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1.
Chem Biol Interact ; 347: 109599, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34343525

RESUMO

BACKGROUND: Geraniol, a natural monoterpene, is a component of many plant essential oils. It contains many medicinal and pharmacological properties. Doxorubicin is an anticancer drug; however, its clinical usage is limited due to its cumulative and dose-dependent cardiotoxicity. This study investigates geraniol as a protective agent against doxorubicin-induced cardiotoxicity and explores possible underlying mechanisms of action. METHODS: Male Sprague-Dawley rats were allocated into five groups. Groups 1 and 2 were administered saline and geraniol 200 mg/kg/day/orally, respectively, for 15 days. Group 3 was administered intraperitoneal doxorubicin (5 mg/kg/IP on the 5th, 10th and 15th days to achieve a cumulative dose of 15 mg/kg) to induce cardiotoxicity. The fourth and fifth groups were treated with either geraniol 100 mg/kg or 200 mg/kg orally and doxorubicin to equal the doxorubicin dose administered to Group 3. RESULTS: Treatment with geraniol significantly ameliorated cardiac damage and restored serum cardiac injury marker levels in doxorubicin treated animals. Geraniol upregulated Nrf2 and HO-1 expression, elevated total antioxidant capacity, decreased the nuclear accumulation of kappa-light-chain enhancer of activated B cells (NF-κB), decreased the phosphorylation and degradation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα), suppressed tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1ß), and interleukin-18 (IL-18) levels, and restored the levels of Bax and caspase-3 and 9 in heart tissue. CONCLUSION: Geraniol may function as a potential activator of nuclear factor erythroid 2-related factor 2 (Nrf2), which subsequently improves Nrf2-dependent antioxidative signaling, diminishes apoptosis and subdues the inflammatory response. The downstream result is protection of the heart from doxorubicin-induced cardiotoxicity.


Assuntos
Monoterpenos Acíclicos/uso terapêutico , Cardiotônicos/uso terapêutico , Cardiotoxicidade/tratamento farmacológico , Cymbopogon/química , Doxorrubicina/toxicidade , Transdução de Sinais/efeitos dos fármacos , Animais , Cardiotoxicidade/patologia , Eletrocardiografia/efeitos dos fármacos , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/metabolismo , Masculino , Mitocôndrias/efeitos dos fármacos , Miocárdio/patologia , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley
2.
Life Sci ; 283: 119849, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34343539

RESUMO

AIMS: Cardiotoxicity of doxorubicin frequently complicates treatment outcome. Aberrantly activated calcium/calmodulin pathway can eventually trigger signaling cascades that mediate cardiotoxicity. Therefore, we tested the hypothesis that trifluoperazine, a strong calmodulin antagonist, may alleviate this morbidity. MATERIALS AND METHODS: Heart failure and cardiotoxicity were assessed via echocardiography, PCR, immunohistochemistry, histopathology, Masson's trichrome staining and transmission electron microscopy. Whereas liver and kidney structural and functional alterations were evaluated histopathologically and biochemically. KEY FINDINGS: Results revealed that combination treatment with trifluoperazine could overcome doxorubicin-induced heart failure with reduced ejection fraction. Moreover, heart weight/body weight ratio and histopathological examination showed that trifluoperazine mitigated doxorubicin-induced cardiac atrophy, inflammation and myofibril degeneration. Transmission electron microscopy further confirmed the marked restoration of the left ventricular ultrastructures by trifluoperazine pretreatment. In addition, Masson's trichrome staining revealed that trifluoperazine could significantly inhibit doxorubicin-induced left ventricular remodeling by fibrosis. Of note, doxorubicin induced the expression of myocardial nuclear NF-κB-p65 and caspase-3 which were markedly inhibited by trifluoperazine, suggesting that cardioprotection conferred by trifluoperazine involved, at least in part, suppression of NF-κB and apoptosis. Furthermore, biochemical and histopathological examinations showed that trifluoperazine improved doxorubicin-induced renal and hepatic impairments both functionally and structurally. SIGNIFICANCE: In conclusion, the present in vivo study is the first to provide evidences underscoring the protective effects of trifluoperazine that may pave the way for repurposing this calmodulin antagonist in ameliorating organ toxicity by doxorubicin.


Assuntos
Apoptose/efeitos dos fármacos , Cardiotoxicidade , Cardiotoxinas/efeitos adversos , Doxorrubicina/efeitos adversos , Miocárdio/metabolismo , Fator de Transcrição RelA/metabolismo , Trifluoperazina/farmacologia , Animais , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Cardiotoxinas/farmacologia , Caspase 3/metabolismo , Doxorrubicina/farmacologia , Masculino , Camundongos , Miocárdio/patologia
3.
J Biochem Mol Toxicol ; 35(9): e22842, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34273911

RESUMO

Doxorubicin (DOX) treatment has been associated with cardiotoxicity. Therefore, it is crucial to search for a therapeutic that can effectively mitigate DOX-induced cardiotoxicity. This study was conducted to investigate the protective effects of valsartan (VAL) against DOX-induced cardiotoxicity. Sprague-Dawley rats were divided into four treatment groups: Group I: Control, Group II: VAL (30 mg/kg, ip), Group III: DOX (15 mg/kg, ip), and Group IV: VAL + DOX (30 + 15 mg/kg, ip). All groups were treated every other day for 14 days. Blood was isolated for biochemical and metabolomics studies, and sections of the heart were also analyzed for histopathological and immunohistochemical alterations to detect changes in P53, BAX, BCL-2, and P62 expression. The combination of VAL + DOX resulted in a marked decrease in cardiac biomarker enzymes (aminotransferase and creatine phosphokinase) compared to DOX monotherapy. In addition, the histopathological examination of the VAL + DOX combination revealed a low percentage of fibrosis and inflammation. Immunohistochemical expression of p53 and BAX was significantly reduced, whereas BCL-2 expression was significantly increased in the VAL + DOX treatment group compared to DOX monotherapy. Also, the combination of VAL + DOX reverses the negative effect of DOX on nuclear p62 expression. Analysis of serum metabolites showed that DOX monotherapy reduced the number of several amino acids, whereas the combination of VAL + DOX restored these metabolic pathways. This study revealed the potential cardioprotective effect of VAL, which may provide novel and promising approaches for managing cardiotoxicity induced by DOX.


Assuntos
Cardiotônicos/farmacologia , Cardiotoxicidade , Doxorrubicina/administração & dosagem , Metabolômica , Valsartana/farmacologia , Animais , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Cardiotoxicidade/prevenção & controle , Doxorrubicina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley
4.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299059

RESUMO

BACKGROUND: Doxorubicin (Dox) is a first-line treatment for triple negative breast cancer (TNBC), but its use may be limited by its cardiotoxicity mediated by the production of reactive oxygen species. We evaluated whether vitamin D may prevent Dox-induced cardiotoxicity in a mouse TNBC model. METHODS: Female Balb/c mice received rodent chow with vitamin D3 (1500 IU/kg; vehicle) or chow supplemented with additional vitamin D3 (total, 11,500 IU/kg). the mice were inoculated with TNBC tumors and treated with intraperitoneal Dox (6 or 10 mg/kg). Cardiac function was evaluated with transthoracic echocardiography. The cardiac tissue was evaluated with immunohistochemistry and immunoblot for levels of 4-hydroxynonenal, NAD(P)H quinone oxidoreductase (NQO1), C-MYC, and dynamin-related protein 1 (DRP1) phosphorylation. RESULTS: At 15 to 18 days, the mean ejection fraction, stroke volume, and fractional shortening were similar between the mice treated with vitamin D + Dox (10 mg/kg) vs. vehicle but significantly greater in mice treated with vitamin D + Dox (10 mg/kg) vs. Dox (10 mg/kg). Dox (10 mg/kg) increased the cardiac tissue levels of 4-hydroxynonenal, NQO1, C-MYC, and DRP1 phosphorylation at serine 616, but these increases were not observed with vitamin D + Dox (10 mg/kg). A decreased tumor volume was observed with Dox (10 mg/kg) and vitamin D + Dox (10 mg/kg). CONCLUSIONS: Vitamin D supplementation decreased Dox-induced cardiotoxicity by decreasing the reactive oxygen species and mitochondrial damage, and did not decrease the anticancer efficacy of Dox against TNBC.


Assuntos
Cardiotoxicidade/prevenção & controle , Citoproteção/efeitos dos fármacos , Doxorrubicina/toxicidade , Substâncias Protetoras/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Vitamina D/farmacologia , Vitaminas/farmacologia , Animais , Antibióticos Antineoplásicos/toxicidade , Cardiotoxicidade/etiologia , Cardiotoxicidade/patologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias de Mama Triplo Negativas/induzido quimicamente , Neoplasias de Mama Triplo Negativas/patologia
5.
Int J Mol Sci ; 22(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207549

RESUMO

Doxorubicin (DOX) is a widely used anticancer drug. However, its clinical use is severely limited due to drug-induced cumulative cardiotoxicity, which leads to progressive cardiomyocyte dysfunction and heart failure. Enormous efforts have been made to identify potential strategies to alleviate DOX-induced cardiotoxicity; however, to date, no universal and highly effective therapy has been introduced. Here we reported that cinnamic acid (CA) derivatives exert a multitarget protective effect against DOX-induced cardiotoxicity. The experiments were performed on rat cardiomyocytes (H9c2) and human induced-pluripotent-stem-cell-derived cardiomyocytes (hiPSC-CMs) as a well-established model for cardiac toxicity assessment. CA derivatives protected cardiomyocytes by ameliorating DOX-induced oxidative stress and viability reduction. Our data indicated that they attenuated the chemotherapeutic's toxicity by downregulating levels of caspase-3 and -7. Pre-incubation of cardiomyocytes with CA derivatives prevented DOX-induced motility inhibition in a wound-healing assay and limited cytoskeleton rearrangement. Detailed safety analyses-including hepatotoxicity, mutagenic potential, and interaction with the hERG channel-were performed for the most promising compounds. We concluded that CA derivatives show a multidirectional protective effect against DOX-induced cardiotoxicity. The results should encourage further research to elucidate the exact molecular mechanism of the compounds' activity. The lead structure of the analyzed CA derivatives may serve as a starting point for the development of novel therapeutics to support patients undergoing DOX therapy.


Assuntos
Cardiotônicos/farmacologia , Cardiotoxicidade , Cinamatos/farmacologia , Doxorrubicina/efeitos adversos , Miócitos Cardíacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Doxorrubicina/farmacologia , Células Hep G2 , Humanos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos
6.
Biomed Pharmacother ; 140: 111779, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34062415

RESUMO

Doxorubicin (DOX) is a widely used antitumor drug that causes severe cardiotoxicity in patients; no effective strategy yet exists to address this problem. We previously reported that 8-formylophiopogonanone B (8-FOB), a natural isoflavone in Ophiopogon japonicas, antagonizes paraquat-induced hepatotoxicity. Here, we explored the mechanisms underlying DOX-induced cardiotoxicity as well as whether 8-FOB can alleviate DOX-induced cardiotoxicity. Acute cardiotoxicity was established by injecting C57BL/6J mice with a single dose of DOX (20 mg/kg, intraperitoneal). To elucidate the mechanisms underlying DOX-induced cardiotoxicity, differentially expressed genes between hearts from DOX-treated and control mice were identified from the Gene Expression Omnibus (GEO) database via GEO2R. Using the Cytoscape software plugin cytoHubba, five hub genes associated with DOX-induced cardiotoxicity were identified: CD68, PTEN, SERPINE1, AIF1, and HMOX1. However, of these, only HMOX1 protein expression levels were significantly increased after DOX treatment. We also confirmed that HMOX1-dependent myocardial inflammation and fibrosis were closely associated with DOX-induced cardiotoxicity. More importantly, 8-FOB protected against DOX-cardiotoxicity by ameliorating cardiac injury and dysfunction, reducing cardiac fibrosis and inflammatory cytokine release, and inhibiting HMOX1 expression. In conclusion, our results suggest that inhibition of HMOX1-dependent myocardial inflammatory insults and fibrosis is essential for 8-FOB to ameliorate DOX-caused cardiotoxicity.


Assuntos
Antineoplásicos , Cardiotônicos/uso terapêutico , Cardiotoxicidade/tratamento farmacológico , Doxorrubicina , Heme Oxigenase-1/antagonistas & inibidores , Isoflavonas/uso terapêutico , Proteínas de Membrana/antagonistas & inibidores , Animais , Cardiotônicos/farmacologia , Cardiotoxicidade/genética , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Citocinas/genética , Fibrose , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Isoflavonas/farmacologia , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miocárdio/patologia
7.
Life Sci ; 280: 119760, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34166713

RESUMO

Cardiotoxicity is a major side effect of the chemotherapeutic drug doxorubicin (Dox), which is further exacerbated when it is combined with trastuzumab, a standard care approach for Human Epidermal growth factor Receptor-type 2 (HER2) positive cancer patients. However, the molecular mechanisms of the underlying cardiotoxicity of this combination are still mostly elusive. Increased oxidative stress, impaired energetic substrate uses and topoisomerase IIB inhibition are among the biological processes proposed to explain Dox-induced cardiomyocyte dysfunction. Since cardiomyocytes express HER2, trastuzumab can also damage these cells by interfering with neuroregulin-1 signaling and mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/Akt and focal adhesion kinase (FAK)-dependent pathways. Nevertheless, Dox and trastuzumab target other cardiac cell types, such as endothelial cells, fibroblasts, cardiac progenitor cells and leukocytes, which can contribute to the clinical cardiotoxicity observed. This review aims to summarize the current knowledge on the cardiac signaling pathways modulated by these two antineoplastic drugs highly used in the management of breast cancer, not only focusing on cardiomyocytes but also to broaden the knowledge of the potential impact on other cells found in the heart.


Assuntos
Antineoplásicos/efeitos adversos , Cardiotoxicidade/etiologia , Doxorrubicina/efeitos adversos , Trastuzumab/efeitos adversos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Humanos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Neuregulina-1/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Receptor ErbB-2/metabolismo , Transdução de Sinais/efeitos dos fármacos
8.
Biochem Biophys Res Commun ; 561: 7-13, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-33992835

RESUMO

Doxorubicin (DOX) is a broad-spectrum antineoplastic drug; however, its serious cardiotoxic side effects in inflammatory responses limit its use in clinical applications. Dopamine D1 receptor (DRD1), a G protein-coupled receptor, is crucial for the development and function of the nervous system; additionally, it also play a role in immune regulation. However, the specific role of DRD1 in DOX-induced cardiac inflammation has not yet been clarified. Here, we discovered that DRD1 expression was induced by DOX treatment in H9C2 cardiomyocytes. DRD1 activation by A-68930, a DRD1-specific agonist, decreased DOX-induced nucleotide-binding domain-like receptor protein 3 (NLRP3) expression, caspase-1 activation, and IL-1ß maturation in H9C2 cells. Expression of the cytokines IL-1ß and IL-18 in the supernatants was also inhibited by A-68930 treatment. DRD1 knockdown, using siRNA, abolished the effects of A-68930 on the DOX-induced NLRP3 inflammasome. Furthermore, we found that DRD1 signaling downregulated the NLRP3 inflammasome in H9C2 cells through cyclic adenosine monophosphate (cAMP). Moreover, application of A-68930 to activate DRD1 reduced cardiac injury and fibrosis in a DOX-treated mouse model by suppressing the NLRP3 inflammasome in the heart. These findings indicate that DRD1 signaling may protect against DOX-induced cardiac injury by inhibiting the NLRP3 inflammasome-mediated inflammation.


Assuntos
Cardiotoxicidade/prevenção & controle , Cromanos/farmacologia , Doxorrubicina/toxicidade , Inflamassomos/antagonistas & inibidores , Miócitos Cardíacos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Receptores de Dopamina D1/agonistas , Animais , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Células Cultivadas , Citocinas/metabolismo , Agonistas de Dopamina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Receptores de Dopamina D1/metabolismo , Transdução de Sinais , Inibidores da Topoisomerase II/toxicidade
9.
Nihon Yakurigaku Zasshi ; 156(3): 146-151, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33952842

RESUMO

Doxorubicin (DOX)-induced cardiomyopathy has a poor prognosis. No early detection or effective treatment methods are available in clinical. The mechanisms of cardiotoxicity were considered as oxidative stress and apoptosis in cardiomyocytes. However, the effect of DOX on cardiac fibroblasts remains to be developed. We investigated the direct effect of DOX on the function of human cardiac fibroblasts (HCFs) independently of cell death pathway. Animal study showed that lower dose of DOX (4 mg/kg/week for 3 weeks, i.p.) than a toxic cumulate dose, induced perivascular fibrosis without cell death in hear of mice. DOX increased the protein expression of α-SMA (a marker of trans-differentiation) in HCFs culture cells, indicating that DOX promoted the trans-differentiation of HCFs into myofibroblast. DOX also increased the mRNA and protein expression of matrix metalloproteinase (MMP)-1 in less than 0.1 µM which did not induce cell apoptosis of HCFs cells via PI3K/Akt pathway in HCFs. DOX increased Interleukin-6 (IL-6) via transforming growth factor (TGF)-ß/Smad pathway. In addition, DOX induced the mitochondrial damage and increased the expression of Interleukin-1 (IL-1) via stress-activated protein kinases (SAPK)/ c-Jun NH-2termial kinase (JNK). A peroxisome proliferator-activated receptor gamma (PPARγ) agonist, pioglitazone hydrochloride attenuated the expression of fibrotic marker such as α-SMA and galectin-3 and collagen1 via SAPK/JNK signaling. Pioglitazone also suppressed DOX-induced early fibrotic response in vivo. In conclusion, these findings suggested that low dose DOX induced reactive fibrotic change of cardiac fibroblasts via cell death-independent pathway. There may be potentially new mechanisms of DOX induced cardiotoxicity in clinical usage.


Assuntos
Doxorrubicina , Fosfatidilinositol 3-Quinases , Animais , Apoptose , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Fibroblastos , Fibrose , Camundongos , Miócitos Cardíacos , Estresse Oxidativo , Fosfatidilinositol 3-Quinases/metabolismo
10.
Biochim Biophys Acta Mol Cell Res ; 1868(7): 119039, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33857568

RESUMO

Although a high cumulative dose of Doxorubicin (Dox) is known to cause cardiotoxicity, there is still a lack of understanding of the subcellular basis of this drug-induced cardiomyopathy. Differential effects of Dox on mitochondria and endoplasmic reticulum (ER) were examined in cardiomyocytes, tumor cells, implanted tumors and hearts of normal as well as tumor-bearing animals. Dox increased mitochondrial (Mito) Bax activation at 3 h in the cardiomyocyte without change in the DNA damage inducible transcriptor-3 (DDIT3) expression in the ER. Increased DDIT3 in these Dox-treated cardiomyocytes at 24 h suggested that increased MitoBax may have promoted ER stress related changes in DDIT3. Dissociation of immunoglobulin-binding protein (Bip) from activating transcription factor 6 (ATF6)-Bip complex in the ER was observed as an adaptive response to Dox. In contrast, breast cancer MCF7 cells showed an ER stress response to Dox with increased DDIT3 as early as 3 h which may have triggered a positive feedback activation of ATF6 at 12 and 24 h and promoted Calnexin. At these later time points, increased Bax activation in cancer cells suggested that MitoBax may be controlled by DDIT3 or by Calnexin. DDIT3 response in tumors was evoked by Dox, however this response was inversely correlated with increased Bip and Bax expression in hearts from tumor bearing animals. It is suggested that in Dox-induced cardiotoxicity both mitochondrial and ER stresses play an integral role through a mutual interaction where an inhibition of DDIT3 or Calnexin may also be crucial to achieve Dox resistance in cardiomyocytes.


Assuntos
Apoptose/efeitos dos fármacos , Doxorrubicina/toxicidade , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fator 6 Ativador da Transcrição/metabolismo , Animais , Apoptose/fisiologia , Proteínas Reguladoras de Apoptose/metabolismo , Cardiomiopatias/metabolismo , Cardiotoxicidade/patologia , Linhagem Celular Tumoral , Doxorrubicina/metabolismo , Doxorrubicina/farmacologia , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/fisiologia , Estresse do Retículo Endoplasmático/fisiologia , Feminino , Humanos , Masculino , Mitocôndrias/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Neoplasias/metabolismo , Neoplasias/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição CHOP/metabolismo
11.
PLoS One ; 16(4): e0234591, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33793552

RESUMO

Paraquat (PQ) is a highly lethal herbicide. Ingestion of large quantities of PQ usually results in cardiovascular collapse and eventual mortality. Recent pieces of evidence indicate possible involvement of oxidative stress- and inflammation-related factors in PQ-induced cardiac toxicity. However, little information exists on the relationship between hemodynamic and cardiac electromechanical effects involved in acute PQ poisoning. The present study investigated the effects of acute PQ exposure on hemodynamics and electrocardiogram (ECG) in vivo, left ventricular (LV) pressure in isolated hearts, as well as contractile and intracellular Ca2+ properties and ionic currents in ventricular myocytes in a rat model. In anesthetized rats, intravenous PQ administration (100 or 180 mg/kg) induced dose-dependent decreases in heart rate, blood pressure, and cardiac contractility (LV +dP/dtmax). Furthermore, PQ administration prolonged the PR, QRS, QT, and rate-corrected QT (QTc) intervals. In Langendorff-perfused isolated hearts, PQ (33 or 60 µM) decreased LV pressure and contractility (LV +dP/dtmax). PQ (10-60 µM) reduced the amplitudes of Ca2+ transients and fractional cell shortening in a concentration-dependent manner in isolated ventricular myocytes. Moreover, whole-cell patch-clamp experiments demonstrated that PQ decreased the current amplitude and availability of the transient outward K+ channel (Ito) and altered its gating kinetics. These results suggest that PQ-induced cardiotoxicity results mainly from diminished Ca2+ transients and inhibited K+ channels in cardiomyocytes, which lead to LV contractile force suppression and QTc interval prolongation. These findings should provide novel cues to understand PQ-induced cardiac suppression and electrical disturbances and may aid in the development of new treatment modalities.


Assuntos
Frequência Cardíaca/efeitos dos fármacos , Coração/efeitos dos fármacos , Coração/fisiopatologia , Miócitos Cardíacos/patologia , Paraquat/toxicidade , Potenciais de Ação , Animais , Cardiotoxicidade/etiologia , Cardiotoxicidade/patologia , Células Cultivadas , Hemodinâmica , Herbicidas/toxicidade , Masculino , Modelos Animais , Contração Miocárdica , Miócitos Cardíacos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
12.
Arch Biochem Biophys ; 704: 108866, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33844974

RESUMO

A tyrosine kinase inhibitor Imatinib (IM) is used in the treatment of different varieties of cancers. The current study was designed to explore the beneficial role of l-carnitine against IM-induced cardiotoxicity in rats. Male albino rats received IM (40 mg/kg, i.p.) either alone or/in combination with l-carnitine (100 mg/kg, i.p.) for 7 days. IM increased serum inflammatory cytokines, concomitant with activation of cardiac MAPK, α-SMA, malondialdehyde (MDA) and nitric oxide(NO), decreased cardiac peroxisome proliferator-activated receptor-γ (PPAR-γ) level, superoxide dismutase (SOD) activity, and glutathione (GSH) content. The expression levels of Bcl-2 and PDGF were significantly decreased, while the expression levels of CTGF and BAX were significantly increased in the IM group. The l-carnitine treatment successfully protected the heart as indicated by the improvement of the biochemical and histopathological parameters. l-carnitine didn't affect the serum concentration of IM and increased intracellular concentration in the combination-treated group as measured by the mass spectrometer. Conclusion: l-carnitine abrogated IM-induced cardiac damage and apoptosis via PDGF/PPARγ/MAPK pathways.


Assuntos
Apoptose/efeitos dos fármacos , Cardiotoxicidade , Carnitina/farmacologia , Mesilato de Imatinib , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Miocárdio/metabolismo , PPAR gama/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Animais , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Mesilato de Imatinib/efeitos adversos , Mesilato de Imatinib/farmacologia , Masculino , Miocárdio/patologia , Ratos , Ratos Wistar
13.
Mol Cell Biochem ; 476(8): 3099-3109, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33835331

RESUMO

While anthracyclines (ACs) are a class of chemotherapeutic agents that have improved the prognosis of many women with breast cancer, it is one of the most cardiotoxic agents used to treat cancer. Despite their reported dose-dependent cardiotoxicity, AC-based chemotherapy has become the mainstay of breast cancer therapy due to its efficacy. Elucidating the mechanisms of anthracycline-mediated cardiotoxicity and associated therapeutic interventions continue to be the main focus in the field of cardio-oncology. Herein, we summarized the current literature surrounding the mechanisms of anthracycline-induced cardiotoxicity, including the role of topoisomerase II inhibition, generation of reactive oxygen species, and elevations in free radicals. Furthermore, this review highlights the molecular mechanisms of potential cardioprotective interventions in this setting. The benefits of pharmaceuticals, including dexrazoxane, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, statins, and antioxidants in this setting, are reviewed. Finally, the mechanisms of emerging preventative interventions within this patient population including nutraceuticals and aerobic exercise are explored.


Assuntos
Antraciclinas/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Cardiotônicos/uso terapêutico , Cardiotoxicidade/prevenção & controle , Animais , Neoplasias da Mama/patologia , Cardiotoxicidade/etiologia , Cardiotoxicidade/patologia , Cardiotoxinas/efeitos adversos , Feminino , Humanos , Prognóstico , Fatores de Risco
14.
Aquat Toxicol ; 235: 105810, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33823483

RESUMO

There is a growing awareness that transient, sublethal embryonic exposure to crude oils cause subtle but important forms of delayed toxicity in fish. While the precise mechanisms for this loss of individual fitness are not well understood, they involve the disruption of early cardiogenesis and a subsequent pathological remodeling of the heart much later in juveniles. This developmental cardiotoxicity is attributable, in turn, to the inhibitory actions of crude oil-derived mixtures of polycyclic aromatic compounds (PACs) on specific ion channels and other proteins that collectively drive the rhythmic contractions of heart muscle cells via excitation-contraction coupling. Here we exposed Pacific herring (Clupea pallasi) embryos to oiled gravel effluent yielding ΣPAC concentrations as low as ~ 1 µg/L (64 ng/g in tissues). Upon hatching in clean seawater, and following the depuration of tissue PACs (as evidenced by basal levels of cyp1a gene expression), the ventricles of larval herring hearts showed a concentration-dependent reduction in posterior growth (ballooning). This was followed weeks later in feeding larvae by abnormal trabeculation, or formation of the finger-like projections of interior spongy myocardium, and months later with hypertrophy (overgrowth) of the spongy myocardium in early juveniles. Given that heart muscle cell differentiation and migration are driven by Ca2+-dependent intracellular signaling, the observed disruption of ventricular morphogenesis was likely a secondary (downstream) consequence of reduced calcium cycling and contractility in embryonic cardiomyocytes. We propose defective trabeculation as a promising phenotypic anchor for novel morphometric indicators of latent cardiac injury in oil-exposed herring, including an abnormal persistence of cardiac jelly in the ventricle wall and cardiomyocyte hyperproliferation. At a corresponding molecular level, quantitative expression assays in the present study also support biomarker roles for genes known to be involved in muscle contractility (atp2a2, myl7, myh7), cardiomyocyte precursor fate (nkx2.5) and ventricular trabeculation (nrg2, and hbegfa). Overall, our findings reinforce both proximal and indirect roles for dysregulated intracellular calcium cycling in the canonical fish early life stage crude oil toxicity syndrome. More work on Ca2+-mediated cellular dynamics and transcription in developing cardiomyocytes is needed. Nevertheless, the highly specific actions of ΣPAC mixtures on the heart at low, parts-per-billion tissue concentrations directly contravene classical assumptions of baseline (i.e., non-specific) crude oil toxicity.


Assuntos
Petróleo/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Cardiotoxicidade/patologia , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/patologia , Peixes/embriologia , Peixes/fisiologia , Coração , Larva , Miocárdio/química , Poluição por Petróleo , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Água do Mar
15.
Oxid Med Cell Longev ; 2021: 5548130, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33859777

RESUMO

The molecular mechanisms underlying the cardiotoxicity associated with bevacizumab, a first-line immunotherapeutic agent used to treat lung cancer, are not fully understood. Here, we examined intracellular signal transduction in cardiomyocytes after exposure to different doses of bevacizumab in vitro. Our results demonstrated that bevacizumab significantly and dose-dependently reduces cardiomyocyte viability and increases cell apoptosis. Bevacizumab treatment also led to mitochondrial dysfunction in cardiomyocytes, as evidenced by the decreased ATP production, increased ROS production, attenuated antioxidative enzyme levels, and reduced respiratory complex function. In addition, bevacizumab induced intracellular calcium overload, ER stress, and caspase-12 activation. Finally, bevacizumab treatment inhibited the ERK signaling pathway, which, in turn, significantly reduced cardiomyocyte viability and contributed to mitochondrial dysfunction. Together, our results demonstrate that bevacizumab-mediated cardiotoxicity is associated with mitochondrial dysfunction, ER stress, and ERK pathway inactivation. These findings may provide potential treatment targets to attenuate myocardial injury during lung cancer immunotherapy.


Assuntos
Bevacizumab/farmacologia , Cardiotoxicidade/etiologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mitocôndrias Cardíacas/efeitos dos fármacos , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacologia , Bevacizumab/efeitos adversos , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Linhagem Celular , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Mitocôndrias Cardíacas/metabolismo , Espécies Reativas de Oxigênio
16.
Biochem Biophys Res Commun ; 555: 67-73, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33813278

RESUMO

A recent in vitro cardiovascular safety pharmacology test uses cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs) to overcome the limitations of the classical test systems, such as species differences and local channel analysis. The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a new proarrhythmia screening paradigm proposed by a CiPA steering expert group, which essentially requires iPSCs derived cardiomyocyte-based electrophysiological evaluation technology. Moreover, the measurement of the contractile force is also emerging as an important parameter to recapitulate non-proarrhythmic cardiotoxicity. Therefore, we constructed an multielectrode assay (MEA) evaluation method that can measure the electrophysiological changes with 6 reference drugs in hiPSC-derived cardiomyocytes. Subsequently, it was confirmed that the electrophysiological were changed in accordance with the mechanism of action of the drugs. Furthermore, based on the multi-probe impedance, we confirmed the decrease in contractile force due to treatment with drugs, and developed a platform to evaluate cardiotoxicity according to drugs along with field potential changes. Our excitation-contraction coupling cardiotoxicity assessment is considered to be more supportive in cardiac safety studies on pharmacologic sensitivity by complementing each assessment parameter.


Assuntos
Cardiotoxicidade/etiologia , Células-Tronco Pluripotentes Induzidas/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Testes de Toxicidade/métodos , Bloqueadores dos Canais de Cálcio/toxicidade , Cardiotoxicidade/patologia , Células Cultivadas , Eletrodos , Humanos , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/citologia , Nifedipino/toxicidade , Quinidina/toxicidade , Testes de Toxicidade/instrumentação
17.
FEBS Lett ; 595(12): 1681-1695, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33876420

RESUMO

Doxorubicin (DOX) is a very effective anticancer agent that is widely used in pediatric cancer patients. Nevertheless, DOX is known to have cardiotoxic effects that may progress to cardiomyopathy later in life. We have recently shown that cotreatment of resveratrol (RES) with DOX in juvenile mice attenuates late-onset hypertension-induced cardiomyopathy. However, the molecular mechanism responsible for these changes remains unknown. Herein, we show that the cardiac NLRP3 inflammasome plays a crucial role in regulating cardiac injury in a DOX -treated juvenile mouse model and the detrimental effects of hypertension in these mice later in life. We further demonstrate that RES significantly reduces systemic inflammation to contribute to the improvements observed in DOX -induced cardiac injury in young mice and late-onset hypertension-induced cardiomyopathy.


Assuntos
Cardiomiopatias/dietoterapia , Cardiotoxicidade/tratamento farmacológico , Doxorrubicina/efeitos adversos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Resveratrol/farmacologia , Animais , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Doxorrubicina/farmacologia , Masculino , Camundongos
18.
Sci Rep ; 11(1): 6330, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33737561

RESUMO

Doxorubicin (DOX)-induced cardiotoxicity in chemotherapy is a major treatment drawback. Clinical trials on the cardioprotective effects of exercise in cancer patients have not yet been published. Thus, we conducted a systematic review and meta-analysis of preclinical studies for to assess the efficacy of exercise training on DOX-induced cardiomyopathy. We included studies with animal models of DOX-induced cardiomyopathy and exercise training from PubMed, Web of Sciences and Scopus databases. The outcome was the mean difference (MD) in fractional shortening (FS, %) assessed by echocardiography between sedentary and trained DOX-treated animals. Trained DOX-treated animals improved 7.40% (95% CI 5.75-9.05, p < 0.001) in FS vs. sedentary animals. Subgroup analyses revealed a superior effect of exercise training execution prior to DOX exposure (MD = 8.20, 95% CI 6.27-10.13, p = 0.010). The assessment of cardiac function up to 10 days after DOX exposure and completion of exercise protocol was also associated with superior effect size in FS (MD = 7.89, 95% CI 6.11-9.67, p = 0.020) vs. an echocardiography after over 4 weeks. Modality and duration of exercise, gender and cumulative DOX dose did were not individually associated with changes on FS. Exercise training is a cardioprotective approach in rodent models of DOX-induced cardiomyopathy. Exercise prior to DOX exposure exerts greater effect sizes on FS preservation.


Assuntos
Cardiomiopatias/terapia , Doxorrubicina/efeitos adversos , Exercício Físico , Neoplasias/terapia , Animais , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/patologia , Cardiotoxicidade/patologia , Cardiotoxicidade/prevenção & controle , Cardiotoxicidade/terapia , Doxorrubicina/uso terapêutico , Ecocardiografia , Feminino , Coração/efeitos dos fármacos , Coração/fisiopatologia , Humanos , Masculino , Neoplasias/complicações , Neoplasias/patologia , Condicionamento Físico Animal , Ratos , Ratos Sprague-Dawley
19.
Gulf J Oncolog ; 1(35): 59-65, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33716214

RESUMO

BACKGROUND: Breast cancer is the most common cancer in women in the world and in Morocco. Anthracyclines and anti-HER2 therapy are major drugs in the therapeutic management of localized breast cancer. The most serious toxicity of these drugs is cardiotoxicity. Our work aims to assess the prevalence of this toxicity in the Moroccan population. PATIENTS AND METHODS: We conducted a prospective longitudinal observational study between January 2017 and June 2018. All our patients were followed in The Cardio-Oncology Unit, 1st unit of its kind in Morocco, created thanks to the collaboration between the Mohammed VI Cancer Treatment Center and The Cardiology Departement of Ibn Rochd University Hospital in Casablanca. Eligible patients (n=549) had Stage I-III localized breast cancer, verified histologically, and a pre-treatment adequate cardiac function with a LVEF = 50%, measured with echocardiography, and received systemic cardiotoxic treatment (anthracycines, anti-her2 drugs). All patients received regular monitoring of cardiac function mainly by echocardiography. Cardiotoxicity was defined as a decrease in LVEF of 10 points and / or <50%. RESULTS: A decrease in LVEF was observed in 8.4% of our patients, with 4% symptomatic heart failure. The baseline average LVEF in the cardiotoxicity group was 63.5% (50-77) versus 60.5% (60-74) in the group without cardiotoxicity. 97.1% of these patients received anthracyclines, 98% received trastuzumab against 97% and 65% in the group without cardiotoxicity respectively. Cardiotoxicity was reversible in 6.4% of patients, permanent discontinuation of cardiotoxic treatment was observed in 2.2%. A statistically significant relationship was found between cardiotoxicity and arterial hypertension (HTA) (p = 0.002), trastuzumab (p = 0.0001) and radiotherapy for left breast cancer (p = 0.023). CONCLUSION: This is one of the first observational studies in Morocco with a large number of patients, which gives us an idea of the cardiotoxicity of systemic treatments in Moroccan localized breast cancer patients. Our results join those of the literature, but are still worrying and invite us, oncologists and cardiologists, to be more vigilant with this toxicity, which influences the oncological and cardiac prognosis of our patients, especially cancer survivors.


Assuntos
Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Cardiotoxicidade/etiologia , Idoso , Neoplasias da Mama/patologia , Cardiotoxicidade/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Marrocos , Prognóstico , Estudos Prospectivos
20.
J Biochem Mol Toxicol ; 35(6): 1-15, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33645892

RESUMO

Tramadol and alcohol are among commonly abused drugs. Although there are potential dangers reported upon their mixing, there are no previous reports describing this mixture's effects on the cardiovascular system (CVS). The aim was to study the effects of mixed alcohol and tramadol on the CVS of adult male rats. Fifty rats were divided into four groups: control, tramadol-treated group, alcohol-treated, and coadministration groups. Tramadol caused a significant increases in creatine kinase-MB, troponin I, malondialdehyde, protein carbonyl, 8-hydroxy-2'-deoxyguanosine, and a significant decrease in total antioxidant capacity with histological alterations in sections of the heart and aorta and a significant increase in the area% of collagen fibers while there was a nonsignificant difference in body weight, heart weight, heart weight/body weight ratio, lipid profile, tissue tumor necrosis factor-α and interferon-γ, intermediate microfilament proteins (IFPs) {desmin, vimentin, connexin43} gene expression, mean area% of elastic fibers in aortic tissue and osteopontin expression in cardiac and aortic tissue. Alcohol treatment caused a significant change in all the measured parameters and more damage in histological sections. The changes were highest in the coadministration group. There was a strong positive correlation between the area% of collagen fibers and vimentin gene expression, and the area% of osteopontin expression was positively correlated to connexin43 in cardiac and vascular tissue. Tramadol causes CVS injury mainly through oxidative stresses, while the alcohol effect is multifactorial; mixing both aggravates CVS injury. The study also highlights the role of IFPs and osteopontin-expression in inducing injury.


Assuntos
Alcoolismo , Cardiotoxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Filamentos Intermediários/metabolismo , Osteopontina/biossíntese , Tramadol/farmacologia , Alcoolismo/tratamento farmacológico , Alcoolismo/metabolismo , Alcoolismo/patologia , Animais , Aorta/metabolismo , Aorta/patologia , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Modelos Animais de Doenças , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Ratos
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