Autor(es):
MACEDO, B. 
; BATISTA, A.R. ; DO AMARAL, J.B. ; SARAIVA, M.J.
Data: 2007
Identificador Persistente: http://hdl.handle.net/10400.16/733
Origem: Repositório Científico do Centro Hospitalar do Porto
Detalhes do Documento
Biomarkers in the assessment of therapies for familial amyloidotic polyneuropathy
Descrição
Mol Med. 2007 Nov-Dec;13(11-12):584-91. Biomarkers in the assessment of therapies for familial amyloidotic polyneuropathy. Macedo B, Batista AR, do Amaral JB, Saraiva MJ. SourceMolecular Neurobiology, Instituto de Biologia Molecular e Celular, Porto, Portugal. Abstract The identification of specific biomarkers provides opportunities to develop early diagnostic parameters, monitor disease progression, and test drug efficiency in clinical trials. We previously demonstrated that in familial amyloidotic polyneuropathy (FAP) related to the abnormal extracellular tissue deposition of mutant transthyretin (TTR), inflammatory and apoptotic pathways are triggered in the presymptomatic stages of the disease, when nonfibrillar TTR deposits are present. In the present work, to better define biomarkers for future assessment of prophylactic and therapeutic drugs in the treatment of FAP, we extended the search for oxidative stress and apoptotic biomarkers to clinical samples and animal models presenting nonfibrillar and fibrillar TTR. We found that lipid peroxidation measured by hydroxynonenal, oxidative DNA damage measured by 8-hydroxy-2'-deoxyguanosine, and cellular redox homeostasis measured by glutaredoxin 1 were consistently increased in biopsy specimens from FAP patients and in tissues from transgenic mouse models presenting nonfibrillar TTR deposition. Death-receptor Fas, caspase-8, and Bax were also found to be increased, indicative of the involvement of death receptors in the observed apoptosis process. Removal of TTR deposition by an immunization protocol resulted in significant decreases of the selected markers we describe, corroborating the relationship between TTR deposition, oxidative stress, and apoptosis. Taken together, our results provide a robust biomarker profile for initial experimental animal studies and clinical trials to assess the application of the selected markers in therapies aimed at removal and/or inhibition of TTR polymerization. PMID: 17932549 [PubMed - indexed for MEDLINE] PMCID: PMC2017105Free PMC Article Images from this publication.See all images (5) Free text Figure 1 (A) Top panels: Representative 4-hydroxy-2-nonenal (HNE) staining of salivary glands from healthy individuals (left, n = 6) and FAP patients (right, n = 6). Middle panels: Representative HNE staining in stomach tissue of hTTR Met30 mice without TTR deposition (−/−, left, n = 5) and with TTR deposition (+/−, right, n = 5) ... Biomarkers in the Assessment of Therapies for Familial Amyloidotic Polyneuropathy Mol Med. ;13(11-12):584-591.Figure 2 Top 2 panels: Representative Grx1 and Trx1 staining of salivary glands from healthy individuals (left, n = 6) and FAP patients (right, n = 6); nuclear staining is indicated by the arrow. Middle panel: Representative Grx1 staining in stomach tissue of hTTR Met30/(+/−)hsf mice without TTR deposition (−/−, left, n = 5) and wi... Biomarkers in the Assessment of Therapies for Familial Amyloidotic Polyneuropathy Mol Med. ;13(11-12):584-591.Figure 3 Representative FasL, Fas, active caspase-8, active caspase-3, and Bax staining of salivary glands from healthy individuals (left, n = 6) and FAP patients (right, n = 6). 20× magnification. Quantitation of IHC images of FasL, Fas, active caspase-8, active caspase-3, and Bax staining are represented a... Biomarkers in the Assessment of Therapies for Familial Amyloidotic Polyneuropathy Mol Med. ;13(11-12):584-591.Figure 4 Representative Fas (upper panels) and Bax (bottom panels) staining in stomach and DRG tissue of TTR transgenic mice. Upper panels: Stomach tissue of hTTR Met30 mice without TTR deposition (−/−, left, n = 5) and with TTR deposition (+/−, right, n = 5), of hTTR Met30/(+/−)HSF1-KO, without TTR deposition (−/−, left, n = 6) and with TTR de... Biomarkers in the Assessment of Therapies for Familial Amyloidotic Polyneuropathy Mol Med. ;13(11-12):584-591.Figure 5 Representative immunohistochemistry of TTR, BiP, Fas, Bax, 8-OHdG and Grx1 in stomach tissue of TTR Y78F immunized transgenic mice 9–10 months old (right; n = 6) and nonimmunized age-matched controls (left; n = 6). 20× magnification; Quantification of IHC images of TTR, BiP, Fas, Bax, 8-OHdG, and Gr... Biomarkers in the Assessment of Therapies for Familial Amyloidotic Polyneuropathy Mol Med. ;13(11-12):584-591.Publication Types, MeSH Terms, SubstancesPublication Types Research Support, Non-U.S. Gov't MeSH Terms Amyloidosis, Familial/metabolism Amyloidosis, Familial/therapy* Animals Animals, Genetically Modified Apoptosis Biological Markers/metabolism* DNA Damage Immunohistochemistry Mice Oxidative Stress Polyneuropathies/metabolism Polyneuropathies/therapy* Prealbumin/metabolism Substances Biological Markers Prealbumin
Mol Med. 2007 Nov-Dec;13(11-12):584-91. Biomarkers in the assessment of therapies for familial amyloidotic polyneuropathy. Macedo B, Batista AR, do Amaral JB, Saraiva MJ. SourceMolecular Neurobiology, Instituto de Biologia Molecular e Celular, Porto, Portugal. Abstract The identification of specific biomarkers provides opportunities to develop early diagnostic parameters, monitor disease progression, and test drug efficiency in clinical trials. We previously demonstrated that in familial amyloidotic polyneuropathy (FAP) related to the abnormal extracellular tissue deposition of mutant transthyretin (TTR), inflammatory and apoptotic pathways are triggered in the presymptomatic stages of the disease, when nonfibrillar TTR deposits are present. In the present work, to better define biomarkers for future assessment of prophylactic and therapeutic drugs in the treatment of FAP, we extended the search for oxidative stress and apoptotic biomarkers to clinical samples and animal models presenting nonfibrillar and fibrillar TTR. We found that lipid peroxidation measured by hydroxynonenal, oxidative DNA damage measured by 8-hydroxy-2'-deoxyguanosine, and cellular redox homeostasis measured by glutaredoxin 1 were consistently increased in biopsy specimens from FAP patients and in tissues from transgenic mouse models presenting nonfibrillar TTR deposition. Death-receptor Fas, caspase-8, and Bax were also found to be increased, indicative of the involvement of death receptors in the observed apoptosis process. Removal of TTR deposition by an immunization protocol resulted in significant decreases of the selected markers we describe, corroborating the relationship between TTR deposition, oxidative stress, and apoptosis. Taken together, our results provide a robust biomarker profile for initial experimental animal studies and clinical trials to assess the application of the selected markers in therapies aimed at removal and/or inhibition of TTR polymerization. PMID: 17932549 [PubMed - indexed for MEDLINE] PMCID: PMC2017105Free PMC Article Images from this publication.See all images (5) Free text Figure 1 (A) Top panels: Representative 4-hydroxy-2-nonenal (HNE) staining of salivary glands from healthy individuals (left, n = 6) and FAP patients (right, n = 6). Middle panels: Representative HNE staining in stomach tissue of hTTR Met30 mice without TTR deposition (−/−, left, n = 5) and with TTR deposition (+/−, right, n = 5) ... Biomarkers in the Assessment of Therapies for Familial Amyloidotic Polyneuropathy Mol Med. ;13(11-12):584-591.Figure 2 Top 2 panels: Representative Grx1 and Trx1 staining of salivary glands from healthy individuals (left, n = 6) and FAP patients (right, n = 6); nuclear staining is indicated by the arrow. Middle panel: Representative Grx1 staining in stomach tissue of hTTR Met30/(+/−)hsf mice without TTR deposition (−/−, left, n = 5) and wi... Biomarkers in the Assessment of Therapies for Familial Amyloidotic Polyneuropathy Mol Med. ;13(11-12):584-591.Figure 3 Representative FasL, Fas, active caspase-8, active caspase-3, and Bax staining of salivary glands from healthy individuals (left, n = 6) and FAP patients (right, n = 6). 20× magnification. Quantitation of IHC images of FasL, Fas, active caspase-8, active caspase-3, and Bax staining are represented a... Biomarkers in the Assessment of Therapies for Familial Amyloidotic Polyneuropathy Mol Med. ;13(11-12):584-591.Figure 4 Representative Fas (upper panels) and Bax (bottom panels) staining in stomach and DRG tissue of TTR transgenic mice. Upper panels: Stomach tissue of hTTR Met30 mice without TTR deposition (−/−, left, n = 5) and with TTR deposition (+/−, right, n = 5), of hTTR Met30/(+/−)HSF1-KO, without TTR deposition (−/−, left, n = 6) and with TTR de... Biomarkers in the Assessment of Therapies for Familial Amyloidotic Polyneuropathy Mol Med. ;13(11-12):584-591.Figure 5 Representative immunohistochemistry of TTR, BiP, Fas, Bax, 8-OHdG and Grx1 in stomach tissue of TTR Y78F immunized transgenic mice 9–10 months old (right; n = 6) and nonimmunized age-matched controls (left; n = 6). 20× magnification; Quantification of IHC images of TTR, BiP, Fas, Bax, 8-OHdG, and Gr... Biomarkers in the Assessment of Therapies for Familial Amyloidotic Polyneuropathy Mol Med. ;13(11-12):584-591.Publication Types, MeSH Terms, SubstancesPublication Types Research Support, Non-U.S. Gov't MeSH Terms Amyloidosis, Familial/metabolism Amyloidosis, Familial/therapy* Animals Animals, Genetically Modified Apoptosis Biological Markers/metabolism* DNA Damage Immunohistochemistry Mice Oxidative Stress Polyneuropathies/metabolism Polyneuropathies/therapy* Prealbumin/metabolism Substances Biological Markers Prealbumin
Tipo de Documento
Artigo
Idioma Inglês
Idioma Inglês
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