Interaction of organodiselenides with sulphydryl groups at the active sites of some thiol containing proteins - in vitro and in vivo mechanistic studies in mammalian models of diabetes
Ano de defesa: | 2008 |
---|---|
Autor(a) principal: | |
Orientador(a): | |
Banca de defesa: | , , , |
Tipo de documento: | Tese |
Tipo de acesso: | Acesso aberto |
Idioma: | por |
Instituição de defesa: |
Universidade Federal de Santa Maria
|
Programa de Pós-Graduação: |
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica
|
Departamento: |
Bioquímica
|
País: |
BR
|
Palavras-chave em Português: | |
Área do conhecimento CNPq: | |
Link de acesso: | http://repositorio.ufsm.br/handle/1/4398 |
Resumo: | The present study sought to compare the in vitro antioxidant potentials of a newly synthesized organodiselenide, dicholesteroyl diselenide (DCDS) and diphenyl diselenide (DPDS) and their possible interactions with some thiol containing enzymes in different tissues from mammalian system. In addition, the potency of DPDS as antioxidant and antihyperglycaemic agents, and its interaction with thiol containing proteins in various mammalian tissues and organs (hepatic, renal and spleenic and more importantly cerebral tissues) were evaluated in animal models of streptozotocin induced diabetic rats. The in vitro results show that DPDS exhibited a higher glutathione-peroxidase mimetic activity as well as increased ability to oxidize both mono- and di- thiols than DCDS. In addition, while DPDS inhibited thiobarbituric acid reactive substances (TBARS) and protein carbonyls formations in both cerebral and hepatic tissues, induced by either iron (II) or SNP, DCDS exhibited a prooxidant effect in both cerebral and hepatic tissues when iron (II) serves as the prooxidant, However, when TBARS was induced by SNP, DCDS slightly modify TBARS formation in both hepatic and cerebral tissues. Also the activities of cerebral and hepatic delata aminolevulinic acid dehydratase (ð-ALA-D), cerebral Na+/K+- ATPase were significantly inhibited by DPDS and only weakly inhibited by the DCDS. Further studies reveal that the inhibition caused by organodiselenides (in this case, DPDS) on Na+/K+-ATPase activity likely involves the modification of the thiol groups at the ATP binding site of the enzyme. Similarly, different isoforms of lactate dehydrogenase (LDH) were significantly inhibited by both DPDS and DCDS in vitro. Likewise, we observed that the in vitro inhibition of different isoforms of lactate dehydrogenase by DCDS and DPDS likely involves the modification of the -SH groups at the NAD+ binding site of the enzyme. Oral administration of DPDS dissolved in soya bean oil administered to streptozotocin induced diabetes in male albino rats shows that there was significant reduction in blood glucose levels accompanied by a marked reduction of glycated proteins in streptozotocin induced diabetic rats treated with DPDS in relation to untreated streptozotocin induced diabetic. In addition, DPDS was able to significantly ameliorate the levels of Vitamin C and GSH (liver, kidney and spleen), which were decreased in streptozotocin treated rats. Similarly, treatment with DPDS was able to markedly abolish the increase levels of TBARS that were observed in STZ diabetes group. Finally, the inhibition of both ð-ALA-D and some isoforms of LDH caused by hyperglycaemia were prevented by DPDS. We also observed that although streptozotocin evoke a significant diminution on brain s antioxidant status and activity of Na+/K+-ATPase, but the activity of acetylcholineesterase and glutamate uptake and release were not altered. However, DPDS was able to markedly restore the observed imbalance in antioxidant status and sodium pump. Finally, we conclude that organodiselenides are promising antioxidant remedy in the management of diseases caused by oxidative stress. However, their toxicity involves an interaction with thiols on proteins and this study has further demonstrated that the sulphydryl groups in question are critical to the normal function of the protein or enzymes. Most likely, these -SH are associated with thiols at the substrate binding (active site) sites of the enzymes. Interestingly, pharmacological doses of organodiselenides 3mg/kg bw for the study on diabetes do not present any observed toxicity. |
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2017-04-242017-04-242008-04-02KADE, Ige Joseph. Interaction of organodiselenides with sulphydryl groups at the active sites of some thiol containing proteins - in vitro and in vivo mechanistic studies in mammalian models of diabetes. 2008. 180 f. Tese (Doutorado em Bioquímica) - Universidade Federal de Santa Maria, Santa Maria, 2008.http://repositorio.ufsm.br/handle/1/4398The present study sought to compare the in vitro antioxidant potentials of a newly synthesized organodiselenide, dicholesteroyl diselenide (DCDS) and diphenyl diselenide (DPDS) and their possible interactions with some thiol containing enzymes in different tissues from mammalian system. In addition, the potency of DPDS as antioxidant and antihyperglycaemic agents, and its interaction with thiol containing proteins in various mammalian tissues and organs (hepatic, renal and spleenic and more importantly cerebral tissues) were evaluated in animal models of streptozotocin induced diabetic rats. The in vitro results show that DPDS exhibited a higher glutathione-peroxidase mimetic activity as well as increased ability to oxidize both mono- and di- thiols than DCDS. In addition, while DPDS inhibited thiobarbituric acid reactive substances (TBARS) and protein carbonyls formations in both cerebral and hepatic tissues, induced by either iron (II) or SNP, DCDS exhibited a prooxidant effect in both cerebral and hepatic tissues when iron (II) serves as the prooxidant, However, when TBARS was induced by SNP, DCDS slightly modify TBARS formation in both hepatic and cerebral tissues. Also the activities of cerebral and hepatic delata aminolevulinic acid dehydratase (ð-ALA-D), cerebral Na+/K+- ATPase were significantly inhibited by DPDS and only weakly inhibited by the DCDS. Further studies reveal that the inhibition caused by organodiselenides (in this case, DPDS) on Na+/K+-ATPase activity likely involves the modification of the thiol groups at the ATP binding site of the enzyme. Similarly, different isoforms of lactate dehydrogenase (LDH) were significantly inhibited by both DPDS and DCDS in vitro. Likewise, we observed that the in vitro inhibition of different isoforms of lactate dehydrogenase by DCDS and DPDS likely involves the modification of the -SH groups at the NAD+ binding site of the enzyme. Oral administration of DPDS dissolved in soya bean oil administered to streptozotocin induced diabetes in male albino rats shows that there was significant reduction in blood glucose levels accompanied by a marked reduction of glycated proteins in streptozotocin induced diabetic rats treated with DPDS in relation to untreated streptozotocin induced diabetic. In addition, DPDS was able to significantly ameliorate the levels of Vitamin C and GSH (liver, kidney and spleen), which were decreased in streptozotocin treated rats. Similarly, treatment with DPDS was able to markedly abolish the increase levels of TBARS that were observed in STZ diabetes group. Finally, the inhibition of both ð-ALA-D and some isoforms of LDH caused by hyperglycaemia were prevented by DPDS. We also observed that although streptozotocin evoke a significant diminution on brain s antioxidant status and activity of Na+/K+-ATPase, but the activity of acetylcholineesterase and glutamate uptake and release were not altered. However, DPDS was able to markedly restore the observed imbalance in antioxidant status and sodium pump. Finally, we conclude that organodiselenides are promising antioxidant remedy in the management of diseases caused by oxidative stress. However, their toxicity involves an interaction with thiols on proteins and this study has further demonstrated that the sulphydryl groups in question are critical to the normal function of the protein or enzymes. Most likely, these -SH are associated with thiols at the substrate binding (active site) sites of the enzymes. Interestingly, pharmacological doses of organodiselenides 3mg/kg bw for the study on diabetes do not present any observed toxicity.O presente estudo quis comparar os potenciais antioxidants in vitro de organoselênios novamente sintetizados, diseleneto dicolesterol e diseleneto de difenila e suas possíveis interações com algumas enzimas contendo tióis em diferentes tecidos de mamíferos. Além disso, o potencial de DPDS como agente antioxidante e antihiperglicêmico, e sua interação com proteínas contendo tióis em vários tecidos e órgãos de mamíferos (hepático, renal, esplênico e, mais importante, tecido cerebral) foram avaliados em modelos animais de streptozotocina induzindo diabetes em ratos. Os resultados in vitro mostram que DPDS exibiu uma maior atividade mimética da glutationa peroxidase bem como aumentada habilidade para oxidar mono e di-tióis que DPDS. Além disso, enquanto o DPDS inibiu substâncias reativas ao ácido tiobarbitpúrico (TBARS) e formação de proteínas carboniladas em tecidos cerebral e hepático, induzidas por ferro(II) ou SNP, DCDS exibiu um efeito pró-oxidante em cérebro e tecido hepático quando ferro(II) serviu como próoxidante, porém, quando TBARS foi induzido por SNP, DCDS modificou a formação de TBARS tanto em tecido cerebral como hepático. Também, as atividades da deltaaminolevulinato desidratase (ð-ALA-D) cerebral e hepática e Na+/K+-ATPase cerebral foram significativamente inibidas por DPDS e somente fracamente inibida por DCDS. Mas estudos revelam que a inibição causada por organodiselenetos (neste caso, DPDS) na atividade da Na+/K+-ATPase envolve a modificação de grupos tiólicos ligados ao sítio ATP da enzima. Similarmente, diferentes isoformas da lactato desidrogenase (LDH) foram significativamente inibidas por DPDS e DCDS in vitro. nós observamos que a inibição in vitro de diferentes isoformas da LDH por DCDS e DPDS envolve a modificação de grupos SH no sítio ligante NAD+ da enzima. a administração oral de DPDS dissolvido em óleo soya administrado a ratos albino machos com diabetes induzida por streptozotocina mostrou que houve uma redução significante nos níveis de glicose sanguínea acompanhada por uma marcada redução nas proteínas glicadas em ratos diabéticos induzidos com streptozitocina tratados com DPDS em relação aos não diabéticos. Além disso, DPDS melhorou significativamente os níveis de vitamina C e GSH (fígado, rim e baço), que foram diminuídos em ratos tratados com streptozotocina. Similarmente, tratamento com DPDS marcadamente aboliu os níveis elevados de TBARS que foram observados no grupo diabético. Finalmente, a inibição da ð-ALA-D e algumas isoformas da LDH causada pela hiperglicemia foram prevenidas por DPDS. Nós também observamos que STZ provocou uma significante diminuição no status antioxidante do cérebro e atividade da Na+/K+- ATPase, mas a atividade da acetilcolinesterase e captação e liberação de glutamato não foram alteradas. Porém, DPDS marcadamente restaurou o desequilíbrio observado no status antioxidante e bomba de sódio. Finalmente, nós concluímos que organoselenetos são remédios antioxidantes promissores no manejo de doenças causadas por estresse oxidativo. Porém, sua toxicidade envolve uma interação com tióis em proteínas e este estudo demonstrou que os grupos sulfidril em questão são críticos para a função normal de enzimas e proteínas. Estes SH são associados com tióis dos sítios de ligação do substrato (sítio ativo) de enzimas. interessantemente, doses farmacológicas de organodiselenetos (3mg/kg para o estudo de diabetes) não apresentou nenhuma toxicidade observada.application/pdfporUniversidade Federal de Santa MariaPrograma de Pós-Graduação em Ciências Biológicas: Bioquímica ToxicológicaUFSMBRBioquímicaBioquímicaFarmacologiaAntioxidantesDiabeteEnzimasCNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICAInteraction of organodiselenides with sulphydryl groups at the active sites of some thiol containing proteins - in vitro and in vivo mechanistic studies in mammalian models of diabetesInteraction of organodiselenides with sulphydryl groups at the active sites of some thiol containing proteins - in vitro and in vivo mechanistic studies in mammalian models of diabetesinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisRocha, João Batista Teixeira dahttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4782281H2Soares, Félix Alexandre Antuneshttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4769181A8Vieira, Leda Querciahttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4787022E7Bem, Andreza Fabro dehttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4767637D2Gonçalves, Carlos Alberto Saraivahttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4785436Y4http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4138257Z0Kade, Ige Joseph20080000000240050030050030030030027186f63-94dd-4f0f-8181-7ce1b0835009036004a2-fde3-4640-9a95-ed0ecb9ad88e97b2e117-480f-4e1c-a62b-9dab79cb9fd3a73aa1b0-8825-410c-8c4f-803db2b31829345b9516-6fba-4add-8d9a-ef8e90d61d012d6af737-12e6-4b93-8051-b65ea70d6667info:eu-repo/semantics/openAccessreponame:Manancial - Repositório Digital da UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSMORIGINALIGEJOSEPHKADE.pdfapplication/pdf2223631http://repositorio.ufsm.br/bitstream/1/4398/1/IGEJOSEPHKADE.pdf3dc7b659474b4bb7e71f6ee1812e3ee2MD51TEXTIGEJOSEPHKADE.pdf.txtIGEJOSEPHKADE.pdf.txtExtracted texttext/plain208205http://repositorio.ufsm.br/bitstream/1/4398/2/IGEJOSEPHKADE.pdf.txt286c94ba6597fdd557a0a94a2ecb8d4cMD52THUMBNAILIGEJOSEPHKADE.pdf.jpgIGEJOSEPHKADE.pdf.jpgIM Thumbnailimage/jpeg4894http://repositorio.ufsm.br/bitstream/1/4398/3/IGEJOSEPHKADE.pdf.jpg300ecb865ccd633cd3848dc3eea8fbcdMD531/43982017-07-25 11:06:33.697oai:repositorio.ufsm.br:1/4398Repositório Institucionalhttp://repositorio.ufsm.br/PUBhttp://repositorio.ufsm.br/oai/requestopendoar:39132017-07-25T14:06:33Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM)false |
dc.title.por.fl_str_mv |
Interaction of organodiselenides with sulphydryl groups at the active sites of some thiol containing proteins - in vitro and in vivo mechanistic studies in mammalian models of diabetes |
dc.title.alternative.eng.fl_str_mv |
Interaction of organodiselenides with sulphydryl groups at the active sites of some thiol containing proteins - in vitro and in vivo mechanistic studies in mammalian models of diabetes |
title |
Interaction of organodiselenides with sulphydryl groups at the active sites of some thiol containing proteins - in vitro and in vivo mechanistic studies in mammalian models of diabetes |
spellingShingle |
Interaction of organodiselenides with sulphydryl groups at the active sites of some thiol containing proteins - in vitro and in vivo mechanistic studies in mammalian models of diabetes Kade, Ige Joseph Bioquímica Farmacologia Antioxidantes Diabete Enzimas CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
title_short |
Interaction of organodiselenides with sulphydryl groups at the active sites of some thiol containing proteins - in vitro and in vivo mechanistic studies in mammalian models of diabetes |
title_full |
Interaction of organodiselenides with sulphydryl groups at the active sites of some thiol containing proteins - in vitro and in vivo mechanistic studies in mammalian models of diabetes |
title_fullStr |
Interaction of organodiselenides with sulphydryl groups at the active sites of some thiol containing proteins - in vitro and in vivo mechanistic studies in mammalian models of diabetes |
title_full_unstemmed |
Interaction of organodiselenides with sulphydryl groups at the active sites of some thiol containing proteins - in vitro and in vivo mechanistic studies in mammalian models of diabetes |
title_sort |
Interaction of organodiselenides with sulphydryl groups at the active sites of some thiol containing proteins - in vitro and in vivo mechanistic studies in mammalian models of diabetes |
author |
Kade, Ige Joseph |
author_facet |
Kade, Ige Joseph |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Rocha, João Batista Teixeira da |
dc.contributor.advisor1Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4782281H2 |
dc.contributor.referee1.fl_str_mv |
Soares, Félix Alexandre Antunes |
dc.contributor.referee1Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4769181A8 |
dc.contributor.referee2.fl_str_mv |
Vieira, Leda Quercia |
dc.contributor.referee2Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4787022E7 |
dc.contributor.referee3.fl_str_mv |
Bem, Andreza Fabro de |
dc.contributor.referee3Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4767637D2 |
dc.contributor.referee4.fl_str_mv |
Gonçalves, Carlos Alberto Saraiva |
dc.contributor.referee4Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4785436Y4 |
dc.contributor.authorLattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4138257Z0 |
dc.contributor.author.fl_str_mv |
Kade, Ige Joseph |
contributor_str_mv |
Rocha, João Batista Teixeira da Soares, Félix Alexandre Antunes Vieira, Leda Quercia Bem, Andreza Fabro de Gonçalves, Carlos Alberto Saraiva |
dc.subject.por.fl_str_mv |
Bioquímica Farmacologia Antioxidantes Diabete Enzimas |
topic |
Bioquímica Farmacologia Antioxidantes Diabete Enzimas CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
description |
The present study sought to compare the in vitro antioxidant potentials of a newly synthesized organodiselenide, dicholesteroyl diselenide (DCDS) and diphenyl diselenide (DPDS) and their possible interactions with some thiol containing enzymes in different tissues from mammalian system. In addition, the potency of DPDS as antioxidant and antihyperglycaemic agents, and its interaction with thiol containing proteins in various mammalian tissues and organs (hepatic, renal and spleenic and more importantly cerebral tissues) were evaluated in animal models of streptozotocin induced diabetic rats. The in vitro results show that DPDS exhibited a higher glutathione-peroxidase mimetic activity as well as increased ability to oxidize both mono- and di- thiols than DCDS. In addition, while DPDS inhibited thiobarbituric acid reactive substances (TBARS) and protein carbonyls formations in both cerebral and hepatic tissues, induced by either iron (II) or SNP, DCDS exhibited a prooxidant effect in both cerebral and hepatic tissues when iron (II) serves as the prooxidant, However, when TBARS was induced by SNP, DCDS slightly modify TBARS formation in both hepatic and cerebral tissues. Also the activities of cerebral and hepatic delata aminolevulinic acid dehydratase (ð-ALA-D), cerebral Na+/K+- ATPase were significantly inhibited by DPDS and only weakly inhibited by the DCDS. Further studies reveal that the inhibition caused by organodiselenides (in this case, DPDS) on Na+/K+-ATPase activity likely involves the modification of the thiol groups at the ATP binding site of the enzyme. Similarly, different isoforms of lactate dehydrogenase (LDH) were significantly inhibited by both DPDS and DCDS in vitro. Likewise, we observed that the in vitro inhibition of different isoforms of lactate dehydrogenase by DCDS and DPDS likely involves the modification of the -SH groups at the NAD+ binding site of the enzyme. Oral administration of DPDS dissolved in soya bean oil administered to streptozotocin induced diabetes in male albino rats shows that there was significant reduction in blood glucose levels accompanied by a marked reduction of glycated proteins in streptozotocin induced diabetic rats treated with DPDS in relation to untreated streptozotocin induced diabetic. In addition, DPDS was able to significantly ameliorate the levels of Vitamin C and GSH (liver, kidney and spleen), which were decreased in streptozotocin treated rats. Similarly, treatment with DPDS was able to markedly abolish the increase levels of TBARS that were observed in STZ diabetes group. Finally, the inhibition of both ð-ALA-D and some isoforms of LDH caused by hyperglycaemia were prevented by DPDS. We also observed that although streptozotocin evoke a significant diminution on brain s antioxidant status and activity of Na+/K+-ATPase, but the activity of acetylcholineesterase and glutamate uptake and release were not altered. However, DPDS was able to markedly restore the observed imbalance in antioxidant status and sodium pump. Finally, we conclude that organodiselenides are promising antioxidant remedy in the management of diseases caused by oxidative stress. However, their toxicity involves an interaction with thiols on proteins and this study has further demonstrated that the sulphydryl groups in question are critical to the normal function of the protein or enzymes. Most likely, these -SH are associated with thiols at the substrate binding (active site) sites of the enzymes. Interestingly, pharmacological doses of organodiselenides 3mg/kg bw for the study on diabetes do not present any observed toxicity. |
publishDate |
2008 |
dc.date.issued.fl_str_mv |
2008-04-02 |
dc.date.accessioned.fl_str_mv |
2017-04-24 |
dc.date.available.fl_str_mv |
2017-04-24 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
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doctoralThesis |
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publishedVersion |
dc.identifier.citation.fl_str_mv |
KADE, Ige Joseph. Interaction of organodiselenides with sulphydryl groups at the active sites of some thiol containing proteins - in vitro and in vivo mechanistic studies in mammalian models of diabetes. 2008. 180 f. Tese (Doutorado em Bioquímica) - Universidade Federal de Santa Maria, Santa Maria, 2008. |
dc.identifier.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/4398 |
identifier_str_mv |
KADE, Ige Joseph. Interaction of organodiselenides with sulphydryl groups at the active sites of some thiol containing proteins - in vitro and in vivo mechanistic studies in mammalian models of diabetes. 2008. 180 f. Tese (Doutorado em Bioquímica) - Universidade Federal de Santa Maria, Santa Maria, 2008. |
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http://repositorio.ufsm.br/handle/1/4398 |
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openAccess |
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Universidade Federal de Santa Maria |
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