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1.
Toxicol Lett ; 319: 40-48, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31706004

RESUMO

Two synthetic tryptamines, namely [3-[2-(diethylamino)ethyl]-1H-indol-4-yl] acetate (4-AcO-DET) and 3-[2-[ethyl(methyl)amino]ethyl]-1H-indol-4-ol (4-HO-MET), are abused by individuals seeking recreational hallucinogens. These new psychoactive substances (NPSs) can cause serious health problems because their adverse effects are mostly unknown. In the present study, we evaluated the cardiotoxicity of 4-AcO-DET and 4-HO-MET using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, electrocardiography (ECG), and the human ether-a-go-go-related gene (hERG) assay. In addition, we analyzed the expression level of p21 (CDC42/RAC)-activated kinase 1 (PAK1), which is known to play various roles in the cardiovascular system. In the MTT assay, 4-AcO-DET- and 4-HO-MET-treated H9c2 cells proliferated in a concentration-dependent manner. Moreover, both substances increased QT intervals (as determined using ECG) in Sprague-Dawley rats and inhibited potassium channels (as verified by the hERG assay) in Chinese hamster ovary cells. However, there was no change in PAK1 expression. Collectively, the results indicated that 4-AcO-DET and 4-HO-MET might cause adverse effects on the cardiovascular system. Further studies are required to confirm the relationship between PAK1 expression and cardiotoxicity. The findings of the present study would provide science-based evidence for scheduling the two NPSs.


Assuntos
Cardiotoxinas/toxicidade , Alucinógenos/toxicidade , Triptaminas/toxicidade , Animais , Células CHO , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cricetulus , Canal de Potássio ERG1/metabolismo , Eletrocardiografia , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/toxicidade , Ratos , Ratos Sprague-Dawley , Quinases Ativadas por p21/biossíntese , Quinases Ativadas por p21/genética
2.
J Environ Pathol Toxicol Oncol ; 38(2): 143-152, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31679277

RESUMO

The current study evaluated the cardioprotective activity of genistein in cases of doxorubicin-(Dox) induced cardiac toxicity and a probable mechanism underlying this protection, such as an antioxidant pathway in cardiac tissues. Animals used in this study were categorized into four groups. The first group was treated with sodium carboxymethylcellulose (0.3%; CMC-Na) solution. The second group received Dox (3.0 mg/kg, i.p.) on days 6, 12, 18, and 24. The third and fourth groups received Dox (3 mg/kg, i.p.) on days 6, 12, 18, and 24 and received protective doses of genistein (100 [group 3] and 200 [group 4] mg/kg/day, p.o.) for 30 days. Treatment with genistein significantly improved the altered cardiac function markers and oxidative stress markers. This was coupled with significant improvement in cardiac histopathological features. Genistein enhanced the Nrf2 and HO-1 expression, which showed protection against oxidative insult induced by Dox. Terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed substantial inhibition of apoptosis by genistein in myocardia. The study showed that genistein has a strong reactive oxygen species scavenging property and potentially (P ≤ .001) decreases the lipid peroxidation as well as inhibits DNA damage in cardiac toxicity induced by Dox. In conclusion, the potential antioxidant effect of genistein may be because of its modulatory effect on Nrf2/HO-1 signalling pathway and by this means exhibits cardioprotective effects from Dox-induced oxidative injury.


Assuntos
Cardiotônicos/farmacologia , Cardiotoxinas/toxicidade , Doxorrubicina/toxicidade , Genisteína/farmacologia , Heme Oxigenase-1/genética , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Animais , Cardiotoxicidade/etiologia , Heme Oxigenase-1/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Ratos Wistar
3.
Nutrients ; 11(4)2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30999708

RESUMO

The effects of lactate on muscle mass and regeneration were investigated using mouse skeletal muscle tissue and cultured C2C12 cells. Male C57BL/6J mice were randomly divided into (1) control, (2) lactate (1 mol/L in distilled water, 8.9 mL/g body weight)-administered, (3) cardio toxin (CTX)-injected (CX), and (4) lactate-administered after CTX-injection (LX) groups. CTX was injected into right tibialis anterior (TA) muscle before the oral administration of sodium lactate (five days/week for two weeks) to the mice. Oral lactate administration increased the muscle weight and fiber cross-sectional area, and the population of Pax7-positive nuclei in mouse TA skeletal muscle. Oral administration of lactate also facilitated the recovery process of CTX-associated injured mouse TA muscle mass accompanied with a transient increase in the population of Pax7-positive nuclei. Mouse myoblast-derived C2C12 cells were differentiated for five days to form myotubes with or without lactate administration. C2C12 myotube formation with an increase in protein content, fiber diameter, length, and myo-nuclei was stimulated by lactate. These observations suggest that lactate may be a potential molecule to stimulate muscle hypertrophy and regeneration of mouse skeletal muscle via the activation of muscle satellite cells.


Assuntos
Músculo Esquelético/efeitos dos fármacos , Mioblastos/efeitos dos fármacos , Regeneração/efeitos dos fármacos , Lactato de Sódio/farmacologia , Animais , Cardiotoxinas/toxicidade , Linhagem Celular , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/crescimento & desenvolvimento , Músculo Esquelético/fisiologia , Distribuição Aleatória , Lactato de Sódio/administração & dosagem
4.
Toxicol Lett ; 307: 41-48, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30817977

RESUMO

Doxorubicin (DOX) is widely used as a broad-spectrum anti-tumor anthracycline to treat various cancers. The serious adverse effects of DOX on cardiotoxicity limit its clinical application. There are several different mechanisms involved in DOX-induced cardiotoxicity. Oxidative stress (OS) is caused by an imbalance between reactive oxygen species (ROS) and endogenous antioxidants in response to injury, which can lead to myocardial toxicity. The aim of this review was to investigate the mechanisms underlying the effects of oxidative stress injury on myocardial toxicity, from three different aspects: the increase in downstream oxidative stress products, the reduction in upstream antioxidative stress products, and subcellular organelles. Finally, there are some anti-oxidative drugs that show efficacy in limiting DOX-induced cardiotoxicity. It is necessary to fully understand the toxicity of DOX to the myocardium and achieve symptomatic treatment.


Assuntos
Cardiotoxicidade/etiologia , Cardiotoxinas/toxicidade , Doxorrubicina/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Animais , Coração/efeitos dos fármacos , Humanos , Miocárdio/metabolismo
5.
Ecotoxicol Environ Saf ; 168: 378-387, 2019 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-30396134

RESUMO

A growing number of epidemiological surveys show that PM2.5 is an important promoter for the cardiovascular dysfunction induced by atmospheric pollution. PM2.5 is a complex mixture of solid and liquid airborne particles and its components determine the health risk of PM2.5to a great extent. However, the individual cardiotoxicities of different PM2.5 fractions are still unclear, especially in the cellular level. Here we used the neonatal rat cardiomyocytes (NRCMs) to evaluate the cardiac toxicity of PM2.5 exposure. The cytotoxicities of Total-PM2.5, water soluble components of PM2.5 (WS-PM2.5) and water insoluble components of PM2.5 (WIS-PM2.5), which include the cell viability, cell membrane damage, reactive oxygen species (ROS) generation, were examined with NRCMs in vitro. The results indicated that Total-PM2.5 or WIS-PM2.5 exposure significantly decreased the cell viability, induced the cell membrane damage and increased the ROS level in NRCMs at concentrations above 50 µg/mL. However, WS-PM2.5 exposure could induce the cytotoxicity on NRCMs until the concentration of WS-PM2.5 was raised to a higher concentration (75 µg/mL). Furthermore, the DNA damage was detected in NRCMs after 48 h of exposure with Total-PM2.5, WS-PM2.5 or WIS-PM2.5 (75 µg/mL) and the adverse effects on mitochondrial function and action potentials of NRCMs were detected only both in the Total-PM2.5 and WIS-PM2.5 treatment group. In summary, our project not only estimates the risk of PM2.5 on cardiac cells but also reveal that Total-PM2.5 and WIS-PM2.5 exposure were predominantly associated with the functional cardiotoxicities in NRCMs.


Assuntos
Cardiotoxinas/toxicidade , Miócitos Cardíacos/efeitos dos fármacos , Material Particulado/toxicidade , Animais , Animais Recém-Nascidos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Dano ao DNA/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Miócitos Cardíacos/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo
6.
Toxicology ; 411: 49-59, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30393206

RESUMO

Anti-cancer drug Sunitinib is linked to adverse cardiovascular events, which have shown to involve mitogen activated kinase kinase 7 (MKK7) pathway. Sunitinib-induced cardiotoxicity in 3, 12 and 24 months old male Sprague-Dawley rats and MKK7 expression and activation was investigated using the Langendorff perfused heart model followed by Western blot analysis. Cardiac function and infarct size were measured during/after 125 min of Sunitinib treatment. Left ventricular cardiac samples were analysed by qRT-PCR for expression of MKK7 mRNA and cardiac injury associated microRNAs. Infarct size was increased in all Sunitinib treated age groups. Haemodynamic alterations were observed following Sunitinib administration. Left ventricular developed pressure (LVDP) was decreased in all age groups, while heart rate (HR) was decreased in 3 and 12 months groups. Sunitinib treatment decreased the expression of miR-27a in all age groups, while miR-133a and miR-133b levels were increased in 3 months and decreased in 24 months groups. MKK7 mRNA and p-MKK7 levels were decreased in the 3 months group after Sunitinib treatment. MKK7 mRNA level was increased in 24 months group and p-MKK7 levels were increased in 12 months group following Sunitinib treatment. This study highlights the importance and impact of ageing and anti-cancer therapy-induced cardiotoxicity.


Assuntos
Envelhecimento/fisiologia , Antineoplásicos/toxicidade , Cardiotoxinas/toxicidade , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sunitinibe/toxicidade , Animais , Testes de Função Cardíaca , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Técnicas In Vitro , Masculino , MicroRNAs , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/patologia , Ratos , Ratos Sprague-Dawley , Função Ventricular Esquerda/efeitos dos fármacos
7.
Heart ; 105(6): 439-448, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30538094

RESUMO

OBJECTIVE: Cardiovascular disease (CVD) is a leading cause of mortality and morbidity in the USA. The role of occupational exposures to chemicals in the development of CVD has rarely been studied even though many agents possess cardiotoxic properties. We therefore evaluated associations of self-reported exposures to organic solvents, metals and pesticides in relation to CVD prevalence among diverse Hispanic/Latino workers. METHODS: Cross-sectional data from 7404 employed individuals, aged 18-74 years, enrolled in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) were analysed. Participants from four US cities provided questionnaire data and underwent clinical examinations, including ECGs. CVD was defined as the presence of at least one of the following: coronary heart disease, atrial fibrillation, heart failure or cerebrovascular disease. Prevalence ratios reflecting the relationship between each occupational exposure and CVD as well as CVD subtypes were calculated using Poisson regression models. RESULTS: Hispanic/Latino workers reported exposures to organic solvents (6.5%), metals (8.5%) and pesticides (4.7%) at their current jobs. Overall, 6.1% of participants had some form of CVD, with coronary heart disease as the most common (4.3%) followed by cerebrovascular disease (1.0%), heart failure (0.8%) and atrial fibrillation (0.7%). For individuals who reported working with pesticides, the prevalence ratios for any CVD were 2.18 (95% CI 1.34 to 3.55), coronary heart disease 2.20 (95% CI 1.31 to 3.71), cerebrovascular disease 1.38 (95% CI 0.62 3.03), heart failure 0.91 (95% CI 0.23 to 3.54) and atrial fibrillation 5.92 (95% CI 1.89 to 18.61) after adjustment for sociodemographic, acculturation, lifestyle and occupational characteristics. Metal exposures were associated with an almost fourfold (3.78, 95% CI 1.24 to 11.46) greater prevalence of atrial fibrillation. Null associations were observed for organic solvent exposures. CONCLUSIONS: Our results suggest that working with metals and pesticides could be risk factors for CVD among Hispanic/Latino workers. Further work is needed to evaluate these relationships prospectively.


Assuntos
Cardiotoxinas , Doenças Cardiovasculares , Metais/toxicidade , Exposição Ocupacional , Praguicidas/toxicidade , Aculturação , Adulto , Idoso , Cardiotoxinas/análise , Cardiotoxinas/toxicidade , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/classificação , Doenças Cardiovasculares/epidemiologia , Estudos Transversais , Feminino , Hispano-Americanos/estatística & dados numéricos , Humanos , Estilo de Vida/etnologia , Masculino , Pessoa de Meia-Idade , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/análise , Exposição Ocupacional/prevenção & controle , Prevalência , Fatores de Risco , Fatores Socioeconômicos , Estados Unidos/epidemiologia
8.
Biomed Pharmacother ; 110: 1-8, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30453253

RESUMO

BACKGROUND: Doxorubicin (DOX) is a chemotherapeutic drug limited in its usefulness by an adverse side effect, cardiotoxicity. The mechanisms leading to this detrimental occurrence are not completely clear, and lately many authors focused their attention on the possible role of microRNAs (miRNAs), small regulators of cardiovascular functions, in this phenomenon. Notably, these molecules recently emerged also as potential circulating biomarkers of several cardiac diseases. Thus, the aim of this study was the simultaneous investigation of circulating and cardiac tissue miRNAs expression upon DOX treatment in vivo. METHODS: Twenty C57BL/6 female mice were administered with 24 mg/Kg cumulative dose of DOX or saline (CTRL) for 2 weeks. Echocardiography was performed at baseline and at the end of treatment (T1). Plasma and heart samples were collected at T1, separating atria from left (LV) and right (RV) ventricles, and miRNAs expression was tested by RT-qPCR-based arrays. All putatively DOX-regulated candidates were then validated by single assays in vivo and then evaluated also in murine immortalized cardiomyocytes (HL-1) treated with 1 µM DOX for 24 h. In the end, bioinformatics target prediction was performed for all DOX-miRNAs. RESULTS: Cardiotoxicity onset was diagnosed upon impairment of six cardiac functional parameters in DOX-treated mice at T1. Samples collection, followed by screening and validation steps, identified eleven miRNAs dysregulated by the drug in plasma, while seven resulted as altered in separate heart chambers. Interestingly, miR-34a-5p and miR-451a showed a dysregulation in both plasma and tissue samples of DOX-administered animals, whereas five additional miRNAs presented chamber specific modulation. Of note, in vitro experiments showed a very modest overlap with in vivo results. Bioinformatics prediction analysis performed on miR-34a-5p and miR-451a identified several putative targets presenting no significant association with cardiotoxicity. Anyhow, the same analyses, conducted by combining all miRNAs regulated by DOX in each heart chamber, evidenced a possible dysregulation of the adherens junctions gene network, known to be involved in the onset and progression of dilated cardiomyopathy, an established detrimental side effect of the drug. CONCLUSIONS: This is the first work investigating miRNAs regulation by DOX both in plasma and heart districts of treated animals. Our results indicate a strong association of miR-34a-5p and miR-451a to DOX-induced cardiotoxicity. In addition, the observed altered expression of diverse miRNAs in separated cardiac chambers hints at a specific response to the drug, implying the existence of different players and pathways leading to dysfunction onset.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Cardiotoxinas/toxicidade , Doxorrubicina/toxicidade , MicroRNAs/biossíntese , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Cardiotoxicidade/sangue , Cardiotoxicidade/patologia , Células Cultivadas , Feminino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Miócitos Cardíacos/patologia
9.
Biomed Pharmacother ; 109: 2527-2538, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30551513

RESUMO

Mesoporous silica nanoparticles (MSNs) represent one of the most promising drug delivery systems. MSNs have attracted considerable attention in recent years both in industry and biomedicine due to their unique properties. Thus, evaluation of the toxic effects of MSNs is necessary before the biomedical and clinical applications. We investigated the in vivo effect of MSNs on the production of reactive oxygen species (ROS), antioxidant defenses and histology of the heart and lung. Rats received 25, 50, 100 and 200 mg/kg body weight of synthesized MSNs intraperitoneally for 30 days and samples were collected for analysis. MSNs induced significant increase in serum cardiac function markers, tumor necrosis factor alpha and lipids. MSNs-induced rats exhibited anemia, thrombocytopenia, leukocytosis, significantly increased ROS, malondialdehyde and nitric oxide, and declined antioxidant defenses in the heart and lung of rats. In addition, MSNs induced histological alterations in the heart and lung of rats. In conclusion, our results demonstrated that MSNs induce cardiotoxicity and pulmonary toxicity via excessive generation of ROS, suppressed antioxidants, inflammation and histological alterations. Further investigations are recommended to understand the molecular mechanism underlying the toxic effects of MSNs and to improve the performance of nanomedicine.


Assuntos
Cardiotoxinas/toxicidade , Coração/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Nanopartículas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Dióxido de Silício/toxicidade , Animais , Cardiotoxinas/farmacocinética , Relação Dose-Resposta a Droga , Pulmão/metabolismo , Masculino , Miocárdio/metabolismo , Nanopartículas/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Porosidade/efeitos dos fármacos , Ratos , Ratos Wistar , Dióxido de Silício/farmacocinética
10.
Acta Neuropathol Commun ; 6(1): 119, 2018 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-30404653

RESUMO

Pompe disease is a metabolic myopathy that is caused by glycogen accumulation as a result of deficiency of the lysosomal enzyme acid alpha glucosidase (GAA). Previously, we showed that adult muscle stem cells termed satellite cells are present at normal levels in muscle from patients with Pompe disease, but that these are insufficiently activated to repair the severe muscle pathology. Here we characterized the muscle regenerative response during disease progression in a mouse model of Pompe disease and investigated the intrinsic capacity of Gaa-/- satellite cells to regenerate muscle damage. Gaa-/- mice showed progressive muscle pathology from 15 weeks of age as reflected by increased lysosomal size, decreased fiber diameter and reduced muscle wet weight. Only during the first 15 weeks of life but not thereafter, we detected a gradual increase in centrally nucleated fibers and proliferating satellite cells in Gaa-/- muscle, indicating a mild regenerative response. The levels of Pax7-positive satellite cells were increased in Gaa-/- mice at all ages, most likely as result of enhanced satellite cell activation in young Gaa-/- animals. Surprisingly, both young and old Gaa-/- mice regenerated experimentally-induced muscle injury efficiently as judged by rapid satellite cell activation and complete restoration of muscle histology. In response to serial injury, Gaa-/- mice also regenerated muscle efficiently and maintained the satellite cell pool. These findings suggest that, similar to human patients, Gaa-/- mice have insufficient satellite cell activation and muscle regeneration during disease progression. The initial endogenous satellite cell response in Gaa-/- mice may contribute to the delayed onset of muscle wasting compared to human patients. The rapid and efficient regeneration after experimental muscle injury suggest that Gaa-/- satellite cells are functional stem cells, opening avenues for developing muscle regenerative therapies for Pompe disease.


Assuntos
Doença de Depósito de Glicogênio Tipo II/patologia , Músculo Esquelético/fisiopatologia , Regeneração/genética , Células Satélites de Músculo Esquelético/fisiologia , Fatores Etários , Animais , Compostos de Bário/toxicidade , Cardiotoxinas/toxicidade , Cloretos/toxicidade , Modelos Animais de Doenças , Feminino , Glicogênio/metabolismo , Doença de Depósito de Glicogênio Tipo II/genética , Antígeno Ki-67/metabolismo , Laminina/metabolismo , Proteína 1 de Membrana Associada ao Lisossomo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Músculo Esquelético/efeitos dos fármacos , Fator de Transcrição PAX7/metabolismo , alfa-Glucosidases/genética , alfa-Glucosidases/metabolismo
11.
Acta Neuropathol Commun ; 6(1): 116, 2018 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-30382921

RESUMO

Pompe disease, which is due to acid alpha-glucosidase deficiency, is characterized by skeletal muscle dysfunction attributed to the accumulation of glycogen-filled lysosomes and autophagic buildup. Despite the extensive tissue damages, a failure of satellite cell (SC) activation and lack of muscle regeneration have been reported in patients. However, the origin of this defective program is unknown. Additionally, whether these deficits occur gradually over the disease course is unclear. Using a longitudinal pathophysiological study of two muscles in a Pompe mouse model, here, we report that the enzymatic defect results in a premature saturating glycogen overload and a high number of enlarged lysosomes. The muscles gradually display profound remodeling as the number of autophagic vesicles, centronucleated fibers, and split fibers increases and larger fibers are lost. Only a few regenerated fibers were observed regardless of age, although the SC pool was preserved. Except for the early age, during which higher numbers of activated SCs and myoblasts were observed, no myogenic commitment was observed in response to the damage. Following in vivo injury, we established that muscle retains regenerative potential, demonstrating that the failure of SC participation in repair is related to an activation signal defect. Altogether, our findings provide new insight into the pathophysiology of Pompe disease and highlight that the activation signal defect of SCs compromises muscle repair, which could be related to the abnormal energetic supply following autophagic flux impairment.


Assuntos
Doença de Depósito de Glicogênio Tipo II/patologia , Músculo Esquelético/fisiopatologia , Regeneração/fisiologia , Células Satélites de Músculo Esquelético/fisiologia , Fatores Etários , Animais , Autofagia/genética , Cardiotoxinas/toxicidade , Colágeno/metabolismo , Modelos Animais de Doenças , Distrofina/metabolismo , Regulação da Expressão Gênica/genética , Glucana 1,4-alfa-Glucosidase/deficiência , Glucana 1,4-alfa-Glucosidase/genética , Glicogênio/metabolismo , Doença de Depósito de Glicogênio Tipo II/etiologia , Humanos , Antígeno Ki-67/metabolismo , Laminina/metabolismo , Estudos Longitudinais , Lisossomos/metabolismo , Lisossomos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/lesões , Regeneração/genética
12.
Biotechnol Adv ; 36(8): 2232-2247, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30342084

RESUMO

With unique characteristics such as high surface area, capacity of various functionalization, low weight, high conductivity, thermal and chemical stability, and free radical scavenging, carbon nanomaterials (CNMs) such as carbon nanotubes (CNTs), fullerene, graphene (oxide), carbon nanohorns (CNHs), and their derivatives have increasingly been utilized in nanomedicine and biomedicine. On the one hand, owing to ever-increasing applications of CNMs in technological and industrial fields as well as presence of combustion-derived CNMs in the ambient air, the skepticism has risen over the adverse effects of CNMs on human being. The influences of CNMs on cardiovascular system and cardiovascular diseases (CVDs) such as atherosclerosis, of which consequences are ischemic heart disease and ischemic stroke, as the main causes of death, is of paramount importance. In this regard, several studies have been devoted to specify the biomedical applications and cardiovascular toxicity of CNMs. Therefore, the aim of this review is to specify the roles and applications of various CNMs in atherosclerosis, and also identify the key role playing parameters in cardiovascular toxicity of CNMs so as to be a clue for prospective deployment of CNMs.


Assuntos
Aterosclerose , Carbono/toxicidade , Cardiotoxinas/toxicidade , Nanoestruturas/toxicidade , Animais , Aterosclerose/induzido quimicamente , Aterosclerose/imunologia , Aterosclerose/fisiopatologia , Fulerenos/toxicidade , Humanos , Camundongos , Nanomedicina
13.
Muscle Nerve ; 58(6): 858-862, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30159908

RESUMO

INTRODUCTION: Efficient repositioning of centralized nuclei after injury has long been assumed, with centralized nuclei frequently cited as indicators of ongoing regeneration. However, reports of centralized nuclei that persist after full recovery of fiber area and muscle force production call into question the time course of nuclear repositioning. METHODS: We evaluated regeneration after cardiotoxin-induced damage in 10-week-old mice by quantifying intracellular and extracellular pathology at 2 and 94 weeks post-injection. RESULTS: Centrally nucleated fibers were still prevalent at 94 weeks post-injection, representing > 25% of muscle fibers. Areas with > 90% centrally nucleated fibers could still be identified. Extra-myocellular indicators of regeneration (e.g., fibrosis and fatty infiltration) also remained significantly elevated at the 94-week time-point. DISCUSSION: These findings indicate that not all nuclei are repositioned at the conclusion of induced muscle regeneration. Muscle Nerve 58:858-862, 2018.


Assuntos
Fibras Musculares Esqueléticas/fisiologia , Regeneração/fisiologia , Animais , Cardiotoxinas/toxicidade , Colágeno/metabolismo , Estudos Longitudinais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Doenças Musculares/induzido quimicamente , Doenças Musculares/patologia , Regeneração/efeitos dos fármacos
14.
J Basic Clin Physiol Pharmacol ; 30(1): 73-79, 2018 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-30110251

RESUMO

Background Because of the antioxidant effects of Zataria multiflora (ZM) and carvacrol (CAR) and also the role of oxidative stress in the induction of cardiotoxicity induced by Adriamycin (ADR), the aim of this study was to investigate the improvement effects of ZM extract and CAR on cardiotoxicity induced by ADR in rats. Methods Twenty-eight male rats were randomly assigned to four groups including (1) the control group; (2) the ADR group, which received ADR intravenously at the beginning of the study and the (3) ZM+ADR and (4) CAR+ADR groups, which received ZM and CAR by gavage for 28 consecutive days and ADR as single dose. Blood samples were collected on days 0 and 28 to determine serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT) and lactate dehydrogenase (LDH). Also, cardiac tissue was removed for redox marker evaluation. Results In the ADR group, malondialdehyde (MDA) significantly increased and superoxide dismutase (SOD) activity and total thiol contents significantly reduced, as compared with the control group, while CAR administration significantly improved this condition. Treatment with ZM significantly increased the SOD activity and total thiol content, as compared with the ADR group. The level of LDH significantly increased on day 28 in the ADR group compared to the control group, and administration of ZM and CAR significantly decreased it. The SGPT and SGOT levels in the ADR group significantly increased, and CAR administration significantly reduced them. Conclusion The results indicate that the administration of ZM hydroalcoholic extracts and its active ingredient, CAR, could reduce the oxidative stress damage through promotion of the cardiac and systemic antioxidant system. Also, CAR administration demonstrated better improvement in cardiotoxicity with ADR in rats.


Assuntos
Cardiotoxinas/toxicidade , Doxorrubicina/toxicidade , Lamiaceae , Monoterpenos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Antibióticos Antineoplásicos/toxicidade , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Masculino , Estresse Oxidativo/fisiologia , Extratos Vegetais/isolamento & purificação , Distribuição Aleatória , Ratos , Ratos Wistar
15.
Toxicol Appl Pharmacol ; 358: 86-101, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29966675

RESUMO

Mitochondrial dysfunction is a central element in the development of doxorubicin (DXR)-induced cardiotoxicity. In this context, melatonin is known to influence mitochondrial homeostasis and function. This study aimed to investigate the effects of melatonin on cardiac function, tumor growth, mitochondrial fission and fusion, PGC1-α and sirtuin activity in an acute model of DXR-induced cardiotoxicity. During the in vitro study, H9c2 rat cardiomyoblasts were pre-treated with melatonin (10 µM, 24 h) followed by DXR exposure (3 µM, 24 h). Following treatment, cellular ATP levels and mitochondrial morphology were assessed. In the in vivo study, female Sprague Dawley rats (16 weeks old), were inoculated with a LA7 rat mammary tumor cell line and tumors were measure daily. Animals were injected with DXR (3 × 4 mg/kg) and/or received melatonin (6 mg/kg) for 14 days in their drinking water. Rat hearts were used to conduct isolated heart perfusions to assess cardiac function and thereafter, heart tissue was used for immunoblot analysis. DXR treatment increased cell death and mitochondrial fission which were reduced with melatonin treatment. Cardiac output increased in rats treated with DXR + melatonin compared to DXR-treated rats. Tumor volumes was significantly reduced in DXR + melatonin-treated rats on Day 8 in comparison to DXR-treated rats. Furthermore, DXR + melatonin treatment increased cellular ATP levels, PGC1-α and SIRT1 expression which was attenuated by DXR treatment. These results indicate that melatonin treatment confers a dual cardio-protective and oncostatic effect by improving mitochondrial function and cardiac function whilst simultaneously retarding tumor growth during DXR-induced cardiotoxicity.


Assuntos
Débito Cardíaco/efeitos dos fármacos , Cardiotoxinas/toxicidade , Doxorrubicina/toxicidade , Melatonina/farmacologia , Mitocôndrias/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sirtuína 1/metabolismo , Animais , Débito Cardíaco/fisiologia , Células Cultivadas , Feminino , Mitocôndrias/fisiologia , Ratos , Ratos Sprague-Dawley
16.
Toxicol Appl Pharmacol ; 353: 1-14, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29885332

RESUMO

Cardiovascular diseases are among the most significant causes of mortality in humans. Pesticides toxicity and risk for human health are controlled at a European level through a well-developed regulatory network, but cardiotoxicity is not described as a separate hazard class. Specific classification criteria should be developed within the frame of Regulation (EC) No 1272/2008 in order to classify chemicals as cardiotoxic, if applicable to avoid long-term cardiovascular complications. The aim of this study was to review the cardiac pathology and function impairment due to exposure to pesticides (i.e. organophosphates, organothiophisphates, organochlorines, carbamates, pyrethroids, dipyridyl herbicides, triazoles, triazines) based on both animal and human data. The majority of human data on cardiotoxicity of pesticides come from poisoning cases and epidemiological data. Several cardiovascular complications have been reported in animal models including electrocardiogram abnormalities, myocardial infarction, impaired systolic and diastolic performance, functional remodeling and histopathological findings, such as haemorrhage, vacuolisation, signs of apoptosis and degeneration.


Assuntos
Cardiotoxicidade/epidemiologia , Cardiotoxinas/toxicidade , Cardiopatias/induzido quimicamente , Cardiopatias/epidemiologia , Praguicidas/toxicidade , Animais , Cardiotoxicidade/prevenção & controle , Cardiotoxicidade/terapia , Cardiotoxinas/envenenamento , Cardiopatias/prevenção & controle , Cardiopatias/terapia , Humanos , Praguicidas/efeitos adversos , Praguicidas/envenenamento
17.
J Pharm Pharmacol ; 70(9): 1209-1215, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29943452

RESUMO

OBJECTIVES: Excessive use of uncoupling agents, previously used as weight loss agents, has led to the increase in body temperature and death. The aim of the present study was to evaluate the acute cardiac effects of mitochondrial protonophore in a rat model at a high dose, and its specific influence on cardiac substrate uptake. METHODS: Eight-week-old male Sprague-Dawley rats were intraperitoneally injected with the protonophore carbonyl cyanide m-chloro phenyl hydrazone (CCCP; 4 mg/kg) or vehicle (dimethyl sulfoxide). Blood pressure, heart rate (HR) and systolic function were recorded. Substrate uptake was monitored by radioactive tracers. KEY FINDINGS: Compared to the control group, the respiratory rate and body temperature increased, the left ventricle was dilated, and systolic function transiently deteriorated in the CCCP group. There was no difference in blood pressure and HR between the two groups. In cardiac substrate uptake, glucose uptake showed a 95% increase (P < 0.05), and fatty acid uptake showed a 52% decrease (P < 0.05) in CCCP-administered group. CONCLUSIONS: The deleterious effects on cardiac function and the changes in substrate uptake were observed when administered with the protonophore at a high dose.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Cardiotoxinas/toxicidade , Modelos Animais de Doenças , Frequência Cardíaca/efeitos dos fármacos , Ionóforos de Próton/toxicidade , Disfunção Ventricular Esquerda/induzido quimicamente , Animais , Pressão Sanguínea/fisiologia , Carbonil Cianeto m-Clorofenil Hidrazona/toxicidade , Frequência Cardíaca/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia
18.
Cell Death Dis ; 9(6): 609, 2018 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-29789544

RESUMO

Limb girdle muscular dystrophy type 2L (LGMD2L) and Miyoshi myopathy type 3 (MMD3) are autosomal recessive muscular dystrophy caused by mutations in the gene encoding anoctamin-5 (ANO5), which belongs to the anoctamin protein family. Two independent lines of mice with complete disruption of ANO5 transcripts did not exhibit overt muscular dystrophy phenotypes; instead, one of these mice was observed to present with some abnormality in sperm motility. In contrast, a third line of ANO5-knockout (KO) mice with residual expression of truncated ANO5 expression was reported to display defective membrane repair and very mild muscle pathology. Many of the ANO5-related patients carry point mutations or small insertions/deletions (indels) in the ANO5 gene. To more closely mimic the human ANO5 mutations, we engineered mutant ANO5 rabbits via co-injection of Cas9 mRNA and sgRNA into the zygotes. CRISPR-mediated small indels in the exon 12 and/or 13 in the mutant rabbits lead to the development of typical signs of muscular dystrophy with increased serum creatine kinase (CK), muscle necrosis, regeneration, fatty replacement and fibrosis. This novel ANO5 mutant rabbit model would be useful in studying the disease pathogenesis and therapeutic treatments for ANO5-deficient muscular dystrophy.


Assuntos
Anoctaminas/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Engenharia Genética , Distrofia Muscular Animal/genética , Mutação/genética , Animais , Sequência de Bases , Cardiotoxinas/toxicidade , Modelos Animais de Doenças , Embrião de Mamíferos/efeitos dos fármacos , Embrião de Mamíferos/metabolismo , Músculos/efeitos dos fármacos , Músculos/patologia , Músculos/fisiopatologia , Distrofia Muscular Animal/patologia , Distrofia Muscular Animal/fisiopatologia , Fenótipo , Coelhos , Regeneração/efeitos dos fármacos
19.
J Forensic Leg Med ; 58: 113-116, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29778924

RESUMO

Cerbera odollam is a plant species of the Apocynaceae family. It is often dubbed the 'suicide tree' due to its strong cardiotoxic effects, which make it a suitable means to attempt suicide. The plant grows in wet areas in South India, Madagascar, and Southeast Asia; and its common names include Pong-Pong and Othalanga. The poison rich part of the plant is the kernel which is present at the core of its fruit. The bioactive toxin in the plant is cerberin, which is a cardiac glycoside of the cardenolide class. Cerberin has a mechanism of action similar to digoxin; hence, Cerbera odollam toxicity manifests similar to acute digoxin poisoning. Ingestion of its kernel causes nausea, vomiting, hyperkalemia, thrombocytopenia, and ECG abnormalities. Exposure to high doses of Cerbera odollam carries the highest risk of mortality. Initial management includes supportive therapy and administration of atropine followed by temporary pacemaker insertion. Administration of digoxin immune Fab may be considered in severe cases, although efficacy is variable and data limited to isolated case reports.


Assuntos
Apocynaceae/toxicidade , Cardenolídeos/toxicidade , Cardiotoxinas/toxicidade , Antiarrítmicos/uso terapêutico , Atropina/uso terapêutico , Toxicologia Forense , Humanos , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Marca-Passo Artificial , Envenenamento/terapia
20.
Nat Commun ; 9(1): 1400, 2018 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-29643389

RESUMO

Regulation of gene expression requires selective incorporation of histone H3 variant H3.3 into chromatin. Histone H3.3 has several subsidiary variants but their functions are unclear. Here we characterize the function of histone H3.3 sub-variant, H3mm7, which is expressed in skeletal muscle satellite cells. H3mm7 knockout mice demonstrate an essential role of H3mm7 in skeletal muscle regeneration. Chromatin analysis reveals that H3mm7 facilitates transcription by forming an open chromatin structure around promoter regions including those of myogenic genes. The crystal structure of the nucleosome containing H3mm7 reveals that, unlike the S57 residue of other H3 proteins, the H3mm7-specific A57 residue cannot form a hydrogen bond with the R40 residue of the cognate H4 molecule. Consequently, the H3mm7 nucleosome is unstable in vitro and exhibited higher mobility in vivo compared with the H3.3 nucleosome. We conclude that the unstable H3mm7 nucleosome may be required for proper skeletal muscle differentiation.


Assuntos
Histonas/genética , Nucleossomos/química , Regeneração/genética , Células Satélites de Músculo Esquelético/metabolismo , Animais , Sistemas CRISPR-Cas , Cardiotoxinas/toxicidade , Montagem e Desmontagem da Cromatina , Edição de Genes , Regulação da Expressão Gênica no Desenvolvimento , Histonas/química , Histonas/metabolismo , Camundongos , Camundongos Knockout , Modelos Moleculares , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Proteína MyoD/genética , Proteína MyoD/metabolismo , Nucleossomos/ultraestrutura , Fator de Transcrição PAX7/genética , Fator de Transcrição PAX7/metabolismo , Regiões Promotoras Genéticas , Estrutura Secundária de Proteína , Células Satélites de Músculo Esquelético/patologia , Transcrição Genética
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