RESUMO
Over the last decade, scientists have shifted their focus to the development of smart carriers for the delivery of chemotherapeutics in order to overcome the problems associated with traditional chemotherapy, such as poor aqueous solubility and bioavailability, low selectivity and targeting specificity, off-target drug side effects, and damage to surrounding healthy tissues. Nanofiber-based drug delivery systems have recently emerged as a promising drug delivery system in cancer therapy owing to their unique structural and functional properties, including tunable interconnected porosity, a high surface-to-volume ratio associated with high entrapment efficiency and drug loading capacity, and high mass transport properties, which allow for controlled and targeted drug delivery. In addition, they are biocompatible, biodegradable, and capable of surface functionalization, allowing for target-specific delivery and drug release. One of the most common fiber production methods is electrospinning, even though the relatively two-dimensional (2D) tightly packed fiber structures and low production rates have limited its performance. Forcespinning is an alternative spinning technology that generates high-throughput, continuous polymeric nanofibers with 3D structures. Unlike electrospinning, forcespinning generates fibers by centrifugal forces rather than electrostatic forces, resulting in significantly higher fiber production. The functionalization of nanocarriers on nanofibers can result in smart nanofibers with anticancer capabilities that can be activated by external stimuli, such as light. This review addresses current trends and potential applications of light-responsive and dual-stimuli-responsive electro- and forcespun smart nanofibers in cancer therapy, with a particular emphasis on functionalizing nanofiber surfaces and developing nano-in-nanofiber emerging delivery systems for dual-controlled drug release and high-precision tumor targeting. In addition, the progress and prospective diagnostic and therapeutic applications of light-responsive and dual-stimuli-responsive smart nanofibers are discussed in the context of combination cancer therapy.
RESUMO
Crotamine (Ctm) is a peptide isolated from Crotalus durissus terrificus venom. This molecule has been demonstrated to diminish body weight gain and enhance browning in adipose tissue, glucose tolerance, and insulin sensitivity; hence, it has been postulated as an anti-obesogenic peptide. However, the mechanism to elicit the anti-obesogenic effects has yet to be elucidated. Thus, we investigated the possible interaction of Ctm with receptors involved in obesity-related metabolic pathways through protein-protein docking and molecular dynamics refinement. To test the anti-obesogenic mechanism of Ctm, we selected and retrieved 18 targets involved in obesity-related drug discovery from Protein Data Bank. Then, we performed protein-protein dockings. The best three Ctm-target models were selected and refined by molecular dynamics simulations. Molecular docking demonstrated that Ctm was able to interact with 13 of the 18 targets tested. Having a better docking score with glucagon-like peptide-1 receptor (GLP-1R) (-1430.2 kcal/mol), DPP-IV (dipeptidyl peptidase-IV) (-1781.7 kcal/mol) and α-glucosidase (-1232.3 kcal/mol). These three models were refined by molecular dynamics. Ctm demonstrated a higher affinity for GLP-1R (ΔG: -41.886 ± 2.289 kcal/mol). However, Ctm interaction was more stable with DPP-IV (RMSD: 0.360 ± 0.015 nm, Radius of gyration: 2.781 ± 0.009 nm). Moreover, the number of interactions and the molecular mechanics energies of Ctm residues suggest that the interaction of Ctm with these receptors is mainly mediated by basic-hydrophobic dyads Y1-K2, W31-R32, and W33-R34. Together, all these results allow elucidating a possible molecular mechanism behind the previously described anti-obesogenic effects.
RESUMO
Heart failure (HF) is a heterogeneous condition that can be categorized according to the left ventricular ejection fraction (EF) into HF with reduced (HFrEF) or preserved (HFpEF) EF. Although HFrEF and HFpEF share some common clinical manifestations, the mechanisms underlying each phenotype are often found to be distinct. Identifying shared and divergent pathophysiological features might expand our insights on HF pathophysiology and assist the search for therapies for each HF subtype. In this study, we evaluated and contrasted two new murine models of non-ischaemic HFrEF and cardiometabolic HFpEF in terms of myocardial structure, left ventricular function, gene expression, cardiomyocyte calcium handling, mitochondrial polarization and protein acetylation in a head-to-head fashion. We found that in conditions of similar haemodynamic stress, the HFrEF myocardium underwent a more pronounced hypertrophic and fibrotic remodelling, whereas inflammation was greater in the HFpEF myocardium. We observed opposing features on calcium release, which was diminished in the HFrEF cardiomyocyte but enhanced in the HFpEF cardiomyocyte. Mitochondria were less polarized in both HFrEF and HFpEF cardiomyocytes, reflecting similarly impaired metabolic capacity. Hyperacetylation of cardiac proteins was observed in both models, but it was more accentuated in the HFpEF heart. Despite shared features, unique triggering mechanisms (neurohormonal overactivation in HFrEF vs. inflammation in HFpEF) appear to determine the distinct phenotypes of HF. The findings of the present research stress the need for further exploration of the differential mechanisms underlying each HF subtype, because they might require specific therapeutic interventions. KEY POINTS: The mechanisms underlying heart failure with either reduced (HFrEF) or preserved (HFpEF) ejection fraction are often found to be different. Previous studies comparing pathophysiological traits between HFrEF and HFpEF have been conducted on animals of different ages and strains. The present research contrasted two age-matched mouse models of non-ischaemic HFrEF and cardiometabolic HFpEF to uncover divergent and shared features. We found that upon similar haemodynamic stress, the HFrEF heart experienced a more pronounced hypertrophic and fibrotic remodelling, whereas inflammation appeared to be greater in the HFpEF myocardium. Calcium release was diminished in the HFrEF cardiomyocyte and enhanced in the HFpEF cardiomyocyte. Mitochondria were comparably less polarized in both HFrEF and HFpEF myocytes. Hyperacetylation of proteins was common to both models, but stronger in the HFpEF heart. Casting light on common and distinguishing features might ease the quest for phenotype-specific therapies for heart failure patients.
RESUMO
The role of the mitochondrial calcium uniporter (MCU) in energy dysfunction and hypertrophy in heart failure (HF) remains unknown. In angiotensin II (ANGII)-induced hypertrophic cardiac cells we have shown that hypertrophic cells overexpress MCU and present bioenergetic dysfunction. However, by silencing MCU, cell hypertrophy and mitochondrial dysfunction are prevented by blocking mitochondrial calcium overload, increase mitochondrial reactive oxygen species, and activation of nuclear factor kappa B-dependent hypertrophic and proinflammatory signaling. Moreover, we identified a calcium/calmodulin-independent protein kinase II/cyclic adenosine monophosphate response element-binding protein signaling modulating MCU upregulation by ANGII. Additionally, we found upregulation of MCU in ANGII-induced left ventricular HF in mice, and in the LV of HF patients, which was correlated with pathological remodeling. Following left ventricular assist device implantation, MCU expression decreased, suggesting tissue plasticity to modulate MCU expression.
RESUMO
The phospholipase A2 (PLA2) superfamily consists of lipolytic enzymes that hydrolyze specific cell membrane phospholipids and have long been considered a central hub of biosynthetic pathways, where their lipid metabolites exert a variety of physiological roles. A misregulated PLA2 activity is associated with mainly inflammatory-derived pathologies and thus has shown relevant therapeutic potential. Many natural and synthetic anti-inflammatory drugs (AIDs) have been proposed as direct modulators of PLA2 activity. However, despite the specific chemical properties that these drugs share in common, little is known about the indirect modulation able to finely tune membrane structural changes at the precise lipid-binding site. Here, we use a novel experimental strategy based on differential scanning calorimetry to systematically study the structural properties of lipid membrane systems during PLA2 cleavage and under the influence of several AIDs. For a better understanding of the AIDs-membrane interaction, we present a comprehensive and comparative set of molecular dynamics (MD) simulations. Our thermodynamic results clearly demonstrate that PLA2 cleavage is hindered by those AIDs that significantly reduce the lipid membrane cooperativity, while the rest of the AIDs oppositely tend to catalyze PLA2 activity to different extents. On the other hand, our MD simulations support experimental results by providing atomistic details on the binding, insertion, and dynamics of each AID on a pure lipid system; the drug efficacy to impact membrane cooperativity is related to the lipid order perturbation. This work suggests a membrane-based mechanism of action for diverse AIDs against PLA2 activity and provides relevant clues that must be considered in its modulation.
Assuntos
Simulação de Dinâmica Molecular , Fosfolipídeos , Fosfolipases A2/química , Fosfolipídeos/química , Membrana Celular/metabolismo , Fenômenos BiofísicosRESUMO
AIMS: Immune checkpoint inhibitors (ICIs) are antineoplastic drugs designed to activate the immune system's response against cancer cells. Evidence suggests that they may lead to immune-related adverse events, particularly when combined (e.g., anti-CTLA-4 plus anti-PD-1), sometimes resulting in severe conditions such as myocarditis. We aimed to investigate whether a previously sustained cardiac injury, such as pathological remodelling due to hypertension, is a prerequisite for ICI therapy-induced myocarditis. METHODS: We evaluated the cardiotoxicity of ICIs in a hypertension (HTN) mouse model (C57BL/6). Weekly doses were administered up to day 21 after the first administration. Our analysis encompassed the following parameters: (i) survival and cardiac pathological remodelling, (ii) cardiac function assessed using pressure-volume (PV)-loops, with brain natriuretic peptide (BNP) serving as a marker of haemodynamic dysfunction and (iii) cardiac inflammation (cytokine levels, infiltration, and cardiac antigen autoantibodies). RESULTS: After the first administration of ICI combined therapy, the treated HTN group showed a 30% increased mortality (P = 0.0002) and earlier signs of hypertrophy and pathological remodelling compared with the untreated HTN group. BNP (P = 0.01) and TNF-α (<0.0001) increased 2.5- and 1.7-fold, respectively, in the treated group, while IL-6 (P = 0.8336) remained unchanged. Myocarditis only developed in the HTN group treated with ICIs on day 21 (score >3), characterised by T cell infiltration and increased cardiac antigen antibodies (86% showed a titre of 1:160). The control group treated with ICI was unaffected in any evaluated feature. CONCLUSIONS: Our findings indicate that pre-existing sustained cardiac damage is a necessary condition for ICI-induced myocarditis.
Assuntos
Hipertensão , Miocardite , Animais , Camundongos , Camundongos Endogâmicos C57BL , Inibidores de Checkpoint Imunológico , CoraçãoRESUMO
BACKGROUND: Domingo de Ramos, or Palm Sunday, is a traditional Christian religious event where devotees use ramos, which are bouquets currently elaborated from palm leaves and other natural elements. In various countries, it is assumed this use of biodiversity leads to the depletion of the species involved. However, other important aspects must be considered, including the role of the people who produce and sell these ramos, the associated symbolism that has been overlooked, as well as commercial aspects that have barely been documented. This ethnobotanical study evaluates the regional-scale cultural, biological and socioeconomic aspects associated with Domingo de Ramos in central Mexico from an emic perspective. METHODS: Ethnographic and commercial information was obtained through interviews with ramos sellers in 28 municipalities in the state of Hidalgo, Mexico. We specifically sought sociodemographic data regarding the interviewees, as well as information pertaining to the ramos themselves and the palms. These aspects were explored with all of the sellers. The free list method was used to describe the uses and key elements associated with the ramos. RESULTS: Although the ramos are used for religious purposes, they have eight different uses in the daily life of the sellers, the main one being "protection." They serve to protect families, crops and animals, as well as against several diseases. Likewise, they are considered valuable for diminishing strong storms. This belief in the protection conferred by the ramos preserves pre-Hispanic concepts and is combined with their use in blessing corresponding to Western beliefs. Ramos are made from 35 introduced and native plant species and comprise a base (made of palm, wheat or sotol), a "reliquia" (palm, rosemary, chamomile and laurel) and natural or artificial flowers. The ramos sellers are mostly adult women of indigenous origin and heads of family. CONCLUSIONS: This study of Domingo de Ramos, carried out at a regional scale, highlights a syncretism that is reflected in both the symbolic importance of ramos palm and in the species used, as well as socioeconomic aspects that had not previously been identified in the study area and reflect the occurrence of complex relationships in non-timber forest products that remain little addressed.
Assuntos
Arecaceae , Etnobotânica , Animais , México , Etnobotânica/métodos , Florestas , Folhas de Planta , FloresRESUMO
The widespread use of titanium dioxide (TiO2) has raised concerns about potential health risks associated with its cytotoxicity in the cardiovascular system. To evaluate the cytotoxicity of TiO2 particles, the H9c2 rat cardiomyoblasts were used as a biological model, and their toxicological susceptibility to TiO2-anatase and TiO2-rutile particles was studied in vitro. The study examined dose and time exposure responses. The cell viability was evaluated based on metabolic inhibition and membrane integrity loss. The results revealed that both TiO2-anatase and TiO2-rutile particles induced similar levels of cytotoxicity at the inhibition concentrations IC25 (1.4-4.4 µg/cm2) and IC50 (7.2-9.3 µg/cm2). However, at more significant concentrations, TiO2-rutile appeared to be more cytotoxic than TiO2-anatase at 24 h. The study found that the TiO2 particles induced apoptosis events, but necrosis was not observed at any of the concentrations of particles used. The study considered the effects of microstructural properties, crystalline phase, and particle size in determining the capability of TiO2 particles to induce cytotoxicity in H9c2 cardiomyoblasts. The microstress in TiO2 particles was assessed using powder X-ray diffraction through Williamson-Hall and Warren-Averbach analysis. The analysis estimated the apparent crystallite domain and microstrain of TiO2-anatase to be 29 nm (ε = 1.03%) and TiO2-rutile to be 21 nm (ε = 0.53%), respectively. Raman spectroscopy, N2 adsorption isotherms, and dynamic light scattering were used to identify the presence of pure crystalline phases (>99.9%), comparative surface areas (10 m2/g), and ζ-potential values (-24 mV). The difference in the properties of TiO2 particles made it difficult to attribute the cytotoxicity solely to one variable.
RESUMO
Cardiovascular diseases (CVDs), the leading cause of death worldwide, share in common mitochondrial dysfunction, in specific a dysregulation of Ca2+ uptake dynamics through the mitochondrial Ca2+ uniporter (MCU) complex. In particular, Ca2+ uptake regulates the mitochondrial ATP production, mitochondrial dynamics, oxidative stress, and cell death. Therefore, modulating the activity of the MCU complex to regulate Ca2+ uptake, has been suggested as a potential therapeutic approach for the treatment of CVDs. Here, the role and implications of the MCU complex in CVDs are presented, followed by a review of the evidence for MCU complex modulation, genetically and pharmacologically. While most approaches have aimed within the MCU complex for the modulation of the Ca2+ pore channel, the MCU subunit, its intra- and extra- mitochondrial implications, including Ca2+ dynamics, oxidative stress, post-translational modifications, and its repercussions in the cardiac function, highlight that targeting the MCU complex has the translational potential for novel CVDs therapeutics.
Assuntos
Canais de Cálcio , Doenças Cardiovasculares , Humanos , Canais de Cálcio/genética , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo , Processamento de Proteína Pós-Traducional , Cálcio/metabolismoRESUMO
Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block CTLA-4, PD-1, or PD-L1 and induce the activation of the immune system against cancer. Despite the efficacy of ICIs, which has improved the oncotherapy for patients with a variety of malignancies, several immune-related adverse events (irAEs) have been described, including those affecting the heart. Cardiac irAEs after ICI therapies, including myocarditis, can become life-threatening, and their pathogenic mechanisms remain unclear. Here, a systematic analysis was performed regarding the potential immune mechanisms underlying cardiac irAEs based on the immune adverse events induced by the ICIs: 1) recruitment of CD4+ and CD8+ T cells, 2) autoantibody-mediated cardiotoxicity, and 3) inflammatory cytokines. Furthermore, the impact of dual therapies in ICI-induced cardiac irAEs and the potential risk factors are reviewed. We propose that self-antigens released from cardiac tissues or cancer cells and the severity/advancement of cancer disease have an important role in ICI cardiotoxicity.
RESUMO
AIMS: This study aimed to estimate the incidence of cardiac immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitors (ICIs). METHODS AND RESULTS: First, we performed an ICI pharmacovigilance analysis, finding 4.2% of cardiac disorders, including myocarditis, for anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapies. Patients treated with anti-PD-1 antibodies presented a greater number of cardiac adverse events (AEs) than those treated with anti-CTLA-4 (69.4% vs. 20%). Then, we analysed the incidence and characteristics of cardiac irAEs in 1265 papers published prior to 31 August 2020. Of the 4751 patients studied, 1.3% presented cardiac irAEs, with myocarditis being the most frequent (50.8%); 15 patients died (24.6%) due to cardiac irAEs. Finally, we conducted a meta-analysis to determine cardiac irAEs in randomized clinical trials, identified through a systematic search from the ClinicalTrials.gov database, finding an incidence of 3.1% for ICI monotherapies, 5.8% for dual ICI therapies, 3.7% (irAEs/AEs) for ICIs plus chemotherapy, and cardiac AEs were reported in 2.5% of patients treated solely with chemotherapy. CONCLUSIONS: Our study provides precise data for the incidence of cardiac irAEs among patients using ICIs, where despite its low incidence, the high rate of mortality is an important issue to consider. ICIs induce mainly myocarditis at the first doses, and dual therapies seem to provoke higher rates of cardiac irAEs than monotherapies or ICIs plus chemotherapy.
Assuntos
Insuficiência Cardíaca , Neoplasias , Cardiotoxicidade/epidemiologia , Cardiotoxicidade/etiologia , Bases de Dados Factuais , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias/complicações , Neoplasias/tratamento farmacológico , FarmacovigilânciaRESUMO
BACKGROUND: Silica nanoparticles (nanoSiO2) are promising systems that can deliver biologically active compounds to tissues such as the heart in a controllable manner. However, cardiac toxicity induced by nanoSiO2 has been recently related to abnormal calcium handling and energetic failure in cardiomyocytes. Moreover, the precise mechanisms underlying this energetic debacle remain unclear. In order to elucidate these mechanisms, this article explores the ex vivo heart function and mitochondria after exposure to nanoSiO2. RESULTS: The cumulative administration of nanoSiO2 reduced the mechanical performance index of the rat heart with a half-maximal inhibitory concentration (IC50) of 93 µg/mL, affecting the relaxation rate. In isolated mitochondria nanoSiO2 was found to be internalized, inhibiting oxidative phosphorylation and significantly reducing the mitochondrial membrane potential (ΔΨm). The mitochondrial permeability transition pore (mPTP) was also induced with an increasing dose of nanoSiO2 and partially recovered with, a potent blocker of the mPTP, Cyclosporine A (CsA). The activity of aconitase and thiol oxidation, in the adenine nucleotide translocase, were found to be reduced due to nanoSiO2 exposure, suggesting that nanoSiO2 induces the mPTP via thiol modification and ROS generation. In cardiac cells exposed to nanoSiO2, enhanced viability and reduction of H2O2 were observed after application of a specific mitochondrial antioxidant, MitoTEMPO. Concomitantly, CsA treatment in adult rat cardiac cells reduced the nanoSiO2-triggered cell death and recovered ATP production (from 32.4 to 65.4%). Additionally, we performed evaluation of the mitochondrial effect of nanoSiO2 in human cardiomyocytes. We observed a 40% inhibition of maximal oxygen consumption rate in mitochondria at 500 µg/mL. Under this condition we identified a remarkable diminution in the spare respiratory capacity. This data indicates that a reduction in the amount of extra ATP that can be produced by mitochondria during a sudden increase in energy demand. In human cardiomyocytes, increased LDH release and necrosis were found at increased doses of nanoSiO2, reaching 85 and 48%, respectively. Such deleterious effects were partially prevented by the application of CsA. Therefore, exposure to nanoSiO2 affects cardiac function via mitochondrial dysfunction through the opening of the mPTP. CONCLUSION: The aforementioned effects can be partially avoided reducing ROS or retarding the opening of the mPTP. These novel strategies which resulted in cardioprotection could be considered as potential therapies to decrease the side effects of nanoSiO2 exposure.
Assuntos
Coração/efeitos dos fármacos , Poro de Transição de Permeabilidade Mitocondrial/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Nanopartículas/toxicidade , Dióxido de Silício/toxicidade , Trifosfato de Adenosina/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Nanopartículas/química , Nanopartículas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Dióxido de Silício/química , Dióxido de Silício/farmacocinética , Propriedades de SuperfícieRESUMO
Pulmonary arterial hypertension (PAH) is a life-threatening disease that is characterized by an increase in pulmonary vascular pressure, leading to ventricular failure and high morbidity and mortality. Resveratrol, a phenolic compound and a sirtuin 1 pathway activator, has known dietary benefits and is used as a treatment for anti-inflammatory and cardiovascular diseases. Its therapeutic effects have been published in the scientific literature; however, its benefits in PAH are yet to be precisely elucidated. Using a murine model of PAH induced by monocrotaline, the macroscopic and microscopic effects of a daily oral dose of resveratrol in rats with PAH were evaluated by determining its impact on the lungs and the right and left ventricular function. While most literature has focused on smooth muscle cell mechanisms and lung pathology, our results highlight the relevance of therapy-mediated improvement of right ventricle and isolated cardiomyocyte physiology in both ventricles. Although significant differences in the pulmonary architecture were not identified either micro- or macroscopically, the effects of resveratrol on right ventricular function and remodeling were observed to be beneficial. The values for the volume, diameter, and contractility of the right ventricular cardiomyocytes returned to those of the control group, suggesting that resveratrol has a protective effect against ventricular dysfunction and pathological remodeling changes in PAH. The effect of resveratrol in the right ventricle delayed the progression of findings associated with right heart failure and had a limited positive effect on the architecture of the lungs. The use of resveratrol could be considered a future potential adjunct therapy, especially when the challenges to making a diagnosis and the current therapy limitations for PAH are taken into consideration.
Assuntos
Antioxidantes/uso terapêutico , Ecocardiografia/métodos , Pulmão/patologia , Hipertensão Arterial Pulmonar/prevenção & controle , Resveratrol/uso terapêutico , Remodelação Ventricular/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-Dawley , Resveratrol/farmacologiaRESUMO
The effective delivery of antioxidants to the cells is hindered by their high metabolization rate. In this work, quercetin was encapsulated in poly(lactic-co-glycolic) acid (PLGA) nanoparticles. They were characterized in terms of its physicochemical properties (particle size distribution, ζ-potential, encapsulation efficiency, quercetin release and biological interactions with cardiac cells regarding nanoparticle association, and internalization and protective capability against relevant challenges). A better delivery of quercetin was achieved when encapsulated versus free. When the cells were challenged with antimycin A, it resulted in lower mitochondrial O2 - (4.65- vs. 5.69- fold) and H2O2 rate production (1.15- vs. 1.73- fold). Similarly, under hypoxia-reoxygenation injury, a better maintenance of cell viability was found (77 vs. 65%), as well as a reduction of thiol groups (~70 vs. 40%). Therefore, the delivery of encapsulated quercetin resulted in the preservation of mitochondrial function and ATP synthesis due to its improved oxidative stress suppression. The results point to the potential of this strategy for the treatment of oxidative stress-based cardiac diseases.
Assuntos
Cardiotônicos/uso terapêutico , Hipóxia Celular/genética , Mitocôndrias/metabolismo , Quercetina/uso terapêutico , Cardiotônicos/farmacologia , Humanos , Nanopartículas , Quercetina/farmacologiaRESUMO
Casiopeinas are a group of copper-based antineoplastic molecules designed as a less toxic and more therapeutic alternative to cisplatin or Doxorubicin; however, there is scarce evidence about their toxic effects on the whole heart and cardiomyocytes. Given this, rat hearts were perfused with Casiopeinas or Doxorubicin and the effects on mechanical performance, energetics, and mitochondrial function were measured. As well, the effects of Casiopeinas-triggered cell death were explored in isolated cardiomyocytes. Casiopeinas III-Ea, II-gly, and III-ia induced a progressive and sustained inhibition of heart contractile function that was dose- and time-dependent with an IC50 of 1.3 ± 0.2, 5.5 ± 0.5, and 10 ± 0.7 µM, correspondingly. Myocardial oxygen consumption was not modified at their respective IC50, although ATP levels were significantly reduced, indicating energy impairment. Isolated mitochondria from Casiopeinas-treated hearts showed a significant loss of membrane potential and reduction of mitochondrial Ca2+ retention capacity. Interestingly, Cyclosporine A inhibited Casiopeinas-induced mitochondrial Ca2+ release, which suggests the involvement of the mitochondrial permeability transition pore opening. In addition, Casiopeinas reduced the viability of cardiomyocytes and stimulated the activation of caspases 3, 7, and 9, demonstrating a cell death mitochondrial-dependent mechanism. Finally, the early perfusion of Cyclosporine A in isolated hearts decreased Casiopeinas-induced dysfunction with reduction of their toxic effect. Our results suggest that heart cardiotoxicity of Casiopeinas is similar to that of Doxorubicin, involving heart mitochondrial dysfunction, loss of membrane potential, changes in energetic metabolites, and apoptosis triggered by mitochondrial permeability.
Assuntos
Antineoplásicos/efeitos adversos , Cardiotoxicidade/etiologia , Mitocôndrias Cardíacas/efeitos dos fármacos , Compostos Organometálicos/efeitos adversos , Animais , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Complexos de Coordenação/efeitos adversos , Complexos de Coordenação/química , Cobre/efeitos adversos , Cobre/química , Masculino , Mitocôndrias Cardíacas/metabolismo , Compostos Organometálicos/administração & dosagem , Ratos , Ratos WistarRESUMO
AIM: To study the biopersistence of a silicon carbide (SiC) nanoaerosol in rat lungs, as time-dependent clearance and spatial distribution. MATERIALS & METHODS: Sprague-Dawley rats were exposed 6 h/day during 5 days to a SiC nanoaerosol at 4.91 mg SiC/l. SiC biopersistence in rat lungs sections was assessed over 28 days by micro-particle-induced x-ray emission (µPIXE) as 2D maps and by particle-induced x-ray emission (PIXE) for whole-lung quantification. 2D maps were analyzed for SiC spatial distribution as skewness and kurtosis. RESULTS: Half-time clearance was 10.9 ± 0.9 days, agreeing with PIXE measurements. Spatial-temporal analysis of SiC indicated decreased symmetry and homogeneity. CONCLUSION: Fast SiC clearance points that current nanoaerosol exposure may not be enough to trigger lung overload. Spatial distribution shows an asymmetric and nonhomogeneous SiC clearance.
Assuntos
Aerossóis/química , Compostos Inorgânicos de Carbono/química , Compostos Inorgânicos de Carbono/metabolismo , Nanoestruturas/química , Compostos de Silício/química , Compostos de Silício/metabolismo , Animais , Feminino , Pulmão/diagnóstico por imagem , Taxa de Depuração Metabólica , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Espectrometria por Raios X , Propriedades de Superfície , Distribuição TecidualRESUMO
Biomedical achievements in the last few decades, leading to successful therapeutic interventions, have considerably improved human life expectancy. Nevertheless, the increasing load and the still suboptimal outcome for patients with cardiac dysfunction underlines the relevance of continuous research to develop novel therapeutics for these diseases. In this context, the field of nanomedicine has attracted a lot of attention due to the potential novel treatment possibilities, such as controlled and sustained release, tissue targeting, and drug protection from degradation. For cardiac myocytes, which constitute the majority of the heart by mass and are the contractile unit, new options have been explored in terms of the use of nanomaterials (NMs) for therapy, diagnosis, and tissue engineering. This review focuses on the advances of nanomedicine targeted to the cardiac myocyte: first presenting the NMs used and the principal cardiac myocyte-based afflictions, followed by an overview of key advances in the field, including NMs interactions with the cardiac myocyte, therapy delivery, diagnosis based on imaging, and tissue engineering for tissue repair and heart-on-a-chip devices.
Assuntos
Miócitos Cardíacos/efeitos dos fármacos , Nanoestruturas/administração & dosagem , Animais , Humanos , Miócitos Cardíacos/patologia , Miócitos Cardíacos/fisiologia , NanomedicinaRESUMO
Recent evidence has shown that nanoparticles that have been used to improve or create new functional properties for common products may pose potential risks to human health. Silicon dioxide (SiO2) has emerged as a promising therapy vector for the heart. However, its potential toxicity and mechanisms of damage remain poorly understood. This study provides the first exploration of SiO2-induced toxicity in cultured cardiomyocytes exposed to 7- or 670-nm SiO2 particles. We evaluated the mechanism of cell death in isolated adult cardiomyocytes exposed to 24-h incubation. The SiO2 cell membrane association and internalization were analyzed. SiO2 showed a dose-dependent cytotoxic effect with a half-maximal inhibitory concentration for the 7 nm (99.5 ± 12.4 µg/ml) and 670 nm (>1,500 µg/ml) particles, which indicates size-dependent toxicity. We evaluated cardiomyocyte shortening and intracellular Ca2+ handling, which showed impaired contractility and intracellular Ca2+ transient amplitude during ß-adrenergic stimulation in SiO2 treatment. The time to 50% Ca2+ decay increased 39%, and the Ca2+ spark frequency and amplitude decreased by 35 and 21%, respectively, which suggest a reduction in sarcoplasmic reticulum Ca2+-ATPase (SERCA) activity. Moreover, SiO2 treatment depolarized the mitochondrial membrane potential and decreased ATP production by 55%. Notable glutathione depletion and H2O2 generation were also observed. These data indicate that SiO2 increases oxidative stress, which leads to mitochondrial dysfunction and low energy status; these underlie reduced SERCA activity, shortened Ca2+ release, and reduced cell shortening. This mechanism of SiO2 cardiotoxicity potentially plays an important role in the pathophysiology mechanism of heart failure, arrhythmias, and sudden death.NEW & NOTEWORTHY Silica particles are used as novel nanotechnology-based vehicles for diagnostics and therapeutics for the heart. However, their potential hazardous effects remain unknown. Here, the cardiotoxicity of silica nanoparticles in rat myocytes has been described for the first time, showing an impairment of mitochondrial function that interfered directly with Ca2+ handling.
Assuntos
Cálcio/metabolismo , Cardiotoxicidade/metabolismo , Metabolismo Energético/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Nanopartículas/toxicidade , Dióxido de Silício/toxicidade , Trifosfato de Adenosina/metabolismo , Animais , Membrana Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Cardíacas/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismoRESUMO
BACKGROUND: Titanium carbide (TiC) is used for ceramic metal composites in several industries and is regarded as a nanomaterial for catalyst and battery applications. However, there are very few studies in regard to the toxicological potential of TiC nanoparticles (NPs). OBJECTIVE: To study the toxicodynamics and toxicokinetics of TiC NPs in Sprague Dawley rats in acute (24 h) and subacute (28 days) oral administrations. The acute doses were 0.5, 5, 50, 300 and 1000 mg kg-1; the subacute doses were 0.5 and 50 mg kg-1. RESULTS: Organ histopathological examination (esophagus, stomach, intestines, spleen, liver, and kidneys) indicates the absence of damage at all applied doses, in both assessments. In the acute administration, alkaline phosphatases increased (5, 300 and 1000 mg kg-1), ASAT increased (1000 mg kg-1) and bile salts decreased (0.5 mg kg-1). No alterations in urine parameters (sodium, potassium, osmolarity) were found. Acute administration of TiC caused mineral changes in organs (liver, spleen, kidneys). TiC was mostly cleared by feces excretion 24 h after administration, in subacute administration causing variations in mineral absorption (Mg, Al, P, S, Ca, Zn). TiC could pass the intestinal barrier as TiC traces were detected in urine. CONCLUSION: No sign of toxicity was found after oral administration. TiC was excreted mostly in feces producing mineral absorption alterations. Low traces were retrieved in urine, indicating that TiC can cross the intestinal barrier.