Os isômeros do isopulegol bloqueiam canais para cálcio tipo-l e atenuam a hipertrofia cardíaca em rato: via PKA e ERK 1/2
Autor(a) principal: | |
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Data de Publicação: | 2019 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Repositório Institucional da UFS |
Texto Completo: | http://ri.ufs.br/jspui/handle/riufs/13071 |
Resumo: | Introduction: Cardiac hypertrophy (CH) is characterized by the remodeling of cardiac muscle associated with change in its contractile and electrical function. Isopulegol is an alcoholic monoterpene with antioxidant, anxiolytic and anticonvulsant activities. Objectives: To investigate the effects of (+)-isopulegol ((+) - ISP) and (-)-isopulegol ((-)-ISP) isomers on intracellular calcium signaling and cardiac hypertrophy induced by isoproterenol (ISO). Methods: The contractile effects of isomers were evaluated in rat left atrium mounted and ventricular cardiomyocyte of rat by shortening fraction using edge detection system (Ionoptix). In ventricular cardiomyocyte were evaluated the L-type calcium current (ICa,L) by patch-clamp technique in ‘whole-cell’ configuration and intracellular calcium transient by confocal microscopy (FLUO 4AM) was investigated in control situation and after incubation with 100 μM of both isomers. The docking was done to analysis the interaction of isomers with the L-type calcium channel. Cardiac hypertrophy was induced by administration of ISO (4.5 mg/kg, 7 days, i.p.). Four groups of animals were evaluated: 1) control (saline 0.9% + DMSO 0.1%), 2) isoproterenol (ISO), 3) ISO + (-)-ISP (50 mg/kg) and 4) ISO + (+)-ISP (50 mg/kg). In hypertrophic and treated animals were evaluated morphometric and electrocardiographic parameters, biochemical markers (LDH, CPK and CK-MB), oxidative stress (TBARS, SOD, CAT e GPx), inflammatory mediators (TNF-α and IL1-β), expression of proteins (PKA C-α, CAMKII, α/β CAMKII, ERK ½ total, p-ERK ½, SERCA, sarcalumenin, PP1γ e NCX. Results: showed that (-)-ISP (EC50 = 533.0 ± 53.80 μM) and (+)-ISP (EC50 = 1836 ± 165.71 μM) reduced the atrial contractility, of concentration dependent manner. In ventricular cardiomyocytes, after incubation with 100 μM of (-)-ISP and (+)-ISP was observed reduction of shortening fraction (40% and 28%) and ICa,L (68% and 59%), respectively. In addition, (-)-ISP e (+)-ISP reduced the intracellular calcium transient in 21% and 22%, respectively. The docking revealed the interaction of (-)-ISP and (+)-ISP with the L-type calcium channel with energies -65.84 Kcal/mol and -63.09 Kcal/mol. Hypertrophic animals presented increase of heart weight/body weight ratio (5.12 ± 0.09 mg/g, p < 0.05) as well as heart weight/tibia length ratio (364.20 ± 13.74 mg/cm, p < 0.05) in compared to control (3.52 ± 0.11 mg/g; 246.2 ± 6.33 mg/cm) and were attenuated with treatment with (-)-ISP (4.26 ± 0.11 mg/g and 299.40 ± 7.45 mg/cm) and (+)-ISP (4.42 ± 0.03 mg/g and 318.10 ± 3.24 mg/cm). (-)-ISP and (+)-ISPs were able to prevent electrocardiographic changes (increase of QRS, QTc and intrinsicoid deflection) and increase of serum levels of LDH, CPK and CPK-MB of hypertrophic animals. In addition, the treatment of hypertrophic animals with (-)-ISP and (+)-ISP the oxidative promoted decrease of TBARS and increase of SOD, CAT and GPx. Furthermore, inflammatory mediators TNF-α (in 59% and 40%) and IL1-β (in 34% and 55%) were reduced in the two groups treated with (-)-ISP and (+)-ISP, respectively. Treatment of animals with (-)-ISP and (+)-ISP decreased the overexpression of proteins involved in cardiac hypertrophy (PKA, ERK1/2, NCX), as well as prevented the decrease of SERCA and sarcalumelin expression. Conclusion: The isopulegol isomers block L-type calcium channels reducing the intracellular calcium transient in the ventricular cardiomyocyte exhibiting cardioprotective effect in isoproterenol-induced cardiac hypertrophy model |
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Menezes Filho, José Evaldo Rodrigues deQuintans Júnior, Lucindo JoséVasconcelos, Carla Maria Lins de2020-03-19T19:35:11Z2020-03-19T19:35:11Z2019-06-17MENEZES FILHO, José Evaldo Rodrigues de. Os isômeros do isopulegol bloqueiam canais para cálcio tipo-l e atenuam a hipertrofia cardíaca em rato: via PKA e ERK 1/2. 2019. 108 f. Tese (Doutorado em Ciências da Saúde) – Universidade Federal de Sergipe, Aracaju, 2019.http://ri.ufs.br/jspui/handle/riufs/13071Introduction: Cardiac hypertrophy (CH) is characterized by the remodeling of cardiac muscle associated with change in its contractile and electrical function. Isopulegol is an alcoholic monoterpene with antioxidant, anxiolytic and anticonvulsant activities. Objectives: To investigate the effects of (+)-isopulegol ((+) - ISP) and (-)-isopulegol ((-)-ISP) isomers on intracellular calcium signaling and cardiac hypertrophy induced by isoproterenol (ISO). Methods: The contractile effects of isomers were evaluated in rat left atrium mounted and ventricular cardiomyocyte of rat by shortening fraction using edge detection system (Ionoptix). In ventricular cardiomyocyte were evaluated the L-type calcium current (ICa,L) by patch-clamp technique in ‘whole-cell’ configuration and intracellular calcium transient by confocal microscopy (FLUO 4AM) was investigated in control situation and after incubation with 100 μM of both isomers. The docking was done to analysis the interaction of isomers with the L-type calcium channel. Cardiac hypertrophy was induced by administration of ISO (4.5 mg/kg, 7 days, i.p.). Four groups of animals were evaluated: 1) control (saline 0.9% + DMSO 0.1%), 2) isoproterenol (ISO), 3) ISO + (-)-ISP (50 mg/kg) and 4) ISO + (+)-ISP (50 mg/kg). In hypertrophic and treated animals were evaluated morphometric and electrocardiographic parameters, biochemical markers (LDH, CPK and CK-MB), oxidative stress (TBARS, SOD, CAT e GPx), inflammatory mediators (TNF-α and IL1-β), expression of proteins (PKA C-α, CAMKII, α/β CAMKII, ERK ½ total, p-ERK ½, SERCA, sarcalumenin, PP1γ e NCX. Results: showed that (-)-ISP (EC50 = 533.0 ± 53.80 μM) and (+)-ISP (EC50 = 1836 ± 165.71 μM) reduced the atrial contractility, of concentration dependent manner. In ventricular cardiomyocytes, after incubation with 100 μM of (-)-ISP and (+)-ISP was observed reduction of shortening fraction (40% and 28%) and ICa,L (68% and 59%), respectively. In addition, (-)-ISP e (+)-ISP reduced the intracellular calcium transient in 21% and 22%, respectively. The docking revealed the interaction of (-)-ISP and (+)-ISP with the L-type calcium channel with energies -65.84 Kcal/mol and -63.09 Kcal/mol. Hypertrophic animals presented increase of heart weight/body weight ratio (5.12 ± 0.09 mg/g, p < 0.05) as well as heart weight/tibia length ratio (364.20 ± 13.74 mg/cm, p < 0.05) in compared to control (3.52 ± 0.11 mg/g; 246.2 ± 6.33 mg/cm) and were attenuated with treatment with (-)-ISP (4.26 ± 0.11 mg/g and 299.40 ± 7.45 mg/cm) and (+)-ISP (4.42 ± 0.03 mg/g and 318.10 ± 3.24 mg/cm). (-)-ISP and (+)-ISPs were able to prevent electrocardiographic changes (increase of QRS, QTc and intrinsicoid deflection) and increase of serum levels of LDH, CPK and CPK-MB of hypertrophic animals. In addition, the treatment of hypertrophic animals with (-)-ISP and (+)-ISP the oxidative promoted decrease of TBARS and increase of SOD, CAT and GPx. Furthermore, inflammatory mediators TNF-α (in 59% and 40%) and IL1-β (in 34% and 55%) were reduced in the two groups treated with (-)-ISP and (+)-ISP, respectively. Treatment of animals with (-)-ISP and (+)-ISP decreased the overexpression of proteins involved in cardiac hypertrophy (PKA, ERK1/2, NCX), as well as prevented the decrease of SERCA and sarcalumelin expression. Conclusion: The isopulegol isomers block L-type calcium channels reducing the intracellular calcium transient in the ventricular cardiomyocyte exhibiting cardioprotective effect in isoproterenol-induced cardiac hypertrophy modelIntrodução: A hipertrofia cardíaca (HC) é caracterizada pelo remodelamento do tecido cardíaco acompanhada de alteração na sua função contrátil e elétrica. O isopulegol é um monoterpeno alcoólico com atividades antioxidante, ansiolítica e anticonvulsivante. Objetivos: Investigar os efeitos dos isômeros (+)-isopulegol ((+)-ISP) e (-)-isopulegol ((-)-ISP) na sinalização do cálcio intracelular e hipertrofia cardíaca induzida por isoproterenol (ISO). Métodos: Os efeitos contráteis dos isômeros foram avaliados em átrio esquerdo montado em cuba para órgão isolado e em cardiomiócito ventricular de rato pela fração de encurtamento usando sistema de detecção de bordas (Ionoptix). Em cardiomiócito ventricular isolado, foram avaliados a corrente de cálcio tipo-L (ICa,L) pela técnica de ‘patch-clamp’ na configuração ‘whole-cell’ bem como o transiente intracelular de cálcio usando a miscroscopia confocal (sonda FLUO 4AM) em situação controle e após a incubação com 100 μM dos isômeros do ISP. O docking foi feito para avaliar a interação dos isômeros com o canal para cálcio tipo-L. A HC foi induzida pela administração de ISO (4,5 mg/kg, 7 dias, i.p). Foram avaliados 4 grupos de animais: 1) controle (salina 0,9% + DMSO 0,1%), 2) isoproterenol (ISO), 3) ISO + (-)-ISP (50 mg/kg) e 4) ISO + (+)-ISP (50 mg/kg). Nos animais hipertróficos e tratados, foram avaliados os parâmetros morfométricos, eletrocardiográficos, marcadores séricos bioquímicos (LDH, CPK e CK-MB), estresse oxidativo (TBARS, SOD, CAT e GPx), mediadores inflamatórios (TNF-α e IL-1β), expressão de proteínas (PKA C-α, CAMKII, α/β CAMKII, ERK½ total, p-ERK½, SERCA, sarcalumelina, PP1γ e NCX). Resultados: o (-)-ISP (CE50 = 533,0 ± 53,80 μM) e o (+)-ISP (CE50 =1836 ± 165,71 μM) reduziram a contratilidade atrial, de modo dependente de concentração. Em cardiomiócito ventricular, após a incubação com 100 μM de (-)-ISP e (+)-ISP, foi observado tanto redução da fração de encurtamento (40% e 28%) quanto redução da ICa,L (em 68% e 59%), respectivamente. Além disso, os (-)-ISP e (+)-ISP reduziram o transiente intracelular do cálcio em 21% e 22%, respectivamente. O docking revelou a interação do (-)-ISP e (+)-ISP com o canal para cálcio do tipo-L com energias -65,84 Kcal/mol e -63,09 Kcal/mol, respectivamente. Os animais hipertróficos apresentaram aumento na relação peso do coração/peso corporal (5,12 ± 0,09 mg/g, p<0,05), bem como do peso do coração/comprimento da tíbia (364,20 ± 13,74 mg/cm, p<0,05) quando comparado ao grupo controle (3,52 ± 0,11 mg/g; 246,2 ± 6,33 mg/cm) e que foram atenuados pelo tratamento com o (-)-ISP (4,26 ± 0,11 mg/g e 299,40 ± 7,45 mg/cm) e (+)-ISP (4,42 ± 0,03 mg/g e 318,10 ± 3,24 mg/cm). O (-)-ISP e (+)-ISP foram capazes de prevenir as alterações eletrocardiográficas (aumento do QRS, QTc e deflexão intrinsecóide) e o aumento dos níveis séricos de LDH, CPK e CPK-MB dos animais hipertróficos. Além disso, o tratamento dos animais com (-)-ISP e (+)-ISP foi capaz de reduzir o estresse oxidativo promovendo diminuição do TBARS e aumento da SOD, CAT e GPx, assim como redução de TNF-α (em 59% e 10,24%) e IL1-β (em 34% e 55%), respectivamente. O tratamento dos animais com (-)-ISP e (+)-ISP diminuiu a superexpressão de proteínas envolvidas na HC (PKA, ERK1/2 e NCX), assim como, preveniu a diminuição da expressão da SERCA e sarcalumelina. Conclusão: Os isômeros do isopulegol bloqueiam canais para cálcio tipo-L reduzindo o transiente intracelular de cálcio no cardiomiócito ventricular apresentando efeito cardioprotetor em modelo de hipertrofia cardíaca induzida por isoproterenol.Fundação de Apoio a Pesquisa e à Inovação Tecnológica do Estado de Sergipe - FAPITEC/SEAracajuporHipertrofia do coraçãoMonoterpenosEstresse oxidativoMonoterpenesCardiac hypertrophyCalcium signalingOxidative stressHeartIsoproterenolCIENCIAS DA SAUDEOs isômeros do isopulegol bloqueiam canais para cálcio tipo-l e atenuam a hipertrofia cardíaca em rato: via PKA e ERK 1/2Isopulegol isomers block L-type calcium channel and attenuate the cardiac hypertrophy in rats: PKA and ERK 1/2 pathwayinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisPós-Graduação em Ciências da SaúdeUniversidade Federal de Sergipereponame:Repositório Institucional da UFSinstname:Universidade Federal de Sergipe (UFS)instacron:UFSinfo:eu-repo/semantics/openAccessTEXTJOSE_EVALDO_RODRIGUES_MENEZES_FILHO.pdf.txtJOSE_EVALDO_RODRIGUES_MENEZES_FILHO.pdf.txtExtracted texttext/plain198904https://ri.ufs.br/jspui/bitstream/riufs/13071/3/JOSE_EVALDO_RODRIGUES_MENEZES_FILHO.pdf.txt0c809c21b73e2dde98eaeb4b745485acMD53THUMBNAILJOSE_EVALDO_RODRIGUES_MENEZES_FILHO.pdf.jpgJOSE_EVALDO_RODRIGUES_MENEZES_FILHO.pdf.jpgGenerated Thumbnailimage/jpeg1310https://ri.ufs.br/jspui/bitstream/riufs/13071/4/JOSE_EVALDO_RODRIGUES_MENEZES_FILHO.pdf.jpgead34b591f5f7925cceca3ee0036145eMD54LICENSElicense.txtlicense.txttext/plain; charset=utf-81475https://ri.ufs.br/jspui/bitstream/riufs/13071/1/license.txt098cbbf65c2c15e1fb2e49c5d306a44cMD51ORIGINALJOSE_EVALDO_RODRIGUES_MENEZES_FILHO.pdfJOSE_EVALDO_RODRIGUES_MENEZES_FILHO.pdfapplication/pdf2813878https://ri.ufs.br/jspui/bitstream/riufs/13071/2/JOSE_EVALDO_RODRIGUES_MENEZES_FILHO.pdf7bf78b48430a24089a2dd2e20747ca72MD52riufs/130712020-03-19 16:35:47.125oai:ufs.br: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Repositório InstitucionalPUBhttps://ri.ufs.br/oai/requestrepositorio@academico.ufs.bropendoar:2020-03-19T19:35:47Repositório Institucional da UFS - Universidade Federal de Sergipe (UFS)false |
dc.title.pt_BR.fl_str_mv |
Os isômeros do isopulegol bloqueiam canais para cálcio tipo-l e atenuam a hipertrofia cardíaca em rato: via PKA e ERK 1/2 |
dc.title.alternative.eng.fl_str_mv |
Isopulegol isomers block L-type calcium channel and attenuate the cardiac hypertrophy in rats: PKA and ERK 1/2 pathway |
title |
Os isômeros do isopulegol bloqueiam canais para cálcio tipo-l e atenuam a hipertrofia cardíaca em rato: via PKA e ERK 1/2 |
spellingShingle |
Os isômeros do isopulegol bloqueiam canais para cálcio tipo-l e atenuam a hipertrofia cardíaca em rato: via PKA e ERK 1/2 Menezes Filho, José Evaldo Rodrigues de Hipertrofia do coração Monoterpenos Estresse oxidativo Monoterpenes Cardiac hypertrophy Calcium signaling Oxidative stress Heart Isoproterenol CIENCIAS DA SAUDE |
title_short |
Os isômeros do isopulegol bloqueiam canais para cálcio tipo-l e atenuam a hipertrofia cardíaca em rato: via PKA e ERK 1/2 |
title_full |
Os isômeros do isopulegol bloqueiam canais para cálcio tipo-l e atenuam a hipertrofia cardíaca em rato: via PKA e ERK 1/2 |
title_fullStr |
Os isômeros do isopulegol bloqueiam canais para cálcio tipo-l e atenuam a hipertrofia cardíaca em rato: via PKA e ERK 1/2 |
title_full_unstemmed |
Os isômeros do isopulegol bloqueiam canais para cálcio tipo-l e atenuam a hipertrofia cardíaca em rato: via PKA e ERK 1/2 |
title_sort |
Os isômeros do isopulegol bloqueiam canais para cálcio tipo-l e atenuam a hipertrofia cardíaca em rato: via PKA e ERK 1/2 |
author |
Menezes Filho, José Evaldo Rodrigues de |
author_facet |
Menezes Filho, José Evaldo Rodrigues de |
author_role |
author |
dc.contributor.author.fl_str_mv |
Menezes Filho, José Evaldo Rodrigues de |
dc.contributor.advisor1.fl_str_mv |
Quintans Júnior, Lucindo José |
dc.contributor.advisor-co1.fl_str_mv |
Vasconcelos, Carla Maria Lins de |
contributor_str_mv |
Quintans Júnior, Lucindo José Vasconcelos, Carla Maria Lins de |
dc.subject.por.fl_str_mv |
Hipertrofia do coração Monoterpenos Estresse oxidativo |
topic |
Hipertrofia do coração Monoterpenos Estresse oxidativo Monoterpenes Cardiac hypertrophy Calcium signaling Oxidative stress Heart Isoproterenol CIENCIAS DA SAUDE |
dc.subject.eng.fl_str_mv |
Monoterpenes Cardiac hypertrophy Calcium signaling Oxidative stress Heart Isoproterenol |
dc.subject.cnpq.fl_str_mv |
CIENCIAS DA SAUDE |
description |
Introduction: Cardiac hypertrophy (CH) is characterized by the remodeling of cardiac muscle associated with change in its contractile and electrical function. Isopulegol is an alcoholic monoterpene with antioxidant, anxiolytic and anticonvulsant activities. Objectives: To investigate the effects of (+)-isopulegol ((+) - ISP) and (-)-isopulegol ((-)-ISP) isomers on intracellular calcium signaling and cardiac hypertrophy induced by isoproterenol (ISO). Methods: The contractile effects of isomers were evaluated in rat left atrium mounted and ventricular cardiomyocyte of rat by shortening fraction using edge detection system (Ionoptix). In ventricular cardiomyocyte were evaluated the L-type calcium current (ICa,L) by patch-clamp technique in ‘whole-cell’ configuration and intracellular calcium transient by confocal microscopy (FLUO 4AM) was investigated in control situation and after incubation with 100 μM of both isomers. The docking was done to analysis the interaction of isomers with the L-type calcium channel. Cardiac hypertrophy was induced by administration of ISO (4.5 mg/kg, 7 days, i.p.). Four groups of animals were evaluated: 1) control (saline 0.9% + DMSO 0.1%), 2) isoproterenol (ISO), 3) ISO + (-)-ISP (50 mg/kg) and 4) ISO + (+)-ISP (50 mg/kg). In hypertrophic and treated animals were evaluated morphometric and electrocardiographic parameters, biochemical markers (LDH, CPK and CK-MB), oxidative stress (TBARS, SOD, CAT e GPx), inflammatory mediators (TNF-α and IL1-β), expression of proteins (PKA C-α, CAMKII, α/β CAMKII, ERK ½ total, p-ERK ½, SERCA, sarcalumenin, PP1γ e NCX. Results: showed that (-)-ISP (EC50 = 533.0 ± 53.80 μM) and (+)-ISP (EC50 = 1836 ± 165.71 μM) reduced the atrial contractility, of concentration dependent manner. In ventricular cardiomyocytes, after incubation with 100 μM of (-)-ISP and (+)-ISP was observed reduction of shortening fraction (40% and 28%) and ICa,L (68% and 59%), respectively. In addition, (-)-ISP e (+)-ISP reduced the intracellular calcium transient in 21% and 22%, respectively. The docking revealed the interaction of (-)-ISP and (+)-ISP with the L-type calcium channel with energies -65.84 Kcal/mol and -63.09 Kcal/mol. Hypertrophic animals presented increase of heart weight/body weight ratio (5.12 ± 0.09 mg/g, p < 0.05) as well as heart weight/tibia length ratio (364.20 ± 13.74 mg/cm, p < 0.05) in compared to control (3.52 ± 0.11 mg/g; 246.2 ± 6.33 mg/cm) and were attenuated with treatment with (-)-ISP (4.26 ± 0.11 mg/g and 299.40 ± 7.45 mg/cm) and (+)-ISP (4.42 ± 0.03 mg/g and 318.10 ± 3.24 mg/cm). (-)-ISP and (+)-ISPs were able to prevent electrocardiographic changes (increase of QRS, QTc and intrinsicoid deflection) and increase of serum levels of LDH, CPK and CPK-MB of hypertrophic animals. In addition, the treatment of hypertrophic animals with (-)-ISP and (+)-ISP the oxidative promoted decrease of TBARS and increase of SOD, CAT and GPx. Furthermore, inflammatory mediators TNF-α (in 59% and 40%) and IL1-β (in 34% and 55%) were reduced in the two groups treated with (-)-ISP and (+)-ISP, respectively. Treatment of animals with (-)-ISP and (+)-ISP decreased the overexpression of proteins involved in cardiac hypertrophy (PKA, ERK1/2, NCX), as well as prevented the decrease of SERCA and sarcalumelin expression. Conclusion: The isopulegol isomers block L-type calcium channels reducing the intracellular calcium transient in the ventricular cardiomyocyte exhibiting cardioprotective effect in isoproterenol-induced cardiac hypertrophy model |
publishDate |
2019 |
dc.date.issued.fl_str_mv |
2019-06-17 |
dc.date.accessioned.fl_str_mv |
2020-03-19T19:35:11Z |
dc.date.available.fl_str_mv |
2020-03-19T19:35:11Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
MENEZES FILHO, José Evaldo Rodrigues de. Os isômeros do isopulegol bloqueiam canais para cálcio tipo-l e atenuam a hipertrofia cardíaca em rato: via PKA e ERK 1/2. 2019. 108 f. Tese (Doutorado em Ciências da Saúde) – Universidade Federal de Sergipe, Aracaju, 2019. |
dc.identifier.uri.fl_str_mv |
http://ri.ufs.br/jspui/handle/riufs/13071 |
identifier_str_mv |
MENEZES FILHO, José Evaldo Rodrigues de. Os isômeros do isopulegol bloqueiam canais para cálcio tipo-l e atenuam a hipertrofia cardíaca em rato: via PKA e ERK 1/2. 2019. 108 f. Tese (Doutorado em Ciências da Saúde) – Universidade Federal de Sergipe, Aracaju, 2019. |
url |
http://ri.ufs.br/jspui/handle/riufs/13071 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.publisher.program.fl_str_mv |
Pós-Graduação em Ciências da Saúde |
dc.publisher.initials.fl_str_mv |
Universidade Federal de Sergipe |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da UFS instname:Universidade Federal de Sergipe (UFS) instacron:UFS |
instname_str |
Universidade Federal de Sergipe (UFS) |
instacron_str |
UFS |
institution |
UFS |
reponame_str |
Repositório Institucional da UFS |
collection |
Repositório Institucional da UFS |
bitstream.url.fl_str_mv |
https://ri.ufs.br/jspui/bitstream/riufs/13071/3/JOSE_EVALDO_RODRIGUES_MENEZES_FILHO.pdf.txt https://ri.ufs.br/jspui/bitstream/riufs/13071/4/JOSE_EVALDO_RODRIGUES_MENEZES_FILHO.pdf.jpg https://ri.ufs.br/jspui/bitstream/riufs/13071/1/license.txt https://ri.ufs.br/jspui/bitstream/riufs/13071/2/JOSE_EVALDO_RODRIGUES_MENEZES_FILHO.pdf |
bitstream.checksum.fl_str_mv |
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bitstream.checksumAlgorithm.fl_str_mv |
MD5 MD5 MD5 MD5 |
repository.name.fl_str_mv |
Repositório Institucional da UFS - Universidade Federal de Sergipe (UFS) |
repository.mail.fl_str_mv |
repositorio@academico.ufs.br |
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1802110748436987904 |