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1.
J Environ Sci (China) ; 125: 650-661, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36375947

RESUMO

The wide use of pesticides has seriously threatened human health and the survival of beneficial organisms. The fungicide mepanipyrim is widely used in viticulture practices. Studies of mepanipyrim-induced toxicity in organisms are still scarce, especially studies on cardiotoxicity. In this study, we aimed to investigate mepanipyrim-induced cardiotoxicity in zebrafish (Danio rerio) larvae. We found that mepanipyrim could induce cardiotoxicity by altering the heart rate and cardiomyocyte diameter of larvae. Meanwhile, RNA sequencing and RT-qPCR data indicated that mepanipyrim exposure could dramatically alter the mRNA expression of calcium signaling pathway-, cardiac muscle contraction-, and oxidative respiratory chain-related genes. Interestingly, by the CALUX cell bioassay, we found that most cytochrome c oxidase (COX) family genes exhibited potential AhR-regulated activity, suggesting that mepanipyrim induced cardiotoxicity via a novel AhR-regulated manner in larvae. Additionally, the AhR antagonist CH223191 could effectively prevent mepanipyrim-induced cardiotoxicity in zebrafish larvae. In conclusion, the AhR agonist mepanipyrim could induce cardiotoxicity in a novel unreported AhR-regulated manner, which could specifically affect the expression of COX family genes involved in the mitochondrial oxidative respiratory chain. Our data will help explain the toxic effects of mepanipyrim on organisms and provide new insight into the AhR agonistic activity pesticide-induced cardiotoxicity.


Assuntos
Cardiotoxicidade , Praguicidas , Poluentes Químicos da Água , Animais , Cardiotoxicidade/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Embrião não Mamífero , Larva , Praguicidas/toxicidade , Receptores de Hidrocarboneto Arílico/metabolismo , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo
2.
Curr Probl Cardiol ; 48(1): 101435, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36183977

RESUMO

Cardiovascular disease and cancer are the leading causes of death worldwide. With advent of novel and improved cancer therapies, a growing population of cancer patients with cardiac complications is seen. Taking this into consideration, the clinical studies have also shifted their focus from the study of a single disease to the interdisciplinary study of oncology and cardiology. This current review article provides a comprehensive review of all major articles and guidelines from the year 2021-2022 in the field of cardio-oncology.


Assuntos
Cardiologia , Doenças Cardiovasculares , Cardiopatias , Neoplasias , Humanos , Cardiotoxicidade/etiologia , Oncologia , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/terapia , Doenças Cardiovasculares/complicações
3.
J Hazard Mater ; 443(Pt B): 130297, 2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36368065

RESUMO

Although triclosan (TCS) is ubiquitously detected in environmental media and organisms, little information is available on its cardiotoxicity and underlying mechanisms. Herein, acute TCS exposure (0.69-1.73 µM) to zebrafish from embryos (6 hpf) to larvae (72 hpf) resulted in cardiac development defects, including increased angle between atrium and ventricle, prolonged SV-BA distance, linearized heart and pericardial cyst in 72-hpf larvae. These malformations resulted from interfered oxidative-stress pathways, reflecting in accumulated ROS and MDA and inhibited SOD and CAT activities. By RT-qPCR, the transcription levels of four cardiac development-related marker genes were significantly up-regulated except for gata4. Besides, miR-144 was identified as a regulatory molecule of TCS-induced cardiac defects by integrating analyses of artificial intervene expression and RNA-Seq data. Interestingly, the target genes of miR-144 were found and interacted with the above marker genes through constructing protein-protein interaction networks. After intervening the expression of miR-144 by microinjecting and activating Wnt pathway by an agonist BML-284, we confirmed that up-regulated miR-144 suppressed the expression of angiogenesis-related genes and negatively regulated Wnt pathway, further triggering angiogenesis disorders and cardiac phenotypic malformation. These findings unravel the underlying molecular mechanisms regarding TCS-induced cardiac development toxicity, and contribute to early warning and risk management of TCS.


Assuntos
MicroRNAs , Triclosan , Poluentes Químicos da Água , Animais , Triclosan/toxicidade , Triclosan/metabolismo , Peixe-Zebra/metabolismo , Larva/metabolismo , Cardiotoxicidade , Regulação para Cima , Poluentes Químicos da Água/toxicidade , Poluentes Químicos da Água/metabolismo , Biomarcadores/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Embrião não Mamífero/metabolismo
4.
Clin Chem Lab Med ; 61(1): 154-161, 2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36287134

RESUMO

OBJECTIVES: Immune checkpoint inhibitors (ICIs) cause a variety of toxicities, including immune-related adverse events (irAEs), but there are no biomarkers to predict their development. Guidelines recommend measuring circulating cardiac troponin I (cTnI) during ICI therapy to detect related cardiotoxicities. Moreover, elevated cTnI has also been associated with worse outcomes in non-cardiac patients, including cancer. Thus here, we investigated whether cTnI levels were higher in patients with irAEs. METHODS: The study consisted of three groups; 21 cancer patients undergoing ICI immunotherapies who presented with irAEs, four patients without irAEs, and 20 healthy controls. Patient samples were assessed at baseline (n=25), during ICI treatment (n=25, median=6 weeks of treatment) and at toxicity (n=6, median=13 weeks of treatment). In addition to blood high sensitivity cardiac troponin I (hs-cTnI), anti-thyroglobulin (TG) and anti-thyroid peroxidase (TPO) antibodies were also quantitated to detect thyroid dysfunction, constituting the second leading toxicity (23.8%) after pneumonitis (28.6%). RESULTS: Four patients with irAEs (n=4/21; 19%) and one without irAEs (n=1/4; 25%) showed higher hs-cTnI levels at any time-point; the remaining had physiological levels. None of these patients developed cardiotoxicity. Concurrent elevated levels of anti-thyroid antibodies and hs-cTnI were detected in one patient with thyroid dysfunction (n=1/5, 20%). However, these antibodies were also elevated in three patients (n=3/16, 19%) with non-thyroid irAEs and in up to 40% of healthy controls. CONCLUSIONS: hs-cTnI was not elevated in patients with irAEs, but larger studies are needed to confirm these observations.


Assuntos
Antineoplásicos Imunológicos , Inibidores de Checkpoint Imunológico , Neoplasias , Humanos , Antineoplásicos Imunológicos/efeitos adversos , Cardiotoxicidade , Estudos de Casos e Controles , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias/tratamento farmacológico , Neoplasias/complicações , Estudos Retrospectivos , Doenças da Glândula Tireoide , Troponina I
5.
PLoS One ; 17(11): e0276541, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36331922

RESUMO

The effectiveness of anthracycline chemotherapeutics (e.g., doxorubicin) is limited by anthracycline-induced cardiotoxicity (ACT). A nonsynonymous variant (S427L) in the retinoic acid receptor-γ (RARG) gene has been associated with ACT. This variant causes reduced RARG activity, which is hypothesized to lead to increased susceptibility to ACT through reduced activation of the retinoic acid pathway. This study explored the effects of activating the retinoic acid pathway using a RAR-agonist, all-trans retinoic acid (ATRA), in human cardiomyocytes and mice treated with doxorubicin. In human cardiomyocytes, ATRA induced the gene expression of RARs (RARG, RARB) and repressed the expression of topoisomerase II enzyme genes (TOP2A, TOP2B), which encode for the molecular targets of anthracyclines and repressed downstream ACT response genes. Importantly, ATRA enhanced cell survival of human cardiomyocytes exposed to doxorubicin. The protective effect of ATRA was also observed in a mouse model (B6C3F1/J) of ACT, in which ATRA treatment improved heart function compared to doxorubicin-only treated mice. Histological analyses of the heart also indicated that ATRA treatment reduced the pathology associated with ACT. These findings provide additional evidence for the retinoic acid pathway's role in ACT and suggest that the RAR activator ATRA can modulate this pathway to reduce ACT.


Assuntos
Antraciclinas , Cardiotoxicidade , Animais , Humanos , Camundongos , Antraciclinas/toxicidade , Antibióticos Antineoplásicos/farmacologia , Cardiotoxicidade/genética , Cardiotoxicidade/prevenção & controle , Cardiotoxicidade/metabolismo , DNA Topoisomerases Tipo II/genética , DNA Topoisomerases Tipo II/metabolismo , Doxorrubicina/toxicidade , Doxorrubicina/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Inibidores da Topoisomerase II/farmacologia , Tretinoína/farmacologia , Tretinoína/metabolismo
6.
Nat Commun ; 13(1): 7171, 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36418322

RESUMO

Anthracyclines, widely used to treat breast cancer, have the potential for cardiotoxicity. We have previously identified and validated a germline single nucleotide polymorphism, rs28714259, associated with an increased risk of anthracycline-induced heart failure. We now provide insights into the mechanism by which rs28714259 might confer increased risk of cardiac damage. Using hiPSC-derived cardiomyocyte cell lines with either intrinsic polymorphism or CRISPR-Cas9-mediated deletion of rs28714259 locus, we demonstrate that glucocorticoid receptor signaling activated by dexamethasone pretreatment prior to doxorubicin exposure preserves cardiomyocyte viability and contractility in cardiomyocytes containing the major allele. Homozygous loss of the rs28714259 major allele diminishes dexamethasone's protective effect. We further demonstrate that the risk allele of rs28714259 disrupts glucocorticoid receptor and rs28714259 binding affinity. Finally, we highlight the activation of genes and pathways involved in cardiac hypertrophy signaling that are blocked by the risk allele, suggesting a decreased adaptive survival response to doxorubicin-related stress.


Assuntos
Células-Tronco Pluripotentes Induzidas , Policetídeos , Humanos , Antraciclinas/toxicidade , Cardiotoxicidade/genética , Cardiotoxicidade/metabolismo , Miócitos Cardíacos/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Estudo de Associação Genômica Ampla , Receptores de Glucocorticoides/metabolismo , Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Inibidores da Topoisomerase II/farmacologia , Fenótipo , Policetídeos/metabolismo , Dexametasona/farmacologia
8.
J Med Life ; 15(9): 1184-1190, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36415530

RESUMO

Dipyridamole is a platelet inhibitor with antithrombotic properties that can help prevent stroke recurrence. Twenty-eight male rats were divided randomly into four groups (7 rats in each group). Control group: rats received a natural diet and water. Normal saline group: rats received 0.9% normal saline for two weeks. Doxorubicin group (induced group): rats received 2.5 mg/kg three times a week for two weeks. Dipyridamole group (dipyridamole treated group): received dipyridamole (6 mg/kg/daily) orally for two weeks. Doxorubicin caused cardiotoxicity as indicated by a significant increase in tumor necrosis factor-α, interleukin-6, malondialdehyde, and caspase-3 level (P<0.05), while total antioxidant capacity and Bcl-2 levels were significantly reduced in cardiac tissues of rats in the doxorubicin group compared to the normal saline control group (P<0.05). Dipyridamole significantly ameliorates doxorubicin-induced cardiotoxicity, as suggested by a significant decrease in inflammatory markers (tumor necrosis factor-α and interleukin-6) (P<0.05). Moreover, the cardiac tissue level of oxidative marker malondialdehyde was significantly decreased (P<0.05), and total antioxidant capacity significantly increased in the dipyridamole group in comparison to the doxorubicin-only group (P<0.05). Dipyridamole exerted a significant heart-protective effect against doxorubicin-induced cardiotoxicity in rats, probably via interfering with oxidative stress, inflammatory response, and apoptotic pathway. The goal of this study was to investigate the potential protective effect of dipyridamole against doxorubicin-induced cardiotoxicity via interfering with pro-inflammatory, oxidative, and apoptotic pathways.


Assuntos
Antioxidantes , Cardiotoxicidade , Masculino , Ratos , Animais , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/etiologia , Cardiotoxicidade/prevenção & controle , Antioxidantes/metabolismo , Dipiridamol/farmacologia , Dipiridamol/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6 , Solução Salina/metabolismo , Solução Salina/farmacologia , Miocárdio/metabolismo , Miocárdio/patologia , Apoptose , Ratos Wistar , Doxorrubicina/toxicidade , Malondialdeído/metabolismo , Biomarcadores/metabolismo
9.
Eur J Pharmacol ; 936: 175362, 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36343692

RESUMO

Cardiotoxicity is one of the major safety concerns in the use of drug and is the most common reason for drug removal from the market. At present, several drugs that have been recognized as the clinically effective drug have been reported to be associated with a high risk of cardiotoxicity during clinical use. The most representative ones are doxorubicin, arsenic trioxide, isoproterenol, cyclophosphamide, etc. The adverse effects seriously affect the human health and limit the clinical application of the drugs mentioned above. Over the past years, many strategies have been carried out to prevent the occurrence of drug-induced cardiotoxicity, including early detection of cardiotoxicity by biomarkers, limitation of doses, changing of drug-delivery way, combining with cardioprotective agent. Among them, combining with cardioprotective agent has gained increased interest and has been considered as a promising approach for continued treatment. Therefore, looking for effective cardioprotective agent to avoid the occurrence of drug-induced cardiotoxicity has become a great challenge for many researchers. Interestingly, some phenolic acids compounds from natural plants have been demonstrated to establish a significant protective effect in drug-induced cardiotoxicity. In this work, we reviewed the cardioprotective potentials and the involved mechanisms of phenolic acids in drug-induced cardiotoxicity. To provide a reference for the further application of phenolic acids in the prevention of drug-induced cardiotoxicity.


Assuntos
Cardiotoxicidade , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Cardiotoxicidade/etiologia , Cardiotoxicidade/prevenção & controle , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Hidroxibenzoatos
10.
Toxicon ; 220: 106961, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36347271

RESUMO

INTRODUCTION: Until now very few cases of an adverse cardiovascular event have been described following European viper envenomation (Aravanis et al., 1982) (Aravanis et al., 1982) (Aravanis et al., 1982) (Aravanis et al., 1982). In fact, cardiac toxicity following snake bite is rare and primary reported from tropical and subtropical areas with only twenty-one cases of myocardial infarction reported in literature. Herein, we report a case of European viper envenomation associated with coronary artery thrombosis complicated by acute myocardial infarction and cardiac arrest. CASE REPORT: A 62-year-old man, with a history of cardiovascular disease, on dual antiplatelet therapy with ticagrelor and acetylsalicylic acid, was admitted to the Emergency Department, after a bite, on the right hand, from a snake recognized by a herpetologist as a Vipera aspis francisciredi. At ED presentation, 2 hours after the bite, he manifested with vomiting, hypotension (90/60 mmHg) and mild oedema at the bite site. Standard electrocardiogram and troponin were normal at admission. One hour after the admission the patient developed cardiocirculatory arrest (ACC) with return of spontaneous circulation (ROSC) after cardiopolmunary resuscitation. Post ROSC-ECG showed an ST-elevation on anteroseptal and lateral leads and 1-vial of Viper Venom Antitoxin (Biomed®) was i.v. administered. During the next 3 hours three other episodes of ACC occurred, always with restoration of spontaneous circulation. Percutaneous transluminal coronary angiography showed a thrombus on the bifurcation of anterior descending coronary artery and diagonal 1 without an underlined atherosclerotic plaque. Neurologic clinical manifestations also occurred 12 hours after the bite: bilateral ptosis and facial paresthesia and a second vial of the same viper antivenom administered. The patient was discharged after 9 days of hospitalization without sequelae. CONCLUSIONS: Our case show that cardiotoxicity is a rare but possible event after snake envenomation in Europe, even if with mechanisms remains to be studied. Vipera aspis has been known to cause primarily neurotoxic manifestations, but a coagulation factor X activator have also been isolated from its venom. Moreover, a specific serine peptidase that can target both PAR1 and PAR3, that are responsible for alternate pathways of platelet aggregation, have been characterized in the venom of a viper. Coronary thrombosis in our case could thus be secondary to a combination of prothrombotic systemic state and platelets dysfunction, in a patient with predisposing factors. Antivenom specific antidotal therapy role in preventing cardiotoxicity still need to be elucidated, but it remains the mainstay of treatment together with coronary angiography if necessary.


Assuntos
Trombose Coronária , Mordeduras de Serpentes , Viperidae , Animais , Masculino , Antivenenos/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Trombose Coronária/induzido quimicamente , Trombose Coronária/complicações , Cardiotoxicidade/complicações , Cardiotoxicidade/tratamento farmacológico , Mordeduras de Serpentes/complicações , Mordeduras de Serpentes/tratamento farmacológico , Venenos de Víboras/toxicidade
11.
Cardiovasc Toxicol ; 22(12): 962-970, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36350556

RESUMO

The heart of higher vertebrates develops early as a tubular structure, which requires cellular and molecular events for proliferation, differentiation and apoptosis for growth, and individualization of cardiac chambers. Exposure to different stressors can cause disturbances in the normal development and functionality of the cardiovascular system. This study aimed to characterize the impact of methylmercury (MeHg) on heart development, specifically related to tissue morphology and parameters of vascular integrity and contractility, also focusing on cell cycle and apoptosis, using Gallus domesticus embryos as a model. The results showed morphological alterations, reduction in the thickness of the ventricular walls, and trabeculae changes in the hearts of embryos exposed to 0.1 µg MeHg/50 µL saline solution. These impacts were associated with increased contents of proteins related to cell cycle arrest and reduced cardiomyocyte proliferation. In addition, the contents of endothelial mediators for contractility and vascular integrity were imbalanced. The quantity and morphology of mitochondria of cardiomyocytes were injured. Together, these negative measurements impacted the reduction of heartbeats. In general, the parameters identified here demonstrate the relevance of combined molecular cellular tissue and physiological diagnosis for a better understanding of the cardiotoxicity of MeHg during development.


Assuntos
Compostos de Metilmercúrio , Animais , Compostos de Metilmercúrio/toxicidade , Miócitos Cardíacos , Apoptose , Diferenciação Celular , Cardiotoxicidade
12.
Dtsch Med Wochenschr ; 147(23): 1513-1522, 2022 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-36384152

RESUMO

Drug-induced cardiovascular side effects have a significant impact on morbidity and mortality. The demographic change and improved long-term survival particularly in cancer patients have caused an increasing number of affected patients, hence emphasizing the importance of the best possible treatment of such complications. This article gives an overview of classic and modern groups of substances with cardiotoxic effects and summarizes the principles of diagnostics and therapy. After characterizing the common cardiovascular side effects caused by anthracycline chemotherapy, we focus on complications caused by modern forms of immunotherapy, considering its significant impact on oncological therapy in the future due to its growing clinical application. In addition to specific cancer therapies, accompanying measures such as blood transfusions in patients with hematologic diseases can also lead to severe cardiovascular complications. In the last section, we classify important features and therapeutic approaches in cardiac involvement of transfusion-related hemochromatosis. A good knowledge of the characteristics of specific cardiovascular side effects can help to improve the management of affected patients.


Assuntos
Cardiomiopatias , Neoplasias , Humanos , Cardiotoxicidade/etiologia , Antraciclinas/efeitos adversos , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/diagnóstico , Cardiomiopatias/terapia , Oncologia , Neoplasias/terapia
13.
Sci Rep ; 12(1): 19660, 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36385153

RESUMO

Multiple myeloma (MM) remains an incurable malignancy of plasma cells despite constantly evolving therapeutic approaches including various types of immunotherapy. Increased arginase activity has been associated with potent suppression of T-cell immune responses in different types of cancer. Here, we investigated the role of arginase 1 (ARG1) in Vκ*MYC model of MM in mice. ARG1 expression in myeloid cells correlated with tumor progression and was accompanied by a systemic drop in ʟ-arginine levels. In MM-bearing mice antigen-induced proliferation of adoptively transferred T-cells was strongly suppressed and T-cell proliferation was restored by pharmacological arginase inhibition. Progression of Vκ*MYC tumors was significantly delayed in mice with myeloid-specific ARG1 deletion. Arginase inhibition effectively inhibited tumor progression although it failed to augment anti-myeloma effects of bortezomib. However, arginase inhibitor completely prevented development of bortezomib-induced cardiotoxicity in mice. Altogether, these findings indicate that arginase inhibitors could be further tested as a complementary strategy in multiple myeloma to mitigate adverse cardiac events without compromising antitumor efficacy of proteasome inhibitors.


Assuntos
Mieloma Múltiplo , Camundongos , Animais , Bortezomib/farmacologia , Bortezomib/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Arginase/metabolismo , Cardiotoxicidade , Inibidores de Proteassoma/farmacologia
14.
Clin Ter ; 173(6): 524-525, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36373448

RESUMO

Abstract: Recently, there has been a worldwide rise in the popularity and abuse of synthetic cathinones. The spectrum of side effects caused by the intake of these drugs of abuse is very wide since they act on different systems with various mechanisms of action, they appear to be involved in different cardiac events, including myocardial infarction and sudden cardiac death due to fatal arrhythmias. Overall, khat users have a higher risk of death, recurrent myocardial ischemia, cardiogenic shock, ventricular arrhythmia, and stroke compared with non-khat user.


Assuntos
Alcaloides , Infarto do Miocárdio , Humanos , Cardiotoxicidade/etiologia , Alcaloides/efeitos adversos , Arritmias Cardíacas/induzido quimicamente
16.
PLoS One ; 17(11): e0272022, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36318537

RESUMO

BACKGROUND: Treatment options for many cancers include immune checkpoint inhibitor (ICI) monotherapy and combination therapy with impressive clinical benefit across cancers. We sought to define the comparative cardiac risks of ICI combination and monotherapy. METHODS: We used VigiBase, the World Health Organization pharmacovigilance database, to identify cardiac ADRs (cADRs), such as carditis, heart failure, arrhythmia, myocardial infarction, and valvular dysfunction, related to ICI therapy. To explore possible relationships, we used the reporting odds ratio (ROR) as a proxy of relative risk. A lower bound of a 95% confidence interval of ROR &gt; 1 reflects a disproportionality signal that more ADRs are observed than expected due to chance. RESULTS: We found 2278 cADR for ICI monotherapy and 353 for ICI combination therapy. Combination therapy was associated with significantly higher odds of carditis (ROR 6.9, 95% CI: 5.6-8.3) versus ICI monotherapy (ROR 5.0, 95% CI: 4.6-5.4). Carditis in ICI combination therapy was fatal in 23.4% of reported ADRs, compared to 15.8% for ICI monotherapy (P = 0.058). CONCLUSIONS: Using validated pharmacovigilance methodology, we found increased odds of carditis for all ICI therapies, with the highest odds for combination therapy. Given the substantial risk of severe ADR and death, clinicians should consider these findings when prescribing checkpoint inhibitors.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Miocardite , Neoplasias , Humanos , Inibidores de Checkpoint Imunológico , Cardiotoxicidade/tratamento farmacológico , Miocardite/tratamento farmacológico , Farmacovigilância , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Neoplasias/tratamento farmacológico , Estudos Retrospectivos
17.
Int J Mol Sci ; 23(22)2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36430599

RESUMO

Myocardial protection against ischemia/reperfusion injury (IRI) is mediated by various ligands, activating different cellular signaling cascades. These include classical cytosolic mediators such as cyclic-GMP (c-GMP), various kinases such as Phosphatydilinositol-3- (PI3K), Protein Kinase B (Akt), Mitogen-Activated-Protein- (MAPK) and AMP-activated (AMPK) kinases, transcription factors such as signal transducer and activator of transcription 3 (STAT3) and bioactive molecules such as vascular endothelial growth factor (VEGF). Most of the aforementioned signaling molecules constitute targets of anticancer therapy; as they are also involved in carcinogenesis, most of the current anti-neoplastic drugs lead to concomitant weakening or even complete abrogation of myocardial cell tolerance to ischemic or oxidative stress. Furthermore, many anti-neoplastic drugs may directly induce cardiotoxicity via their pharmacological effects, or indirectly via their cardiovascular side effects. The combination of direct drug cardiotoxicity, indirect cardiovascular side effects and neutralization of the cardioprotective defense mechanisms of the heart by prolonged cancer treatment may induce long-term ventricular dysfunction, or even clinically manifested heart failure. We present a narrative review of three therapeutic interventions, namely VEGF, proteasome and Immune Checkpoint inhibitors, having opposing effects on the same intracellular signal cascades thereby affecting the heart. Moreover, we herein comment on the current guidelines for managing cardiotoxicity in the clinical setting and on the role of cardiovascular confounders in cardiotoxicity.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Neoplasias , Humanos , Cardiotoxicidade , Fator A de Crescimento do Endotélio Vascular , Miocárdio , Neoplasias/tratamento farmacológico , Miócitos Cardíacos
18.
Medicine (Baltimore) ; 101(46): e31873, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36401466

RESUMO

RATIONALE: Immune checkpoint inhibitors (ICIs) are currently approved for a variety of cancers and their use is expanding from advanced disease to first-line metastatic and adjuvant therapies. With the wide application of immunotherapy, its adverse reactions are also the object we need to pay attention to. Among its adverse events, immune myocarditis has low morbidity, but a high fatality rate. Simultaneously, the unique biological properties of thymic epithelial tumors (TETs) increase the risk of immune-mediated toxicity. PATIENT CONCERNS: Patient 1 underwent chest computed tomography (CT) in April 2019 due to physical examination, which showed pleural metastasis of thymoma. Tissue puncture under CT guidance revealed type B2 thymoma. First-line chemotherapy with docetaxel combined with nedaplatin was administered, and apatinib was administered as a maintenance therapy after chemotherapy. After a regular review, progression of the disease was observed in April 12, 2021.Patient 2 underwent anterior mediastinal tumor resection on August 2, 2019, due to the completion of the CT examination during myasthenia gravis to suggest a thymic tumor. Postoperative pathology revealed type B3 thymoma. The patient underwent local radiotherapy from October 2019 to November 2019. After irregular reexamination, the patient's condition was stable. Disease progression has been observed in June 2021. DIAGNOSIS: Both patients were diagnosed with thymoma. INTERVENTIONS: Patient 1 was administered one cycle of gemcitabine, carboplatin, and sintilimab after disease progression. Patient 2 was treated with docetaxel and cisplatin for 2 cycles, and tislelizumab was added in the second cycle. OUTCOMES: Both patient 1 and patient 2 developed immune myocarditis after one cycle of immunotherapy. The difference was that patient 1 died within a few days. After a few days of active treatment for patient 2, the immune myocarditis did not improve significantly, and the patient chose to give up the treatment and go home. The shocking outcome is that the patient remains alive and stable. LESSONS: Oncologists should be wary of ICI-related myocarditis owing to its early onset, nonspecific symptoms, and fulminant progression, especially when ICIs are used in combination. The patient's cardiac condition should be assessed before administering ICIs.


Assuntos
Miocardite , Timoma , Neoplasias do Timo , Humanos , Timoma/tratamento farmacológico , Inibidores de Checkpoint Imunológico/efeitos adversos , Cardiotoxicidade/tratamento farmacológico , Docetaxel/uso terapêutico , Miocardite/induzido quimicamente , Miocardite/tratamento farmacológico , Neoplasias do Timo/tratamento farmacológico , Progressão da Doença
20.
Sci Data ; 9(1): 699, 2022 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-36376331

RESUMO

The data currently described was generated within the EU/FP7 HeCaToS project (Hepatic and Cardiac Toxicity Systems modeling). The project aimed to develop an in silico prediction system to contribute to drug safety assessment for humans. For this purpose, multi-omics data of repeated dose toxicity were obtained for 10 hepatotoxic and 10 cardiotoxic compounds. Most data were gained from in vitro experiments in which 3D microtissues (either hepatic or cardiac) were exposed to a therapeutic (physiologically relevant concentrations calculated through PBPK-modeling) or a toxic dosing profile (IC20 after 7 days). Exposures lasted for 14 days and samples were obtained at 7 time points (therapeutic doses: 2-8-24-72-168-240-336 h; toxic doses 0-2-8-24-72-168-240 h). Transcriptomics (RNA sequencing & microRNA sequencing), proteomics (LC-MS), epigenomics (MeDIP sequencing) and metabolomics (LC-MS & NMR) data were obtained from these samples. Furthermore, functional endpoints (ATP content, Caspase3/7 and O2 consumption) were measured in exposed microtissues. Additionally, multi-omics data from human biopsies from patients are available. This data is now being released to the scientific community through the BioStudies data repository ( https://www.ebi.ac.uk/biostudies/ ).


Assuntos
Cardiotoxicidade , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Epigenômica , Metabolômica , Proteômica , Transcriptoma
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