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FEBS Letters Aug 2012Increasing evidence indicates that accumulation of misfolded proteins in the form of oligomers, protofibrils or amyloid fibrils, and their consequences in triggering... (Review)
Review
Increasing evidence indicates that accumulation of misfolded proteins in the form of oligomers, protofibrils or amyloid fibrils, and their consequences in triggering intracellular signaling cascades with toxic consequences represent unifying events in many of slowly progressive neurodegenerative disorders. Studies with small compounds or molecules, known to recognize and disrupt amyloidogenic structures, have proven efficient in promoting clearance of protein aggregates in experimental models of systemic and localized forms of amyloidoses. Doxycycline and EGCG were efficient in removing aggregates in pre-clinical studies in a transgenic mouse model for transthyretin (TTR) systemic amyloidosis and represent an opportunity to address mechanisms and key players in deposit removal. Extracellular chaperones, such as clusterin and metalloproteinases play an important role in this process.
Topics: Amyloidosis; Animals; Doxycycline; Mice; Mice, Transgenic; Prealbumin; Protein Folding
PubMed: 22819819
DOI: 10.1016/j.febslet.2012.07.029 -
Singapore Medical Journal Jan 2023
Topics: Humans; Cardiomyopathies; Prealbumin
PubMed: 36722520
DOI: 10.4103/singaporemedj.SMJ-2021-300 -
European Journal of Heart Failure Aug 2022
Topics: Amyloid Neuropathies, Familial; Cardiomyopathies; Embolism; Heart Failure; Humans; Prealbumin
PubMed: 35790492
DOI: 10.1002/ejhf.2610 -
JACC. Heart Failure May 2021
Topics: Amyloid Neuropathies, Familial; Cardiomyopathies; Heart Failure; Humans; Prealbumin
PubMed: 33926733
DOI: 10.1016/j.jchf.2020.12.016 -
Redox Biology Oct 2022Human transthyretin (TTR) is a tetrameric protein transporting thyroid hormones and retinol. TTR is a neuroprotective factor and sensor of oxidative stress which...
Human transthyretin (TTR) is a tetrameric protein transporting thyroid hormones and retinol. TTR is a neuroprotective factor and sensor of oxidative stress which stability is diminished due to mutations and aging, leading to amyloid deposition. Adverse environmental conditions, such as redox and metal ion imbalances, induce destabilization of the TTR structure. We have previously shown that the stability of TTR was disturbed by Ca and other factors, including DTT, and led to the formation of an intrinsic fluorophore(s) emitting blue light, termed deep blue autofluorescence (dbAF). Here, we show that the redox state of TTR affects the formation dynamics and properties of dbAF. Free thiols lead to highly unstable subpopulations of TTR and the frequent ocurrence of dbAF. Oxidative conditions counteracted the destabilizing effects of free thiols to some extent. However, strong oxidative conditions led to modifications of TTR, which altered the stability of TTR and resulted in unique dbAF spectra. Riboflavin and/or riboflavin photoproducts bound to TTR and crosslinked TTR subunits. Riboflavin-sensitized photooxidation increased TTR unfolding, while photooxidation, either in the absence or presence of riboflavin, increased proteolysis and resulted in multiple oxidative modifications and dityrosine formation in TTR molecules. Therefore, oxidation can switch the role of TTR from a protective to pathogenic factor.
Topics: Amyloid; Humans; Oxidation-Reduction; Prealbumin; Riboflavin; Sulfhydryl Compounds; Vitamin A
PubMed: 35987087
DOI: 10.1016/j.redox.2022.102434 -
Journal of Neuromuscular Diseases 2019Systemic amyloidosis can be hereditary or acquired with autosomal dominant mutations in the transthyretin gene (TTR) being the most common cause of hereditary... (Review)
Review
Systemic amyloidosis can be hereditary or acquired with autosomal dominant mutations in the transthyretin gene (TTR) being the most common cause of hereditary amyloidosis. ATTRm amyloidosis is a multi-system disorder with cardiovascular, peripheral and autonomic nerve involvement that can be difficult to diagnose due to phenotypic heterogeneity. This review will focus on the neuropathic manifestations of ATTRm, the genotype-phenotype variability, the diagnostic approach and the recent therapeutic advances in this disabling condition.
Topics: Amyloidosis; Genetic Association Studies; Humans; Mutation; Prealbumin
PubMed: 30829617
DOI: 10.3233/JND-180371 -
IUBMB Life Jun 2010Transthyretin (TTR) is a plasma and cerebrospinal fluid protein mainly recognized as the transporter of thyroxine (T(4)) and retinol. Mutated TTR leads to familial... (Review)
Review
Transthyretin (TTR) is a plasma and cerebrospinal fluid protein mainly recognized as the transporter of thyroxine (T(4)) and retinol. Mutated TTR leads to familial amyloid polyneuropathy, a neurodegenerative disorder characterized by TTR amyloid deposition particularly in peripheral nerves. Beside its transport activities, TTR is a cryptic protease and participates in the biology of the nervous system. Several studies have been directed at finding new ligands of TTR to further explore the biology of the protein. From the identified ligands, some were in fact TTR protease substrates. In this review, we will discuss the existent information concerning TTR ligands/substrates.
Topics: Amyloid Neuropathies, Familial; Humans; Ligands; Mutation; Prealbumin
PubMed: 20503435
DOI: 10.1002/iub.340 -
Journal of the American Heart... Aug 2023Background Transthyretin cardiac amyloidosis (ATTR-CM), found in 6% to 15% of cohorts with heart failure with preserved ejection fraction, has long been considered a... (Comparative Study)
Comparative Study
Background Transthyretin cardiac amyloidosis (ATTR-CM), found in 6% to 15% of cohorts with heart failure with preserved ejection fraction, has long been considered a rare disease with poor prognosis. New treatments have made it one of the few directly treatable causes of heart failure. This study sought to determine whether patients with ATTR-CM, particularly those treated with tafamidis, have comparable survival to an unselected cohort with heart failure with preserved ejection fraction. Methods and Results We compared the clinical characteristics and outcomes between a single-center cohort of patients with ATTR-CM (n=114) and patients with heart failure with preserved ejection fraction enrolled in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial (n=1761, excluding Russia and Georgia). The primary outcome was a composite of all-cause death, heart failure hospitalization, myocardial infarction, and stroke. Subgroup analysis of patients with ATTR-CM treated with tafamidis was also performed. Patients with ATTR-CM had higher rates of the primary composite outcome compared with patients enrolled in the TOPCAT trial (hazard ratio [HR], 1.44 [95% CI, 1.09-1.91]; =0.01), with similar rates of all-cause death (HR, 1.43 [95% CI, 0.99-2.06]; =0.06) but higher rates of heart failure hospitalizations (HR, 1.62 [95% CI, 1.15-2.28]; <0.01). Compared with patients enrolled in TOPCAT, patients with ATTR-CM treated with tafamidis had similar rates of the primary composite outcome (HR, 1.30 [95% CI, 0.86-1.96]; =0.21) and all-cause death (HR, 1.10 [95% CI, 0.57-2.14]; =0.78) but higher rates of heart failure hospitalizations (HR, 1.96 [95% CI, 1.27-3.02]; <0.01). Conclusions Patients with ATTR-CM treated with tafamidis have similar rates of all-cause death compared with patients with heart failure with preserved ejection fraction, with higher rates of heart failure hospitalizations.
Topics: Humans; Amyloidosis; Cardiomyopathies; Heart Failure; Prealbumin; Spironolactone; Stroke Volume; Treatment Outcome
PubMed: 37522238
DOI: 10.1161/JAHA.123.029705 -
The Journal of International Medical... Aug 2023To explore the association between the controlling nutritional status (CONUT) score and disease activity in patients with ulcerative colitis (UC).
OBJECTIVE
To explore the association between the controlling nutritional status (CONUT) score and disease activity in patients with ulcerative colitis (UC).
METHODS
This retrospective study enrolled patients with UC. Demographic, clinical and laboratory data were collected and compared. The CONUT score was obtained for each patient. The association between the CONUT score and laboratory parameters was analysed and the ability of the score to assess disease activity was evaluated.
RESULTS
A total of 182 patients with UC were enrolled. Patients with active disease showed significantly increased inflammatory biomarkers and decreased nutritional biomarkers compared with patients in remission. Malnourished individuals had significantly elevated inflammatory biomarkers and significantly reduced haemoglobin, prealbumin and retinol-binding protein. The CONUT score was inversely correlated with haemoglobin, prealbumin, retinol-binding protein and was positively correlated with faecal calprotectin, C-reactive protein, erythrocyte sedimentation rate, neutrophil/lymphocyte ratio and platelet/lymphocyte ratio. The area under the receiver operating characteristic curve was 0.655 (95% confidence interval, 0.557-0.752). The optimal cut-off value was 1.5 points, with a sensitivity of 75.7% and a specificity of 50.0%.
CONCLUSION
The CONUT score may evaluate the inflammatory response and nutritional status of UC patients, so it could be a potential biomarker to assess disease activity in UC.
Topics: Humans; Nutritional Status; Colitis, Ulcerative; Retrospective Studies; Prealbumin; Biomarkers; Retinol-Binding Proteins
PubMed: 37548189
DOI: 10.1177/03000605231184046 -
Biological & Pharmaceutical Bulletin 2018Transthyretin (TTR) is a tetrameric beta-sheet-rich protein that is important in the plasma transport of thyroxine and retinol. Mutations in the TTR gene cause TTR...
Transthyretin (TTR) is a tetrameric beta-sheet-rich protein that is important in the plasma transport of thyroxine and retinol. Mutations in the TTR gene cause TTR tetramer protein to dissociate to monomer, which is the rate-limiting step in familial amyloid polyneuropathy. Amyloidogenicity of individual TTR variants depends on the types of mutation that induce significant changes in biophysical, biochemical and/or biological properties. G101S TTR variant was previously identified in a Japanese male without amyloidotic symptom, and was considered as a non-amyloidogenic TTR variant. However, little is known about G101S TTR. Here, we found slight but possibly important biophysical differences between wild-type (WT) and G101S TTR. G101S TTR had slower rate of tetramer dissociation and lower propensity for amyloid fibril formation, especially at mild low pH (4.2 and 4.5), and was likely to have strong hydrophobic interaction among TTR monomers, suggesting relatively higher stability of G101S TTR compared with WT TTR. Cycloheximide (CHX)-based assay in HEK293 cells revealed that intracellular G101S TTR expression level was lower, but extracellular expression was higher than WT TTR, implying enhanced secretion efficiency of G101S TTR protein compared with WT TTR. Moreover, we found that STT3B-dependent posttranslational N-glycosylation at N98 residue occurred in G101S TTR but not in other TTR variants, possibly due to amino acid alterations that increase N-glycosylation preference or accelerate rigid structure formation susceptible to N-glycosylation. Taken together, our study characterizes G101S TTR as a stable and N-glycosylable TTR, which may be linked to its non-amyloidogenic characteristic.
Topics: Amyloid; Amyloid Neuropathies, Familial; Glycosylation; HEK293 Cells; HeLa Cells; Hexosyltransferases; Humans; Membrane Proteins; Prealbumin
PubMed: 29607936
DOI: 10.1248/bpb.b17-01021