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1.
J Biomed Nanotechnol ; 16(6): 922-930, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33187587

RESUMO

Doxorubicin (DOX) is a widely used and effective anticancer drug. However, it shows high cardiotoxicity in several patients. The exact biological mechanisms of DOX-induced cardiotoxicity remain unclear. In the present study, we developed and assessed novel injectable hydrogel matrices combined with nanoparticles and secretome biomolecules to reduce DOXinduced cytotoxicity in human stem cell-derived cardiomyocytes. A Fe2O3 nanoparticle-loaded biocompatible silk sericin nanocomposite form was fabricated and used as an injectable carrier for secretome for in vivo cardiomyocyte metabolism. The formulated hydrogels carrying secretome were analyzed in vitro for proliferation, migration, and tube formation of human stem cell-derived cardiomyocytes. Biological analyses revealed that the secretome-encapsulated florescent Fe3O2 Silk sericin (Sec@MSS) hydrogel markedly reduced calcein-PI dual staining in cardiomyocytes, revealing significantly induced apoptosis. Furthermore, we evaluated the mitochondrial membrane potential for DOX and Sec@MSS hydrogel, and demonstrated apoptosis of the cardiomyocytes in the DOX-alone and Sec@MSS groups. However, the cardiotoxicity of Sec@MSS sericin was much lower than that in the DOX group, and was further evaluated via VEGFR and TUNEL analyses. The results indicate that Sec@MSS hydrogel might serve as an effective treatment agent in cardiac diseases in the future.


Assuntos
Compostos Férricos , Miócitos Cardíacos , Apoptose , Cardiotoxicidade , Doxorrubicina/toxicidade , Humanos , Hidrogéis , Fenômenos Magnéticos
2.
J Biomed Nanotechnol ; 16(4): 419-431, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32970975

RESUMO

Many promising pharmaceutically active compounds have low solubility in aqueous environments and their encapsulation into efficient drug delivery vehicles is crucial to increase their bioavailability. Lipodisq nanoparticles are approximately 10 nm in diameter and consist of a circular phospholipid bilayer, stabilized by an annulus of SMA (a hydrolysed copolymer of styrene and maleic anhydride). SMA is used extensively in structural biology to extract and stabilize integral membrane proteins for biophysical studies. Here, we assess the potential of these nanoparticles as drug delivery vehicles, determining their cytotoxicity and the in vivo excretion pathways of their polymer and lipid components. Doxorubicin-loaded Lipodisqs were cytotoxic across a panel of cancer cell lines, whereas nanoparticles without the drug had no effect on cell proliferation. Intracellular doxorubicin release from Lipodisqs in HeLa cells occurred in the low-pH environment of the endolysosomal system, consistent with the breakdown of the discoidal structure as the carboxylate groups of the SMA polymer become protonated. Biodistribution studies in mice showed that, unlike other nanoparticles injected intravenously, most of the Lipodisq components were recovered in the colon, consistent with rapid uptake by hepatocytes and excretion into bile. These data suggest that Lipodisqs have the potential to act as delivery vehicles for drugs and contrast agents.


Assuntos
Nanopartículas , Distribuição Tecidual , Animais , Linhagem Celular Tumoral , Doxorrubicina/toxicidade , Células HeLa , Humanos , Maleatos/toxicidade , Camundongos , Nanopartículas/toxicidade
3.
Life Sci ; 261: 118346, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32853656

RESUMO

Doxorubicin is an antineoplastic in the anthracycline class widely used for the treatment of several solid tumors and blood cancers. Cardiotoxicity is the major dose-limiting adverse effect of the drug. Chronic and accumulated doxorubicin administration cause myocyte damage and myocardial fibrosis. Doxorubicin-associated cardiotoxicity can be also observed after a short-course drug treatment even without clinical evidence of cardiac disease. Nevertheless, acute underlying mechanisms involved in the initiation of drug-induced cardiotoxicity remain poorly explored despite their similarities with pathophysiological conditions where cardiac TRH (cTRH) plays a central role. We showed that cTRH mediates myocardial injury induced by hypertension, and angiotensin II. Further, cTRH overexpression induces cardiac apoptosis, hypertrophy and fibrosis. AIM: To demonstrate that cTRH could mediate acute doxorubicin cardiotoxicity. MAIN METHOD: A single injection of doxorubicin (10 mg kg/day i.p.) was used to evaluate acute cardiac damage in a short-term experimental model of doxorubicin-induced cardiotoxicity. While inhibiting cTRH by small interfering RNA (siRNA), we evaluated the progression of cardiotoxicity. KEY FINDINGS: We found a doxorubicin-induced TRH overexpression in the LV, which was associated with apoptosis, hypertrophy and fibrosis. siRNA-mediated cTRH suppression prevented the doxorubicin-associated cardiac histological lesions. SIGNIFICANCES: doxorubicin requires an active cardiac TRH system to promote heart injury.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Cardiotoxicidade/etiologia , Doxorrubicina/toxicidade , Hormônio Liberador de Tireotropina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Cardiomegalia/induzido quimicamente , Cardiotoxicidade/fisiopatologia , Progressão da Doença , Fibrose/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Interferente Pequeno , Hormônio Liberador de Tireotropina/genética
4.
Life Sci ; 260: 118216, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32768582

RESUMO

AIMS: Doxorubicin (DOX) is a potent anticancer drug with severe dose-dependent cardiotoxicity. To address this issue, previous research primarily focused on DOX-induced toxicity on cardiomyocytes. However, more recent research has looked into the endothelium as a therapeutic target due to the emerging role of endothelial cells in the support of cardiomyocyte survival and function. MAIN METHODS: We investigated a novel role of endothelial cell (EC) primary cilia in the prevention of DOX-mediated cardiotoxicity. Mice lacking EC primary cilia, via the deletion of EC-specific intraflagellar protein 88 (IFT88) expression, were administered DOX (20 mg/kg i.p.), and assessed for survival, cardiac function, cardiac structure changes, and indices of cardiomyocyte injury. KEY FINDINGS: DOX-treatment resulted in reduced survival and cardiac function (ejection fraction and fractional shortening) in EC-IFT88-/- mice vs. their similarly treated wild-type littermates. Cardiomyocyte vacuolization, cardiac fibrosis, and serum CK-MB levels were also increased in DOX-treated mice compared to saline-treated controls. However, these parameters were not significantly different when comparing WT and EC-IFT88-/- mice after DOX treatment. SIGNIFICANCE: The loss of EC primary cilia accelerated DOX-mediated mortality and reduced cardiac function, suggesting pathways downstream of ciliary-mediated signal transduction as potential targets to promote EC support of cardiomyocyte function during DOX treatment.


Assuntos
Cílios/fisiologia , Doxorrubicina/toxicidade , Células Endoteliais/fisiologia , Cardiopatias/induzido quimicamente , Proteínas Supressoras de Tumor/fisiologia , Animais , Cruzamentos Genéticos , Células Endoteliais/ultraestrutura , Cardiopatias/fisiopatologia , Cardiopatias/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteínas Supressoras de Tumor/deficiência
5.
Chem Biol Interact ; 330: 109219, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32846153

RESUMO

The lack of tissue selectivity of anticancer drugs generates intense collateral and adverse effects of cancer patients, making the incorporation of vitamins or micronutrients into the diet of individuals to reduce side or adverse effects of antineoplastics. The study aimed to evaluate the effects of retinol palmitate (RP) on the toxicogenic damages induced by cyclophosphamide (CPA), doxorubicin (DOX) and its association with the AC protocol (CPA + DOX), in Sarcoma 180 (S-180) tumor cell line, using the micronuclei test with a block of cytokinesis (CBMN); and in non-tumor cells derived from Mus musculus using the comet assay. The results suggest that CPA, DOX and AC protocol induced significant toxicogenic damages (P < 0.05) on the S-180 cells by induction of micronuclei, cytoplasmic bridges, nuclear buds, apoptosis, and cell necrosis, proving their antitumor effects, and significant damage (P < 0.001) to the genetic material of peripheral blood cells of healthy mice, proving the genotoxic potential of these drugs. However, RP modulated the toxicogenic effects of antineoplastic tested both in the CBMN test (P < 0.05), at the concentrations of 1, 10 and 100 IU/mL; as in the comet assay (P < 0.001) at the concentration of 100 IU/kg for the index and frequency of genotoxic damage. The accumulated results suggest that RP reduced the action of antineoplastics in non-tumor cells as well as the cytotoxic, mutagenic, and cell death in neoplastic cells.


Assuntos
Antineoplásicos/toxicidade , Diterpenos/farmacologia , Vitamina A/análogos & derivados , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Ensaio Cometa , Ciclofosfamida/efeitos adversos , Ciclofosfamida/toxicidade , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Doxorrubicina/efeitos adversos , Doxorrubicina/toxicidade , Interações Medicamentosas , Humanos , Camundongos , Testes para Micronúcleos , Mutagênese/efeitos dos fármacos , Vitamina A/farmacologia
6.
Environ Toxicol ; 35(12): 1374-1385, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32691977

RESUMO

Cardiovascular disease created enormous health and economic burdens worldwide, which is responsible for the highest mobility and mortality that results in nearly 6.2% of in-hospital deaths every year. Plumbagin is a major bioactive compound that occurs in the Plumbago indica and P. zeylanica with numerous therapeutic benefits. The current research exploration was planned to investigate the therapeutic role of plumbagin against doxorubicin stimulated cardiotoxicity in rats. The cardiotoxicity was stimulated to the rats by administering the 2.5 mg/kg of doxorubicin for 14 days with concurrent supplementation with plumbagin. The hemodynamic parameters were studied by using the tail-cuff plethysmography. The lipid peroxidation and antioxidant status was examined by the standard procedures. The myocardial function and damage markers were assessed with the help of commercial kits. The expression status of inflammatory markers and PI3K/Akt signaling markers were investigated by reverse transcription polymerase chain reaction (RT-PCR) and western blotting analysis, respectively. The plumbagin supplementation appreciably regained the body weight and heart weight of the investigational animals. Hemodynamic parameters and antioxidants statuses were escalated by the plumbagin treatment. The severe elevation in the cardiac damage markers and inflammatory markers were noticeably ameliorated by the plumbagin treatment. The plumbagin treatment also assuaged the overexpression of inflammatory and apoptotic proteins in the heart tissues of doxorubicin-challenged rats. The histopathological analysis revealed that the plumbagin appreciably protected the heart tissues from the doxorubicin-induced damages. The findings of this exploration evidenced that plumbagin treatment attenuated the doxorubicin-stimulated cardiotoxicity in rats.


Assuntos
Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Doxorrubicina/toxicidade , Coração/efeitos dos fármacos , Miocárdio , Naftoquinonas/farmacologia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Biomarcadores/sangue , Cardiotoxicidade , Citocinas/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais
8.
Life Sci ; 257: 118074, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32673667

RESUMO

AIM: Doxorubicin (DOX) induces dose-dependent cardiotoxicity due to reactive oxygen species (ROS)-mediated oxidative stress and subsequent apoptosis of cardiomyocytes. We aimed to assess whether sodium thiosulfate (STS), which has antioxidant and antiapoptotic properties, exerts cardioprotective effects on DOX-induced cardiomyopathy. MAIN METHODS: Male C57BL/6N mice were divided into four groups, control, DOX, STS, and DOX + STS, and administered DOX (20 or 30 mg/kg) or normal saline intraperitoneally, followed by an injection of STS (2 g/kg) or normal saline 4 h later. KEY FINDINGS: The DOX group showed a poorer 6-day survival and decreased cardiac function than the DOX + STS group. The DOX group showed a marked increase in the plasma creatine kinase isoenzyme myocardial band (CK-MB) and lactate dehydrogenase (LDH) levels 10 h after DOX injection, while the DOX + STS group showed suppression of DOX-induced elevation of CK-MB and LDH levels. The DOX group showed increased 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in the heart, whereas the DOX + STS group showed increased catalase and superoxide dismutase (SOD) activities and decreased 8-OHdG levels in the heart compared with DOX group, suggesting that STS reduces DOX-induced DNA damage by improving antioxidant enzymes activities in cardiomyocytes. Additionally, the DOX + STS group showed attenuation of cleaved caspase-3 and DNA fragmentation in cardiomyocytes compared with the DOX group, suggesting that STS suppresses DOX-induced apoptosis in cardiomyocytes. SIGNIFICANCE: STS exerts cardioprotective effects against DOX-induced cardiac dysfunction partly by improving antioxidant defense and suppressing apoptosis, indicating the therapeutic potential of STS against DOX-induced cardiomyopathy.


Assuntos
Cardiotoxicidade/prevenção & controle , Dano ao DNA/efeitos dos fármacos , Doxorrubicina/toxicidade , Miócitos Cardíacos/efeitos dos fármacos , Tiossulfatos/farmacologia , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/toxicidade , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Cardiotoxicidade/etiologia , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
9.
Toxicology ; 441: 152508, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32525084

RESUMO

Doxorubicin (DOX) is one of the most effective and irreplaceable chemotherapeutic agents but its clinical use is limited due to its cardiotoxicity. Glycyrrhizin(GL) has been applied to liver disorders for long. However, little is known that if GL could be meaningful in attenuating cardiotoxicity. The aim of this study is to investigate the cardioprotective effects of GL in DOX-induced cardiotoxicity (DIC) and the underlying mechanism. Here, H9c2 cardiomyoblasts, Neonatal rat cardiomyocytes (NRCMs), and Rats were introduced as test models. A single dose of 20 mg/kg DOX (i.p.) was applied to induce acute cardiotoxicity in vivo, as reflected by growth inhibition, increased levels of AST and CK-MB, and reduction of SOD activity, while GL (25 or 50 mg/kg/d, 14 d, i.p.) could counteract these effects. Moreover, pre-incubation with GL (0.8 mM for 12 h) in H9c2 cells protected against DOX-induced cytotoxicity, oxidative stress and depolarization of mitochondrial membrane potential (MMP). Besides, Western blot analysis showed that DOX upregulated the expression of LC3 II and p62 whereas GL reversed that both in vitro and in vivo and improved the obstructed autophagy flux in DOX-treated H9c2 cells with an autophagy inhibitor Bafilomycin A1 (Baf A1, 50 nM, 2 h). It has been previously documented that High-mobility group box 1 (HMGB1) was involved in DIC. In our work, knockdown of HMGB1 significantly increased cell viability and LC3 II level in H9c2, suggesting HMGB1 was crucial in DOX-induced autophagy-triggering cell death. Intriguingly, GL is a direct inhibitor of HMGB1. We found that GL downregulated Akt/mTOR autophagy signaling pathway in DOX-treated H9c2 cells. More importantly, in non-silencing H9c2 cells (transfected with negative control siRNA) cells, the expression of phospho-Akt, phospho-mTOR, p62, and LC3 II was significantly decreased with GL pretreament compared to DOX alone. However, in H9c2/HMGB1-(transfected with HMGB1 siRNA) cells exposed to DOX, the expression of p-Akt, p-mTOR, p62, LC3 II had no statistical difference with or without GL, revealing that HMGB1 mediated the cardioprotective action of GL in DIC. Taken together, our findings demonstrate that improved autophagy flux via HMGB1-dependent Akt/mTOR signaling pathway might contribute to attenuate DIC and go a novel insight into the underlying mechanisms of GL's cardioprotective action. GL could be a potential candidate for the prevention of DIC.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Autofagia/efeitos dos fármacos , Cardiotoxinas/toxicidade , Doxorrubicina/toxicidade , Ácido Glicirrízico/farmacologia , Proteína HMGB1/metabolismo , Coração/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Animais , Western Blotting , Cardiotoxinas/antagonistas & inibidores , Linhagem Celular , Doxorrubicina/antagonistas & inibidores , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
10.
Life Sci ; 253: 117732, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32360570

RESUMO

AIMS: Recently, the zebrafish has gained attention as an innovative experimental model to decipher molecular and cellular mechanisms involved in cardiovascular development and diseases. Nevertheless, the use of zebrafish models has been challenged because the transparency of these fish, which allows for accurate cardiac evaluation, disappears in adulthood. In this study, the epicardial outline method was performed to investigate the feasibility of echocardiography in assessing cardiac function in pathological adult zebrafish. MATERIALS AND METHODS: We attempted to estimate heart failure in adult zebrafish treated with three distinct regulators of cardiac function: phenylhydrazine hydrochloride (PHZ), doxorubicin (DOX), and ethanol. B-mode and Doppler images were evaluated at frequencies of up to 50 MHz and 40 MHz, respectively. The correlation between alterations in cardiac function, haemoglobin concentration, and myocardial histopathology were assessed. KEY FINDINGS: Cardiac output (CO) in PHZ-treated zebrafish was significantly higher than that in control zebrafish (151 ± 67 vs. 84 ± 37 µl/min, P = 0.004), whereas ejection fraction (EF) was lower (36.3 ± 10.9 vs. 50.9 ± 8.7%, P < 0.001), indicating typical high output heart failure derived from anaemia. Additionally, ventricular dysfunction in DOX-treated zebrafish was characterised by low CO (57 ± 38 µl/min) and EF (28.8 ± 10.4%), accompanied by an enlarged ventricle in diastole and systole, representing low output heart failure. For ethanol-treated zebrafish, EF was markedly reduced (39.6 ± 7.2%) indicating a dilated heart, while CO remained unchanged (90 ± 40 µl/min). SIGNIFICANCE: The epicardial outline method is an effective way of using echocardiography to assess cardiac dysfunction in pathological adult zebrafish, unlocking a major bottleneck in this research field with limited cardiac functional assays.


Assuntos
Ecocardiografia/métodos , Cardiopatias/diagnóstico por imagem , Insuficiência Cardíaca/diagnóstico por imagem , Pericárdio/diagnóstico por imagem , Animais , Débito Cardíaco/fisiologia , Modelos Animais de Doenças , Doxorrubicina/toxicidade , Etanol/toxicidade , Estudos de Viabilidade , Feminino , Cardiopatias/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Fenil-Hidrazinas/toxicidade , Disfunção Ventricular/diagnóstico por imagem , Disfunção Ventricular/fisiopatologia , Peixe-Zebra
11.
Phytomedicine ; 70: 153215, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32388040

RESUMO

BACKGROUND: Recalcitrant cancers appear as a major obstacle to chemotherapy, prompting scientists to intensify the search for novel drugs to tackle the cell lines expressing multi-drug resistant (MDR) phenotypes. PURPOSE: The purpose of this study was to evaluate the antiproliferative potential of a ferrulic acid derivative, 8,8-bis-(dihydroconiferyl)-diferulate (DHCF2) on a panel of 18 cancer cell lines, including various sensitive and drug-resistant phenotypes, belonging to human and animals. The mode of induction of cell death by this compound was further studied. METHODS: The antiproliferative activity, autophagy, ferroptotic and necroptotic cell death were evaluated by the resazurin reduction assay (RRA). CCRF-CEM leukemia cells were used for all mechanistic studies. A caspase-Glo assay was applied to evaluate the activity of caspases. Cell cycle analysis (PI staining), apoptosis (annexin V/PI staining), mitochondrial membrane potential (MMP) (JC-1) and reactive oxygen species (ROS) (H2DCFH-DA) were assessed by flow cytometry. RESULTS: DHCF2 demonstrated impressive cytotoxic effects towards the 18 cancer cell lines tested, with IC50 values all below 6.5 µM. The obtained IC50 values were in the range of 1.17 µM (towards CCRF-CEM leukemia cells) to 6.34 µM (towards drug-resistant HCT116 p53-/- human colon adenocarcinoma cells) for DHCF2 and from 0.02 µM (against CCRF-CEM cells) to 122.96 µM (against multidrug-resistant CEM/ADR5000 leukemia cells) for the reference drug, doxorubicin. DHCF2 had IC50 values lower than those of doxorubicin, against CEM/ADR5000 cells and on some melanoma cell lines, such as MaMel-80a cells, Mel-2a cells, MV3 cells and SKMel-505 cells. DHCF2 induced autophagy as well as apoptosis in CCRF-CEM cells though caspases activation, MMP alteration and increase of ROS production. CONCLUSION: The studied diferulic acid, DHCF2, is a promising antiproliferative compound. It deserves further indepth investigations with the ultimate aim to develop a novel drug to fight cancer drug resistance.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Doxorrubicina/uso terapêutico , Doxorrubicina/toxicidade , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Humanos , Camundongos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Extratos Vegetais/toxicidade
12.
Life Sci ; 255: 117844, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32464124

RESUMO

AIMS: Interleukin (IL) 9 is a pleiotropic cytokine, and recent studies have demonstrated that IL-9 is associated with several cardiovascular diseases, via regulation of the inflammatory response. Doxorubicin (DOX) is known to induce severe cardiac injury and dysfunction by enhancing inflammation. This study aimed to investigate the role of IL-9 in DOX-induced cardiotoxicity. MATERIALS AND METHODS: DOX was used to induce cardiac dysfunction and the expression of IL-9 in the murine cardiac tissues was measured. The mice were intraperitoneally injected with recombinant mouse IL-9 (rmIL-9) or anti-IL-9 neutralizing antibody (IL-9nAb) for investigating the effect of IL-9 on DOX-induced cardiac injury and dysfunction. The messenger ribonucleic acid (mRNA) expression levels of the pro-inflammatory cytokines were determined in each group by quantitative real-time polymerase chain reaction (RT-qPCR). The effect of rmIL-9 or IL-9nAb on DOX-induced apoptosis was determined both in vivo and vitro. KEY FINDINGS: IL-9 levels significantly increased in the heart following DOX injection. Cardiac injury and dysfunction were induced by DOX, and treatment with IL-9nAb significantly alleviated DOX-induced injury, whereas rmIL-9 administration aggravated the cardiac damage. IL-9nAb decreased the expression of pro-inflammatory cytokines in the DOX-treated mice, while rmIL-9 administration increased the levels of pro-inflammatory cytokines. IL-9nAb reduced DOX-induced myocardial apoptosis, whereas rmIL-9 administration produced the opposite results. Additionally, IL-9nAb mitigated the DOX-induced apoptosis in H9C2 cells, while administration of rmIL-9 produced the opposite effect. SIGNIFICANCE: Our results demonstrated that IL-9 aggravated DOX-induced cardiac injury and dysfunction by promoting the inflammatory response and cardiomyocyte apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Cardiotoxicidade/etiologia , Doxorrubicina/toxicidade , Inflamação/induzido quimicamente , Interleucina-9/metabolismo , Animais , Antibióticos Antineoplásicos/toxicidade , Cardiotoxicidade/fisiopatologia , Linhagem Celular , Citocinas/metabolismo , Inflamação/patologia , Interleucina-9/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos
13.
Am J Physiol Heart Circ Physiol ; 319(1): H133-H143, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32469636

RESUMO

In clinical studies, platelet aggregation and risk of thrombosis are increased in patients after doxorubicin treatment. However, the exact role of doxorubicin in platelet functions and thrombus formation in vivo remain unclear. The present study is to investigate the role of doxorubicin in platelet function in relation to thrombus formation and vascular toxicity, as well as the efficacy of antiplatelet therapy. Mice were treated with doxorubicin or vehicle (5 mg/kg iv, 4 wk), and the following parameters were determined: platelet count and size, platelet surface adhesive receptors by flow cytometry, density of granules by electron microscopy, platelet aggregation and degranulation at resting or agonist-stimulated state, platelet adhesion on fibrinogen or endothelial cells, and thrombus formation on collagen matrix. The efficacy of clopidogrel (15 mg·kg-1·day-1, followed by 5 mg·kg-1·day-1) on doxorubicin-induced changes in the aforementioned parameters as well as vascular injury were also determined. Whereas platelet count and size were similar between doxorubicin-treated and vehicle-treated mice, doxorubicin promoted thrombus formation evidenced by greater platelet aggregation, degranulation, and adhesion to endothelial cells evoked by agonists. Clopidogrel treatment attenuated the enhanced platelet activity and thrombus formation by doxorubicin, as well as vascular platelet infiltration and reactive oxygen species generation. Collectively, this study demonstrates that platelet functions are enhanced after long-term doxorubicin administration, which leads to thrombus formation and vascular toxicity, and that doxorubicin-induced changes in the functionality of platelets can be effectively inhibited by antiplatelet drugs.NEW & NOTEWORTHY Doxorubicin therapy in mice (antitumor dosage) markedly enhanced platelet functions measured as agonist-induced platelet aggregation, degranulation, and adhesion to endothelial cells, actions leading to thrombus formation and thrombosis-independent vascular injury. Clopidogrel treatment ameliorated thrombus formation and vascular toxicity induced by doxorubicin via inhibiting platelet activity.


Assuntos
Antineoplásicos/toxicidade , Plaquetas/efeitos dos fármacos , Doxorrubicina/toxicidade , Endotélio Vascular/efeitos dos fármacos , Trombose/etiologia , Animais , Antineoplásicos/farmacologia , Plaquetas/fisiologia , Células Cultivadas , Doxorrubicina/farmacologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Agregação Plaquetária
14.
Nucleic Acids Res ; 48(9): 4992-5005, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32239217

RESUMO

SIRT6 deacetylase activity improves stress resistance via gene silencing and genome maintenance. Here, we reveal a deacetylase-independent function of SIRT6, which promotes anti-apoptotic gene expression via the transcription factor GATA4. SIRT6 recruits TIP60 acetyltransferase to acetylate GATA4 at K328/330, thus enhancing its chromatin binding capacity. In turn, GATA4 inhibits the deacetylase activity of SIRT6, thus ensuring the local chromatin accessibility via TIP60-promoted H3K9 acetylation. Significantly, the treatment of doxorubicin (DOX), an anti-cancer chemotherapeutic, impairs the SIRT6-TIP60-GATA4 trimeric complex, blocking GATA4 acetylation and causing cardiomyocyte apoptosis. While GATA4 hyperacetylation-mimic retains the protective effect against DOX, the hypoacetylation-mimic loses such ability. Thus, the data reveal a novel SIRT6-TIP60-GATA4 axis, which promotes the anti-apoptotic pathway to prevent DOX toxicity. Targeting the trimeric complex constitutes a new strategy to improve the safety of DOX chemotherapy in clinical application.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Doxorrubicina/toxicidade , Epigênese Genética , Fator de Transcrição GATA4/metabolismo , Miócitos Cardíacos/metabolismo , Sirtuínas/metabolismo , Acetilação , Animais , Apoptose , Células Cultivadas , Expressão Gênica , Células HEK293 , Humanos , Lisina Acetiltransferase 5/metabolismo , Camundongos , Camundongos Knockout , Miócitos Cardíacos/efeitos dos fármacos , Ratos , Sirtuínas/genética
15.
BMC Complement Med Ther ; 20(1): 112, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32293408

RESUMO

BACKGROUND: Shenmai injection (SMI) has been used in the treatment of cardiovascular disease (CVD), such as heart failure, myocardial ischemia and coronary heart disease. It has been found to have efficacy on doxorubicin (DOX)-induced cardiomyopathy. The aims of this study were to explore the underlying molecular mechanisms of SMI treatment on CVD by using network pharmacology and its protective effect on DOX-induced cardiotoxicity by in vitro and in vivo experiment based on network pharmacology prediction. METHODS: Network pharmacology method was used to reveal the relationship between ingredient-target-disease and function-pathway of SMI on the treatment of CVD. Chemical ingredients of SMI were collected form TCMSP, BATMAN-TCM and HIT Database. Drugbank, DisGeNET and OMIM Database were used to obtain potential targets for CVD. Networks were visualized utilizing Cytoscape software, and the enrichment analysis was performed using IPA system. Finally, cardioprotective effects and predictive mechanism confirmation of SMI were investigated in H9c2 rat cardiomyocytes and DOX-injured C57BL/6 mice. RESULTS: An ingredient-target-disease & function-pathway network demonstrated that 28 ingredients derived from SMI modulated 132 common targets shared by SMI and CVD. The analysis of diseases & functions, top pathways and upstream regulators indicated that the cardioprotective effects of SMI might be associated with 28 potential ingredients, which regulated the 132 targets in cardiovascular disease through regulation of G protein-coupled receptor signaling. In DOX-injured H9c2 cardiomyocytes, SMI increased cardiomyocytes viability, prevented cell apoptosis and increased PI3K and p-Akt expression. This protective effect was markedly weakened by PI3K inhibitor LY294002. In DOX-treated mice, SMI treatment improved cardiac function, including enhancement of ejection fraction and fractional shortening. CONCLUSIONS: Collectively, the protective effects of SMI on DOX-induced cardiotoxicity are possibly related to the activation of the PI3K/Akt pathway, as the downstream of G protein-coupled receptor signaling pathway.


Assuntos
Apoptose/efeitos dos fármacos , Cardiomiopatias/tratamento farmacológico , Cardiotoxicidade/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , Animais , Cardiomiopatias/induzido quimicamente , Linhagem Celular , Modelos Animais de Doenças , Doxorrubicina/toxicidade , Combinação de Medicamentos , Injeções , Camundongos , Camundongos Endogâmicos C57BL , Mapas de Interação de Proteínas , Ratos
16.
Arch Razi Inst ; 75(1): 55-62, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32292003

RESUMO

Doxorubicin (DOX) is one of the secondary metabolites of Streptomyces peucetius var. caesius. It is a common and effective chemotherapeutic agent used for the treatment of different diseases, including lymphoma, leukemia, breast cancer, and solid tumors. However, this medicine causes cardiotoxic side effects, which limit its clinical application. The present study examined the cardiomyopathy induced by DOX via echocardiography and transmission electron microscopy (TEM). The main objective was to evaluate the capacity of echocardiography and TEM as diagnostic tools for DOX-induced cardiotoxicity. Moreover, the correlation between intracellular and functional changes due to cardiotoxicity was assessed in a rat model. Cardiomyopathy was induced in rats by two cumulative doses of DOX. Group I received DOX 12 [i.e., 12 mg/kg, intraperitoneal (IP)] and group II received DOX 15 (i.e., 15 mg/kg, IP) in six equal doses over two weeks. Group III as the control (Ctrl) group received normal saline as a vehicle. Mortality during the study was only observed in the DOX 15 group. The echocardiographic assessments revealed significant changes in ejection fraction, fractional shortening, and heart rate in the groups which received DOX. In addition, severe cardiac arrhythmia was evident in DOX-treated groups. Remarkable adverse effects, such as moderately degenerated cells and inflated mitochondria were observed in the TEM analysis of rat hearts in the DOX groups. The present study indicated that rat models are suitable for investigating DOX-induced cardiomyopathy, especially at the dose of 12 mg/kg. Furthermore, echocardiography and TEM examinations were found to be valuable methods for the determination of cardiotoxicity in rats due to DOX.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Doxorrubicina/toxicidade , Ecocardiografia/veterinária , Coração/efeitos dos fármacos , Miocárdio/ultraestrutura , Animais , Cardiotoxicidade/veterinária , Masculino , Microscopia Eletrônica de Transmissão/veterinária , Miocárdio/patologia , Distribuição Aleatória , Ratos , Ratos Wistar
17.
Life Sci ; 249: 117498, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32142765

RESUMO

AIMS: Doxorubicin (DOX) is an effective anthracycline anticancer drug. However, the clinical usage of it is limited due to its severe cardiotoxicity side effects. Metformin (Met) is a kind of first-line antihyperglycemic drug which has a potential protective effect on the heart,it is often used for oral treatment of type 2 diabetes. In this study, we explored whether Met could attenuate cardiotoxicity induced by DOX. MATERIALS AND METHODS: For the sake of exploring the Met protective effect and mechanism, we established the DOX-induced cardiotoxicity models both in H9C2 cells incubated with 5 µM DOX in vitro and Sprague-Dawley rats treated with 20 mg/kg cumulative dose of DOX. KEY FINDINGS: Met is able to inhibit growth inhibition and apoptosis of H9C2 cells induced by DOX. The heart indexes of rats were examined to evaluate the Met cardiotoxicity protection. Met improved the abnormal indexes, serum markers of cardiac heart injury, echocardiography, electrocardiogram, cardiac pathology, cardiomyocyte apoptosis, and oxidative stress markers induced by DOX. Furthermore, in vivo and in vitro studies demonstrated that Met protected against DOX-induced increasing cleaved caspase-3 and Bax. Met also prevented the downregulation of Bcl-2, activated the AMPK pathway, and inhibited the MAPK pathway. SIGNIFICANCE: Met showed protective effects on DOX-induced cardiotoxicity by reducing oxidative stress and apoptosis, as well as regulating AMPK and MAPK signaling pathways.


Assuntos
Adenilato Quinase/metabolismo , Antibióticos Antineoplásicos/toxicidade , Doxorrubicina/toxicidade , Coração/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases , Metformina/farmacologia , Animais , Linhagem Celular , Ratos , Ratos Sprague-Dawley
18.
Biochem Pharmacol ; 175: 113888, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32112883

RESUMO

Doxorubicin (DOX) is a powerful anthracycline antineoplastic drug whose clinical application is limited by serious cardiotoxic side effects. Dihydromyricetin (DHM), a flavonoid compound extracted from the Japanese raisin tree (Hovenia dulcis), is cardioprotective in patients with heart failure; however, the underlying mechanisms are poorly understood. The aim of this study was to assess the possible anti-inflammatory properties of DHM in a rat model of DOX-induced cardiotoxicity and DOX-treated H9C2 cells, and gain insights into the molecular mechanisms that mediate these effects. The results showed that DHM treatment significantly improved the myocardial structure and function in DOX-exposed rats by alleviating NLRP3 inflammasome-mediated inflammation. DHM also inhibited DOX-induced activation of the NLRP3 inflammasome in H9C2 cells. This effect was mediated by inhibition of caspase-1 activity, suppression of IL-1ß and IL-18 release, and upregulation of SIRT1 protein levels in vivo and in vitro. Moreover, selective inhibition of SIRT1 blocked the protective effects of DHM. Collectively, our findings indicate that DHM protects against DOX-induced cardiotoxicity by inhibiting NLRP3 inflammasome activation via stimulation of the SIRT1 pathway.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Doxorrubicina/toxicidade , Flavonóis/farmacologia , Coração/efeitos dos fármacos , Inflamassomos/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Sirtuína 1/metabolismo , Animais , Apoptose/efeitos dos fármacos , Cardiotoxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Masculino , Miocárdio/imunologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Ratos , Ratos Sprague-Dawley , Sirtuína 1/antagonistas & inibidores , Disfunção Ventricular Esquerda/induzido quimicamente , Disfunção Ventricular Esquerda/prevenção & controle
19.
Artigo em Inglês | MEDLINE | ID: mdl-32083974

RESUMO

Doxorubicin (Dox) is an effective chemotherapeutic for a variety of pediatric malignancies. Unfortunately, Dox administration often results in a cumulative dose-dependent cardiotoxicity that manifests with marked oxidative stress, leading to heart failure. Adjunct therapies are needed to mitigate Dox cardiotoxicity and enhance quality of life in pediatric patients with cancer. Angiotensin-(1-7) [Ang-(1-7)] is an endogenous hormone with cardioprotective properties. This study investigated whether adjunct Ang-(1-7) attenuates cardiotoxicity resulting from exposure to Dox in male and female juvenile rats. Dox significantly reduced body mass, and the addition of Ang-(1-7) had no effect. However, adjunct Ang-(1-7) prevented Dox-mediated diastolic dysfunction, including markers of decreased passive filling as measured by reduced early diastole mitral valve flow velocity peak (E) (P < 0.05) and early diastole mitral valve annulus peak velocity (e'; P < 0.001) and increased E/e' (P < 0.001), an echocardiographic measure of diastolic dysfunction. Since Dox treatment increases reactive oxygen species (ROS), the effect of Ang-(1-7) on oxidative by-products and enzymes that generate or reduce ROS was investigated. In hearts of male and female juvenile rats, Dox increased NADPH oxidase 4 (P < 0.05), a major cardiovascular NADPH oxidase isozyme that generates ROS, as well as 4-hydroxynonenal (P < 0.001) and malondialdehyde (P < 0.001), markers of lipid peroxidation; Ang-(1-7) prevented these effects of Dox. Cotreatment with Dox and Ang-(1-7) increased the antioxidant enzymes SOD1 (male: P < 0.05; female: P < 0.01) and catalase (P < 0.05), which likely contributed to reduced ROS. These results demonstrate that Ang-(1-7) prevents diastolic dysfunction in association with a reduction in ROS, suggesting that the heptapeptide hormone may serve as an effective adjuvant to improve Dox-induced cardiotoxicity.NEW & NOTEWORTHY Ang-(1-7) is a clinically safe peptide hormone with cardioprotective and antineoplastic properties that could be used as an adjuvant therapy to improve cancer treatment and mitigate the long-term cardiotoxicity associated with doxorubicin in pediatric patients with cancer.


Assuntos
Angiotensina I/uso terapêutico , Antineoplásicos/toxicidade , Antioxidantes/uso terapêutico , Doxorrubicina/toxicidade , Cardiopatias/tratamento farmacológico , Fragmentos de Peptídeos/uso terapêutico , Animais , Cardiotoxicidade , Catalase/metabolismo , Feminino , Cardiopatias/etiologia , Frequência Cardíaca , Masculino , Malondialdeído/metabolismo , Valva Mitral/fisiopatologia , Miocárdio/metabolismo , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
20.
Toxicology ; 435: 152410, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32068018

RESUMO

Epidemiologic studies show that the levels of air pollutants and particulate matter are positively associated with the morbidity and mortality of cardiovascular diseases. Here we demonstrate that the intratracheal instillation of multi-walled carbon nanotubes (MWCNTs), a standard fine particle, exacerbate doxorubicin (DOX)-induced cardiotoxicity in mice through altering gut microbiota and pulmonary and colonic macrophage phenotype. MWCNTs (25 µg/kg per day, 5 days a week for 3 weeks) promoted cardiotoxicity and apoptosis in the DOX (2 mg/kg, twice a week for 5 weeks)-treated C57BL/6 mice. MWCNTs exaggerated DOX-induced gut microbiota dysbiosis characterized by the increased abundances of Helicobacteraceae and Coriobacteriaceae. In addition, MWCNTs promoted DOX-induced M1-like polarization of colonic macrophages with an increase in TNF-α, IL-1ß and CC chemokine ligand 2 in peripheral blood. Importantly, treatment with the antibiotics attenuated MWCNTs plus DOX-induced apoptosis of cardiomyocytes and M1-like polarization of colonic macrophages. The fecal microbiota transplantation demonstrated that MWCNTs exaggerated DOX-induced cardiotoxicity with M1-like polarization of colonic macrophages. The conditioned medium from MWCNTs-treated pulmonary macrophages promoted DOX-induced gut microbiota dysbiosis and colonic macrophage polarization. Furthermore, the co-culture of macrophages and fecal bacteria promoted M1-like macrophage polarization and their production of TNF-α and IL-1ß, and thereby exacerbated the effects of MWCNTs. Moreover, IL-1ß and TNF-α blockade, either alone or in combination attenuated MWCNTs-exacerbated cardiotoxicity. In summary, MWCNTs exacerbate DOX-induced cardiotoxicity in mice through gut microbiota and pulmonary and colonic macrophage interaction. Our findings identify a novel mechanism of action of inhaled particle-driven cardiotoxicity.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Colo/efeitos dos fármacos , Doxorrubicina/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Cardiopatias/induzido quimicamente , Pulmão/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Nanotubos de Carbono/toxicidade , Animais , Antibacterianos/farmacologia , Apoptose/efeitos dos fármacos , Células Cultivadas , Quimiocina CCL2/sangue , Colo/imunologia , Colo/metabolismo , Colo/microbiologia , Disbiose , Fezes/microbiologia , Cardiopatias/sangue , Cardiopatias/imunologia , Cardiopatias/microbiologia , Interleucina-1beta/sangue , Pulmão/imunologia , Pulmão/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fenótipo , Fator de Necrose Tumoral alfa/sangue
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