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1.
Chemosphere ; 254: 126900, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32957295

RESUMO

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous pollutants in marine environments and have arouse great concern since they pose adverse effects to marine ecosystem. To determine the potential impacts of environmentally relevant PAHs on early life stages of marine fish, this study exposed embryos of marine medaka (Oryzias melastigma) to 0, 2, 10, 50, and 250 µg/L of phenanthrene (Phe), one of the most abundant PAHs. The results demonstrated that Phe exposure decreased hatching rates, delayed hatching time of embryos, and increased deformity rate of newly-hatched larvae. Exposure to 10 and 50 µg/L Phe decreased the survival rate of marine medaka larvae at 28 days post-fertilization (dpf), and no embryo successfully hatched in 250 µg/L Phe exposure group. Morphology results showed that 10, 50, and 250 µg/L Phe exposure significantly retarded the development of embryos, and 2, 10, and 50 µg/L caused yolk sac edema and pericardial edema in newly-hatched larvae, indicating that low concentrations of Phe could induce developmental cardiac toxicity. Furthermore, the changes in the expression of heart development-related genes were determined, and the results showed that Phe-induced cardiac malformation might be related with fgf8, bmp4, smyd1, ATPase and gata4 genes. Overall, environmentally relevant PAHs could disrupt heart morphogenesis and hatching process of marine medaka, which might have profound consequences for sustainability of fish population.


Assuntos
Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Oryzias/crescimento & desenvolvimento , Fenantrenos/toxicidade , Teratogênios/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Ecossistema , Embrião não Mamífero/anormalidades , Desenvolvimento Embrionário/genética , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Coração/efeitos dos fármacos , Coração/embriologia , Larva/efeitos dos fármacos , Larva/genética , Oryzias/genética , Fenantrenos/análise , Teratogênios/análise , Poluentes Químicos da Água/análise
2.
Ecotoxicol Environ Saf ; 205: 111339, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32961491

RESUMO

Famoxadone-cymoxanil is a new protective and therapeutic fungicide, but little research has been done on it or its toxicity in aquatic organisms. In this study, we used zebrafish to investigate the cardiotoxicity of famoxadone-cymoxanil and the potential mechanisms involved. Zebrafish embryos were exposed to different concentrations of famoxadone-cymoxanil until 72 h post-fertilization (hpf), then changes of heart morphology in zebrafish embryos were observed. We also detected the levels of oxidative stress, myocardial-cell proliferation and apoptosis, ATPase activity, and the expression of genes related to the cardiac development and calcium-signaling pathway. After famoxadone-cymoxanil exposure, pericardial edema, cardiac linearization, and reductions in the heart rate and cardiac output positively correlated with concentration. Although myocardial-cell apoptosis was not detected, proliferation of the cells was severely reduced and ATPase activity significantly decreased, resulting in a severe deficiency in heart function. In addition, indicators of oxidative stress changed significantly after exposure of the embryos to the fungicide. To better understand the possible molecular mechanisms of cardiovascular toxicity in zebrafish, we studied the transcriptional levels of cardiac development, calcium-signaling pathways, and genes associated with myocardial contractility. The mRNA expression levels of key genes in heart development were significantly down-regulated, while the expression of genes related to the calcium-signaling pathway (ATPase [atp2a1], cardiac troponin C [tnnc1a], and calcium channel [cacna1a]) was significantly inhibited. Expression of klf2a, a major endocardial flow-responsive gene, was also significantly inhibited. Mechanistically, famoxadone-cymoxanil toxicity might be due to the downregulation of genes associated with the calcium-signaling pathway and cardiac muscle contraction. Our results found that famoxadone-cymoxanil exposure causes cardiac developmental toxicity and severe energy deficiency in zebrafish.


Assuntos
Acetamidas/toxicidade , Embrião não Mamífero/efeitos dos fármacos , Fungicidas Industriais/toxicidade , Coração/efeitos dos fármacos , Estrobilurinas/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo , Animais , Apoptose/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/genética , Cardiotoxicidade , Regulação para Baixo , Embrião não Mamífero/metabolismo , Embrião não Mamífero/patologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Coração/embriologia , Frequência Cardíaca/efeitos dos fármacos , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peixe-Zebra/crescimento & desenvolvimento , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
3.
Toxicon ; 186: 58-66, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-32755648

RESUMO

Envenomation by coralsnakes (Micrurus spp.) is characterized by blockade of peripheral neurotransmission mediated by the presence of α- and ß-neurotoxins. However, little is known about their cardiovascular activity. Micrurus lemniscatus lemniscatus is a coralsnake found in the Amazon basin and occasionally causes envenomation in humans. In this study, we examined the hemodynamic, vascular and atrial responses to M. l. lemniscatus venom. Anesthetized rats were used for hemodynamic and electrocardiogram (ECG) recordings; in vitro experiments were carried out in rat isolated thoracic aorta and atria preparations. In vivo, venom (0.1 and 0.3 mg/kg) caused immediate and persistent hypotension that was maximal within the first minute with both doses being lethal after ~40 and ~20 min, respectively. ECG, heart and respiratory rates were not altered during the transient hypotension phase induced by venom but all altered prior to death. There was no evidence of myonecrosis in cardiac muscle tissue, pulmonary hemorrhage nor thrombosis in anesthetized rats exposed to venom. In vitro, venom (10 µg/ml) did not contract aortic strips nor affected the maximal responses to pre-contraction with phenylephrine (PE, 0.0001-30 µM) in strips with and without endothelium. However, venom (10 µg/ml) relaxed aortic strips with endothelium pre-contracted with PE. In aortic strips pre-contracted with PE, venom prevented acetylcholine (0.0001-30 µM)-induced relaxation in strips with endothelium without affecting relaxation induced by sodium nitroprusside (0.1-100 nM) in strips without endothelium. Venom (30 µg/ml) produced a transient increase of atrial contractile force without affecting atrial rate. Taken together these findings indicate a predominantly vascular action of the venom, most likely involving toxins interacting with muscarinic receptors.


Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Cobras Corais , Venenos Elapídicos/toxicidade , Coração/efeitos dos fármacos , Animais , Hemodinâmica , Hipotensão/induzido quimicamente , Miocárdio , Ratos
4.
Food Chem Toxicol ; 145: 111694, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32822775

RESUMO

We investigated the effects of tocilizumab on endothelial glycocalyx, a determinant of vascular permeability, and myocardial function in rheumatoid arthritis (RA). Eighty RA patients were randomized to tocilizumab (n = 40) or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and glucocorticoids (GC) (n = 40) for 3 months. Forty healthy subjects with similar age and sex served as controls. We measured: (a)perfused boundary region (PBR) of the sublingual arterial microvessels (increased PBR indicates reduced glycocalyx thickness), (b)pulse wave velocity (PWV), (c)global LV longitudinal strain (GLS), (d)global work index (GWI) using speckle tracking echocardiography and e)C-reactive protein (CRP), malondialdehyde (MDA) and protein carbonyls (PCs) as oxidative stress markers at baseline and post-treatment. Compared to controls, RA patients had impaired glycocalyx and myocardial deformation markers (P < 0.05). Compared with baseline, tocilizumab reduced PBR(2.14 ± 0.2 versus 1.97 ± 0.2 µm; P < 0.05) while no significant differences were observed post-csDMARDs + GC(P > 0.05). Compared with csDMARDs + GC, tocilizumab achieved a greater increase of GLS, GWI and reduction of MDA, PCs and CRP(P < 0.05). The percent improvement of glycocalyx thickness (PBR) was associated with the percent decrease of PWV, MDA, PCs and the percent improvement of GLS and GWI(P < 0.05). Tocilizumab improves endothelial function leading to a greater increase of effective myocardial work than csDMARDs + GC through a profound reduction of inflammatory burden and oxidative stress. This mechanism may explain the effects of tocilizumab on COVID-19. CLINICAL TRIAL REGISTRATION: url: https://www.clinicaltrials.gov. Unique identifier: NCT03288584.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Endotélio/efeitos dos fármacos , Glicocálix/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Idoso , Betacoronavirus , Permeabilidade Capilar/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Feminino , Coração/efeitos dos fármacos , Humanos , Inflamação/tratamento farmacológico , Interleucina-6/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/tratamento farmacológico , Análise de Onda de Pulso
5.
PLoS One ; 15(8): e0238039, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32853284

RESUMO

Sepsis is a global economic and health burden. Dipeptidyl peptidase 3 (DPP3) is elevated in the plasma of septic patients. The highest levels of circulating DPP3 (cDPP3) are found in non-survivor septic shock patients. The aim of this study was to evaluate the benefits of inhibiting cDPP3 by a specific antibody, Procizumab (PCZ), on cardiac function in an experimental model of sepsis, the caecal ligature and puncture (CLP) model. Rats were monitored by invasive blood pressure and echocardiography. Results are presented as mean ± SD, with p <0.05 considered significant. PCZ rapidly restored left ventricular shortening fraction (from 39 ± 4% to 51 ± 2% before and 30 min after PCZ administration (p = 0.004)). Cardiac output and stroke volume were higher in the CLP + PCZ group when compared to the CLP + PBS group (152 ± 33 mL/min vs 97 ± 25 mL/min (p = 0.0079), and 0.5 ± 0.1 mL vs 0.3 ± 1.0 mL (p = 0.009), respectively) with a markedly reduced plasma DPP3 activity (138 ± 70 U/L in CLP + PCZ group versus 735 ± 255 U/L (p = 0.048) in the CLP + PBS group). Of note, PCZ rapidly reduced oxidative stress in the heart of the CLP + PCZ group when compared to those of the CLP + PBS group (13.3 ± 8.2 vs 6.2 ± 2.5 UI, p = 0.005, 120 min after administration, respectively). Our study demonstrates that inhibition of cDPP3 by PCZ restored altered cardiac function during sepsis in rats.


Assuntos
Dipeptidil Peptidases e Tripeptidil Peptidases/antagonistas & inibidores , Dipeptidil Peptidases e Tripeptidil Peptidases/sangue , Inibidores Enzimáticos/farmacologia , Coração/efeitos dos fármacos , Coração/fisiopatologia , Sepse/sangue , Sepse/fisiopatologia , Animais , Modelos Animais de Doenças , Hemodinâmica/efeitos dos fármacos , Masculino , Estudo de Prova de Conceito , Ratos , Ratos Wistar , Sepse/enzimologia , Sístole/efeitos dos fármacos , Sístole/fisiologia
6.
Life Sci ; 257: 118127, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32707052

RESUMO

BACKGROUND: Cigarette smoking or nicotine replacement therapy has been associated with cardiometabolic disorders (CMD). Hyperuricemia has been implicated in the pathogenesis of CMD and cardiorenal dysfunction. Gut microbiota-derived short chain fatty acids (SCFAs) have been reported to have beneficial glucoregulatory and cardiorenal protective effects. This study aimed at investigating the effect of acetate, a gut-derived SCFA, on nicotine-induced CMD and associated cardiorenal dysmetabolism. MATERIALS AND METHOD: Twenty-four male Wistar rats (n = 6/group) were grouped as: vehicle (p.o.), nicotine-exposed (1.0 mg/kg; p.o.), and sodium acetate-treated (200 mg/kg; p.o.) with or without nicotine exposure daily for 6 weeks. Glucose regulation was evaluated by oral glucose tolerance test and homeostatic model assessment of insulin resistance. Cardiac and renal triacylglycerol (TG), lactate, nitric oxide (NO), uric acid (UA) levels, lactate dehydrogenase (LDH), creatine kinase (CK), adenosine deaminase (ADA), and xanthine oxidase (XO) activities were measured. RESULTS: The CMD were confirmed in the nicotine-exposed rats that exhibited lower body weight, insulin resistance, endothelial dysfunction, glucose intolerance, increased cardiac and renal TG, TG/HDL-cholesterol, UA, lactate, lipid peroxidation, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, LDH, CK, ADA and XO activities. Concurrent treatment with acetate prevented nicotine-induced glucometabolic and cardiorenal alterations. CONCLUSION: In summary, these results implied that nicotine exposure caused glucometabolic dysregulation and surplus lipid deposit in the heart and kidney through increased UA production and CK activity. Therefore, oral acetate administration prevents cardiorenal lipotoxicity and glucometabolic dysregulation via suppression of UA production and CK activity in nicotine-exposed rats.


Assuntos
Creatina Quinase/metabolismo , Coração/efeitos dos fármacos , Rim/efeitos dos fármacos , Redes e Vias Metabólicas/efeitos dos fármacos , Miocárdio/metabolismo , Nicotina/efeitos adversos , Acetato de Sódio/farmacologia , Ácido Úrico/metabolismo , Animais , Glucose/metabolismo , Teste de Tolerância a Glucose , Resistência à Insulina , Rim/metabolismo , Masculino , Nicotina/antagonistas & inibidores , Ratos , Ratos Wistar
7.
Life Sci ; 257: 118132, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32710949

RESUMO

AIM: Arsenic, an environmental contaminant, represents a public health problem worldwide. Studies have shown its association with molecular mechanisms related to cardiomyocytes redox balance. However, the microstructure and ultrastructure of cardiac tissue, as well as the activity of its antioxidant defenses front of disturbances in the mineral bioavailability induced by arsenic are still scarce. Thus, the aim of this study was to evaluate if arsenic exposure might induce structural and ultrastructural damages in cardiac tissue, including pathological remodeling of the parenchyma and stroma. Moreover, its impact on micromineral distribution and antioxidant enzymes activity in heart tissue was also evaluated. MAIN METHODS: Adult male Wistar rats were divided into three groups that received 0, 1 and 10 mg/L sodium arsenite in drinking water for eight weeks. The hearts were collected and subjected to structural and ultrastructural analysis, mineral microanalysis and antioxidant enzymes quantification. Functional markers of cardiac damages were evaluated using serum samples. KEY FINDINGS: Arsenic exposure induced dose-dependent structural and ultrastructural remodeling of cardiac tissue, with parenchyma loss, increase of stroma components, collagen deposition, and pathological damages such as inflammation, sarcomere disorganization, mitochondria degeneration and myofilament dissociation. Moreover, this metalloid was bioaccumulated in the tissue affecting its micromineral content, which resulted in antioxidant imbalance and increased levels of oxidative stress and cardiac markers. SIGNIFICANCE: Taken together, our findings indicate that the heart is a potential target to arsenic toxicity, and long-term exposure to this metalloid must be avoided, once it might induce several cardiac tissue pathologies.


Assuntos
Arsênico/toxicidade , Coração/efeitos dos fármacos , Miocárdio/patologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Arsênico/administração & dosagem , Arsênico/análise , Catalase/metabolismo , Relação Dose-Resposta a Droga , Glutationa Transferase/metabolismo , Masculino , Miocárdio/química , Miocárdio/ultraestrutura , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo
9.
Int J Nanomedicine ; 15: 4393-4405, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606684

RESUMO

Aim: The effects of polyamidoamine (PAMAM) dendrimers on the mammalian heart are not completely understood. In this study, we have investigated the effects of a sixth-generation cationic dendrimer (G6 PAMAM) on cardiac function in control and diabetic rat hearts following ischemia-reperfusion (I/R) injury. Methods: Isolated hearts from healthy non-diabetic (Ctr) male Wistar rats were subjected to ischemia and reperfusion (I/R). LV contractility and hemodynamics data were computed digitally whereas cardiac damage following I/R injury was assessed by measuring cardiac enzymes. For ex vivo acute exposure experiments, G6 PAMAM was administered during the first 10 mins of reperfusion in Ctr animals. In chronic in vivo studies, nondiabetic rats (Ctr) received either vehicle or daily i.p. injections of G6 PAMAM (40 mg/kg) for 4 weeks. Diabetic (D) animals received either vehicle or daily i.p. injections of G6 PAMAM (10, 20 or 40 mg/kg) for 4 weeks. The impact of G6 PAMAM on pacing-postconditioning (PPC) was also studied in Ctr and D rats. Results: In ex vivo studies, acute administration of G6 PAMAM to isolated Ctr hearts during reperfusion dose-dependently impaired recovery of cardiac hemodynamics and vascular dynamics parameters following I/R injury. Chronic daily i.p. injections of G6 PAMAM significantly (P<0.01) impaired recovery of cardiac function following I/R injury in nondiabetic animals but this was not generally observed in diabetic animals except for CF which was impaired by about 50%. G6 PAMAM treatment completely blocked the protective effects of PPC in the Ctr animals. Conclusion: Acute ex vivo or chronic in vivo treatment with naked G6 PAMAM dendrimer can significantly compromise recovery of non-diabetic hearts from I/R injury and can further negate the beneficial effects of PPC. Our findings are therefore extremely important in the nanotoxicological evaluation of G6 PAMAM dendrimers for potential clinical applications in physiological and pathological settings.


Assuntos
Dendrímeros/toxicidade , Coração/fisiopatologia , Mamíferos/fisiologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Nanopartículas/toxicidade , Poliaminas/administração & dosagem , Recuperação de Função Fisiológica/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Coração/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Pós-Condicionamento Isquêmico , Masculino , Contração Miocárdica/efeitos dos fármacos , Miocárdio/enzimologia , Ratos Wistar
10.
PLoS One ; 15(7): e0236680, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32722688

RESUMO

Cachexia is a common multifactorial syndrome in the advanced stages of cancer and accounts for approximately 20-30% of all cancer-related fatalities. In addition to the progressive loss of skeletal muscle mass, cancer results in impairments in cardiac function. We recently demonstrated that WFA attenuates the cachectic skeletal muscle phenotype induced by ovarian cancer. The purpose of this study was to investigate whether ovarian cancer induces cardiac cachexia, the possible pathway involved, and whether WFA attenuates cardiac cachexia. Xenografting of ovarian cancer induced cardiac cachexia, leading to the loss of normal heart functions. Treatment with WFA rescued the heart weight. Further, ovarian cancer induced systolic dysfunction and diastolic dysfunction Treatment with WFA preserved systolic function in tumor-bearing mice, but diastolic dysfunction was partially improved. In addition, WFA abrogated the ovarian cancer-induced reduction in cardiomyocyte cross-sectional area. Finally, treatment with WFA ameliorated fibrotic deposition in the hearts of tumor-bearing animals. We observed a tumor-induced MHC isoform switching from the adult MHCα to the embryonic MHCß isoform, which was prevented by WFA treatment. Circulating Ang II level was increased significantly in the tumor-bearing, which was lowered by WFA treatment. Our results clearly demonstrated the induction of cardiac cachexia in response to ovarian tumors in female NSG mice. Further, we observed induction of proinflammatory markers through the AT1R pathway, which was ameliorated by WFA, in addition to amelioration of the cachectic phenotype, suggesting WFA as a potential therapeutic agent for cardiac cachexia in oncological paradigms.


Assuntos
Caquexia/tratamento farmacológico , Caquexia/etiologia , Coração/efeitos dos fármacos , Miocárdio/patologia , Neoplasias Ovarianas/complicações , Vitanolídeos/farmacologia , Animais , Caquexia/patologia , Caquexia/fisiopatologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Diástole/efeitos dos fármacos , Diástole/fisiologia , Feminino , Coração/fisiopatologia , Camundongos , Fenótipo , Sístole/efeitos dos fármacos , Sístole/fisiologia , Vitanolídeos/uso terapêutico
11.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 40(7): 958-964, 2020 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-32701234

RESUMO

OBJECTIVE: To investigate the protective effect of melatonin against myocardial ischemia reperfusion (IR) injury in isolated rat hearts and explore the underlying mechanisms. METHODS: The isolated hearts from 40 male SD rats were randomly divided into 4 groups (n=10): the control group, where the hearts were perfused with KH solution for 175 min; IR group, where the hearts were subjected to global ischemia for 45 min followed by reperfusion for 120 min; IR+melatonin (Mel+IR) group, where melatonin (5 µmol/L) was administered to the hearts 1 min before ischemia and during the first 5 min of reperfusion, followed by 115 min of reperfusion; and IR+2, 3-butanedione monoxime (IR+BDM) group, where the hearts were treated with BDM (20 mmol/L) in the same manner as melatonin treatment. Myocardial injury in the isolated hearts was assessed based on myocardial injury area, caspase-3 activity, and expressions of cytochrome C and cleaved caspase-3 proteins. Cardiac contracture was assessed using HE staining and by detecting lactate dehydrogenase (LDH) activity and the content of cardiac troponin I (cTnI) in the coronary outflow, measurement of left ventricular end-diastolic pressure (LVEDP) and electron microscopy. The content of ATP in the cardiac tissue was also determined. RESULTS: Compared with those in the control group, the isolated hearts in IR group showed significantly larger myocardial injury area and higher caspase-3 activity and the protein expressions of cytochrome C and cleaved caspase-3 with significantly increased LDH activity and cTnI content in the coronary outflow and elevated LVEDP at the end of reperfusion; HE staining showed obvious fractures of the myocardial fibers and the content of ATP was significantly decreased in the cardiac tissue; electron microscopy revealed the development of contraction bands. In the isolated hearts with IR, treatment with Mel or BDM significantly reduced the myocardial injury area, caspase-3 activity, and protein expressions of cytochrome C and cleaved caspase-3, obviously inhibited LDH activity, lowered the content of cTnI and LVEDP, reduced myocardial fiber fracture, and increased ATP content in the cardiac tissue. Both Mel and BDM inhibited the formation of contraction bands in the isolated hearts with IR injury. CONCLUSIONS: Mel can alleviate myocardial IR injury in isolated rat hearts by inhibiting cardiac contracture, the mechanism of which may involve the upregulation of ATP in the cardiac myocytes to lessen the tear of membrane and reduce cell content leakage.


Assuntos
Coração , Melatonina , Contração Muscular , Traumatismo por Reperfusão Miocárdica , Animais , Coração/efeitos dos fármacos , Masculino , Melatonina/farmacologia , Melatonina/uso terapêutico , Contração Muscular/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
12.
Hipertens. riesgo vasc ; 37(2): 64-71, abr.-jun. 2020. graf
Artigo em Espanhol | IBECS | ID: ibc-189193

RESUMO

El riñón del diabético presenta un exceso de expresión y actividad del trasportador SGLT2 del túbulo proximal. Esta situación aumenta la reabsorción renal de Na y glucosa, y reduce la oferta distal de los mismos. Además de los efectos metabólicos sobre el medio interno de este exceso de glucosa reabsorbida, el túbulo renal se ve sometido a un estrés glicosilativo capaz de activar localmente tanto apoptosis como inflamasoma. El resultado es la pérdida progresiva de unidades nefronales, la activación de la transición epitelio mensangial y del depósito de colágeno. Se produce la activación de la señalización de insulina por la vía de la MAP kinasa y la resistencia a los efectos metabólicos de la insulina. Simultáneamente se superpone una vasodilatación aferente por la hiperglucemia, una inhibición del feed-back túbulo-glomerular por la reducción en la oferta distal de fluido, la desdiferenciación de los podocitos y la reducción en su número, estos últimos efectos debidos a la resistencia a la insulina. El resultado es un daño renal autoalimentado, con hiperpresión intraglomerular, desdiferenciación podocitaria, apoptosis tubular y activación local y a distancia del inflamasoma. Todos estos efectos son susceptibles de corregirse total o parcialmente al inhibir el trasporte de glucosa a través de los SGLT2


The diabetic kidney presents excess expression and activity of the SGLT2 transporter of the proximal tubule. This situation increases the renal reabsorption of Na and glucose and reduces their distal supply. In addition to the metabolic effects on the internal environment of this excess reabsorbed glucose, the renal tubule is subjected to glycosylated stress capable of locally activating both apoptosis and inflammasome. The result is a progressive loss of nephron units, activation of transition of mesangial epithelium and collagen deposition. Activation of insulin signalling by the MAP kinase pathway and resistance to the metabolic effects of insulin take place. This is simultaneously combined with afferent vasodilation due to hyperglycaemia, tubuloglomerular feedback inhibition due to reduced distal fluid supply, podocyte dedifferentiation and reduction in their number, the latter effects being due to insulin resistance. The result is self-feeding renal damage, with intraglomerular hyper-pressure, podocyte dedifferentiation, tubular apoptosis, and local and distant activation of inflammasome. All these effects are susceptible to be totally or partially corrected by inhibiting glucose transport via the SGLT transporters


Assuntos
Humanos , Coração/efeitos dos fármacos , Rim/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/metabolismo , Túbulos Renais Proximais/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Índice Glicêmico/efeitos dos fármacos , Glicosúria/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
13.
Heart Rhythm ; 17(9): 1445-1451, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32479900

RESUMO

BACKGROUND: Early during the current coronavirus disease 19 (COVID-19) pandemic, hydroxychloroquine (HCQ) received a significant amount of attention as a potential antiviral treatment, such that it became one of the most commonly prescribed medications for COVID-19 patients. However, not only has the effectiveness of HCQ remained questionable, but mainly based on preclinical and a few small clinical studies, HCQ is known to be potentially arrhythmogenic, especially as a result of QT prolongation. OBJECTIVE: The purpose of this study was to investigate the arrhythmic effects of HCQ, as the heightened risk is especially relevant to COVID-19 patients, who are at higher risk for cardiac complications and arrhythmias at baseline. METHODS: An optical mapping technique utilizing voltage-sensitive fluorescent dyes was used to determine the arrhythmic effects of HCQ in ex vivo guinea pig and rabbit hearts perfused with the upper therapeutic serum dose of HCQ (1000 ng/mL). RESULTS: HCQ markedly increased action potential dispersion, resulted in development of repolarization alternans, and initiated polymorphic ventricular tachycardia. CONCLUSION: The study results further highlight the proarrhythmic effects of HCQ.


Assuntos
Antimaláricos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Coração/efeitos dos fármacos , Coração/fisiopatologia , Hidroxicloroquina/farmacologia , Animais , Estimulação Cardíaca Artificial , Infecções por Coronavirus/tratamento farmacológico , Cobaias , Coração/diagnóstico por imagem , Coelhos , Técnicas de Cultura de Tecidos , Imagens com Corantes Sensíveis à Voltagem
14.
Internist (Berl) ; 61(8): 854-859, 2020 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-32504300

RESUMO

A case report is presented of fulminant hydroxychloroquine-induced cardiomyopathy in a 57 year-old female patient with a long history of systemic lupus erythematosus. Diagnosis was established based on clinical findings, imaging (echocardiography and cardiac magnetic resonance imaging) as well as endomyocardial biopsy. Despite immediate discontinuation of the medication, the patient died from heart failure within a few days. Since the rare adverse effect described here might be reversible, early diagnosis and discontinuation of hydroxychloroquine are crucial for the prognosis of these patients.


Assuntos
Cardiomiopatias/induzido quimicamente , Insuficiência Cardíaca/mortalidade , Hidroxicloroquina/efeitos adversos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Doenças Musculares/induzido quimicamente , Biópsia , Cardiomiopatias/mortalidade , Ecocardiografia , Evolução Fatal , Feminino , Coração/efeitos dos fármacos , Insuficiência Cardíaca/induzido quimicamente , Humanos , Hidroxicloroquina/uso terapêutico , Imagem por Ressonância Magnética , Pessoa de Meia-Idade
15.
Toxicology ; 441: 152508, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32525084

RESUMO

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


Assuntos
Antibióticos Antineoplásicos/toxicidade , Autofagia/efeitos dos fármacos , Cardiotoxinas/toxicidade , Doxorrubicina/toxicidade , Ácido Glicirrízico/farmacologia , Proteína HMGB1/metabolismo , Coração/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Animais , Western Blotting , Cardiotoxinas/antagonistas & inibidores , Linhagem Celular , Doxorrubicina/antagonistas & inibidores , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
16.
Ecotoxicol Environ Saf ; 201: 110808, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32516676

RESUMO

Cyprodinil is a broad-spectrum pyrimidine amine fungicide that has been reportedly used worldwide. However, toxicity studies of cyprodinil on aquatic organisms, specifically zebrafish (Danio rerio), are lacking. In our present study, we predicted cyprodinil binding to the aryl hydrocarbon receptor (AhR) by using molecular docking simulation. Then, we used recombinant HepG2 cells and Tg(cyp1a1-12DRE:egfp) transgenic zebrafish to further assess the AhR agonistic activity of cyprodinil. Besides, the significant upregulation of cyp1a1 further verified that statement. Moreover, we found that zebrafish exposure to cyprodinil induced developmental toxicity in the larvae, particularly during cardiac development. The expression levels of cardiac development-related genes, namely tbx5, nkx2.5, gata4, and tnnt2, were markedly altered, which might cause the adverse effects of cyprodinil on cardiac function and development. In summary, we found that cyprodinil, as an AhR agonist, induced development toxicity in zebrafish larvae, especially on cardiac. Data here can assess the potential effects on organisms in the aquatic environment and promote the regulation and safe use of cyprodinil.


Assuntos
Animais Geneticamente Modificados/metabolismo , Larva/efeitos dos fármacos , Pirimidinas/toxicidade , Receptores de Hidrocarboneto Arílico/agonistas , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo , Animais , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Fungicidas Industriais/metabolismo , Coração/efeitos dos fármacos , Coração/embriologia , Células Hep G2 , Humanos , Larva/genética , Larva/metabolismo , Simulação de Acoplamento Molecular , Organogênese/efeitos dos fármacos , Organogênese/genética , Ligação Proteica , Peixe-Zebra/genética
17.
Medicina (B Aires) ; 80(3): 271-274, 2020.
Artigo em Espanhol | MEDLINE | ID: covidwho-344356

RESUMO

Due to the coronavirus disease 2019 (COVID-19) pandemic, a wide number of compounds are under scrutiny regarding their antiviral activity, one of them being hydroxychloroquine. Cardiac aspects of the use of chloroquine and hydroxychloroquine are reviewed in this manuscript. A non-systematic review of the medical literature was performed. Information about their safety and efficacy as antimalarials, antivirals, as well as in the long-term treatment of rheumatic diseases was collected. We found an anti-inflammatory effect with reduction of longterm cardiovascular events, a very infrequent heart disease due to a lysosomal effect of the drug, and at the hemodynamic level hypotension, tachycardia, and QT interval prolongation, exacerbated when combined with azithromycin. However, the rate of adverse cardiac events of hydroxychloroquine (and chloroquine) was low.


Assuntos
Antivirais/efeitos adversos , Betacoronavirus , Doenças Cardiovasculares/induzido quimicamente , Cloroquina/efeitos adversos , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/efeitos adversos , Pneumonia Viral/tratamento farmacológico , Anti-Inflamatórios/efeitos adversos , Antirreumáticos/efeitos adversos , Coração/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Humanos , Pandemias , Fatores de Risco
18.
FASEB J ; 34(5): 6027-6037, 2020 05.
Artigo em Inglês | MEDLINE | ID: covidwho-143943

RESUMO

There are currently no proven or approved treatments for coronavirus disease 2019 (COVID-19). Early anecdotal reports and limited in vitro data led to the significant uptake of hydroxychloroquine (HCQ), and to lesser extent chloroquine (CQ), for many patients with this disease. As an increasing number of patients with COVID-19 are treated with these agents and more evidence accumulates, there continues to be no high-quality clinical data showing a clear benefit of these agents for this disease. Moreover, these agents have the potential to cause harm, including a broad range of adverse events including serious cardiac side effects when combined with other agents. In addition, the known and potent immunomodulatory effects of these agents which support their use in the treatment of auto-immune conditions, and provided a component in the original rationale for their use in patients with COVID-19, may, in fact, undermine their utility in the context of the treatment of this respiratory viral infection. Specifically, the impact of HCQ on cytokine production and suppression of antigen presentation may have immunologic consequences that hamper innate and adaptive antiviral immune responses for patients with COVID-19. Similarly, the reported in vitro inhibition of viral proliferation is largely derived from the blockade of viral fusion that initiates infection rather than the direct inhibition of viral replication as seen with nucleoside/tide analogs in other viral infections. Given these facts and the growing uncertainty about these agents for the treatment of COVID-19, it is clear that at the very least thoughtful planning and data collection from randomized clinical trials are needed to understand what if any role these agents may have in this disease. In this article, we review the datasets that support or detract from the use of these agents for the treatment of COVID-19 and render a data informed opinion that they should only be used with caution and in the context of carefully thought out clinical trials, or on a case-by-case basis after rigorous consideration of the risks and benefits of this therapeutic approach.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/efeitos adversos , Hidroxicloroquina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Conjuntos de Dados como Assunto/normas , Coração/efeitos dos fármacos , Humanos , Hidroxicloroquina/farmacologia , Imunidade Inata/efeitos dos fármacos , Pandemias , Ensaios Clínicos Controlados Aleatórios como Assunto/normas
19.
Artigo em Inglês | MEDLINE | ID: mdl-32357113

RESUMO

Cell-autonomous circadian clocks have emerged as temporal orchestrators of numerous biological processes. For example, the cardiomyocyte circadian clock modulates transcription, translation, posttranslational modifications, ion homeostasis, signaling cascades, metabolism, and contractility of the heart over the course of the day. Circadian clocks are composed of more than 10 interconnected transcriptional modulators, all of which have the potential to influence the cardiac transcriptome (and ultimately cardiac processes). These transcriptional modulators include BMAL1 and REV-ERBα/ß; BMAL1 induces REV-ERBα/ß, which in turn feeds back to inhibit BMAL1. Previous studies indicate that cardiomyocyte-specific BMAL1-knockout (CBK) mice exhibit a dysfunctional circadian clock (including decreased REV-ERBα/ß expression) in the heart associated with abnormalities in cardiac mitochondrial function, metabolism, signaling, and contractile function. Here, we hypothesized that decreased REV-ERBα/ß activity is responsible for distinct phenotypical alterations observed in CBK hearts. To test this hypothesis, CBK (and littermate control) mice were administered with the selective REV-ERBα/ß agonist SR-9009 (100 mg·kg-1·day-1 for 8 days). SR-9009 administration was sufficient to normalize cardiac glycogen synthesis rates, cardiomyocyte size, interstitial fibrosis, and contractility in CBK hearts (without influencing mitochondrial complex activities, nor normalizing substrate oxidation and Akt/mTOR/GSK3ß signaling). Collectively, these observations highlight a role for REV-ERBα/ß as a mediator of a subset of circadian clock-controlled processes in the heart.


Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Miocárdio/metabolismo , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/agonistas , Fatores de Transcrição ARNTL/metabolismo , Animais , Ritmo Circadiano/efeitos dos fármacos , Expressão Gênica , Regulação da Expressão Gênica , Coração/efeitos dos fármacos , Camundongos , Camundongos Knockout , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Pirrolidinas/farmacologia , Tiofenos/farmacologia
20.
Medicina (B Aires) ; 80(3): 271-274, 2020.
Artigo em Espanhol | MEDLINE | ID: mdl-32442941

RESUMO

Due to the coronavirus disease 2019 (COVID-19) pandemic, a wide number of compounds are under scrutiny regarding their antiviral activity, one of them being hydroxychloroquine. Cardiac aspects of the use of chloroquine and hydroxychloroquine are reviewed in this manuscript. A non-systematic review of the medical literature was performed. Information about their safety and efficacy as antimalarials, antivirals, as well as in the long-term treatment of rheumatic diseases was collected. We found an anti-inflammatory effect with reduction of longterm cardiovascular events, a very infrequent heart disease due to a lysosomal effect of the drug, and at the hemodynamic level hypotension, tachycardia, and QT interval prolongation, exacerbated when combined with azithromycin. However, the rate of adverse cardiac events of hydroxychloroquine (and chloroquine) was low.


Assuntos
Antivirais/efeitos adversos , Betacoronavirus , Doenças Cardiovasculares/induzido quimicamente , Cloroquina/efeitos adversos , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/efeitos adversos , Pneumonia Viral/tratamento farmacológico , Anti-Inflamatórios/efeitos adversos , Antirreumáticos/efeitos adversos , Coração/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Humanos , Pandemias , Fatores de Risco
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