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Xiong W, Li B, Pan J, Li D, Yuan H, Wan X, Zhang Y, Fu L, Zhang J, Lei M, Chang ACY. Mitochondrial Amount Determines Doxorubicin-Induced Cardiotoxicity in Cardiomyocytes. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2412017. [PMID: 39921259 PMCID: PMC11948046 DOI: 10.1002/advs.202412017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 12/30/2024] [Indexed: 02/10/2025]
Abstract
Doxorubicin, an anthracycline commonly used for treating cancer patients, is known for its cardiotoxic side-effects. Although dose-dependent, but susceptibility remains variable among patients, and childhood-exposure-adult-onset remains challenging. Besides topoisomerase toxicity, Doxorubicin is also toxic to the mitochondria yet the underlying late onset mechanism remains elusive. Here, it is observed that the mitochondrial copy number in PBMCs of patients treated with anthracycline chemotherapy is negatively correlated with the change in plasma BNP levels after treatment. Isogenic hiPSC-CMs are generated with high, norm, and low mitochondrial copy numbers using mitochondrial transplantation and the YFP-Parkin system. Remarkably, lower mitochondria copy number translates to lower IC50, suggesting increased susceptibility. Mitochondria supplementation by intramyocardial injection prevents doxorubicin induced heart failure. Mechanistically, doxorubicin treatment leads to mPTP opening and mitochondrial DNA (mtDNA) leakage. This mtDNA leakage event activates the cGAS-STING pathway and drives inflammation and myocardial senescence. Cardiomyocyte-specific knockout of Sting (Myh6-Cre/Stingflox/flox; StingCKO) and over expression of mitochondrial tagged DNase1 in mice partially rescue doxorubicin-induced cardiac dysfunction. In conclusion, the work establishes a negative correlation between cardiomyocyte mitochondrial copy number and doxorubicin toxicity. Molecularly, it is demonstrated that mtDNA leakage activates cGAS-STING pathway and accelerates myocardial dysfunction. These insights offer new co-administration strategies for cancer patients.
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Affiliation(s)
- Weiyao Xiong
- Department of CardiologyShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghai200011China
- Shanghai Institute of Precision MedicineShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghai200125China
| | - Bin Li
- Department of CardiologyShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghai200011China
- Shanghai Institute of Precision MedicineShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghai200125China
| | - Jianan Pan
- Department of CardiologyShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghai200011China
| | - Dongjiu Li
- Department of CardiologyShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghai200011China
| | - Haihua Yuan
- Department of OncologyShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghai200011China
| | - Xin Wan
- Department of CardiologyShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghai200011China
- Shanghai Institute of Precision MedicineShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghai200125China
| | - Yanjie Zhang
- Department of OncologyShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghai200011China
| | - Lijun Fu
- Department of CardiologyShanghai Children's Medical CentreShanghai Jiao Tong University School of MedicineShanghai200127China
| | - Junfeng Zhang
- Department of CardiologyShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghai200011China
| | - Ming Lei
- Shanghai Institute of Precision MedicineShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghai200125China
| | - Alex Chia Yu Chang
- Department of CardiologyShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghai200011China
- Shanghai Institute of Precision MedicineShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghai200125China
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Liu X, Li Z. The role and mechanism of epigenetics in anticancer drug-induced cardiotoxicity. Basic Res Cardiol 2025; 120:11-24. [PMID: 38724618 DOI: 10.1007/s00395-024-01054-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 04/20/2024] [Accepted: 05/03/2024] [Indexed: 05/23/2024]
Abstract
Cardiovascular disease is the main factor contributing to the global burden of diseases, and the cardiotoxicity caused by anticancer drugs is an essential component that cannot be ignored. With the development of anticancer drugs, the survival period of cancer patients is prolonged; however, the cardiotoxicity caused by anticancer drugs is becoming increasingly prominent. Currently, cardiovascular disease has emerged as the second leading cause of mortality among long-term cancer survivors. Anticancer drug-induced cardiotoxicity has become a frontier and hot topic. The discovery of epigenetics has given the possibility of environmental changes in gene expression, protein synthesis, and traits. It has been found that epigenetics plays a pivotal role in promoting cardiovascular diseases, such as heart failure, coronary heart disease, and hypertension. In recent years, increasing studies have underscored the crucial roles played by epigenetics in anticancer drug-induced cardiotoxicity. Here, we provide a comprehensive overview of the role and mechanisms of epigenetics in anticancer drug-induced cardiotoxicity.
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Affiliation(s)
- Xuening Liu
- Department of Pharmacy, Peking University Third Hospital, Beijing, 100191, China
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Zijian Li
- Department of Pharmacy, Peking University Third Hospital, Beijing, 100191, China.
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China.
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Al Khafaji AT, Barakat AM, Shayyal AJ, Taan AA, Aboqader Al-Aouadi RF. Managing Doxorubicin Cardiotoxicity: Insights Into Molecular Mechanisms and Protective Strategies. J Biochem Mol Toxicol 2025; 39:e70155. [PMID: 39887483 DOI: 10.1002/jbt.70155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 12/30/2024] [Accepted: 01/16/2025] [Indexed: 02/01/2025]
Abstract
Cancer ranks as the second leading cause of death in the United States and poses a significant health challenge globally. Numerous therapeutic options exist for treating cancer, with chemotherapy being one of the most prominent. Chemotherapy involves the use of antineoplastic drugs, either alone or in combination with other medications, to target and kill cancer cells. However, these drugs can also adversely affect healthy cells, leading to various side effects. Among the most commonly used chemotherapy agents are anthracyclines, which include doxorubicin, daunorubicin, and epirubicin. Doxorubicin is particularly notable for its effectiveness but is also associated with significant cardiotoxicity, a common concern for patients undergoing chemotherapy. Unfortunately, there is currently no definitive treatment to prevent or reverse this cardiotoxicity. The cardiac effects of doxorubicin can manifest in several ways, including changes in electrocardiograms, arrhythmias, myocarditis, pericarditis, myocardial infarction, cardiomyopathy, heart failure, and congestive heart failure. These complications may arise during treatment, shortly after it concludes, or even weeks later. Various mechanisms have been proposed to explain doxorubicin-induced cardiotoxicity. Key factors include the inhibition of topoisomerase IIβ, mitochondrial damage, reactive oxygen species (ROS) production due to iron metabolism, increased oxidative stress, heightened inflammatory responses, and elevated rates of apoptosis and necrosis within cardiac tissue. This review article will provide a comprehensive overview of the current state of knowledge regarding doxorubicin-induced cardiomyopathy. We will explore the underlying molecular mechanisms contributing to this condition and discuss emerging therapeutic strategies aimed at mitigating its impact on cancer survivors.
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Affiliation(s)
| | | | | | - Ali Adnan Taan
- Nasr City Hospital for Health Insurance, Ministry of Health, Cairo, Egypt
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Zheng Y, Fang Y, Luo Y, Fan Y, Fang Z. Qianyang yuyin granule ameliorates mitochondrial dysfunction of hypertensive myocardial remodeling. JOURNAL OF ETHNOPHARMACOLOGY 2024; 335:118610. [PMID: 39047880 DOI: 10.1016/j.jep.2024.118610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 07/16/2024] [Accepted: 07/21/2024] [Indexed: 07/27/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Clinical studies have found that Qianyang Yuyin granule (QYYYG), a kind of oral Chinese patent medicine, had definite clinical effect for hypertensive myocardial remodeling. However, the potential mechanism is not entirely clear. AIM OF THE STUDY The purpose of this research was to explore the underlying mechanism QYYYG on the treatment of hypertensive myocardial remodeling. MATERIALS AND METHODS Analysis the transcriptome data from the NCBI public platform GEO database and our study to explore the key pathological change of myocardial tissues in hypertensive mice and the main pathway of QYYYG in treating hypertensive myocardial remodeling. Network pharmacological analysis was used to predict the potential target of QYYYG. The molecular docking and molecular dynamics simulation was used for molecular binding analysis of specific compounds and target proteins. In the experiment in vivo, the effect of QYYYG on hypertensive myocardial remodeling and myocardial mitochondrial dysfunction in hypertensive mice caused by Ang Ⅱ was estimated. In the experiment in vitro, the Ang Ⅱ-induced myocardial remodeling model in H9c2 cells was constructed, and the effect of QYYYG on ameliorating myocardial remodeling and mitochondrial dysfunction was evaluated. RESULTS Transcriptome analysis suggested that mitochondrial dysfunction was a key pathological change of myocardial tissues in hypertensive mice, and QYYYG could improve hypertensive myocardial remodeling through enhancing mitochondrial biogenesis to repair myocardial mitochondrial dysfunction. Network pharmacological analysis predicted that SIRT1 was an important potential target of QYYYG in treating hypertensive myocardial remodeling, and basically all the active components, especially quercetin, had a great binding affinity with SIRT1. Experiments in vivo proved that QYYYG had great efficacy hypertensive myocardial remodeling in Ang Ⅱ-treated mice. It was found that QYYYG improved the quality and quantity of mitochondria, and increased SIRT1 levels in myocardial tissue of Ang Ⅱ-treated mice. In Ang Ⅱ-treated H9c2 cells, with intervention of QYYYG, myocardial remodeling and myocardial mitochondrial dysfunction was ameliorated. In addition, QYYYG up-regulated SIRT1 expression and enhanced mitochondrial biogenesis in Ang Ⅱ-treated H9c2 cells. CONCLUSION This study suggested that mitochondrial dysfunction was an important pathological change of myocardial tissues in hypertensive mice. QYYYG might ameliorate the mitochondrial dysfunction of hypertensive myocardial remodeling through up-regulating SIRT1 expression to enhance the mitochondrial biogenesis.
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Affiliation(s)
- Yawei Zheng
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China; Nanjing University of Chinese Medicine, Nanjing, China
| | - Yuan Fang
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China; Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Yu Luo
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China; Nanjing University of Chinese Medicine, Nanjing, China
| | - Yadong Fan
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China; Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Zhuyuan Fang
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China; Jiangsu Province Hospital of Chinese Medicine, Nanjing, China; Nanjing University of Chinese Medicine, Nanjing, China.
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Maiese K. Cardiovascular and nonalcoholic fatty liver disease: Sharing common ground through SIRT1 pathways. World J Cardiol 2024; 16:632-643. [PMID: 39600987 PMCID: PMC11586725 DOI: 10.4330/wjc.v16.i11.632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Revised: 08/27/2024] [Accepted: 10/10/2024] [Indexed: 10/30/2024] Open
Abstract
As a non-communicable disease, cardiovascular disorders have become the leading cause of death for men and women. Of additional concern is that cardiovascular disease is linked to chronic comorbidity disorders that include nonalcoholic fatty liver disease (NAFLD). NAFLD, also termed metabolic-dysfunction-associated steatotic liver disease, is the greatest cause of liver disease throughout the world, increasing in prevalence concurrently with diabetes mellitus (DM), and can progress to nonalcoholic steatohepatitis that leads to cirrhosis and liver fibrosis. Individuals with metabolic disorders, such as DM, are more than two times likely to experience cardiac disease, stroke, and liver disease that includes NAFLD when compared individuals without metabolic disorders. Interestingly, cardiovascular disorders and NAFLD share a common underlying cellular mechanism for disease pathology, namely the silent mating type information regulation 2 homolog 1 (SIRT1; Saccharomyces cerevisiae). SIRT1, a histone deacetylase, is linked to metabolic pathways through nicotinamide adenine dinucleotide and can offer cellular protection though multiple avenues, including trophic factors such as erythropoietin, stem cells, and AMP-activated protein kinase. Translating SIRT1 pathways into clinical care for cardiovascular and hepatic disease can offer significant hope for patients, but further insights into the complexity of SIRT1 pathways are necessary for effective treatment regimens.
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Affiliation(s)
- Kenneth Maiese
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20810, United States.
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Packer M, Ferreira JP, Butler J, Filippatos G, Januzzi JL, González Maldonado S, Panova-Noeva M, Pocock SJ, Prochaska JH, Saadati M, Sattar N, Sumin M, Anker SD, Zannad F. Reaffirmation of Mechanistic Proteomic Signatures Accompanying SGLT2 Inhibition in Patients With Heart Failure: A Validation Cohort of the EMPEROR Program. J Am Coll Cardiol 2024; 84:1979-1994. [PMID: 39217550 DOI: 10.1016/j.jacc.2024.07.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 07/17/2024] [Accepted: 07/18/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert a distinctive pattern of direct biological effects on the heart and kidney under experimental conditions, but the meaningfulness of these signatures for patients with heart failure has not been fully defined. OBJECTIVES We performed the first mechanistic validation study of large-scale proteomics in a double-blind randomized trial of any treatment in patients with heart failure. METHODS In a discovery cohort from the EMPEROR (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure and Reduced Ejection Fraction) program, we studied the effect of randomized treatment with placebo or empagliflozin on 1,283 circulating proteins in 1,134 patients with heart failure with a reduced or preserved ejection fraction. In a validation cohort, we expanded the number to 2,155 assessed proteins, which were measured in 1,120 EMPEROR participants who had not been studied previously. RESULTS In the validation cohort, 25 proteins were the most differentially enriched by empagliflozin (ie, ≥15% between-group difference and false discovery rate <1% at 12 weeks with known effects on the heart or kidney): 1) 13 proteins promote autophagy and other cellular quality-control functions (IGFBP1, OTUB1, DNAJB1, DNAJC9, RBP2, IST1, HSPA8, H-FABP, FABP6, ATPIFI, TfR1, EPO, IGBP1); 2) 12 proteins enhance mitochondrial health and ATP production (UMtCK, TBCA, L-FABP, H-FABP, FABP5, FABP6, RBP2, IST1, HSPA8, ATPIFI, TfR1, EPO); 3) 7 proteins augment cellular iron mobilization or erythropoiesis (TfR1, EPO, IGBP1, ERMAP, UROD, ATPIF1, SNCA); 4) 3 proteins influence renal tubular sodium handling; and 5) 9 proteins have restorative effects in the heart or kidneys, with many proteins exerting effects in >1 domain. These biological signatures replicated those observed in our discovery cohort. When the threshold for a meaningful between-group difference was lowered to ≥10%, there were 58 additional differentially enriched proteins with actions on the heart and kidney, but the biological signatures remained the same. CONCLUSIONS The replication of mechanistic signatures across discovery and validation cohorts closely aligns with the experimental effects of SGLT2 inhibitors. Thus, the actions of SGLT2 inhibitors-to promote autophagy, restore mitochondrial health and production of ATP, promote iron mobilization and erythropoiesis, influence renal tubular ion reabsorption, and normalize cardiac and renal structure and function-are likely to be relevant to patients with heart failure. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction [EMPEROR-Preserved], NCT03057951; EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced], NCT03057977).
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Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas, USA; Imperial College London, London, United Kingdom.
| | - João Pedro Ferreira
- UnIC@RISE, Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal; Baylor Scott and White Research Institute, Dallas, Texas, USA
| | - Javed Butler
- Baylor Scott and White Research Institute, Dallas, Texas, USA; University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Gerasimos Filippatos
- National and Kapodistrian University of Athens School of Medicine, Athens University Hospital Attikon, Athens, Greece
| | - James L Januzzi
- National and Kapodistrian University of Athens School of Medicine, Athens University Hospital Attikon, Athens, Greece; Massachusetts General Hospital and Baim Institute for Clinical Research, Boston, Massachusetts, USA
| | | | - Marina Panova-Noeva
- Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany; Center for Thrombosis and Haemostasis, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany
| | - Stuart J Pocock
- London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Jürgen H Prochaska
- Boehringer Ingelheim International GmbH, Ingelheim, Germany; Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Maral Saadati
- Elderbrook Solutions GmbH, on behalf of Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Germany
| | - Naveed Sattar
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Mikhail Sumin
- Boehringer Ingelheim International GmbH, Ingelheim, Germany
| | - Stefan D Anker
- Department of Cardiology (CVK) of German Heart Center Charité, Institute of Health Center for Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin, Berlin, Germany
| | - Faiez Zannad
- Centre d'Investigations Cliniques Plurithématique 1433, INSERM, Université de Lorraine, Nancy, France; F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), INSERM U1116, Centre Hospitalier Régional Universitaire de Nancy, Nancy, France
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Liu X, Ge S, Zhang A. Pediatric Cardio-Oncology: Screening, Risk Stratification, and Prevention of Cardiotoxicity Associated with Anthracyclines. CHILDREN (BASEL, SWITZERLAND) 2024; 11:884. [PMID: 39062333 PMCID: PMC11276082 DOI: 10.3390/children11070884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 07/02/2024] [Accepted: 07/16/2024] [Indexed: 07/28/2024]
Abstract
Anthracyclines have significantly improved the survival of children with malignant tumors, but the associated cardiotoxicity, an effect now under the purview of pediatric cardio-oncology, due to its cumulative and irreversible effects on the heart, limits their clinical application. A systematic screening and risk stratification approach provides the opportunity for early identification and intervention to mitigate, reverse, or prevent myocardial injury, remodeling, and dysfunction associated with anthracyclines. This review summarizes the risk factors, surveillance indexes, and preventive strategies of anthracycline-related cardiotoxicity to improve the safety and efficacy of anthracyclines.
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Affiliation(s)
- Xiaomeng Liu
- Department of Pediatrics, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Shuping Ge
- Department of Pediatric and Adult Congenital Cardiology, Geisinger Clinic, Danville, PA 17822, USA
| | - Aijun Zhang
- Department of Pediatrics, Qilu Hospital of Shandong University, Jinan 250012, China
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Chen Y, Tu Y, Du L, Nan R, Ren Y. Warming Yang Promoting Blood Circulation and Diuresis Alleviates Myocardial Damage by Inhibiting Collagen Fiber and Myocardial Fibrosis and Attenuating Mitochondria Signaling Pathway Mediated Apoptosis in Chronic Heart Failure Rats. TOHOKU J EXP MED 2024; 263:141-150. [PMID: 38522897 DOI: 10.1620/tjem.2024.j022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/26/2024]
Abstract
Warming Yang promoting blood circulation and diuresis (WYPBD) has been proven effective in treating some diseases. This study aimed to evaluate therapeutic effect of WYPBD in treating chronic heart failure (CHF). CHF rats were established by intraperitoneally injecting doxorubicin (DOX). Therapeutic effects of WYPBD on cardiac function and hemodynamic parameters of myocardial tissues were analyzed. Collagen fiber production and myocardial fibrosis were evaluated. Transcriptions of COL1A1 gene, COL3A1 gene, and TGFB1 gene were evaluated with RT-PCR. Expression of BNP, AVP, PARP, caspase-3, and Bcl-2 in myocardial tissues were evaluated. TUNEL assay was used to identify apoptosis of cardiomyocytes. WYPBD alleviated degree of myocardial hypertrophy in CHF rats compared to the rats in CHF model group (P < 0.05). WYPBD significantly improved cardiac hemodynamics (increased LVEF and LVSF) of CHF rats compared to rats in the CHF model group (P < 0.05). WYPBD protected myocardial structure and inhibited collagen fiber production in myocardial tissues of CHF rats. WYPBD markedly decreased myocardial fibrosis mediators (Col1α, Col3α, TGF-β1) transcription in myocardial tissues of CHF rats compared to rats in CHF model group (P < 0.05). WYPBD significantly reduced BNP and AVP expression in myocardial tissues of CHF rats compared to rats in the CHF model group (P < 0.05). WYPBD markedly reduced the expression of PRAP and caspase-3, and increased Bcl-2 expression in myocardial tissues of CHF rats compared to rats in the CHF model group (P < 0.05). In conclusion, WYPBD alleviated CHF myocardial damage by inhibiting collagen fiber and myocardial fibrosis, attenuating apoptosis associated with the mitochondria signaling pathway of cardiomyocytes.
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Affiliation(s)
- Yong Chen
- Department of Classical Chinese Medicine, Chongqing Hospital of Traditional Chinese Medicine
| | - Yadan Tu
- Department of Classical Chinese Medicine, Chongqing Hospital of Traditional Chinese Medicine
| | - Lei Du
- Department of Classical Chinese Medicine, Chongqing Hospital of Traditional Chinese Medicine
| | - Ruixue Nan
- Department of Classical Chinese Medicine, Chongqing Hospital of Traditional Chinese Medicine
| | - Yi Ren
- Department of Classical Chinese Medicine, Chongqing Hospital of Traditional Chinese Medicine
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Wang Q, Zhu K, Zhang A. SIRT1-mediated tunnelling nanotubes may be a potential intervention target for arsenic-induced hepatocyte senescence and liver damage. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 947:174502. [PMID: 38971248 DOI: 10.1016/j.scitotenv.2024.174502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 06/03/2024] [Accepted: 07/02/2024] [Indexed: 07/08/2024]
Abstract
Arsenic, a widespread environmental poison, can cause significant liver damage upon exposure. Mitochondria are the most sensitive organelles to external factors. Dysfunctional mitochondria play a crucial role in cellular senescence and liver damage. Tunnelling nanotubes (TNTs), membrane structures formed between cells, with fibrous actin (F-actin) serving as the scaffold, facilitate mitochondrial transfer between cells. Notably, TNTs mediate the delivery of healthy mitochondria to damaged cells, thereby mitigating cellular damage. Although limited studies have suggested that F-actin may be modulated by the longevity gene SIRT1, the association between arsenic-induced liver damage and this mechanism remains unexplored. The findings of the current study indicate that arsenic suppresses SIRT1 and F-actin in the rat liver and MIHA cells, impeding the formation of TNTs and mitochondrial transfer between MIHA cells, thereby playing a pivotal role in mitochondrial dysfunction, cellular senescence and liver damage induced by arsenic. Notably, increasing SIRT1 levels effectively mitigated liver mitochondrial dysfunction and cellular senescence triggered by arsenic, highlighting SIRT1's crucial regulatory function. This research provides novel insights into the mechanisms underlying arsenic-induced liver damage, paving the way for the development of targeted preventive and therapeutic drugs to address arsenic-induced liver damage.
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Affiliation(s)
- Qi Wang
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang 561113, Guizhou, People's Republic of China; Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases, Co-Constructed by the Province and Ministry, Guizhou Medical University, Guiyang 561113, Guizhou, People's Republic of China
| | - Kai Zhu
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang 561113, Guizhou, People's Republic of China
| | - Aihua Zhang
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang 561113, Guizhou, People's Republic of China; Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases, Co-Constructed by the Province and Ministry, Guizhou Medical University, Guiyang 561113, Guizhou, People's Republic of China.
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Maiese K. The impact of aging and oxidative stress in metabolic and nervous system disorders: programmed cell death and molecular signal transduction crosstalk. Front Immunol 2023; 14:1273570. [PMID: 38022638 PMCID: PMC10663950 DOI: 10.3389/fimmu.2023.1273570] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Accepted: 10/23/2023] [Indexed: 12/01/2023] Open
Abstract
Life expectancy is increasing throughout the world and coincides with a rise in non-communicable diseases (NCDs), especially for metabolic disease that includes diabetes mellitus (DM) and neurodegenerative disorders. The debilitating effects of metabolic disorders influence the entire body and significantly affect the nervous system impacting greater than one billion people with disability in the peripheral nervous system as well as with cognitive loss, now the seventh leading cause of death worldwide. Metabolic disorders, such as DM, and neurologic disease remain a significant challenge for the treatment and care of individuals since present therapies may limit symptoms but do not halt overall disease progression. These clinical challenges to address the interplay between metabolic and neurodegenerative disorders warrant innovative strategies that can focus upon the underlying mechanisms of aging-related disorders, oxidative stress, cell senescence, and cell death. Programmed cell death pathways that involve autophagy, apoptosis, ferroptosis, and pyroptosis can play a critical role in metabolic and neurodegenerative disorders and oversee processes that include insulin resistance, β-cell function, mitochondrial integrity, reactive oxygen species release, and inflammatory cell activation. The silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), AMP activated protein kinase (AMPK), and Wnt1 inducible signaling pathway protein 1 (WISP1) are novel targets that can oversee programmed cell death pathways tied to β-nicotinamide adenine dinucleotide (NAD+), nicotinamide, apolipoprotein E (APOE), severe acute respiratory syndrome (SARS-CoV-2) exposure with coronavirus disease 2019 (COVID-19), and trophic factors, such as erythropoietin (EPO). The pathways of programmed cell death, SIRT1, AMPK, and WISP1 offer exciting prospects for maintaining metabolic homeostasis and nervous system function that can be compromised during aging-related disorders and lead to cognitive impairment, but these pathways have dual roles in determining the ultimate fate of cells and organ systems that warrant thoughtful insight into complex autofeedback mechanisms.
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Affiliation(s)
- Kenneth Maiese
- Innovation and Commercialization, National Institutes of Health, Bethesda, MD, United States
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Khalifa AA, Ali MA, Elsokkary NH, Elblehi SS, El-Mas MM. Mitochondrial modulation of amplified preconditioning influences of remote ischemia plus erythropoietin against skeletal muscle ischemia/reperfusion injury in rats. Life Sci 2023; 329:121979. [PMID: 37516431 DOI: 10.1016/j.lfs.2023.121979] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 07/17/2023] [Accepted: 07/23/2023] [Indexed: 07/31/2023]
Abstract
AIMS Skeletal muscle ischemia and reperfusion (S-I/R) injury is relieved by interventions like remote ischemic preconditioning (RIPC). Here, we tested the hypothesis that simultaneous exposure to a minimal dose of erythropoietin (EPO) boosts the protection conferred by RIPC against S-I/R injury and concomitant mitochondrial oxidative and apoptotic defects. MAIN METHODS S-I/R injury was induced in rats by 3-h right hindlimb ischemia followed by 3-h of reperfusion, whereas RIPC involved 3 brief consecutive I/R cycles of the contralateral hindlimb. KEY FINDINGS S-I/R injury caused (i) rises in serum lactate dehydrogenase and creatine kinase and falls in serum pyruvate, (ii) structural deformities like sarcoplasm vacuolations, segmental necrosis, and inflammatory cells infiltration, and (iii) decreased amplitude and increased duration of electromyography action potentials. These defects were partially ameliorated by RIPC and dose-dependently by EPO (500 or 5000 IU/kg). Further, greater repairs of S-I/R-evoked damages were seen after prior exposure to the combined RIPC/EPO-500 intervention. The latter also caused more effective (i) preservation of mitochondrial number (confocal microscopy assessed Mitotracker red staining) and function (citrate synthase activity), (ii) suppression of mitochondrial DNA damage and indices of oxidative stress and apoptosis (succinate dehydrogenase, myeloperoxidase, cardiolipin, and cytochrome c), (iii) preventing calcium and nitric oxide metabolites (NOx) accumulation and glycogen consumption, and (iv) upregulating EPO receptors (EPO-R) gene expression. SIGNIFICANCE dual RIPC/EPO conditioning exceptionally mends structural, functional, and neuronal deficits caused by I/R injury and interrelated mitochondrial oxidative and apoptotic damage. Clinically, the utilization of relatively low EPO doses could minimize the hormone-related adverse effects.
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Affiliation(s)
- Asmaa A Khalifa
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt.
| | - Mennatallah A Ali
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt.
| | - Nahed H Elsokkary
- Department of Physiology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Samar S Elblehi
- Department of Pathology, Faculty of Veterinary Medicine, Alexandria University, Edfina, Behera, Egypt.
| | - Mahmoud M El-Mas
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt; Department of Pharmacology and Toxicology, College of Medicine, Kuwait University, Kuwait.
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Baena-Montes JM, Kraśny MJ, O’Halloran M, Dunne E, Quinlan LR. In Vitro Models for Improved Therapeutic Interventions in Atrial Fibrillation. J Pers Med 2023; 13:1237. [PMID: 37623487 PMCID: PMC10455620 DOI: 10.3390/jpm13081237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/28/2023] [Accepted: 08/01/2023] [Indexed: 08/26/2023] Open
Abstract
Atrial fibrillation is the most common type of cardiac arrhythmias in humans, mostly caused by hyper excitation of specific areas in the atrium resulting in dyssynchronous atrial contractions, leading to severe consequences such as heart failure and stroke. Current therapeutics aim to target this condition through both pharmacological and non-pharmacological approaches. To test and validate any of these treatments, an appropriate preclinical model must be carefully chosen to refine and optimise the therapy features to correctly reverse this condition. A broad range of preclinical models have been developed over the years, with specific features and advantages to closely mimic the pathophysiology of atrial fibrillation. In this review, currently available models are described, from traditional animal models and in vitro cell cultures to state-of-the-art organoids and organs-on-a-chip. The advantages, applications and limitations of each model are discussed, providing the information to select the appropriate model for each research application.
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Affiliation(s)
- Jara M. Baena-Montes
- Physiology and Cellular Physiology Research Laboratory, School of Medicine, Human Biology Building, University of Galway, H91 TK33 Galway, Ireland
| | - Marcin J. Kraśny
- Smart Sensors Lab, Lambe Institute for Translational Research, School of Medicine, University of Galway, H91 TK33 Galway, Ireland
- Translational Medical Device Lab (TMDLab), Lambe Institute for Translational Research, School of Medicine, University of Galway, H91 TK33 Galway, Ireland
| | - Martin O’Halloran
- Translational Medical Device Lab (TMDLab), Lambe Institute for Translational Research, School of Medicine, University of Galway, H91 TK33 Galway, Ireland
- Electrical & Electronic Engineering, School of Engineering, University of Galway, H91 TK33 Galway, Ireland
| | - Eoghan Dunne
- Translational Medical Device Lab (TMDLab), Lambe Institute for Translational Research, School of Medicine, University of Galway, H91 TK33 Galway, Ireland
| | - Leo R. Quinlan
- Physiology and Cellular Physiology Research Laboratory, School of Medicine, Human Biology Building, University of Galway, H91 TK33 Galway, Ireland
- CÚRAM SFI Centre for Research in Medical Devices, University of Galway, H91 TK33 Galway, Ireland
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Zhang Q, Zhang Y, Xie B, Liu D, Wang Y, Zhou Z, Zhang Y, King E, Tse G, Liu T. Resveratrol activation of SIRT1/MFN2 can improve mitochondria function, alleviating doxorubicin-induced myocardial injury. CANCER INNOVATION 2023; 2:253-264. [PMID: 38089747 PMCID: PMC10686119 DOI: 10.1002/cai2.64] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 02/28/2023] [Accepted: 03/08/2023] [Indexed: 10/11/2023]
Abstract
BACKGROUND Doxorubicin is a widely used cytotoxic chemotherapy agent for treating different malignancies. However, its use is associated with dose-dependent cardiotoxicity, causing irreversible myocardial damage and significantly reducing the patient's quality of life and survival. In this study, an animal model of doxorubicin-induced cardiomyopathy was used to investigate the pathogenesis of doxorubicin-induced myocardial injury. This study also investigated a possible treatment strategy for alleviating myocardial injury through resveratrol therapy in vitro. METHODS Adult male C57BL/6J mice were randomly divided into a control group and a doxorubicin group. Body weight, echocardiography, surface electrocardiogram, and myocardial histomorphology were measured. The mechanisms of doxorubicin cardiotoxicity in H9c2 cell lines were explored by comparing three groups (phosphate-buffered saline, doxorubicin, and doxorubicin with resveratrol). RESULTS Compared to the control group, the doxorubicin group showed a lower body weight and higher systolic arterial pressure, associated with reduced left ventricular ejection fraction and left ventricular fractional shortening, prolonged PR interval, and QT interval. These abnormalities were associated with vacuolation and increased disorder in the mitochondria of cardiomyocytes, increased protein expression levels of α-smooth muscle actin and caspase 3, and reduced protein expression levels of Mitofusin2 (MFN2) and Sirtuin1 (SIRT1). Compared to the doxorubicin group, doxorubicin + resveratrol treatment reduced caspase 3 and manganese superoxide dismutase, and increased MFN2 and SIRT1 expression levels. CONCLUSION Doxorubicin toxicity leads to abnormal mitochondrial morphology and dysfunction in cardiomyocytes and induces apoptosis by interfering with mitochondrial fusion. Resveratrol ameliorates doxorubicin-induced cardiotoxicity by activating SIRT1/MFN2 to improve mitochondria function.
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Affiliation(s)
- Qingling Zhang
- Department of Cardiology, Tianjin Key Laboratory of Ionic‐Molecular Function of Cardiovascular Disease, Tianjin Institute of CardiologyThe Second Hospital of Tianjin Medical UniversityTianjinChina
| | - Yunpeng Zhang
- Department of Cardiology, Tianjin Key Laboratory of Ionic‐Molecular Function of Cardiovascular Disease, Tianjin Institute of CardiologyThe Second Hospital of Tianjin Medical UniversityTianjinChina
| | - Bingxin Xie
- Department of Cardiology, Tianjin Key Laboratory of Ionic‐Molecular Function of Cardiovascular Disease, Tianjin Institute of CardiologyThe Second Hospital of Tianjin Medical UniversityTianjinChina
| | - Daiqi Liu
- Department of Cardiology, Tianjin Key Laboratory of Ionic‐Molecular Function of Cardiovascular Disease, Tianjin Institute of CardiologyThe Second Hospital of Tianjin Medical UniversityTianjinChina
| | - Yueying Wang
- Department of Cardiology, Tianjin Key Laboratory of Ionic‐Molecular Function of Cardiovascular Disease, Tianjin Institute of CardiologyThe Second Hospital of Tianjin Medical UniversityTianjinChina
| | - Zandong Zhou
- Department of Cardiology, Tianjin Key Laboratory of Ionic‐Molecular Function of Cardiovascular Disease, Tianjin Institute of CardiologyThe Second Hospital of Tianjin Medical UniversityTianjinChina
| | - Yue Zhang
- Department of Cardiology, Tianjin Key Laboratory of Ionic‐Molecular Function of Cardiovascular Disease, Tianjin Institute of CardiologyThe Second Hospital of Tianjin Medical UniversityTianjinChina
| | - Emma King
- Epidemiology Research Unit, Cardiovascular Analytics GroupChina‐UK CollaborationHong KongChina
| | - Gary Tse
- Department of Cardiology, Tianjin Key Laboratory of Ionic‐Molecular Function of Cardiovascular Disease, Tianjin Institute of CardiologyThe Second Hospital of Tianjin Medical UniversityTianjinChina
- Epidemiology Research Unit, Cardiovascular Analytics GroupChina‐UK CollaborationHong KongChina
- Kent and Medway Medical SchoolCanterburyKentUK
| | - Tong Liu
- Department of Cardiology, Tianjin Key Laboratory of Ionic‐Molecular Function of Cardiovascular Disease, Tianjin Institute of CardiologyThe Second Hospital of Tianjin Medical UniversityTianjinChina
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Packer M. SGLT2 inhibitors: role in protective reprogramming of cardiac nutrient transport and metabolism. Nat Rev Cardiol 2023; 20:443-462. [PMID: 36609604 DOI: 10.1038/s41569-022-00824-4] [Citation(s) in RCA: 88] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/29/2022] [Indexed: 01/09/2023]
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce heart failure events by direct action on the failing heart that is independent of changes in renal tubular function. In the failing heart, nutrient transport into cardiomyocytes is increased, but nutrient utilization is impaired, leading to deficient ATP production and the cytosolic accumulation of deleterious glucose and lipid by-products. These by-products trigger downregulation of cytoprotective nutrient-deprivation pathways, thereby promoting cellular stress and undermining cellular survival. SGLT2 inhibitors restore cellular homeostasis through three complementary mechanisms: they might bind directly to nutrient-deprivation and nutrient-surplus sensors to promote their cytoprotective actions; they can increase the synthesis of ATP by promoting mitochondrial health (mediated by increasing autophagic flux) and potentially by alleviating the cytosolic deficiency in ferrous iron; and they might directly inhibit glucose transporter type 1, thereby diminishing the cytosolic accumulation of toxic metabolic by-products and promoting the oxidation of long-chain fatty acids. The increase in autophagic flux mediated by SGLT2 inhibitors also promotes the clearance of harmful glucose and lipid by-products and the disposal of dysfunctional mitochondria, allowing for mitochondrial renewal through mitochondrial biogenesis. This Review describes the orchestrated interplay between nutrient transport and metabolism and nutrient-deprivation and nutrient-surplus signalling, to explain how SGLT2 inhibitors reverse the profound nutrient, metabolic and cellular abnormalities observed in heart failure, thereby restoring the myocardium to a healthy molecular and cellular phenotype.
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Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular Institute, Dallas, TX, USA.
- Imperial College London, London, UK.
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15
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Li K, Gao L, Zhou S, Ma YR, Xiao X, Jiang Q, Kang ZH, Liu ML, Liu TX. Erythropoietin promotes energy metabolism to improve LPS-induced injury in HK-2 cells via SIRT1/PGC1-α pathway. Mol Cell Biochem 2023; 478:651-663. [PMID: 36001204 DOI: 10.1007/s11010-022-04540-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 08/08/2022] [Indexed: 11/25/2022]
Abstract
Acute kidney injury (AKI) is one of frequent complications of sepsis with high mortality. Mitochondria is the center of energy metabolism participating in the pathogenesis of sepsis-associated AKI, and SIRT1/PGC1-α signaling pathway plays a crucial role in the modulation of energy metabolism. Erythropoietin (EPO) exerts protective functions on chronic kidney disease. We aimed to assess the effects of EPO on cell damage and energy metabolism in a cell model of septic AKI. Renal tubular epithelial cells HK-2 were treated with LPS and human recombinant erythropoietin (rhEPO). Cell viability was detected by CCK-8 and mitochondrial membrane potential was determined using JC-1 fluorescent probe. Then the content of ATP, ADP and NADPH, as well as lactic acid, were measured for the assessment of energy metabolism. Oxidative stress was evaluated by detecting the levels of ROS, MDA, SOD and GSH. Pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, were measured with ELISA. Moreover, qRT-PCR and western blot were performed to detect mRNA and protein expressions. shSIRT1 was used to knockdown SIRT1, while EX527 and SR-18292 were applied to inhibit SIRT1 and PGC1-α, respectively, to investigate the regulatory mechanism of rhEPO on inflammatory injury and energy metabolism. In LPS-exposed HK-2 cells, rhEPO attenuated cell damage, inflammation and abnormal energy metabolism, as indicated by the elevated cell viability, the inhibited oxidative stress, cell apoptosis and inflammation, as well as the increased mitochondrial membrane potential and energy metabolism. However, these protective effects induced by rhEPO were reversed after SIRT1 or PGC1-α inhibition. EPO activated SIRT1/PGC1-α pathway to alleviate LPS-induced abnormal energy metabolism and cell damage in HK-2 cells. Our study suggested that rhEPO played a renoprotective role through SIRT1/PGC1-α pathway, which supported its therapeutic potential in septic AKI.
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Affiliation(s)
- Kan Li
- Department of Nephrology, The First Hospital of Lanzhou University, No.1 Donggangxi Road, Chengguan District, Lanzhou, 730000, Gansu Province, China
| | - Li Gao
- Department of Gynaecology, The First Hospital of Lanzhou University, Lanzhou, 730000, Gansu Province, China
| | - Sen Zhou
- Department of Nephrology, The First Hospital of Lanzhou University, No.1 Donggangxi Road, Chengguan District, Lanzhou, 730000, Gansu Province, China
| | - Yan-Rong Ma
- Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, 730000, Gansu Province, China
| | - Xiao Xiao
- The First Clinical Medical School of Lanzhou University, Lanzhou, 730000, Gansu Province, China
| | - Qian Jiang
- The First Clinical Medical School of Lanzhou University, Lanzhou, 730000, Gansu Province, China
| | - Zhi-Hong Kang
- The First Clinical Medical School of Lanzhou University, Lanzhou, 730000, Gansu Province, China
| | - Ming-Long Liu
- Department of Nephrology, The First Hospital of Lanzhou University, No.1 Donggangxi Road, Chengguan District, Lanzhou, 730000, Gansu Province, China
| | - Tian-Xi Liu
- Department of Nephrology, The First Hospital of Lanzhou University, No.1 Donggangxi Road, Chengguan District, Lanzhou, 730000, Gansu Province, China.
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Pharmacological Activation of Rev-erb α Attenuates Doxorubicin-Induced Cardiotoxicity by PGC-1 α Signaling Pathway. Cardiovasc Ther 2023; 2023:2108584. [PMID: 36874248 PMCID: PMC9977526 DOI: 10.1155/2023/2108584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 01/12/2023] [Accepted: 01/27/2023] [Indexed: 02/24/2023] Open
Abstract
Background Doxorubicin-induced cardiotoxicity has been closely concerned in clinical practice. Rev-erbα is a transcriptional repressor that emerges as a drug target for heart diseases recently. This study is aimed at investigating the role and mechanism of Rev-erbα in doxorubicin-induced cardiotoxicity. Methods H9c2 cells were treated with 1.5 μM doxorubicin, and C57BL/6 mice were treated with a 20 mg/kg cumulative dose of doxorubicin to construct doxorubicin-induced cardiotoxicity models in vitro and in vivo. Agonist SR9009 was used to activate Rev-erbα. PGC-1α expression level was downregulated by specific siRNA in H9c2 cells. Cell apoptosis, cardiomyocyte morphology, mitochondrial function, oxidative stress, and signaling pathways were measured. Results SR9009 alleviated doxorubicin-induced cell apoptosis, morphological disorder, mitochondrial dysfunction, and oxidative stress in H9c2 cells and C57BL/6 mice. Meanwhile, PGC-1α and downstream signaling NRF1, TAFM, and UCP2 expression levels were preserved by SR9009 in doxorubicin-treated cardiomyocytes in vitro and in vivo. When downregulating PGC-1α expression level by specific siRNA, the protective role of SR9009 in doxorubicin-treated cardiomyocytes was attenuated with increased cell apoptosis, mitochondrial dysfunction, and oxidative stress. Conclusion Pharmacological activation of Rev-erbα by SR9009 could attenuate doxorubicin-induced cardiotoxicity through preservation of mitochondrial function and alleviation of apoptosis and oxidative stress. The mechanism is associated with the activation of PGC-1α signaling pathways, suggesting that PGC-1α signaling is a mechanism for the protective effect of Rev-erbα against doxorubicin-induced cardiotoxicity.
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Wu L, Wang L, Du Y, Zhang Y, Ren J. Mitochondrial quality control mechanisms as therapeutic targets in doxorubicin-induced cardiotoxicity. Trends Pharmacol Sci 2023; 44:34-49. [PMID: 36396497 DOI: 10.1016/j.tips.2022.10.003] [Citation(s) in RCA: 122] [Impact Index Per Article: 61.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/21/2022] [Accepted: 10/25/2022] [Indexed: 11/16/2022]
Abstract
Doxorubicin (DOX) is a chemotherapeutic drug that is utilized for solid tumors and hematologic malignancies, but its clinical application is hampered by life-threatening cardiotoxicity including cardiac dilation and heart failure. Mitochondrial quality control processes, including mitochondrial proteostasis, mitophagy, and mitochondrial dynamics and biogenesis, serve to maintain mitochondrial homeostasis in the cardiovascular system. Importantly, recent advances have unveiled a major role for defective mitochondrial quality control in the etiology of DOX cardiomyopathy. Moreover, specific interventions targeting these quality control mechanisms to preserve mitochondrial function have emerged as potential therapeutic strategies to attenuate DOX cardiotoxicity. However, clinical translation is challenging because of obscure mechanisms of action and potential adverse effects. The purpose of this review is to provide new insights regarding the role of mitochondrial quality control in the pathogenesis of DOX cardiotoxicity, and to explore promising therapeutic approaches targeting these mechanisms to aid clinical management.
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Affiliation(s)
- Lin Wu
- Department of Cardiology and Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Litao Wang
- Department of Cardiology and Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yuxin Du
- Department of Cardiology and Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yingmei Zhang
- Department of Cardiology and Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jun Ren
- Department of Cardiology and Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
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18
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Liang Z, He Y, Hu X. Cardio-Oncology: Mechanisms, Drug Combinations, and Reverse Cardio-Oncology. Int J Mol Sci 2022; 23:10617. [PMID: 36142538 PMCID: PMC9501315 DOI: 10.3390/ijms231810617] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/07/2022] [Accepted: 09/08/2022] [Indexed: 11/16/2022] Open
Abstract
Chemotherapy, radiotherapy, targeted therapy, and immunotherapy have brought hope to cancer patients. With the prolongation of survival of cancer patients and increased clinical experience, cancer-therapy-induced cardiovascular toxicity has attracted attention. The adverse effects of cancer therapy that can lead to life-threatening or induce long-term morbidity require rational approaches to prevention and treatment, which requires deeper understanding of the molecular biology underpinning the disease. In addition to the drugs used widely for cardio-protection, traditional Chinese medicine (TCM) formulations are also efficacious and can be expected to achieve "personalized treatment" from multiple perspectives. Moreover, the increased prevalence of cancer in patients with cardiovascular disease has spurred the development of "reverse cardio-oncology", which underscores the urgency of collaboration between cardiologists and oncologists. This review summarizes the mechanisms by which cancer therapy induces cardiovascular toxicity, the combination of antineoplastic and cardioprotective drugs, and recent advances in reverse cardio-oncology.
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Affiliation(s)
| | | | - Xin Hu
- China–Japan Union Hospital of Jilin University, Jilin University, Changchun 130033, China
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19
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Zannad F, Ferreira JP, Butler J, Filippatos G, Januzzi JL, Sumin M, Zwick M, Saadati M, Pocock SJ, Sattar N, Anker SD, Packer M. Effect of empagliflozin on circulating proteomics in heart failure: mechanistic insights into the EMPEROR programme. Eur Heart J 2022; 43:4991-5002. [PMID: 36017745 PMCID: PMC9769969 DOI: 10.1093/eurheartj/ehac495] [Citation(s) in RCA: 105] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/15/2022] [Accepted: 08/25/2022] [Indexed: 01/12/2023] Open
Abstract
AIMS Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in diverse patient populations, but their mechanism of action requires further study. The aim is to explore the effect of empagliflozin on the circulating levels of intracellular proteins in patients with heart failure, using large-scale proteomics. METHODS AND RESULTS Over 1250 circulating proteins were measured at baseline, Week 12, and Week 52 in 1134 patients from EMPEROR-Reduced and EMPEROR-Preserved, using the Olink® Explore 1536 platform. Statistical and bioinformatical analyses identified differentially expressed proteins (empagliflozin vs. placebo), which were then linked to demonstrated biological actions in the heart and kidneys. At Week 12, 32 of 1283 proteins fulfilled our threshold for being differentially expressed, i.e. their levels were changed by ≥10% with a false discovery rate <1% (empagliflozin vs. placebo). Among these, nine proteins demonstrated the largest treatment effect of empagliflozin: insulin-like growth factor-binding protein 1, transferrin receptor protein 1, carbonic anhydrase 2, erythropoietin, protein-glutamine gamma-glutamyltransferase 2, thymosin beta-10, U-type mitochondrial creatine kinase, insulin-like growth factor-binding protein 4, and adipocyte fatty acid-binding protein 4. The changes of the proteins from baseline to Week 52 were generally concordant with the changes from the baseline to Week 12, except empagliflozin reduced levels of kidney injury molecule-1 by ≥10% at Week 52, but not at Week 12. The most common biological action of differentially expressed proteins appeared to be the promotion of autophagic flux in the heart, kidney or endothelium, a feature of 6 proteins. Other effects of differentially expressed proteins on the heart included the reduction of oxidative stress, inhibition of inflammation and fibrosis, and the enhancement of mitochondrial health and energy, repair, and regenerative capacity. The actions of differentially expressed proteins in the kidney involved promotion of autophagy, integrity and regeneration, suppression of renal inflammation and fibrosis, and modulation of renal tubular sodium reabsorption. CONCLUSIONS Changes in circulating protein levels in patients with heart failure are consistent with the findings of experimental studies that have shown that the effects of SGLT2 inhibitors are likely related to actions on the heart and kidney to promote autophagic flux, nutrient deprivation signalling and transmembrane sodium transport.
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Affiliation(s)
- Faiez Zannad
- Corresponding author. Tel: +33 3 83 15 73 15, Fax: +33 3 83 15 73 24, Emails: ;
| | - João Pedro Ferreira
- Corresponding author. Tel: +33 3 83 15 73 15, Fax: +33 3 83 15 73 24, Emails: ;
| | - Javed Butler
- Heart and Vascular Research, Baylor Scott and White Research Institute, 34 Live Oak St Ste 501, Dallas, TX 75204, USA,University of Mississippi Medical Center, 2500 North State Street Jackson, MS 39216, USA
| | - Gerasimos Filippatos
- Heart Failure Unit, National and Kapodistrian University of Athens School of Medicine, Mikras Asias 75, Athina 115 27 Athens, Greece
| | - James L Januzzi
- Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, Boston, MA 02114USA,The Baim Institute for Clinical Research, 930 Commonwealth Ave #3, Boston, MA 02215USA
| | - Mikhail Sumin
- Boehringer Ingelheim International GmbH, Binger Str. 173, 55218 Ingelheim am RheinGermany
| | - Matthias Zwick
- Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88400 Biberach an der RissGermany
| | - Maral Saadati
- Elderbrook Solutions GmbH on behalf of Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88400 Biberach an der Riss, Germany
| | - Stuart J Pocock
- London School of Hygiene and Tropical Medicine, Keppel St, London WC1E 7HTUK
| | - Naveed Sattar
- BHF, UK School of Cardiovascular and Metabolic Health, University of Glasgow, 126 University Place, Glasgow G12 8TAUK
| | - Stefan D Anker
- Department of Cardiology (CVK) Berlin Institute of Health Center for Regenerative Therapies (BCRT) German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin Berlin, Charité, Campus Virchow-Klinikum, Augustenburger Platz 1, D-13353 Berlin, Germany,Institute of Heart Diseases, Wroclaw Medical University, Borowska Street 213, 50-556 Warsaw, Poland
| | - Milton Packer
- Baylor Heart and Vascular Hospital, Baylor University Medical Center, 621 N Hall St, Dallas, TX 75226, USA,Imperial College, London, Exhibition Rd, South Kensington, London SW7 2BX, UK
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Bhullar KS, Ashkar F, Wu J. Peptides GWN and GW protect kidney cells against Dasatinib induced mitochondrial injury in a SIRT1 dependent manner. FOOD CHEMISTRY. MOLECULAR SCIENCES 2022; 4:100069. [PMID: 35415678 PMCID: PMC8991994 DOI: 10.1016/j.fochms.2021.100069] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 12/21/2021] [Accepted: 12/23/2021] [Indexed: 01/10/2023]
Abstract
Dasatinib, a small-molecule drug used as a treatment for chronic myeloid leukemia induces mitochondrial damage in embryonic kidney (293 T) cells (p < 0.05). This dasatinib induced mitochondrial injury in kidney cells was mitigated by H3K36me3 activating ovotransferrin-derived peptides GWN and GW. Pre-treatment of kidney cells with GWN and GW lead to elevation of cytoprotective sirtuins, SIRT1 and SIRT3, in response to dasatinib injury (p < 0.01) in vitro. Both peptides, GWN and GW, also reversed dasatinib induced the loss of mitochondria in kidney cells and promoted the protein expression of COX4 (p < 0.01). Mechanistically, loss of SIRT1 in kidney cells abolished the ability of GWN and GW to protect embryonic kidney cells against dasatinib injury in vitro. Overall, we provide cell based evidence showing that GWN and GW exhibit the ability to protect mitochondria against dasatinib-induced mitochondrial damage in a SIRT1 dependent manner.
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Affiliation(s)
- Khushwant S Bhullar
- Department of Agricultural, Food, and Nutritional Science, University of Alberta, Edmonton, AB, Canada.,Department of Pharmacology, University of Alberta, Edmonton, AB, Canada
| | - Fatemeh Ashkar
- Department of Agricultural, Food, and Nutritional Science, University of Alberta, Edmonton, AB, Canada
| | - Jianping Wu
- Department of Agricultural, Food, and Nutritional Science, University of Alberta, Edmonton, AB, Canada
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21
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Benjanuwattra J, Apaijai N, Chunchai T, Singhanat K, Arunsak B, Intachai K, Chattipakorn SC, Chattipakorn N. The temporal impact of erythropoietin administration on mitochondrial function and dynamics in cardiac ischemia/reperfusion injury. Exp Mol Pathol 2022; 127:104802. [DOI: 10.1016/j.yexmp.2022.104802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 04/24/2022] [Accepted: 06/01/2022] [Indexed: 11/28/2022]
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22
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Yi X, Yan W, Guo T, Liu N, Wang Z, Shang J, Wei X, Cui X, Sun Y, Ren S, Chen L. Erythropoietin Mitigates Diabetic Nephropathy by Restoring PINK1/Parkin-Mediated Mitophagy. Front Pharmacol 2022; 13:883057. [PMID: 35656290 PMCID: PMC9152250 DOI: 10.3389/fphar.2022.883057] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 03/31/2022] [Indexed: 11/13/2022] Open
Abstract
Diabetic nephropathy (DN), one of the most detrimental microvascular complications of diabetes, is the leading cause of end-stage renal disease. The pathogenesis of DN is complicated, including hemodynamic changes, inflammatory response, oxidative stress, among others. Recently, many studies have demonstrated that mitophagy, especially PINK1/Parkin-mediated mitophagy, plays an important role in the pathogenesis of DN. Erythropoietin (EPO), a glycoprotein hormone mainly secreted by the kidney, regulates the production of erythrocytes. This research intends to explore the beneficial effects of EPO on DN and investigate related mechanisms. In in vitro experiments, we found that EPO promoted autophagic flux and alleviated mitochondrial dysfunction in terms of mitochondrial fragmentation, elevated mitochondrial ROS as well as the loss of mitochondrial potential, and lowered the apoptosis level in high-glucose-treated mesangial cells. Moreover, EPO increased protein expressions of PINK1 and Parkin, enhanced the co-localization of LC3 with mitochondria, Parkin with mitochondria as well as LC3 with Parkin, and increased the number of GFP-LC3 puncta, resulting in increased level of PINK1/Parkin-mediated mitophagy in mesangial cells. The knockdown of PINK1 abrogated the effect of EPO on mitophagy. In addition, in vivo experiments demonstrated that EPO attenuated renal injury, reduced oxidative stress, and promoted expressions of genes related to PINK1/Parkin-mediated mitophagy in the kidneys of DN mice. In summary, these results suggest that PINK1/Parkin-mediated mitophagy is involved in the development of DN and EPO mitigates DN by restoring PINK1/Parkin-mediated mitophagy.
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Affiliation(s)
- Xinyao Yi
- Department of Pharmacology, School of Basic Medical Sciences, Health Science Center, Xi’an Jiaotong University, Xi’an, China
| | - Wenhui Yan
- Department of Pharmacology, School of Basic Medical Sciences, Health Science Center, Xi’an Jiaotong University, Xi’an, China
| | - Tingli Guo
- Department of Pharmacology, School of Basic Medical Sciences, Health Science Center, Xi’an Jiaotong University, Xi’an, China
| | - Na Liu
- Department of Pharmacology, School of Basic Medical Sciences, Health Science Center, Xi’an Jiaotong University, Xi’an, China
| | - Zhuanzhuan Wang
- Department of Pharmacology, School of Basic Medical Sciences, Health Science Center, Xi’an Jiaotong University, Xi’an, China
| | - Jia Shang
- Department of Pharmacology, School of Basic Medical Sciences, Health Science Center, Xi’an Jiaotong University, Xi’an, China
| | - Xiaotong Wei
- Department of Pharmacology, School of Basic Medical Sciences, Health Science Center, Xi’an Jiaotong University, Xi’an, China
| | - Xin Cui
- Department of Pharmacology, School of Basic Medical Sciences, Health Science Center, Xi’an Jiaotong University, Xi’an, China
| | - Yuzhuo Sun
- Department of Pharmacology, School of Basic Medical Sciences, Health Science Center, Xi’an Jiaotong University, Xi’an, China
| | - Shuting Ren
- Department of Phathology, School of Basic Medical Sciences, Health Science Center, Xi’an Jiaotong University, Xi’an, China
| | - Lina Chen
- Department of Pharmacology, School of Basic Medical Sciences, Health Science Center, Xi’an Jiaotong University, Xi’an, China
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an Jiaotong University, Xi’an, China
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23
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Wu BB, Leung KT, Poon ENY. Mitochondrial-Targeted Therapy for Doxorubicin-Induced Cardiotoxicity. Int J Mol Sci 2022; 23:1912. [PMID: 35163838 PMCID: PMC8837080 DOI: 10.3390/ijms23031912] [Citation(s) in RCA: 96] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 01/27/2022] [Accepted: 02/01/2022] [Indexed: 01/27/2023] Open
Abstract
Anthracyclines, such as doxorubicin, are effective chemotherapeutic agents for the treatment of cancer, but their clinical use is associated with severe and potentially life-threatening cardiotoxicity. Despite decades of research, treatment options remain limited. The mitochondria is commonly considered to be the main target of doxorubicin and mitochondrial dysfunction is the hallmark of doxorubicin-induced cardiotoxicity. Here, we review the pathogenic mechanisms of doxorubicin-induced cardiotoxicity and present an update on cardioprotective strategies for this disorder. Specifically, we focus on strategies that can protect the mitochondria and cover different therapeutic modalities encompassing small molecules, post-transcriptional regulators, and mitochondrial transfer. We also discuss the shortcomings of existing models of doxorubicin-induced cardiotoxicity and explore advances in the use of human pluripotent stem cell derived cardiomyocytes as a platform to facilitate the identification of novel treatments against this disorder.
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Affiliation(s)
- Bin Bin Wu
- Centre for Cardiovascular Genomics and Medicine, Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong (CUHK), Hong Kong SAR, China;
- Hong Kong Hub of Paediatric Excellence (HK HOPE), The Chinese University of Hong Kong (CUHK), Hong Kong SAR, China;
| | - Kam Tong Leung
- Hong Kong Hub of Paediatric Excellence (HK HOPE), The Chinese University of Hong Kong (CUHK), Hong Kong SAR, China;
- Department of Paediatrics, The Chinese University of Hong Kong (CUHK), Hong Kong SAR, China
| | - Ellen Ngar-Yun Poon
- Centre for Cardiovascular Genomics and Medicine, Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong (CUHK), Hong Kong SAR, China;
- Hong Kong Hub of Paediatric Excellence (HK HOPE), The Chinese University of Hong Kong (CUHK), Hong Kong SAR, China;
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong (CUHK), Hong Kong SAR, China
- School of Biomedical Sciences, The Chinese University of Hong Kong (CUHK), Hong Kong SAR, China
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24
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Kitakata H, Endo J, Ikura H, Moriyama H, Shirakawa K, Katsumata Y, Sano M. Therapeutic Targets for DOX-Induced Cardiomyopathy: Role of Apoptosis vs. Ferroptosis. Int J Mol Sci 2022; 23:1414. [PMID: 35163335 PMCID: PMC8835899 DOI: 10.3390/ijms23031414] [Citation(s) in RCA: 82] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/20/2022] [Accepted: 01/24/2022] [Indexed: 01/04/2023] Open
Abstract
Doxorubicin (DOX) is the most widely used anthracycline anticancer agent; however, its cardiotoxicity limits its clinical efficacy. Numerous studies have elucidated the mechanisms underlying DOX-induced cardiotoxicity, wherein apoptosis has been reported as the most common final step leading to cardiomyocyte death. However, in the past two years, the involvement of ferroptosis, a novel programmed cell death, has been proposed. The purpose of this review is to summarize the historical background that led to each form of cell death, focusing on DOX-induced cardiotoxicity and the molecular mechanisms that trigger each form of cell death. Furthermore, based on this understanding, possible therapeutic strategies to prevent DOX cardiotoxicity are outlined. DNA damage, oxidative stress, intracellular signaling, transcription factors, epigenetic regulators, autophagy, and metabolic inflammation are important factors in the molecular mechanisms of DOX-induced cardiomyocyte apoptosis. Conversely, the accumulation of lipid peroxides, iron ion accumulation, and decreased expression of glutathione and glutathione peroxidase 4 are important in ferroptosis. In both cascades, the mitochondria are an important site of DOX cardiotoxicity. The last part of this review focuses on the significance of the disruption of mitochondrial homeostasis in DOX cardiotoxicity.
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Affiliation(s)
| | | | | | | | | | | | - Motoaki Sano
- Department of Cardiology, Keio University School of Medicine, Tokyo 160-8582, Japan; (H.K.); (J.E.); (H.I.); (H.M.); (K.S.); (Y.K.)
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25
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Multiple targeted doxorubicin-lonidamine liposomes modified with p-hydroxybenzoic acid and triphenylphosphonium to synergistically treat glioma. Eur J Med Chem 2021; 230:114093. [PMID: 35007860 DOI: 10.1016/j.ejmech.2021.114093] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 12/23/2021] [Accepted: 12/26/2021] [Indexed: 12/30/2022]
Abstract
A type of pH-sensitive multi-targeted brain tumor site-specific liposomes (Lip-CTPP) co-modified with p-hydroxybenzoic acid (p-HA) and triphenylphosphonium (TPP) were designed and prepared to co-load doxorubicin (DOX) and lonidamine (LND). Lip-CTPP are promising potential carriers to exert the anti-glioma effect of DOX and LND collaboratively given the following features: 1) Lip-CTPP have a good pharmacokinetic behavior; 2) Lip-CTPP can cross the blood-brain barrier (BBB) and recognize tumor cells through the affinity of p-HA and dopamine/sigma receptors; 3) Lip-CTPP are highly positive charged once the acid-sensitive amide bonds are cleaved in endo/lysosomes to expose TPP and protonate amine groups; 4) the positive charged Lip-CTPP escape from endo/lysosomes and accumulate in mitochondria through electrostatic adsorption; 5) DOX and LND are released and synergistically increase anti-tumor efficacy. Our in vitro and in vivo results confirmed that Lip-CTPP could greatly elevate the inhibition rate of tumor cell proliferation, migration and invasion, promote apoptosis and necrosis, and interfere with mitochondrial function. In addition, Lip-CTPP could significantly prolong the survival time of glioma bearing mice, narrow the tumor region and inhibit the infiltration and metastasis capability of glioma cells. Collectively, Lip-CTPP are promising nano formulations to enhance the synergistic effect of DOX and LND in glioma treatment.
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26
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Gui M, Yao L, Lu B, Wang J, Zhou X, Li J, Dong Z, Fu D. Huoxue Qianyang Qutan recipe attenuates Ang II-induced cardiomyocyte hypertrophy by regulating reactive oxygen species production. Exp Ther Med 2021; 22:1446. [PMID: 34721688 PMCID: PMC8549094 DOI: 10.3892/etm.2021.10881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 09/15/2021] [Indexed: 12/03/2022] Open
Abstract
Continuous and irreversible cardiac hypertrophy can induce cardiac maladaptation and cardiac remodeling, resulting in increased risk of developing cardiovascular diseases. The present study was conducted to investigate the therapeutic effect of Huoxue Qianyang Qutan recipe (HQQR) on angiotensin II (Ang II)-induced cardiomyocyte hypertrophy. Primary cardiomyocytes were isolated from the cardiac tissue of neonatal rats, followed by flow cytometry detection to confirm the proportion of primary cardiomyocytes. Cell Counting Kit-8 assay and immunofluorescence detection were performed to examine the effect of Ang II and HQQR on cardiomyocyte hypertrophy. Reactive oxygen species (ROS) and a series of metabolic indicators were quantified to investigate the effect of HQQR on Ang II-induced cardiomyocyte hypertrophy. Mitochondrial electron transport chain complex activity and related coding gene expression were determined to explore the effect of HQQR on mitochondrial function. HQQR significantly inhibited Ang II-induced cardiomyocyte hypertrophy and restored Ang II-induced ROS accumulation, metabolic indicators, and membrane potential levels. HQQR also regulated the mitochondrial function related to the sirtuin 1 pathway in Ang II-induced cardiomyocytes by increasing the activity of the mitochondrial electron transport chain complex and affecting the expression of genes encoding mitochondrial electron transport chain complex subunits. HQQR could alleviate Ang II-induced cardiomyocyte hypertrophy by modulating oxidative stress, accumulating ROS and increasing mitochondrial electron transport chain activity.
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Affiliation(s)
- Mingtai Gui
- Department of Cardiology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, P.R. China
| | - Lei Yao
- Department of Cardiology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, P.R. China
| | - Bo Lu
- Department of Cardiology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, P.R. China
| | - Jing Wang
- Department of Cardiology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, P.R. China
| | - Xunjie Zhou
- Department of Cardiology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, P.R. China
| | - Jianhua Li
- Department of Cardiology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, P.R. China
| | - Zhenhua Dong
- Department of Cardiology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, P.R. China
| | - Deyu Fu
- Department of Cardiology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, P.R. China
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27
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Emerging methods for and novel insights gained by absolute quantification of mitochondrial DNA copy number and its clinical applications. Pharmacol Ther 2021; 232:107995. [PMID: 34592204 DOI: 10.1016/j.pharmthera.2021.107995] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 08/26/2021] [Accepted: 09/01/2021] [Indexed: 02/07/2023]
Abstract
The past thirty years have seen a surge in interest in pathophysiological roles of mitochondria, and the accurate quantification of mitochondrial DNA copy number (mCN) in cells and tissue samples is a fundamental aspect of assessing changes in mitochondrial health and biogenesis. Quantification of mCN between studies is surprisingly variable due to a combination of physiological variability and diverse protocols being used to measure this endpoint. The advent of novel methods to quantify nucleic acids like digital polymerase chain reaction (dPCR) and high throughput sequencing offer the ability to measure absolute values of mCN. We conducted an in-depth survey of articles published between 1969 -- 2020 to create an overview of mCN values, to assess consensus values of tissue-specific mCN, and to evaluate consistency between methods of assessing mCN. We identify best practices for methods used to assess mCN, and we address the impact of using specific loci on the mitochondrial genome to determine mCN. Current data suggest that clinical measurement of mCN can provide diagnostic and prognostic value in a range of diseases and health conditions, with emphasis on cancer and cardiovascular disease, and the advent of means to measure absolute mCN should improve future clinical applications of mCN measurements.
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28
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Li D, Yang Y, Wang S, He X, Liu M, Bai B, Tian C, Sun R, Yu T, Chu X. Role of acetylation in doxorubicin-induced cardiotoxicity. Redox Biol 2021; 46:102089. [PMID: 34364220 PMCID: PMC8350499 DOI: 10.1016/j.redox.2021.102089] [Citation(s) in RCA: 89] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/23/2021] [Accepted: 07/30/2021] [Indexed: 02/06/2023] Open
Abstract
As a potent chemotherapeutic agent, doxorubicin (DOX) is widely used for the treatment of a variety of cancers However, its clinical utility is limited by dose-dependent cardiotoxicity, and pathogenesis has traditionally been attributed to the formation of reactive oxygen species (ROS). Accordingly, the prevention of DOX-induced cardiotoxicity is an indispensable goal to optimize therapeutic regimens and reduce morbidity. Acetylation is an emerging and important epigenetic modification regulated by histone deacetylases (HDACs) and histone acetyltransferases (HATs). Despite extensive studies of the molecular basis and biological functions of acetylation, the application of acetylation as a therapeutic target for cardiotoxicity is in the initial stage, and further studies are required to clarify the complex acetylation network and improve the clinical management of cardiotoxicity. In this review, we summarize the pivotal functions of HDACs and HATs in DOX-induced oxidative stress, the underlying mechanisms, the contributions of noncoding RNAs (ncRNAs) and exercise-mediated deacetylases to cardiotoxicity. Furthermore, we describe research progress related to several important SIRT activators and HDAC inhibitors with potential clinical value for chemotherapy and cardiotoxicity. Collectively, a comprehensive understanding of specific roles and recent developments of acetylation in doxorubicin-induced cardiotoxicity will provide a basis for improved treatment outcomes in cancer and cardiovascular diseases.
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Affiliation(s)
- Daisong Li
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Yanyan Yang
- Department of Immunology, Basic Medicine School, Qingdao University, Qingdao, 266071, China
| | - Shizhong Wang
- Department of Cardiovascular Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Xiangqin He
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Meixin Liu
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Baochen Bai
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Chao Tian
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Ruicong Sun
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Tao Yu
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China; Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Basic Medicine School, Qingdao University, 38 Deng Zhou Road, Qingdao, 266021, China.
| | - Xianming Chu
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China; Department of Cardiology, The Affiliated Cardiovascular Hospital of Qingdao University, No. 59 Haier Road, Qingdao, 266071, China.
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29
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Maiese K. Cognitive Impairment and Dementia: Gaining Insight through Circadian Clock Gene Pathways. Biomolecules 2021; 11:1002. [PMID: 34356626 PMCID: PMC8301848 DOI: 10.3390/biom11071002] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 07/05/2021] [Accepted: 07/07/2021] [Indexed: 01/18/2023] Open
Abstract
Neurodegenerative disorders affect fifteen percent of the world's population and pose a significant financial burden to all nations. Cognitive impairment is the seventh leading cause of death throughout the globe. Given the enormous challenges to treat cognitive disorders, such as Alzheimer's disease, and the inability to markedly limit disease progression, circadian clock gene pathways offer an exciting strategy to address cognitive loss. Alterations in circadian clock genes can result in age-related motor deficits, affect treatment regimens with neurodegenerative disorders, and lead to the onset and progression of dementia. Interestingly, circadian pathways hold an intricate relationship with autophagy, the mechanistic target of rapamycin (mTOR), the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mammalian forkhead transcription factors (FoxOs), and the trophic factor erythropoietin. Autophagy induction is necessary to maintain circadian rhythm homeostasis and limit cortical neurodegenerative disease, but requires a fine balance in biological activity to foster proper circadian clock gene regulation that is intimately dependent upon mTOR, SIRT1, FoxOs, and growth factor expression. Circadian rhythm mechanisms offer innovative prospects for the development of new avenues to comprehend the underlying mechanisms of cognitive loss and forge ahead with new therapeutics for dementia that can offer effective clinical treatments.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, NY 10022, USA
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30
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Gu J, Huang H, Liu C, Jiang B, Li M, Liu L, Zhang S. Pinocembrin inhibited cardiomyocyte pyroptosis against doxorubicin-induced cardiac dysfunction via regulating Nrf2/Sirt3 signaling pathway. Int Immunopharmacol 2021; 95:107533. [PMID: 33752080 DOI: 10.1016/j.intimp.2021.107533] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 02/22/2021] [Accepted: 02/23/2021] [Indexed: 01/25/2023]
Abstract
Doxorubicin (DOX) is a potent chemotherapeutic drug but the clinical use was limited by its dose-dependent cardiotoxicity. Pinocembrin (PCB), a flavonoid originally isolated from honeybee propolis and rhizomes of Boesenbergia pandurate displays diverse biological activities. However, the role of PCB in DOX-induced cardiac injury and its underlying molecular mechanism are not fully elucidated. The present study was designed to evaluate the protective role of PCB in a DOX-induced cardiotoxicity in vivo and in vitro. Our results revealed that PCB administration greatly improved cardiac function and reduced cardiac fibrosis manifested by LVEF, LVFS, LVIDd, LVIDs, and myocardial fibrotic area which were impaired by DOX treatment. The cardiac injury evidenced by LDH and CK-MB activities were reduced while the levels of IL-1β and IL-18 were decreased following PCB treatment compared to DOX-treated mice. Mechanically, our present results showed that PCB significantly inhibited DOX-induced cardiomyocyte pyroptosis via activating Nrf2/Sirt3 signal pathway. Furthermore, the inhibition of Nrf2 in H9c2 cells abolished the protective role of PCB against DOX-induced cell toxicity, which was at least partly via upregulation of NLRP3-mediated pyroptosis. In conclusion, our study clearly demonstrated that PCB reduced cardiomyocyte pyroptosis to protect hearts from DOX-induced cardiotoxicity through activation of Nrf2/Sirt3 signal pathway.
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Affiliation(s)
- Jiwei Gu
- Department of Cardiovascular Surgery, General Hospital of Ningxia Medical University, Yinchuan 750004, China
| | - Hui Huang
- Department of Cardiology, General Hospital of Ningxia Medical University, Yinchuan 750004, China
| | - Chunlian Liu
- Department of Cardiovascular Surgery, General Hospital of Ningxia Medical University, Yinchuan 750004, China
| | - Bo Jiang
- Department of Cardiovascular Surgery, General Hospital of Ningxia Medical University, Yinchuan 750004, China
| | - Mingliang Li
- Department of Cardiovascular Surgery, General Hospital of Ningxia Medical University, Yinchuan 750004, China
| | - Li Liu
- Department of Cardiovascular Surgery, General Hospital of Ningxia Medical University, Yinchuan 750004, China
| | - Shuya Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China.
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31
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Iwata Y, Sakai N, Nakajima Y, Oshima M, Nakagawa-Yoneda S, Ogura H, Sato K, Minami T, Kitajima S, Toyama T, Yamamura Y, Miyagawa T, Hara A, Shimizu M, Furuichi K, Wada T. Anti-fibrotic potential of erythropoietin signaling on bone marrow derived fibrotic cell. BMC Nephrol 2021; 22:203. [PMID: 34059008 PMCID: PMC8167964 DOI: 10.1186/s12882-021-02411-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 05/13/2021] [Indexed: 11/10/2022] Open
Abstract
INTRODUCTION The number of patients with end stage kidney disease (ESKD) are increasing world-side. While interstitial fibrosis (IF) is a common step for the progression to ESKD, therapeutic options for IF is still limited in clinical settings. We have reported that bone marrow-derived fibrotic cell, fibrocyte, is involved in the pathogenesis of kidney fibrosis. Also recent studies revealed that erythropoietin has protective effect on kidney diseases. However, it is unknown whether erythropoietin (EPO) inhibits fibrosis in progressive kidney injury. Therefore, we explored the impacts of EPO on kidney fibrosis with focusing on fibrocyte. METHOD Fibrocyte was differentiated from peripheral mononuclear cells of healthy donor. Fibrocyte was stimulated with transforming growth factor beta (TGF)-β with/without EPO treatment. Moreover, the therapeutic effect of EPO was evaluated in murine unilateral ureteral obstruction (UUO) model. RESULT TGF-β stimulation increased the expression of COL1 mRNA in fibrocyte. EPO signal reduced the expression of COL1 mRNA in dose dependent manner. EPO reduced mitochondrial oxidative stress and ameliorated mitochondrial membrane depolarization induced by TGF-β stimulation. Moreover, EPO reduced the mRNA expression of mitochondria related molecules, TRAF6, in fibrocyte. In addition, the count of CD45+/αSMA + double-positive fibrocyte was decreased in the EPO-administered UUO kidneys. CONCLUSION EPO signals function to prevent kidney fibrosis, particularly in fibrocyte. Regulating the renal accumulation of fibrocyte is a part of the anti-fibrotic functions of EPO.
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Affiliation(s)
- Yasunori Iwata
- Division of Infection Control, Department of Nephrology and Laboratory Medicine, Kanazawa University, 13-1 Takara-machi, 920-8641, Kanazawa , Japan. .,Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan.
| | - Norihiko Sakai
- Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan.,Division of Blood Purification, Kanazawa University Hospital, Ishikawa, Kanazawa, Japan
| | - Yuki Nakajima
- Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Megumi Oshima
- Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | | | - Hisayuki Ogura
- Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Koichi Sato
- Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Taichiro Minami
- Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Shinji Kitajima
- Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan.,Division of Blood Purification, Kanazawa University Hospital, Ishikawa, Kanazawa, Japan
| | - Tadashi Toyama
- Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Yuta Yamamura
- Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Taro Miyagawa
- Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Akinori Hara
- Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Miho Shimizu
- Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Kengo Furuichi
- Division of Nephrology, Kanazawa Medical University School of Medicine, Ishikawa, Japan
| | - Takashi Wada
- Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
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32
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Wang R, Xu Y, Niu X, Fang Y, Guo D, Chen J, Zhu H, Dong J, Zhao R, Wang Y, Qi B, Ren G, Li X, Liu L, Zhang M. MiR-22 Inhibition Alleviates Cardiac Dysfunction in Doxorubicin-Induced Cardiomyopathy by Targeting the sirt1/PGC-1α Pathway. Front Physiol 2021; 12:646903. [PMID: 33868015 PMCID: PMC8047466 DOI: 10.3389/fphys.2021.646903] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 02/22/2021] [Indexed: 11/13/2022] Open
Abstract
Doxorubicin (DOX) cardiotoxicity is a life-threatening side effect that leads to a poor prognosis in patients receiving chemotherapy. We investigated the role of miR-22 in doxorubicin-induced cardiomyopathy and the underlying mechanism in vivo and in vitro. Specifically, we designed loss-of-function and gain-of-function experiments to identify the role of miR-22 in doxorubicin-induced cardiomyopathy. Our data suggested that inhibiting miR-22 alleviated cardiac fibrosis and cardiac dysfunction induced by doxorubicin. In addition, inhibiting miR-22 mitigated mitochondrial dysfunction through the sirt1/PGC-1α pathway. Knocking out miR-22 enhanced mitochondrial biogenesis, as evidenced by increased PGC-1α, TFAM, and NRF-1 expression in vivo. Furthermore, knocking out miR-22 rescued mitophagy, which was confirmed by increased expression of PINK1 and parkin and by the colocalization of LC3 and mitochondria. These protective effects were abolished by overexpressing miR-22. In conclusion, miR-22 may represent a new target to alleviate cardiac dysfunction in doxorubicin-induced cardiomyopathy and improve prognosis in patients receiving chemotherapy.
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Affiliation(s)
- Runze Wang
- Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.,Department of Hematology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Yuerong Xu
- Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, China
| | - Xiaolin Niu
- Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Yexian Fang
- Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Dong Guo
- Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Jiangwei Chen
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Hanzhao Zhu
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Jiaying Dong
- Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Ran Zhao
- Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Ying Wang
- Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Bingchao Qi
- Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Gaotong Ren
- Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Xue Li
- Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Li Liu
- Department of Hematology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Mingming Zhang
- Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
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Fu Q, Pan H, Tang Y, Rong J, Zheng Z. MiR-200a-3p Aggravates DOX-Induced Cardiotoxicity by Targeting PEG3 Through SIRT1/NF-κB Signal Pathway. Cardiovasc Toxicol 2021; 21:302-313. [PMID: 33638775 DOI: 10.1007/s12012-020-09620-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 11/23/2020] [Indexed: 02/07/2023]
Abstract
Doxorubicin (DOX) is a widely used cytotoxic drug whose application is limited by its severe side effects. Little was known regarding how to offset its side effects. Therefore this study aims to explore the role of miR-200a-3p in DOX-induced cardiotoxicity and its possible mechanism. DOX-induced myocardial injury rat models were established, which were then injected with miR-200a-3p inhibitor (miR-200a-3p suppression) to observe the effects of miR-200a-3p on cell proliferation, and apoptosis. Heart function and weights of rat models were also measured. Cardiomyocytes were induced by DOX, in which PEG3 knockdown or corresponding plasmids were transfected to assess the possible effect of PEG3 on cell activity. Dual luciferase reporter assay was applied to verify the binding of PEG3 with miR-200a-3p. Elevated levels of lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB) and left ventricular end-diastolic pressure (LVEDP), as well as suppressed left ventricular systolic pressure (LVSP) and ± dp/dt max were showed in myocardial injury rat models. DOX induced myocardial injury and increased miR-200a-3p expression levels. miR-200a-3p inhibitor could partially attenuate DOX-induced cardiotoxicity in rat models, while PEG3 could regulate myocardial injury in DOX-treated cell models. miR-200a-3p, by targeting PEG3 through SIRT1/NF-κB signal pathway, regulated cell proliferation, inflammation and apoptosis of myocardiocytes. The results in current study demonstrated that miR-200a-3p regulates cell proliferation and apoptosis of cardiomyocytes by targeting PEG3 through SIRT1/NF-κB signal pathway. This result may provide a potential clue for the treatment of DOX-induced cardiotoxicity.
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Affiliation(s)
- Qinghua Fu
- Department of Cardiovasology, Hunan Provincial People's Hospital, Changsha, Hunan, 410000, People's Republic of China.
| | - Hongwei Pan
- Department of Cardiovasology, Hunan Provincial People's Hospital, Changsha, Hunan, 410000, People's Republic of China
| | - Yi Tang
- Department of Cardiovasology, Hunan Provincial People's Hospital, Changsha, Hunan, 410000, People's Republic of China
| | - Jingjing Rong
- Department of Cardiovasology, Hunan Provincial People's Hospital, Changsha, Hunan, 410000, People's Republic of China
| | - Zhaofen Zheng
- Department of Cardiovasology, Hunan Provincial People's Hospital, Changsha, Hunan, 410000, People's Republic of China
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Wang A J, Zhang J, Xiao M, Wang S, Wang B J, Guo Y, Tang Y, Gu J. Molecular mechanisms of doxorubicin-induced cardiotoxicity: novel roles of sirtuin 1-mediated signaling pathways. Cell Mol Life Sci 2021; 78:3105-3125. [PMID: 33438055 PMCID: PMC11072696 DOI: 10.1007/s00018-020-03729-y] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 11/16/2020] [Accepted: 12/04/2020] [Indexed: 02/07/2023]
Abstract
Doxorubicin (DOX) is an anthracycline chemotherapy drug used in the treatment of various types of cancer. However, short-term and long-term cardiotoxicity limits the clinical application of DOX. Currently, dexrazoxane is the only approved treatment by the United States Food and Drug Administration to prevent DOX-induced cardiotoxicity. However, a recent study found that pre-treatment with dexrazoxane could not fully improve myocardial toxicity of DOX. Therefore, further targeted cardioprotective prophylaxis and treatment strategies are an urgent requirement for cancer patients receiving DOX treatment to reduce the occurrence of cardiotoxicity. Accumulating evidence manifested that Sirtuin 1 (SIRT1) could play a crucially protective role in heart diseases. Recently, numerous studies have concentrated on the role of SIRT1 in DOX-induced cardiotoxicity, which might be related to the activity and deacetylation of SIRT1 downstream targets. Therefore, the aim of this review was to summarize the recent advances related to the protective effects, mechanisms, and deficiencies in clinical application of SIRT1 in DOX-induced cardiotoxicity. Also, the pharmaceutical preparations that activate SIRT1 and affect DOX-induced cardiotoxicity have been listed in this review.
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Affiliation(s)
- Jie Wang A
- School of Nursing, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Jingjing Zhang
- Department of Cardiology, The First Hospital of China Medical University, Shenyang, 110016, Liaoning, China
- Department of Cardiology, The People's Hospital of Liaoning Province, Shenyang, 110016, Liaoning, China
| | - Mengjie Xiao
- School of Nursing, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Shudong Wang
- Department of Cardiology, The First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Jie Wang B
- School of Nursing, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Yuanfang Guo
- School of Nursing, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Yufeng Tang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014, Shandong, China
| | - Junlian Gu
- School of Nursing, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
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Cadeddu Dessalvi C, Deidda M, Noto A, Madeddu C, Cugusi L, Santoro C, López-Fernández T, Galderisi M, Mercuro G. Antioxidant Approach as a Cardioprotective Strategy in Chemotherapy-Induced Cardiotoxicity. Antioxid Redox Signal 2021; 34:572-588. [PMID: 32151144 DOI: 10.1089/ars.2020.8055] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Significance: Chemotherapy-induced cardiotoxicity (CTX) has been associated with redox signaling imbalance. In fact, redox reactions are crucial for normal heart physiology, whereas excessive oxidative stress can cause cardiomyocyte structural damage. Recent Advances: An antioxidant approach as a cardioprotective strategy in this setting has shown encouraging results in preventing anticancer drug-induced CTX. Critical Issues: In fact, traditional heart failure drugs as well as many other compounds and nonpharmacological strategies, with a partial effect in reducing oxidative stress, have been shown to counterbalance chemotherapy-induced CTX in this setting to some extent. Future Directions: Given the various pathways of toxicity involved in different chemotherapeutic schemes, interactions with redox balance need to be fine-tuned and a personalized cardioprotective approach seems to be required.
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Affiliation(s)
| | - Martino Deidda
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Antonio Noto
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Clelia Madeddu
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Lucia Cugusi
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Ciro Santoro
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
| | - Teresa López-Fernández
- Cardiology Service, Cardio-Oncology Unit, La Paz University Hospital, IdiPAz Research Institute, Ciber CV, Madrid, Spain
| | - Maurizio Galderisi
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
| | - Giuseppe Mercuro
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
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Maiese K. Nicotinamide as a Foundation for Treating Neurodegenerative Disease and Metabolic Disorders. Curr Neurovasc Res 2021; 18:134-149. [PMID: 33397266 PMCID: PMC8254823 DOI: 10.2174/1567202617999210104220334] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/18/2020] [Accepted: 12/22/2020] [Indexed: 02/06/2023]
Abstract
Neurodegenerative disorders impact more than one billion individuals worldwide and are intimately tied to metabolic disease that can affect another nine hundred individuals throughout the globe. Nicotinamide is a critical agent that may offer fruitful prospects for neurodegenerative diseases and metabolic disorders, such as diabetes mellitus. Nicotinamide protects against multiple toxic environments that include reactive oxygen species exposure, anoxia, excitotoxicity, ethanolinduced neuronal injury, amyloid (Aß) toxicity, age-related vascular disease, mitochondrial dysfunction, insulin resistance, excess lactate production, and loss of glucose homeostasis with pancreatic β-cell dysfunction. However, nicotinamide offers cellular protection in a specific concentration range, with dosing outside of this range leading to detrimental effects. The underlying biological pathways of nicotinamide that involve the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), and mammalian forkhead transcription factors (FoxOs) may offer insight for the clinical translation of nicotinamide into a safe and efficacious therapy through the modulation of oxidative stress, apoptosis, and autophagy. Nicotinamide is a highly promising target for the development of innovative strategies for neurodegenerative disorders and metabolic disease, but the benefits of this foundation depend greatly on gaining a further understanding of nicotinamide's complex biology.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, New York 10022
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Zhou S, Qiao YM, Liu YG, Liu D, Hu JM, Liao J, Li M, Guo Y, Fan LP, Li LY, Zhao M. Bone marrow derived mesenchymal stem cells pretreated with erythropoietin accelerate the repair of acute kidney injury. Cell Biosci 2020; 10:130. [PMID: 33292452 PMCID: PMC7667799 DOI: 10.1186/s13578-020-00492-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 10/30/2020] [Indexed: 12/18/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) represent a promising treatment option for acute kidney injury (AKI). The main drawbacks of MSCs therapy, including the lack of specific homing after systemic infusion and early cell death in the inflammatory microenvironment, directly affect the therapeutic efficacy of MSCs. Erythropoietin (EPO)-preconditioning of MSCs promotes their therapeutic effect, however, the underlying mechanism remains unknown. In this study, we sought to investigate the efficacy and mechanism of EPO in bone marrow derived mesenchymal stem cells (BMSCs) for AKI treatment. Results We found that incubation of BMSCs with ischemia/reperfusion(I/R)-induced AKI kidney homogenate supernatant (KHS) caused apoptosis in BMSCs, which was decreased by EPO pretreatment, indicating that EPO protected the cells from apoptosis. Further, we showed that EPO up-regulated silent information regulator 1 (SIRT1) and Bcl-2 expression and down-regulated p53 expression. This effect was partially reversed by SIRT1 siRNA intervention. The anti-apoptotic effect of EPO in pretreated BMSCs may be mediated through the SIRT1 pathway. In a rat AKI model, 24 h after intravenous infusion, GFP-BMSCs were predominantly located in the lungs. However, EPO pretreatment reduced the lung entrapment of BMSCs and increased their distribution in the target organs. AKI rats infused with EPO-BMSCs had significantly lower levels of serum IL-1β and TNF-α, and a significantly higher level of IL-10 as compared to rats infused with untreated BMSCs. The administration of EPO-BMSCs after reperfusion reduced serum creatinine, blood urea nitrogen, and pathological scores in I/R-AKI rats more effectively than BMSCs treatment did. Conclusions Our data suggest that EPO pretreatment enhances the efficacy of BMSCs to improve the renal function and pathological presentation of I/R-AKI rats.
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Affiliation(s)
- Song Zhou
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Haizhu District, Guangzhou, 510280, Guangdong Province, China
| | - Yu-Ming Qiao
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Haizhu District, Guangzhou, 510280, Guangdong Province, China
| | - Yong-Guang Liu
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Haizhu District, Guangzhou, 510280, Guangdong Province, China
| | - Ding Liu
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Haizhu District, Guangzhou, 510280, Guangdong Province, China
| | - Jian-Min Hu
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Haizhu District, Guangzhou, 510280, Guangdong Province, China
| | - Jun Liao
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Haizhu District, Guangzhou, 510280, Guangdong Province, China
| | - Min Li
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Haizhu District, Guangzhou, 510280, Guangdong Province, China
| | - Ying Guo
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Haizhu District, Guangzhou, 510280, Guangdong Province, China
| | - Li-Pei Fan
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Haizhu District, Guangzhou, 510280, Guangdong Province, China
| | - Liu-Yang Li
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Haizhu District, Guangzhou, 510280, Guangdong Province, China
| | - Ming Zhao
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Haizhu District, Guangzhou, 510280, Guangdong Province, China.
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HuoXue QianYang QuTan Recipe attenuates left ventricular hypertrophy in obese hypertensive rats by improving mitochondrial function through SIRT1/PGC-1α deacetylation pathway. Biosci Rep 2020; 39:221366. [PMID: 31778153 PMCID: PMC6923340 DOI: 10.1042/bsr20192909] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 11/15/2019] [Accepted: 11/25/2019] [Indexed: 12/11/2022] Open
Abstract
Mitochondrial dysfunction plays a vital role in the progression of left ventricular hypertrophy (LVH). Previous studies have confirmed that the disorder of SIRT1/PGC-1α deacetylation pathway aggravated mitochondrial dysfunction. HuoXue QianYang QuTan Recipe (HQQR) is a commonly used prescription that has shown therapeutic effects on obesity hypertension and its complications. However, the potential mechanisms are still unclear. In the present study, obesity hypertension (OBH) was established in rats and we investigated the efficacy and mechanisms of HQQR on LVH. Rats were divided into the five groups: (1) WKY-ND group, (2) SHR-ND group, (3) OBH-HF group, (4) OBH-HF/V group and (5) OBH-HF/H group. We evaluated body weight, Lee index and blood pressure (BP) before and every 2 weeks after treatment. After 10 weeks of treatment, we mainly detected glycolipid metabolic index, the severity of LVH, mitochondrial function along with SIRT1/PGC-1α deacetylation pathway. Our results showed that HQQR significantly lowered body weight, Lee index, BP and improved the disorder of glycolipid metabolism in OBH rats. Importantly, we uncovered HQQR could alleviate mitochondrial dysfunction in OBH rats by regulating SIRT1/PGC-1α deacetylation pathway. These changes could be associated with the inhibition of LVH.
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39
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Penna F, Ballarò R, Costelli P. The Redox Balance: A Target for Interventions Against Muscle Wasting in Cancer Cachexia? Antioxid Redox Signal 2020; 33:542-558. [PMID: 32037856 DOI: 10.1089/ars.2020.8041] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Significance: The management of cancer patients is frequently complicated by the occurrence of a complex syndrome known as cachexia. It is mainly characterized by muscle wasting, a condition that associates with enhanced protein breakdown and with negative energy balance. While the mechanisms underlying cachexia have been only partially elucidated, understanding the pathogenesis of muscle wasting in cancer hosts is mandatory to design new targeted therapeutic strategies. Indeed, most of cancer patients will experience cachexia during the course of their disease, and about 25% of cancer-related deaths are due to this syndrome, rather than to the tumor itself. Recent Advances: Compelling evidence suggests that an altered redox homeostasis likely contributes to cancer-induced muscle protein depletion, directly or indirectly activating the intracellular degradative pathways. In addition, oxidative stress impinges on both mitochondrial number and function; the other way round, altered mitochondria lead to enhanced redox imbalance, creating a vicious loop that eventually results in negative energy metabolism. Critical Issues: The present review focuses on the possibility that pharmacological and nonpharmacological strategies able to restore a physiologic redox balance could be useful components of treatment schedules aimed at counteracting cancer-induced muscle wasting. Future Directions: Exercise and the use of exercise mimetic drugs represent the most promising approaches capable of reinforcing the muscle antioxidant defenses of cancer patients. The results from ongoing and new clinical trials are needed to validate the preclinical studies and provide effective therapies for cancer cachexia. Antioxid. Redox Signal. 33, 542-558.
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Affiliation(s)
- Fabio Penna
- Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
| | - Riccardo Ballarò
- Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
| | - Paola Costelli
- Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
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40
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Packer M. Cardioprotective Effects of Sirtuin-1 and Its Downstream Effectors: Potential Role in Mediating the Heart Failure Benefits of SGLT2 (Sodium-Glucose Cotransporter 2) Inhibitors. Circ Heart Fail 2020; 13:e007197. [PMID: 32894987 DOI: 10.1161/circheartfailure.120.007197] [Citation(s) in RCA: 122] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The cardioprotective effects of SGLT2 (sodium-glucose cotransporter 2) inhibitors may be related to their ability to induce a fasting-like paradigm, which triggers the activation of nutrient deprivation pathways to promote cellular homeostasis. The most distinctive metabolic manifestations of this fasting mimicry are enhanced gluconeogenesis and ketogenesis, which are not seen with other antihyperglycemic drugs. The principal molecular stimulus to gluconeogenesis and ketogenesis is activation of SIRT1 (sirtuin-1) and its downstream mediators: PGC-1α (proliferator-activated receptor gamma coactivator 1-alpha) and FGF21 (fibroblast growth factor 21). These three nutrient deprivation sensors exert striking cardioprotective effects in a broad range of experimental models. This benefit appears to be related to their actions to alleviate oxidative stress and promote autophagy-a lysosome-dependent degradative pathway that disposes of dysfunctional organelles that are major sources of cellular injury. Nutrient deprivation sensors are suppressed in states of perceived energy surplus (ie, type 2 diabetes mellitus and chronic heart failure), but SGLT2 inhibitors activate SIRT1/PGC-1α/FGF21 signaling and promote autophagy. This effect may be related to their action to trigger the perception of a system-wide decrease in environmental nutrients, but SGLT2 inhibitors may also upregulate SIRT1, PGC-1α, and FGF21 by a direct effect on the heart. Interestingly, metformin-induced stimulation of AMP-activated protein kinase (a nutrient deprivation sensor that does not promote ketogenesis) has not been shown to reduce heart failure events in clinical trials. Therefore, promotion of ketogenic nutrient deprivation signaling by SGLT2 inhibitors may explain their cardioprotective effects, even though SGLT2 is not expressed in the heart.
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Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX;and Imperial College, London, United Kingdom
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41
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Packer M. Role of ketogenic starvation sensors in mediating the renal protective effects of SGLT2 inhibitors in type 2 diabetes. J Diabetes Complications 2020; 34:107647. [PMID: 32534886 DOI: 10.1016/j.jdiacomp.2020.107647] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 05/15/2020] [Accepted: 05/28/2020] [Indexed: 02/08/2023]
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors ameliorate the progression of diabetic chronic kidney disease, but the mechanisms underlying this nephroprotective effect have not been fully elucidated. These drugs induce a fasting-like transcriptional paradigm, which includes activation of sirtuin-1 (SIRT1) and its downstream effectors, peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and fibroblast growth factor 21 (FGF21). This triad of enzymes and transcription factors serve as master regulators of nutrient and cellular homeostasis, and each acts to enhance gluconeogenesis, fatty acid oxidation and ketogenesis, the hallmarks of treatment with SGLT2 inhibitors. At the same time, SIRT1/PGC-1α/FGF21 signaling also promotes autophagy, a lysosome-dependent degradative pathway that cleanses the cytosol of dysfunctional organelles. This action alleviates cellular stress, ameliorates inflammation, and is strikingly nephroprotective. Interestingly, type 2 diabetes is characterized by both a deficiency of SIRT1/PGC-1α signaling and an impairment of autophagic flux, thus explaining the high levels of oxidative stress in the diabetic kidney. SIRT1 gene polymorphisms have been linked with an increased risk of diabetic nephropathy in several epidemiological studies. Importantly, there is an inverse relationship between the activity of SGLT2 and signaling through the SIRT1/PGC-1α/FGF21 pathway, and SGLT2 inhibition leads to activation of these ketogenic nutrient deprivation sensors. Therefore, activation of SIRT1/PGC-1α/FGF21 may explain the effect of SGLT2 inhibitors not only to promote ketogenesis, but also to preserve renal function in type 2 diabetes.
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Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX, USA; Imperial College, London, UK.
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Wei J, Liu J, Zhang L, Zhu Y, Li X, Zhou G, Zhao Y, Sun Z, Zhou X. Endosulfan induces cardiotoxicity through apoptosis via unbalance of pro-survival and mitochondrial-mediated apoptotic pathways. THE SCIENCE OF THE TOTAL ENVIRONMENT 2020; 727:138790. [PMID: 32344260 DOI: 10.1016/j.scitotenv.2020.138790] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 03/31/2020] [Accepted: 04/16/2020] [Indexed: 06/11/2023]
Abstract
Although the associations between endosulfan and adverse cardiovascular health have been reported, the toxic effects and underlying mechanism of endosulfan on the heart are not well understood. In this study, we examined the cardiotoxicity induced by endosulfan using Wistar rats and human cardiomyocytes (AC16) cells. Wistar rats were divided into control group (received corn oil alone) and three concentrations of endosulfan groups (1, 5 and 10 mg/kg·bw) by gavage. The AC16 cells were treated with three various concentrations (0, 1.25, 5, and 20 μg/mL) of endosulfan. The results showed that endosulfan induced cytotoxicity through damaging myocardial structure, decreasing the viability of cardiomyocytes, and elevating the serum levels of cardiac troponin I, heart fatty acid binding protein, aspartate aminotransferase, and reactive oxygen species (p < 0.05). Moreover, measurement of mitochondrial function showed that endosulfan could significantly decrease adenosine triphosphate levels and cytochrome c oxidase IV expression in AC16 cells (p < 0.05). In addition, endosulfan obviously inhibited Bcl-2 expression, activated the expressions of cytochrome c/Caspase-9/Caspase-3 signaling pathway, and induced the apoptosis of AC16 cells (p < 0.05). Furthermore, endosulfan significantly increased the expression of Bim, and inhibited the expressions of PI3K/Akt/FoxO3a signaling pathways in cardiomyocytes (p < 0.05). These results suggest that endosulfan may induce cardiotoxicity by inducing myocardial apoptosis resulting from activation of mitochondria-mediated apoptosis pathway and inhibition of pro-survival signaling pathways, which might be helpful in elucidating the mechanism of cardiac dysfunction induced by endosulfan.
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Affiliation(s)
- Jialiu Wei
- Key Laboratory of Cardiovascular Epidemiology & Department of Epidemiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, China
| | - Jianhui Liu
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, China
| | - Lianshuang Zhang
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, China
| | - Yupeng Zhu
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, China
| | - Xiangyang Li
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, China
| | - Guiqing Zhou
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, China
| | - Yanzhi Zhao
- Yanjing Medical College, Capital Medical University, Beijing, China.
| | - Zhiwei Sun
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, China
| | - Xianqing Zhou
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, China.
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Abstract
Metabolic disorders, such as diabetes mellitus (DM), are increasingly becoming significant risk factors for the health of the global population and consume substantial portions of the gross domestic product of all nations. Although conventional therapies that include early diagnosis, nutritional modification of diet, and pharmacological treatments may limit disease progression, tight serum glucose control cannot prevent the onset of future disease complications. With these concerns, novel strategies for the treatment of metabolic disorders that involve the vitamin nicotinamide, the mechanistic target of rapamycin (mTOR), mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP activated protein kinase (AMPK), and the cellular pathways of autophagy and apoptosis offer exceptional promise to provide new avenues of treatment. Oversight of these pathways can promote cellular energy homeostasis, maintain mitochondrial function, improve glucose utilization, and preserve pancreatic beta-cell function. Yet, the interplay among mTOR, AMPK, and autophagy pathways can be complex and affect desired clinical outcomes, necessitating further investigations to provide efficacious treatment strategies for metabolic dysfunction and DM.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, New York 10022,
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44
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Abstract
Experimental models of cardiac disease play a key role in understanding the pathophysiology of the disease and developing new therapies. The features of the experimental models should reflect the clinical phenotype, which can have a wide spectrum of underlying mechanisms. We review characteristics of commonly used experimental models of cardiac physiology and pathophysiology in all translational steps including in vitro, small animal, and large animal models. Understanding their characteristics and relevance to clinical disease is the key for successful translation to effective therapies.
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45
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Packer M. Critical examination of mechanisms underlying the reduction in heart failure events with SGLT2 inhibitors: identification of a molecular link between their actions to stimulate erythrocytosis and to alleviate cellular stress. Cardiovasc Res 2020; 117:74-84. [PMID: 32243505 DOI: 10.1093/cvr/cvaa064] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 02/10/2020] [Accepted: 03/30/2020] [Indexed: 12/13/2022] Open
Abstract
Sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of serious heart failure events, even though SGLT2 is not expressed in the myocardium. This cardioprotective benefit is not related to an effect of these drugs to lower blood glucose, promote ketone body utilization or enhance natriuresis, but it is linked statistically with their action to increase haematocrit. SGLT2 inhibitors increase both erythropoietin and erythropoiesis, but the increase in red blood cell mass does not directly prevent heart failure events. Instead, erythrocytosis is a biomarker of a state of hypoxia mimicry, which is induced by SGLT2 inhibitors in manner akin to cobalt chloride. The primary mediators of the cellular response to states of energy depletion are sirtuin-1 and hypoxia-inducible factors (HIF-1α/HIF-2α). These master regulators promote the cellular adaptation to states of nutrient and oxygen deprivation, promoting mitochondrial capacity and minimizing the generation of oxidative stress. Activation of sirtuin-1 and HIF-1α/HIF-2α also stimulates autophagy, a lysosome-mediated degradative pathway that maintains cellular homoeostasis by removing dangerous constituents (particularly unhealthy mitochondria and peroxisomes), which are a major source of oxidative stress and cardiomyocyte dysfunction and demise. SGLT2 inhibitors can activate SIRT-1 and stimulate autophagy in the heart, and thereby, favourably influence the course of cardiomyopathy. Therefore, the linkage between erythrocytosis and the reduction in heart failure events with SGLT2 inhibitors may be related to a shared underlying molecular mechanism that is triggered by the action of these drugs to induce a perceived state of oxygen and nutrient deprivation.
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Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular Institute, Baylor University Medical Center, 621 N. Hall Street, Dallas, TX 75226, USA.,Imperial College, London, UK
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46
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Knockdown of TFAM in Tumor Cells Retarded Autophagic Flux through Regulating p53 Acetylation and PISD Expression. Cancers (Basel) 2020; 12:cancers12020493. [PMID: 32093281 PMCID: PMC7072172 DOI: 10.3390/cancers12020493] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 02/17/2020] [Accepted: 02/19/2020] [Indexed: 12/28/2022] Open
Abstract
Mitochondrial transcription factor A (TFAM) is required for mitochondrial DNA replication and transcription, which are essential for mitochondrial biogenesis. Previous studies reported that depleting mitochondrial functions by genetic deletion of TFAM impaired autophagic activities. However, the underlying mechanisms remain largely unknown. In the current study, we identified that knockdown of TFAM repressed the synthesis of autophagy bio-marker LC3-II in tumor cells and decreased the expression of phosphatidyl-serine decarboxylase (PISD). Besides, downregulation of PISD with siRNA reduced the level of LC3-II, indicating that depletion of TFAM retarded autophagy via inhibiting PISD expression. Furthermore, it was found that the tumor repressor p53 could stimulate the transcription and expression of PISD by binding the PISD enhancer. Additionally, the protein stability and transcriptional activity of p53 in TFAM knockdown tumor cells was attenuated, and this was associated with decreased acetylation, especially the acetylation of lysine 382 of p53. Finally, we identified that TFAM knockdown increased the NAD+/NADH ratio in tumor cells. This led to the upregulation of Sirtuin1 (SIRT1), a NAD-dependent protein deacetylase, to deacetylate p53 and attenuated its transcriptional activation on PISD. In summary, our study discovered a new mechanism regarding disturbed autophagy in tumor cells with mitochondrial dysfunction due to the depletion of TFAM.
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47
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Norouzi M, Amerian M, Amerian M, Atyabi F. Clinical applications of nanomedicine in cancer therapy. Drug Discov Today 2020; 25:107-125. [DOI: 10.1016/j.drudis.2019.09.017] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 09/03/2019] [Accepted: 09/24/2019] [Indexed: 12/23/2022]
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48
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Maiese K. Nicotinamide: Oversight of Metabolic Dysfunction Through SIRT1, mTOR, and Clock Genes. Curr Neurovasc Res 2020; 17:765-783. [PMID: 33183203 PMCID: PMC7914159 DOI: 10.2174/1567202617999201111195232] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 10/24/2020] [Accepted: 10/27/2020] [Indexed: 12/13/2022]
Abstract
Metabolic disorders that include diabetes mellitus present significant challenges for maintaining the welfare of the global population. Metabolic diseases impact all systems of the body and despite current therapies that offer some protection through tight serum glucose control, ultimately such treatments cannot block the progression of disability and death realized with metabolic disorders. As a result, novel therapeutic avenues are critical for further development to address these concerns. An innovative strategy involves the vitamin nicotinamide and the pathways associated with the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), the mechanistic target of rapamycin (mTOR), mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP activated protein kinase (AMPK), and clock genes. Nicotinamide maintains an intimate relationship with these pathways to oversee metabolic disease and improve glucose utilization, limit mitochondrial dysfunction, block oxidative stress, potentially function as antiviral therapy, and foster cellular survival through mechanisms involving autophagy. However, the pathways of nicotinamide, SIRT1, mTOR, AMPK, and clock genes are complex and involve feedback pathways as well as trophic factors such as erythropoietin that require a careful balance to ensure metabolic homeostasis. Future work is warranted to gain additional insight into these vital pathways that can oversee both normal metabolic physiology and metabolic disease.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, New York 10022
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49
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Najafi M, Hooshangi Shayesteh MR, Mortezaee K, Farhood B, Haghi-Aminjan H. The role of melatonin on doxorubicin-induced cardiotoxicity: A systematic review. Life Sci 2019; 241:117173. [PMID: 31843530 DOI: 10.1016/j.lfs.2019.117173] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 11/30/2019] [Accepted: 12/11/2019] [Indexed: 12/31/2022]
Abstract
PURPOSE Doxorubicin, as an effective chemotherapeutic drug, is commonly used for combating various solid and hematological tumors. However, doxorubicin-induced cardiotoxicity is considered as a serious adverse effect, and it limits the clinical use of this chemotherapeutic drug. The use of melatonin can lead to a decrease in the cardiotoxic effect induced by doxorubicin. The aim of this review was to evaluate the potential role of melatonin in the prevention of doxorubicin-induced cardiotoxicity. METHODS This review was conducted by a full systematic search strategy based on PRISMA guidelines for the identification of relevant literature in the electronic databases of PubMed, Web of Science, Embase, and Scopus up to January 2019 using search terms in the titles and abstracts. 286 articles were screened in accordance with our inclusion and exclusion criteria. Finally, 28 articles were selected in this systematic review. RESULTS The findings demonstrated that doxorubicin-treated groups had increased mortality, decreased body weight and heart weight, and increased ascites compared to the control groups; the co-administration of melatonin revealed an opposite pattern compared to the doxorubicin-treated groups. Also, this chemotherapeutic agent can lead to biochemical and histopathological changes; as for most of the cases, these alterations were reversed near to normal levels (control groups) by melatonin co-administration. Melatonin exerts these protection effects through mechanisms of anti-oxidant, anti-apoptosis, anti-inflammatory, and mitochondrial function. CONCLUSION The results of this systematic review indicated that co-administration of melatonin ameliorates the doxorubicin-induced cardiotoxicity.
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Affiliation(s)
- Masoud Najafi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | | | - Keywan Mortezaee
- Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Bagher Farhood
- Department of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| | - Hamed Haghi-Aminjan
- Pharmaceutical Sciences Research Center, Ardabil University of Medical Sciences, Ardabil, Iran.
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50
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Ferreira LL, Cervantes M, Froufe HJC, Egas C, Cunha-Oliveira T, Sassone-Corsi P, Oliveira PJ. Doxorubicin persistently rewires cardiac circadian homeostasis in mice. Arch Toxicol 2019; 94:257-271. [PMID: 31768571 DOI: 10.1007/s00204-019-02626-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 11/13/2019] [Indexed: 12/29/2022]
Abstract
Circadian rhythms disruption can be the cause of chronic diseases. External cues, including therapeutic drugs, have been shown to modulate peripheral-circadian clocks. Since anthracycline cardiotoxicity is associated with loss of mitochondrial function and metabolic remodeling, we investigated whether the energetic failure induced by sub-chronic doxorubicin (DOX) treatment in juvenile mice was associated with persistent disruption of circadian regulators. Juvenile C57BL/6J male mice were subjected to a sub-chronic DOX treatment (4 weekly injections of 5 mg/kg DOX) and several cardiac parameters, as well as circadian-gene expression and acetylation patterns, were analyzed after 6 weeks of recovery time. Complementary experiments were performed with Mouse Embryonic Fibroblasts (MEFs) and Human Embryonic Kidney 293 cells. DOX-treated juvenile mice showed cardiotoxicity markers and persistent alterations of transcriptional- and signaling cardiac circadian homeostasis. The results showed a delayed influence of DOX on gene expression, accompanied by changes in SIRT1-mediated cyclic deacetylation. The mechanism behind DOX interference with the circadian clock was further studied in vitro, in which were observed alterations of circadian-gene expression and increased BMAL1 SIRT1-mediated deacetylation. In conclusion, DOX treatment in juvenile mice resulted in disruption of oscillatory molecular mechanisms including gene expression and acetylation profiles.
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Affiliation(s)
- Luciana L Ferreira
- Mitochondrial Toxicology and Experimental Therapeutics Laboratory (MitoXT), CNC, Center for Neuroscience and Cell Biology, University of Coimbra, UC Biotech Building (Lote 8A), Biocant Park, 3060-197, Cantanhede, Portugal
| | - Marlene Cervantes
- Department of Biological Chemistry, Center for Epigenetics and Metabolism, University of California, Irvine, CA, 92697, USA
| | - Hugo J C Froufe
- Next Generation Sequencing Unit, Biocant, Biocant Park, Núcleo 04, Lote 8, Cantanhede, Portugal
| | - Conceição Egas
- Mitochondrial Toxicology and Experimental Therapeutics Laboratory (MitoXT), CNC, Center for Neuroscience and Cell Biology, University of Coimbra, UC Biotech Building (Lote 8A), Biocant Park, 3060-197, Cantanhede, Portugal.,Next Generation Sequencing Unit, Biocant, Biocant Park, Núcleo 04, Lote 8, Cantanhede, Portugal
| | - Teresa Cunha-Oliveira
- Mitochondrial Toxicology and Experimental Therapeutics Laboratory (MitoXT), CNC, Center for Neuroscience and Cell Biology, University of Coimbra, UC Biotech Building (Lote 8A), Biocant Park, 3060-197, Cantanhede, Portugal
| | - Paolo Sassone-Corsi
- Department of Biological Chemistry, Center for Epigenetics and Metabolism, University of California, Irvine, CA, 92697, USA
| | - Paulo J Oliveira
- Mitochondrial Toxicology and Experimental Therapeutics Laboratory (MitoXT), CNC, Center for Neuroscience and Cell Biology, University of Coimbra, UC Biotech Building (Lote 8A), Biocant Park, 3060-197, Cantanhede, Portugal. .,Institute for Interdisciplinary Research (I.I.I.), University of Coimbra, Coimbra, Portugal.
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