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mitochondria and cardiotoxity

Chowdhury S Abdullah, Shafiul Alam, Richa Aishwarya, Sumitra Miriyala, Mohammad Alfrad Nobel Bhuiyan, Manikandan Panchatcharam, Christopher B Pattillo, A Wayne Orr, Junichi Sadoshima, Joseph A Hill, Md Shenuarin Bhuiyan
Doxorubicin (Dox) is a highly effective anticancer drug but cause acute ventricular dysfunction, and also induce late-onset cardiomyopathy and heart failure. Despite extensive studies, the pathogenic sequelae leading to the progression of Dox-associated cardiomyopathy remains unknown. We assessed temporal changes in autophagy, mitochondrial dynamics, and bioenergetics in mouse models of acute and chronic Dox-cardiomyopathy. Time course study of acute Dox-treatment showed accumulation of LC3B II in heart lysates...
February 14, 2019: Scientific Reports
Meric A Altinoz, Aysel Ozpinar
The transcription factor, PPARδ is involved in suppressing inflammation, stimulating oligodendroglial biogenesis and myelination. Furthermore, activation of PPARδ directly protects mitochondria against noxious stimuli and stimulates biogenesis of new mitochondria. PPARδ activation directly inhibits neuronal cell death and reduces both the level and neurotoxicity of Amyloid-β fibers in Alzheimer's Disease (AD) models. Among the important ligands of PPARδ is erucic acid (EA, 22:1 n9), an edible omega-9 fatty acid and a component of Lorenzo's oil, which is used in the treatment of adrenoleukodystrophy (ALD)...
February 7, 2019: International Immunopharmacology
Xuexian Fang, Hao Wang, Dan Han, Enjun Xie, Xiang Yang, Jiayu Wei, Shanshan Gu, Feng Gao, Nali Zhu, Xiangju Yin, Qi Cheng, Pan Zhang, Wei Dai, Jinghai Chen, Fuquan Yang, Huang-Tian Yang, Andreas Linkermann, Wei Gu, Junxia Min, Fudi Wang
Heart disease is the leading cause of death worldwide. A key pathogenic factor in the development of lethal heart failure is loss of terminally differentiated cardiomyocytes. However, mechanisms of cardiomyocyte death remain unclear. Here, we discovered and demonstrated that ferroptosis, a programmed iron-dependent cell death, as a mechanism in murine models of doxorubicin (DOX)- and ischemia/reperfusion (I/R)-induced cardiomyopathy. In canonical apoptosis and/or necroptosis-defective Ripk3 -/- , Mlkl -/- , or Fadd -/- Mlkl -/- mice, DOX-treated cardiomyocytes showed features of typical ferroptotic cell death...
January 28, 2019: Proceedings of the National Academy of Sciences of the United States of America
Xuanying Chen, Xiaoping Peng, Yong Luo, Jiegen You, Dong Yin, Qiang Xu, Huan He, Ming He
Cardiotoxicity limits the clinical applications of doxorubicin (Dox), which mechanism might be excess generation of intracellular ROS. Quercetin (Que) is a flavonoid that possesses anti-oxidative activities, exerts myocardial protection. We hypothesized that the cardioprotection against Dox injury of Que involved 14-3-3γ, and mitochondria. To investigate the hypothesis, we treated primary cardiomyocytes with Dox and determined the effects of Que pretreatment with or without 14-3-3γ knockdown. We analyzed various cellular and molecular indexes...
January 14, 2019: Toxicology Mechanisms and Methods
Mengmeng Huang, Fanghuan Zhu, Jingjing Jiao, Jun Wang, Yu Zhang
Acrylamide (AA), a ubiquitous chemical that is present in surrounding environment and baked or fried carbohydrate-rich food, has recently been linked to cardiac developmental toxicity. However, the toxicological role of AA exposure in the cardiac development remains largely unknown. Here we showed the cardiotoxicity of AA and its role in cardiomyocyte interactions in zebrafish embryos during ventricular morphogenesis. Using the embryo model of transgenic zebrafish Tg(Tp1:d2GFP;myl7:mCherry), we found AA interfered the dynamics of Notch signaling in the endocardium during early cardiogenesis...
March 15, 2019: Science of the Total Environment
Samukelisiwe C Shabalala, Phiwayinkosi V Dludla, Christo J F Muller, Xolisa Nxele, Abidemi P Kappo, Johan Louw, Rabia Johnson
Aspalathin (ASP) is a C-dihydrochalcone abundantly found in Aspalathus linearis. While we have provide evidence that ASP can protect H9c2 cardiomyoblasts against doxorubicin (Dox)-induced apoptosis through regulation of autophagy, the complete mechanism involved in the cardioprotective effect of this dihydrochalcone remains to be explored. Here we provide evidence that ASP reverses Dox-induced apoptosis through the amelioration of oxidative stress in H9c2 cardiomyoblasts. Cultured cells were treated with 0...
December 19, 2018: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Taiyi Wang, Xiaonan Chen, Jiahui Yu, Qunqun Du, Jie Zhu, Mingzhu Yang, Honghua Wu, Meng Wang, Yan Zhu
Although the efficacy and the health care advantages of Chinese herbal medicine (CHM) have become increasingly recognized worldwide, the potential side effects and toxicity still restrict its broader application. This study established and applied an integrated platform anchored on automatic patch clamp system to screen and evaluate a collection of CHM extracts, compositions and monomeric compounds for in vitro cardiac toxicity. Of 1036 CHM samples screened, 2.79% significantly inhibited hERG channel activity...
December 14, 2018: American Journal of Chinese Medicine
Guo-Xing Wan, Lan Cheng, Hai-Lun Qin, Yun-Zhang Zhang, Ling-Yu Wang, Yong-Gang Zhang
The wide use of anthracyclines represented by doxorubicin (DOX) has benefited cancer patients, yet the clinical application is limited due to its cardiotoxicity. Although numerous evidences have supported a role of microRNAs (miRNAs) in DOX-induced myocardial damage, the exact etiology and pathogenesis remain largely obscure. In this study, we focused on the role of miR-15b-5p in DOX-induced cardiotoxicity. We employed a public miRNA and gene microarray to screen differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) in rat cardiomyocytes, and 33 DEMs including miR-15b-5p and 237 DEGs including Bmpr1a and Gata4 were identified...
December 7, 2018: Cardiovascular Toxicology
Payal Rana, Michael D Aleo, Mark Gosink, Yvonne Will
Mitochondrial toxicity has been shown to contribute to a variety of organ toxicities such as liver, cardiac and kidney. In the past decades, two high throughput applicable screening assays (isolated rat liver mitochondria; glucose-galactose grown HepG2 cells) to assess mitochondrial toxicity have been deployed in many pharmaceutical companies and numerous publications have demonstrated its usefulness for mechanistic investigations. However, only two publications have demonstrated the utility of these screens as a predictor of human drug induced liver injury...
December 10, 2018: Chemical Research in Toxicology
Siwen Li, Hongjing Zhao, Yu Wang, Yizhi Shao, Juanjuan Liu, Mingwei Xing
Arsenic-based drugs as food additive were used in poultry. However, excessive arsenic exposure can disturb myocardial cell metabolism, which results in the inhibition of growth and development of chickens. Since disordered mitochondria influences cardiac physiology and pathology, a better understanding of the mechanisms modulating cardiomyocyte mitochondria process is critical for identifying the potent detoxication targets under arsenic exposure in chickens. Male Hy-line chickens (1-day-old) were fed either a basal diet or an arsenic trioxide (As2O3)-supplemented diet containing 7...
October 18, 2018: Poultry Science
Adam J Smith, Peter J Gawne, Michelle T Ma, Philip J Blower, Richard Southworth, Nicholas J Long
Radiolabelled lipophilic cations that accumulate in mitochondria according to the magnitude of the mitochondrial membrane potential can be used to report non-invasively on mitochondrial dysfunction in cardiovascular disease, cardiotoxicity, and cancer. While several such cations are already commercially available for SPECT imaging, PET offers greater promise in terms of sensitivity, resolution, and capacity for dynamic imaging and pharmacokinetic modelling. We have therefore synthesised a series of three triarylphosphonium-functionalised DO3A chelators for positron emitter gallium-68, with differing alkyl-functionalisation motifs to provide opportunities for tunable lipophilicity as a means of optimising their pharmacokinetics...
October 17, 2018: Dalton Transactions: An International Journal of Inorganic Chemistry
Rui Song, Yurong Yang, Han Lei, Guangxue Wang, Yong Huang, Wenlong Xue, Yinfang Wang, Lingling Yao, Yichun Zhu
Doxorubicin (Dox) is an efficacious antineoplastic drug but is limited used for its cardiotoxicity. Histone Deacetylase 6 (HDAC6) has been indicated to participate in cardiomyopathies, however, its role in Dox-induced cardiac injury is largely unknown. In this study, we firstly aimed to determine the role of HDAC6 in Dox-induced cardiomyopathy. Immunoblotting revealed that Dox increased HDAC6 protein level and activity and decreased α-tubulin acetylation level in vitro and vivo. HDAC6 knockout (HDAC6-/- ) mice showed obvious anti-Dox cardiotoxicity by conserved cardiac function monitored by echocardiography and the protection was reversed by Nocodazole, one drug lowering α-tubulin acetylation...
October 10, 2018: Journal of Molecular and Cellular Cardiology
Wen-Juan Li, Xian-Yi Zhang, Rui-Ting Wu, Ye-Hao Song, Ming-Yong Xie
The present study aimed to determine the cardioprotective effect of Ganoderma atrum polysaccharide (PSG-1) in doxorubicin (DOX)-treated mice and its underlying mechanism. Results indicated that PSG-1 treatment significantly alleviated DOX-induced myocardial damage via attenuating apoptosis and maintaining the structure of myocardial mitochondria. Meanwhile, PSG-1-evoked cardioprotection was associated with an increase of manganese superoxide dismutase activity and decrease of caspases activities. Moreover, administration of PSG-1 suppressed DOX-induced mitochondrial disorders, which was evidenced by reducing reactive oxygen species, elevating mitochondrial membrane potential and inhibiting the opening of mitochondrial permeability transition pore...
December 15, 2018: Carbohydrate Polymers
Jun Li, Ran Duan, Yingying Zhang, Xin Zhao, Yanxin Cheng, Yongxue Chen, Jinge Yuan, Hong Li, Jianping Zhang, Li Chu, Dengyun Xia, Senming Zhao
In order to determine the role of the adrenergic system in bupivacaine-induced cardiotoxicity, a series of experiments were performed. In an animal experiment, male Sprague-Dawley (SD) rats under chloral hydrate anesthesia received intravenous bupivacaine, followed by an intravenous injection of adrenalin or isoprenalin, and the electrocardiogram (ECG), left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), the maximum rate of rise of left ventricular pressure (+dP/dtmax) and the maximum rate of pressure decrease (-dP/dtmax) were continually monitored...
2018: PloS One
Philippe Hantson
BACKGROUND: Dilated cardiomyopathy is a frequent disease responsible for 40-50% of cases of heart failure. Idiopathic cardiomyopathy is a primary disorder often related to familial/genetic predisposition. Before the diagnosis of idiopathic cardiomyopathy is made, clinicians must not only rule out viral and immune causes, but also toxic causes such as drugs, environmental agents, illicit substances and natural toxins. OBJECTIVE: The objective of this review is to present recent data on the mechanisms underlying toxic cardiomyopathy...
September 27, 2018: Clinical Toxicology
Ting Chen, Zhiyong Deng, Ruilian Zhao, Hongmei Shen, Wenhui Li
Backgrounds. Doxorubicin (DOX) is an effective therapeutic drug for malignant tumors; however, its clinical applications were limited by its side effects, especially the cardiotoxicity caused by ROS-mediated p53 and MAPK signal pathways' activation-induced cell apoptosis. Sanyang Xuedai mixture (SYKT) has been reported as an antioxidant agent and attenuated DOX-induced cardiotoxicity by targeting ROS-mediated apoptosis, but the mechanisms are still not fully delineated. Objective. This study aimed at investigating whether SYKT alleviated DOX-induced cardiotoxicity by inhibiting ROS-mediated apoptosis and elucidating the role of ROS-mediated p53 and MAPK signal pathways' activation in this process...
2018: Evidence-based Complementary and Alternative Medicine: ECAM
Xilei Xie, Fuyan Tang, Guangzhao Liu, Yong Li, Xingxing Su, Xiaoyun Jiao, Xu Wang, Bo Tang
Anthracyclines rank among the most efficacious anticancer medications. However, their clinical utility and oncologic efficacy are severely compromised by the cardiotoxicity risk facing the early-diagnosis difficulty and their unclear molecular mechanism. Herein, a two-photon-excitable and near-infrared-emissive fluorescent probe, TPNIR-FP, was fabricated and endowed with extraordinary specificity and sensitivity and a rapid response toward peroxynitrite (ONOO- ), as well as mitochondria-targeting ability. With the aid of TPNIR-FP, we demonstrate that mitochondrial ONOO- is upregulated in the early stage and contributes to the onset and progression of anthracycline cardiotoxicity in cardiomyocyte and mouse models; therefore, it represents an early biomarker to predict subclinical cardiotoxicity induced by drug challenge...
October 2, 2018: Analytical Chemistry
Meric A Altinoz, Ayhan Bilir, İlhan Elmaci
BACKGROUND: PPAR-δ is a transcription factor which has crucial roles in stimulating oligodendroglial differentiation and myelination and its activation was also shown to differentiate malignant C6 glioma cells into oligodendrocytes. OBJECTIVE: One of the ligands of PPAR-δ is erucic acid (EA), an edible omega-9 fatty acid consumed more by Asian populations and exists highly in Chinese womens milk. There exist epidemiological evidence that pediatric brain tumor incidence is among the lowest in the Chinese population...
October 1, 2018: Chemico-biological Interactions
Huan He, Yong Luo, Yang Qiao, Zeyu Zhang, Dong Yin, Jianguo Yao, Jiegen You, Ming He
Doxorubicin (Dox) induces cardiotoxicity, thereby limiting its clinical application for chemotherapy of cancer. The mechanism of cardiotoxicity includes the production of excess intracellular ROS. 14-3-3s have been found to protect the myocardium against various types of injury. Curcumin (Cur) is a polyphenolic compound that is derived from turmeric and has multiple bioactivities, including anti-oxidative and radical-scavenging activities that exert cytoprotection. We hypothesize that the cardioprotective effects of Cur are exerted by regulating 14-3-3γ...
August 15, 2018: Food & Function
Xibo Jing, Jingxiao Yang, Lu Jiang, Jianghong Chen, Haiyan Wang
BACKGROUND/AIMS: Myocardial apoptosis plays an important role in doxorubicin (Dox) cardiotoxicity. MicroRNA-29 (miR-29) is suggested to function as an anti-fibrotic factor with potential therapeutic effects on cardiac fibrosis. However, it has not been shown whether there is an association between miR-29b and myocardial apoptosis. METHODS: Male Wistar rats were transfected with miR-29b agomir by local delivery to the myocardium prior to Dox treatment. Rat cardiomyocytes were pretreated with miR-29b mimics or inhibitor followed by Dox incubation in vitro...
2018: Cellular Physiology and Biochemistry
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