to its cardioprotective effects. PMID:28594376

  12. The Roles of Reactive Oxygen Species and Nitric Oxide in Perfluorooctanoic Acid-Induced Developmental Cardiotoxicity and l-Carnitine Mediated Protection.

    PubMed

    Zhao, Meng; Jiang, Qixiao; Wang, Wencheng; Geng, Min; Wang, Meng; Han, Yantao; Wang, Chunbo

    2017-06-08

    Perfluorooctanoic acid (PFOA) is an environmental contaminant that could induce developmental cardiotoxicity in a chicken embryo, which may be alleviated by l-carnitine. To explore the roles of reactive oxygen species (ROS) and nitric oxide (NO) in such changes and the potential effects of l-carnitine, fertile chicken eggs were exposed to PFOA via an air cell injection, with or without l-carnitine co-treatment. The ROS and NO levels in chicken embryo hearts were determined with electron spin resonance (ESR), and the protein levels of the nuclear factor κ-light chain-enhancer of activated B cells (NF-κB) p65 and inducible nitric oxide synthase (iNOS) in chicken embryo hearts were assessed with western blotting. The results of ESR indicated that PFOA exposure induced an elevation in the ROS levels in ED19 chicken embryo hearts and hatchling chicken hearts, while l-carnitine could alleviate such changes. Meanwhile, increased NO levels were observed in ED19 embryo hearts and hatchling hearts following PFOA exposure, while l-carnitine co-treatment exerted modulatory effects. Western blotting revealed that p65 translocation in ED19 embryo hearts and hatchling hearts was enhanced by PFOA, while l-carnitine co-treatment alleviated such changes. iNOS expression levels in ED19 embryo hearts followed the same pattern as NO levels, while a suppression of expression was observed in hatchling hearts exposed to PFOA. ROS/NF-κB p65 and iNOS/NO seem to be involved in the late stage (ED19 and post hatch) of PFOA-induced developmental cardiotoxicity in a chicken embryo. l-carnitine could exert anti-oxidant and NO modulatory effects in the developing chicken embryo hearts, which likely contribute to its cardioprotective effects.

  13. [Early cardiotoxicity of Hydroxychloroquine].

    PubMed

    Zerbib, Y; Guillaumont, M P; Touati, G; Duhaut, P; Schmidt, J

    2016-03-01

    Hydroxychloroquine (HCQ) is most frequently used in the treatment of systemic inflammatory diseases. Cardiac complications of anti-malarial drugs are uncommon, and most of the time are the result of a long-term exposition. In this case, cardiotoxicity is the consequence of the lysosomal dysfunction and the result of intracytoplasmic granular material inclusions. We report a 77-year-old woman who presented a very early and reversible cardiotoxicity, probably related to the quinidine like effect of the HCQ, 10 days after initiation of therapy for Whipple endocarditis. We discuss the different mechanisms of cardiotoxicity of anti-malarial drugs and their clinical manifestations. Copyright © 2015 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  14. Radiation Induced Oral Mucositis

    PubMed Central

    PS, Satheesh Kumar; Balan, Anita; Sankar, Arun; Bose, Tinky

    2009-01-01

    Patients receiving radiotherapy or chemotherapy will receive some degree of oral mucositis The incidence of oral mucositis was especially high in patients: (i) With primary tumors in the oral cavity, oropharynx, or nasopharynx; (ii) who also received concomitant chemotherapy; (iii) who received a total dose over 5,000 cGy; and (iv) who were treated with altered fractionation radiation schedules. Radiation-induced oral mucositis affects the quality of life of the patients and the family concerned. The present day management of oral mucositis is mostly palliative and or supportive care. The newer guidelines are suggesting Palifermin, which is the first active mucositis drug as well as Amifostine, for radiation protection and cryotherapy. The current management should focus more on palliative measures, such as pain management, nutritional support, and maintenance, of good oral hygiene PMID:20668585

  15. Radiation-induced schwannomas

    SciTech Connect

    Rubinstein, A.B.; Reichenthal, E.; Borohov, H.

    1989-06-01

    The histopathology and clinical course of three patients with schwannomas of the brain and high cervical cord after therapeutic irradiation for intracranial malignancy and for ringworm of the scalp are described. Earlier reports in the literature indicated that radiation of the scalp may induce tumors in the head and neck. It is therefore suggested that therapeutic irradiation in these instances was a causative factor in the genesis of these tumors.

  16. Radiation Induced Genomic Instability

    SciTech Connect

    Morgan, William F.

    2011-03-01

    Radiation induced genomic instability can be observed in the progeny of irradiated cells multiple generations after irradiation of parental cells. The phenotype is well established both in vivo (Morgan 2003) and in vitro (Morgan 2003), and may be critical in radiation carcinogenesis (Little 2000, Huang et al. 2003). Instability can be induced by both the deposition of energy in irradiated cells as well as by signals transmitted by irradiated (targeted) cells to non-irradiated (non-targeted) cells (Kadhim et al. 1992, Lorimore et al. 1998). Thus both targeted and non-targeted cells can pass on the legacy of radiation to their progeny. However the radiation induced events and cellular processes that respond to both targeted and non-targeted radiation effects that lead to the unstable phenotype remain elusive. The cell system we have used to study radiation induced genomic instability utilizes human hamster GM10115 cells. These cells have a single copy of human chromosome 4 in a background of hamster chromosomes. Instability is evaluated in the clonal progeny of irradiated cells and a clone is considered unstable if it contains three or more metaphase sub-populations involving unique rearrangements of the human chromosome (Marder and Morgan 1993). Many of these unstable clones have been maintained in culture for many years and have been extensively characterized. As initially described by Clutton et al., (Clutton et al. 1996) many of our unstable clones exhibit persistently elevated levels of reactive oxygen species (Limoli et al. 2003), which appear to be due dysfunctional mitochondria (Kim et al. 2006, Kim et al. 2006). Interestingly, but perhaps not surprisingly, our unstable clones do not demonstrate a “mutator phenotype” (Limoli et al. 1997), but they do continue to rearrange their genomes for many years. The limiting factor with this system is the target – the human chromosome. While some clones demonstrate amplification of this chromosome and thus lend

  17. Myricitrin Protects against Doxorubicin-Induced Cardiotoxicity by Counteracting Oxidative Stress and Inhibiting Mitochondrial Apoptosis via ERK/P53 Pathway

    PubMed Central

    Meng, Xiangbao; Qin, Meng

    2016-01-01

    Doxorubicin (Dox) is one of the most effective and widely used anthracycline antineoplastic antibiotics. Unfortunately, the use of Dox is limited by its cumulative and dose-dependent cardiac toxicity. Myricitrin, a natural flavonoid which is isolated from the ground bark of Myrica rubra, has recently been found to have a strong antioxidative effect. This study aimed to evaluate the possible protective effect of myricitrin against Dox-induced cardiotoxicity and the underlying mechanisms. An in vivo investigation in SD rats demonstrated that myricitrin significantly reduced the Dox-induced myocardial damage, as indicated by the decreases in the cardiac index, amelioration of heart pathological injuries, and decreases in the serum cardiac enzyme levels. In addition, in vitro studies showed that myricitrin effectively reduced the Dox-induced cell toxicity. Further study showed that myricitrin exerted its function by counteracting oxidative stress and increasing the activities of antioxidant enzymes. Moreover, myricitrin suppressed the myocardial apoptosis induced by Dox, as indicated by decreases in the activation of caspase-3 and the numbers of TUNEL-positive cells, maintenance of the mitochondrial membrane potential, and increase in the Bcl-2/Bax ratio. Further mechanism study revealed that myricitrin-induced suppression of myocardial apoptosis relied on the ERK/p53-mediated mitochondrial apoptosis pathway. PMID:27703489

  18. Acute doxorubicin cardiotoxicity is associated with miR-146a-induced inhibition of the neuregulin-ErbB pathway

    PubMed Central

    Horie, Takahiro; Ono, Koh; Nishi, Hitoo; Nagao, Kazuya; Kinoshita, Minako; Watanabe, Shin; Kuwabara, Yasuhide; Nakashima, Yasuhiro; Takanabe-Mori, Rieko; Nishi, Eiichiro; Hasegawa, Koji; Kita, Toru; Kimura, Takeshi

    2010-01-01

    Aims A significant increase in congestive heart failure (CHF) was reported when the anti-ErbB2 antibody trastuzumab was used in combination with the chemotherapy drug doxorubicin (Dox). The aim of the present study was to investigate the role(s) of miRNAs in acute Dox-induced cardiotoxicity. Methods and results Neuregulin-1-ErbB signalling is essential for maintaining adult cardiac function. We found a significant reduction in ErbB4 expression in the hearts of mice after Dox treatment. Because the proteasome pathway was only partially involved in the reduction of ErbB4 expression, we examined the involvement of microRNAs (miRs) in the reduction of ErbB4 expression. miR-146a was shown to be up-regulated by Dox in neonatal rat cardiac myocytes. Using a luciferase reporter assay and overexpression of miR-146a, we confirmed that miR-146a targets the ErbB4 3′UTR. After Dox treatment, overexpression of miR-146a, as well as that of siRNA against ErbB4, induced cell death in cardiomyocytes. Re-expression of ErbB4 in miR-146a-overexpressing cardiomyocytes ameliorated Dox-induced cell death. To examine the loss of miR-146a function, we constructed ‘decoy’ genes that had tandem complementary sequences for miR-146a in the 3′UTR of a luciferase gene. When miR-146a ‘decoy’ genes were introduced into cardiomyocytes, ErbB4 expression was up-regulated and Dox-induced cell death was reduced. Conclusion These findings suggested that the up-regulation of miR-146a after Dox treatment is involved in acute Dox-induced cardiotoxicity by targeting ErbB4. Inhibition of both ErbB2 and ErbB4 signalling may be one of the reasons why those patients who receive concurrent therapy with Dox and trastuzumab suffer from CHF. PMID:20495188

  19. Heart disease induced by AAS abuse, using experimental mice/rats models and the role of exercise-induced cardiotoxicity.

    PubMed

    Riezzo, I; De Carlo, D; Neri, M; Nieddu, A; Turillazzi, E; Fineschi, V

    2011-05-01

    The anabolic-androgenic steroids (AAS) are all synthetic derivates of testosterone and are commonly used as sport performance enhancers in athletes. The heart is one of the organs most frequently affected by administration of anabolic steroids. A direct myocardial injury caused by AAS is supposed to determine marked hypertrophy in myocardial cells, extensive regional fibrosis and necrosis. A number of excellent studies, using animal models, were performed to evaluate the cardiac effects of AAS. It is known that exogenous administration induced cardiac hypertrophy in vitro and in vivo, and when combined with exercise, anabolic steroid use has been shown to change exercise-induced physiological cardiac hypertrophy to pathophysiological cardiac hypertrophy. However the molecular mechanisms are still poorly understood. It's described that sudden cardiac death, myocardial infarct; ventricular remodelling and cardiomyopathy do to AAS is related to apoptosis and oxidative stress when associated with exercise. Mechanical stimuli and circulating humoral factors (TNF-α, HSP-70, IL-1β) released by the heart and peripheral organs are responsible. Testosterone and derivates can work through genomic (activation of specific androgen receptor, interaction with coactivators and co-repressors transcription factors, gene regulation) and non-genomic mechanism (membrane-receptor-second messenger cascades). Chronic AAS abuse results in different patterns of pathologic alterations, which depend on type, dose, frequency, and mode of use. The difficulty in interpreting experimental data on animals (mice and rats) lies in the diversity of experiments (the diversity of substances, which show different properties, different mice / rats by sex and age, duration of treatment with AAS, dosages used, type, scope and exercise duration).

  20. Predicting and preventing the cardiotoxicity of cancer therapy.

    PubMed

    Anderson, Brent; Sawyer, Douglas B

    2008-08-01

    For the past 40 years, cardiovascular disease and malignant neoplasms have been the leading causes of death in the USA. As treatments for cancer, cardiovascular disease, diabetes and other chronic illnesses improve, we are seeing more complicated patients in our clinics. Cancer therapies such as anthracyclines and radiation therapy continue to pose a risk for delayed-onset cardiovascular disease, in spite of decades of research. It has been reported that the risk of congestive heart failure is the second most common, late, long-term disabling health condition among cancer survivors. Improved understanding of an individual's risk for cardiovascular complications of these therapies and earlier intervention for selected patients may help to improve the overall outcome for patients requiring these therapies. New therapies targeting oncogenes and the process of angiogenesis have 'off-target' effects regarding the cardiovascular system that remain poorly understood. Our knowledge and experience in the cardiovascular care of patients with cancer must continue to grow if we are to assure the best possible outcome for these people. The aim of this review is to highlight the risk of chemotherapy-induced cardiotoxicity among several of the most commonly used cancer therapies, various ways to screen for patients at highest risk of cardiotoxicity and management of cardiac complications of cancer therapy. We spend a disproportionate amount of space and time on the subject of anthracycline toxicity due to its often devastating nature, and its persistence as a clinical problem despite decades of use and research.

  1. Sorafenib Cardiotoxicity Increases Mortality after Myocardial Infarction

    PubMed Central

    Trappanese, Danielle; Gross, Polina; Husain, Sharmeen; Dunn, Jonathan; Lal, Hind; Sharp, Thomas E.; Starosta, Timothy; Vagnozzi, Ronald J.; Berretta, Remus M.; Barbe, Mary; Yu, Daohai; Gao, Erhe; Kubo, Hajime; Force, Thomas; Houser, Steven R

    2014-01-01

    Rationale Sorafenib is an effective treatment for renal cell carcinoma, but recent clinical reports have documented its cardiotoxicity through an unknown mechanism. Objective Determining the mechanism of sorafenib-mediated cardiotoxicity. Methods and Results Mice treated with sorafenib or vehicle for 3 weeks underwent induced myocardial infarction (MI) after 1 week of treatment. Sorafenib markedly decreased 2-week survival relative to vehicle-treated controls but echocardiography at 1 and 2 weeks post-MI detected no differences in cardiac function. Sorafenib-treated hearts had significantly smaller diastolic and systolic volumes and reduced heart weights. High doses of sorafenib induced necrotic death of isolated myocytes in vitro, but lower doses did not induce myocyte death or affect inotropy. Histological analysis documented increased myocyte cross-sectional area despite smaller heart sizes following sorafenib treatment, further suggesting myocyte loss. Sorafenib caused apoptotic cell death of cardiac- and bone-derived c-kit+ stem cells in vitro and decreased the number of BrdU+ myocytes detected at the infarct border zone in fixed tissues. Sorafenib had no effect on infarct size, fibrosis or post-MI neovascularization. When sorafenib-treated animals received metoprolol treatment post-MI, the sorafenib-induced increase in post MI mortality was eliminated, cardiac function was improved, and myocyte loss was ameliorated. Conclusions Sorafenib cardiotoxicity results from myocyte necrosis rather than from any direct effect on myocyte function. Surviving myocytes undergo pathological hypertrophy. Inhibition of c-kit+ stem cell proliferation by inducing apoptosis exacerbates damage by decreasing endogenous cardiac repair. In the setting of MI, which also causes large-scale cell loss, sorafenib cardiotoxicity dramatically increases mortality. PMID:24718482

  2. Platinum Complexes-Induced Cardiotoxicity of Isolated, Perfused Rat Heart: Comparison of Pt(II) and Pt(IV) Analogues Versus Cisplatin.

    PubMed

    Misic, Miroslav M; Jakovljevic, Vladimir L; Bugarcic, Zivadin D; Zivkovic, Vladimir I; Srejovic, Ivan M; Barudzic, Nevena S; Djuric, Dragan M; Novokmet, Slobodan S

    2015-07-01

    We have compared the cardiotoxicity of five platinum complexes in a model of isolated rat heart using the Langendorff technique. These effects were assessed via coronary flow (CF) and cardiac functional parameters. cis-Diamminedichloroplatinum(II) (cisplatin, CDDP), dichloro-(1,2-diaminocyclohexane)platinum(II) (Pt((II))DACHCl2), dichloro-(ethylenediamine)platinum(II) (Pt((II))ENCl2), tetrachloro-(1,2-diaminocyclohexane)platinum(IV) (Pt((IV))DACHCl4) and tetrachloro-(ethylenediamine)platinum(IV) (Pt((II))ENCl4) were perfused at increasing concentrations of 10(-8), 10(-7), 10(-6), 10(-5) and 10(-4) M during 30 min. In this paper, we report that cisplatin-induced dose-dependent effects on cardiac contractility and coronary flow both manifested as decrease in cardiac contractile force (dP/dt)max, heart rate and significant reduction in CF. Pt((II))ENCl2, Pt((IV))ENCl2 and Pt((IV))DACHCl4 did induce dose-dependent response only in case of CF. Our results could be also important for better understanding dose-dependent side effects of potential metal-based anticancer drugs.

  3. A review of the protective role of melatonin during phosphine-induced cardiotoxicity: focus on mitochondrial dysfunction, oxidative stress and apoptosis.

    PubMed

    Asghari, Mohammad Hossein; Abdollahi, Mohammad; de Oliveira, Marcos Roberto; Nabavi, Seyed Mohammad

    2017-03-01

    Acute poisoning with aluminium phosphide (AlP) is a major cause of mortality in developing countries. AlP mortality is due to cardiac dysfunction leading to cardiomyocyte death. The main mechanism is an inhibition of cytochrome c oxidase in the cardiomyocyte mitochondria, resulting in a decreased ATP production and oxidative stress. Unfortunately, the administration of exogenous drugs does not meet the desired requirements of an effective therapy. Melatonin is an amphiphilic molecule and can easily pass through all cellular compartments with the highest concentration recorded in mitochondria. It is known as a vigorous antioxidant, acting as a potent reactive oxygen species (ROS) scavenger. Our aim is to summarize the mechanisms by which melatonin may modulate the deteriorating effects of AlP poisoning on cardiac mitochondria. Melatonin not only mitigates the inhibition of respiratory chain complexes, but also increases ATP generation. Moreover, it can directly inhibit the mitochondrial permeability transition pore (mPTP) opening, thus preventing apoptosis. In addition, melatonin inhibits the release of cytochrome c from mitochondria to hinder caspase activation leading to cell survival. Based on the promising effects of melatonin on mitochondria, melatonin may mitigate AlP-induced cardiotoxicity and might be potentially suggested as cardioprotective in AlP-intoxicated patients. © 2016 Royal Pharmaceutical Society.

  4. Modulation of gene-expression profiles associated with sodium arsenite-induced cardiotoxicity by p-coumaric acid, a common dietary polyphenol.

    PubMed

    Prasanna, Nagalakshmi; Rasool, Mahaboobkhan

    2014-04-01

    In the present study, the purpose was to investigate the effect of p-coumaric acid on the mRNA-expression levels of inflammatory cytokines, transcription factor, MAP kinases, and apoptotic proteins by real time reverse transcription polymerase chain reaction in the cardiac tissue of sodium arsenite exposed rats. Sodium arsenite administration (5 mg/kg/b.wt, once daily for 30 days) upregulated the mRNA-expression levels of inflammatory cytokines (interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, and tumor growth factor-beta), transcription factor (NF-Kb-Rel A), protein kinases (Janus kinase and p38), caspase 3, and proapoptotic protein Bax in the cardiac tissue of rats, but the antiapoptotic protein Bcl-2 mRNA expression was found be downregulated. However, p-coumaric acid (75, 100 mg/kg/b. wt. oral) pretreatment daily before the sodium arsenite exposure protected the changes in the above mRNA-expression profiles observed in the cardiac tissues. In conclusion, this study confirmed that p-coumaric acid could be a promising dietary agent for protecting against the sodium arsenite-induced cardiotoxicity.

  5. Radiation-induced disease.

    PubMed

    Bobrow, M

    1993-01-01

    The term radiation covers a wide spectrum of forms of energy, most of which have at one stage or another been suspected of causing human ill health. In general, study of the effects of radiation on health involves a mix of scientific disciplines, from population epidemiology to physics, which are seldom if ever found in a single scientist. As a result, interdisciplinary communication is of the utmost importance, and is a potent source of misunderstanding and misinformation. The forms of radiation which have been most specifically associated with health effects include ionizing and ultraviolet radiation. Claimed effects of electromagnetic and microwave radiation (excluding thermal effects) are too indefinite for detailed consideration. Ionizing radiation is a well-documented mutagen, which clearly causes cancers in humans, and human exposure has been increased by atomic weapons testing and medical and industrial uses of radioactivity. There is also a growing awareness of the possible role of some types of natural radiation, such as radon, in causing disease. Ultraviolet radiation is also associated with cancers, and is suspected of involvement in the increasing incidence of skin cancers in European populations. Factors thought to underlie recent changes in exposure to these mutagens are discussed.

  6. Polyphenol-rich apple (Malus domestica L.) peel extract attenuates arsenic trioxide induced cardiotoxicity in H9c2 cells via its antioxidant activity.

    PubMed

    Vineetha, Vadavanath Prabhakaran; Girija, Seetharaman; Soumya, Rema Sreenivasan; Raghu, Kozhiparambil Gopalan

    2014-03-01

    Evidences suggest that apple peel has a wide range of polyphenols having antioxidant activity and its consumption has been linked with improved health benefits. Arsenic trioxide (ATO) is a very effective drug for the treatment of acute promyelocytic leukemia (APL) but it leads to cardiotoxicity mediated through alterations in various cardiac ion channels and by increasing the intracellular calcium level and reactive oxygen species (ROS). The aim of the present investigation was to study the effect of methanolic extract of apple peel (APME) and aqueous extract of apple peel (APAE) on ATO (5 μM) induced toxicity in the H9c2 cardiac myoblast cell line. We estimated the cellular status of innate antioxidant enzymes, level of ROS, mitochondrial superoxide, glutathione and intracellular calcium with ATO and apple peel extracts. Prior to the cell line based study, we had evaluated the antioxidant potential of apple peel extract by 1,1-diphenyl-2-picrylhydrazyl (DPPH), total reducing power (TRP), superoxide anion and hydroxyl radical scavenging activity, in addition to quantifying total phenolic and flavonoid content. Both the extracts showed considerable antioxidant activity in cell-free chemical assays. In addition, both APME and APAE prevented the alteration in antioxidant status induced by ATO in H9c2 cells. Significant differential alterations had been observed in the activity of lactate dehydrogenase, superoxide dismutase, catalase, glutathione, glutathione peroxidase, thioredoxin reductase, xanthine oxidase, calcium overload and caspase 3 activity with ATO. The overall result revealed the protective property of polyphenol-rich apple peel extract against ATO induced cardiac toxicity via its antioxidant activity.

  7. Aryl phosphate esters within a major PentaBDE replacement product induce cardiotoxicity in developing zebrafish embryos: potential role of the aryl hydrocarbon receptor.

    PubMed

    McGee, Sean P; Konstantinov, Alex; Stapleton, Heather M; Volz, David C

    2013-05-01

    Firemaster 550 (FM550) is an additive flame retardant formulation of brominated and aryl phosphate ester (APE) components introduced as a major replacement product for the commercial polybrominated diphenyl ether mixture (known as PentaBDE) used primarily in polyurethane foam. However, little is known about the potential effects of FM550-based ingredients during early vertebrate development. Therefore, we first screened the developmental toxicity of each FM550 component using zebrafish as an animal model. Based on these initial screening assays, we found that exposure to the brominated components as high as 10µM resulted in no significant effects on embryonic survival or development, whereas exposure to triphenyl phosphate (TPP) or mono-substituted isopropylated triaryl phosphate (mono-ITP)-two APEs comprising almost 50% of FM550-resulted in targeted effects on cardiac looping and function during embryogenesis. As these cardiac abnormalities resembled aryl hydrocarbon receptor (AHR) agonist-induced phenotypes, we then exposed developing embryos to TPP or mono-ITP in the presence or absence of an AHR antagonist (CH223191) or AHR2-specific morpholino. Based on these studies, we found that CH223191 blocked heart malformations following exposure to mono-ITP but not TPP, whereas AHR2 knockdown failed to block the cardiotoxic effects of both components. Finally, using a cell-based human AHR reporter assay, we found that mono-ITP (but not TPP) exposure resulted in a significant increase in human AHR-driven luciferase activity at similar nominal concentrations as a potent reference AHR agonist (β-naphthoflavone). Overall, our findings suggest that two major APE components of FM550 induce severe cardiac abnormalities during early vertebrate development.

  8. Kv11.1 (hERG)-induced cardiotoxicity: a molecular insight from a binding kinetics study of prototypical Kv11.1 (hERG) inhibitors

    PubMed Central

    Yu, Z; IJzerman, A P; Heitman, L H

    2015-01-01

    Background and Purpose Drug-induced arrhythmia due to blockade of the Kv11.1 channel (also known as the hERG K+ channel) is a frequent side effect. Previous studies have primarily focused on equilibrium parameters, i.e. affinity or potency, of drug candidates at the channel. The aim of this study was to determine the kinetics of the interaction with the channel for a number of known Kv11.1 blockers and to explore a possible correlation with the affinity or physicochemical properties of these compounds. Experimental Approach The affinity and kinetic parameters of 15 prototypical Kv11.1 inhibitors were evaluated in a number of [3H]-dofetilide binding assays. The lipophilicity (logKW-C8) and membrane partitioning (logKW-IAM) of these compounds were determined by means of HPLC analysis. Key Results A novel [3H]-dofetilide competition association assay was set up and validated, which allowed us to determine the binding kinetics of the Kv11.1 blockers used in this study. Interestingly, the compounds' affinities (Ki values) were correlated to their association rates rather than dissociation rates. Overall lipophilicity or membrane partitioning of the compounds were not correlated to their affinity or rate constants for the channel. Conclusions and Implications A compound's affinity for the Kv11.1 channel is determined by its rate of association with the channel, while overall lipophilicity and membrane affinity are not. In more general terms, our findings provide novel insights into the mechanism of action for a compound's activity at the Kv11.1 channel. This may help to elucidate how Kv11.1-induced cardiotoxicity is governed and how it can be circumvented in the future. PMID:25296617

  9. Radiation-induced genomic instability

    NASA Technical Reports Server (NTRS)

    Kronenberg, A.

    1994-01-01

    Quantitative assessment of the heritable somatic effects of ionizing radiation exposures has relied upon the assumption that radiation-induced lesions were 'fixed' in the DNA prior to the first postirradiation mitosis. Lesion conversion was thought to occur during the initial round of DNA replication or as a consequence of error-prone enzymatic processing of lesions. The standard experimental protocols for the assessment of a variety of radiation-induced endpoints (cell death, specific locus mutations, neoplastic transformation and chromosome aberrations) evaluate these various endpoints at a single snapshot in time. In contrast with the aforementioned approaches, some studies have specifically assessed radiation effects as a function of time following exposure. Evidence has accumulated in support of the hypothesis that radiation exposure induces a persistent destabilization of the genome. This instability has been observed as a delayed expression of lethal mutations, as an enhanced rate of accumulation of non-lethal heritable alterations, and as a progressive intraclonal chromosomal heterogeneity. The genetic controls and biochemical mechanisms underlying radiation-induced genomic instability have not yet been delineated. The aim is to integrate the accumulated evidence that suggests that radiation exposure has a persistent effect on the stability of the mammalian genome.

  10. Radiation-induced genomic instability

    NASA Technical Reports Server (NTRS)

    Kronenberg, A.

    1994-01-01

    Quantitative assessment of the heritable somatic effects of ionizing radiation exposures has relied upon the assumption that radiation-induced lesions were 'fixed' in the DNA prior to the first postirradiation mitosis. Lesion conversion was thought to occur during the initial round of DNA replication or as a consequence of error-prone enzymatic processing of lesions. The standard experimental protocols for the assessment of a variety of radiation-induced endpoints (cell death, specific locus mutations, neoplastic transformation and chromosome aberrations) evaluate these various endpoints at a single snapshot in time. In contrast with the aforementioned approaches, some studies have specifically assessed radiation effects as a function of time following exposure. Evidence has accumulated in support of the hypothesis that radiation exposure induces a persistent destabilization of the genome. This instability has been observed as a delayed expression of lethal mutations, as an enhanced rate of accumulation of non-lethal heritable alterations, and as a progressive intraclonal chromosomal heterogeneity. The genetic controls and biochemical mechanisms underlying radiation-induced genomic instability have not yet been delineated. The aim is to integrate the accumulated evidence that suggests that radiation exposure has a persistent effect on the stability of the mammalian genome.

  11. Cancer Treatment-Related Cardiotoxicity

    Cancer.gov

    Cancer Treatment-Related Cardiotoxicity includes efforts to identify individual toxicity risks and prevention strategies support the National Cancer Insitute's goal of reducing the burden of cancer diagnoses and treatment outcomes.

  12. Novel self-emulsifying formulation of quercetin for improved in vivo antioxidant potential: implications for drug-induced cardiotoxicity and nephrotoxicity.

    PubMed

    Jain, Sanyog; Jain, Amit K; Pohekar, Milind; Thanki, Kaushik

    2013-12-01

    Quercetin (QT) was formulated into a novel self-emulsifying drug delivery system (SEDDS) to improve its oral bioavailability and antioxidant potential compared to free drug. Capmul MCM was selected as the oily phase on the basis of optimum solubility of QT in oil. Tween 20 and ethanol were selected as surfactant and cosurfactant from a large pool of excipients, depending upon their spontaneous self-emulsifying ability with the selected oily phase. Pseudoternary-phase diagrams were constructed to identify the efficient self-emulsification regions in various dilution media, viz., water, pH 1.2, and pH 6.8. The ratio of 40:40:20 w/w, Capmul MCM:QT (19:1)/Tween 20/ethanol was optimized based on its ability to form a spontaneous submicrometer emulsion in simulated gastrointestinal fluids. DPPH scavenging assay showed comparable antioxidant activity of QT-SEDDS to free QT. QT-SEDDS was robust in terms of stability against short-term excursion of freeze/thaw cycles and accelerated stability for 6 months as per International Conference on Harmonisation guidelines. A fluorescent dye-loaded SEDDS formulation showed rapid internalization within 1h of incubation with Caco-2 cells as evident by confocal laser scanning microscopy. QT-SEDDS showed a significant increase in cellular uptake by 23.75-fold in comparison with free QT cultured with Caco-2 cells. The SEDDS demonstrated ~5-fold enhancement in oral bioavailability compared to free QT suspension. The in vitro-in vivo relation between in vitro Caco-2 cell uptake and in vivo pharmacokinetics of QT-SEDDS showed a correlation coefficient of ~0.9961, as evident from a Levy plot. Finally, QT-SEDDS showed a significantly higher in vivo antioxidant potential compared to free QT when evaluated as a function of ability to combat doxorubicin- and cyclosporin A-induced cardiotoxicity and nephrotoxicity, respectively. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. Incidence and identification of risk factors for trastuzumab-induced cardiotoxicity in breast cancer patients: an audit of a single "real-world" setting.

    PubMed

    Tang, Grace H; Acuna, Sergio A; Sevick, Laura; Yan, Andrew T; Brezden-Masley, Christine

    2017-09-01

    Management of human epidermal growth factor receptor-2-positive (HER2+) breast cancer patients includes the combination of adjuvant chemotherapy and trastuzumab. A meta-analysis reported that <5% of HER2+ breast cancer patients will develop trastuzumab-induced cardiotoxicity (TIC). Observational data suggest that incidence is much higher. We aimed to determine the incidence, time to development, and risk factors associated with TIC among less selected patients. A retrospective cohort study was carried out in 160 HER2+ breast cancer patients who received adjuvant chemotherapy with trastuzumab from January 2006 to June 2014 at St. Michael's Hospital, Toronto, Canada. Patient demographics, cardiovascular history, and TIC were recorded. TIC was defined as symptomatic (heart failure) or asymptomatic [decline in left ventricular ejection fraction (LVEF) by ≥10% or LVEF ≤ 50%]. Of the 160 patients [median age 52 (IQR 45-60), 48.1% on anthracycline-based chemotherapy], 34 patients (21.3%) experienced TIC (median follow-up 55.4 months). The median time to development of TIC was 28.5 weeks during trastuzumab therapy. Those with TIC were more likely to have undergone a mastectomy (52.9 vs. 33.3%, p = 0.04). However, after adjusting for anthracycline-based chemotherapy, and radiotherapy, mastectomy was not independently associated with TIC (HR 2.02; 95% CI 0.88-4.63). The incidence of TIC is higher in our "real-world" population compared to clinical trial data. The median time to development of TIC was 28 weeks after trastuzumab initiation, approximately the 10th treatment of trastuzumab. Timely identification and management of patients is important to avoid irreversible cardiac toxicity and improve breast cancer survival.

  14. Radiation-induced cardiovascular effects

    NASA Astrophysics Data System (ADS)

    Tapio, Soile

    Recent epidemiological studies indicate that exposure to ionising radiation enhances the risk of cardiovascular mortality and morbidity in a moderate but significant manner. Our goal is to identify molecular mechanisms involved in the pathogenesis of radiation-induced cardiovascular disease using cellular and mouse models. Two radiation targets are studied in detail: the vascular endothelium that plays a pivotal role in the regulation of cardiac function, and the myocardium, in particular damage to the cardiac mitochondria. Ionising radiation causes immediate and persistent alterations in several biological pathways in the endothelium in a dose- and dose-rate dependent manner. High acute and cumulative doses result in rapid, non-transient remodelling of the endothelial cytoskeleton, as well as increased lipid peroxidation and protein oxidation of the heart tissue, independent of whether exposure is local or total body. Proteomic and functional changes are observed in lipid metabolism, glycolysis, mitochondrial function (respiration, ROS production etc.), oxidative stress, cellular adhesion, and cellular structure. The transcriptional regulators Akt and PPAR alpha seem to play a central role in the radiation-response of the endothelium and myocardium, respectively. We have recently started co-operation with GSI in Darmstadt to study the effect of heavy ions on the endothelium. Our research will facilitate the identification of biomarkers associated with adverse cardiac effects of ionising radiation and may lead to the development of countermeasures against radiation-induced cardiac damage.

  15. Research progress of cardioprotective agents for prevention of anthracycline cardiotoxicity

    PubMed Central

    Zhang, Jing; Cui, Xiaohai; Yan, Yan; Li, Min; Yang, Ya; Wang, Jiansheng; Zhang, Jia

    2016-01-01

    Anthracyclines, including doxorubicin, epirubicin, daunorubicin and aclarubicin, are widely used as chemotherapeutic agents in the treatment of hematologic and solid tumor, including acute leukemia, lymphoma, breast cancer, gastric cancer, soft tissue sarcomas and ovarian cancer. In the cancer treatment, anthracyclines also can be combined with other chemotherapies and molecular-targeted drugs. The combination of anthracyclines with other therapies is usually the first-line treatment. Anthracyclines are effective and potent agents with a broad antitumor spectrum, but may cause adverse reactions, including hair loss, myelotoxicity, as well as cardiotoxicity. We used hematopoietic stimulating factors to control the myelotoxicity, such as G-CSF, EPO and TPO. However, the cardiotoxicity is the most serious side effect of anthracyclines. Clinical research and practical observations indicated that the cardiotoxicity of anthracyclines is commonly progressive and irreversible. Especially to those patients who have the first time use of anthracyclines, the damage is common. Therefore, early detection and prevention of anthracyclines induced cardiotoxicity are particularly important and has already aroused more attention in clinic. By literature review, we reviewed the research progress of cardioprotective agents for prevention of anthracycline cardiotoxicity. PMID:27508008

  16. Protective Effects of Carvedilol and Vitamin C against Azithromycin-Induced Cardiotoxicity in Rats via Decreasing ROS, IL1-β, and TNF-α Production and Inhibiting NF-κB and Caspase-3 Expression

    PubMed Central

    El-Shitany, Nagla A.; El-Desoky, Karema

    2016-01-01

    The Food and Drug Administration recently warned of the fatal cardiovascular risks of azithromycin in humans. In addition, a recently published study documented azithromycin-induced cardiotoxicity in rats. This study aimed to justify the exact cardiovascular events accompanying azithromycin administration in rats, focusing on electrocardiographic, biochemical, and histopathological changes. In addition, the underlying mechanisms were studied regarding reactive oxygen species production, cytokine release, and apoptotic cell-death. Finally, the supposed protective effects of both carvedilol and vitamin C were assessed. Four groups of rats were used: (1) control, (2) azithromycin, (3) azithromycin + carvedilol, and (4) azithromycin + vitamin C. Azithromycin resulted in marked atrophy of cardiac muscle fibers and electrocardiographic segment alteration. It increased the heart rate, lactate dehydrogenase, creatine phosphokinase, malondialdehyde, nitric oxide, interleukin-1 beta (IL1-β), tumor necrosis factor alpha (TNF-α), nuclear factor kappa beta (NF-κB), and caspase-3. It decreased reduced glutathione, glutathione peroxidase, and superoxide dismutase. Carvedilol and vitamin C prevented most of the azithromycin-induced electrocardiographic and histopathological changes. Carvedilol and vitamin C decreased lactate dehydrogenase, malondialdehyde, IL1-β, TNF-α, NF-κB, and caspase-3. Both agents increased glutathione peroxidase. This study shows that both carvedilol and vitamin C protect against azithromycin-induced cardiotoxicity through antioxidant, immunomodulatory, and antiapoptotic mechanisms. PMID:27274777

  17. Action potential-based MEA platform for in vitro screening of drug-induced cardiotoxicity using human iPSCs and rat neonatal myocytes.

    PubMed

    Jans, Danny; Callewaert, Geert; Krylychkina, Olga; Hoffman, Luis; Gullo, Francesco; Prodanov, Dimiter; Braeken, Dries

    2017-09-01

    Drug-induced cardiotoxicity poses a negative impact on public health and drug development. Cardiac safety pharmacology issues urged for the preclinical assessment of drug-induced ventricular arrhythmia leading to the design of several in vitro electrophysiological screening assays. In general, patch clamp systems allow for intracellular recordings, while multi-electrode array (MEA) technology detect extracellular activity. Here, we demonstrate a complementary metal oxide semiconductor (CMOS)-based MEA system as a reliable platform for non-invasive, long-term intracellular recording of cardiac action potentials at high resolution. Quinidine (8 concentrations from 10(-7) to 2.10(-5)M) and verapamil (7 concentrations from 10(-11) to 10(-5)M) were tested for dose-dependent responses in a network of cardiomyocytes. Electrophysiological parameters, such as the action potential duration (APD), rates of depolarization and repolarization and beating frequency were assessed. In hiPSC, quinidine prolonged APD with EC50 of 2.2·10(-6)M. Further analysis indicated a multifactorial action potential prolongation by quinidine: (1) decreasing fast repolarization with IC50 of 1.1·10(-6)M; (2) reducing maximum upstroke velocity with IC50 of 2.6·10(-6)M; and (3) suppressing spontaneous activity with EC50 of 3.8·10(-6)M. In rat neonatal cardiomyocytes, verapamil blocked spontaneous activity with EC50 of 5.3·10(-8)M and prolonged the APD with EC50 of 2.5·10(-8)M. Verapamil reduced rates of fast depolarization and repolarization with IC50s of 1.8 and 2.2·10(-7)M, respectively. In conclusion, the proposed action potential-based MEA platform offers high quality and stable long-term recordings with high information content allowing to characterize multi-ion channel blocking drugs. We anticipate application of the system as a screening platform to efficiently and cost-effectively test drugs for cardiac safety. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Genomic Profiling Reveals the Potential Role of TCL1A and MDR1 Deficiency in Chemotherapy-Induced Cardiotoxicity

    PubMed Central

    McCaffrey, Timothy A.; Tziros, Constantine; Lewis, Jannet; Katz, Richard; Siegel, Robert; Weglicki, William; Kramer, Jay; Mak, I. Tong; Toma, Ian; Chen, Liang; Benas, Elizabeth; Lowitt, Alexander; Rao, Shruti; Witkin, Linda; Lian, Yi; Lai, Yinglei; Yang, Zhaoqing; Fu, Sidney W.

    2013-01-01

    Background: Anthracyclines, such as doxorubicin (Adriamycin), are highly effective chemotherapeutic agents, but are well known to cause myocardial dysfunction and life-threatening congestive heart failure (CHF) in some patients. Methods: To generate new hypotheses about its etiology, genome-wide transcript analysis was performed on whole blood RNA from women that received doxorubicin-based chemotherapy and either did, or did not develop CHF, as defined by ejection fractions (EF)≤40%. Women with non-ischemic cardiomyopathy unrelated to chemotherapy were compared to breast cancer patients prior to chemo with normal EF to identify heart failure-related transcripts in women not receiving chemotherapy. Byproducts of oxidative stress in plasma were measured in a subset of patients. Results: The results indicate that patients treated with doxorubicin showed sustained elevations in oxidative byproducts in plasma. At the RNA level, women who exhibited low EFs after chemotherapy had 260 transcripts that differed >2-fold (p<0.05) compared to women who received chemo but maintained normal EFs. Most of these transcripts (201) were not altered in non-chemotherapy patients with low EFs. Pathway analysis of the differentially expressed genes indicated enrichment in apoptosis-related transcripts. Notably, women with chemo-induced low EFs had a 4.8-fold decrease in T-cell leukemia/lymphoma 1A (TCL1A) transcripts. TCL1A is expressed in both cardiac and skeletal muscle, and is a known co-activator for AKT, one of the major pro-survival factors for cardiomyocytes. Further, women who developed low EFs had a 2-fold lower level of ABCB1 transcript, encoding the multidrug resistance protein 1 (MDR1), which is an efflux pump for doxorubicin, potentially leading to higher cardiac levels of drug. In vitro studies confirmed that inhibition of MDR1 by verapamil in rat H9C2 cardiomyocytes increased their susceptibility to doxorubicin-induced toxicity. Conclusions: It is proposed that chemo-induced

  19. Myocardial performance index and biochemical markers for early detection of doxorubicin-induced cardiotoxicity in children with acute lymphoblastic leukaemia.

    PubMed

    Ruggiero, Antonio; De Rosa, Gabriella; Rizzo, Daniela; Leo, Andrea; Maurizi, Palma; De Nisco, Alessia; Vendittelli, Francesca; Zuppi, Cecilia; Mordente, Alvaro; Riccardi, Riccardo

    2013-10-01

    Despite significant improvements in the prognosis of childhood acute lymphoblastic leukaemia (ALL), the risk of anthracycline-induced cardiovascular disease remains a major concern. This study was designed to investigate the role of the myocardial performance index (MPI) and serum concentrations of biomarkers (cTnT and NT-pro-BNP) in the early detection of subclinical anthracycline-induced functional alterations in children with ALL. All children consecutively admitted to our Pediatric Oncologic Department from January 2009 to October 2010 with a diagnosis of ALL were enrolled in this study. cTnT and NT-pro-BNP were evaluated in all patients at diagnosis, before doxorubicin therapy and 2 and 24 h following each anthracycline administration. ECG and echocardiography were performed at diagnosis and 24 h after each anthracycline course. Nineteen children with standard-risk ALL were evaluated. The mean age was 6 years. The cumulative doxorubicin dosage was 240 mg/m(2) according to the AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) ALL 2000 protocol. None of the 19 patients developed congestive heart failure. With increasing cumulative dosages of anthracyclines a significant increase was observed in MPI. This increase was statistically significant starting from the cumulative dosage of 120 mg/m(2) compared to baseline, while the median NT-pro-BNP level did not change significantly during treatment and cTnT levels never exceeded the cut-off value for cardiac injury. MPI value is a sensitive and accurate parameter, allowing subclinical cardiac dysfunction to be detected in children receiving anthracyclines. Lifelong cardiac surveillance of these patients is warranted in order to determine the clinical implications of increased MPI on long-term cardiac status.

  20. Effect of Piper betle on cardiac function, marker enzymes, and oxidative stress in isoproterenol-induced cardiotoxicity in rats.

    PubMed

    Arya, Dharamvir Singh; Arora, Sachin; Malik, Salma; Nepal, Saroj; Kumari, Santosh; Ojha, Shreesh

    2010-11-01

    The present study was designed to investigate the cardioprotective potential of Piper betle (P. betle) against isoproterenol (ISP)-induced myocardial infarction in rats. Rats were randomly divided into eight groups viz. control, ISP, P. betle (75, 150, and 300 mg/kg) and P. betle (75, 150, and 300 mg/kg) + ISP treated group. P. betle leaf extract (75, 150, or 300 mg/kg) or saline was orally administered for 30 days. ISP (85 mg/kg, s.c.) was administered at an interval of 24 h on the 28(th) and 29(th) day and on day 30 the functional and biochemical parameters were measured. ISP administration showed a significant decrease in systolic, diastolic, mean arterial pressure (SAP, DAP, MAP), heart rate (HR), contractility (+LVdP/dt), and relaxation (-LVdP/dt) and increased left ventricular end-diastolic pressure (LVEDP). ISP also caused significant decrease in myocardial antioxidants; superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), and myocyte injury marker enzymes; creatine phosphokinase-MB (CK-MB) isoenzyme and lactate dehydrogenase (LDH) along with enhanced lipid peroxidation; thiobarbituric acid reacting species (TBARS) in heart. Pre-treatment with P. betle favorably modulated hemodynamic (SAP, DAP, and MAP) and ventricular function parameters (-LVdP/dt and LVEDP). P. betle pre-treatment also restored SOD, CAT, GSH, and GPx, reduced the leakage of CK-MB isoenzyme and LDH along with decreased lipid peroxidation in the heart. Taken together, the biochemical and functional parameters indicate that P. betle 150 and 300 mg/kg has a significant cardioprotective effect against ISP-induced myocardial infarction. Results of the present study suggest the cardioprotective potential of P. betle.

  1. Radiation-induced bladder carcinoma

    SciTech Connect

    Uyama, T.; Nakamura, S.; Moriwaki, S.

    1981-01-01

    Two cases are presented of radiation-induced bladder carcinoma which followed prior irradiation for cervical carcinoma of the uterus. One was a sixty-eight-year-old woman with bladder carcinoma fourteen years after irradiation (total dose of 4,500 rad) for cervical carcinoma of the uterus. The other was a sixty-four-year-old woman with bladder carcinoma twenty-five years after irradiation with 150-K volt apparatus for cervical carcinoma of the uterus. From the late radiation change of the skin, it was estimated that the total dose of prior radiation might be 4,000 rad or more. Both had high-grade, high-stage transitional cell bladder carcinoma, and the former was with marked mucus-forming adenomatous metaplasia.

  2. Radiation-Induced Oral Mucositis

    PubMed Central

    Maria, Osama Muhammad; Eliopoulos, Nicoletta; Muanza, Thierry

    2017-01-01

    Radiation-induced oral mucositis (RIOM) is a major dose-limiting toxicity in head and neck cancer patients. It is a normal tissue injury caused by radiation/radiotherapy (RT), which has marked adverse effects on patient quality of life and cancer therapy continuity. It is a challenge for radiation oncologists since it leads to cancer therapy interruption, poor local tumor control, and changes in dose fractionation. RIOM occurs in 100% of altered fractionation radiotherapy head and neck cancer patients. In the United Sates, its economic cost was estimated to reach 17,000.00 USD per patient with head and neck cancers. This review will discuss RIOM definition, epidemiology, impact and side effects, pathogenesis, scoring scales, diagnosis, differential diagnosis, prevention, and treatment. PMID:28589080

  3. Radiation-Induced Oral Mucositis.

    PubMed

    Maria, Osama Muhammad; Eliopoulos, Nicoletta; Muanza, Thierry

    2017-01-01

    Radiation-induced oral mucositis (RIOM) is a major dose-limiting toxicity in head and neck cancer patients. It is a normal tissue injury caused by radiation/radiotherapy (RT), which has marked adverse effects on patient quality of life and cancer therapy continuity. It is a challenge for radiation oncologists since it leads to cancer therapy interruption, poor local tumor control, and changes in dose fractionation. RIOM occurs in 100% of altered fractionation radiotherapy head and neck cancer patients. In the United Sates, its economic cost was estimated to reach 17,000.00 USD per patient with head and neck cancers. This review will discuss RIOM definition, epidemiology, impact and side effects, pathogenesis, scoring scales, diagnosis, differential diagnosis, prevention, and treatment.

  4. Entanglement-induced quantum radiation

    NASA Astrophysics Data System (ADS)

    Iso, Satoshi; Tatsukawa, Rumi; Ueda, Kazushige; Yamamoto, Kazuhiro

    2017-08-01

    Quantum entanglement of the Minkowski vacuum state between left and right Rindler wedges generates thermal behavior in the right Rindler wedge, which is known as the Unruh effect. In this paper, we show that there is another consequence of this entanglement, namely entanglement-induced quantum radiation emanating from a uniformly accelerated object. We clarify why it is in agreement with our intuition that incoming and outgoing energy fluxes should cancel each other out in a thermalized state.

  5. Cardiotoxicity | Division of Cancer Prevention

    Cancer.gov

    Damage to the heart (cardiotoxicity), or blood vessels (cardiovascular toxicity) can occur during or after cancer treatment. As treatments have improved, more patients are surviving longer after a diagnosis of cancer than at any time in the past. See the article, Treating Cancer without Harming the Heart. |

  6. Oxidative stress, redox signaling, and metal chelation in anthracycline cardiotoxicity and pharmacological cardioprotection.

    PubMed

    Stěrba, Martin; Popelová, Olga; Vávrová, Anna; Jirkovský, Eduard; Kovaříková, Petra; Geršl, Vladimír; Simůnek, Tomáš

    2013-03-10

    Anthracyclines (doxorubicin, daunorubicin, or epirubicin) rank among the most effective anticancer drugs, but their clinical usefulness is hampered by the risk of cardiotoxicity. The most feared are the chronic forms of cardiotoxicity, characterized by irreversible cardiac damage and congestive heart failure. Although the pathogenesis of anthracycline cardiotoxicity seems to be complex, the pivotal role has been traditionally attributed to the iron-mediated formation of reactive oxygen species (ROS). In clinics, the bisdioxopiperazine agent dexrazoxane (ICRF-187) reduces the risk of anthracycline cardiotoxicity without a significant effect on response to chemotherapy. The prevailing concept describes dexrazoxane as a prodrug undergoing bioactivation to an iron-chelating agent ADR-925, which may inhibit anthracycline-induced ROS formation and oxidative damage to cardiomyocytes. A considerable body of evidence points to mitochondria as the key targets for anthracycline cardiotoxicity, and therefore it could be also crucial for effective cardioprotection. Numerous antioxidants and several iron chelators have been tested in vitro and in vivo with variable outcomes. None of these compounds have matched or even surpassed the effectiveness of dexrazoxane in chronic anthracycline cardiotoxicity settings, despite being stronger chelators and/or antioxidants. The interpretation of many findings is complicated by the heterogeneity of experimental models and frequent employment of acute high-dose treatments with limited translatability to clinical practice. Dexrazoxane may be the key to the enigma of anthracycline cardiotoxicity, and therefore it warrants further investigation, including the search for alternative/complementary modes of cardioprotective action beyond simple iron chelation.

  7. Prospective evaluation of Doppler echocardiography, tissue Doppler imaging and biomarkers measurement for the detection of doxorubicin-induced cardiotoxicity in dogs: A pilot study.

    PubMed

    Gallay-Lepoutre, J; Bélanger, M C; Nadeau, M E

    2016-04-01

    The purpose of this pilot study was to evaluate the usefulness of selected echocardiographic parameters, NT-proBNP and cardiac troponin I (cTnI) in the detection of cardiotoxicity in dogs treated with doxorubicin for various malignancies. Echocardiographic studies and biomarker measurements were performed before each administration of doxorubicin, then 1 and 3 months after completion of therapy. Thirteen dogs were included, with a total cumulative dose of doxorubicin ranging from 30 to 150 mg/m(2). E/A ratio significantly decreased during doxorubicin administration (p=0.047). cTnI level was also significantly affected by treatment (p=0.046), increasing above normal at least at one time point in 11 of 13 dogs. The results of this pilot study suggest that monitoring of left ventricular diastolic function and cTnI level measurement might be useful in the early detection of cardiotoxic signs of doxorubicin therapy in dogs. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Quercetin attenuates doxorubicin cardiotoxicity by modulating Bmi-1 expression

    PubMed Central

    Dong, Qinghua; Chen, Long; Lu, Qunwei; Sharma, Sherven; Li, Lei; Morimoto, Sachio; Wang, Guanyu

    2014-01-01

    Background and Purpose Doxorubicin-based chemotherapy induces cardiotoxicity, which limits its clinical application. We previously reported the protective effects of quercetin against doxorubicin-induced hepatotoxicity. In this study, we tested the effects of quercetin on the expression of Bmi-1, a protein regulating mitochondrial function and ROS generation, as a mechanism underlying quercetin-mediated protection against doxorubicin-induced cardiotoxicity. Experimental Approach Effects of quercetin on doxorubicin-induced cardiotoxicity was evaluated using H9c2 cardiomyocytes and C57BL/6 mice. Changes in apoptosis, mitochondrial function, oxidative stress and related signalling were evaluated in H9c2 cells. Cardiac function, serum enzyme activity and reactive oxygen species (ROS) generation were measured in mice after a single injection of doxorubicin with or without quercetin pre-treatment. Key Results In H9c2 cells, quercetin reduced doxorubicin-induced apoptosis, mitochondrial dysfunction, ROS generation and DNA double-strand breaks. The quercetin-mediated protection against doxorubicin toxicity was characterized by decreased expression of Bid, p53 and oxidase (p47 and Nox1) and by increased expression of Bcl-2 and Bmi-1. Bmi-1 siRNA abolished the protective effect of quercetin against doxorubicin-induced toxicity in H9c2 cells. Furthermore, quercetin protected mice from doxorubicin-induced cardiac dysfunction that was accompanied by reduced ROS levels and lipid peroxidation, but enhanced the expression of Bmi-1 and anti-oxidative superoxide dismutase. Conclusions and Implications Our results demonstrate that quercetin decreased doxorubicin-induced cardiotoxicity in vitro and in vivo by reducing oxidative stress by up-regulation of Bmi-1 expression. The findings presented in this study have potential applications in preventing doxorubicin-induced cardiomyopathy. PMID:24902966

  9. Quercetin attenuates doxorubicin cardiotoxicity by modulating Bmi-1 expression.

    PubMed

    Dong, Qinghua; Chen, Long; Lu, Qunwei; Sharma, Sherven; Li, Lei; Morimoto, Sachio; Wang, Guanyu

    2014-10-01

    Doxorubicin-based chemotherapy induces cardiotoxicity, which limits its clinical application. We previously reported the protective effects of quercetin against doxorubicin-induced hepatotoxicity. In this study, we tested the effects of quercetin on the expression of Bmi-1, a protein regulating mitochondrial function and ROS generation, as a mechanism underlying quercetin-mediated protection against doxorubicin-induced cardiotoxicity. Effects of quercetin on doxorubicin-induced cardiotoxicity was evaluated using H9c2 cardiomyocytes and C57BL/6 mice. Changes in apoptosis, mitochondrial function, oxidative stress and related signalling were evaluated in H9c2 cells. Cardiac function, serum enzyme activity and reactive oxygen species (ROS) generation were measured in mice after a single injection of doxorubicin with or without quercetin pre-treatment. In H9c2 cells, quercetin reduced doxorubicin-induced apoptosis, mitochondrial dysfunction, ROS generation and DNA double-strand breaks. The quercetin-mediated protection against doxorubicin toxicity was characterized by decreased expression of Bid, p53 and oxidase (p47 and Nox1) and by increased expression of Bcl-2 and Bmi-1. Bmi-1 siRNA abolished the protective effect of quercetin against doxorubicin-induced toxicity in H9c2 cells. Furthermore, quercetin protected mice from doxorubicin-induced cardiac dysfunction that was accompanied by reduced ROS levels and lipid peroxidation, but enhanced the expression of Bmi-1 and anti-oxidative superoxide dismutase. Our results demonstrate that quercetin decreased doxorubicin-induced cardiotoxicity in vitro and in vivo by reducing oxidative stress by up-regulation of Bmi-1 expression. The findings presented in this study have potential applications in preventing doxorubicin-induced cardiomyopathy. © 2014 The British Pharmacological Society.

  10. Ageing is a risk factor in imatinib mesylate cardiotoxicity

    PubMed Central

    Maharsy, Wael; Aries, Anne; Mansour, Omar; Komati, Hiba; Nemer, Mona

    2014-01-01

    Aims Chemotherapy-induced heart failure is increasingly recognized as a major clinical challenge. Cardiotoxicity of imatinib mesylate, a highly selective and effective anticancer drug belonging to the new class of tyrosine kinase inhibitors, is being reported in patients, some progressing to congestive heart failure. This represents an unanticipated challenge that could limit effective drug use. Understanding the mechanisms and risk factors of imatinib mesylate cardiotoxicity is crucial for prevention of cardiovascular complications in cancer patients. Methods and results We used genetically engineered mice and primary rat neonatal cardiomyocytes to analyse the action of imatinib on the heart. We found that treatment with imatinib (200 mg/kg/day for 5 weeks) leads to mitochondrial-dependent myocyte loss and cardiac dysfunction, as confirmed by electron microscopy, RNA analysis, and echocardiography. Imatinib cardiotoxicity was more severe in older mice, in part due to an age-dependent increase in oxidative stress. Mechanistically, depletion of the transcription factor GATA4 resulting in decreased levels of its prosurvival targets Bcl-2 and Bcl-XL was an underlying cause of imatinib toxicity. Consistent with this, GATA4 haploinsufficient mice were more susceptible to imatinib, and myocyte-specific up-regulation of GATA4 or Bcl-2 protected against drug-induced cardiotoxicity. Conclusion The results indicate that imatinib action on the heart targets cardiomyocytes and involves mitochondrial impairment and cell death that can be further aggravated by oxidative stress. This in turn offers a possible explanation for the current conflicting data regarding imatinib cardiotoxicity in cancer patients and suggests that cardiac monitoring of older patients receiving imatinib therapy may be especially warranted. PMID:24504921

  11. Treatment of Radiation-Induced Urethral Strictures.

    PubMed

    Hofer, Matthias D; Liu, Joceline S; Morey, Allen F

    2017-02-01

    Radiation therapy may result in urethral strictures from vascular damage. Most radiation-induced urethral strictures occur in the bulbomembranous junction, and urinary incontinence may result as a consequence of treatment. Radiation therapy may compromise reconstruction due to poor tissue healing and radionecrosis. Excision and primary anastomosis is the preferred urethroplasty technique for radiation-induced urethral stricture. Principles of posterior urethroplasty for trauma may be applied to the treatment of radiation-induced urethral strictures. Chronic management with suprapubic tube is an option based on patient comorbidities and preference.

  12. Molecular basis of cardiotoxicity upon cobra envenomation.

    PubMed

    Cher, C D N; Armugam, A; Zhu, Y Z; Jeyaseelan, K

    2005-01-01

    Various clinical manifestations leading to death have been documented in most cases of bites caused by venomous snakes. Cobra envenomation is an extremely variable process and known to cause profound neurological abnormalities. The complexity of cobra venom can induce multiple-organ failure, leading to death in case of severe envenomation. Intramuscular administration of Malayan spitting cobra (Naja sputatrix) crude venom at 1 microg/g dose caused death in mice in approximately 3 h. Analysis of gene expression profiles in the heart, brain, kidney, liver and lung revealed 203 genes whose expression was altered by at least 3-fold in response to venom treatment. Of these, 50% were differentially expressed in the heart and included genes involved in inflammation, apoptosis, ion transport and energy metabolism. Electrocardiogram recordings and serum troponin T measurements indicated declining cardiac function and myocardial damage. This not only sheds light on the cardiotoxicity of cobra venom but also reveals the molecular networks affected during envenomation.

  13. Radiation-induced moyamoya syndrome

    SciTech Connect

    Desai, Snehal S.; Paulino, Arnold C. . E-mail: apaulino@tmh.tmc.edu; Mai, Wei Y.; Teh, Bin S.

    2006-07-15

    Purpose: The moyamoya syndrome is an uncommon late complication after radiotherapy (RT). Methods and Materials: A PubMed search of English-language articles, with radiation, radiotherapy, and moyamoya syndrome used as search key words, yielded 33 articles from 1967 to 2002. Results: The series included 54 patients with a median age at initial RT of 3.8 years (range, 0.4 to 47). Age at RT was less than 5 years in 56.3%, 5 to 10 years in 22.9%, 11 to 20 years in 8.3%, 21 to 30 years in 6.3%, 31 to 40 years in 2.1%, and 41 to 50 years in 4.2%. Fourteen of 54 patients (25.9%) were diagnosed with neurofibromatosis type 1 (NF-1). The most common tumor treated with RT was low-grade glioma in 37 tumors (68.5%) of which 29 were optic-pathway glioma. The average RT dose was 46.5 Gy (range, 22-120 Gy). For NF-1-positive patients, the average RT dose was 46.5 Gy, and for NF-1-negative patients, it was 58.1 Gy. The median latent period for development of moyamoya syndrome was 40 months after RT (range, 4-240). Radiation-induced moyamoya syndrome occurred in 27.7% of patients by 2 years, 53.2% of patients by 4 years, 74.5% of patients by 6 years, and 95.7% of patients by 12 years after RT. Conclusions: Patients who received RT to the parasellar region at a young age (<5 years) are the most susceptible to moyamoya syndrome. The incidence for moyamoya syndrome continues to increase with time, with half of cases occurring within 4 years of RT and 95% of cases occurring within 12 years. Patients with NF-1 have a lower radiation-dose threshold for development of moyamoya syndrome.

  14. Hypopharyngeal carcinoma after radiation for tuberculosis: radiation-induced carcinoma.

    PubMed

    van der Putten, Lisa; de Bree, Remco; Kuik, Dirk J; Rietveld, Derek H F; Langendijk, Johannes A; Leemans, C René

    2010-09-01

    Radiation may cause radiation-induced cancers after a long latency period. In a group of 111 patients surgically treated for hypopharyngeal carcinoma, patients previously treated with radiotherapy for tuberculosis in the neck were compared to patients without previous radiotherapy. Seven patients (7.4%) underwent radiotherapy (median age 15 years) and developed a hypopharyngeal carcinoma (median age 70 years, median latency period 54.4 year). Considering this long latency period and the localisation in the previous radiation field these tumours can be classified as potentially radiation-induced carcinomas. Patients with potentially radiation-induced carcinomas were significantly older when the hypopharyngeal carcinoma was diagnosed (p=0.048), were more frequently females (p=0.05) and had a worse 5-year regional control rate (p=0.048). When radiotherapy is considered in young patients the risk of induction of tumours has to be kept in mind. Copyright 2010 Elsevier Ltd. All rights reserved.

  15. Hyperbaric Oxygen Preconditioning Provides Preliminary Protection Against Doxorubicin Cardiotoxicity

    PubMed Central

    Tezcan, Orhan; Karahan, Oguz; Alan, Mustafa; Ekinci, Cenap; Yavuz, Celal; Demirtas, Sinan; Ekinci, Aysun; Caliskan, Ahmet

    2017-01-01

    Background Doxorubicin (DOX) is generally recognized to have important cardiotoxic side effects. Studies are contradictory about the interaction between hyperbaric oxygen (HBO2) therapy and doxorubicin-induced cardiomyotoxicity. Recent data suggests that HBO2 therapy can lead to preconditioning of myocardium while generating oxidative stress. Herein we have investigated the effect of HBO2 therapy in a DOX-induced cardiomyocyte injury animal model. Methods Twenty-one rats were divided into three equal groups as follows: 1) Group 1 is a control group (without any intervention), used for evaluating the basal cardiac structures and determining the normal value of cardiacs and serum oxidative markers; 2) Group 2 is the doxorubicin group (single dose i.p. 20 mg/kg doxorubicin) for detecting the cardiotoxic and systemic effects of doxorubicin; 3) Group 3 is the doxorubicin and HBO2 group (100% oxygen at 2.5 atmospheric for 90 minutes, daily), for evaluating the effect of HBO2 in doxorubicin induced cardiotoxicity. At the end of the protocols, the hearts were harvested and blood samples (2 ml) were obtained. Results The doxorubicin treated animals (Group 2) had increased oxidative stress markers (both cardiac and serum) and severe cardiac injury as compared to the basal findings in the control group. Nevertheless, the highest cardiac oxidative stress index was detected in Group 3 (control vs. Group 3, p = 0.01). However, histological examination revealed that cardiac structures were well preserved in Group 3 when compared with Group 2. Conclusions Our results suggest that HBO2 preconditioning appears to be protective in the doxorubicin-induced cardiotoxicity model. Future studies are required to better elucidate the basis of this preconditioning effect of HBO2. PMID:28344418

  16. Factors that modify radiation-induced carcinogenesis.

    PubMed

    Kennedy, Ann R

    2009-11-01

    It is known that numerous factors can influence radiation carcinogenesis in animals; these factors include the specific characteristics of the radiation (radiation type and dose, dose-rate, dose-fractionation, dose distribution, etc.) as well as many other contributing elements that are not specific to the radiation exposure, such as animal genetic characteristics and age, the environment of the animal, dietary factors and whether specific modifying agents for radiation carcinogenesis have been utilized in the studies. This overview focuses on the modifying factors for radiation carcinogenesis, in both in vivo and in vitro systems, and includes a discussion of agents that enhance (e.g., promoting agents) or suppress (e.g., cancer preventive agents) radiation-induced carcinogenesis. The agents that enhance or suppress radiation carcinogenesis in experimental model systems have been shown to lead to effects equally as large as other known modifying factors for radiation-induced carcinogenesis (e.g., dose-rate, dose-fractionation, linear energy transfer). It is known that dietary factors play an important role in determining the yields of radiation-induced cancers in animal model systems, and it is likely that they also influence radiation-induced cancer risks in human populations.

  17. Echinochrome A Protects Mitochondrial Function in Cardiomyocytes against Cardiotoxic Drugs

    PubMed Central

    Jeong, Seung Hun; Kim, Hyoung Kyu; Song, In-Sung; Lee, Seon Joong; Ko, Kyung Soo; Rhee, Byoung Doo; Kim, Nari; Mishchenko, Natalia P.; Fedoryev, Sergey A.; Stonik, Valentin A.; Han, Jin

    2014-01-01

    Echinochrome A (Ech A) is a naphthoquinoid pigment from sea urchins that possesses antioxidant, antimicrobial, anti-inflammatory and chelating abilities. Although Ech A is the active substance in the ophthalmic and cardiac drug Histochrome®, its underlying cardioprotective mechanisms are not well understood. In this study, we investigated the protective role of Ech A against toxic agents that induce death of rat cardiac myoblast H9c2 cells and isolated rat cardiomyocytes. We found that the cardiotoxic agents tert-Butyl hydroperoxide (tBHP, organic reactive oxygen species (ROS) inducer), sodium nitroprusside (SNP; anti-hypertension drug), and doxorubicin (anti-cancer drug) caused mitochondrial dysfunction such as increased ROS level and decreased mitochondrial membrane potential. Co-treatment with Ech A, however, prevented this decrease in membrane potential and increase in ROS level. Co-treatment of Ech A also reduced the effects of these cardiotoxic agents on mitochondrial oxidative phosphorylation and adenosine triphosphate level. These findings indicate the therapeutic potential of Ech A for reducing cardiotoxic agent-induced damage. PMID:24828295

  18. Radiation-induced genomic instability: radiation quality and dose response

    NASA Technical Reports Server (NTRS)

    Smith, Leslie E.; Nagar, Shruti; Kim, Grace J.; Morgan, William F.

    2003-01-01

    Genomic instability is a term used to describe a phenomenon that results in the accumulation of multiple changes required to convert a stable genome of a normal cell to an unstable genome characteristic of a tumor. There has been considerable recent debate concerning the importance of genomic instability in human cancer and its temporal occurrence in the carcinogenic process. Radiation is capable of inducing genomic instability in mammalian cells and instability is thought to be the driving force responsible for radiation carcinogenesis. Genomic instability is characterized by a large collection of diverse endpoints that include large-scale chromosomal rearrangements and aberrations, amplification of genetic material, aneuploidy, micronucleus formation, microsatellite instability, and gene mutation. The capacity of radiation to induce genomic instability depends to a large extent on radiation quality or linear energy transfer (LET) and dose. There appears to be a low dose threshold effect with low LET, beyond which no additional genomic instability is induced. Low doses of both high and low LET radiation are capable of inducing this phenomenon. This report reviews data concerning dose rate effects of high and low LET radiation and their capacity to induce genomic instability assayed by chromosomal aberrations, delayed lethal mutations, micronuclei and apoptosis.

  19. Radiation-induced genomic instability: radiation quality and dose response

    NASA Technical Reports Server (NTRS)

    Smith, Leslie E.; Nagar, Shruti; Kim, Grace J.; Morgan, William F.

    2003-01-01

    Genomic instability is a term used to describe a phenomenon that results in the accumulation of multiple changes required to convert a stable genome of a normal cell to an unstable genome characteristic of a tumor. There has been considerable recent debate concerning the importance of genomic instability in human cancer and its temporal occurrence in the carcinogenic process. Radiation is capable of inducing genomic instability in mammalian cells and instability is thought to be the driving force responsible for radiation carcinogenesis. Genomic instability is characterized by a large collection of diverse endpoints that include large-scale chromosomal rearrangements and aberrations, amplification of genetic material, aneuploidy, micronucleus formation, microsatellite instability, and gene mutation. The capacity of radiation to induce genomic instability depends to a large extent on radiation quality or linear energy transfer (LET) and dose. There appears to be a low dose threshold effect with low LET, beyond which no additional genomic instability is induced. Low doses of both high and low LET radiation are capable of inducing this phenomenon. This report reviews data concerning dose rate effects of high and low LET radiation and their capacity to induce genomic instability assayed by chromosomal aberrations, delayed lethal mutations, micronuclei and apoptosis.

  20. Radiation-induced gene responses

    SciTech Connect

    Woloschak, G.E.; Paunesku, T.; Shearin-Jones, P.; Oryhon, J.

    1996-12-31

    In the process of identifying genes that are differentially regulated in cells exposed to ultraviolet radiation (UV), we identified a transcript that was repressed following the exposure of cells to a combination of UV and salicylate, a known inhibitor of NF-kappaB. Sequencing this band determined that it has identify to lactate dehydrogenase, and Northern blots confirmed the initial expression pattern. Analysis of the sequence of the LDH 5` region established the presence of NF-kappaB, Sp1, and two Ap-2 elements; two partial AP- 1; one partial RE, and two halves of E-UV elements were also found. Electromobility shift assays were then performed for the AP-1, NF- kappaB, and E-UV elements. These experiments revealed that binding to NF-kappaB was induced by UV but repressed with salicylic acid; UV did not affect AP-1 binding, but salicylic acid inhibited it alone or following UV exposure; and E-UV binding was repressed by UV, and salicylic acid had little effect. Since the binding of no single element correlated with the expression pattern of LDH, it is likely that multiple elements govern UV/salicylate-mediated expression.

  1. Physiological Sample Uniformity and Time-Course Stability in Lined-Up Structure of Human Cardiomyocyte Network for In vitro Predictive Drug-Induced Cardiotoxicity

    NASA Astrophysics Data System (ADS)

    Hamada, Tomoyo; Kaneko, Tomoyuki; Nomura, Fumimasa; Yasuda, Kenji

    2013-06-01

    We have evaluated the electrophysiological characteristics of a line-shaped network of a three-dimensionally controlled in vitro human cardiomyocyte assay (hCM line) against conventional cell clusters as the standard model (hCM cluster) from the viewpoint of quality control of sample variety and time-course stability. The beating intervals of the hCM line demonstrated a more stable uniformity of samples (846 +/-130 ms, 15.3% fluctuation) and better time-course stability, whereas those of the hCM cluster showed a much larger variety of samples (2001 +/-1127 ms, 56.3% fluctuation) and weaker time-course stability. The field potential amplitude of the hCM line also showed better uniformity of samples (629 +/-428 µV, 68.0% fluctuation) against those of the hCM cluster (1984 +/-2288 µV, 115.3% fluctuation). The results suggested the importance of the cell-network shape control for the uniformity and stability of the beating interval and the field potential amplitude. They also suggest that the hCM line can improve the reproducibility and accuracy of the samples, which is important for a functional human cardiotoxicity model.

  2. A cell culture assay for the detection of cardiotoxicity

    SciTech Connect

    Loew-Friedrich, Iv.; von Bredow, F.; Schoeppe, W. )

    1991-04-01

    An important step in minimizing the number of animal experiments in medical research is the study of in vitro model systems. The authors propose the use of shock protein formation, which is a cellular response to cell-damaging stress as an assay to monitor cardiotoxicity. Isolated and cultured cardiac myocytes were prepared by a trypsin digestion method from 18-day-old fetal mice. These cells respond to typical substances inducing shock protein formation in other cellular systems as well as to known cardiotoxins with the de novo synthesis of shock proteins. Pharmaceuticals relevant in transplant medicine were tested for possible cardiotoxic effects: Cyclosporine A evokes shock protein formation at subtherapeutic concentrations. Azathioprine and methyl-prednisolone exert the same effect but at concentration ranges highly above the therapeutic level. The ability to induce shock protein synthesis obviously seems to be restricted to toxic drugs. The data presented demonstrate that the proposed in vitro model system for cardiotoxicity is animal saving and sensitive.

  3. Risk factors for anthracycline-associated cardiotoxicity

    PubMed Central

    Patel, Roshan; Pan, Xueliang; Timmers, Cynthia Dawn; Pilarski, Robert; Shapiro, Charles L.; Lustberg, Maryam B.

    2016-01-01

    Purpose Carbonyl reductase (CBR) catalyzes anthracycline metabolism, and single nucleotide polymorphisms (SNPs) in CBR impact metabolic efficiency. In pediatric patients, homo-zygosity for the major allele (G) in the CBR3 gene was associated with increased risk of anthracycline cardiotoxicity. We hypothesized that CBR SNPs contribute to cardiotoxicity in adults Methods We retrospectively identified female breast cancer patients in the Columbus Breast Tissue Bank Registry treated with adriamycin and cytoxan (AC) from 2003 to 2012. We selected patients who developed cardiomyopathy, defined as a drop in ejection fraction to <50 % or >15 % decrease from pre-therapy. Univariate and multivariate logistic regressions were performed to identify cardiotoxicity risk factors. SNPs were genotyped, and frequency of the major allele (G)/minor allele (A) of the CBR3 and CBR1 genes was calculated. Results We identified 52 cases of cardiotoxicity after AC and 110 controls. Multivariate analysis showed that trastuzumab (p=0.009), diabetes (p=0.05), and consumption of >8 alcoholic drinks/week (p=0.024) were associated with higher cardiotoxicity risk. Moderate alcohol consumption (<8 drinks/week) was associated with lower risk (p=0.009). No association was identified between CBR SNPs and cardiotoxicity (CBR1 p= 0.261; CBR3 p=0.556). Conclusions This is the first study to evaluate SNPs in the CBR pathway as predictors of AC cardiotoxicity in adults. We did not observe any significant correlation between cardiotoxicity and SNPs within the CBR pathway. Further investigation into CBR SNPs in a larger adult sample is needed. Additional exploration into genomic predictors of anthracycline cardiotoxicity may allow for the development of preventative and therapeutic strategies for those at risk. PMID:26563179

  4. Risk factors for anthracycline-associated cardiotoxicity.

    PubMed

    Reinbolt, Raquel E; Patel, Roshan; Pan, Xueliang; Timmers, Cynthia Dawn; Pilarski, Robert; Shapiro, Charles L; Lustberg, Maryam B

    2016-05-01

    Carbonyl reductase (CBR) catalyzes anthracycline metabolism, and single nucleotide polymorphisms (SNPs) in CBR impact metabolic efficiency. In pediatric patients, homozygosity for the major allele (G) in the CBR3 gene was associated with increased risk of anthracycline cardiotoxicity. We hypothesized that CBR SNPs contribute to cardiotoxicity in adults. We retrospectively identified female breast cancer patients in the Columbus Breast Tissue Bank Registry treated with adriamycin and cytoxan (AC) from 2003 to 2012. We selected patients who developed cardiomyopathy, defined as a drop in ejection fraction to <50 % or >15 % decrease from pre-therapy. Univariate and multivariate logistic regressions were performed to identify cardiotoxicity risk factors. SNPs were genotyped, and frequency of the major allele (G)/minor allele (A) of the CBR3 and CBR1 genes was calculated. We identified 52 cases of cardiotoxicity after AC and 110 controls. Multivariate analysis showed that trastuzumab (p = 0.009), diabetes (p = 0.05), and consumption of >8 alcoholic drinks/week (p = 0.024) were associated with higher cardiotoxicity risk. Moderate alcohol consumption (<8 drinks/week) was associated with lower risk (p = 0.009). No association was identified between CBR SNPs and cardiotoxicity (CBR1 p = 0.261; CBR3 p = 0.556). This is the first study to evaluate SNPs in the CBR pathway as predictors of AC cardiotoxicity in adults. We did not observe any significant correlation between cardiotoxicity and SNPs within the CBR pathway. Further investigation into CBR SNPs in a larger adult sample is needed. Additional exploration into genomic predictors of anthracycline cardiotoxicity may allow for the development of preventative and therapeutic strategies for those at risk.

  5. Radiation-induced thyroid disease

    SciTech Connect

    Maxon, H.R.

    1985-09-01

    Ionizing radiation has been demonstrated to result in a number of changes in the human thyroid gland. At lower radiation dose levels (between 10 and 1500 rads), benign and malignant neoplasms appear to be the dominant effect, whereas at higher dose levels functional changes and thyroiditis become more prevalent. In all instances, the likelihood of the effect is related to the amount and type of radiation exposure, time since exposure, and host factors such as age, sex, and heredity. The author's current approach to the evaluation of patients with past external radiation therapy to the thyroid is discussed. The use of prophylactic thyroxine (T4) therapy is controversial. While T4 therapy may not be useful in preventing carcinogenesis when instituted many years after radiation exposure, theoretically T4 may block TSH secretion and stimulation of damaged cells to undergo malignant transformation when instituted soon after radiation exposure.

  6. Ionizing radiation and heart risks.

    PubMed

    Bhattacharya, Souparno; Asaithamby, Aroumougame

    2016-10-01

    Cardiovascular disease and cancer are the two leading causes of morbidity and mortality worldwide. As advancements in radiation therapy (RT) have significantly increased the number of cancer survivors, the risk of radiation-induced cardiovascular disease (RICD) in this group is a growing concern. Recent epidemiological data suggest that accidental or occupational exposure to low dose radiation, in addition to therapeutic ionizing radiation, can result in cardiovascular complications. The progression of radiation-induced cardiotoxicity often takes years to manifest but is also multifaceted, as the heart may be affected by a variety of pathologies. The risk of cardiovascular disease development in RT cancer survivors has been known for 40 years and several risk factors have been identified in the last two decades. However, most of the early work focused on clinical symptoms and manifestations, rather than understanding cellular processes regulating homeostatic processes of the cardiovascular system in response to radiation. Recent studies have suggested that a different approach may be needed to refute the risk of cardiovascular disease following radiation exposure. In this review, we will focus on how different radiation types and doses may induce cardiovascular complications, highlighting clinical manifestations and the mechanisms involved in the pathophysiology of radiation-induced cardiotoxicity. We will finally discuss how current and future research on heart development and homeostasis can help reduce the incidence of RICD.

  7. Cardiotoxicity in childhood cancer survivors: strategies for prevention and management.

    PubMed

    Harake, Danielle; Franco, Vivian I; Henkel, Jacqueline M; Miller, Tracie L; Lipshultz, Steven E

    2012-07-01

    Advances in cancer treatment have greatly improved survival rates of children with cancer. However, these same chemotherapeutic or radiologic treatments may result in long-term health consequences. Anthracyclines, chemotherapeutic drugs commonly used to treat children with cancer, are known to be cardiotoxic, but the mechanism by which they induce cardiac damage is still not fully understood. A higher cumulative anthracycline dose and a younger age of diagnosis are only a few of the many risk factors that identify the children at increased risk of developing cardiotoxicity. While cardiotoxicity can develop at anytime, starting from treatment initiation and well into adulthood, identifying the best cardioprotective measures to minimize the long-term damage caused by anthracyclines in children is imperative. Dexrazoxane is the only known agent to date, that is associated with less cardiac dysfunction, without reducing the oncologic efficacy of the anthracycline doxorubicin in children. Given the serious long-term health consequences of cancer treatments on survivors of childhood cancers, it is essential to investigate new approaches to improving the safety of cancer treatments.

  8. Cardiotoxicity in childhood cancer survivors: strategies for prevention and management

    PubMed Central

    Harake, Danielle; Franco, Vivian I; Henkel, Jacqueline M; Miller, Tracie L; Lipshultz, Steven E

    2013-01-01

    Advances in cancer treatment have greatly improved survival rates of children with cancer. However, these same chemotherapeutic or radiologic treatments may result in long-term health consequences. Anthracyclines, chemotherapeutic drugs commonly used to treat children with cancer, are known to be cardiotoxic, but the mechanism by which they induce cardiac damage is still not fully understood. A higher cumulative anthracycline dose and a younger age of diagnosis are only a few of the many risk factors that identify the children at increased risk of developing cardiotoxicity. While cardiotoxicity can develop at anytime, starting from treatment initiation and well into adulthood, identifying the best cardioprotective measures to minimize the long-term damage caused by anthracyclines in children is imperative. Dexrazoxane is the only known agent to date, that is associated with less cardiac dysfunction, without reducing the oncologic efficacy of the anthracycline doxorubicin in children. Given the serious long-term health consequences of cancer treatments on survivors of childhood cancers, it is essential to investigate new approaches to improving the safety of cancer treatments. PMID:22871201

  9. Chemotherapy-related cardiotoxicity: new diagnostic and preventive strategies.

    PubMed

    Benvenuto, Giuseppe Marino; Ometto, Renato; Fontanelli, Alessandro; Fortunato, Antonio; Ruffini, Pier Adelchi; Fosser, Vinicio; Morandi, Paolo

    2003-10-01

    Chemotherapy is an established approach for several malignancies, but its utility may be hampered by induced cardiac toxicity possibly leading to heart failure, with a negative impact on the patient's quality of life and ultimately survival. Prospective left ventricular systolic function monitoring has demonstrated that cardiotoxicity could be subclinically present for many months or years before its overt manifestation. Although considered irreversible, some reports suggested recovery or delayed progression of cardiac dysfunction by preventive cardioactive therapies. Thus, the identification of earlier instrumental or biochemical markers of cardiac injury able to predict heart failure remains a major task. Diastolic indexes as a primary expression of hemodynamic dysfunction after cardiac damage, analyzed by means of conventional or newer Doppler technologies (tissue Doppler, color M-mode, etc.) are discussed. Moreover, brain natriuretic peptides, troponins and endothelin-1, as possible sensitive/specific markers/predictors of subclinical cardiotoxicity are reviewed in order to update and possibly improve the strategy for the detection and clinical management of chemotherapy-related cardiotoxic effects.

  10. Radiation-induced lung injury

    SciTech Connect

    Rosiello, R.A.; Merrill, W.W. )

    1990-03-01

    The use of radiation therapy is limited by the occurrence of the potentially fatal clinical syndromes of radiation pneumonitis and fibrosis. Radiation pneumonitis usually becomes clinically apparent from 2 to 6 months after completion of radiation therapy. It is characterized by fever, cough, dyspnea, and alveolar infiltrates on chest roentgenogram and may be difficult to differentiate from infection or recurrent malignancy. The pathogenesis is uncertain, but appears to involve both direct lung tissue toxicity and an inflammatory response. The syndrome may resolve spontaneously or may progress to respiratory failure. Corticosteroids may be effective therapy if started early in the course of the disease. The time course for the development of radiation fibrosis is later than that for radiation pneumonitis. It is usually present by 1 year following irradiation, but may not become clinically apparent until 2 years after radiation therapy. It is characterized by the insidious onset of dyspnea on exertion. It most often is mild, but can progress to chronic respiratory failure. There is no known successful treatment for this condition. 51 references.

  11. Subacute Cardiotoxicity of Yessotoxin: In Vitro and in Vivo Studies.

    PubMed

    Ferreiro, Sara F; Vilariño, Natalia; Carrera, Cristina; Louzao, M Carmen; Cantalapiedra, Antonio G; Santamarina, Germán; Cifuentes, J Manuel; Vieira, Andrés C; Botana, Luis M

    2016-06-20

    Yessotoxin (YTX) is a marine phycotoxin produced by dinoflagellates and accumulated in filter feeding shellfish. Although no human intoxication episodes have been reported, YTX content in shellfish is regulated by many food safety authorities due to their worldwide distribution. YTXs have been related to ultrastructural heart damage in vivo, but the functional consequences in the long term have not been evaluated. In this study, we explored the accumulative cardiotoxic potential of YTX in vitro and in vivo. Preliminary in vitro evaluation of cardiotoxicity was based on the effect on hERG (human ether-a-go-go related gene) channel trafficking. In vivo experiments were performed in rats that received repeated administrations of YTX followed by recordings of electrocardiograms, arterial blood pressure, plasmatic cardiac biomarkers, and analysis of myocardium structure and ultrastructure. Our results showed that an exposure to 100 nM YTX for 12 or 24 h caused an increase of extracellular surface hERG channels. Furthermore, remarkable bradycardia and hypotension, structural heart alterations, and increased plasma levels of tissue inhibitor of metalloproteinases-1 were observed in rats after four intraperitoneal injections of YTX at doses of 50 or 70 μg/kg that were administered every 4 days along a period of 15 days. Therefore, and for the first time, YTX-induced subacute cardiotoxicity is supported by evidence of cardiovascular function alterations related to its repeated administration. Considering international criteria for marine toxin risk estimation and that the regulatory limit for YTX has been recently raised in many countries, YTX cardiotoxicity might pose a health risk to humans and especially to people with previous cardiovascular risk.

  12. Radiation-induced accelerated coronary arteriosclerosis

    SciTech Connect

    Mittal, B.; Deutsch, M.; Thompson, M.; Dameshek, H.L.

    1986-07-01

    There is a paucity of information on radiation-induced coronary heart disease. A young patient with myocardial infarction following mediastinal irradiation is described. The role of radiotherapy and chemotherapy on the subsequent development of coronary heart disease is discussed.

  13. Ultraviolet radiation induced discharge laser

    DOEpatents

    Gilson, Verle A.; Schriever, Richard L.; Shearer, James W.

    1978-01-01

    An ultraviolet radiation source associated with a suitable cathode-anode electrode structure, disposed in a gas-filled cavity of a high pressure pulsed laser, such as a transverse electric atmosphere (TEA) laser, to achieve free electron production in the gas by photoelectric interaction between ultraviolet radiation and the cathode prior to the gas-exciting cathode-to-anode electrical discharge, thereby providing volume ionization of the gas. The ultraviolet radiation is produced by a light source or by a spark discharge.

  14. Molecular pathways: radiation-induced cognitive impairment.

    PubMed

    Greene-Schloesser, Dana; Moore, Elizabeth; Robbins, Mike E

    2013-05-01

    Each year, approximately 200,000 patients in the United States will receive partial- or whole-brain irradiation for the treatment of primary or metastatic brain cancer. Early and delayed radiation effects are transient and reversible with modern therapeutic standards; yet, late radiation effects (≥6 months postirradiation) remain a significant risk, resulting in progressive cognitive impairment. These risks include functional deficits in memory, attention, and executive function that severely affect the patient's quality of life. The mechanisms underlying radiation-induced cognitive impairment remain ill defined. Classically, radiation-induced alterations in vascular and neuroinflammatory glial cell clonogenic populations were hypothesized to be responsible for radiation-induced brain injury. Recently, preclinical studies have focused on the hippocampus, one of two sites of adult neurogenesis within the brain, which plays an important role in learning and memory. Radiation ablates hippocampal neurogenesis, alters neuronal function, and induces neuroinflammation. Neuronal stem cells implanted into the hippocampus prevent the decrease in neurogenesis and improve cognition after irradiation. Clinically prescribed drugs, including PPARα and PPARγ agonists, as well as RAS blockers, prevent radiation-induced neuroinflammation and cognitive impairment independent of improved neurogenesis. Translating these exciting findings to the clinic offers the promise of improving the quality of life of brain tumor patients who receive radiotherapy. ©2013 AACR.

  15. Catechin protects against oxidative stress and inflammatory-mediated cardiotoxicity in adriamycin-treated rats.

    PubMed

    Abd El-Aziz, Tarek A; Mohamed, Randa H; Pasha, Heba F; Abdel-Aziz, Hisham R

    2012-12-01

    Catechin has anti-inflammatory and antioxidative effects. Cardiotoxicity, which results from intense cardiac oxidative stress and inflammation, is the main limiting factor of the adriamycin use in the treatment of malignant tumors. Thus, the present study aimed to assess the antioxidant and anti-inflammatory effects of catechin on adriamycin-induced cardiotoxicity in rats. Forty-five rats were allocated to three groups: control group, adriamycin group and adriamycin + catechin group. We performed the following measurements: lipid peroxidation (MDA), catalase (CAT), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities as well as, the expression of inflammatory cytokines genes namely nuclear factor kappa-B, tumor necrosis factor and inducible nitric oxide synthase. Catechin administration significantly decreased MDA level and significantly increased CAT, GSH-Px and SOD activities. Also, catechin significantly decreased the expression levels of inflammatory cytokines. Catechin provided cardioprotection on adriamycin-induced cardiotoxicity through their antioxidant and anti-inflammatory properties.

  16. Radiation-induced sarcoma of the thyroid

    SciTech Connect

    Griem, K.L.; Robb, P.K.; Caldarelli, D.D.; Templeton, A.C. )

    1989-08-01

    A 23-year-old white man presented with a thyroid mass 12 years after receiving high-dose radiotherapy for a T2 and N1 lymphoepithelioma of the nasopharynx. Following subtotal thyroidectomy, a histopathologic examination revealed liposarcoma of the thyroid gland. The relationship between sarcomas and irradiation is described and Cahan and colleagues' criteria for radiation-induced sarcomas are reviewed. To our knowledge, we are presenting the first such case of a radiation-induced sarcoma of the thyroid gland.

  17. Radiation induced detwinning in nanotwinned Cu

    SciTech Connect

    Chen, Youxing; Wang, Haiyan; Kirk, Mark A.; Li, Meimei; Wang, Jian; Zhang, Xinghang

    2016-11-15

    Superior radiation tolerance has been experimentally examined in nanotwinned metals. The stability of nanotwinned structure under radiation is the key factor for advancing the application of nanotwinned metals for nuclear reactors. We thus performed in situ radiation tests for nanotwinned Cu with various twin thicknesses inside a transmission electron microscope. We found that there is a critical twin thickness (10 nm), below which, radiation induced detwinning is primarily accomplished through migration of incoherent twin boundaries. Lastly, detwinning is faster for thinner twins in this range, while thicker twins are more stable.

  18. Radiation-induced vaginal stenosis: current perspectives

    PubMed Central

    Morris, Lucinda; Do, Viet; Chard, Jennifer; Brand, Alison H

    2017-01-01

    Treatment of gynecological cancer commonly involves pelvic radiation therapy (RT) and/or brachytherapy. A commonly observed side effect of such treatment is radiation-induced vaginal stenosis (VS). This review analyzed the incidence, pathogenesis, clinical manifestation(s) and assessment and grading of radiation-induced VS. In addition, risk factors, prevention and treatment options and follow-up schedules are also discussed. The limited available literature on many of these aspects suggests that additional studies are required to more precisely determine the best management strategy of this prevalent group after RT. PMID:28496367

  19. Triptolide Mitigates Radiation-Induced Pulmonary Fibrosis.

    PubMed

    Yang, Shanmin; Zhang, Mei; Chen, Chun; Cao, Yongbin; Tian, Yeping; Guo, Yangsong; Zhang, Bingrong; Wang, Xiaohui; Yin, Liangjie; Zhang, Zhenhuan; O'Dell, Walter; Okunieff, Paul; Zhang, Lurong

    2015-11-01

    Triptolide (TPL) may mitigate radiation-induced late pulmonary side effects through its inhibition of global pro-inflammatory cytokines. In this study, we evaluated the effect of TPL in C57BL/6 mice, the animals were exposed to radiation with vehicle (15 Gy), radiation with TPL (0.25 mg/kg i.v., twice weekly for 1, 2 and 3 months), radiation and celecoxib (CLX) (30 mg/kg) and sham irradiation. Cultured supernatant of irradiated RAW 264.7 and MLE-15 cells and lung lysate in different groups were enzyme-linked immunosorbent assays at 33 h. Respiratory rate, pulmonary compliance and pulmonary density were measured at 5 months in all groups. The groups exposed to radiation with vehicle and radiation with TPL exhibited significant differences in respiratory rate and pulmonary compliance (480 ± 75/min vs. 378 ± 76/min; 0.6 ± 0.1 ml/cm H2O/p kg vs. 0.9 ± 0.2 ml/cm H2O/p kg). Seventeen cytokines were significantly reduced in the lung lysate of the radiation exposure with TPL group at 5 months compared to that of the radiation with vehicle group, including profibrotic cytokines implicated in pulmonary fibrosis, such as IL-1β, TGF- β1 and IL-13. The radiation exposure with TPL mice exhibited a 41% reduction of pulmonary density and a 25% reduction of hydroxyproline in the lung, compared to that of radiation with vehicle mice. The trichrome-stained area of fibrotic foci and pathological scaling in sections of the mice treated with radiation and TPL mice were significantly less than those of the radiation with vehicle-treated group. In addition, the radiation with TPL-treated mice exhibited a trend of improved survival rate compared to that of the radiation with vehicle-treated mice at 5 months (83% vs. 53%). Three radiation-induced profibrotic cytokines in the radiation with vehicle-treated group were significantly reduced by TPL treatment, and this partly contributed to the trend of improved survival rate and pulmonary density and function and the decreased severity of

  20. Radiation-induced instability and its relation to radiation carcinogenesis

    NASA Technical Reports Server (NTRS)

    Ullrich, R. L.; Ponnaiya, B.

    1998-01-01

    PURPOSE: A model that identifies radiation-induced genetic instability as the earliest cellular event in the multi-step sequence leading to radiation-induced cancer was previously proposed. In this paper ongoing experiments are discussed which are designed to test this model and its predictions in mouse mammary epithelial cells. RESULTS: Several lines of evidence are presented that appear to support this model: first, the development of delayed mutations in p53 following irradiation in altered growth variants; secondly, the high frequencies for the induction of both instability and transformation following irradiation in mammary epithelial cells; and finally, the demonstration that susceptibility to the induction of cytogenetic instability is a heritable trait that correlates with susceptibility to transformation and radiation-induced mammary cancer. Mice resistant to transformation and mammary cancer development are also resistant to the development of instability after irradiation. In contrast, mice sensitive to transformation and cancer are also sensitive to the development of cytogenetic instability. CONCLUSIONS: Data from this laboratory and from the studies cited above suggest a specific, and perhaps unique, role for radiation-induced instability as a critical early event associated with initiation of the carcinogenic process.

  1. Radiation-induced instability and its relation to radiation carcinogenesis

    NASA Technical Reports Server (NTRS)

    Ullrich, R. L.; Ponnaiya, B.

    1998-01-01

    PURPOSE: A model that identifies radiation-induced genetic instability as the earliest cellular event in the multi-step sequence leading to radiation-induced cancer was previously proposed. In this paper ongoing experiments are discussed which are designed to test this model and its predictions in mouse mammary epithelial cells. RESULTS: Several lines of evidence are presented that appear to support this model: first, the development of delayed mutations in p53 following irradiation in altered growth variants; secondly, the high frequencies for the induction of both instability and transformation following irradiation in mammary epithelial cells; and finally, the demonstration that susceptibility to the induction of cytogenetic instability is a heritable trait that correlates with susceptibility to transformation and radiation-induced mammary cancer. Mice resistant to transformation and mammary cancer development are also resistant to the development of instability after irradiation. In contrast, mice sensitive to transformation and cancer are also sensitive to the development of cytogenetic instability. CONCLUSIONS: Data from this laboratory and from the studies cited above suggest a specific, and perhaps unique, role for radiation-induced instability as a critical early event associated with initiation of the carcinogenic process.

  2. Comparative Investigation of Protective Effects of Metyrosine and Metoprolol Against Ketamine Cardiotoxicity in Rats.

    PubMed

    Ahiskalioglu, Ali; Ince, Ilker; Aksoy, Mehmet; Ahiskalioglu, Elif Oral; Comez, Mehmet; Dostbil, Aysenur; Celik, Mine; Alp, Hamit Hakan; Coskun, Resit; Taghizadehghalehjoughi, Ali; Suleyman, Bahadir

    2015-10-01

    This study investigated the effect of metyrosine against ketamine-induced cardiotoxicity in rats and compared the results with the effect of metoprolol. In this study, rats were divided into groups A, B and C. In group A, we investigated the effects of a single dose of metyrosine (150 mg/kg) and metoprolol (20 mg/kg) on single dose ketamine (60 mg/kg)-induced cardiotoxicity. In group B, we investigated the effect of metyrosine and metoprolol, which were given together with ketamine for 30 days. In group C, we investigated the effect of metyrosine and metoprolol given 15 days before ketamine and 30 days together with ketamine on ketamine cardiotoxicity. By the end of this process, we evaluated the effects of the levels of oxidant-antioxidant parameters such as MDA, MPO, 8-OHGua, tGSH, and SOD in addition to CK-MB and TP I on cardiotoxicity in rat heart tissue. The experimental results show that metyrosine prevented ketamine cardiotoxicity in groups A, B and C and metoprolol prevented it in only group C.

  3. Oxidative Stress, Redox Signaling, and Metal Chelation in Anthracycline Cardiotoxicity and Pharmacological Cardioprotection

    PubMed Central

    Popelová, Olga; Vávrová, Anna; Jirkovský, Eduard; Kovaříková, Petra; Geršl, Vladimír

    2013-01-01

    Abstract Significance: Anthracyclines (doxorubicin, daunorubicin, or epirubicin) rank among the most effective anticancer drugs, but their clinical usefulness is hampered by the risk of cardiotoxicity. The most feared are the chronic forms of cardiotoxicity, characterized by irreversible cardiac damage and congestive heart failure. Although the pathogenesis of anthracycline cardiotoxicity seems to be complex, the pivotal role has been traditionally attributed to the iron-mediated formation of reactive oxygen species (ROS). In clinics, the bisdioxopiperazine agent dexrazoxane (ICRF-187) reduces the risk of anthracycline cardiotoxicity without a significant effect on response to chemotherapy. The prevailing concept describes dexrazoxane as a prodrug undergoing bioactivation to an iron-chelating agent ADR-925, which may inhibit anthracycline-induced ROS formation and oxidative damage to cardiomyocytes. Recent Advances: A considerable body of evidence points to mitochondria as the key targets for anthracycline cardiotoxicity, and therefore it could be also crucial for effective cardioprotection. Numerous antioxidants and several iron chelators have been tested in vitro and in vivo with variable outcomes. None of these compounds have matched or even surpassed the effectiveness of dexrazoxane in chronic anthracycline cardiotoxicity settings, despite being stronger chelators and/or antioxidants. Critical Issues: The interpretation of many findings is complicated by the heterogeneity of experimental models and frequent employment of acute high-dose treatments with limited translatability to clinical practice. Future Directions: Dexrazoxane may be the key to the enigma of anthracycline cardiotoxicity, and therefore it warrants further investigation, including the search for alternative/complementary modes of cardioprotective action beyond simple iron chelation. Antioxid. Redox Signal. 00, 000–000. PMID:22794198

  4. [Quantification of radiation-induced genetic risk].

    PubMed

    Ehling, U H

    1987-05-01

    Associated with technical advances of our civilization is a radiation- and chemically-induced increase in the germ cell mutation rate in man. This would result in an increase in the frequency of genetic diseases and would be detrimental to future generations. It is the duty of our generation to keep this risk as low as possible. The estimation of the radiation-induced genetic risk of human populations is based on the extrapolation of results from animal experiments. Radiation-induced mutations are stochastic events. The probability of the event depends on the dose; the degree of the damage does not. The different methods to estimate the radiation-induced genetic risk will be discussed. The accuracy of the predicted results will be evaluated by a comparison with the observed incidence of dominant mutations in offspring born to radiation exposed survivors of the Hiroshima and Nagasaki atomic bombings. These methods will be used to predict the genetic damage from the fallout of the reactor accident at Chernobyl. For the exposure dose we used the upper limits of the mean effective life time equivalent dose from the fallout values in the Munich region. According to the direct method for the risk estimation we will expect for each 100 to 500 spontaneous dominant mutations one radiation-induced mutation in the first generation. With the indirect method we estimate a ratio of 100 dominant spontaneous mutations to one radiation-induced dominant mutation. The possibilities and the limitations of the different methods to estimate the genetic risk will be discussed. The discrepancy between the high safety standards for radiation protection and the low level of knowledge for the toxicological evaluation of chemical mutagens will be emphasized.

  5. Cancer therapy and cardiotoxicity: The need of serial Doppler echocardiography

    PubMed Central

    Galderisi, Maurizio; Marra, Francesco; Esposito, Roberta; Lomoriello, Vincenzo Schiano; Pardo, Moira; de Divitiis, Oreste

    2007-01-01

    Cancer therapy has shown terrific progress leading to important reduction of morbidity and mortality of several kinds of cancer. The therapeutic management of oncologic patients includes combinations of drugs, radiation therapy and surgery. Many of these therapies produce adverse cardiovascular complications which may negatively affect both the quality of life and the prognosis. For several years the most common noninvasive method of monitoring cardiotoxicity has been represented by radionuclide ventriculography while other tests as effort EKG and stress myocardial perfusion imaging may detect ischemic complications, and 24-hour Holter monitoring unmask suspected arrhythmias. Also biomarkers such as troponine I and T and B-type natriuretic peptide may be useful for early detection of cardiotoxicity. Today, the widely used non-invasive method of monitoring cardiotoxicity of cancer therapy is, however, represented by Doppler-echocardiography which allows to identify the main forms of cardiac complications of cancer therapy: left ventricular (systolic and diastolic) dysfunction, valve heart disease, pericarditis and pericardial effusion, carotid artery lesions. Advanced ultrasound tools, as Integrated Backscatter and Tissue Doppler, but also simple ultrasound detection of "lung comet" on the anterior and lateral chest can be helpful for early, subclinical diagnosis of cardiac involvement. Serial Doppler echocardiographic evaluation has to be encouraged in the oncologic patients, before, during and even late after therapy completion. This is crucial when using anthracyclines, which have early but, most importantly, late, cumulative cardiac toxicity. The echocardiographic monitoring appears even indispensable after radiation therapy, whose detrimental effects may appear several years after the end of irradiation. PMID:17254324

  6. Radiation-induced Genomic Instability and Radiation Sensitivity

    SciTech Connect

    Varnum, Susan M.; Sowa, Marianne B.; Kim, Grace J.; Morgan, William F.

    2013-01-19

    The obvious relationships between reactive oxygen and nitrogen species, mitochondrial dysfunction, inflammatory type responses and reactive chemokines and cytokines suggests a general stress response induced by ionizing radiation most likely leads to the non-targeted effects described after radiation exposure. We argue that true bystander effects do not occur in the radiation therapy clinic. But there is no question that effects outside the target volume do occur. These “out of field effects” are considered very low dose effects in the context of therapy. So what are the implications of non-targeted effects on radiation sensitivity? The primary goal of therapy is to eradicate the tumor. Given the genetic diversity of the human population, lifestyle and environment factors it is likely some combination of these will influence patient outcome. Non-targeted effects may contribute to a greater or lesser extent. But consider the potential situation involving a partial body exposure due to a radiation accident or radiological terrorism. Non-targeted effects suggest that the tissue at risk for demonstrating possible detrimental effects of radiation exposure might be greater than the volume actually irradiated.

  7. Biokinetically-based in vitro cardiotoxicity of residual oil fly ash: hazard identification and mechanisms of injury.

    PubMed

    Knuckles, Travis L; Jaskot, Richard; Richards, Judy H; Miller, C Andrew; Ledbetter, Allen; McGee, John; Linak, William P; Dreher, Kevin L

    2013-12-01

    Epidemiological studies have associated air pollution particulate matter (PM) exposure with adverse cardiovascular effects. Identification of causal PM sources is critically needed to support regulatory decisions to protect public health. This research examines the in vitro cardiotoxicity of bioavailable constituents of residual oil fly ash (ROFA) employing in vivo, biokinetically-based, concentrations determined from their pulmonary deposition. Pulmonary deposition of ROFA led to a rapid increase in plasma vanadium (V) levels that were prolonged in hypertensive animals without systemic inflammation. ROFA cardiotoxicity was evaluated using neonatal rat cardiomyocyte (RCM) cultures exposed to particle-free leachates of ROFA (ROFA-L) at levels present in exposed rat plasma. Cardiotoxicity was observed at low levels (3.13 μg/mL) of ROFA-L 24 h post-exposure. Dimethylthiourea (28 mM) inhibited ROFA-L-induced cytotoxicity at high (25-12.5 μg/mL) doses, suggesting that oxidative stress is responsible at high ROFA-L doses. Cardiotoxicity could not be reproduced using a V + Ni + Fe mixture or a ROFA-L depleted of these metals, suggesting that ROFA-L cardiotoxicity requires the full complement of bioavailable constituents. Susceptibility of RCMs to ROFA-L-induced cytotoxicity was increased following tyrosine phosphorylation inhibition, suggesting that phosphotyrosine signaling pathways play a critical role in regulating ROFA-L-induced cardiotoxicity. These data demonstrate that bioavailable constituents of ROFA are capable of direct adverse cardiac effects.

  8. Epigenetics in radiation-induced fibrosis.

    PubMed

    Weigel, C; Schmezer, P; Plass, C; Popanda, O

    2015-04-23

    Radiotherapy is a major cancer treatment option but dose-limiting side effects such as late-onset fibrosis in the irradiated tissue severely impair quality of life in cancer survivors. Efforts to explain radiation-induced fibrosis, for example, by genetic variation remained largely inconclusive. Recently published molecular analyses on radiation response and fibrogenesis showed a prominent role of epigenetic gene regulation. This review summarizes the current knowledge on epigenetic modifications in fibrotic disease and radiation response, and it points out the important role for epigenetic mechanisms such as DNA methylation, microRNAs and histone modifications in the development of this disease. The synopsis illustrates the complexity of radiation-induced fibrosis and reveals the need for investigations to further unravel its molecular mechanisms. Importantly, epigenetic changes are long-term determinants of gene expression and can therefore support those mechanisms that induce and perpetuate fibrogenesis even in the absence of the initial damaging stimulus. Future work must comprise the interconnection of acute radiation response and long-lasting epigenetic effects in order to assess their role in late-onset radiation fibrosis. An improved understanding of the underlying biology is fundamental to better comprehend the origin of this disease and to improve both preventive and therapeutic strategies.

  9. Radiation induced conductivity in space dielectric materials

    SciTech Connect

    Hanna, R.; Paulmier, T. Belhaj, M.; Dirassen, B.; Molinie, P.; Payan, D.; Balcon, N.

    2014-01-21

    The radiation-induced conductivity of some polymers was described mainly in literature by a competition between ionization, trapping/detrapping, and recombination processes or by radiation assisted ageing mechanisms. Our aim is to revise the effect of the aforementioned mechanisms on the complex evolution of Teflon{sup ®} FEP under space representative ionizing radiation. Through the definition of a new experimental protocol, revealing the effect of radiation dose and relaxation time, we have been able to demonstrate that the trapping/recombination model devised in this study agrees correctly with the observed experimental phenomenology at qualitative level and allows describing very well the evolution of radiation induced conductivity with irradiation time (or received radiation dose). According to this model, the complex behavior observed on Teflon{sup ®} FEP may be basically ascribed to the competition between electron/hole pairs generation and recombination: electrons are deeply trapped and act as recombination centers for free holes. Relaxation effects have been characterized through successive irradiations steps and have been again well described with the defined model at qualitative level: recombination centers created by the irradiation induce long term alteration on the electric properties, especially the effective bulk conductivity. One-month relaxation does not allow a complete recovery of the material initial charging behavior.

  10. Imaging radiation-induced normal tissue injury.

    PubMed

    Robbins, Mike E; Brunso-Bechtold, Judy K; Peiffer, Ann M; Tsien, Christina I; Bailey, Janet E; Marks, Lawrence B

    2012-04-01

    Technological developments in radiation therapy and other cancer therapies have led to a progressive increase in five-year survival rates over the last few decades. Although acute effects have been largely minimized by both technical advances and medical interventions, late effects remain a concern. Indeed, the need to identify those individuals who will develop radiation-induced late effects, and to develop interventions to prevent or ameliorate these late effects is a critical area of radiobiology research. In the last two decades, preclinical studies have clearly established that late radiation injury can be prevented/ameliorated by pharmacological therapies aimed at modulating the cascade of events leading to the clinical expression of radiation-induced late effects. These insights have been accompanied by significant technological advances in imaging that are moving radiation oncology and normal tissue radiobiology from disciplines driven by anatomy and macrostructure to ones in which important quantitative functional, microstructural, and metabolic data can be noninvasively and serially determined. In the current article, we review use of positron emission tomography (PET), single photon emission tomography (SPECT), magnetic resonance (MR) imaging and MR spectroscopy to generate pathophysiological and functional data in the central nervous system, lung, and heart that offer the promise of, (1) identifying individuals who are at risk of developing radiation-induced late effects, and (2) monitoring the efficacy of interventions to prevent/ameliorate them.

  11. Radiation induced conductivity in space dielectric materials

    NASA Astrophysics Data System (ADS)

    Hanna, R.; Paulmier, T.; Molinie, P.; Belhaj, M.; Dirassen, B.; Payan, D.; Balcon, N.

    2014-01-01

    The radiation-induced conductivity of some polymers was described mainly in literature by a competition between ionization, trapping/detrapping, and recombination processes or by radiation assisted ageing mechanisms. Our aim is to revise the effect of the aforementioned mechanisms on the complex evolution of Teflon® FEP under space representative ionizing radiation. Through the definition of a new experimental protocol, revealing the effect of radiation dose and relaxation time, we have been able to demonstrate that the trapping/recombination model devised in this study agrees correctly with the observed experimental phenomenology at qualitative level and allows describing very well the evolution of radiation induced conductivity with irradiation time (or received radiation dose). According to this model, the complex behavior observed on Teflon® FEP may be basically ascribed to the competition between electron/hole pairs generation and recombination: electrons are deeply trapped and act as recombination centers for free holes. Relaxation effects have been characterized through successive irradiations steps and have been again well described with the defined model at qualitative level: recombination centers created by the irradiation induce long term alteration on the electric properties, especially the effective bulk conductivity. One-month relaxation does not allow a complete recovery of the material initial charging behavior.

  12. A report on radiation-induced gliomas

    SciTech Connect

    Salvati, M.; Artico, M.; Caruso, R.; Rocchi, G.; Orlando, E.R.; Nucci, F. )

    1991-01-15

    Radiation-induced gliomas are uncommon, with only 73 cases on record to date. The disease that most frequently occasioned radiation therapy has been acute lymphoblastic leukemia (ALL). Three more cases are added here, two after irradiation for ALL and one after irradiation for tinea capitis. In a review of the relevant literature, the authors stress the possibility that the ALL-glioma and the retinoblastoma-glioma links point to syndromes in their own right that may occur without radiation therapy.56 references.

  13. Are cardioprotective effects of NO-releasing drug molsidomine translatable to chronic anthracycline cardiotoxicity settings?

    PubMed

    Lenčová-Popelová, Olga; Jansová, Hana; Jirkovský, Eduard; Bureš, Jan; Jirkovská-Vávrová, Anna; Mazurová, Yvona; Reimerová, Petra; Vostatková, Lucie; Adamcová, Michaela; Hroch, Miloš; Pokorná, Zuzana; Kovaříková, Petra; Šimůnek, Tomáš; Štěrba, Martin

    2016-11-30

    Chronic anthracycline (ANT) cardiotoxicity is a serious complication of cancer chemotherapy. Molsidomine, a NO-releasing drug, has been found cardioprotective in different models of I/R injury and recently in acute high-dose ANT cardiotoxicity. Hence, we examined whether its cardioprotective effects are translatable to chronic ANT cardiotoxicity settings without induction of nitrosative stress and interference with antiproliferative action of ANTs. The effects of molsidomine (0.025 and 0.5mg/kg, i.v.) were studied on the well-established model of chronic ANT cardiotoxicity in rabbits (daunorubicin/DAU/3mg/kg/week for 10 weeks). Molsidomine was unable to significantly attenuate mortality, development of heart failure and morphological damage induced by DAU. Molsidomine did not alter DAU-induced myocardial lipoperoxidation, MnSOD down-regulation, up-regulation of HO-1, IL-6, and molecular markers of cardiac remodeling. Although molsidomine increased 3-nitrotyrosine in the myocardium, this event had no impact on cardiotoxicity development. Using H9c2 myoblasts and isolated cardiomyocytes, it was found that SIN-1 (an active metabolite of molsidomine) induces significant protection against ANT toxicity, but only at high concentrations. In leukemic HL-60 cells, SIN-1 initially augmented ANT cytotoxicity (in low and clinically achievable concentrations), but it protected these cells against ANT in the high concentrations. UHPLC-MS/MS investigation demonstrated that the loss of ANT cytotoxicity after co-incubation of the cells in vitro with high concentrations of SIN-1 is caused by unexpected chemical depletion of DAU molecule. The present study demonstrates that cardioprotective effects of molsidomine are not translatable to clinically relevant chronic form of ANT cardiotoxicity. The augmentation of antineoplastic effects of ANT in low (nM) concentrations may deserve further study. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  14. Radiation-induced intestinal pseudoobstruction

    SciTech Connect

    Perino, L.E.; Schuffler, M.D.; Mehta, S.J.; Everson, G.T.

    1986-10-01

    A case of intestinal pseudoobstruction occurring 30 yr after radiation therapy is described. Mechanical causes of obstruction were excluded by laparotomy. Histology of full-thickness sections of the small bowel revealed vascular ectasia and sclerosis, serosal fibrosis, neuronal proliferation within the submucosa, and degeneration of the muscle fibers of the circular layer of the muscularis propria. On the basis of the clinical and histologic findings we conclude that, in this patient, intestinal pseudoobstruction was due to muscular and neuronal injury from abdominal irradiation.

  15. Radiation-induced amorphization of intermetallic compounds

    NASA Astrophysics Data System (ADS)

    Lam, N. Q.; Sabochick, M. J.; Okamoto, P. R.

    1994-06-01

    In the present paper, important results of our recent computer simulation of radiation-induced amorphization in the ordered compounds CuTi and Cu4Ti3 are summarized. The energetic, structural, thermodynamic and mechanical responses of these intermetallics during chemical disordering, point-defect production and heating were simulated, using molecular dynamics and embedded-atom potentials. From the atomistic details obtained, the critical role of radiation-induced structural disorder in driving the crystalline-to-amorphous phase transformation is discussed.

  16. Current and emerging modalities for detection of cardiotoxicity in cardio-oncology.

    PubMed

    Khouri, Michel G; Klein, Michael R; Velazquez, Eric J; Jones, Lee W

    2015-07-01

    Advancements in diagnostic tools and curative-intent therapies have improved cancer-specific survival. With prolonged survival, patients are now subject to increased aging and development of cardiovascular risk factors such that further improvements in cancer-specific mortality are at risk of being offset by increased cardiovascular mortality. Moreover, established and novel adjuvant therapies used in cancer treatment are associated with unique and varying degrees of direct as well as indirect myocardial and cardiovascular injury (i.e., cardiotoxicity). Current approaches for evaluating anticancer therapy-induced injury have limitations, particularly lack of sensitivity for early detection of subclinical cardiac and cardiovascular dysfunction. With emerging evidence suggesting early prevention and treatment can mitigate the degree of cardiotoxicity and limit interruption of life-saving cancer therapy, the importance of early detection is increasingly paramount. Newer imaging modalities, functional capacity testing and blood biomarkers have the potential to improve early detection of cardiotoxicity and reduce cardiovascular morbidity and mortality.

  17. Radiation-induced valvular heart disease.

    PubMed

    Gujral, Dorothy M; Lloyd, Guy; Bhattacharyya, Sanjeev

    2016-02-15

    Radiation to the mediastinum is a key component of treatment with curative intent for a range of cancers including Hodgkin's lymphoma and breast cancer. Exposure to radiation is associated with a risk of radiation-induced heart valve damage characterised by valve fibrosis and calcification. There is a latent interval of 10-20 years between radiation exposure and development of clinically significant heart valve disease. Risk is related to radiation dose received, interval from exposure and use of concomitant chemotherapy. Long-term outlook and the risk of valve surgery are related to the effects of radiation on mediastinal structures including pulmonary fibrosis and pericardial constriction. Dose prediction models to predict the risk of heart valve disease in the future and newer radiation techniques to reduce the radiation dose to the heart are being developed. Surveillance strategies for this cohort of cancer survivors at risk of developing significant heart valve complications are required. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  18. Roles of oxidative stress and Akt signaling in doxorubicin cardiotoxicity

    SciTech Connect

    Ichihara, Sahoko . E-mail: saho@gene.mie-u.ac.jp; Yamada, Yoshiji; Kawai, Yoshichika; Osawa, Toshihiko; Furuhashi, Koichi; Duan Zhiwen; Ichihara, Gaku

    2007-07-20

    Cardiotoxicity is a treatment-limiting side effect of the anticancer drug doxorubicin (DOX). We have now investigated the roles of oxidative stress and signaling by the protein kinase Akt in DOX-induced cardiotoxicity as well as the effects on such toxicity both of fenofibrate, an agonist of peroxisome proliferator-activated receptor-{alpha}, and of polyethylene glycol-conjugated superoxide dismutase (PEG-SOD), an antioxidant. Mice injected intraperitoneally with DOX were treated for 4 days with fenofibrate or PEG-SOD. Fenofibrate and PEG-SOD each prevented the induction of cardiac dysfunction by DOX. Both drugs also inhibited the activation of the transcription factor NF-{kappa}B and increase in lipid peroxidation in the left ventricle induced by DOX, whereas only PEG-SOD inhibited the DOX-induced activation of Akt and Akt-regulated gene expression. These results suggest that fenofibrate and PEG-SOD prevented cardiac dysfunction induced by DOX through normalization of oxidative stress and redox-regulated NF-{kappa}B signaling.

  19. Quercetin inhibits radiation-induced skin fibrosis.

    PubMed

    Horton, Jason A; Li, Fei; Chung, Eun Joo; Hudak, Kathryn; White, Ayla; Krausz, Kristopher; Gonzalez, Frank; Citrin, Deborah

    2013-08-01

    Radiation induced fibrosis of the skin is a late toxicity that may result in loss of function due to reduced range of motion and pain. The current study sought to determine if oral delivery of quercetin mitigates radiation-induced cutaneous injury. Female C3H/HeN mice were fed control chow or quercetin-formulated chow (1% by weight). The right hind leg was exposed to 35 Gy of X rays and the mice were followed serially to assess acute toxicity and hind leg extension. Tissue samples were collected for assessment of soluble collagen and tissue cytokines. Human and murine fibroblasts were subjected to clonogenic assays to determine the effects of quercetin on radiation response. Contractility of fibroblasts was assessed with a collagen contraction assay in the presence or absence of quercetin and transforming growth factor-β (TGF-β). Western blotting of proteins involved in fibroblast contractility and TGF-β signaling were performed. Quercetin treatment significantly reduced hind limb contracture, collagen accumulation and expression of TGF-β in irradiated skin. Quercetin had no effect on the radioresponse of fibroblasts or murine tumors, but was capable of reducing the contractility of fibroblasts in response to TGF-β, an effect that correlated with partial stabilization of phosphorylated cofilin. Quercetin is capable of mitigating radiation induced skin fibrosis and should be further explored as a therapy for radiation fibrosis.

  20. Quercetin Inhibits Radiation-Induced Skin Fibrosis

    PubMed Central

    Horton, Jason A.; Li, Fei; Chung, Eun Joo; Hudak, Kathryn; White, Ayla; Krausz, Kristopher; Gonzalez, Frank; Citrin, Deborah

    2013-01-01

    Radiation induced fibrosis of the skin is a late toxicity that may result in loss of function due to reduced range of motion and pain. The current study sought to determine if oral delivery of quercetin mitigates radiation-induced cutaneous injury. Female C3H/HeN mice were fed control chow or quercetin-formulated chow (1% by weight). The right hind leg was exposed to 35 Gy of X rays and the mice were followed serially to assess acute toxicity and hind leg extension. Tissue samples were collected for assessment of soluble collagen and tissue cytokines. Human and murine fibroblasts were subjected to clonogenic assays to determine the effects of quercetin on radiation response. Contractility of fibroblasts was assessed with a collagen contraction assay in the presence or absence of quercetin and transforming growth factor-β (TGF-β). Western blotting of proteins involved in fibroblast contractility and TGF-β signaling were performed. Quercetin treatment significantly reduced hind limb contracture, collagen accumulation and expression of TGF-β in irradiated skin. Quercetin had no effect on the radioresponse of fibroblasts or murine tumors, but was capable of reducing the contractility of fibroblasts in response to TGF-β, an effect that correlated with partial stabilization of phosphorylated cofilin. Quercetin is capable of mitigating radiation induced skin fibrosis and should be further explored as a therapy for radiation fibrosis. PMID:23819596

  1. Radiation-induced meningiomas in pediatric patients

    SciTech Connect

    Moss, S.D.; Rockswold, G.L.; Chou, S.N.; Yock, D.; Berger, M.S.

    1988-04-01

    Radiation-induced meningiomas rarely have latency periods short enough from the time of irradiation to the clinical presentation of the tumor to present in the pediatric patient. Three cases of radiation-induced intracranial meningiomas in pediatric patients are presented. The first involved a meningioma of the right frontal region in a 10-year-old boy 6 years after the resection and irradiation of a 4th ventricular medulloblastoma. Review of our pediatric tumor cases produced a second case of a left temporal fossa meningioma presenting in a 15-year-old boy with a history of irradiation for retinoblastoma at age 3 years and a third case of a right frontoparietal meningioma in a 15-year-old girl after irradiation for acute lymphoblastic leukemia. Only three cases of meningiomas presenting in the pediatric age group after radiation therapy to the head were detected in our review of the literature.

  2. Radiation-induced meningiomas in pediatric patients.

    PubMed

    Moss, S D; Rockswold, G L; Chou, S N; Yock, D; Berger, M S

    1988-04-01

    Radiation-induced meningiomas rarely have latency periods short enough from the time of irradiation to the clinical presentation of the tumor to present in the pediatric patient. Three cases of radiation-induced intracranial meningiomas in pediatric patients are presented. The first involved a meningioma of the right frontal region in a 10-year-old boy 6 years after the resection and irradiation of a 4th ventricular medulloblastoma. Review of our pediatric tumor cases produced a second case of a left temporal fossa meningioma presenting in a 15-year-old boy with a history of irradiation for retinoblastoma at age 3 years and a third case of a right frontoparietal meningioma in a 15-year-old girl after irradiation for acute lymphoblastic leukemia. Only three cases of meningiomas presenting in the pediatric age group after radiation therapy to the head were detected in our review of the literature.

  3. Radiation-induced mutations and plant breeding

    SciTech Connect

    Naqvi, S.H.M.

    1985-01-01

    Ionizing radiation could cause genetic changes in an organism and could modify gene linkages. The induction of mutation through radiation is random and the probability of getting the desired genetic change is low but can be increased by manipulating different parameters such as dose rate, physical conditions under which the material has been irradiated, etc. Induced mutations have been used as a supplement to conventional plant breeding, particularly for creating genetic variability for specific characters such as improved plant structure, pest and disease resistance, and desired changes in maturity period; more than 200 varieties of crop plants have been developed by this technique. The Pakistan Atomic Energy Commission has used this technique fruitfully to evolve better germplasm in cotton, rice, chickpea, wheat and mungbean; some of the mutants have become popular commercial varieties. This paper describes some uses of radiation induced mutations and the results achieved in Pakistan so far.

  4. Cardioprotective effects of inorganic nitrate/nitrite in chronic anthracycline cardiotoxicity: Comparison with dexrazoxane.

    PubMed

    Lenčová-Popelová, Olga; Jirkovský, Eduard; Jansová, Hana; Jirkovská-Vávrová, Anna; Vostatková-Tichotová, Lucie; Mazurová, Yvona; Adamcová, Michaela; Chládek, Jaroslav; Hroch, Miloš; Pokorná, Zuzana; Geršl, Vladimír; Šimůnek, Tomáš; Štěrba, Martin

    2016-02-01

    Dexrazoxane (DEX) is a clinically available cardioprotectant that reduces the toxicity induced by anthracycline (ANT) anticancer drugs; however, DEX is seldom used and its action is poorly understood. Inorganic nitrate/nitrite has shown promising results in myocardial ischemia-reperfusion injury and recently in acute high-dose ANT cardiotoxicity. However, the utility of this approach for overcoming clinically more relevant chronic forms of cardiotoxicity remains elusive. Hence, in this study, the protective potential of inorganic nitrate and nitrite against chronic ANT cardiotoxicity was investigated, and the results were compared to those using DEX. Chronic cardiotoxicity was induced in rabbits with daunorubicin (DAU). Sodium nitrate (1g/L) was administered daily in drinking water, while sodium nitrite (0.15 or 5mg/kg) or DEX (60mg/kg) was administered parenterally before each DAU dose. Although oral nitrate induced a marked increase in plasma NOx, it showed no improvement in DAU-induced mortality, myocardial damage or heart failure. Instead, the higher nitrite dose reduced the incidence of end-stage cardiotoxicity, prevented related premature deaths and significantly ameliorated several molecular and cellular perturbations induced by DAU, particularly those concerning mitochondria. The latter result was also confirmed in vitro. Nevertheless, inorganic nitrite failed to prevent DAU-induced cardiac dysfunction and molecular remodeling in vivo and failed to overcome the cytotoxicity of DAU to cardiomyocytes in vitro. In contrast, DEX completely prevented all of the investigated molecular, cellular and functional perturbations that were induced by DAU. Our data suggest that the difference in cardioprotective efficacy between DEX and inorganic nitrite may be related to their different abilities to address a recently proposed upstream target for ANT in the heart - topoisomerase IIβ. Copyright © 2015. Published by Elsevier Ltd.

  5. Alginate Oligosaccharide Prevents Acute Doxorubicin Cardiotoxicity by Suppressing Oxidative Stress and Endoplasmic Reticulum-Mediated Apoptosis.

    PubMed

    Guo, Jun-Jie; Ma, Lei-Lei; Shi, Hong-Tao; Zhu, Jian-Bing; Wu, Jian; Ding, Zhi-Wen; An, Yi; Zou, Yun-Zeng; Ge, Jun-Bo

    2016-12-20

    Doxorubicin (DOX) is a highly potent chemotherapeutic agent, but its usage is limited by dose-dependent cardiotoxicity. DOX-induced cardiotoxicity involves increased oxidative stress and activated endoplasmic reticulum-mediated apoptosis. Alginate oligosaccharide (AOS) is a non-immunogenic, non-toxic and biodegradable polymer, with anti-oxidative, anti-inflammatory and anti-endoplasmic reticulum stress properties. The present study examined whether AOS pretreatment could protect against acute DOX cardiotoxicity, and the underlying mechanisms focused on oxidative stress and endoplasmic reticulum-mediated apoptosis. We found that AOS pretreatment markedly increased the survival rate of mice insulted with DOX, improved DOX-induced cardiac dysfunction and attenuated DOX-induced myocardial apoptosis. AOS pretreatment mitigated DOX-induced cardiac oxidative stress, as shown by the decreased expressions of gp91 (phox) and 4-hydroxynonenal (4-HNE). Moreover, AOS pretreatment significantly decreased the expression of Caspase-12, C/EBP homologous protein (CHOP) (markers for endoplasmic reticulum-mediated apoptosis) and Bax (a downstream molecule of CHOP), while up-regulating the expression of anti-apoptotic protein Bcl-2. Taken together, these findings identify AOS as a potent compound that prevents acute DOX cardiotoxicity, at least in part, by suppression of oxidative stress and endoplasmic reticulum-mediated apoptosis.

  6. Alginate Oligosaccharide Prevents Acute Doxorubicin Cardiotoxicity by Suppressing Oxidative Stress and Endoplasmic Reticulum-Mediated Apoptosis

    PubMed Central

    Guo, Jun-Jie; Ma, Lei-Lei; Shi, Hong-Tao; Zhu, Jian-Bing; Wu, Jian; Ding, Zhi-Wen; An, Yi; Zou, Yun-Zeng; Ge, Jun-Bo

    2016-01-01

    Doxorubicin (DOX) is a highly potent chemotherapeutic agent, but its usage is limited by dose-dependent cardiotoxicity. DOX-induced cardiotoxicity involves increased oxidative stress and activated endoplasmic reticulum-mediated apoptosis. Alginate oligosaccharide (AOS) is a non-immunogenic, non-toxic and biodegradable polymer, with anti-oxidative, anti-inflammatory and anti-endoplasmic reticulum stress properties. The present study examined whether AOS pretreatment could protect against acute DOX cardiotoxicity, and the underlying mechanisms focused on oxidative stress and endoplasmic reticulum-mediated apoptosis. We found that AOS pretreatment markedly increased the survival rate of mice insulted with DOX, improved DOX-induced cardiac dysfunction and attenuated DOX-induced myocardial apoptosis. AOS pretreatment mitigated DOX-induced cardiac oxidative stress, as shown by the decreased expressions of gp91 (phox) and 4-hydroxynonenal (4-HNE). Moreover, AOS pretreatment significantly decreased the expression of Caspase-12, C/EBP homologous protein (CHOP) (markers for endoplasmic reticulum-mediated apoptosis) and Bax (a downstream molecule of CHOP), while up-regulating the expression of anti-apoptotic protein Bcl-2. Taken together, these findings identify AOS as a potent compound that prevents acute DOX cardiotoxicity, at least in part, by suppression of oxidative stress and endoplasmic reticulum-mediated apoptosis. PMID:27999379

  7. Cataracts induced by microwave and ionizing radiation

    SciTech Connect

    Lipman, R.M.; Tripathi, B.J.; Tripathi, R.C.

    1988-11-01

    Microwaves most commonly cause anterior and/or posterior subcapsular lenticular opacities in experimental animals and, as shown in epidemiologic studies and case reports, in human subjects. The formation of cataracts seems to be related directly to the power of the microwave and the duration of exposure. The mechanism of cataractogenesis includes deformation of heat-labile enzymes, such as glutathione peroxide, that ordinarily protect lens cell proteins and membrane lipids from oxidative damage. Oxidation of protein sulfhydryl groups and the formation of high-molecular-weight aggregates cause local variations in the orderly structure of the lens cells. An alternative mechanism is thermoelastic expansion through which pressure waves in the aqueous humor cause direct physical damage to the lens cells. Cataracts induced by ionizing radiation (e.g., X-rays and gamma rays) usually are observed in the posterior region of the lens, often in the form of a posterior subcapsular cataract. Increasing the dose of ionizing radiation causes increasing opacification of the lens, which appears after a decreasing latency period. Like cataract formation by microwaves, cataractogenesis induced by ionizing radiation is associated with damage to the lens cell membrane. Another possible mechanism is damage to lens cell DNA, with decreases in the production of protective enzymes and in sulfur-sulfur bond formation, and with altered protein concentrations. Until further definitive conclusions about the mechanisms of microwaves and ionizing radiation induced cataracts are reached, and alternative protective measures are found, one can only recommend mechanical shielding from these radiations to minimize the possibility of development of radiation-induced cataracts. 74 references.

  8. Radiation-induced brain injury: A review

    PubMed Central

    Greene-Schloesser, Dana; Robbins, Mike E.; Peiffer, Ann M.; Shaw, Edward G.; Wheeler, Kenneth T.; Chan, Michael D.

    2012-01-01

    Approximately 100,000 primary and metastatic brain tumor patients/year in the US survive long enough (>6 months) to experience radiation-induced brain injury. Prior to 1970, the human brain was thought to be highly radioresistant; the acute CNS syndrome occurs after single doses >30 Gy; white matter necrosis occurs at fractionated doses >60 Gy. Although white matter necrosis is uncommon with modern techniques, functional deficits, including progressive impairments in memory, attention, and executive function have become important, because they have profound effects on quality of life. Preclinical studies have provided valuable insights into the pathogenesis of radiation-induced cognitive impairment. Given its central role in memory and neurogenesis, the majority of these studies have focused on the hippocampus. Irradiating pediatric and young adult rodent brains leads to several hippocampal changes including neuroinflammation and a marked reduction in neurogenesis. These data have been interpreted to suggest that shielding the hippocampus will prevent clinical radiation-induced cognitive impairment. However, this interpretation may be overly simplistic. Studies using older rodents, that more closely match the adult human brain tumor population, indicate that, unlike pediatric and young adult rats, older rats fail to show a radiation-induced decrease in neurogenesis or a loss of mature neurons. Nevertheless, older rats still exhibit cognitive impairment. This occurs in the absence of demyelination and/or white matter necrosis similar to what is observed clinically, suggesting that more subtle molecular, cellular and/or microanatomic modifications are involved in this radiation-induced brain injury. Given that radiation-induced cognitive impairment likely reflects damage to both hippocampal- and non-hippocampal-dependent domains, there is a critical need to investigate the microanatomic and functional effects of radiation in various brain regions as well as their

  9. Bile acids in radiation-induced diarrhea

    SciTech Connect

    Arlow, F.L.; Dekovich, A.A.; Priest, R.J.; Beher, W.T.

    1987-10-01

    Radiation-induced bowel disease manifested by debilitating diarrhea is an unfortunate consequence of therapeutic irradiation for pelvic malignancies. Although the mechanism for this diarrhea is not well understood, many believe it is the result of damage to small bowel mucosa and subsequent bile acid malabsorption. Excess amounts of bile acids, especially the dihydroxy components, are known to induce water and electrolyte secretion and increase bowel motility. We have directly measured individual and total bile acids in the stool samples of 11 patients with radiation-induced diarrhea and have found bile acids elevated two to six times normal in eight of them. Our patients with diarrhea and increased bile acids in their stools had prompt improvement when given cholestyramine. They had fewer stools and returned to a more normal life-style.

  10. Ionizing Radiation-induced Diseases in Korea

    PubMed Central

    Jeong, Meeseon; Moon, Kieun; Jo, Min-Heui; Kang, Seong-Kyu

    2010-01-01

    Radiation risk has become well known through epidemiological studies of clinically or occupationally exposed populations, animal experiments, and in vitro studies; however, the study of radiation related or induced disease has been limited in Korea. This study is to find the level of occupational radiation exposure for various kinds of accidents, compensated occupational diseases, related studies, and estimations on future occupational disease risks. Research data of related institutions were additionally investigated. About 67% of 62,553 radiation workers had no exposure or less than 1.2 mSv per year. The 5 reported cases on radiation accident patients in Korea occurred during nondestructive testing. According to the recent rapid increase in the number of workers exposed to radiation, a higher social recognition of cancer, and an increasing cancer mortality rate, it is expected that occupational disease compensation will rapidly increase as well. Therefore, it is important to develop scientific and objective decision methods, such as probability of causation and screening dose in the establishment of an exposure and health surveillance system. PMID:21258594

  11. Delayed Radiation-Induced Vasculitic Leukoencephalopathy

    SciTech Connect

    Rauch, Philipp J.; Park, Henry S.; Knisely, Jonathan P.S.; Chiang, Veronica L.; Vortmeyer, Alexander O.

    2012-05-01

    Purpose: Recently, single-fraction, high-dosed focused radiation therapy such as that administered by Gamma Knife radiosurgery has been used increasingly for the treatment of metastatic brain cancer. Radiation therapy to the brain can cause delayed leukoencephalopathy, which carries its own significant morbidity and mortality. While radiosurgery-induced leukoencephalopathy is known to be clinically different from that following fractionated radiation, pathological differences are not well characterized. In this study, we aimed to integrate novel radiographic and histopathologic observations to gain a conceptual understanding of radiosurgery-induced leukoencephalopathy. Methods and Materials: We examined resected tissues of 10 patients treated at Yale New Haven Hospital between January 1, 2009, and June 30, 2010, for brain metastases that had been previously treated with Gamma Knife radiosurgery, who subsequently required surgical management of a symptomatic regrowing lesion. None of the patients showed pathological evidence of tumor recurrence. Clinical and magnetic resonance imaging data for each of the 10 patients were then studied retrospectively. Results: We provide evidence to show that radiosurgery-induced leukoencephalopathy may present as an advancing process that extends beyond the original high-dose radiation field. Neuropathologic examination of the resected tissue revealed traditionally known leukoencephalopathic changes including demyelination, coagulation necrosis, and vascular sclerosis. Unexpectedly, small and medium-sized vessels revealed transmural T-cell infiltration indicative of active vasculitis. Conclusions: We propose that the presence of a vasculitic component in association with radiation-induced leukoencephalopathy may facilitate the progressive nature of the condition. It may also explain the resemblance of delayed leukoencephalopathy with recurring tumor on virtually all imaging modalities used for posttreatment follow-up.

  12. Cardiotoxicity of the Anticancer Therapeutic Agent Bortezomib

    PubMed Central

    Nowis, Dominika; Mączewski, Michał; Mackiewicz, Urszula; Kujawa, Marek; Ratajska, Anna; Wieckowski, Mariusz R.; Wilczyński, Grzegorz M.; Malinowska, Monika; Bil, Jacek; Salwa, Paweł; Bugajski, Marek; Wójcik, Cezary; Siński, Maciej; Abramczyk, Piotr; Winiarska, Magdalena; Dąbrowska-Iwanicka, Anna; Duszyński, Jerzy; Jakóbisiak, Marek; Golab, Jakub

    2010-01-01

    Recent case reports provided alarming signals that treatment with bortezomib might be associated with cardiac events. In all reported cases, patients experiencing cardiac problems were previously or concomitantly treated with other chemotherapeutics including cardiotoxic anthracyclines. Therefore, it is difficult to distinguish which components of the therapeutic regimens contribute to cardiotoxicity. Here, we addressed the influence of bortezomib on cardiac function in rats that were not treated with other drugs. Rats were treated with bortezomib at a dose of 0.2 mg/kg thrice weekly. Echocardiography, histopathology, and electron microscopy were used to evaluate cardiac function and structural changes. Respiration of the rat heart mitochondria was measured polarographically. Cell culture experiments were used to determine the influence of bortezomib on cardiomyocyte survival, contractility, Ca2+ fluxes, induction of endoplasmic reticulum stress, and autophagy. Our findings indicate that bortezomib treatment leads to left ventricular contractile dysfunction manifested by a significant drop in left ventricle ejection fraction. Dramatic ultrastructural abnormalities of cardiomyocytes, especially within mitochondria, were accompanied by decreased ATP synthesis and decreased cardiomyocyte contractility. Monitoring of cardiac function in bortezomib-treated patients should be implemented to evaluate how frequently cardiotoxicity develops especially in patients with pre-existing cardiac conditions, as well as when using additional cardiotoxic drugs. PMID:20519734

  13. Radiation-induced mutation at minisatellite loci

    SciTech Connect

    Dubrova, Y.E. |; Nesterov, V.N.; Krouchinsky, N.G.

    1997-10-01

    We are studying the radiation-induced increase of mutation rate in minisatellite loci in mice and humans. Minisatellite mutations were scored by multilocus DNA fingerprint analysis in the progeny of {gamma}-irradiated and non-irradiated mice. The frequency of mutation in offspring of irradiated males was 1.7 higher that in the control group. Germline mutation at human minisatellite loci was studied among children born in heavily polluted areas of the Mogilev district of Belarus after the Chernobyl accident and in a control population. The frequency of mutation assayed both by DNA fingerprinting and by eight single locus probes was found to be two times higher in the exposed families than in the control group. Furthermore, mutation rate was correlated with the parental radiation dose for chronic exposure {sup 137}Cs, consistent with radiation-induction of germline mutation. The potential use of minisatellites in monitoring germline mutation in humans will be discussed.

  14. Mouse models for radiation-induced cancers.

    PubMed

    Rivina, Leena; Davoren, Michael J; Schiestl, Robert H

    2016-09-01

    Potential ionising radiation exposure scenarios are varied, but all bring risks beyond the simple issues of short-term survival. Whether accidentally exposed to a single, whole-body dose in an act of terrorism or purposefully exposed to fractionated doses as part of a therapeutic regimen, radiation exposure carries the consequence of elevated cancer risk. The long-term impact of both intentional and unintentional exposure could potentially be mitigated by treatments specifically developed to limit the mutations and precancerous replication that ensue in the wake of irradiation The development of such agents would undoubtedly require a substantial degree of in vitro testing, but in order to accurately recapitulate the complex process of radiation-induced carcinogenesis, well-understood animal models are necessary. Inbred strains of the laboratory mouse, Mus musculus, present the most logical choice due to the high number of molecular and physiological similarities they share with humans. Their small size, high rate of breeding and fully sequenced genome further increase its value for use in cancer research. This chapter will review relevant m. musculus inbred and F1 hybrid animals of radiation-induced myeloid leukemia, thymic lymphoma, breast and lung cancers. Method of cancer induction and associated molecular pathologies will also be described for each model. © The Author 2016. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  15. Molecular Mechanisms of the Cardiotoxicity of the Proteasomal-Targeted Drugs Bortezomib and Carfilzomib.

    PubMed

    Hasinoff, Brian B; Patel, Daywin; Wu, Xing

    2016-07-07

    Bortezomib and carfilzomib are anticancer drugs that target the proteasome. However, these agents have been shown to exhibit some specific cardiac toxicities by as yet unknown mechanisms. Bortezomib and carfilzomib are also being used clinically in combination with doxorubicin, which is also cardiotoxic. A primary neonatal rat myocyte model was used to study these cardiotoxic mechanisms. Exposure to submicromolar concentrations of bortezomib and carfilzomib resulted in significant myocyte damage and induced apoptosis. Both bortezomib and carfilzomib inhibited the chymotrypsin-like proteasomal activity of myocyte lysate in the low nanomolar concentration range and exhibited time-dependent inhibition kinetics. The high sensitivity of myocytes, which were determined to contain high specific levels of chymotrypsin-like proteasomal activity, to the damaging effects of bortezomib and carfilzomib was likely due to the inhibition of proteasomal-dependent ongoing sarcomeric protein turnover. A brief preexposure of myocytes to non-toxic nanomolar concentrations of bortezomib or carfilzomib greatly increased doxorubicin-mediated damage, which suggests that the combination of doxorubicin with either bortezomib or carfilzomib may produce more than additive cardiotoxicity. The doxorubicin cardioprotective agent dexrazoxane partially protected myocytes from doxorubicin plus bortezomib or carfilzomib treatment, in spite of the fact that bortezomib and carfilzomib inhibited the dexrazoxane-induced decreases in topoisomerase IIβ protein levels in myocytes. These latter results suggest that the doxorubicin cardioprotective effects of dexrazoxane and the doxorubicin-mediated cardiotoxicity were not exclusively due to targeting of topoisomerase IIβ.

  16. Use of human stem cell derived cardiomyocytes to examine sunitinib mediated cardiotoxicity and electrophysiological alterations

    SciTech Connect

    Cohen, J.D.; Babiarz, J.E.; Abrams, R.M.; Guo, L.; Kameoka, S.; Chiao, E.; Taunton, J.; Kolaja, K.L.

    2011-11-15

    Sunitinib, an oral tyrosine kinase inhibitor approved to treat advanced renal cell carcinoma and gastrointestinal stroma tumor, is associated with clinical cardiac toxicity. Although the precise mechanism of sunitinib cardiotoxicity is not known, both the key metabolic energy regulator, AMP-activated protein kinase (AMPK), and ribosomal S 6 kinase (RSK) have been hypothesized as causative, albeit based on rodent models. To study the mechanism of sunitinib-mediated cardiotoxicity in a human model, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) having electrophysiological and contractile properties of native cardiac tissue were investigated. Sunitinib was cardiotoxic in a dose-dependent manner with an IC{sub 50} in the low micromolar range, observed by a loss of cellular ATP, an increase in oxidized glutathione, and induction of apoptosis in iPSC-CMs. Pretreatment of iPSC-CMs with AMPK activators AICAR or metformin, increased the phosphorylation of pAMPK-T172 and pACC-S79, but only marginally attenuated sunitinib mediated cell death. Furthermore, additional inhibitors of AMPK were not directly cytotoxic to iPSC-CMs up to 250 {mu}M concentrations. Inhibition of RSK with a highly specific, irreversible, small molecule inhibitor (RSK-FMK-MEA) did not induce cytotoxicity in iPSC-CMs below 250 {mu}M. Extensive electrophysiological analysis of sunitinib and RSK-FMK-MEA mediated conduction effects were performed. Taken together, these findings suggest that inhibition of AMPK and RSK are not a major component of sunitinib-induced cardiotoxicity. Although the exact mechanism of cardiotoxicity of sunitinib is not known, it is likely due to inhibition of multiple kinases simultaneously. These data highlight the utility of human iPSC-CMs in investigating the potential molecular mechanisms underlying drug-induced cardiotoxicity. -- Highlights: Black-Right-Pointing-Pointer Cytoxic effect of sunitinib on human stem cell derived cardiomyocytes Black

  17. Study of chemical and radiation induced carcinogenesis

    SciTech Connect

    Chmura, A.

    1995-11-01

    The study of chemical and radiation induced carcinogenesis has up to now based many of its results on the detection of genetic aberrations using the fluorescent in situ hybridization (FISH) technique. FISH is time consuming and this tends to hinder its use for looking at large numbers of samples. We are currently developing new technological advances which will increase the speed, clarity and functionality of the FISH technique. These advances include multi-labeled probes, amplification techniques, and separation techniques.

  18. Radiation-induced heart disease in rats

    SciTech Connect

    Lauk, S.; Kiszel, Z.; Buschmann, J.; Trott, K.R.

    1985-04-01

    After local irradiation of the rat heart with X ray doses of over 10 Gy (single dose), animals developed symptoms of radiation-induced heart disease, which at higher doses would lead to fatal cardiac failure. The LD 50 at 1 year was between 15 Gy and 20 Gy. The pericardium and epicardium responded to irradiation with exudative pericarditis after 4 months. Focal myocardial damage was secondary to progressive capillary damage.

  19. Heat pump processes induced by laser radiation

    NASA Technical Reports Server (NTRS)

    Garbuny, M.; Henningsen, T.

    1980-01-01

    A carbon dioxide laser system was constructed for the demonstration of heat pump processes induced by laser radiation. The system consisted of a frequency doubling stage, a gas reaction cell with its vacuum and high purity gas supply system, and provisions to measure the temperature changes by pressure, or alternatively, by density changes. The theoretical considerations for the choice of designs and components are dicussed.

  20. Radiation induced fracture of the scapula

    SciTech Connect

    Riggs, J.H. III; Schultz, G.D.; Hanes, S.A. )

    1990-10-01

    A case of radiation induced osteonecrosis resulting in a fracture of the scapula in a 76-yr-old female patient with a history of breast carcinoma is presented. Diagnostic imaging, laboratory recommendations and clinical findings are discussed along with an algorithm for the safe management of patients with a history of cancer and musculoskeletal complaints. This case demonstrates the necessity of a thorough investigation of musculoskeletal complaints in patients with previous bone-seeking carcinomas.

  1. Lagerstroemia speciosa L. attenuates apoptosis in isoproterenol-induced cardiotoxic mice by inhibiting oxidative stress: possible role of Nrf2/HO-1.

    PubMed

    Sahu, Bidya Dhar; Kuncha, Madhusudana; Rachamalla, Shyam Sunder; Sistla, Ramakrishna

    2015-01-01

    Myocardial oxidative stress leading to apoptosis and remodeling is the major consequence of ischemic heart disease. In the present study, we investigated the effect of Lagerstroemia speciosa L. leave (LS) extract containing 1 % corosolic acid in the context of cardiovascular disorder by using isoproterenol (ISO)-induced myocardial injury mouse model. Serum was analyzed for specific cardiac injury biomarkers. Cardiac tissue was examined for lipid peroxidation, protein carbonyl content, antioxidant (GSH, GR, GPx, GST, SOD, CAT, NQO1, and HO-1), and apoptosis (cleaved caspase-3, Bax, Bcl-2, p53, and DNA fragmentation) status. Myocardial protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) in different experimental groups was evaluated. Pathological changes in heart tissue and activities of matrix metalloproteinases (MMPs) were also analyzed. Our results demonstrated that LS pretreatment augmented myocardial antioxidant status and attenuated myocardial oxidative stress. Myocardial apoptosis as well as MMPs activities was significantly prevented by LS pretreatment in ISO-induced mice. In addition, the immunoblot of Nrf2 revealed that LS pretreatment enhanced the nuclear protein expression of Nrf2 when compared to ISO control group. Thus, the overall results indicate that LS has cardioprotective effect and may prevent the myocardial stress by suppressing apoptosis through up-regulation of myocardial antioxidant levels.

  2. Role of neurotensin in radiation-induced hypothermia in rats

    SciTech Connect

    Kandasamy, S.B.; Hunt, W.A.; Harris, A.H. )

    1991-05-01

    The role of neurotensin in radiation-induced hypothermia was examined. Intracerebroventricular (ICV) administration of neurotensin produced dose-dependent hypothermia. Histamine appears to mediate neurotensin-induced hypothermia because the mast cell stabilizer disodium cromoglycate and antihistamines blocked the hypothermic effects of neurotensin. An ICV pretreatment with neurotensin antibody attenuated neurotensin-induced hypothermia, but did not attenuate radiation-induced hypothermia, suggesting that radiation-induced hypothermia was not mediated by neurotensin.

  3. Radiation induced dynamic mutations and transgenerational effects.

    PubMed

    Niwa, Ohtsura

    2006-01-01

    Many studies have confirmed that radiation can induce genomic instability in whole body systems. Although the molecular mechanisms underlying induced genomic instability are not known at present, this interesting phenomenon could be the manifestation of a cellular fail-safe system in which fidelity of repair and replication is down-regulated to tolerate DNA damage. Two features of genomic instability namely, delayed mutation and untargeted mutation, require two mechanisms of ;damage memory' and ;damage sensing, signal transduction and execution' to induce mutations at a non damaged-site. In this report, the phenomenon of transgenerational genomic instability and possible mechanisms are discussed using mouse data collected in our laboratory as the main bases.

  4. Radiation induced genomic instability in bystander cells

    NASA Astrophysics Data System (ADS)

    Zhou, H.; Gu, S.; Randers-Pehrson, G.; Hei, T.

    There is considerable evidence that exposure to ionizing radiation may induce a heritable genomic instability that leads to a persisting increased frequency of genetic and functional changes in the non-irradiated progeny of a wide variety of irradiated cells Genomic instability is measured as delayed expressions in chromosomal alterations micronucleus formation gene mutations and decreased plating efficiency During the last decade numerous studies have shown that radiation could induce bystander effect in non-irradiated neighboring cells similar endpoints have also been used in genomic instability studies Both genomic instability and the bystander effect are phenomena that result in a paradigm shift in our understanding of radiation biology In the past it seemed reasonable to assume that the production of single- and double-strand DNA breaks are due to direct energy deposition of energy by a charged particle to the nucleus It turns out that biology is not quite that simple Using the Columbia University charged particle microbeam and the highly sensitive human hamster hybrid AL cell mutagenic assay we irradiated 10 of the cells with a lethal dose of 30 alpha particles through the nucleus After overnight incubation the remaining viable bystander cells were replated in dishes for colony formation Clonal isolates were expanded and cultured for 6 consecutive weeks to assess plating efficiency and mutation frequency Preliminary results indicated that there was no significant decrease in plating efficiency among the bystander colonies when compared with

  5. Effects of fullerenol C60(OH)24 nanoparticles on a single-dose doxorubicin-induced cardiotoxicity in pigs: an ultrastructural study.

    PubMed

    Borović, Milica Labudović; Ičević, Ivana; Kanački, Zdenko; Žikić, Dragan; Seke, Mariana; Injac, Rade; Djordjević, Aleksandar

    2014-04-01

    Cardioprotective effects of fullerenol C60(OH)24 nanoparticles (FNP) were investigated in pigs after a single treatment with doxorubicin (DOX). Semithin and ultrathin sections of myocardial tissue routinely prepared for transmission electron microscopy were analyzed. Extensive intracellular damage was confirmed in cardiomyocytes of DOX-treated animals. By means of ultrastructural analysis, a certain degree of parenchymal degeneration was confirmed even in animals treated with FNP alone, including both the oral and the intraperitoneal application of the substance. The cardioprotective effects of FNP in animals previously treated with DOX were recognized to a certain extent, but were not fully confirmed at the ultrastructural level. Nevertheless, the myocardial morphology of DOX-treated animals improved after the admission of FNP. Irregular orientation of myofibrils, myofibrillar disruption, intracellular edema, and vacuolization were reduced, but not completely eliminated. Reduction of these cellular alterations was achieved if FNP was applied orally 6 h prior to DOX treatment in a dose of 18 mg/kg. However, numerous defects, including the inner mitochondrial membrane and the plasma membrane disruption of certain cells persisted. In FNP/DOX-treated animals, the presence of multinuclear cells with mitosis-like figures resembling metaphase or anaphase were observed, indicating that DOX and FNP could have a complex influence on the cell cycle of cardiomyocytes. Based on this experiment, further careful increase in dosage may be advised to enhance FNP-induced cardioprotection. These investigations should, however, always be combined with ultrastructural analysis. The FNP/DOX interaction is an excellent model for the investigation of cardiomyocyte cell death and cell cycle mechanisms.

  6. Radiation induced carcinoma of the larynx

    SciTech Connect

    Amendola, B.E.; Amendola, M.A.; McClatchey, K.D.

    1985-07-01

    A squamous cell carcinoma presented in a 20 year old female nonsmoker three years after receiving a high dosage of radiation therapy to the base of the skull, face and entire neuroaxis and intense combination chemotherapy for a parameningeal rhabdomyosarcoma of the paranasal sinuses is reported. The larynx received a dose of about 3,500 rads over an eight week period. This dosage in conjunction with the associated intense chemotherapy regimen given to the patient may explain the appearance of a radiation induced tumor in an unusually short latent period. This certainly represents a risk in young patients in whom an aggressive combined approach is taken and the physician should be aware of.

  7. Management of radiation-induced rectal bleeding.

    PubMed

    Laterza, Liboria; Cecinato, Paolo; Guido, Alessandra; Mussetto, Alessandro; Fuccio, Lorenzo

    2013-11-01

    Pelvic radiation disease is one of the major complication after radiotherapy for pelvic cancers. The most commonly reported symptom is rectal bleeding which affects patients' quality of life. Therapeutic strategies for rectal bleeding are generally ignored and include medical, endoscopic, and hyperbaric oxygen treatments. Most cases of radiation-induced bleeding are mild and self-limiting, and treatment is normally not indicated. In cases of clinically significant bleeding (i.e. anaemia), medical therapies, including stool softeners, sucralfate enemas, and metronidazole, should be considered as first-line treatment options. In cases of failure, endoscopic therapy, mainly represented by argon plasma coagulation and hyperbaric oxygen treatments, are valid and complementary second-line treatment strategies. Although current treatment options are not always supported by high-quality studies, patients should be reassured that treatment options exist and success is achieved in most cases if the patient is referred to a dedicated centre.

  8. Dietary inorganic nitrate alleviates doxorubicin cardiotoxicity: mechanisms and implications.

    PubMed

    Xi, Lei; Zhu, Shu-Guang; Das, Anindita; Chen, Qun; Durrant, David; Hobbs, Daniel C; Lesnefsky, Edward J; Kukreja, Rakesh C

    2012-05-15

    Doxorubicin (DOX) is one of the most powerful and widely prescribed chemotherapeutic agents to treat divergent human cancers. However, the clinical use of DOX is restricted due to its severe cardiotoxic side-effects. There has been ongoing search for cardioprotectants against DOX toxicity. Inorganic nitrate has emerged as a bioactive compound that can be reduced into nitrite and nitric oxide in vivo and in turn plays a therapeutic role in diseases associated with nitric oxide insufficiency or dysregulation. In this review, we describe a novel concept of using dietary supplementation of inorganic nitrate to reduce DOX-induced cardiac cellular damage and dysfunction, based on our recent promising studies in a mouse model of DOX cardiotoxicity. Our data show that chronic oral ingestion of sodium nitrate, at a dose equivalent to ~400% of the Acceptable Daily Intake of the World Health Organization, alleviated DOX-induced left ventricular dysfunction and mitochondrial respiratory chain damage. Such cardioprotective effects were associated with reduction of cardiomyocyte necrosis/apoptosis, tissue lipid peroxidation, and mitochondrial H(2)O(2) generation following DOX treatment. Furthermore, proteomic studies revealed enhanced cardiac expression of mitochondrial antioxidant enzyme - peroxiredoxin 5 in the nitrate-treated animals. These studies suggest that inorganic nitrate could be an inexpensive therapeutic agent for long-term oral administration in preventing DOX-induced cardiac toxicity and myopathy during the prolonged pathological process. Future clinical trials in the cancer patients undergoing DOX chemotherapy are warranted to translate these experimental findings into an effective new therapy in preventing the DOX-induced cardiomyopathy. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Dietary Inorganic Nitrate Alleviates Doxorubicin Cardiotoxicity: Mechanisms and Implications

    PubMed Central

    Xi, Lei; Zhu, Shu-Guang; Das, Anindita; Chen, Qun; Durrant, David; Hobbs, Daniel C.; Lesnefsky, Edward J.; Kukreja, Rakesh C.

    2012-01-01

    Doxorubicin (DOX) is one of the most powerful and widely prescribed chemotherapeutic agents to treat divergent human cancers. However, the clinical use of DOX is restricted due to its severe cardiotoxic side-effects. There has been ongoing search for cardioprotectants against DOX toxicity. Inorganic nitrate has emerged as a bioactive compound that can be reduced into nitrite and nitric oxide in vivo and in turn plays a therapeutic role in diseases associated with nitric oxide insufficiency or dysregulation. In this review, we describe a novel concept of using dietary supplementation of inorganic nitrate to reduce DOX-induced cardiac cellular damage and dysfunction, based on our recent promising studies in a mouse model of DOX cardiotoxicity. Our data show that chronic oral ingestion of sodium nitrate, at a dose equivalent to ~400% of the Acceptable Daily Intake of the World Health Organization, alleviated DOX-induced left ventricular dysfunction and mitochondrial respiratory chain damage. Such cardioprotective effects were associated with reduction of cardiomyocyte necrosis/apoptosis, tissue lipid peroxidation, and mitochondrial H2O2 generation following DOX treatment. Furthermore, proteomic studies revealed enhanced cardiac expression of mitochondrial antioxidant enzyme – peroxiredoxin 5 in the nitrate-treated animals. These studies suggest that inorganic nitrate could be an inexpensive therapeutic agent for long-term oral administration in preventing DOX-induced cardiac toxicity and myopathy during the prolonged pathological process. Future clinical trials in the cancer patients undergoing DOX chemotherapy are warranted to translate these experimental findings into an effective new therapy in preventing the DOX-induced cardiomyopathy. PMID:22484629

  10. The cardiotoxicity and myocyte damage caused by small molecule anticancer tyrosine kinase inhibitors is correlated with lack of target specificity

    SciTech Connect

    Hasinoff, Brian B.

    2010-04-15

    The use of the new anticancer tyrosine kinase inhibitors (TKI) has revolutionized the treatment of certain cancers. However, the use of some of these results in cardiotoxicity. Large-scale profiling data recently made available for the binding of 7 of the 9 FDA-approved tyrosine kinase inhibitors to a panel of 317 kinases has allowed us to correlate kinase inhibitor binding selectivity scores with TKI-induced damage to neonatal rat cardiac myocytes. The tyrosine kinase selectivity scores, but not the serine-threonine kinase scores, were highly correlated with the myocyte damaging effects of the TKIs. Additionally, we showed that damage to myocytes gave a good rank order correlation with clinical cardiotoxicity. Finally, strength of TKI binding to colony-stimulating factor 1 receptor (CSF1R) was highly correlated with myocyte damage, thus possibly implicating this kinase in contributing to TKI-induced cardiotoxicity.

  11. Adriamycin cardiotoxicity amelioration by alpha-tocopherol.

    PubMed

    Krivit, W

    1979-01-01

    Adriamycin has become a potent member of the cancer chemotherapeutic program. However, the full utilization of adriamycin is limited by its cardiotoxicity. In experimental animals, alpha-tocopherol has been shown by some to ameliorate or prevent cardiac dysfunction without impairing antitumor effectiveness. During adriamycin therapy, future clinical research should consist of biochemical measurements of vitamin E in plasma, lipoperoxidation in red cells and platelets, while cars to indicate deficiency, should be considered as one method of ameliorating toxicity.

  12. Radiation-induced osteosarcoma of the sphenoid bone

    SciTech Connect

    Tanaka, S.; Nishio, S.; Morioka, T.; Fukui, M.; Kitamura, K.; Hikita, K. )

    1989-10-01

    The case of a patient who developed osteosarcoma in the sphenoid bone 15 years after radiation therapy for a craniopharyngioma is reported. Radiation-induced osteosarcoma of the sphenoid bone has not been reported previously. Reported cases of radiation-induced osteosarcomas are reviewed.

  13. Noninvasive Diagnosis of Chemotherapy Related Cardiotoxicity

    PubMed Central

    Gillespie, Hamilton S; McGann, Christopher J; Wilson, Brent D

    2011-01-01

    Chemotherapeutic agents reduce mortality and can prevent morbidity in a wide range of malignancies. These agents are, however, associated with toxicities of their own, and the treating physician must remain ever vigilant against the risk outgrowing the benefit of therapy. Thus, pre-treatment evaluation and monitoring for toxicity during and following administration is a fundamental tenet of oncologic practice. Among the most insidious and deadly toxicities of anti-tumor agents is cardiac toxicity, which in some cases may be irreversible. Early detection of cardiotoxicity allows the treating oncologist to redirect therapy or dose modify, taking into account the cost of a reduction in therapy against the potential of further injury to the patient. In these instances, the role of the cardiologist is to assist and advise the oncologist by providing diagnostic and prognostic information regarding developing cardiotoxicity. This review discusses noninvasive diagnostic options to identify and characterize cardiotoxicity and their use in prognosis and guiding therapy. We also review established protocols for cardiac safety monitoring in the treatment of malignancy. PMID:22758624

  14. Radiation-induced injury of the esophagus

    SciTech Connect

    Lepke, R.A.; Libshitz, H.I.

    1983-08-01

    Forty patients with functional or morphologic esophageal abnormalities following radiotherapy were identified. Abnormalities included abnormal motility with and without mucosal edema, stricture, ulceration and pseudodiverticulum, and fistula. Abnormal motility occurred 4 to 12 weeks following radiotherapy alone and as early as 1 week after therapy when concomitant chemotherapy had been given. Strictures developed 4 to 8 months following completion of radiotherapy. Ulceration, pseudodiverticulum, and fistula formation did not develop in a uniform time frame. Radiation-induced esophageal injury is more frequent when radiotherapy and chemotherapy are combined than it is with radiotherapy alone.

  15. Radiation-induced esophagitis in lung cancer

    PubMed Central

    Baker, Sarah; Fairchild, Alysa

    2016-01-01

    Radiation-induced esophagitis is the most common local acute toxicity of radiotherapy (RT) delivered for the curative or palliative intent treatment of lung cancer. Although concurrent chemotherapy and higher RT dose are associated with increased esophagitis risk, advancements in RT techniques as well as adherence to esophageal dosimetric constraints may reduce the incidence and severity. Mild acute esophagitis symptoms are generally self-limited, and supportive management options include analgesics, acid suppression, diet modification, treatment for candidiasis, and maintenance of adequate nutrition. Esophageal stricture is the most common late sequela from esophageal irradiation and can be addressed with endoscopic dilatation. Approaches to prevent or mitigate these toxicities are also discussed. PMID:28210168

  16. Knockdown of Mtfp1 can minimize doxorubicin cardiotoxicity by inhibiting Dnm1l-mediated mitochondrial fission.

    PubMed

    Aung, Lynn H H; Li, Ruibei; Prabhakar, Bellur S; Li, Peifeng

    2017-06-23

    The long-term usage of doxorubicin (DOX) is largely limited due to the development of severe cardiomyopathy. Many studies indicate that DOX-induced cardiac injury is related to reactive oxygen species generation and ultimate activation of apoptosis. The role of novel mitochondrial fission protein 1 (Mtfp1) in DOX-induced cardiotoxicity remains elusive. Here, we report the pro-mitochondrial fission and pro-apoptotic roles of Mtfp1 in DOX-induced cardiotoxicity. DOX up-regulates the Mtfp1 expression in HL-1 cardiac myocytes. Knockdown of Mtfp1 prevents cardiac myocyte from undergoing mitochondrial fission, and subsequently reduces the DOX-induced apoptosis by preventing dynamin 1-like (Dnm1l) accumulation in mitochondria. In contrast, when Mtfp1 is overexpressed, a suboptimal dose of DOX can induce a significant percentage of cells to undergo mitochondrial fission and apoptosis. These data suggest that knocking down of Mtfp1 can minimize the cardiomyocytes loss in DOX-induced cardiotoxicity. Thus, the regulation of Mtfp1 expression could be a novel therapeutic approach in chemotherapy-induced cardiotoxicity. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  17. Radiation-induced segregation, hardening, and IASCC

    SciTech Connect

    Eason, E.D.; Nelson, E.E.

    1995-12-31

    Intergranular cracking has been discovered after extended radiation exposure in several boiling water reactor (BWR) internal components made of austenitic stainless steel and nickel-based alloys. There are fewer field observations of intergranular cracking in pressurized water reactors (PWR), but failures have occurred in bolts, springs, and fuel cladding. There is concern for other PWR components, some of which will receive greater radiation doses than BWR components during the plant lifetime. This paper presents the results of an investigation on the connection between radiation induced segregation, hardening and irradiation-assisted stress corrosion cracking (IASCC). A data base was developed containing the available data on austenitic stainless steel where the grain boundary composition was measured by Field Emission Gun-Scanning Transmission Election Microscopy (FEG-STEM), the stress corrosion susceptibility was measured by constant extension rate tests (CERT) in light water reactor environments, some estimate of irradiated strength was available and the irradiation was conducted in a power reactor. The data base was analyzed using advanced data analysis techniques, including tree-structured pattern recognition and transformation analysis codes. The most sensitive variables and optimal modeling forms were identified using these techniques, then preliminary models were calibrated using nonlinear least squares. The results suggest that more than one mechanism causes IASCC.

  18. Radiation-induced uterine changes: MR imaging

    SciTech Connect

    Arrive, L.; Chang, Y.C.; Hricak, H.; Brescia, R.J.; Auffermann, W.; Quivey, J.M.

    1989-01-01

    To assess the capability of magnetic resonance (MR) imaging to demonstrate postirradiation changes in the uterus, MR studies of 23 patients who had undergone radiation therapy were retrospectively examined and compared with those of 30 patients who had not undergone radiation therapy. MR findings were correlated with posthysterectomy histologic findings. In premenopausal women, radiation therapy induced (a) a decrease in uterine size demonstrable as early as 3 months after therapy ended; (b) a decrease in signal intensity of the myometrium on T2-predominant MR images, reflecting a significant decrease in T2 relaxation time, demonstrable as early as 1 month after therapy; (c) a decrease in thickness and signal intensity of the endometrium demonstrable on T2-predominant images 6 months after therapy; and (d) loss of uterine zonal anatomy as early as 3 months after therapy. In postmenopausal women, irradiation did not significantly alter the MR imaging appearance of the uterus. These postirradiation MR changes in both the premenopausal and postmenopausal uteri appeared similar to the changes ordinarily seen on MR images of the nonirradiated postmenopausal uterus.

  19. Evaluation of the pharmacokinetics and cardiotoxicity of doxorubicin in rat receiving nilotinib

    SciTech Connect

    Zhou, Zhi-yong; Wan, Li-li; Yang, Quan-jun; Han, Yong-long; Li, Yan; Yu, Qi; Guo, Cheng; Li, Xiao

    2013-10-01

    Doxorubicin (DOX) is a potent chemotherapy drug with a narrow therapeutic window. Nilotinib, a small-molecule Bcr-Abl tyrosine kinase inhibitor, was reported to reverse multidrug resistance (MDR) mediated by P-glycoprotein (P-gp) transmembrane transporters. The present study aimed to investigate nilotinib's affection on the steady-state pharmacokinetics, disposition and cardiotoxicity of DOX. A total of 24 male Sprague–Dawley rats were randomized into four groups (6 in each) and received the following regimens: saline, intravenous DOX (5 mg/kg) alone, and DOX co-administrated with either 20 or 40 mg/kg nilotinib. Blood was withdrawn at 12 time points till 72 h after DOX injection and the concentrations of DOX and its metabolite doxorubicinol (DOXol) in serum and cardiac tissue were assayed by LC–MS–MS method. To determine the cardiotoxicity, the following parameters were investigated: creatine kinase, lactate dehydrogenase, malondialdehyde, and superoxide dismutase. Histopathological examination of heart section was carried out to evaluate the extent of cardiotoxicity after treatments. The results showed that pretreatment of 40 mg/kg nilotinib increased the AUC{sub 0–t} and C{sub max} of DOX and DOXol. However, their accumulation in cardiac tissue was significantly decreased when compared with the group that received DOX alone. In addition, biochemical and histopathological results showed that 40 mg/kg nilotinib reduced the cardiotoxicity induced by DOX administration. In conclusion, co-administration of nilotinib increased serum exposure, but significantly decreased the accumulation of DOX in cardiac tissue. Consistent with in vitro profile, oral dose of 40 mg/kg nilotinib significantly decreased the cardiotoxicity of DOX in rat by enhancing P-gp activity in the heart.

  20. Mouse models of radiation-induced cancers.

    PubMed

    Rivina, Leena; Schiestl, Robert

    2013-01-01

    Radiation-induced (RI) secondary cancers were not a major clinical concern even as little as 15 years ago. However, advances in cancer diagnostics, therapy, and supportive care have saved numerous lives and many former cancer patients are now living for 5, 10, 20, and more years beyond their initial diagnosis. The majority of these patients have received radiotherapy as a part of their treatment regimen and are now beginning to develop secondary cancers arising from normal tissue exposure to damaging effects of ionizing radiation. Because historically patients rarely survived past the extended latency periods inherent to these RI cancers, very little effort was channeled towards the research leading to the development of therapeutic agents intended to prevent or ameliorate oncogenic effects of normal tissue exposure to radiation. The number of RI cancers is expected to increase very rapidly in the near future, but the field of cancer biology might not be prepared to address important issues related to this phenomena. One such issue is the ability to accurately differentiate between primary tumors and de novo arising secondary tumors in the same patient. Another issue is the lack of therapeutic agents intended to reduce such cancers in the future. To address these issues, large-scale epidemiological studies must be supplemented with appropriate animal modeling studies. This work reviews relevant mouse (Mus musculus) models of inbred and F1 animals and methodologies of induction of most relevant radiation-associated cancers: leukemia, lymphoma, and lung and breast cancers. Where available, underlying molecular pathologies are included. © 2013 Elsevier Inc. All rights reserved.

  1. Radar detection of radiation-induced ionization in air

    DOEpatents

    Gopalsami, Nachappa; Heifetz, Alexander; Chien, Hual-Te; Liao, Shaolin; Koehl, Eugene R.; Raptis, Apostolos C.

    2015-07-21

    A millimeter wave measurement system has been developed for remote detection of airborne nuclear radiation, based on electromagnetic scattering from radiation-induced ionization in air. Specifically, methods of monitoring radiation-induced ionization of air have been investigated, and the ionized air has been identified as a source of millimeter wave radar reflection, which can be utilized to determine the size and strength of a radiation source.

  2. Radiation induced micrencephaly in guinea pigs

    SciTech Connect

    Wagner, L.K.; Johnston, D.A.; Felleman, D.J.

    1991-01-01

    A brain weight deficit of about 70 mg was induced at doses of approximately 75-mGy and a deficit of 60 mg was induced at 100 mGy. This confirms the effects projected and observed by Wanner and Edwards. Although the data do not demonstrate a clear dose-response relationship between the 75-mGy and 100-mGy groups, the data are statistically consistent with a dose-response effect because of the overlapping confidence intervals. The lack of a statistically significant observation is most likely related to the small difference in doses and the limited numbers of animals examined. There are several factors that can influence the brain weight of guinea pig pups, such as caging and housing conditions, the sex of the animal, and litter size. These should be taken into account for accurate analysis. Dam weight did not appear to have a significant effect. The confirmation of a micrencephalic effect induced x rays at doses of 75-mGy during this late embryonic stage of development is consistent with the findings of small head size induced in those exposed prior to the eight week of conception at Hiroshima. This implies a mechanism for micrencephaly different from those previously suggested and lends credence to a causal relation between radiation and small head size in humans at low doses as reported by Miller and Mulvihill. 16 refs., 13 tabs.

  3. A recommended practical approach to the management of target therapy and angiogenesis inhibitors cardiotoxicity: an opinion paper of the working group on drug cardiotoxicity and cardioprotection, Italian Society of Cardiology

    PubMed Central

    Maurea, Nicola; Spallarossa, Paolo; Cadeddu, Christian; Madonna, Rosalinda; Mele, Donato; Monte, Ines; Novo, Giuseppina; Pagliaro, Pasquale; Pepe, Alessia; Tocchetti, Carlo G.; Zito, Concetta; Mercuro, Giuseppe

    2016-01-01

    The US National Cancer Institute estimates that cardiotoxicity (CTX) from target therapy refers mostly to four groups of drugs: epidermal growth factor receptor 2 inhibitors, angiogenic inhibitors, directed Abelson murine leukemia viral oncogene homolog inhibitors, and proteasome inhibitors. The main cardiotoxic side-effects related to antiepidermal growth factor receptor 2 therapy are left ventricular systolic dysfunction and heart failure. Angiogenesis inhibitors are associated with hypertension, left ventricular dysfunction/heart failure, myocardial ischemia, QT prolongation, and thrombosis. Moreover, other agents may be related to CTX induced by treatment. In this study, we review the guidelines for a practical approach for the management of CTX in patients under anticancer target therapy. PMID:27183530

  4. A STUDY ON MICROWAVE INSTABILITY INDUCED RADIATION.

    SciTech Connect

    MURPHY,J.B.; WANG,J.M.

    1999-03-29

    It has been shown in the context of a solvable model that the microwave instability can be described in terms of ''coherent states'' [1]. Building on this model, we first show that the simplicity of the model arises from the fact that the key integral-differential equation can be reduced to the Karhunen-Loeve equation of the theory of stochastic processes. We present results on the correlation functions of the electric field. In particular, for the second order correlation function, we show that a relation akin to the Hanbury Brown-Twiss correlation holds for the coherent states of the microwave-instability induced radiation. We define an entropy-like quantity and we introduce a Wigner distribution function representation.

  5. Transesophageal Echocardiography and Radiation-induced Damages

    PubMed Central

    Cottini, Marzia; Polizzi, Vincenzo; Pino, Paolo Giuseppe; Buffa, Vitaliano; Musumeci, Francesco

    2016-01-01

    The long-term sequelae of mantle therapy include, especially lung and cardiac disease but also involve the vessels and the organs in the neck and thorax (such as thyroid, aorta, and esophagus). We presented the case of 66-year-old female admitted for congestive heart failure in radiation-induced heart disease. The patient had undergone to massive radiotherapy 42 years ago for Hodgkin's disease (type 1A). Transesophageal echocardiography was performed unsuccessfully with difficulty because of the rigidity and impedance of esophageal walls. Our case is an extraordinary report of radiotherapy's latency effect as a result of dramatic changes in the structure of mediastinum, in particular in the esophagus, causing unavailability of a transesophageal echocardiogram. PMID:27867461

  6. [Medical prevention and treatment of radiation-induced pulmonary complications].

    PubMed

    Vallard, A; Rancoule, C; Le Floch, H; Guy, J-B; Espenel, S; Le Péchoux, C; Deutsch, É; Magné, N; Chargari, C

    2017-08-01

    Radiation-induced lung injuries mainly include the (acute or sub-acute) radiation pneumonitis, the lung fibrosis and the bronchiolitis obliterans organizing pneumonia (BOOP). The present review aims at describing the diagnostic process, the current physiopathological knowledge, and the available (non dosimetric) preventive and curative treatments. Radiation-induced lung injury is a diagnosis of exclusion, since clinical, radiological, or biological pathognomonic evidences do not exist. Investigations should necessarily include a thoracic high resolution CT-scan and lung function tests with a diffusing capacity of the lung for carbon monoxide. No treatment ever really showed efficacy to prevent acute radiation-induced lung injury, or to treat radiation-induced lung fibrosis. The most promising drugs in order to prevent radiation-induced lung injury are amifostine, angiotensin-converting-enzyme inhibitors and pentoxifylline. Inhibitors of collagen synthesis are currently tested at a pre-clinical stage to limit the radiation-induced lung fibrosis. Regarding available treatments of radiation-induced pneumonitis, corticoids can be considered the cornerstone. However, no standardized program or guidelines concerning the initial dose and the gradual tapering have been scientifically established. Alternative treatments can be prescribed, based on clinical cases reporting on the efficacy of immunosuppressive drugs. Such data highlight the major role of the lung dosimetric protection in order to efficiently prevent radiation-induced lung injury. Copyright © 2017 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

  7. Cardioprotective Potentials of Plant-Derived Small Molecules against Doxorubicin Associated Cardiotoxicity

    PubMed Central

    Ojha, Shreesh; Al Taee, Hasan; Goyal, Sameer; Mahajan, Umesh B.; Patil, Chandrgouda R.; Arya, D. S.; Rajesh, Mohanraj

    2016-01-01

    Doxorubicin (DOX) is a potent and widely used anthracycline antibiotic for the treatment of several malignancies. Unfortunately, the clinical utility of DOX is often restricted due to the elicitation of organ toxicity. Particularly, the increased risk for the development of dilated cardiomyopathy by DOX among the cancer survivors warrants major attention from the physicians as well as researchers to develop adjuvant agents to neutralize the noxious effects of DOX on the healthy myocardium. Despite these pitfalls, the use of traditional cytotoxic drugs continues to be the mainstay treatment for several types of cancer. Recently, phytochemicals have gained attention for their anticancer, chemopreventive, and cardioprotective activities. The ideal cardioprotective agents should not compromise the clinical efficacy of DOX and should be devoid of cumulative or irreversible toxicity on the naïve tissues. Furthermore, adjuvants possessing synergistic anticancer activity and quelling of chemoresistance would significantly enhance the clinical utility in combating DOX-induced cardiotoxicity. The present review renders an overview of cardioprotective effects of plant-derived small molecules and their purported mechanisms against DOX-induced cardiotoxicity. Phytochemicals serve as the reservoirs of pharmacophore which can be utilized as templates for developing safe and potential novel cardioprotective agents in combating DOX-induced cardiotoxicity. PMID:27313831

  8. Update on cardiotoxicity of anti-cancer treatments.

    PubMed

    Rosa, Gian Marco; Gigli, Lorenzo; Tagliasacchi, Maria Isabella; Di Iorio, Cecilia; Carbone, Federico; Nencioni, Alessio; Montecucco, Fabrizio; Brunelli, Claudio

    2016-03-01

    Anti-cancer treatments markedly improved the prognosis of patients, but unfortunately might be hampered by cardiotoxicity. Both symptomatic and asymptomatic clinical forms of heart failure have been reported, which may be reversible or irreversible. The aim of this review is to provide an overview of the antineoplastic agents associated with cardiac toxicity and of the available diagnostic techniques. This narrative review is based on material from MEDLINE and PUBMED up to November 2015. We looked at the terms antineoplastic drugs and cardiac toxicity in combination with echocardiography, troponins, cardiac magnetic resonance, and positron emission tomography. Anthracyclines, monoclonal antibodies, fluoropyrimidines, taxanes, alkylating agents, vinka alkaloids were reported to induce different clinical manifestations of cardioxicity. Chest radiotherapy is also associated with various forms of cardiac damage, which are indistinguishable from those found in patients with heart disease of other aetiologies and that may even appear several years after administration. Among diagnostic techniques, echocardiography is a noninvasive, cost-effective, and widely available imaging tool. Nuclear imaging and cardiac magnetic resonance may be used but are not so widely available and are more difficult to perform. Finally, some biomarkers, such as troponins, may be used to evaluate cardiac damage, but establishing the optimal timing of troponin assessment remains unclear and defining the cut-off point for positivity is still an important goal. Cardiotoxicity of anti-cancer treatments is associated with development of heart failure. Novel diagnostic tools might be relevant to early recognize irreversible forms cardiac diseases. © 2016 Stichting European Society for Clinical Investigation Journal Foundation.

  9. Obstructive jaundice due to radiation-induced hepatic duct stricture

    SciTech Connect

    Chandrasekhara, K.L.; Iyer, S.K.

    1984-10-01

    A case of obstructive jaundice due to radiation-induced hepatic duct stricture is reported. The patient received postoperative radiation for left adrenal carcinoma, seven years prior to this admission. The sequelae of hepatobiliary radiation and their management are discussed briefly.

  10. Radiation health: mechanisms of radiation-induced cataracts in astronauts.

    PubMed

    Frey, Mary Anne

    2009-06-01

    Dr. Blakely and colleagues have conducted a series of experiments to explain the molecular basis by which space radiation causes cataracts, particularly with regard to elucidating how space radiation alters gene expression profiles in the process of lens cell differentiation. To do this, they "developed an in vitro model of differentiating human lens epithelial cells...that mimicked the normal growth environment in the tissue" (2). They have shown that radiation, especially high-LET (linear energy transfer) iron ion radiation, affects gene and protein expression of many cells involved in lens cell differentiation and cell cycle regulation. They have also developed a schematic model to explain the action of ionizing radiation on specific molecules leading to perturbations in cell cycle regulation and ultimately affecting lens cell differentiation. These results can provide a basis for developing countermeasures to protect astronauts in long-duration spaceflight and for improving risk assessments of space-radiation-caused cataracts. This research can also benefit individuals on Earth who are exposed to clinical and occupational radiation.

  11. Folic acid ameliorates celecoxib cardiotoxicity in a doxorubicin heart failure rat model.

    PubMed

    Ahmad, Shafique; Panda, Bibhu Prasad; Kohli, Kanchan; Fahim, Mohammad; Dubey, Kiran

    2017-12-01

    The cardiotoxic effect of selective cyclo-oxygenase-2 inhibitors is well known. While rofecoxib and valdecoxib have been withdrawn, celecoxib remains on the market. Folic acid, a naturally occurring vitamin, has been shown to reduce myocardial ischemia and post-reperfusion injury in rats. This study examined the cardiac effects of celecoxib and folic acid on doxorubicin-induced cardiomyopathy in rats. Cardiomyopathy was induced in male Wistar rats with six intraperitoneal injections of 2.5 mg/kg doxorubicin over a period of two weeks. The effect of 28 days of celecoxib (100 mg/kg/day) and its combination with folic acid (10 mg/kg/day) was studied on doxorubicin-induced cardiomyopathy according to serum lactate dehydrogenase (LDH), creatine kinase (CK-MB), troponin-T (Tn-T), tumor necrosis factor alpha (TNF-α), cardiac thiobarbituric acid reactive substance (TBARS), and glutathione (GSH) levels as well as systolic blood pressure (SBP), heart rate (HR) and ultrastructural studies. Celecoxib cardiotoxicity was manifested by significant increases in the LDH, Tn-T, TNF-α, CK-MB, SBP, HR (p < 0.001) and TBARS (p < 0.01) levels and a significant decrease in the GSH (p < 0.05) level when used alone or administered with doxorubicin. However, the combination of folic acid with celecoxib caused a significant reversal of these parameters and reduced the cardiotoxicity of celecoxib that was aggravated by doxorubicin. The ultrastructural study also revealed myocardial protection with this combination. Folic acid protects against the cardiotoxic effects of celecoxib, which are aggravated in the presence of doxorubicin. Folic acid may act as a useful adjunct in patients who are taking celecoxib.

  12. Radiation-Induced Alopecia after Endovascular Embolization under Fluoroscopy

    PubMed Central

    Ounsakul, Vipawee; Iamsumang, Wimolsiri

    2016-01-01

    Radiation-induced alopecia after fluoroscopically guided procedures is becoming more common due to an increasing use of endovascular procedures. It is characterized by geometric shapes of nonscarring alopecia related to the area of radiation. We report a case of a 46-year-old man presenting with asymptomatic, sharply demarcated rectangular, nonscarring alopecic patch on the occipital scalp following cerebral angiography with fistula embolization under fluoroscopy. His presentations were compatible with radiation-induced alopecia. Herein, we also report a novel scalp dermoscopic finding of blue-grey dots in a target pattern around yellow dots and follicles, which we detected in the lesion of radiation-induced alopecia. PMID:28074164

  13. Embryonic cardiotoxicity of weak aryl hydrocarbon receptor agonists and CYP1A inhibitor fluoranthene in the Atlantic killifish (Fundulus heteroclitus).

    PubMed

    Brown, D R; Clark, B W; Garner, L V T; Di Giulio, R T

    2016-10-01

    High affinity aryl hydrocarbon receptor (AHR) ligands, such as certain polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), cause severe cardiac teratogenesis in fish embryos. Moderately strong AHR agonists, for example benzo[a]pyrene and β-naphthoflavone, are capable of causing similar cardiotoxic effects, particularly when coupled with cytochrome P450 1A (CYP1A) inhibitors (e.g., fluoranthene (FL). Additionally, some weaker AHR agonists (carbaryl, 2-methylindole, 3-methylindole, and phenanthrene) are known to also cause cardiotoxicity in zebrafish (Danio rerio) embryos when coupled with FL; however, the cardiotoxic effects were not mediated specifically by AHR stimulation. This study was performed to determine if binary exposure to weak AHR agonists and FL were also capable of causing cardiotoxicity in Atlantic killifish Fundulus heteroclitus embryos. Binary exposures were performed in both naïve and PAH-adapted killifish embryos to examine resistance to weak agonists and FL binary exposures. Weak agonists used in this study included the following: carbaryl, phenanthrene, 2-methylindole, 3-methylindole, indigo, and indirubin. Carbaryl, indigo, and indirubin induced the highest CYP1 activity levels in naïve killifish embryos, but no significant CYP1 induction was observed in the PAH-adapted killifish. Embryos were coexposed to subteratogenic levels of each agonist and 500μg/L FL to assess if binary administration could cause cardiotoxicity. Indigo and indirubin coupled with FL caused cardiac teratogenesis in naïve killifish, but coexposures did not produce cardiac chamber abnormalities in the PAH-adapted population. Knockdown of AHR2 in naïve killifish embryos did not prevent cardiac teratogenesis. The data suggest a unique mechanism of cardiotoxicity that is not driven by AHR2 activation.

  14. Thermodynamic models of radiation-induced processes in solids

    NASA Astrophysics Data System (ADS)

    Yurov, V. M.; Eremin, E. N.; Kasymov, S. S.; Laurinas, V. CH; Chernyavskii, A. V.

    2017-01-01

    A thermodynamic model is proposed to qualitatively describe the radiation-induced processes in solids: temperature dependence of the X-ray radio luminescence output, dependence of these processes on the excitation density, energy accumulating in a solid under exposure to ionizing radiation and its temperature dependence. The proposed model and the formula derived can be used to develop radiation-resistant and radiation-sensitive materials.

  15. Ion beam induced luminescence: Relevance to radiation induced bystander effects

    NASA Astrophysics Data System (ADS)

    Ahmad, S. B.; McNeill, F. E.; Byun, S. H.; Prestwich, W. V.; Seymour, C.; Mothersill, C. E.

    2012-10-01

    The aim of this work is quantify the light emitted as a result of charged particle interaction in materials which may be of relevance to radiation induced "bystander effects" studies. We have developed a system which employs single photon counting to measure the light emitted from samples irradiated under vacuum by a charged particle beam. The system uses a fast photomultiplier tube with a peak cathode response at 420 nm. It has been tested in a proof-of-principle experiment using polystyrene targets. Light output, as a result of irradiation, was measured. The luminescence yield appears to have a non-linear behavior with the incident ion fluence: it rises exponentially to an asymptotic value. The target was irradiated with beam energies varying from 1 to 2 MeV and showed saturation at or before an incident fluence rate of 3 × 1013 H+/cm2 s. The average saturation value for the photon output was found to be 40 × 106 cps. Some measurements were performed using filters to study the emission at specific wavelengths. In the case of filtered light measurements, the photon output was found to saturate at 28 × 103, 10 × 106, and 35 × 106 cps for wavelengths of 280 ± 5 nm, 320 ± 5 nm and 340 ± 5 nm respectively. The light output reaches a maximum value because of damage induced in the polymer. Our measurements indicate a "damage cross section" of the order of 10-14 cm2. The average radiant intensity was found to increase at wavelengths of 280 and 320 nm when the proton energy was increased. This was not found to occur at 340 nm. In conclusion, the light emission at specific wavelengths was found to depend upon the incident proton fluence and the proton energy. The wavelengths of the emitted light measured in this study have significance for the understanding of radiation induced bystander effects.

  16. Cardiovascular imaging in the diagnosis and monitoring of cardiotoxicity: cardiovascular magnetic resonance and nuclear cardiology.

    PubMed

    Pepe, Alessia; Pizzino, Fausto; Gargiulo, Paola; Perrone-Filardi, Pasquale; Cadeddu, Christian; Mele, Donato; Monte, Ines; Novo, Giuseppina; Zito, Concetta; Di Bella, Gianluca

    2016-05-01

    Chemotherapy-induced cardiotoxicity (CTX) is a determining factor for the quality of life and mortality of patients administered potentially cardiotoxic drugs and in long-term cancer survivors. Therefore, prevention and early detection of CTX are highly desirable, as is the exploration of alternative therapeutic strategies and/or the proposal of potentially cardioprotective treatments. In recent years, cardiovascular imaging has acquired a pivotal role in this setting. Although echocardiography remains the diagnostic method most used to monitor cancer patients, the need for more reliable, reproducible and accurate detection of early chemotherapy-induced CTX has encouraged the introduction of second-line advanced imaging modalities, such as cardiac magnetic resonance (CMR) and nuclear techniques, into the clinical setting. This review of the Working Group on Drug Cardiotoxicity and Cardioprotection of the Italian Society of Cardiology aims to afford an overview of the most important findings from the literature about the role of CMR and nuclear techniques in the management of chemotherapy-treated patients, describe conventional and new parameters for detecting CTX from both diagnostic and prognostic perspectives and provide integrated insight into the role of CMR and nuclear techniques compared with other imaging tools and versus the positions of the most important international societies.

  17. Analog of microwave-induced resistance oscillations induced in GaAs heterostructures by terahertz radiation

    NASA Astrophysics Data System (ADS)

    Herrmann, T.; Dmitriev, I. A.; Kozlov, D. A.; Schneider, M.; Jentzsch, B.; Kvon, Z. D.; Olbrich, P.; Bel'kov, V. V.; Bayer, A.; Schuh, D.; Bougeard, D.; Kuczmik, T.; Oltscher, M.; Weiss, D.; Ganichev, S. D.

    2016-08-01

    We report on the study of terahertz radiation-induced MIRO-like oscillations of magnetoresistivity in GaAs heterostructures. Our experiments provide an answer on two most intriguing questions—effect of radiation helicity and the role of the edges—yielding crucial information for an understanding of the MIRO (microwave-induced resistance oscillations) origin. Moreover, we demonstrate that the range of materials exhibiting radiation-induced magneto-oscillations can be largely extended by using high-frequency radiation.

  18. [Spontaneous and radiation-induced chromosome breaks].

    PubMed

    Lebedeva, L I; Chubykin, V L

    1975-01-01

    It is shown by the study of the location of acentric fragments of chromosomes at metaphase and anaphase in the root cells of pea (cultivar "Capital"), in the cornea of rats (strain Wistar), in the bone marrow of mice (strain BALB), in the cultures of embryonic fibroblasts of mice (strain C57B1) and of embryonic human fibroblasts that some fragments are situated outside the equatorial plates, while others are situated within the plane of the equatorial plate. The fragments of the first type initiate mainly spontaneously, while the fragments of the second type are mainly induced by irradiation. These principles are observed in all the types of animal and plant cells studied. The location of the fragments observed in non-radiated cells could be explained if it be assumed, that all the chromosome breaks are realized before the prometaphase and by the beginning of the prometaphase the fragments are randomly distributed within the volume of the nucleus. At the prometaphase most fragments move from the equator to the pole of the cell and thus at the metaphase and anaphase are found to be located outside the equatorial plate. For the explanation of the observed ratio of the two types of fragments in an irradiated cell it is assumed that chromosome fragments resulting from breaks induced by irradiation are completely detached from chromosomes only after the beginning of the prometaphase. Possibly, the process of development of breaks is also not yet completed by this time, it continues and is completed at the metaphase, partially, at the anaphase of the mitosis.

  19. Radiation-induced degradation of DNA bases

    NASA Astrophysics Data System (ADS)

    Douki, T.; Delatour, T.; Martini, R.; Cadet, J.

    1999-01-01

    Radio-induced degradation of DNA involves radical processes. A series of lesions among the major bases degradation products has been measured in isolated DNA exposed to gamma radiation in aerated aqueous solution. Degradation can be accounted for by the formation of hydroxyl radicals upon radiolysis of water (indirect effect). The four bases are degraded in high yield. Direct effect has been mimicked by photo-induced electron abstraction from the bases producing their radical cation. Quantification of the modified bases showed that guanine is the preferential target. This can be explained by its lower oxidation potential and charge transfer phenomena. La décomposition radio-induite de l'ADN fait intervenir des processus radicalaires. Une série de lésions choisies parmi les produits majeurs de dégradation des bases a été mesurée dans de l'ADN isolé exposé au rayonnement en solution aqueuse aérée. Les modifications sont alors dues aux radicaux hydroxyles produits par la radiolyse de l'eau (effet indirect) et les quatre bases sont efficacement dégradées. L'arrachement d'électrons aux bases par photosensibilisation pour produire leur radical cation, a été utilisé comme modèle de l'effet direct. La quantification des bases modifiées montre que la guanine est préférentiellement dégradée. Cette observation peut s'expliquer par le plus faible potentiel d'oxydation de cette base ainsi que par les phénomènes de transfert de charge vers les guanines.

  20. Radiation-induced degradation of aqueous fluoranthene

    NASA Astrophysics Data System (ADS)

    Popov, Petar; Getoff, Nikola

    2005-01-01

    The radiation-induced degradation of fluoranthene (FA) in slightly alkaline aqueous solution was investigated in the presence of air as well as of N 2O. Depending on the starting FA-concentration the determined Gi(-FA) was 0.34 for 1×10 -5 mol/l FA upto 0.67 for 4.6×10 -5 mol/l FA. As major radiolytic products found by HPLC-analysis were: 9-fluorene carboxylic acid ( Gi =0.006), 9-fluorenone ( Gi=0.004) and fluorene ( Gi=0.002) in addition to a mixture of carboxylic acids and aldehydes. In the presence of N 2O (90% OH, 10% H) practically the same products were observed, however in this case the yield of the carboxylic acids was about 2-times higher than in solutions saturated with air, but 4-times less aldehydes, resp. For illustration of the rather complicated degradation process a probable reaction mechanism is presented.

  1. Pathogenesis and Prevention of Radiation-induced Myocardial Fibrosis

    PubMed

    Liu, Li Kun; Ouyang, Weiwei; Zhao, Xing; Su, Sheng Fa; Yang, Yan; Ding, Wen Jin; Luo, Da Xian; He, Zhi Xu; Lu, Bing

    2017-03-01

    Radiation therapy is one of the most important methods for the treatment of malignant tumors. However, in radiotherapy for thoracic tumors such as breast cancer, lung cancer, esophageal cancer, and mediastinal lymphoma, the heart, located in the mediastinum, is inevitably affected by the irradiation, leading to pericardial disease, myocardial fibrosis, coronary artery disease, valvular lesions, and cardiac conduction system injury, which are considered radiation-induced heart diseases. Delayed cardiac injury especially myocardial fibrosis is more prominent, and its incidence is as high as 20–80%. Myocardial fibrosis is the final stage of radiation-induced heart diseases, and it increases the stiffness of the myocardium and decreases myocardial systolic and diastolic function, resulting in myocardial electrical physiological disorder, arrhythmia, incomplete heart function, or even sudden death. This article reviews the pathogenesis and prevention of radiation-induced myocardial fibrosis for providing references for the prevention and treatment of radiation-induced myocardial fibrosis. Creative Commons Attribution License

  2. Ionizing Radiation-Induced Endothelial Cell Senescence and Cardiovascular Diseases

    PubMed Central

    Wang, Yingying; Boerma, Marjan; Zhou, Daohong

    2016-01-01

    Exposure to ionizing radiation induces not only apoptosis but also senescence. While the role of endothelial cell apoptosis in mediating radiation-induced acute tissue injury has been extensively studied, little is known about the role of endothelial cell senescence in the pathogenesis of radiation-induced late effects. Senescent endothelial cells exhibit decreased production of nitric oxide and expression of thrombomodulin, increased expression of adhesion molecules, elevated production of reactive oxygen species and inflammatory cytokines and an inability to proliferate and form capillary-like structures in vitro. These findings suggest that endothelial cell senescence can lead to endothelial dysfunction by dysregulation of vasodilation and hemostasis, induction of oxidative stress and inflammation and inhibition of angiogenesis, which can potentially contribute to radiation-induced late effects such as cardiovascular diseases (CVDs). In this article, we discuss the mechanisms by which radiation induces endothelial cell senescence, the roles of endothelial cell senescence in radiation-induced CVDs and potential strategies to prevent, mitigate and treat radiation-induced CVDs by targeting senescent endothelial cells. PMID:27387862

  3. Radiation induces senescence and a bystander effect through metabolic alterations.

    PubMed

    Liao, E-C; Hsu, Y-T; Chuah, Q-Y; Lee, Y-J; Hu, J-Y; Huang, T-C; Yang, P-M; Chiu, S-J

    2014-05-22

    Cellular senescence is a state of irreversible growth arrest; however, the metabolic processes of senescent cells remain active. Our previous studies have shown that radiation induces senescence of human breast cancer cells that display low expression of securin, a protein involved in control of the metaphase-anaphase transition and anaphase onset. In this study, the protein expression profile of senescent cells was resolved by two-dimensional gel electrophoresis to investigate associated metabolic alterations. We found that radiation induced the expression and activation of glyceraldehyde-3-phosphate dehydrogenase that has an important role in glycolysis. The activity of lactate dehydrogenase A, which is involved in the conversion of pyruvate to lactate, the release of lactate and the acidification of the extracellular environment, was also induced. Inhibition of glycolysis by dichloroacetate attenuated radiation-induced senescence. In addition, radiation also induced activation of the 5'-adenosine monophosphate-activated protein kinase (AMPK) and nuclear factor kappa B (NF-κB) pathways to promote senescence. We also found that radiation increased the expression of monocarboxylate transporter 1 (MCT1) that facilitates the export of lactate into the extracellular environment. Inhibition of glycolysis or the AMPK/NF-κB signalling pathways reduced MCT1 expression and rescued the acidification of the extracellular environment. Interestingly, these metabolic-altering signalling pathways were also involved in radiation-induced invasion of the surrounding, non-irradiated breast cancer and normal endothelial cells. Taken together, radiation can induce the senescence of human breast cancer cells through metabolic alterations.

  4. Dose-dependent radiation-induced hypotension in the canine

    SciTech Connect

    Cockerham, L.G.; Hampton, J.D.; Doyle, T.F.

    1986-01-01

    Radiation-induced early transient incapacitation (ETI) is often accompanied by severe systemic hypotension. However, postradiation hypotension does not occur with equal frequency in all species and is not reported with consistency in the canine. In an attempt to clarify the differences in reported canine post-radiation blood pressures, canine systemic blood pressures were determined both before and after exposure to gamma radiation of either 80 or 100 Gy. Data obtained from six sham-radiated beagles and 12 radiated beagles indicated that 100-Gy, whole-body, gamma radiation produced a decrease in systemic mean blood pressure while 80-Gy, whole-body, gamma radiation did not. Analysis of this data could be consistent with a quantal response to a gamma radiation dose between 80 Gy and 100 Gy.

  5. Potential Therapeutic Strategies for Hypertension-Exacerbated Cardiotoxicity of Anticancer Drugs

    PubMed Central

    Kuriakose, Robin K.; Kukreja, Rakesh C.

    2016-01-01

    Despite their recognized cardiotoxic effects, anthracyclines remain an essential component in many anticancer regimens due to their superior antitumor efficacy. Epidemiologic data revealed that about one-third of cancer patients have hypertension, which is the most common comorbidity in cancer registries. The purpose of this review is to assess whether anthracycline chemotherapy exacerbates cardiotoxicity in patients with hypertension. A link between hypertension comorbidity and anthracycline-induced cardiotoxicity (AIC) was first suggested in 1979. Subsequent preclinical and clinical studies have supported the notion that hypertension is a major risk factor for AIC, along with the cumulative anthracycline dosage. There are several common or overlapping pathological mechanisms in AIC and hypertension, such as oxidative stress. Current evidence supports the utility of cardioprotective modalities as adjunct treatment prior to and during anthracycline chemotherapy. Several promising cardioprotective approaches against AIC pathologies include dexrazoxane, early hypertension management, and dietary supplementation of nitrate with beetroot juice or other medicinal botanical derivatives (e.g., visnagin and Danshen), which have both antihypertensive and anti-AIC properties. Future research is warranted to further elucidate the mechanisms of hypertension and AIC comorbidity and to conduct well-controlled clinical trials for identifying effective clinical strategies to improve long-term prognoses in this subgroup of cancer patients. PMID:27829985

  6. Honokiol protects against doxorubicin cardiotoxicity via improving mitochondrial function in mouse hearts.

    PubMed

    Huang, Lizhen; Zhang, Kailiang; Guo, Yingying; Huang, Fengyuan; Yang, Kevin; Chen, Long; Huang, Kai; Zhang, Fengxue; Long, Qinqiang; Yang, Qinglin

    2017-09-20

    Honokiol is a key component of a medicinal herb, Magnolia bark. Honokiol possesses potential pharmacological benefits for many disease conditions, especially cancer. Recent studies demonstrate that Honokiol exerts beneficial effects on cardiac hypertrophy and doxorubicin (Dox)-cardiotoxicity via deacetylation of mitochondrial proteins. However, the effects and mechanisms of Honokiol on cardiac mitochondrial respiration remain unclear. In the present study, we investigate the effect of Honokiol on cardiac mitochondrial respiration in mice subjected to Dox treatment. Oxygen consumption in freshly isolated mitochondria from mice treated with Honokiol showed enhanced mitochondrial respiration. The Dox-induced impairment of mitochondrial respiration was less pronounced in honokiol-treated than control mice. Furthermore, Luciferase reporter assay reveals that Honokiol modestly increased PPARγ transcriptional activities in cultured embryonic rat cardiomyocytes (H9c2). Honokiol upregulated the expression of PPARγ in the mouse heart. Honokiol repressed cardiac inflammatory responses and oxidative stress in mice subjected to Dox treatment. As a result, Honokiol alleviated Dox-cardiotoxicity with improved cardiac function and reduced cardiomyocyte apoptosis. We conclude that Honokiol protects the heart from Dox-cardiotoxicity via improving mitochondrial function by not only repressing mitochondrial protein acetylation but also enhancing PPARγ activity in the heart. This study further supports Honokiol as a promising therapy for cancer patients receiving Dox treatment.

  7. Mitochondrial topoisomerase I (Top1mt) is a novel limiting factor of doxorubicin cardiotoxicity

    PubMed Central

    Khiati, Salim; Dalla Rosa, Ilaria; Sourbier, Carole; Ma, Xuefei; Rao, V. Ashutosh; Neckers, Leonard M; Zhang, Hongliang; Pommier, Yves

    2014-01-01

    Purpose Doxorubicin (DOX) is one of the most effective chemotherapeutic agents. However, up to 30% of the patients treated with DOX suffer from congestive heart failure. The mechanism of DOX cardiotoxicity is likely multifactorial and most importantly, the genetic factors predisposing to DOX cardiotoxicity are unknown. Based on the fact that mtDNA lesions and mitochondrial dysfunctions have been found in human hearts exposed to DOX and that mitochondrial topoisomerase 1 (Top1mt) specifically controls mtDNA homeostasis, we hypothesized that Top1mt knockout (KO) mice might exhibit hypersensitivity to DOX. Experimental Design Wild type (WT) and knockout Top1mt mice were treated once a week with 4 mg/kg DOX for 8 weeks. Heart tissues were analyzed one week after the last treatment. Results Genetic inactivation of Top1mt in mice accentuates mtDNA copy number loss and mtDNA damage in heart tissue following DOX treatment. Top1mt knockout mice also fail to maintain respiratory chain protein production and mitochondrial cristae ultrastructure organization. These mitochondrial defects result in decreased O2 consumption, increased ROS production and enhanced heart muscle damage in animals treated with DOX. Accordingly, Top1mt knockout mice die within 45 days after the last DOX injection under conditions whereas the wild type mice survive. Conclusions Our results provide evidence that mitochondrial topoisomerase I, Top1mt, which is conserved across vertebrates, is critical for cardiac tolerance to DOX and adaptive response to DOX cardiotoxicity. They also suggest the potential of Top1mt single nucleotide polymorphisms (SNP) testing to investigate patient susceptibility to DOX induced cardiotoxicity. PMID:24714774

  8. Creatine Kinase-Overexpression Improves Myocardial Energetics, Contractile Dysfunction and Survival in Murine Doxorubicin Cardiotoxicity

    PubMed Central

    Gupta, Ashish; Rohlfsen, Cory; Leppo, Michelle K.; Chacko, Vadappuram P.; Wang, Yibin; Steenbergen, Charles; Weiss, Robert G.

    2013-01-01

    Doxorubicin (DOX) is a commonly used life-saving antineoplastic agent that also causes dose-dependent cardiotoxicity. Because ATP is absolutely required to sustain normal cardiac contractile function and because impaired ATP synthesis through creatine kinase (CK), the primary myocardial energy reserve reaction, may contribute to contractile dysfunction in heart failure, we hypothesized that impaired CK energy metabolism contributes to DOX-induced cardiotoxicity. We therefore overexpressed the myofibrillar isoform of CK (CK-M) in the heart and determined the energetic, contractile and survival effects of CK-M following weekly DOX (5mg/kg) administration using in vivo31P MRS and 1H MRI. In control animals, in vivo cardiac energetics were reduced at 7 weeks of DOX protocol and this was followed by a mild but significant reduction in left ventricular ejection fraction (EF) at 8 weeks of DOX, as compared to baseline. At baseline, CK-M overexpression (CK-M-OE) increased rates of ATP synthesis through cardiac CK (CK flux) but did not affect contractile function. Following DOX however, CK-M-OE hearts had better preservation of creatine phosphate and higher CK flux and higher EF as compared to control DOX hearts. Survival after DOX administration was significantly better in CK-M-OE than in control animals (p<0.02). Thus CK-M-OE attenuates the early decline in myocardial high-energy phosphates and contractile function caused by chronic DOX administration and increases survival. These findings suggest that CK impairment plays an energetic and functional role in this DOX-cardiotoxicity model and suggests that metabolic strategies, particularly those targeting CK, offer an appealing new strategy for limiting DOX-associated cardiotoxicity. PMID:24098344

  9. Selenomethionine protects against adverse biological effects induced by space radiation.

    PubMed

    Kennedy, Ann R; Ware, Jeffrey H; Guan, Jun; Donahue, Jeremiah J; Biaglow, John E; Zhou, Zhaozong; Stewart, Jelena; Vazquez, Marcelo; Wan, X Steven

    2004-01-15

    Ionizing radiation-induced adverse biological effects impose serious challenges to astronauts during extended space travel. Of particular concern is the radiation from highly energetic, heavy, charged particles known as HZE particles. The objective of the present study was to characterize HZE particle radiation-induced adverse biological effects and evaluate the effect of D-selenomethionine (SeM) on the HZE particle radiation-induced adverse biological effects. The results showed that HZE particle radiation can increase oxidative stress, cytotoxicity, and cell transformation in vitro, and decrease the total antioxidant status in irradiated Sprague-Dawley rats. These adverse biological effects were all preventable by treatment with SeM, suggesting that SeM is potentially useful as a countermeasure against space radiation-induced adverse effects. Treatment with SeM was shown to enhance ATR and CHK2 gene expression in cultured human thyroid epithelial cells. As ionizing radiation is known to result in DNA damage and both ATR and CHK2 gene products are involved in DNA damage, it is possible that SeM may prevent HZE particle radiation-induced adverse biological effects by enhancing the DNA repair machinery in irradiated cells.

  10. Chronic doxorubicin cardiotoxicity is mediated by oxidative DNA damage-ATM-p53-apoptosis pathway and attenuated by pitavastatin through the inhibition of Rac1 activity.

    PubMed

    Yoshida, Masashi; Shiojima, Ichiro; Ikeda, Hiroyuki; Komuro, Issei

    2009-11-01

    Doxorubicin is known to have cumulative dose-dependent cardiotoxicity, and a tumor suppressor protein p53 has been implicated in the pathogenesis of doxorubicin cardiotoxicity. However, how p53 is induced by doxorubicin and mediates the cardiotoxic effects of doxorubicin remains elusive. In cultured cardiac myocytes, doxorubicin induced oxidative stress, DNA damage, ATM activation, and p53 induction. A free radical scavenger NAC attenuated all of these events, whereas an ATM kinase inhibitor wortmannin attenuated doxorubicin-induced ATM activation and p53 induction but not oxidative stress. Doxorubicin treatment in vivo also induced oxidative stress, DNA damage, ATM activation, and p53 accumulation. These observations suggest that p53 induction by doxorubicin is mediated by oxidative DNA damage-ATM pathway. Doxorubicin-induced contractile dysfunction and myocyte apoptosis in vivo were attenuated in heterozygous p53 deficient mice and cardiac-restricted Bcl-2 transgenic mice, suggesting that myocyte apoptosis plays a central role downstream of p53 in doxorubicin cardiotoxicity. We also tested whether pitavastatin exerts protective effects on doxorubicin cardiotoxicity. Pitavastatin attenuated doxorubicin-induced oxidative stress, DNA damage, ATM activation, p53 accumulation, and apoptosis in vitro. Pitavastatin also attenuated myocyte apoptosis and contractile dysfunction in vivo. The beneficial effects of pitavastatin were reversed by intermediate products of the mevalonate pathway that are required for the activation of Rac1, and Rac1 inhibitor exhibited cardioprotective effects comparable to those of pitavastatin. These data collectively suggest that doxorubicin-induced cardiotoxicity is mediated by oxidative DNA damage-ATM-p53-apoptosis pathway, and is attenuated by pitavastatin through its antioxidant effect involving Rac1 inhibition.

  11. Lipotransfer for radiation-induced skin fibrosis.

    PubMed

    Kumar, R; Griffin, M; Adigbli, G; Kalavrezos, N; Butler, P E M

    2016-07-01

    Radiation-induced fibrosis (RIF) is a late complication of radiotherapy that results in progressive functional and cosmetic impairment. Autologous fat has emerged as an option for soft tissue reconstruction. There are also sporadic reports suggesting regression of fibrosis following regional lipotransfer. This systematic review aimed to identify cellular mechanisms driving RIF, and the potential role of lipotransfer in attenuating these processes. PubMed, OVID and Google Scholar databases were searched to identify all original articles regarding lipotransfer for RIF. All articles describing irradiated fibroblast or myofibroblast behaviour were included. Data elucidating the mechanisms of RIF, role of lipotransfer in RIF and methods to quantify fibrosis were extracted. Ninety-eight studies met the inclusion criteria. A single, definitive model of RIF is yet to be established, but four cellular mechanisms were identified through in vitro studies. Twenty-one studies identified connective tissue growth factor and transforming growth factor β1 cytokines as drivers of fibrotic cascades. Hypoxia was demonstrated to propagate fibrogenesis in three studies. Oxidative stress from the release of reactive oxygen species and free radicals was also linked to RIF in 11 studies. Purified autologous fat grafts contain cellular and non-cellular properties that potentially interact with these processes. Six methods for quantifying fibrotic changes were evaluated including durometry, ultrasound shear wave elastography, thermography, dark field imaging, and laser Doppler and laser speckle flowmetry. Understanding how lipotransfer causes regression of RIF remains unclear; there are a number of new hypotheses for future research. © 2016 BJS Society Ltd Published by John Wiley & Sons Ltd.

  12. Radiation-Induced Second Cancer Risk Estimates From Radionuclide Therapy

    NASA Astrophysics Data System (ADS)

    Bednarz, Bryan; Besemer, Abigail

    2017-09-01

    The use of radionuclide therapy in the clinical setting is expected to increase significantly over the next decade. There is an important need to understand the radiation-induced second cancer risk associated with these procedures. In this study the radiation-induced cancer risk in five radionuclide therapy patients was investigated. These patients underwent serial SPECT imaging scans following injection as part of a clinical trial testing the efficacy of a 131Iodine-labeled radiopharmaceutical. Using these datasets the committed absorbed doses to multiple sensitive structures were calculated using RAPID, which is a novel Monte Carlo-based 3D dosimetry platform developed for personalized dosimetry. The excess relative risk (ERR) for radiation-induced cancer in these structures was then derived from these dose estimates following the recommendations set forth in the BEIR VII report. The radiation-induced leukemia ERR was highest among all sites considered reaching a maximum value of approximately 4.5. The radiation-induced cancer risk in the kidneys, liver and spleen ranged between 0.3 and 1.3. The lifetime attributable risks (LARs) were also calculated, which ranged from 30 to 1700 cancers per 100,000 persons and were highest for leukemia and the liver for both males and females followed by radiation-induced spleen and kidney cancer. The risks associated with radionuclide therapy are similar to the risk associated with external beam radiation therapy.

  13. Radiation-Induced Impairment of Neuronal Excitability

    DTIC Science & Technology

    1988-01-01

    population spike. A dose rate of 20 Gy/min shifts to the left the dose response curve for radiation at 5 Gy/min. At 5 Gy/min, significant deficits...postsynaptic damage is likely to result from a different molecular mechanism. 100 , , t 50 0) 000 FIUR 2 6 5 200Radiation Dose (Gy) FIGURE 2 Dose response curve of

  14. CE: Cardiotoxicity and Breast Cancer as Late Effects of Pediatric and Adolescent Hodgkin Lymphoma Treatment.

    PubMed

    Candela, Joanne Lee

    2016-04-01

    The American Cancer Society estimates that in 2014 nearly 16,000 U.S. children and adolescents developed cancer, and in roughly 1,200 of these cases the cancer was Hodgkin lymphoma (HL). The great majority of these patients will survive, joining the thousands who have been diagnosed and treated successfully in decades past. Nurses' familiarity with and attention to the late effects of the chemotherapy and radiation therapy used to treat HL, which include breast cancer as well as cardiotoxicity and its sequelae, are essential in helping these patients maintain their overall health.

  15. Simulating Space Radiation-Induced Breast Tumor Incidence Using Automata.

    PubMed

    Heuskin, A C; Osseiran, A I; Tang, J; Costes, S V

    2016-07-01

    Estimating cancer risk from space radiation has been an ongoing challenge for decades primarily because most of the reported epidemiological data on radiation-induced risks are derived from studies of atomic bomb survivors who were exposed to an acute dose of gamma rays instead of chronic high-LET cosmic radiation. In this study, we introduce a formalism using cellular automata to model the long-term effects of ionizing radiation in human breast for different radiation qualities. We first validated and tuned parameters for an automata-based two-stage clonal expansion model simulating the age dependence of spontaneous breast cancer incidence in an unexposed U.S. We then tested the impact of radiation perturbation in the model by modifying parameters to reflect both targeted and nontargeted radiation effects. Targeted effects (TE) reflect the immediate impact of radiation on a cell's DNA with classic end points being gene mutations and cell death. They are well known and are directly derived from experimental data. In contrast, nontargeted effects (NTE) are persistent and affect both damaged and undamaged cells, are nonlinear with dose and are not well characterized in the literature. In this study, we introduced TE in our model and compared predictions against epidemiologic data of the atomic bomb survivor cohort. TE alone are not sufficient for inducing enough cancer. NTE independent of dose and lasting ∼100 days postirradiation need to be added to accurately predict dose dependence of breast cancer induced by gamma rays. Finally, by integrating experimental relative biological effectiveness (RBE) for TE and keeping NTE (i.e., radiation-induced genomic instability) constant with dose and LET, the model predicts that RBE for breast cancer induced by cosmic radiation would be maximum at 220 keV/μm. This approach lays the groundwork for further investigation into the impact of chronic low-dose exposure, inter-individual variation and more complex space radiation

  16. Clinical and dosimetric factors of radiation-induced esophageal injury: Radiation-induced esophageal toxicity

    PubMed Central

    Qiao, Wen-Bo; Zhao, Yan-Hui; Zhao, Yan-Bin; Wang, Rui-Zhi

    2005-01-01

    AIM: To analyze the clinical and dosimetric predictive factors for radiation-induced esophageal injury in patients with non-small-cell lung cancer (NSCLC) during three-dimensional conformal radiotherapy (3D-CRT). METHODS: We retrospectively analyzed 208 consecutive patients (146 men and 62 women) with NSCLC treated with 3D-CRT. The median age of the patients was 64 years (range 35-87 years). The clinical and treatment parameters including gender, age, performance status, sequential chemotherapy, concurrent chemotherapy, presence of carinal or subcarinal lymph nodes, pretreatment weight loss, mean dose to the entire esophagus, maximal point dose to the esophagus, and percentage of volume of esophagus receiving >55 Gy were studied. Clinical and dosimetric factors for radiation-induced acute and late grade 3-5 esophageal injury were analyzed according to Radiation Therapy Oncology Group (RTOG) criteria. RESULTS: Twenty-five (12%) of the two hundred and eight patients developed acute or late grade 3-5 esophageal injury. Among them, nine patients had both acute and late grade 3-5 esophageal injury, two died of late esophageal perforation. Concurrent chemotherapy and maximal point dose to the esophagus ≥60 Gy were significantly associated with the risk of grade 3-5 esophageal injury. Fifty-four (26%) of the two hundred and eight patients received concurrent chemotherapy. Among them, 25 (46%) developed grade 3-5 esophageal injury (P = 0.0001<0.01). However, no grade 3-5 esophageal injury occurred in patients who received a maximal point dose to the esophagus <60 Gy (P = 0.0001<0.01). CONCLUSION: Concurrent chemotherapy and the maximal esophageal point dose ≥60 Gy are significantly associated with the risk of grade 3-5 esophageal injury in patients with NSCLC treated with 3D-CRT. PMID:15849822

  17. Heavy-ion radiation induced bystander effect in mice

    NASA Astrophysics Data System (ADS)

    Liang, Shujian; Sun, Yeqing; Zhang, Meng; Wang, Wei; Cui, Changna

    2012-07-01

    Radiation-induced bystander effect is defined as the induction of damage in neighboring non-hit cells by signals released from directly-irradiated cells. Recently, Low dose of high LET radiation induced bystander effects in vivo have been reported more and more. It has been indicated that radiation induced bystander effect was localized not only in bystander tissues but also in distant organs. Genomic, epigenetic, metabolomics and proteomics play significant roles in regulating heavy-ion radiation stress responses in mice. To identify the molecular mechanism that underlies bystander effects of heavy-ion radiation, the male mice head were exposed to 2000mGy dose of 12C heavy-ion radiation and the distant organ liver was detected on 1h, 6h, 12h and 24h after radiation, respectively. MSAP was used to monitor the level of polymorphic DNA methylation changes. The results show that heavy-ion irradiate mouse head can induce liver DNA methylation changes significantly. The percent of DNA methylation changes are time-dependent and highest at 6h after radiation. We also prove that the hypo-methylation changes on 1h and 6h after irradiation. But the expression level of DNA methyltransferase DNMT3a is not changed. UPLC/Synapt HDMS G2 was employed to detect the proteomics of bystander liver 1h after irradiation. 64 proteins are found significantly different between treatment and control group. GO process show that six of 64 which were unique in irradiation group are associated with apoptosis and DNA damage response. The results suggest that mice head exposed to heavy-ion radiation can induce damage and methylation pattern changed in distant organ liver. Moreover, our findings are important to understand the molecular mechanism of radiation induced bystander effects in vivo.

  18. Biodegradable Polymeric Nanocapsules Prevent Cardiotoxicity of Anti-Trypanosomal Lychnopholide

    PubMed Central

    Branquinho, Renata Tupinambá; Roy, Jérôme; Farah, Charlotte; Garcia, Giani Martins; Aimond, Franck; Le Guennec, Jean-Yves; Saude-Guimarães, Dênia Antunes; Grabe-Guimaraes, Andrea; Mosqueira, Vanessa Carla Furtado; de Lana, Marta; Richard, Sylvain

    2017-01-01

    Chagas disease is a neglected parasitic disease caused by the protozoan Trypanosoma cruzi. New antitrypanosomal options are desirable to prevent complications, including a high rate of cardiomyopathy. Recently, a natural substance, lychnopholide, has shown therapeutic potential, especially when encapsulated in biodegradable polymeric nanocapsules. However, little is known regarding possible adverse effects of lychnopholide. Here we show that repeated-dose intravenous administration of free lychnopholide (2.0 mg/kg/day) for 20 days caused cardiopathy and mortality in healthy C57BL/6 mice. Echocardiography revealed concentric left ventricular hypertrophy with preserved ejection fraction, diastolic dysfunction and chamber dilatation at end-stage. Single cardiomyocytes presented altered contractility and Ca2+ handling, with spontaneous Ca2+ waves in diastole. Acute in vitro lychnopholide application on cardiomyocytes from healthy mice also induced Ca2+ handling alterations with abnormal RyR2-mediated diastolic Ca2+ release. Strikingly, the encapsulation of lychnopholide prevented the cardiac alterations induced in vivo by the free form repeated doses. Nanocapsules alone had no adverse cardiac effects. Altogether, our data establish lychnopholide presented in nanocapsule form more firmly as a promising new drug candidate to cure Chagas disease with minimal cardiotoxicity. Our study also highlights the potential of nanotechnology not only to improve the efficacy of a drug but also to protect against its adverse effects. PMID:28349937

  19. PNU-159548, a novel cytotoxic antitumor agent with a low cardiotoxic potential.

    PubMed

    Della Torre, P; Podestà, A; Imondi, A R; Moneta, D; Sammartini, U; Arrigoni, C; Terron, A; Brughera, M

    2001-04-01

    PNU-159548 (4-demethoxy-3'-deamino-3'aziridinyl-4'-methylsulphonyl-daunorubicin), a derivative of the anticancer idarubicin, has a broad spectrum of antitumoral activity in vitro and in vivo attributable to its DNA intercalating and alkylating properties. The present study was conducted to determine the cardiotoxic activity of PNU-159548 relative to doxorubicin in a chronic rat model sensitive to anthracycline-induced cardiomyopathy. Young adult male rats were allocated to the following treatment groups: group 1, PNU-159548 vehicle control (colloidal dispersion); group 2, doxorubicin control (saline); groups 3, 4, 5, 6, and 7, PNU-159548 at 0.12, 0.25, 0.50, 0.75, and 1.0 mg/kg, respectively; and group 8, 1.0 mg/kg doxorubicin. Treatments were administered intravenously once weekly for 4 weeks (first sacrifice time) or for 7 weeks (rats killed at weeks 8, 12, 22, 27, or 35). Body weights, organ weights, serum chemistry, hematology, serum troponin-T, and cardiac histopathology were followed throughout the study. Doxorubicin caused irreversible cardiomyopathy evident at week 4 in some rats and progressing in severity in all rats by week 8. There were also marked myelotoxicity, increased liver and kidney weights, testicular atrophy, and about 20% mortality by week 27 in doxorubicin-treated rats. The deaths were attributed to cardiomyopathy and/or nephropathy. PNU-159548 caused a dose-dependent myelotoxicity, with the dose of 0.5 mg/kg per week being equimyelotoxic to 1.0 mg/kg per week doxorubicin. PNU-159548 also caused an increase in liver weight that was reversible and a non-reversible testicular atrophy but, unlike doxorubicin, had no effect on kidney weight. At equimyelotoxic doses, the cardiotoxicity caused by PNU-159548, expressed as the mean total score, was less than one-twentieth of that induced by doxorubicin, and much less than that predicted on the basis of its content of idarubicin, which is in turn markedly less cardiotoxic than doxorubicin. The novel

  20. Radiation-induced charge trapping in bipolar base oxides

    SciTech Connect

    Fleetwood, D.M.; Riewe, L.C.; Witczak, Schrimpf, R.D.

    1996-03-01

    Capacitance-voltage and thermally stimulated current methods are used to investigate radiation induced charge trapping in bipolar base oxides. Results are compared with models of oxide and interface trap charge buildup at low electric fields.

  1. Trastuzumab-induced cardiomyopathy.

    PubMed

    Guglin, Maya; Cutro, Raymond; Mishkin, Joseph D

    2008-06-01

    Trastuzumab is a recombinant humanized monoclonal antibody used for the treatment of advanced breast cancer. It improves survival and increases response to chemotherapy. The major side effect of trastuzumab is cardiotoxicity manifesting as a reduction in left ventricular systolic function, either asymptomatic or with signs and symptoms of heart failure. Although reversible in most cases, cardiotoxicity frequently results in the discontinuation of trastuzumab. The objective of this review is to summarize facts about trastuzumab-induced cardiotoxicity and to highlight the areas of future investigations. We searched PubMed for trials involving trastuzumab used as an adjuvant therapy for breast cancer, including the metastatic breast cancer setting, and focused on cardiotoxicity.

  2. Radiation-induced myeloid leukemia in murine models

    PubMed Central

    2014-01-01

    The use of radiation therapy is a cornerstone of modern cancer treatment. The number of patients that undergo radiation as a part of their therapy regimen is only increasing every year, but this does not come without cost. As this number increases, so too does the incidence of secondary, radiation-induced neoplasias, creating a need for therapeutic agents targeted specifically towards incidence reduction and treatment of these cancers. Development and efficacy testing of these agents requires not only extensive in vitro testing but also a set of reliable animal models to accurately recreate the complex situations of radiation-induced carcinogenesis. As radiation-induced leukemic progression often involves genomic changes such as rearrangements, deletions, and changes in methylation, the laboratory mouse Mus musculus, with its fully sequenced genome, is a powerful tool in cancer research. This fact, combined with the molecular and physiological similarities it shares with man and its small size and high rate of breeding in captivity, makes it the most relevant model to use in radiation-induced leukemia research. In this work, we review relevant M. musculus inbred and F1 hybrid animal models, as well as methods of induction of radiation-induced myeloid leukemia. Associated molecular pathologies are also included. PMID:25062865

  3. Radiation-induced myeloid leukemia in murine models.

    PubMed

    Rivina, Leena; Davoren, Michael; Schiestl, Robert H

    2014-07-25

    The use of radiation therapy is a cornerstone of modern cancer treatment. The number of patients that undergo radiation as a part of their therapy regimen is only increasing every year, but this does not come without cost. As this number increases, so too does the incidence of secondary, radiation-induced neoplasias, creating a need for therapeutic agents targeted specifically towards incidence reduction and treatment of these cancers. Development and efficacy testing of these agents requires not only extensive in vitro testing but also a set of reliable animal models to accurately recreate the complex situations of radiation-induced carcinogenesis. As radiation-induced leukemic progression often involves genomic changes such as rearrangements, deletions, and changes in methylation, the laboratory mouse Mus musculus, with its fully sequenced genome, is a powerful tool in cancer research. This fact, combined with the molecular and physiological similarities it shares with man and its small size and high rate of breeding in captivity, makes it the most relevant model to use in radiation-induced leukemia research. In this work, we review relevant M. musculus inbred and F1 hybrid animal models, as well as methods of induction of radiation-induced myeloid leukemia. Associated molecular pathologies are also included.

  4. Genetic variation in radiation-induced cell death.

    PubMed

    Smirnov, Denis A; Brady, Lauren; Halasa, Krzysztof; Morley, Michael; Solomon, Sonia; Cheung, Vivian G

    2012-02-01

    Radiation exposure through environmental, medical, and occupational settings is increasingly common. While radiation has harmful effects, it has utility in many applications such as radiotherapy for cancer. To increase the efficacy of radiation treatment and minimize its risks, a better understanding of the individual differences in radiosensitivity and the molecular basis of radiation response is needed. Here, we integrated human genetic and functional genomic approaches to study the response of human cells to radiation. We measured radiation-induced changes in gene expression and cell death in B cells from normal individuals. We found extensive individual variation in gene expression and cellular responses. To understand the genetic basis of this variation, we mapped the DNA sequence variants that influence expression response to radiation. We also identified radiation-responsive genes that regulate cell death; silencing of these genes by small interfering RNA led to an increase in radiation-induced cell death in human B cells, colorectal and prostate cancer cells. Together these results uncovered DNA variants that contribute to radiosensitivity and identified genes that can be targeted to increase the sensitivity of tumors to radiation.

  5. Radiation-induced coronary artery disease

    SciTech Connect

    Dunsmore, L.D.; LoPonte, M.A.; Dunsmore, R.A.

    1986-07-01

    This report describes three patients who developed myocardial infarction at an untimely age, 4 to 12 years after radiation therapy for Hodgkin's disease. These cases lend credence to the cause and effect relation of such therapy to coronary artery disease.

  6. Radiation-induced biomarkers for the detection and assessment of absorbed radiation doses

    PubMed Central

    Rana, Sudha; Kumar, Raj; Sultana, Sarwat; Sharma, Rakesh Kumar

    2010-01-01

    Radiation incident involving living organisms is an uncommon but a very serious situation. The first step in medical management including triage is high-throughput assessment of the radiation dose received. Radiation exposure levels can be assessed from viability of cells, cellular organelles such as chromosome and different intermediate metabolites. Oxidative damages by ionizing radiation result in carcinogenesis, lowering of the immune response and, ultimately, damage to the hematopoietic system, gastrointestinal system and central nervous system. Biodosimetry is based on the measurement of the radiation-induced changes, which can correlate them with the absorbed dose. Radiation biomarkers such as chromosome aberration are most widely used. Serum enzymes such as serum amylase and diamine oxidase are the most promising biodosimeters. The level of gene expression and protein are also good biomarkers of radiation. PMID:21829314

  7. [Update in radiation-induced neoplasms: genetic studies].

    PubMed

    Chauveinc, Laurent; Lefevre, Sandrine; Malfoy, Bernard; Dutrillaux, Bernard

    2002-02-01

    Radiation induced tumors are a possible (very) late complications of radiotherapy. The evaluation of the risks of radiation-induced tumors has been presented in different epidemiological studies, with the evaluation of the relative risk for different tissues. But, the genetic studies are rare, and no global theory exists. Two cytogenetic profiles are described, one with translocations and one with genetic material losses, evoking two different genetic evolutions. Two questions are stated. What are the radiation-induced genetic mechanisms? Is it possible to differentiate the radiation-induced and spontaneous tumors with genetic approaches? With 37 cytogenetic cases, 12 analyzed in our laboratory, the radiation-induced tumors were characterized by genetic material losses. An anti-oncogenic evolution is probable. A new molecularly study confirm these results. Only thyroid tumors do not have this evolution. For tumors with simple karyotype, like meningioma, radiation-induced tumors seem to be more complex than spontaneous tumors. But for the others, the differentiation is impossible to be done with cytogenetic. The mechanism of the chromosomic material losses in unknown, but some hypothesis are discussed.

  8. Risk and survival outcomes of radiation-induced CNS tumors.

    PubMed

    Lee, Jessica W; Wernicke, A Gabriella

    2016-08-01

    Patients treated with cranial radiation are at risk of developing secondary CNS tumors. Understanding the incidence, treatment, and long-term outcomes of radiation-induced CNS tumors plays a role in clinical decision-making and patient education. Additionally, as meningiomas and pituitary tumors have been detected at increasing rates across all ages and may potentially be treated with radiation, it is important to know and communicate the risk of secondary tumors in children and adults. After conducting an extensive literature search, we identified publications that report incidence and long-term outcomes of radiation-induced CNS tumors. We reviewed 14 studies in children, which reported that radiation confers a 7- to 10-fold increase in subsequent CNS tumors, with a 20-year cumulative incidence ranging from 1.03 to 28.9 %. The latency period for secondary tumors ranged from 5.5 to 30 years, with gliomas developing in 5-10 years and meningiomas developing around 15 years after radiation. We also reviewed seven studies in adults, where the two strongest studies showed no increased risk while the remaining studies found a higher risk compared to the general population. The latency period for secondary CNS tumors in adults ranged from 5 to 34 years. Treatment and long-term outcomes of radiation-induced CNS tumors have been documented in four case series, which did not conclusively demonstrate that secondary CNS tumors fared worse than primary CNS tumors. Radiation-induced CNS tumors remain a rare occurrence that should not by itself impede radiation treatment. Additional investigation is needed on the risk of radiation-induced tumors in adults and the long-term outcomes of these tumors.

  9. Radiation-induced malignant and atypical peripheral nerve sheath tumors

    SciTech Connect

    Foley, K.M.; Woodruff, J.M.; Ellis, F.T.; Posner, J.B.

    1980-04-01

    The reported peripheral nerve complications of therapeutic irradiation in humans include brachial and lumbar plexus fibrosis and cranial and peripheral nerve atrophy. We have encountered 9 patients with malignant (7) and atypical (2) peripheral nerve tumors occurring in an irradiated site suggesting that such tumors represent another delayed effect of radiation treatment on peripheral nerve. In all instances the radio-theray was within an acceptable radiation dosage, yet 3 patients developed local radiation-induced skin and bony abnormalities. The malignant peripheral nerve sheath tumors developed only in the radiation port. Animal studies support the clinical observation that malignant peripheral nerve sheath tumors can occur as a delayed effect of irradiation.

  10. Pathology and biology of radiation-induced cardiac disease

    PubMed Central

    Tapio, Soile

    2016-01-01

    Heart disease is the leading global cause of death. The risk for this disease is significantly increased in populations exposed to ionizing radiation, but the mechanisms are not fully elucidated yet. This review aims to gather and discuss the latest data about pathological and biological consequences in the radiation-exposed heart in a comprehensive manner. A better understanding of the molecular and cellular mechanisms underlying radiation-induced damage in heart tissue and cardiac vasculature will provide novel targets for therapeutic interventions. These may be valuable for individuals clinically or occupationally exposed to varying doses of ionizing radiation. PMID:27422929

  11. Radiation Induced DNA Double-Strand Breaks in Radiology.

    PubMed

    Kuefner, M A; Brand, M; Engert, C; Schwab, S A; Uder, M

    2015-10-01

    Shortly after the discovery of X-rays, their damaging effect on biological tissues was observed. The determination of radiation exposure in diagnostic and interventional radiology is usually based on physical measurements or mathematical algorithms with standardized dose simulations. γ-H2AX immunofluorescence microscopy is a reliable and sensitive method for the quantification of radiation induced DNA double-strand breaks (DSB) in blood lymphocytes. The detectable amount of these DNA damages correlates well with the dose received. However, the biological radiation damage depends not only on dose but also on other individual factors like radiation sensitivity and DNA repair capacity. Iodinated contrast agents can enhance the x-ray induced DNA damage level. After their induction DSB are quickly repaired. A protective effect of antioxidants has been postulated in experimental studies. This review explains the prinicple of the γ-H2AX technique and provides an overview on studies evaluating DSB in radiologic examinations. Radiologic examinations including CT and angiography induce DNA double-strand breaks. Even after mammography a slight but significant increase is detectable in peripheral blood lymphocytes. The number of radiation induced double-strand breaks correlates well with the radiation dose. Individual factors including radiation sensitivity, DNA repair capacity and the application of iodinated contrast media has an influence on the DNA damage level. © Georg Thieme Verlag KG Stuttgart · New York.

  12. Faecal microbiota transplantation protects against radiation-induced toxicity.

    PubMed

    Cui, Ming; Xiao, Huiwen; Li, Yuan; Zhou, Lixin; Zhao, Shuyi; Luo, Dan; Zheng, Qisheng; Dong, Jiali; Zhao, Yu; Zhang, Xin; Zhang, Junling; Lu, Lu; Wang, Haichao; Fan, Saijun

    2017-04-01

    Severe radiation exposure may cause acute radiation syndrome, a possibly fatal condition requiring effective therapy. Gut microbiota can be manipulated to fight against many diseases. We explored whether intestinal microbe transplantation could alleviate radiation-induced toxicity. High-throughput sequencing showed that gastrointestinal bacterial community composition differed between male and female mice and was associated with susceptibility to radiation toxicity. Faecal microbiota transplantation (FMT) increased the survival rate of irradiated animals, elevated peripheral white blood cell counts and improved gastrointestinal tract function and intestinal epithelial integrity in irradiated male and female mice. FMT preserved the intestinal bacterial composition and retained mRNA and long non-coding RNA expression profiles of host small intestines in a sex-specific fashion. Despite promoting angiogenesis, sex-matched FMT did not accelerate the proliferation of cancer cells in vivo FMT might serve as a therapeutic to mitigate radiation-induced toxicity and improve the prognosis of tumour patients after radiotherapy.

  13. Thermodynamic processes induced by coherent radiation

    NASA Technical Reports Server (NTRS)

    Garbuny, M.

    1977-01-01

    It is shown by quantum statistics that under certain stated conditions the entropy of coherent radiation is zero and it is still negligible for multimode laser operation. This makes possible gas kinetic processes which, to a small extent, have already been observed or even utilized, but which can be greatly enhanced by an optimized choice of molecular structures and radiation conditions. Radiative cooling of gases is discussed in detail. The conditions for maximum heat withdrawal are derived, and it is proposed that the processes of cooling and relaxation heating can be sufficiently separated in time to achieve certain effects and thermodynamic cycles. One of these is the complete conversion, possible in principle, of coherent radiation into work. This concept is based on a heat pump process followed by heat-to-work conversion, the heat rejected being just equal to that withdrawn by radiation. The conditions for complete conversion turn out to be the same as for maximum heat withdrawal. The feasibility of these processes depends on the degree to which practical conditions can be met, and on the validity of certain assumptions which have to await experimental verification.

  14. Thermodynamic processes induced by coherent radiation

    NASA Technical Reports Server (NTRS)

    Garbuny, M.

    1977-01-01

    It is shown by quantum statistics that under certain stated conditions the entropy of coherent radiation is zero and it is still negligible for multimode laser operation. This makes possible gas kinetic processes which, to a small extent, have already been observed or even utilized, but which can be greatly enhanced by an optimized choice of molecular structures and radiation conditions. Radiative cooling of gases is discussed in detail. The conditions for maximum heat withdrawal are derived, and it is proposed that the processes of cooling and relaxation heating can be sufficiently separated in time to achieve certain effects and thermodynamic cycles. One of these is the complete conversion, possible in principle, of coherent radiation into work. This concept is based on a heat pump process followed by heat-to-work conversion, the heat rejected being just equal to that withdrawn by radiation. The conditions for complete conversion turn out to be the same as for maximum heat withdrawal. The feasibility of these processes depends on the degree to which practical conditions can be met, and on the validity of certain assumptions which have to await experimental verification.

  15. A mechanistic study on the cardiotoxicity of 5-fluorouracil in vitro and clinical and occupational perspectives.

    PubMed

    Lamberti, Monica; Porto, Stefania; Zappavigna, Silvia; Addeo, Erasmo; Marra, Monica; Miraglia, Nadia; Sannolo, Nicola; Vanacore, Daniela; Stiuso, Paola; Caraglia, Michele

    2014-06-16

    Fluoropyrimidines are key agents for the treatment of gastrointestinal tract adenocarcinomas. The possible cardiotoxic effects in patients and occupationally exposed workers are multifactorial and remain a puzzle to solve for investigators. In the present study, we study what cell death pathways and what doses can determine direct cardiotoxic effects of 5-fluorouracil (5-FU) and doxorubicin (DOXO) on rat cardiocytes (H9c2) and a human colon adenocarcinoma (HT-29) cell line, already reported to be sensitive to 5-FU. We have found that 5-FU induced 50% growth inhibition (IC:50) at 72 h with concentrations of 400 μM and 4 μM on H9c2 and HT-29, respectively. Moreover, we have found that the addition of Levofolinic Acid (LF) to 5-FU potentiated the growth inhibition induced by 5-FU. The growth inhibition induced by 5-FU alone or in combination with LF in cardiocytes was paralleled by an increase of thiobarbituric acid-reactive species (Tbars) and end products of nitric oxide (NO) suggesting the increase of the oxidative stress status in cardiocytes. Interestingly, these effects were strongly potentiated by the addition of LF, a biochemical modulator of 5-FU activity. Our data suggest that agents such as 5-FU different from anthracyclines, conventionally related to the induction of cardiotoxic effects, can also induce cardiocyte damage paralleled by oxidative stress. The strategies based upon the use of scavengers could be used in order to prevent this effect. Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  16. Cardiotoxic Antiemetics Metoclopramide and Domperidone Block Cardiac Voltage-Gated Na+ Channels.

    PubMed

    Stoetzer, Carsten; Voelker, Marc; Doll, Thorben; Heineke, Joerg; Wegner, Florian; Leffler, Andreas

    2017-01-01

    Metoclopramide and domperidone are prokinetic and antiemetic substances often used in clinical practice. Although domperidone has a more favorable side effect profile and is considered the first-line agent, severe cardiac side effects were reported during the administration of both substances. Cardiac Na channels are common targets of therapeutics inducing cardiotoxicity. Therefore, the aim of this study was to investigate whether the differential cardiotoxicities of metoclopramide and domperidone correlate with the block of Na channels. Effects of metoclopramide and domperidone on the human α-subunit Nav1.5 expressed in human embryonic kidney 293 cells and on Na currents in neonatal rat cardiomyocytes were investigated by means of whole-cell patch clamp recordings. Tonic block of resting Nav1.5 channels was more potent for domperidone (IC50 85 ± 25 μM; 95% confidence interval [CI], 36-134) compared with metoclopramide (IC50 458 ± 28 μM; 95% CI, 403-513). Both agents induced use-dependent block at 10 and 1 Hz, stabilized fast and slow inactivation, and delayed recovery from inactivation. However, metoclopramide induced considerably smaller effects compared with domperidone. Na currents in rat cardiomyocytes displayed tonic and use-dependent block by both substances, and in this system, domperidone (IC50 312 ± 15 μM; 95% CI, 22-602) and metoclopramide (IC50 250 ± 30 μM; 95% CI, 191-309) induced a similar degree of tonic block. Our data demonstrate that the clinically relevant cardiotoxicity of domperidone and metoclopramide corresponds to a rather potent and local anesthetic-like inhibition of cardiac Na channels including Nav1.5. These data suggest that Nav1.5 might be a hitherto unrecognized molecular mechanism of some cardiovascular side effects, for example, malignant arrhythmias of prokinetic and antiemetic agents.

  17. Optical imaging of radiation-induced metabolic changes in radiation-sensitive and resistant cancer cells

    NASA Astrophysics Data System (ADS)

    Alhallak, Kinan; Jenkins, Samir V.; Lee, David E.; Greene, Nicholas P.; Quinn, Kyle P.; Griffin, Robert J.; Dings, Ruud P. M.; Rajaram, Narasimhan

    2017-06-01

    Radiation resistance remains a significant problem for cancer patients, especially due to the time required to definitively determine treatment outcome. For fractionated radiation therapy, nearly 7 to 8 weeks can elapse before a tumor is deemed to be radiation-resistant. We used the optical redox ratio of FAD/(FAD+NADH) to identify early metabolic changes in radiation-resistant lung cancer cells. These radiation-resistant human A549 lung cancer cells were developed by exposing the parental A549 cells to repeated doses of radiation (2 Gy). Although there were no significant differences in the optical redox ratio between the parental and resistant cell lines prior to radiation, there was a significant decrease in the optical redox ratio of the radiation-resistant cells 24 h after a single radiation exposure (p=0.01). This change in the redox ratio was indicative of increased catabolism of glucose in the resistant cells after radiation and was associated with significantly greater protein content of hypoxia-inducible factor 1 (HIF-1α), a key promoter of glycolytic metabolism. Our results demonstrate that the optical redox ratio could provide a rapid method of determining radiation resistance status based on early metabolic changes in cancer cells.

  18. Radioprotectors and Mitigators of Radiation-Induced Normal Tissue Injury

    PubMed Central

    Cotrim, Ana P.; Hyodo, Fuminori; Baum, Bruce J.; Krishna, Murali C.; Mitchell, James B.

    2010-01-01

    Radiation is used in the treatment of a broad range of malignancies. Exposure of normal tissue to radiation may result in both acute and chronic toxicities that can result in an inability to deliver the intended therapy, a range of symptoms, and a decrease in quality of life. Radioprotectors are compounds that are designed to reduce the damage in normal tissues caused by radiation. These compounds are often antioxidants and must be present before or at the time of radiation for effectiveness. Other agents, termed mitigators, may be used to minimize toxicity even after radiation has been delivered. Herein, we review agents in clinical use or in development as radioprotectors and mitigators of radiation-induced normal tissue injury. Few agents are approved for clinical use, but many new compounds show promising results in preclinical testing. PMID:20413641

  19. Biochemical effects of Solidago virgaurea extract on experimental cardiotoxicity.

    PubMed

    El-Tantawy, Walid Hamdy

    2014-03-01

    Cardiovascular diseases (CVDs) are the major health problem of advanced as well as developing countries of the world. The aim of the present study was to investigate the protective effect of the Solidago virgaurea extract on isoproterenol-induced cardiotoxicity in rats. The subcutaneous injection of isoproterenol (30 mg/kg) into rats twice at an interval of 24 h, for two consecutive days, led to a significant increase in serum lactate dehydrogenase, creatine phosphokinase, alanine transaminase, aspartate transaminase, and angiotensin-converting enzyme activities, total cholesterol, triglycerides, free serum fatty acid, cardiac tissue malondialdehyde (MDA), and nitric oxide levels and a significant decrease in levels of glutathione and superoxide dismutase in cardiac tissue as compared to the normal control group (P < 0.05). Pretreatment with S. virgaurea extract for 5 weeks at a dose of 250 mg/kg followed by isoproterenol injection significantly prevented the observed alterations. Captopril (50 mg/kg/day, given orally), an inhibitor of angiotensin-converting enzyme used as a standard cardioprotective drug, was used as a positive control in this study. The data of the present study suggest that S. virgaurea extract exerts its protective effect by decreasing MDA level and increasing the antioxidant status in isoproterenol-treated rats. The study emphasizes the beneficial action of S. virgaurea extract as a cardioprotective agent.

  20. A Novel Insight into the Cardiotoxicity of Antineoplastic Drug Doxorubicin

    PubMed Central

    Heger, Zbynek; Cernei, Natalia; Kudr, Jiri; Gumulec, Jaromir; Blazkova, Iva; Zitka, Ondrej; Eckschlager, Tomas; Stiborova, Marie; Adam, Vojtech; Kizek, Rene

    2013-01-01

    Doxorubicin is a commonly used antineoplastic agent in the treatment of many types of cancer. Little is known about the interactions of doxorubicin with cardiac biomolecules. Serious cardiotoxicity including dilated cardiomyopathy often resulting in a fatal congestive heart failure may occur as a consequence of chemotherapy with doxorubicin. The purpose of this study was to determine the effect of exposure to doxorubicin on the changes in major amino acids in tissue of cardiac muscle (proline, taurine, glutamic acid, arginine, aspartic acid, leucine, glycine, valine, alanine, isoleucine, threonine, lysine and serine). An in vitro interaction study was performed as a comparison of amino acid profiles in heart tissue before and after application of doxorubicin. We found that doxorubicin directly influences myocardial amino acid representation even at low concentrations. In addition, we performed an interaction study that resulted in the determination of breaking points for each of analyzed amino acids. Lysine, arginine, β-alanine, valine and serine were determined as the most sensitive amino acids. Additionally we compared amino acid profiles of myocardium before and after exposure to doxorubicin. The amount of amino acids after interaction with doxorubicin was significantly reduced (p = 0.05). This fact points at an ability of doxorubicin to induce changes in quantitative composition of amino acids in myocardium. Moreover, this confirms that the interactions between doxorubicin and amino acids may act as another factor most likely responsible for adverse effects of doxorubicin on myocardium. PMID:24185911

  1. Obesity As a Risk Factor for Anthracyclines and Trastuzumab Cardiotoxicity in Breast Cancer: A Systematic Review and Meta-Analysis.

    PubMed

    Guenancia, Charles; Lefebvre, Annick; Cardinale, Daniela; Yu, Anthony F; Ladoire, Sylvain; Ghiringhelli, François; Zeller, Marianne; Rochette, Luc; Cottin, Yves; Vergely, Catherine

    2016-09-10

    Patients with metabolic syndrome have a greater risk of cardiovascular disease, although their susceptibility to chemotherapy-induced cardiac disease is not well documented. The aim of this meta-analysis was to assess associations between obesity or being overweight and cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab in patients with breast cancer. We performed a random-effects analysis and a network meta-analysis and assessed publication bias. We included 15 studies and 8,745 patients with breast cancers who were treated with anthracyclines and sequential anthracyclines and trastuzumab. Combination of obesity and being overweight was significantly associated with a greater risk of developing cardiotoxicity after anthracyclines and a sequential anthracyclines and trastuzumab regimen in patients with breast cancer. Pooled odds ratio for cardiotoxicity was 1.38 (95% CI, 1.06 to 1.80; I(2) = 43%; N = 8,745) for overweight or obesity (body mass index > 25 kg/m(2)), 1.47 (95% CI, 0.95 to 2.28; I(2) = 47%; n = 2,615) for obesity, and 1.15 (95% CI, 0.83 to 1.58; I(2) = 27%; n = 2,708) for overweight. Associations were independent of study design, year of publication, drug regimen (anthracyclines alone v sequential anthracyclines and trastuzumab), or definitions of cardiotoxicity and of overweight or obesity. There was no evidence of publication bias; however, we could not separate the contributions of obesity-related cardiovascular risk factors, such as diabetes and hypertension, from that of obesity itself in this largely unadjusted analysis. Our findings in a largely unadjusted analysis suggest that overweight and obesity are risk factors for cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab. © 2016 by American Society of Clinical Oncology.

  2. Obesity As a Risk Factor for Anthracyclines and Trastuzumab Cardiotoxicity in Breast Cancer: A Systematic Review and Meta-Analysis

    PubMed Central

    Lefebvre, Annick; Cardinale, Daniela; Yu, Anthony F.; Ladoire, Sylvain; Ghiringhelli, François; Zeller, Marianne; Rochette, Luc; Cottin, Yves; Vergely, Catherine

    2016-01-01

    Purpose Patients with metabolic syndrome have a greater risk of cardiovascular disease, although their susceptibility to chemotherapy-induced cardiac disease is not well documented. The aim of this meta-analysis was to assess associations between obesity or being overweight and cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab in patients with breast cancer. Methods We performed a random-effects analysis and a network meta-analysis and assessed publication bias. We included 15 studies and 8,745 patients with breast cancers who were treated with anthracyclines and sequential anthracyclines and trastuzumab. Results Combination of obesity and being overweight was significantly associated with a greater risk of developing cardiotoxicity after anthracyclines and a sequential anthracyclines and trastuzumab regimen in patients with breast cancer. Pooled odds ratio for cardiotoxicity was 1.38 (95% CI, 1.06 to 1.80; I2 = 43%; N = 8,745) for overweight or obesity (body mass index > 25 kg/m2), 1.47 (95% CI, 0.95 to 2.28; I2 = 47%; n = 2,615) for obesity, and 1.15 (95% CI, 0.83 to 1.58; I2 = 27%; n = 2,708) for overweight. Associations were independent of study design, year of publication, drug regimen (anthracyclines alone v sequential anthracyclines and trastuzumab), or definitions of cardiotoxicity and of overweight or obesity. There was no evidence of publication bias; however, we could not separate the contributions of obesity-related cardiovascular risk factors, such as diabetes and hypertension, from that of obesity itself in this largely unadjusted analysis. Conclusion Our findings in a largely unadjusted analysis suggest that overweight and obesity are risk factors for cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab. PMID:27458291

  3. Hyperprolactinemia from radiation-induced hypothalamic hypopituitarism

    SciTech Connect

    Corkill, G.; Hanson, F.W.; Gold, E.M.; White, V.A.

    1980-01-01

    In 1975 Samaan et al., described the effects of radiation damage of the hypothalamus in 15 patients with head and neck cancer. Shalet et al., in 1977 described endocrine morbidity in adults who as children had been irradiated for brain tumors. This report describes instances of hyperprolactinemia and associated hypothalamic, pituitary, and thyroid dysfunction following irradiation of a young adult female for brain neoplasia.

  4. RADIATION INDUCED VULCANIZATION OF RUBBER LATEX

    DOEpatents

    Mesrobian, R.B.; Ballantine, D.S.; Metz, D.J.

    1964-04-28

    A method of vulcanizing rubber latex by exposing a mixture containing rubber latex and from about 15 to about 21.3 wt% of 2,5-dichlorostyrene to about 1.1 megarads of gamma radiation while maintaining the temperature of the mixture at a temperature ranging between from about 56 to about 59 deg C is described. (AEC)

  5. Neutron Radiation Induced Degradation of Diode Characteristics

    DTIC Science & Technology

    1992-12-01

    de fluance utilis6 dans ce travail (diode du type 3). La plupart des r~sultats anterieurs sur les, diodes A jonction p-n correspondent aux rdsultats...termes des thories pour une jonction p-n et pour les effects de radiations sur semiconducteurs. II est prddit qu’une diode du type 3 pourrait &tre

  6. Factors Associated with Occurrence of Radiation-induced Optic Neuropathy at "Safe" Radiation Dosage.

    PubMed

    Doroslovački, Pavle; Tamhankar, Madhura A; Liu, Grant T; Shindler, Kenneth S; Ying, Gui-Shuang; Alonso-Basanta, Michelle

    2017-07-13

    Radiation-induced optic neuropathy (RION) is a rare, and often visually devastating, complication of radiation therapy (RT) near the anterior visual pathways. A retrospective case series of patients who developed RION at a tertiary medical center, followed by a case-control study comparing RION cases with matched controls who received RT. Thirteen patients (18 eyes) with RION were identified. Radiation modalities included external beam photon radiation, whole brain radiation, stereotactic radiosurgery, proton beam, and unknown. Most patients received doses below published "safe" thresholds (<55 Gy; <8-10 Gy for stereotactic radiosurgery). There was no statistically significant difference in prevalence of vasculopathic factors between cases and controls; on subgroup analysis in three patients who received surprisingly low radiation doses, smoking (p=0.05) and hypertension (p=0.02) appeared more prevalent. RION can occur at doses below published "safe" thresholds and with different RT modalities. Smoking and hypertension might be risk factors for RION.

  7. Cardiotoxic changes of colchicine intoxication in rats: electrocardiographic, histopathological and blood chemical analysis.

    PubMed

    Tochinai, Ryota; Suzuki, Katsuya; Nagata, Yuriko; Ando, Minoru; Hata, Chie; Komatsu, Kayoko; Suzuki, Tomo; Uchida, Kazumi; Kado, Shoichi; Kaneko, Kimiyuki; Kuwahara, Masayoshi

    2014-10-01

    The microtubule inhibitor colchicine is cardiotoxic and is suggested to impair impulse formation and conduction. However, little is known about the electrocardiographic (ECG) changes induced by colchicine in experimental animals and the detailed pathogenesis of its cardiotoxicity. Therefore, we analyzed cardiotoxicity in colchicine-treated rats using electrocardiographic, histopathological and blood-chemistry approaches. A telemetry device for transmitting ECG data was implanted into male Crl:CD(SD) rats, and ECG tracings were obtained. At 6 weeks of age, 1.25 mg/kg colchicine was injected intravenously once daily for 2 consecutive days, and ECG waveforms and heart rate variability were analyzed. Furthermore, 1.25 mg/kg colchicine or vehicle was injected for 1 or 2 consecutive days in other rats at 6 weeks of age. One day after the final dosing, heart and blood samples were taken for histopathological and bloodchemical examination. ECG analysis revealed a prolonged RR interval, QRS duration, PR interval and QT interval. Heart rate variability analysis showed an increase in high frequency (HF) components as an index of parasympathetic nervous activity. In blood chemical examinations, colchicine induced high levels of parameters of cardiac injury and low levels and/or variations in Ca, inorganic phosphorus, potassium and chloride. Histopathologically, colchicine-treated rats showed eosinophilic granular degeneration and cytoplasmic vacuolation of ventricular myocardial cells but no remarkable change in the atrioventricular node. Not only blood chemical and histopathological changes but also ECG changes were induced in colchicine-treated rats, which indicated a decrease in myocardium excitability and conductivity, and these changes might be related to increased parasympathetic nervous activity and low blood Ca levels.

  8. Novel Radiomitigator for Radiation-Induced Bone Loss

    NASA Technical Reports Server (NTRS)

    Schreurs, A-S; Shirazi-fard, Y.; Terada, M.; Alwood, J. S.; Steczina, S.; Medina, C.; Tahimic, C. G. T.; Globus, R. K.

    2016-01-01

    Radiation-induced bone loss can occur with radiotherapy patients, accidental radiation exposure and during long-term spaceflight. Bone loss due to radiation is due to an early increase in oxidative stress, inflammation and bone resorption, resulting in an imbalance in bone remodeling. Furthermore, exposure to high-Linear Energy Transfer (LET) radiation will impair the bone forming progenitors and reduce bone formation. Radiation can be classified as high-LET or low-LET based on the amount of energy released. Dried Plum (DP) diet prevents bone loss in mice exposed to total body irradiation with both low-LET and high-LET radiation. DP prevents the early radiation-induced bone resorption, but furthermore, we show that DP protects the bone forming osteoblast progenitors from high-LET radiation. These results provide insight that DP re-balances the bone remodeling by preventing resorption and protecting the bone formation capacity. This data is important considering that most of the current osteoporosis treatments only block the bone resorption but do not protect bone formation. In addition, DP seems to act on both the oxidative stress and inflammation pathways. Finally, we have preliminary data showing the potential of DP to be radio-protective at a systemic effect and could possible protect other tissues at risk of total body-irradiation such as skin, brain and heart.

  9. Characterization of radiation-induced emesis in the ferret

    SciTech Connect

    King, G.L.

    1988-01-01

    Forty-eight ferrets (Mustela putorius furo) were individually head-shielded and radiated with bilateral cobalt 60 gamma radiation at 100 cGy min at doses ranging between 49 and 601 cGy. The emetic threshold was observed at 69 cGy, the ED 50 was calculated as 77 cGy, and 100% incidence of emesis occurred at 201 cGy. With increasing doses of radiation, the latency to first emesis after radiation decreased dramatically, whereas the duration of the prodromal period increased. Two other sets of experiments suggest that dopaminergic mechanisms play a minor role in radiation-induced emesis in the ferret. Twenty-two animals were injected either intravenously or subcutaneously with 30 to 300 micrograms /kg of apomorphine. Fewer than 50% of the animals vomited to 300 micrograms/kg apomorphine; central dopaminergic receptor activation was apparent at all doses. Another eight animals received 1 mg/kg domperidone prior to either 201 (n=4) or 401 (n=4) cGy radiation and their emetic responses were compared with NaCi-injected-irradiated controls (n=8). At 201 cGy, domperidone significantly reduced only the total time in emetic behavior. At 401 cGy, domperidone had no salutary effect on radiation-induced emesis. The emetic responses of the ferret to radiation and apomorphine are compared with these responses in other vomiting species.

  10. Characterization of radiation-induced emesis in the ferret

    SciTech Connect

    King, G.L.

    1988-06-01

    Forty-eight ferrets (Mustela putorius furo) were individually head-shielded and radiated with bilateral /sup 60/Co gamma radiation at 100 cGy min-1 at doses ranging between 49 and 601 cGy. The emetic threshold was observed at 69 cGy, the ED50 was calculated at 77 cGy, and 100% incidence of emesis occurred at 201 cGy. With increasing doses of radiation, the latency to first emesis after radiation decreased dramatically, whereas the duration of the prodromal period increased. Two other sets of experiments suggest that dopaminergic mechanisms play a minor role in radiation-induced emesis in the ferret. Twenty-two animals were injected either intravenously or subcutaneously with 30 to 300 micrograms/kg of apomorphine. Fewer than 50% of the animals vomited to 300 micrograms/kg apomorphine; central dopaminergic receptor activation was apparent at all doses. Another eight animals received 1 mg/kg domperidone prior to either 201 (n = 4) or 401 (n = 4) cGy radiation and their emetic responses were compared with NaCl-injected-irradiated controls (n = 8). At 201 cGy, domperidone significantly reduced only the total time in emetic behavior. At 401 cGy, domperidone had no salutary effect on radiation-induced emesis. The emetic responses of the ferret to radiation and apomorphine are compared with these responses in other vomiting species.

  11. Use of probiotics for prevention of radiation-induced diarrhea

    PubMed Central

    Delia, P; Sansotta, G; Donato, V; Frosina, P; Messina, G; De Renzis, C; Famularo, G

    2007-01-01

    AIM: To investigate the efficacy of a high-potency probiotic preparation on prevention of radiation-induced diarrhea in cancer patients. METHODS: This was a double-blind, placebo-controlled trial. Four hundred and ninety patients who underwent adjuvant postoperative radiation therapy after surgery for sigmoid, rectal, or cervical cancer were assigned to either the high-potency probiotic preparation VSL#3 (one sachet t.i.d.,) or placebo starting from the first day of radiation therapy. Efficacy endpoints were incidence and severity of radiation-induced diarrhea, daily number of bowel movements, and the time from the start of the study to the use of loperamide as rescue medication. RESULTS: More placebo patients had radiation-induced diarrhea than VSL#3 patients (124 of 239 patients, 51.8%, and 77 of 243 patients, 31.6%; P < 0.001) and more patients given placebo suffered grade 3 or 4 diarrhea compared with VSL#3 recipients (55.4% and 1.4%, P < 0.001). Daily bowel movements were 14.7 ± 6 and 5.1 ± 3 among placebo and VSL#3 recipients (P < 0.05), and the mean time to the use of loperamide was 86 ± 6 h for placebo patients and 122 ± 8 h for VSL#3 patients (P < 0.001). CONCLUSION: Probiotic lactic acid-producing bacteria are an easy, safe, and feasible approach to protect cancer patients against the risk of radiation-induced diarrhea. PMID:17352022

  12. Radiation-induced cognitive impairment-from bench to bedside

    PubMed Central

    Greene-Schloesser, Dana; Robbins, Mike E.

    2012-01-01

    Approximately 100 000 patients per year in the United States with primary and metastatic brain tumor survive long enough (>6 months) to develop radiation-induced brain injury. Before 1970, the human brain was thought to be radioresistant; the acute central nervous system (CNS) syndrome occurs after single doses of ≥30 Gy, and white matter necrosis can occur at fractionated doses of ≥60 Gy. Although white matter necrosis is uncommon with modern radiation therapy techniques, functional deficits, including progressive impairments in memory, attention, and executive function have become increasingly important, having profound effects on quality of life. Preclinical studies have provided valuable insights into the pathogenic mechanisms involved in radiation-induced cognitive impairment. Although reductions in hippocampal neurogenesis and hippocampal-dependent cognitive function have been observed in rodent models, it is important to recognize that other brain regions are affected; non–hippocampal-dependent reductions in cognitive function occur. Neuroinflammation is viewed as playing a major role in radiation-induced cognitive impairment. During the past 5 years, several preclinical studies have demonstrated that interventional therapies aimed at modulating neuroinflammation can prevent/ameliorate radiation-induced cognitive impairment independent of changes in neurogenesis. Translating these exciting preclinical findings to the clinic offers the promise of improving the quality of life in patients with brain tumors who receive radiation therapy. PMID:23095829

  13. Case 242: Radiation-induced Angiosarcoma.

    PubMed

    Disharoon, Meredith; Kozlowski, Kamilia F; Kaniowski, Jessica M

    2017-06-01

    History In 2004, this woman received a diagnosis of invasive mammillary carcinoma, tubular variant, strongly positive for estrogen and progesterone receptors. Her lesion was found at screening mammography performed at an outside institution when she was 59 years old. She underwent partial mastectomy, with partial axillary node dissection and sentinel node mapping. A 0.6 × 0.5 cm Nottingham grade 1 infiltrating ductal carcinoma was removed from the right upper outer quadrant, margins were free of tumor, and there was no angiolymphatic invasion. The six dissected lymph nodes were negative for malignancy. Her surgical history was otherwise unremarkable. Her medical history was positive for hypercholesterolemia and depression. Pertinent family history included breast cancer in both her mother and her sister. Given the patient's age, tumor size, lack of nodal involvement, and clear surgical margins, she met recommended MammoSite criteria, and she underwent accelerated partial breast radiation. She subsequently received 340 cGy of radiation twice a day for a total dose of 3400 cGy in 10 administrations in February 2005. Accelerated partial breast radiation treatment was completed in February 2005, and she received subsequent routine care. Prior to 2014, the only postoperative complication was a chronic radiation bed seroma, which required periodic percutaneous drainage. She did not develop postsurgical lymphedema. In December 2013, 9 years after accelerated partial breast radiation treatment, she experienced progressive painful pruritic breast fullness, skin dimpling, and skin discoloration of the mastectomy scar and radiation bed. She sought medical care in January 2014 after she noticed a periareolar ulcerating skin plaque, more noticeable nipple retraction, and new onset of retroareolar aching. At physical examination ( Fig 1 ), there was generalized periareolar erythema, dimpling, firmness, and fixation involving the central breast and right upper outer quadrant

  14. Radiation recall dermatitis induced by trastuzumab.

    PubMed

    Moon, Dochang; Koo, Ja Seung; Suh, Chang-Ok; Yoon, Chang Yun; Bae, Jaehyun; Lee, Soohyeon

    2016-01-01

    We report a case of radiation recall dermatitis caused by trastuzumab. A 55-year-old woman with metastatic breast cancer received palliative first-line trastuzumab/paclitaxel and a salvage partial mastectomy with lymph node dissection was subsequently performed. In spite of the palliative setting, the pathology report indicated that no residual carcinoma was present, and then she underwent locoregional radiotherapy to ensure a definitive response. After radiotherapy, she has maintained trastuzumab monotherapy. Nine days after the fifth cycle of trastuzumab monotherapy, dermatitis in previously irradiated skin developed, with fever. Radiation recall dermatitis triggered by trastuzumab is extremely rare. A high fever developed abruptly with a skin rash. This may be the first case of this sort to be reported.

  15. Mitigation of radiation induced surface contamination

    DOEpatents

    Klebanoff, Leonard E.; Stulen, Richard H.

    2003-01-01

    A process for mitigating or eliminating contamination and/or degradation of surfaces having common, adventitious atmospheric contaminants adsorbed thereon and exposed to radiation. A gas or a mixture of gases is introduced into the environment of a surface(s) to be protected. The choice of the gaseous species to be introduced (typically a hydrocarbon gas, water vapor, or oxygen or mixtures thereof) is dependent upon the contaminant as well as the ability of the gaseous species to bind to the surface to be protected. When the surface and associated bound species are exposed to radiation reactive species are formed that react with surface contaminants such as carbon or oxide films to form volatile products (e.g., CO, CO.sub.2) which desorb from the surface.

  16. DECOHERENCE EFFECTS OF MOTION-INDUCED RADIATION

    SciTech Connect

    P. NETO; D. DALVIT

    2000-12-01

    The radiation pressure coupling with vacuum fluctuations gives rise to energy damping and decoherence of an oscillating particle. Both effects result from the emission of pairs of photons, a quantum effect related to the fluctuations of the Casimir force. We discuss different alternative methods for the computation of the decoherence time scale. We take the example of a spherical perfectly-reflecting particle, and consider the zero and high temperature limits. We also present short general reviews on decoherence and dynamical Casimir effect.

  17. Sudden Cardiac Death of a Body Packer Due to Cocaine Cardiotoxicity

    PubMed Central

    Pramanik, Parthasarathi; Vidua, Raghvendra Kumar

    2016-01-01

    This article presents a case of sudden cardiac death due to the effects of cocaine concealed in the body of a male drug smuggler in his 40s, a so-called body packer. A total of 57 body packets filled with cocaine powder were discovered in his body cavities. The detailed autopsy examination, including histopathology and toxicology findings, is discussed with the aim of describing the mechanism of cocaine intoxication in the body packer and an analysis of cocaine-induced cardiotoxicity and sudden death. PMID:27932899

  18. Metabolomics reveals the mechanisms for the cardiotoxicity of Pinelliae Rhizoma and the toxicity-reducing effect of processing

    PubMed Central

    Su, Tao; Tan, Yong; Tsui, Man-Shan; Yi, Hua; Fu, Xiu-Qiong; Li, Ting; Chan, Chi Leung; Guo, Hui; Li, Ya-Xi; Zhu, Pei-Li; Tse, Anfernee Kai Wing; Cao, Hui; Lu, Ai-Ping; Yu, Zhi-Ling

    2016-01-01

    Pinelliae Rhizoma (PR) is a commonly used Chinese medicinal herb, but it has been frequently reported about its toxicity. According to the traditional Chinese medicine theory, processing can reduce the toxicity of the herbs. Here, we aim to determine if processing reduces the toxicity of raw PR, and to explore the underlying mechanisms of raw PR-induced toxicities and the toxicity-reducing effect of processing. Biochemical and histopathological approaches were used to evaluate the toxicities of raw and processed PR. Rat serum metabolites were analyzed by LC-TOF-MS. Ingenuity pathway analysis of the metabolomics data highlighted the biological pathways and network functions involved in raw PR-induced toxicities and the toxicity-reducing effect of processing, which were verified by molecular approaches. Results showed that raw PR caused cardiotoxicity, and processing reduced the toxicity. Inhibition of mTOR signaling and activation of the TGF-β pathway contributed to raw PR-induced cardiotoxicity, and free radical scavenging might be responsible for the toxicity-reducing effect of processing. Our data shed new light on the mechanisms of raw PR-induced cardiotoxicity and the toxicity-reducing effect of processing. This study provides scientific justifications for the traditional processing theory of PR, and should help in optimizing the processing protocol and clinical combinational application of PR. PMID:27698376

  19. Metabolomics reveals the mechanisms for the cardiotoxicity of Pinelliae Rhizoma and the toxicity-reducing effect of processing

    NASA Astrophysics Data System (ADS)

    Su, Tao; Tan, Yong; Tsui, Man-Shan; Yi, Hua; Fu, Xiu-Qiong; Li, Ting; Chan, Chi Leung; Guo, Hui; Li, Ya-Xi; Zhu, Pei-Li; Tse, Anfernee Kai Wing; Cao, Hui; Lu, Ai-Ping; Yu, Zhi-Ling

    2016-10-01

    Pinelliae Rhizoma (PR) is a commonly used Chinese medicinal herb, but it has been frequently reported about its toxicity. According to the traditional Chinese medicine theory, processing can reduce the toxicity of the herbs. Here, we aim to determine if processing reduces the toxicity of raw PR, and to explore the underlying mechanisms of raw PR-induced toxicities and the toxicity-reducing effect of processing. Biochemical and histopathological approaches were used to evaluate the toxicities of raw and processed PR. Rat serum metabolites were analyzed by LC-TOF-MS. Ingenuity pathway analysis of the metabolomics data highlighted the biological pathways and network functions involved in raw PR-induced toxicities and the toxicity-reducing effect of processing, which were verified by molecular approaches. Results showed that raw PR caused cardiotoxicity, and processing reduced the toxicity. Inhibition of mTOR signaling and activation of the TGF-β pathway contributed to raw PR-induced cardiotoxicity, and free radical scavenging might be responsible for the toxicity-reducing effect of processing. Our data shed new light on the mechanisms of raw PR-induced cardiotoxicity and the toxicity-reducing effect of processing. This study provides scientific justifications for the traditional processing theory of PR, and should help in optimizing the processing protocol and clinical combinational application of PR.

  20. [Nonsurgical treatment of chronic radiation-induced hemorrhagic proctitis].

    PubMed

    de Parades, Vincent; Bauer, Pierre; Marteau, Philippe; Chauveinc, Laurent; Bouillet, Thierry; Atienza, Patrick

    2008-01-01

    The incidence of radiation-induced chronic hemorrhagic proctitis is less than 10 to 20%. The onset of this proctitis is delayed relative to the radiation therapy and generally develops from 6 to 24 months later. There are numerous predisposing factors, the most important of which is the radiation therapy dose: risk increases exponentially above 40-45 Gy. Its pathophysiology involves progressive obliterating endarteritis and transmural interstitial fibrosis, which induce chronic ischemia that is irreversible and progressive during the years after radiation therapy. Its diagnosis depends most often on the combination of clinical history and typical endoscopic appearance (congestive mucosa and/or telangiectases). Topical administrative of sucralfate or corticosteroids as well as argon plasma coagulation, with formalin treatment if necessary, provides relief for most patients.

  1. Process and Radiation Induced Defects in Electronic Materials and Devices

    NASA Technical Reports Server (NTRS)

    Washington, Kenneth; Fogarty, T. N.

    1997-01-01

    Process and radiation induced defects are characterized by a variety of electrical techniques, including capacitance-voltage measurements and charge pumping. Separation of defect type into stacking faults, displacement damage, oxide traps, interface states, etc. and their related causes are discussed. The defects are then related to effects on device parameters. Silicon MOS technology is emphasized. Several reviews of radiation effects and silicon processing exist.

  2. Process and Radiation Induced Defects in Electronic Materials and Devices

    NASA Technical Reports Server (NTRS)

    Washington, Kenneth; Fogarty, T. N.

    1997-01-01

    Process and radiation induced defects are characterized by a variety of electrical techniques, including capacitance-voltage measurements and charge pumping. Separation of defect type into stacking faults, displacement damage, oxide traps, interface states, etc. and their related causes are discussed. The defects are then related to effects on device parameters. Silicon MOS technology is emphasized. Several reviews of radiation effects and silicon processing exist.

  3. Lisinopril or Coreg CR in reducing cardiotoxicity in women with breast cancer receiving trastuzumab: A rationale and design of a randomized clinical trial.

    PubMed

    Guglin, Maya; Munster, Pamela; Fink, Angelina; Krischer, Jeffrey

    2017-06-01

    Trastuzumab (TZB) is an established therapy for HER2-positive breast cancer. The use of TZB is commonly associated with cardiotoxicity manifesting as asymptomatic decrease in left ventricular ejection fraction (LVEF) or overt heart failure. Several studies demonstrated favorable effects of angiotensin-converting enzyme (ACE) inhibitors and β-blockers (BBs) in the prevention of chemotherapy-induced cardiotoxicity. We hypothesize that patients, randomized to receive an ACE inhibitor or a BB during trastuzumab therapy for breast cancer, will maintain a higher LVEF than patients randomized to placebo. We designed a prospective, multicenter, randomized, phase II placebo-controlled clinical trial to evaluate the effects of an ACE inhibitor (lisinopril) and a BB (carvedilol phosphate-extended release) on cardiotoxicity in patients with breast cancer who are receiving adjuvant or neoadjuvant TZB therapy. The primary objectives include (1) comparison of incidence of cardiotoxicity and (2) comparison of LVEF as a continuous variable in between the arms. Cardiotoxicity was defined as an absolute decrease in LVEF from baseline of ≥10% at follow-up or an absolute decrease of ≥5% in LVEF from baseline for individuals with <50% LVEF at follow-up. The target accrual is 468 participants, representing patients both with and without anthracycline exposure. The enrollment is completed. The trial is co-sponsored by University of South Florida and National Cancer Institute. The LVEF is being evaluated by echocardiography or multigated acquisition scan. If we can demonstrate that the use of an ACE inhibitor or a BB can reduce the degree of TZB-induced cardiotoxicity, it is hoped that patients will receive complete and uninterrupted TZB therapy for breast cancer without compromising cardiac function. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Radiation-induced cataract in astronauts and cosmonauts.

    PubMed

    Rastegar, Noushin; Eckart, Peter; Mertz, Manfred

    2002-07-01

    Opacification of the ocular lens is an important effect of exposure to ionizing radiation. Astronauts and cosmonauts are exposed to relatively high doses of all types of radiation in space, including high-energy particle radiation. A study was initiated to examine the lenses of the eyes of astronauts/cosmonauts to detect signs of radiation-induced cataracts. The aim of this study was to take a first step towards gaining improved, quantitative insight into the risk of radiation-induced cataract associated with long space missions. The lenses of 21 former astronauts and cosmonauts were examined, using an upgraded Topcon SL-45 B Scheimpflug camera system. The degrees of opacification in this group of astronauts and cosmonauts were compared with the measurements in a reference group. This reference group was established by examining a cohort of 395 persons using the same Scheimpflug system. Initial results indicated that opacity values in most of the astronauts and cosmonauts were slightly to strongly increased in regions IV (posterior cortex) and V (posterior capsule), compared with the average opacity values for the respective age-group of the reference cohort. The aim of this study - to conduct first examinations of astronauts' and cosmonauts' ocular lenses with regard to signs of radiation-induced cataract - was successfully achieved in a total of 21 astronauts and cosmonauts using a Scheimpflug camera system. It is planned to examine a larger group of astronauts and cosmonauts in the future.

  5. Inhibition of radiation-induced polyuria by histamine receptor antagonists

    SciTech Connect

    Donlon, M.A.; Melia, J.A.; Helgeson, E.A.; Wolfe, W.W.

    1986-03-01

    In previous studies the authors have demonstrated that gamma radiation results in polyuria, which is preceded by polydypsia. This suggests that the increased thirst elicited by radiation causes increased urinary volume (UV). Histamine, which is released following radiation exposure, also elicits drinking by nonirradiated rats when administered exogenously. In this study the authors have investigated both the role of water deprivation and the effect of histamine receptor antagonists (HRA) on radiation-induced polyuria. Sprague-Dawley rats were housed individually in metabolic cages. Water was allowed ad libitum except in deprivation experiments where water was removed for 24 hr immediately following radiation. Cimetidine (CIM), an H2 HRA, and dexbromopheniramine (DXB), an H1 HRA, were administered i.p. (16 and 1 mg/kg, respectively) 30 min prior to irradiation (950 rads from a cobalt source). UV was determined at 24-hr intervals for 3 days preceding irradiation and 24 hr postirradiation. UV in DXB treated rats was significantly reduced 24 hr postirradiation (CON = 427 +/- 54%; DXB = 247 +/- 39% of preirradiated CON) compared to postirradiation control values. CIM did not affect postirradiation UV. These data suggest that radiation-induced polyuria is caused by polydypsia which is, in part, mediated by histamine induced by an H1 receptor.

  6. Pharmacogenomics as a risk mitigation strategy for chemotherapeutic cardiotoxicity.

    PubMed

    Jensen, Brian C; McLeod, Howard L

    2013-01-01

    Damage to the heart can result from both traditional chemotherapeutic agents, such as doxorubicin, and newer 'targeted' therapies, such as trastuzumab. This chemotherapeutic cardiotoxicity is potentially life-threatening and necessitates limiting or discontinuing an otherwise-effective cancer treatment. Clinical strategies focus on surveillance rather than prevention, although there are no specific therapies for this highly morbid adverse effect. Current models for prospectively predicting risk of chemotherapeutic cardiotoxicity are limited. Cardiotoxicity can occur idiosyncratically in patients without obvious demographic risk factors, suggesting a genetically determined susceptibility, and candidate-gene studies have identified a limited number of variants that increase risk. In this commentary we indicate a need for more powerful means to identify risk prospectively, and suggest that broad pharmacogenomic approaches may be fruitful.

  7. Exaggerated radiation-induced fibrosis in patients with systemic sclerosis

    SciTech Connect

    Varga, J.; Haustein, U.F.; Creech, R.H.; Dwyer, J.P.; Jimenez, S.A. )

    1991-06-26

    Four patients with stable systemic sclerosis and limited skin involvement received radiation for the treatment of solid malignant neoplasms. Following localized irradiation, each patient developed an exaggerated cutaneous and internal fibrotic reaction in the irradiated areas. The surface area of fibrosis extended beyond the radiation portals employed, and the fibrotic process was poorly responsive to antifibrotic therapy. Three of the patients died of complications caused by fibrous encasement of internal organs. The extent and severity of postradiation fibrosis in these patients was distinctly unusual. These observations suggest that patients with systemic sclerosis are particularly susceptible to developing excessive radiation-induced fibrosis.

  8. Peroxidase changes in barley induced by ionizing and thermal radiation.

    PubMed

    Sah, N K; Pramanik, S; Raychaudhuri, S S

    1996-01-01

    Thermal and ionizing (gamma-ray) radiations were used to induce damage to barley seeds (IB65). The activity and isozyme banding patterns of peroxidase were compared. It was found that both physical agents caused damage to barley seeds (as observed from seedling height), but their action on peroxidase activity is not similar. Gamma-Rays enhance peroxidase activity. Thermal radiation, on the other hand, tends to reduce it but fails to alter the number of peroxidase isozymes. It is conjectured that the pathways of damage by thermal and ionizing radiations are not the same.

  9. [Mechanism of cytogenetic adaptive response induced by low dose radiation].

    PubMed

    Cai, L; Liu, S

    1990-11-01

    Cytogenetic observation on human lymphocytes indicated that pre-exposure of 10, 50 and 75 mGy X-rays could induced the adaptive response. Experimental results with different temperature treatment showed that the adaptive response induced by low dose radiation could be enhanced by 41 degrees C and 43 degrees C, but inhibited by 4 degrees C in addition the treatment by 41 degrees C for one hour could also cause the adaptive response as did low dose radiation. Results showed that adaptive response induced by low dose radiation (10 or 50 mGy X-rays) could be eliminated by the protein synthesis inhibitor, implying that the adaptive response is related with the metabolism of cells, especially with the production of certain protective proteins.

  10. Mechanisms of radiation-induced neoplastic cell transformation

    SciTech Connect

    Yang, T.C.H.; Tobias, C.A.

    1984-04-01

    Studies with cultured mammalian cells demonstrated clearly that radiation can transform cells directly and can enhance the cell transformation by oncogenic DNA viruses. In general, high-LET heavy-ion radiation can be more effective than X and gamma rays in inducing neoplastic cell transformation. Various experimental results indicate that radiation-induced DNA damage, most likely double-strand breaks, is important for both the initiation of cell transformation and for the enhancement of viral transformation. Some of the transformation and enhancement lesions can be repaired properly in the cell, and the amount of irrepairable lesions produced by a given dose depends on the quality of radiation. An inhibition of repair processes with chemical agents can increase the transformation frequency of cells exposed to radiation and/or oncogenic viruses, suggesting that repair mechanisms may play an important role in the radiation transformation. The progression of radiation-transformed cells appears to be a long and complicated process that can be modulated by some nonmutagenic chemical agents, e.g., DMSO. Normal cells can inhibit the expression of transforming properties of tumorigenic cells through an as yet unknown mechanism. The progression and expression of transformation may involve some epigenetic changes in the irradiated cells. 38 references, 15 figures, 1 table.

  11. Low dose radiation-induced endothelial cell retraction.

    PubMed

    Kantak, S S; Diglio, C A; Onoda, J M

    1993-09-01

    We characterized in vitro the effects of gamma-radiation (12.5-100 cGy) on pulmonary microvascular endothelial cell (PMEC) morphology and F-actin organization. Cellular retraction was documented by phase-contrast microscopy and the organization of actin microfilaments was determined by immunofluorescence. Characterization included radiation dose effects, their temporal duration and reversibility of the effects. A dose-dependent relationship between the level of exposure (12.5-100 cGy) and the rate and extent of endothelial retraction was observed. Moreover, analysis of radiation-induced depolymerization of F-actin microfilament stress fibres correlated positively with the changes in PMEC morphology. The depolymerization of the stress fibre bundles was dependent on radiation dose and time. Cells recovered from exposure to reform contact inhibited monolayers > or = 24 h post-irradiation. Concomitantly, the depolymerized microfilaments reorganized to their preirradiated state as microfilament stress fibres arrayed parallel to the boundaries of adjacent contact-inhibited cells. The data presented here are representative of a series of studies designed to characterize low-dose radiation effects on pulmonary microvascular endothelium. Our data suggest that post-irradiation lung injuries (e.g. oedema) may be induced with only a single fraction of therapeutic radiation, and thus microscopic oedema may initiate prior to the lethal effects of radiation on the microvascular endothelium, and much earlier than would be suggested by the time course for clinically-detectable oedema.

  12. Chemoprevention of Radiation Induced Rat Mammary Neoplasms

    NASA Technical Reports Server (NTRS)

    Huso, David L.

    1999-01-01

    Radiations encountered in space include protons and heavy ions such as iron as well as their secondaries. The relative biological effect (RBE) of these ions is not known, particularly at the doses and dose-rates expected for planetary missions. Neutrons, are not particularly relevant to space travel, but have been found experimentally to have an increase in their RBE with decreasing dose. If a similar trend of increasing RBE with decreasing dose is present for heavy ions and protons during irradiation in space, the small doses received during space travel could potentially have substantial carcinogenic risk. Clearly more investigation of the effects of heavy ions and protons is needed before accurate risk assessment for prolonged travel in space can be done. One means to mitigate the increased risk of cancer due to radiation exposure in space is by developing effective countermeasures that can reduce the incidence of tumor development. Tamoxifen has recently been shown to be an effective chemopreventive agent in both animal models and humans for the prevention of mammary tumors. Tamoxifen is a unique drug, with a highly specific mechanism of action affecting a specific radiation-sensitive population of epithelial cells in the mammary gland. In human studies, the annual incidence of a primary tumor in the contralateral breast of women with previous breast cancer is about 8 per 1000, making them an exceedingly high-risk group for the development of breast cancer. In this high risk group, treated with tamoxifen, daily, for 2 years, the incidence of a new primary tumor in the contralateral breast was approximately one third of that noted in the non-tamoxifen treatment group. Tamoxifen antagonizes the action of estrogen by competing for the nuclear receptor complex thereby altering the association of the receptor complex and nuclear binding sites. Its effects in reducing the development of breast cancer could be accomplished by controlling clinically undetectable

  13. Chemoprevention of Radiation Induced Rat Mammary Neoplasms

    NASA Technical Reports Server (NTRS)

    Huso, David L.

    1999-01-01

    Radiations encountered in space include protons and heavy ions such as iron as well as their secondaries. The relative biological effect (RBE) of these ions is not known, particularly at the doses and dose-rates expected for planetary missions. Neutrons, are not particularly relevant to space travel, but have been found experimentally to have an increase in their RBE with decreasing dose. If a similar trend of increasing RBE with decreasing dose is present for heavy ions and protons during irradiation in space, the small doses received during space travel could potentially have substantial carcinogenic risk. Clearly more investigation of the effects of heavy ions and protons is needed before accurate risk assessment for prolonged travel in space can be done. One means to mitigate the increased risk of cancer due to radiation exposure in space is by developing effective countermeasures that can reduce the incidence of tumor development. Tamoxifen has recently been shown to be an effective chemopreventive agent in both animal models and humans for the prevention of mammary tumors. Tamoxifen is a unique drug, with a highly specific mechanism of action affecting a specific radiation-sensitive population of epithelial cells in the mammary gland. In human studies, the annual incidence of a primary tumor in the contralateral breast of women with previous breast cancer is about 8 per 1000, making them an exceedingly high-risk group for the development of breast cancer. In this high risk group, treated with tamoxifen, daily, for 2 years, the incidence of a new primary tumor in the contralateral breast was approximately one third of that noted in the non-tamoxifen treatment group. Tamoxifen antagonizes the action of estrogen by competing for the nuclear receptor complex thereby altering the association of the receptor complex and nuclear binding sites. Its effects in reducing the development of breast cancer could be accomplished by controlling clinically undetectable

  14. Radiation Induced Vaccination to Breast Cancer

    DTIC Science & Technology

    2016-12-01

    PET / CT imaging...8 10 time [wk] surivin T cells N01 N01* N03 N05 N09 N10 N14 N02 N04 N15 U03 U07 1mg 10mg healthy controls su rv iv in -r ea ct iv e C D 8+ T c el...r ea ct iv e C D 8+ T c el ls [% o f C D 8+ ] A’ B’ C’ 19 FIGURE 4: Breast cancer patients responded to 10mg Fesolimumab and Radiation

  15. H- - H Collision Induced Radiative Transitions

    NASA Astrophysics Data System (ADS)

    Dadonova, A. V.; Devdariani, A. Z.

    2012-12-01

    Exchange interaction leads to the formation of gerade and ungerade states of temporary molecules (quasimolecules) formed during the H- +H slow collisions. The work deals with the radiation produced by optical transitions between those states. The main characteristics involved in the description of optical transitions in quasimolecules, i.e., energy terms, an optical dipole transition moments, have been calculated in the frame of zero-range potentials model. The main feature of calculations is that the results can be expressed analytically in closed forms via the Lambert W function.

  16. Radiation-induced nonlinear optical response of quartz fibers

    NASA Astrophysics Data System (ADS)

    Plaksin, O. A.

    2006-10-01

    The intensity of radiation-induced luminescence and transient optical losses in KU-1 (Russia) and K-3 (Japan) quartz glass optical tibers irradiated in a fast pulsed fission reactor (a pulse duration of 80 μs and a neutron flux up to 7 × 1016 cm 2 s 2) has been measured in the visible range. The intensity of the fast luminescence component nonlinearly depends on the neutron flux. The luminescence intensity and the transient optical losses depend on the probe light intensity. Suppression of radiation-induced luminescence is observed at wavelengths that are longer or shorter than the probe light wavelength. Light probing leads to an increase in transient optical losses and a more rapid recovery of transparency. A model of two photon fluxes is proposed to analyze the relationship of the effects of suppression of radiation-induced luminescence and the increase in optical losses upon light probing. The effect of suppression of radiation-induced luminescence can be used to control the optical properties of fibers in radiation fields.

  17. Radiation-induced endometriosis in Macaca mulatta

    SciTech Connect

    Fanton, J.W.; Golden, J.G. )

    1991-05-01

    Female rhesus monkeys received whole-body doses of ionizing radiation in the form of single-energy protons, mixed-energy protons, X rays, and electrons. Endometriosis developed in 53% of the monkeys during a 17-year period after exposure. Incidence rates for endometriosis related to radiation type were: single-energy protons, 54%; mixed-energy protons, 73%; X rays, 71%; and electrons, 57%. The incidence of endometriosis in nonirradiated control monkeys was 26%. Monkeys exposed to single-energy protons, mixed-energy protons, and X rays developed endometriosis at a significantly higher rate than control monkeys (chi 2, P less than 0.05). Severity of endometriosis was staged as massive, moderate, and minimal. The incidence of these stages were 65, 16, and 19%, respectively. Observations of clinical disease included weight loss in 43% of the monkeys, anorexia in 35%, space-occupying masses detected by abdominal palpation in 55%, abnormal ovarian/uterine anatomy on rectal examination in 89%, and radiographic evidence of abdominal masses in 38%. Pathological lesions were endometrial cyst formation in 69% of the monkeys, adhesions of the colon in 66%, urinary bladder in 50%, ovaries in 86%, and ureters in 44%, focal nodules of endometrial tissue throughout the omentum in 59%, and metastasis in 9%. Clinical management of endometriosis consisted of debulking surgery and bilateral salpingo-oophorectomy combined in some cases with total abdominal hysterectomy. Postoperative survival rates at 1 and 5 years for monkeys recovering from surgery were 48 and 36%, respectively.

  18. The influence of infrared radiation on short-term ultraviolet-radiation-induced injuries

    SciTech Connect

    Kaidbey, K.H.; Witkowski, T.A.; Kligman, A.M.

    1982-05-01

    Because heat has been reported to influence adversely short- and long-term ultraviolet (UV)-radiation-induced skin damage in animals, we investigated the short-term effects of infrared radiation on sunburn and on phototoxic reactions to topical methoxsalen and anthracene in human volunteers. Prior heating of the skin caused suppression of the phototoxic response to methoxsalen as evidenced by an increase in the threshold erythema dose. Heat administered either before or after exposure to UV radiation had no detectable influence on sunburn erythema or on phototoxic reactions provoked by anthracene.

  19. Panretinal photocoagulation for radiation-induced ocular ischemia

    SciTech Connect

    Augsburger, J.J.; Roth, S.E.; Magargal, L.E.; Shields, J.A.

    1987-08-01

    We present preliminary findings on the effectiveness of panretinal photocoagulation in preventing neovascular glaucoma in eyes with radiation-induced ocular ischemia. Our study group consisted of 20 patients who developed radiation-induced ocular ischemia following cobalt-60 plaque radiotherapy for a choroidal or ciliary body melanoma. Eleven of the 20 patients were treated by panretinal photocoagulation shortly after the diagnosis of ocular ischemia, but nine patients were left untreated. In this non-randomized study, the rate of development of neovascular glaucoma was significantly lower (p = 0.024) for the 11 photocoagulated patients than for the nine who were left untreated.

  20. The Mechanisms of Radiation-Induced Bystander Effect

    PubMed Central

    Najafi, M; Fardid, R; Hadadi, Gh; Fardid, M

    2014-01-01

    The radiation-induced bystander effect is the phenomenon which non-irradiated cells exhibit effects along with their different levels as a result of signals received from nearby irradiated cells. Responses of non-irradiated cells may include changes in process of translation, gene expression, cell proliferation, apoptosis and cells death. These changes are confirmed by results of some In-Vivo studies. Most well-known important factors affecting radiation-induced bystander effect include free radicals, immune system factors, expression changes of some genes involved in inflammation pathway and epigenetic factors. PMID:25599062

  1. Intraoperative radiation therapy-induced sarcomas in dogs

    SciTech Connect

    Hoekstra, H.J.; Sindelar, W.F.; Kinsella, T.J.; Mehta, D.M. )

    1989-12-01

    In a canine model the tolerance of normal and surgically manipulated tissue to intraoperative radiotherapy (IORT) was investigated to provide guidelines for the clinical use of IORT in human cancer patients. A dose of 20 Gy IORT, with or without external beam radiotherapy, was generally well tolerated without significant increased treatment morbidity. Higher doses of IORT (over 30 Gy) have produced radiation-induced sarcomas in some animals followed over a long period. Therefore IORT should be used only in human cancer patients in well controlled studies, in which complications are well documented, and the possibility of radiation-induced malignancies in long-term survival should be considered.

  2. [Symptoms, diagnosis and treatment of radiation-induced enteritis].

    PubMed

    Sinkó, Dániel; Baranyai, Zsolt; Nemeskéri, Csaba; Teknos, Dániel; Jósa, Valéria; Hegedus, László; Mayer, Arpád

    2010-09-05

    The number of radiotherapy in the treatment of malignant diseases is increasing worldwide. During the radiotherapy of tumors in the minor pelvis and abdomen intestinal inflammation of different degree may occur even if special attention is paid. Irradiation to the minor pelvis causes in half of the cases radiation induced acute enteritis, whereas in 25% chronic enteritis and colitis will develop. Chronic enteritis following radiotherapy raises a number of diagnostic and therapeutic problems that can be solved only with cooperation of different specialties. Authors present a short review regarding therapeutical options of radiation induced enteritis.

  3. Radiation-induced genomic instability and its implications for radiation carcinogenesis

    NASA Technical Reports Server (NTRS)

    Huang, Lei; Snyder, Andrew R.; Morgan, William F.

    2003-01-01

    Radiation-induced genomic instability is characterized by an increased rate of genetic alterations including cytogenetic rearrangements, mutations, gene amplifications, transformation and cell death in the progeny of irradiated cells multiple generations after the initial insult. Chromosomal rearrangements are the best-characterized end point of radiation-induced genomic instability, and many of the rearrangements described are similar to those found in human cancers. Chromosome breakage syndromes are defined by chromosome instability, and individuals with these diseases are cancer prone. Consequently, chromosomal instability as a phenotype may underlie some fraction of those changes leading to cancer. Here we attempt to relate current knowledge regarding radiation-induced chromosome instability with the emerging molecular information on the chromosome breakage syndromes. The goal is to understand how genetic and epigenetic factors might influence the onset of chromosome instability and the role of chromosomal instability in carcinogenesis.

  4. Radiation-induced genomic instability and its implications for radiation carcinogenesis

    NASA Technical Reports Server (NTRS)

    Huang, Lei; Snyder, Andrew R.; Morgan, William F.

    2003-01-01

    Radiation-induced genomic instability is characterized by an increased rate of genetic alterations including cytogenetic rearrangements, mutations, gene amplifications, transformation and cell death in the progeny of irradiated cells multiple generations after the initial insult. Chromosomal rearrangements are the best-characterized end point of radiation-induced genomic instability, and many of the rearrangements described are similar to those found in human cancers. Chromosome breakage syndromes are defined by chromosome instability, and individuals with these diseases are cancer prone. Consequently, chromosomal instability as a phenotype may underlie some fraction of those changes leading to cancer. Here we attempt to relate current knowledge regarding radiation-induced chromosome instability with the emerging molecular information on the chromosome breakage syndromes. The goal is to understand how genetic and epigenetic factors might influence the onset of chromosome instability and the role of chromosomal instability in carcinogenesis.

  5. Ionizing radiation-induced mutagenesis: radiation studies in Neurospora predictive for results in mammalian cells

    NASA Technical Reports Server (NTRS)

    Evans, H. H.; DeMarini, D. M.

    1999-01-01

    Ionizing radiation was the first mutagen discovered and was used to develop the first mutagenicity assay. In the ensuing 70+ years, ionizing radiation became a fundamental tool in understanding mutagenesis and is still a subject of intensive research. Frederick de Serres et al. developed and used the Neurospora crassa ad-3 system initially to explore the mutagenic effects of ionizing radiation. Using this system, de Serres et al. demonstrated the dependence of the frequency and spectra of mutations induced by ionizing radiation on the dose, dose rate, radiation quality, repair capabilities of the cells, and the target gene employed. This work in Neurospora predicted the subsequent observations of the mutagenic effects of ionizing radiation in mammalian cells. Modeled originally on the mouse specific-locus system developed by William L. Russell, the N. crassa ad-3 system developed by de Serres has itself served as a model for interpreting the results in subsequent systems in mammalian cells. This review describes the primary findings on the nature of ionizing radiation-induced mutagenesis in the N. crassa ad-3 system and the parallel observations made years later in mammalian cells.

  6. Ionizing radiation-induced mutagenesis: radiation studies in Neurospora predictive for results in mammalian cells

    NASA Technical Reports Server (NTRS)

    Evans, H. H.; DeMarini, D. M.

    1999-01-01

    Ionizing radiation was the first mutagen discovered and was used to develop the first mutagenicity assay. In the ensuing 70+ years, ionizing radiation became a fundamental tool in understanding mutagenesis and is still a subject of intensive research. Frederick de Serres et al. developed and used the Neurospora crassa ad-3 system initially to explore the mutagenic effects of ionizing radiation. Using this system, de Serres et al. demonstrated the dependence of the frequency and spectra of mutations induced by ionizing radiation on the dose, dose rate, radiation quality, repair capabilities of the cells, and the target gene employed. This work in Neurospora predicted the subsequent observations of the mutagenic effects of ionizing radiation in mammalian cells. Modeled originally on the mouse specific-locus system developed by William L. Russell, the N. crassa ad-3 system developed by de Serres has itself served as a model for interpreting the results in subsequent systems in mammalian cells. This review describes the primary findings on the nature of ionizing radiation-induced mutagenesis in the N. crassa ad-3 system and the parallel observations made years later in mammalian cells.

  7. Modulation of Radiation-Induced Apoptosis by Thiolamines

    NASA Technical Reports Server (NTRS)

    Warters, R. L.; Roberts, J. C.; Wilmore, B. H.; Kelley, L. L.

    1997-01-01

    Exposure to the thiolamine radioprotector N-(2-mercaptoethyl)-1,3-propanediamine (WR-1065) induced apoptosis in the mouse TB8-3 hybridoma after 60-minute (LD(sub50) = 4.5mM) or during a 20-hour (LD(sub50) = 0.15 mM) exposure. In contrast, a 20-hour exposure to 17 mM L-cysteine or 10 mM cysteamine was required to induce 50 percent apoptosis within 20 hours. Apoptosis was not induced by either a 60-minute or 20-hour exposure to 10 mM of the thiazolidime prodrugs ribose-cysteine (RibCys) or ribose-cysteamine (RibCyst). Thiolamine-induced apoptosis appeared to be a p53-independent process since it was induced by WR-1065 exposure in human HL60 cells. Exposure to WR-1065 (4mM for 15 minutes) or cysteine (10mM for 60 minutes) before and during irradiation protected cells against the induction of both DNA double-strand breaks and apoptosis, while exposure to RibCys (10 mM for 3 hours) did not. Treatment with either WR-1065, cysteine, RibCys or RibCyst for 60 minutes beginning 60 minutes after irradiation did not affect the level of radiation-induced apoptosis. In contrast, treatment with either cysteine, cysteamine or RibCys for 20 hours beginning 60 minutes after irradiation enhanced radiation-induced apoptosis. Similar experiments could not be conducted with WR-1065 because of its extreme toxicity. Our results indicate that thiolamine enhancement of radiation-induced apoptosis is not involved in their previously reported capacity to reduce radiation-induced mutations.

  8. Modulation of Radiation-Induced Apoptosis by Thiolamines

    NASA Technical Reports Server (NTRS)

    Warters, R. L.; Roberts, J. C.; Wilmore, B. H.; Kelley, L. L.

    1997-01-01

    Exposure to the thiolamine radioprotector N-(2-mercaptoethyl)-1,3-propanediamine (WR-1065) induced apoptosis in the mouse TB8-3 hybridoma after 60-minute (LD(sub50) = 4.5mM) or during a 20-hour (LD(sub50) = 0.15 mM) exposure. In contrast, a 20-hour exposure to 17 mM L-cysteine or 10 mM cysteamine was required to induce 50 percent apoptosis within 20 hours. Apoptosis was not induced by either a 60-minute or 20-hour exposure to 10 mM of the thiazolidime prodrugs ribose-cysteine (RibCys) or ribose-cysteamine (RibCyst). Thiolamine-induced apoptosis appeared to be a p53-independent process since it was induced by WR-1065 exposure in human HL60 cells. Exposure to WR-1065 (4mM for 15 minutes) or cysteine (10mM for 60 minutes) before and during irradiation protected cells against the induction of both DNA double-strand breaks and apoptosis, while exposure to RibCys (10 mM for 3 hours) did not. Treatment with either WR-1065, cysteine, RibCys or RibCyst for 60 minutes beginning 60 minutes after irradiation did not affect the level of radiation-induced apoptosis. In contrast, treatment with either cysteine, cysteamine or RibCys for 20 hours beginning 60 minutes after irradiation enhanced radiation-induced apoptosis. Similar experiments could not be conducted with WR-1065 because of its extreme toxicity. Our results indicate that thiolamine enhancement of radiation-induced apoptosis is not involved in their previously reported capacity to reduce radiation-induced mutations.

  9. Contribution of radiation-induced, nitric oxide-mediated bystander effect to radiation-induced adaptive response.

    NASA Astrophysics Data System (ADS)

    Matsumoto, H.; Ohnishi, T.

    There has been a recent upsurge of interest in radiation-induced adaptive response and bystander effect which are specific modes in stress response to low-dose low-dose rate radiation Recently we found that the accumulation of inducible nitric oxide NO synthase iNOS in wt p53 cells was induced by chronic irradiation with gamma rays followed by acute irradiation with X-rays but not by each one resulting in an increase in nitrite concentrations of medium It is suggested that the accumulation of iNOS may be due to the depression of acute irradiation-induced p53 functions by pre-chronic irradiation In addition we found that the radiosensitivity of wt p53 cells against acute irradiation with X-rays was reduced after chronic irradiation with gamma rays This reduction of radiosensitivity of wt p53 cells was nearly completely suppressed by the addition of NO scavenger carboxy-PTIO to the medium This reduction of radiosensitivity of wt p53 cells is just radiation-induced adaptive response suggesting that NO-mediated bystander effect may considerably contribute to adaptive response induced by radiation

  10. Atorvastatin Ameliorates Radiation-Induced Cardiac Fibrosis in Rats.

    PubMed

    Zhang, KunYi; He, XuYu; Zhou, Yingling; Gao, Lijuan; Qi, Zhengyu; Chen, Jiyan; Gao, Xiuren

    2015-12-01

    Radiation-induced heart injury is one of the major side effects of radiotherapy for thoracic malignancies. Previous studies have shown that radiotherapy induced myocardial fibrosis and intensified myocardial remodeling. In this study, we investigated whether atorvastatin could inhibit radiation-induced heart fibrosis in Sprague-Dawley rats, which were randomly divided into six groups: control; radiation only; and four treatment groups receiving atorvastatin plus radiation (E1, E2, E3 and E4). All rats, except the control group, received local heart irradiation in 7 daily fractions of 3 Gy for a total of 21 Gy. Rats in groups E1 (10 mg/kg/day) and E2 (20 mg/kg/day) received atorvastatin and radiation treatment until week 12 after exposure. Rats in groups E3 (10 mg/kg/day) and E4 (20 mg/kg/day) received atorvastatin treatment from 3 months before irradiation to week 12 after irradiation. The expressions of TGF-β1, Smad2, Smad3, fibronectin, ROCK I and p-Akt in heart tissues were evaluated using real-time PCR or Western blot analyses. Atorvastatin significantly reduced the expression of TGF-β1, Smad3/P-Smad3, ROCK I and p-Akt in rats of the E1-E4 groups and in a dose-dependent manner. Fibronectin exhibited a similar pattern of expression changes. In addition, echocardiography showed that atorvastatin treatment can inhibit the increase of left ventricular end-diastolic dimension, left ventricular end-systolic diameter and left ventricular posterior wall thickness, and prevent the decrease of ejection fraction and fraction shortening in E1-E4 groups compared with the radiation only group. This study demonstrated that radiation exposure increased the expression of fibronectin in cardiac fibroblasts and induced cardiac fibrosis through activation of the TGF-β1/Smad3, RhoA/ROCK, and PI3K/AKT signaling pathways. Statins ameliorated radiation-induced cardiac fibrosis in Sprague-Dawley rats. Our results suggest that atorvastatin is effective for the treatment of radiation-induced

  11. The axiverse induced dark radiation problem

    NASA Astrophysics Data System (ADS)

    Acharya, Bobby; Pongkitivanichkul, Chakrit

    2016-04-01

    The string/ M theory Axiverse — a plethora of very light Axion Like Particles (ALPs) with a vast range of masses — is arguably a generic prediction of string/ M theory. String/ M theory also tends to predict that the early Universe is dominated by moduli fields. When the heavy moduli decay, before nucleosynthesis, they produce dark radiation in the form of relativistic ALPs. Generically one estimates that the number of relativistic species grows with the number of axions in the Axiverse, in contradiction to the observations that N eff ≤ 4. We explain this problem in detail and suggest some possible solutions to it. The simplest solution requires that the lightest modulus decays only into its own axion superpartner plus Standard Model particles and this severely constrains the moduli Kahler potential and mass matrix.

  12. Radiation-induced cardiomyopathy as a function of radiation beam gating to the cardiac cycle

    NASA Astrophysics Data System (ADS)

    Gladstone, David J.; Flanagan, Michael F.; Southworth, Jean B.; Hadley, Vaughn; Thibualt, Melissa Wei; Hug, Eugen B.; Hoopes, P. Jack

    2004-04-01

    Portions of the heart are often unavoidably included in the primary treatment volume during thoracic radiotherapy, and radiation-induced heart disease has been observed as a treatment-related complication. Such complications have been observed in humans following radiation therapy for Hodgkin's disease and treatment of the left breast for carcinoma. Recent attempts have been made to prevent re-stenosis following angioplasty procedures using external beam irradiation. These attempts were not successful, however, due to the large volume of heart included in the treatment field and subsequent cardiac morbidity. We suggest a mechanism for sparing the heart from radiation damage by synchronizing the radiation beam with the cardiac cycle and delivering radiation only when the heart is in a relatively hypoxic state. We present data from a rat model testing this hypothesis and show that radiation damage to the heart can be altered by synchronizing the radiation beam with the cardiac cycle. This technique may be useful in reducing radiation damage to the heart secondary to treatment for diseases such as Hodgkin's disease and breast cancer.

  13. Radiation-induced dural fibrosarcoma with unusually short latent period

    SciTech Connect

    Ghatak, N.R.; Aydin, F.; Leshner, R.T. Tulane Univ., New Orleans, LA )

    1993-05-01

    Although rare, the occurrence of radiation-induced intracranial neoplasms of various types is well known. Among these tumors, fibrosarcomas, especially in the region of seila turcica, seem to be the most common type. These tumors characteristically occur after a long latent period, usually several years, following radiation therapy. The authors now report a case of apparently radiation-induced fibrosarcoma with some unusual features in a 10-year-old boy who was treated with radiation for medulloblastoma. He received a total dose of 53.2 Gy radiation delivered at 1.8 per fraction with 6 MV acceleration using the standard craniospinal technique. An MRI at 15 months after the completion of radiotherapy showed a mass over the cerebral convexity, which increased two-fold in size within a period of 4 months. A well circumscribed tumor was removed from the fronto-parietal convexity. The tumor measured 5x4.5x1.5 cm and was attached to the dura with invasion of the overlying bone. Histologically, it displayed the characteristic features of a low-grade fibrosarcoma. The patient remains free of tumor 18 months after the surgery. This case emphasizes the potential risk for the development of a second neoplasm following therapeutic radiation and also documents, to the authors' knowledge, the shortest latent period reported so far between administration of radiotherapy and development of an intracranial tumor.

  14. Radiation-Induced Bystander Response: Mechanism and Clinical Implications

    PubMed Central

    Suzuki, Keiji; Yamashita, Shunichi

    2014-01-01

    Significance: Absorption of energy from ionizing radiation (IR) to the genetic material in the cell gives rise to damage to DNA in a dose-dependent manner. There are two types of DNA damage; by a high dose (causing acute or deterministic effects) and by a low dose (related to chronic or stochastic effects), both of which induce different health effects. Among radiation effects, acute cutaneous radiation syndrome results from cell killing as a consequence of high-dose exposure. Recent advances: Recent advances in radiation biology and oncology have demonstrated that bystander effects, which are emerged in cells that have never been exposed, but neighboring irradiated cells, are also involved in radiation effects. Bystander effects are now recognized as an indispensable component of tissue response related to deleterious effects of IR. Critical issues: Evidence has indicated that nonapoptotic premature senescence is commonly observed in various tissues and organs. Senesced cells were found to secrete various proteins, including cytokines, chemokines, and growth factors, most of which are equivalent to those identified as bystander factors. Secreted factors could trigger cell proliferation, angiogenesis, cell migration, inflammatory response, etc., which provide a tissue microenvironment assisting tissue repair and remodeling. Future directions: Understandings of the mechanisms and physiological relevance of radiation-induced bystander effects are quite essential for the beneficial control of wound healing and care. Further studies should extend our knowledge of the mechanisms of bystander effects and mode of cell death in response to IR. PMID:24761341

  15. Investigation of the interaction of cardiotoxic anticancer agents using the fetal mouse heart organ culture system

    SciTech Connect

    Kimler, B.F.; Rethorst, R.D.; Cox, G.G.

    1986-01-01

    The fetal mouse heart organ culture system was utilized in an effort to document and predict the potential cardiotoxic effects of ionizing radiation, Adriamycin (ADR), and Dihydroxyanthraquinone (DHAQ); alone and in combination. These antineoplastic agents have been shown to produce clinical cardiomyopathy which is often dose-limiting. Fetal mouse hearts (gestational day 17) were removed and placed in a culture system of 6-well microtiter plates. A single heart was placed in each well on a piece of aluminium mesh, above the culture medium but bathed by capillary action. The plates were then placed in a 100% oxygen environment and incubated at 37/sup 0/C. Treatments performed on day 1 after culture were Cs-137 irradiation (10, 20, or 40 Gy); ADR (10, 30, or 100 micrograms/ml); DHAQ (5, 20, or 50 micrograms/ml); or various combinations of drugs and radiation. Hearts were checked every day for functional activity as evidenced by continuous heart best. Untreated hearts beat rhythmically for up to 9 days (average = 6.8 days); treated hearts stopped beating between 2 and 7 days after treatment. Using this endpoint of functional retention time (FRT), dose response curves were obtained for all individual agents. Combinations of ADR and DHAQ (at concentrations that resulted in FRTs of 3.5 days) produced no greater effect than either agent alone. However, the combination of radiation (FRT = 5.3 days) with ADR, DHAQ or both drugs was more effective than was drug alone. This system may help to predict the cardiotoxic effects that result from the use of these drugs and radiation.

  16. Radiation-induced conductivity control in polyaniline blends/composites

    NASA Astrophysics Data System (ADS)

    Güven, Olgun

    2007-08-01

    Polyaniline (PANI) blends with chlorine-containing polymers and copolymers and composites with HCl-releasing compounds were prepared to investigate their radiation response in terms of induced conductivities. Blends of non-conductive PANI with poly(vinyl chloride) (PVC), poly(vinylidene chloride- co-vinyl acetate), [P(VDC- co-VAc)], poly(vinylidene chloride- co-vinyl chloride), [P(VDC- co-VC)] were prepared in the form of as-cast films. A number of blends which are different in composition were exposed to gamma radiation and accelerated electrons to various doses, and the effects of irradiation type and composition of polymers on the conductivity of films were investigated by using conductivity measurements and UV-vis and FT-IR spectroscopy. The results clearly showed that ionizing radiation is an effective tool to induce and control conductivity in the blends of PANI-base with chlorine-carrying polymers as well as its composites prepared from HCl-releasing compounds such as chloral hydrate. The main mechanism behind this radiation-induced conductivity is in situ doping of PANI-base with HCl released from partner polymers and low molecular weight compounds by the effect of radiation.

  17. Clarithromycin Attenuates Radiation-Induced Lung Injury in Mice.

    PubMed

    Lee, Seung Jun; Yi, Chin-ok; Heo, Rok Won; Song, Dae Hyun; Cho, Yu Ji; Jeong, Yi Yeong; Kang, Ki Mun; Roh, Gu Seob; Lee, Jong Deog

    2015-01-01

    Radiation-induced lung injury (RILI) is a common and unavoidable complication of thoracic radiotherapy. The current study was conducted to evaluate the ability of clarithromycin (CLA) to prevent radiation-induced pneumonitis, oxidative stress, and lung fibrosis in an animal model. C57BL/6J mice were assigned to control, irradiation only, irradiation plus CLA, and CLA only groups. Test mice received single thoracic exposures to radiation and/or oral CLA (100 mg/kg/day). Histopathologic findings and markers of inflammation, fibrosis, and oxidative stress were compared by group. On a microscopic level, CLA inhibited macrophage influx, alveolar fibrosis, parenchymal collapse, consolidation, and epithelial cell changes. The concentration of collagen in lung tissue was lower in irradiation plus CLA mice. Radiation-induced expression of tumor necrosis factor (TNF)-α, TNF receptor 1, acetylated nuclear factor kappa B, cyclooxygenase 2, vascular cell adhesion molecule 1, and matrix metallopeptidase 9 were also attenuated by CLA. Expression levels of nuclear factor erythroid 2-related factor 2 and heme oxygenase 1, transforming growth factor-β1, connective tissue growth factor, and type I collagen in radiation-treated lungs were also attenuated by CLA. These findings indicate that CLA ameliorates the deleterious effects of thoracic irradiation in mice by reducing pulmonary inflammation, oxidative damage, and fibrosis.

  18. Clarithromycin Attenuates Radiation-Induced Lung Injury in Mice

    PubMed Central

    Lee, Seung Jun; Yi, Chin-ok; Heo, Rok Won; Song, Dae Hyun; Cho, Yu Ji; Jeong, Yi Yeong; Kang, Ki Mun; Roh, Gu Seob; Lee, Jong Deog

    2015-01-01

    Radiation-induced lung injury (RILI) is a common and unavoidable complication of thoracic radiotherapy. The current study was conducted to evaluate the ability of clarithromycin (CLA) to prevent radiation-induced pneumonitis, oxidative stress, and lung fibrosis in an animal model. C57BL/6J mice were assigned to control, irradiation only, irradiation plus CLA, and CLA only groups. Test mice received single thoracic exposures to radiation and/or oral CLA (100 mg/kg/day). Histopathologic findings and markers of inflammation, fibrosis, and oxidative stress were compared by group. On a microscopic level, CLA inhibited macrophage influx, alveolar fibrosis, parenchymal collapse, consolidation, and epithelial cell changes. The concentration of collagen in lung tissue was lower in irradiation plus CLA mice. Radiation-induced expression of tumor necrosis factor (TNF)-α, TNF receptor 1, acetylated nuclear factor kappa B, cyclooxygenase 2, vascular cell adhesion molecule 1, and matrix metallopeptidase 9 were also attenuated by CLA. Expression levels of nuclear factor erythroid 2-related factor 2 and heme oxygenase 1, transforming growth factor-β1, connective tissue growth factor, and type I collagen in radiation-treated lungs were also attenuated by CLA. These findings indicate that CLA ameliorates the deleterious effects of thoracic irradiation in mice by reducing pulmonary inflammation, oxidative damage, and fibrosis. PMID:26114656

  19. Stimulation of respiration in rat thymocytes induced by ionizing radiation.

    PubMed

    Gudz, T I; Pandelova, I G; Novgorodov, S A

    1994-04-01

    The effect of X irradiation on the respiration of rat thymocytes was studied. An increase in the rate of O2 uptake was observed 1 h after cells were irradiated with doses of 6-10 Gy. The radiation-induced increase in respiration could be blocked by oligomycin, an inhibitor of mitochondrial ATP synthase, suggesting control by increased cytoplasmic ATP turnover. The stimulation of respiration was not associated with changes in the activity of mitochondrial electron transfer enzymes or permeability of the inner membrane. Several inhibitors of processes which used ATP were screened for their effects on the basal respiration rate and on the radiation response. In irradiated thymocytes, an enhancement of inhibition of respiration by ouabain, La3+ and cycloheximide was observed. These results indicate that the radiation-induced stimulation of respiration is due to changes in ion homeostasis and protein synthesis. The effect of X irradiation was shown to be independent of the redox status of nonprotein thiols and was not associated with detectable changes in some products of lipid peroxidation. The radiation-induced decrease in activity of superoxide dismutase suggests free radical involvement in deleterious effects of radiation.

  20. Dynamics of radiation-induced amorphization in intermetallic compounds

    SciTech Connect

    Lam, N.Q.; Okamoto, P.R. ); Devanathan, R. Northwestern Univ., Evanston, IL . Dept. of Materials Science and Engineering); Meshii, M. . Dept. of Materials Science and Engineering)

    1992-06-01

    Recent progress in molecular-dynamics simulations of radiation-induced crystalline-to-amorphous transition in intermetallic compounds and the relationship between amorphization and melting are discussed. By focusing on the mean-square static displacement, which provides a generic measure of energy stored in the lattice in the forms of chemical and topological disorder, a unified description of solid-state amorphization as a disorder-induced, isothermal melting process can be developed within the framework of a generalized Lindemann criterion.

  1. Arsenic trioxide and resveratrol show synergistic anti-leukemia activity and neutralized cardiotoxicity.

    PubMed

    Fan, Yuhua; Chen, Meng; Meng, Jia; Yu, Lei; Tu, Yingfeng; Wan, Lin; Fang, Kun; Zhu, Wenliang

    2014-01-01

    Cardiotoxicity is an aggravating side effect of many clinical antineoplastic agents such as arsenic trioxide (As2O3), which is the first-line treatment for acute promyelocytic leukemia (APL). Clinically, drug combination strategies are widely applied for complex disease management. Here, an optimized, cardiac-friendly therapeutic strategy for APL was investigated using a combination of As2O3 and genistein or resveratrol. Potential combinations were explored with respect to their effects on mitochondrial membrane potential, reactive oxygen species, superoxide dismutase activity, autophagy, and apoptosis in both NB4 cells and neonatal rat left ventricular myocytes. All experiments consistently suggested that 5 µM resveratrol remarkably alleviates As2O3-induced cardiotoxicity. To achieve an equivalent effect, a 10-fold dosage of genistein was required, thus highlighting the dose advantage of resveratrol, as poor bioavailability is a common concern for its clinical application. Co-administration of resveratrol substantially amplified the anticancer effect of As2O3 in NB4 cells. Furthermore, resveratrol exacerbated oxidative stress, mitochondrial damage, and apoptosis, thereby reflecting its full range of synergism with As2O3. Addition of 5 µM resveratrol to the single drug formula of As2O3 also further increased the expression of LC3, a marker of cellular autophagy activity, indicating an involvement of autophagy-mediated tumor cell death in the synergistic action. Our results suggest a possible application of an As2O3 and resveratrol combination to treat APL in order to achieve superior therapeutics effects and prevent cardiotoxicity.

  2. Arsenic Trioxide and Resveratrol Show Synergistic Anti-Leukemia Activity and Neutralized Cardiotoxicity

    PubMed Central

    Meng, Jia; Yu, Lei; Tu, Yingfeng; Wan, Lin; Fang, Kun; Zhu, Wenliang

    2014-01-01

    Cardiotoxicity is an aggravating side effect of many clinical antineoplastic agents such as arsenic trioxide (As2O3), which is the first-line treatment for acute promyelocytic leukemia (APL). Clinically, drug combination strategies are widely applied for complex disease management. Here, an optimized, cardiac-friendly therapeutic strategy for APL was investigated using a combination of As2O3 and genistein or resveratrol. Potential combinations were explored with respect to their effects on mitochondrial membrane potential, reactive oxygen species, superoxide dismutase activity, autophagy, and apoptosis in both NB4 cells and neonatal rat left ventricular myocytes. All experiments consistently suggested that 5 µM resveratrol remarkably alleviates As2O3-induced cardiotoxicity. To achieve an equivalent effect, a 10-fold dosage of genistein was required, thus highlighting the dose advantage of resveratrol, as poor bioavailability is a common concern for its clinical application. Co-administration of resveratrol substantially amplified the anticancer effect of As2O3 in NB4 cells. Furthermore, resveratrol exacerbated oxidative stress, mitochondrial damage, and apoptosis, thereby reflecting its full range of synergism with As2O3. Addition of 5 µM resveratrol to the single drug formula of As2O3 also further increased the expression of LC3, a marker of cellular autophagy activity, indicating an involvement of autophagy-mediated tumor cell death in the synergistic action. Our results suggest a possible application of an As2O3 and resveratrol combination to treat APL in order to achieve superior therapeutics effects and prevent cardiotoxicity. PMID:25144547

  3. Study of the Cardiotoxicity of Venenum Bufonis in Rats using an 1H NMR-Based Metabolomics Approach

    PubMed Central

    Wang, Junsong; Guo, Pingping; Li, Minghui; Yang, Minghua; Kong, Lingyi

    2015-01-01

    Venenum Bufonis, a well-known traditional Chinese medicine, has been widely used in Asia and has gained popularity in Western countries over the last decade. Venenum Bufonis has obvious side effects that have been observed in clinical settings, but few studies have reported on its cardiotoxicity. In this work, the cardiotoxicity of Venenum Bufonis was investigated using a 11H NMR-based metabolomics approach. The 1H NMR profiles of the serum, myocardial extracts and liver extracts of specific-pathogen-free rats showed that Venenum Bufonis produced significant metabolic perturbations dose-dependently with a distinct time effect, peaking at 2 hr after dosing and attenuating gradually. Clinical chemistry, electrocardiographic recordings, and histopathological evaluation provided additional evidence of Venenum Bufonis-induced cardiac damage that complemented and supported the metabolomics findings. The combined results demonstrated that oxidative stress, mitochondrial dysfunction, and energy metabolism perturbations were associated with the cardiac damage that results from Venenum Bufonis. PMID:25781638

  4. Interleukin-32 Positively Regulates Radiation-Induced Vascular Inflammation

    SciTech Connect

    Kobayashi, Hanako; Yazlovitskaya, Eugenia M.; Lin, P. Charles

    2009-08-01

    Purpose: To study the role of interleukin-32 (IL-32), a novel protein only detected in human tissues, in ionizing radiation (IR)-induced vascular inflammation. Methods and Materials: Irradiated (0-6 Gy) human umbilical vein endothelial cells treated with or without various agents-a cytosolic phospholipase A2 (cPLA2) inhibitor, a cyclooxygenase-2 (Cox-2) inhibitor, or lysophosphatidylcholines (LPCs)-were used to assess IL-32 expression by Northern blot analysis and quantitative reverse transcriptase-polymerase chain reaction. Expression of cell adhesion molecules and leukocyte adhesion to endothelial cells using human acute monocytic leukemia cell line (THP-1) cells was also analyzed. Results: Ionizing radiation dramatically increased IL-32 expression in vascular endothelial cells through multiple pathways. Ionizing radiation induced IL-32 expression through nuclear factor {kappa}B activation, through induction of cPLA2 and LPC, as well as induction of Cox-2 and subsequent conversion of arachidonic acid to prostacyclin. Conversely, blocking nuclear factor {kappa}B, cPLA2, and Cox-2 activity impaired IR-induced IL-32 expression. Importantly, IL-32 significantly enhanced IR-induced expression of vascular cell adhesion molecules and leukocyte adhesion on endothelial cells. Conclusion: This study identifies IL-32 as a positive regulator in IR-induced vascular inflammation, and neutralization of IL-32 may be beneficial in protecting from IR-induced inflammation.

  5. Radiation-induced DNA damage and chromatin structure

    NASA Technical Reports Server (NTRS)

    Rydberg, B.; Chatterjee, A. (Principal Investigator)

    2001-01-01

    DNA lesions induced by ionizing radiation in cells are clustered and not randomly distributed. For low linear energy transfer (LET) radiation this clustering occurs mainly on the small scales of DNA molecules and nucleosomes. For example, experimental evidence suggests that both strands of DNA on the nucleosomal surface can be damaged in single events and that this damage occurs with a 10-bp modulation because of protection by histones. For high LET radiation, clustering also occurs on a larger scale and depends on chromatin organization. A particularly significant clustering occurs when an ionizing particle traverses the 30 nm chromatin fiber with generation of heavily damaged DNA regions with an average size of about 2 kbp. On an even larger scale, high LET radiation can produce several DNA double-strand breaks in closer proximity than expected from randomness. It is suggested that this increases the probability of misrejoining of DNA ends and generation of lethal chromosome aberrations.

  6. Factors that modify risks of radiation-induced cancer

    SciTech Connect

    Fabrikant, J.I.

    1988-11-01

    The collective influence of biologic and physical factors that modify risks of radiation-induced cancer introduces uncertainties sufficient to deny precision of estimates of human cancer risk that can be calculated for low-dose radiation in exposed populations. The important biologic characteristics include the tissue sites and cell types, baseline cancer incidence, minimum latent period, time-to-tumor recognition, and the influence of individual host (age and sex) and competing etiologic influences. Physical factors include radiation dose, dose rate, and radiation quality. Statistical factors include time-response projection models, risk coefficients, and dose-response relationships. Other modifying factors include other carcinogens, and other biological sources (hormonal status, immune status, hereditary factors).

  7. Radiation Induced Cystitis and Proctitis - Prediction, Assessment and Management.

    PubMed

    Mallick, Supriya; Madan, Renu; Julka, Pramod K; Rath, Goura K

    2015-01-01

    Cystitis and proctitis are defined as inflammation of bladder and rectum respectively. Haemorrhagic cystitis is the most severe clinical manifestation of radiation and chemical cystitis. Radiation proctitis and cystitis are major complications following radiotherapy. Prevention of radiation-induced haemorrhagic cystitis has been investigated using various oral agents with minimal benefit. Bladder irrigation remains the most frequently adopted modality followed by intra-vesical instillation of alum or formalin. In intractable cases, surgical intervention is required in the form of diversion ureterostomy or cystectomy. Proctitis is more common in even low dose ranges but is self-limiting and improves on treatment interruption. However, treatment of radiation proctitis is broadly non-invasive or invasive. Non-invasive treatment consists of non-steroid anti-inflammatory drugs (NSAIDs), anti-oxidants, sucralfate, short chain fatty acids and hyperbaric oxygen. Invasive treatment consists of ablative procedures like formalin application, endoscopic YAG laser coagulation or argon plasma coagulation and surgery as a last resort.

  8. The Dose Window for Radiation-Induced Protective Adaptive Responses

    PubMed Central

    Mitchel, Ronald E. J.

    2009-01-01

    Adaptive responses to low doses of low LET radiation occur in all organisms thus far examined, from single cell lower eukaryotes to mammals. These responses reduce the deleterious consequences of DNA damaging events, including radiation-induced or spontaneous cancer and non-cancer diseases in mice. The adaptive response in mammalian cells and mammals operates within a certain window that can be defined by upper and lower dose thresholds, typically between about 1 and 100 mGy for a single low dose rate exposure. However, these thresholds for protection are not a fixed function of total dose, but also vary with dose rate, additional radiation or non-radiation stressors, tissue type and p53 functional status. Exposures above the upper threshold are generally detrimental, while exposures below the lower threshold may or may not increase either cancer or non-cancer disease risk. PMID:20585438

  9. Radiation-induced DNA damage and chromatin structure

    NASA Technical Reports Server (NTRS)

    Rydberg, B.; Chatterjee, A. (Principal Investigator)

    2001-01-01

    DNA lesions induced by ionizing radiation in cells are clustered and not randomly distributed. For low linear energy transfer (LET) radiation this clustering occurs mainly on the small scales of DNA molecules and nucleosomes. For example, experimental evidence suggests that both strands of DNA on the nucleosomal surface can be damaged in single events and that this damage occurs with a 10-bp modulation because of protection by histones. For high LET radiation, clustering also occurs on a larger scale and depends on chromatin organization. A particularly significant clustering occurs when an ionizing particle traverses the 30 nm chromatin fiber with generation of heavily damaged DNA regions with an average size of about 2 kbp. On an even larger scale, high LET radiation can produce several DNA double-strand breaks in closer proximity than expected from randomness. It is suggested that this increases the probability of misrejoining of DNA ends and generation of lethal chromosome aberrations.

  10. Pulsed radiation-induced attenuation in certain optical fibers

    SciTech Connect

    Weiss, J.D. )

    1992-05-01

    Using the X-ray pulse from the HERMES II simulation machine at Sandia National Laboratories, the pulsed radiation-induced attenuation was measured in two optical fibers considered to be 'nonrad-hard': the 50-micron-core, graded-index fiber from Corning and the plastic (PMMA) fiber from the Mitsubishi Rayon Company. These fibers were exposed to radiation up to doses of 19.5 and 28 krad(Si), respectively. In addition, fits of their post-radiation recovery were made to the geminate recombination model, from which the recombination-rate and generation constants, characteristic of this theory, were determined. These parameters should be useful in determining the response of the fibers to radiation conditions other than those encountered here. 18 refs.

  11. Radiation-induced mutagenicity and lethality in Salmonella typhimurium

    SciTech Connect

    Isildar, M.; Bakale, G.

    1983-01-01

    The mutagenic and lethal effects of ionizing radiation on histidine-deficient auxotrophs of Salmonella typhimurium were studied to improve the understanding of radiation damage to DNA. The auxotrophs were divided into two groups - one which is sensitive to base-pair substitutions and another sensitive to frameshifts. These groups were composed of parent-daughter pairs in which the chemical mutagenicity enhancing plasmid, pKM101, is absent in the parent strain and present in the daughter. Co-60 ..gamma..-radiation and 250 kV x-rays were used to irradiate the bacteria. Irradiation of the frameshift - sensitive strains which carry the pKm101 plasmid doubled the absolute number of induced revertants whereas irradiation of the base-pair substitution sensitive strain which also carries the pKm101 plasmid produced nearly no change in the number of induced revertants. A nearly negligible effect on the mutation rate was observed for all parent strains. (ACR)

  12. Radiation-induced decomposition of explosives under extreme conditions

    SciTech Connect

    Giefers, Hubertus; Pravica, Michael; Yang, Wenge; Liermann, Peter

    2008-11-03

    We present high-pressure and high temperature studies of the synchrotron radiation-induced decomposition of powder secondary high explosives pentaerythritol tetranitrate (PETN) and 1,3,5-triamino-2,4,6-trinitrobenzene (TATB) using white beam synchrotron radiation at the 16 BM-B and 16 BM-D sectors of the HP-CAT beamline at the Advanced Photon Source. The radiation-induced decomposition rate TATB showed dramatic slowing with pressure up to 26.6 GPa (the highest pressure studied), implying a positive activation volume of the activated complex. The decomposition rate of PETN varied little with pressure up to 15.7 GPa (the highest pressure studied). Diffraction line intensities were measured as a function of time using energy-dispersive methods. By measuring the decomposition rate as a function of pressure and temperature, kinetic and other constants associated with the decomposition reactions were extracted.

  13. Radioadaptive response for protection against radiation-induced teratogenesis.

    PubMed

    Okazaki, Ryuji; Ootsuyama, Akira; Norimura, Toshiyuki

    2005-03-01

    To clarify the characteristics of the radioadaptive response in mice, we compared the incidence of radiation-induced malformations in ICR mice. Pregnant ICR mice were exposed to a priming dose of 2 cGy (667 muGy/min) on day 9.5 of gestation and to a challenging dose of 2 Gy (1.04 Gy/min) 4 h later and were killed on day 18.5 of gestation. The incidence of malformations and prenatal death and fetal body weights were studied. The incidence of external malformations was significantly lower (by approximately 10%) in the primed (2 cGy + 2 Gy) mice compared to the unprimed (2 Gy alone) mice. However, there were no differences in the incidence of prenatal death or the skeletal malformations or the body weights between primed and unprimed mice. These results suggest that primary conditioning with low doses of radiation suppresses radiation-induced teratogenesis.

  14. Modulation of radiation-induced hemopoietic suppression by acute thrombocytopenia

    SciTech Connect

    Ebbe, S.; Phalen, E.; Threatte, G.; Londe, H.