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1.
Int J Mol Sci ; 22(19)2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34639037

RESUMO

Amyloids are self-assembled protein aggregates that take cross-ß fibrillar morphology. Although some amyloid proteins are best known for their association with Alzheimer's and Parkinson's disease, many other amyloids are found across diverse organisms, from bacteria to humans, and they play vital functional roles. The rigidity, chemical stability, high aspect ratio, and sequence programmability of amyloid fibrils have made them attractive candidates for functional materials with applications in environmental sciences, material engineering, and translational medicines. This review focuses on recent advances in fabricating various types of macroscopic functional amyloid materials. We discuss different design strategies for the fabrication of amyloid hydrogels, high-strength materials, composite materials, responsive materials, extracellular matrix mimics, conductive materials, and catalytic materials.


Assuntos
Amiloide/química , Amiloide/metabolismo , Proteínas Amiloidogênicas/metabolismo , Aminoácidos/química , Amiloide/ultraestrutura , Proteínas Amiloidogênicas/química , Amiloidose/etiologia , Amiloidose/metabolismo , Amiloidose/patologia , Matriz Extracelular/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Conformação Proteica , Relação Estrutura-Atividade
2.
Medicina (Kaunas) ; 57(10)2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34684086

RESUMO

Familial Mediterranean fever (FMF) is a genetic autoinflammatory disease with autosomal recessive transmission, characterized by periodic fever attacks with self-limited serositis. Secondary amyloidosis due to amyloid A renal deposition represents the most fearsome complication in up to 8.6% of patients. Amyloidosis A typically reveals a nephrotic syndrome with a rapid progression to end-stage kidney disease still. It may also involve the cardiovascular system, the gastrointestinal tract and the central nervous system. Other glomerulonephritis may equally affect FMF patients, including vasculitis such as IgA vasculitis and polyarteritis nodosa. A differential diagnosis among different primary and secondary causes of nephrotic syndrome is mandatory to determine the right therapeutic choice for the patients. Early detection of microalbuminuria is the first signal of kidney impairment in FMF, but new markers such as Neutrophil Gelatinase-Associated Lipocalin (NGAL) may radically change renal outcomes. Serum amyloid A protein (SAA) is currently considered a reliable indicator of subclinical inflammation and compliance to therapy. According to new evidence, SAA may also have an active pathogenic role in the regulation of NALP3 inflammasome activity as well as being a predictor of the clinical course of AA amyloidosis. Beyond colchicine, new monoclonal antibodies such as IL-1 inhibitors anakinra and canakinumab, and anti-IL-6 tocilizumab may represent a key in optimizing FMF treatment and prevention or control of AA amyloidosis.


Assuntos
Amiloidose , Febre Familiar do Mediterrâneo , Nefropatias , Amiloidose/diagnóstico , Amiloidose/tratamento farmacológico , Amiloidose/etiologia , Colchicina/uso terapêutico , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Humanos , Rim
3.
Medicine (Baltimore) ; 100(32): e26843, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34397890

RESUMO

INTRODUCTION: Secondary amyloidosis is a rare complication of rheumatoid arthritis (RA) that is histologically characterized by the deposition of amyloid fibrils in target organs, such as the kidneys and gastrointestinal tract. Controlling the inflammatory response is essential to prevent organ dysfunction in amyloid A (AA) amyloidosis secondary to RA, and no clear treatment strategy exists. PATIENT CONCERNS AND DIAGNOSIS: A 66-year-old woman with RA, who had been treated with disease-modifying anti-rheumatic drugs for 1 year, presented with recurrent abdominal pain and prolonged diarrhea. Endoscopy showed chronic inflammation, and colon tissue histology confirmed AA amyloidosis. INTERVENTIONS AND OUTCOMES: After tocilizumab therapy was begun, her diarrhea and abdominal pain subsided, and articular symptoms improved. Biologic drugs for RA have been used in patients with secondary AA amyloidosis, including tumor necrosis factor and Janus kinase inhibitors, interleukin 6 blockers, and a T cell modulator. Here, we systematically review existing case reports and compare the outcomes of RA-related AA amyloidosis after treatment with various drugs. CONCLUSION: The data indicate that biologic drugs like tocilizumab might be treatments of choice for AA amyloidosis secondary to RA.


Assuntos
Amiloidose , Anticorpos Monoclonais Humanizados/administração & dosagem , Artrite Reumatoide , Terapia Biológica/métodos , Colo , Proteína Amiloide A Sérica/análise , Dor Abdominal/diagnóstico , Dor Abdominal/etiologia , Idoso , Amiloidose/etiologia , Amiloidose/imunologia , Amiloidose/fisiopatologia , Amiloidose/terapia , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Produtos Biológicos/administração & dosagem , Colo/imunologia , Colo/patologia , Diarreia/diagnóstico , Diarreia/etiologia , Feminino , Humanos , Interleucina-6/antagonistas & inibidores , Resultado do Tratamento
4.
Cell Mol Life Sci ; 78(17-18): 6105-6117, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34297165

RESUMO

Transthyretin (TTR) is an extracellular protein mainly produced in the liver and choroid plexus, with a well-stablished role in the transport of thyroxin and retinol throughout the body and brain. TTR is prone to aggregation, as both wild-type and mutated forms of the protein can lead to the accumulation of amyloid deposits, resulting in a disease called TTR amyloidosis. Recently, novel activities for TTR in cell biology have emerged, ranging from neuronal health preservation in both central and peripheral nervous systems, to cellular fate determination, regulation of proliferation and metabolism. Here, we review the novel literature regarding TTR new cellular effects. We pinpoint TTR as major player on brain health and nerve biology, activities that might impact on nervous systems pathologies, and assign a new link between TTR and angiogenesis and cancer. We also explore the molecular mechanisms underlying TTR activities at the cellular level, and suggest that these might go beyond its most acknowledged carrier functions and include interaction with receptors and activation of intracellular signaling pathways.


Assuntos
Amiloidose/etiologia , Pré-Albumina/metabolismo , Amiloidose/metabolismo , Sistema Nervoso Central/metabolismo , Humanos , Neurônios/citologia , Neurônios/metabolismo , Pré-Albumina/química , Pré-Albumina/genética , Agregados Proteicos/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Tiroxina/química , Tiroxina/metabolismo , Vitamina A/química , Vitamina A/metabolismo
5.
J Biol Chem ; 297(2): 100936, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34217702

RESUMO

Recent studies have renewed the debate on infectious etiology in late-onset Alzheimer's disease. Bocharova et al. reported that abundant expression of human beta amyloid (Aß) in the mouse brain (5XFAD animals) failed to protect against acute herpes simplex virus type 1 infection relative to control mice. While this study does not confirm the antiviral actions of Aß, it neither supports nor disproves the hypothesis that infection with microbial pathogens is the major cause of Alzheimer's disease.


Assuntos
Doença de Alzheimer , Amiloidose , Herpes Simples , Doença de Alzheimer/etiologia , Peptídeos beta-Amiloides , Amiloidose/etiologia , Animais , Camundongos
6.
Spinal Cord Ser Cases ; 7(1): 40, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34035225

RESUMO

INTRODUCTION: Dialysis-related amyloidosis (DRA) can lead to various degenerative conditions but rarely involves the spine with a spinal cord compression. CASE REPORT: The authors describe a progressive tetraparesis (AIS-B) in a 57-year-old woman with upper cervical dialysis-related amyloidoma. Magnetic resonance imaging (MRI) showed a solid focal mass lesion at the C2-odotoid level with severe spinal cord compression. Computed tomography (CT) outlined multiple lytic lesions in C1 lateral masses and odontoid process. The patient underwent urgent surgical treatment. A posterior C1-C2 spinal cord decompression with biopsy followed by occipito-cervical posterior fixation was performed. Histopathological examination revealed amyloid deposits representing DRA. An immediately postoperative neurological improvement was observed. DISCUSSION: Even if the spinal amyloidoma is extremely rare, this condition has to be suspected in a long-term hemodialysis patient suffering from progressive neurological deficits. Differential diagnosis is mandatory between infections, rheumatologic and neoplastic lesions. Imaging evaluation with CT and MRI is recommended in order to assess the characteristics of the pathological mass, the extension of lytic lesions and the entity of neurological compression. Surgical treatment is mandatory if clinical evidence of root or spinal cord compression is present.


Assuntos
Amiloidose , Processo Odontoide , Compressão da Medula Espinal , Amiloidose/diagnóstico , Amiloidose/etiologia , Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/cirurgia , Feminino , Humanos , Pessoa de Meia-Idade , Diálise Renal/efeitos adversos , Compressão da Medula Espinal/diagnóstico , Compressão da Medula Espinal/etiologia , Compressão da Medula Espinal/cirurgia
7.
Medicine (Baltimore) ; 100(21): e25961, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34032706

RESUMO

RATIONALE: Amyloidosis is a heterogeneous group of diseases characterized by extracellular deposition of amyloid fibrils. Lung carcinoma is rarely reported to be associated with AA amyloidosis. With regard to the manifestation of amyloidosis infiltrating organs, most of the cases focus on the heart, liver, kidneys, and peripheral nervous system. Amyloidosis with diffuse abdominal involvement in combination with pulmonary squamous cell carcinoma carcinoma is an exceptionally rare occurrence. PATIENT CONCERNS: A 70-year-old man was admitted to hospital for a 2-month history of repeated cough, low grade fever, hemoptysis and left back shoulder pain, which was not relieved by nonsteroid anti-inflammatory drugs. Meanwhile, he complained of intermittent diffuse abdominal discomfort and chronic persistent constipation. DIAGNOSES: The patient was diagnosed with poorly differentiated lung squamous cell carcinoma and diffuse peritoneal and mesenteric amyloidosis based on the pathological biopsy. INTERVENTIONS: The patient received surgery and chemotherapy for lung tumor. He did not receive any treatment against amyloidosis. OUTCOMES: The patient died of a severe respiratory infection. LESSONS: This case indicates that lung carcinoma is suspected to play a causative role in the development of amyloidosis. In addition, amyloidosis should be considered in the differential diagnosis in cases in which diffuse greater omentum, peritoneal, and mesenteric calcifications on 18F-2-fluoro-2-deoxy-D-glucose(18F-FDG) photon emission computed tomography (PET/CT).


Assuntos
Amiloidose/diagnóstico , Carcinoma de Células Escamosas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Pulmão/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Idoso , Amiloidose/etiologia , Amiloidose/patologia , Carcinoma de Células Escamosas/complicações , Carcinoma de Células Escamosas/terapia , Quimioterapia Adjuvante , Evolução Fatal , Fluordesoxiglucose F18/administração & dosagem , Humanos , Pulmão/patologia , Pulmão/cirurgia , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/terapia , Masculino , Mesentério/diagnóstico por imagem , Mesentério/patologia , Omento/diagnóstico por imagem , Omento/patologia , Pneumonectomia
8.
J Alzheimers Dis ; 81(1): 389-401, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33814427

RESUMO

BACKGROUND: Serum uric acid (SUA) affects the reaction of oxidative stress and free radicals in the neurodegenerative processes. However, whether SUA impacts Alzheimer's disease (AD) pathology remains unclear. OBJECTIVE: We aimed to explore whether high SUA levels can aggravate the neurobiological changes of AD in preclinical AD. METHODS: We analyzed cognitively intact participants (n = 839, age 62.16 years) who received SUA and cerebrospinal fluid (CSF) biomarkers (amyloid-ß [Aß], total tau [t-Tau], and phosphorylated tau [p-Tau]) measurements from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database using multivariable-adjusted linear models. RESULTS: Levels of SUA in the preclinical AD elevated compared with the healthy controls (p = 0.007) and subjects with amyloid pathology had higher concentration of SUA than controls (p = 0.017). Roughly, equivalent levels of SUA displayed among cognitively intact individuals with or without tau pathology and neurodegeneration. CSF Aß1 - 42 (p = 0.019) and Aß1 - 42/Aß1 - 40 (p = 0.027) were decreased and CSF p-Tau/Aß1 - 42 (p = 0.009) and t-Tau/Aß1 - 42 (p = 0.043) were increased with the highest (> 75th percentile) SUA when compared to lowest SUA, implying a high burden of cerebral amyloidosis in individuals with high SUA. Sensitivity analyses using the usual threshold to define hyperuricemia and precluding drug effects yielded robust associations. Nevertheless, the quadratic model did not show any U-shaped relationships between them. CONCLUSION: SUA may aggravate brain amyloid deposition in preclinical AD, which corroborated the detrimental role of SUA.


Assuntos
Doença de Alzheimer/etiologia , Amiloidose/etiologia , Cognição/fisiologia , Ácido Úrico/sangue , Idoso , Doença de Alzheimer/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Amiloidose/sangue , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fosforilação , Proteínas tau/líquido cefalorraquidiano
9.
Trends Microbiol ; 29(11): 967-969, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33795156

RESUMO

Severe coronavirus disease 2019 (COVID-19) infection leads to multifactorial acute respiratory distress syndrome (ARDS), with little therapeutic success. The pathophysiology associated with ARDS or post-ARDS is not yet well understood. We hypothesize that amyloid formation occurring due to protein homeostasis disruption can be one of the complications associated with COVID-19-induced-ARDS.


Assuntos
Amiloide/metabolismo , COVID-19/complicações , COVID-19/virologia , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/metabolismo , SARS-CoV-2 , Amiloidose/etiologia , Amiloidose/metabolismo , Amiloidose/patologia , Animais , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Síndrome do Desconforto Respiratório/diagnóstico
10.
Tohoku J Exp Med ; 253(4): 241-248, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33828023

RESUMO

Dialysis-related amyloidosis (DRA) is characterized by the deposition of amyloid consisting of beta2-microglobulin in the musculoskeletal system, causing carpal tunnel syndrome, destructive spondyloarthropathy, and/or bone cysts. Increased cystic radiolucency of the bones and tendon thickening due to inflammation are common findings in DRA. We have developed a new dialysis method, extended-hours hemodialysis without dietary restrictions for the aim of improving both hypertension and malnutrition. We retrospectively evaluated the clinical effects of dialysis time on the risk for developing of DRA. The study subjects were all of the 30 patients who had received this treatment for more than 11 years. They were divided into two groups according to the weekly dialysis hours: 15 patients ≥ 16.5 hours/week (L-group) and 15 patients ≤ 15.5 hours/week (S-group). Plain x-ray imaging and ultrasonography were used to assess cystic radiolucency of the bones and thickness/diameter of the soft tissues. The proportion of the carpal bone cystic radiolucency was lower in the L-group. The severity of median nerve compression at the wrist was significantly less in the L-group (right hand: p = 0.0082, left hand: p = 0.0137). Multivariate regression analysis showed that dialysis time was a predictor of median nerve compression (ß = -0.559, p = 0.005). In conclusion, extended-hours hemodialysis without dietary restrictions contributes to lower the risk for developing of DRA at the wrist. We therefore propose that extended-hours hemodialysis without dietary restrictions is a preferred method which maintains the patients' quality of life compared with the conventional hemodialysis method.


Assuntos
Amiloidose/etiologia , Dietoterapia , Diálise Renal/efeitos adversos , Adulto , Amiloidose/diagnóstico por imagem , Síndrome do Túnel Carpal/diagnóstico por imagem , Feminino , Humanos , Modelos Logísticos , Masculino , Nervo Mediano/diagnóstico por imagem , Pessoa de Meia-Idade , Fatores de Risco , Articulação do Ombro/diagnóstico por imagem , Espondiloartropatias/diagnóstico por imagem , Ultrassonografia
11.
Int J Mol Sci ; 22(8)2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33920986

RESUMO

Amyloidoses are a group of diseases associated with the formation of pathological protein fibrils with cross-ß structures. Approximately 5-10% of the cases of these diseases are determined by amyloidogenic mutations, as well as by transmission of infectious amyloids (prions) between organisms. The most common group of so-called sporadic amyloidoses is associated with abnormal aggregation of wild-type proteins. Some sporadic amyloidoses are known to be induced only against the background of certain pathologies, but in some cases the cause of amyloidosis is unclear. It is assumed that these diseases often occur by accident. Here we present facts and hypotheses about the association of sporadic amyloidoses with vascular pathologies, trauma, oxidative stress, cancer, metabolic diseases, chronic infections and COVID-19. Generalization of current data shows that all sporadic amyloidoses can be regarded as a secondary event occurring against the background of diseases provoking a cellular stress response. Various factors causing the stress response provoke protein overproduction, a local increase in the concentration or modifications, which contributes to amyloidogenesis. Progress in the treatment of vascular, metabolic and infectious diseases, as well as cancers, should lead to a significant reduction in the risk of sporadic amyloidoses.


Assuntos
Amiloidose/etiologia , Estresse Fisiológico , Lesões Encefálicas/complicações , Doenças Transmissíveis/complicações , Humanos , Doenças Metabólicas/complicações , Neoplasias/complicações , Estresse Oxidativo , Doenças Vasculares/complicações
13.
Life Sci ; 273: 119310, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33667517

RESUMO

AIMS: Alzheimer's disease (AD) is a leading health problem in which increased amyloid ß (Aß) accumulation may occur due to abnormal Aß precursor protein processing by ß-secretase 1 (BACE1) enzyme. Lately, neuro-inflammation was recognized as a significant contributor to its pathogenesis. Although the causes of AD are not yet well understood, much evidence has suggested that dyslipidemia has harmful effects on cognitive function and is inextricably involved in AD pathogenesis. Cholesterol is a vital molecule involved in neuronal development. Alteration in neuronal cholesterol levels affects Aß metabolism and results in neurodegeneration. Proprotein-convertase-subtilisin/kexin type-9 (PCSK9) was found to decrease neuronal cholesterol uptake by degradation of LDL-receptor related protein 1 (LRP-1) responsible for neuronal cholesterol uptake. Accordingly, this study was designed to evaluate the effect of PCSK9-inhibition by alirocumab (Aliro) in high-fat-cholesterol-diet (HFCD)-induced-AD-like condition. MAIN METHODS: Wistar Rats were divided into six groups; control; HFCD; HFCD and Memantine; HFCD and Aliro (4, 8 and 16 mg/kg/week) to test for ability of Aliro to modulate cognitive impairment, amyloidosis, brain cholesterol homeostasis and neuro-inflammation in HFCD-induced-AD-like condition. KEY FINDINGS: Our results demonstrated an association between PCSK9 inhibition by Aliro and amelioration of cognitive deficit, cholesterol hemostasis and reduction of neuro-inflammation. Aliro was able to alleviate hippocampal LRP-1expression levels and reduce brain cholesterol, hippocampal BACE1, Aß42, high-mobility-group-box-1 protein, receptor for advanced-glycation-end-products and toll like receptor-4 with subsequent decrease of different inflammatory mediators as nuclear-factor-kappa-B (NF-κB), tumor-necrosis-factor-alpha (TNF-α), interleukin-1beta (IL-1ß) and IL-6. SIGNIFICANCE: PCSK9-inhibition may represent a new therapeutic target in AD especially for HFCD-induced-AD-like condition.


Assuntos
Amiloidose/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacologia , Colesterol/toxicidade , Disfunção Cognitiva/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Memantina/farmacologia , Pró-Proteína Convertase 9/antagonistas & inibidores , Amiloidose/etiologia , Amiloidose/metabolismo , Amiloidose/patologia , Animais , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/metabolismo , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Ratos , Ratos Wistar , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
14.
Am J Cardiol ; 146: 89-94, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33529617

RESUMO

Diagnosing cardiac amyloidosis is challenging and requires a high index of suspicion in patients with an increased left ventricular wall thickness (LVWT). Low QRS voltage on electrocardiogram (ECG) has been regarded as the hallmark ECG finding in cardiac amyloidosis; however, the presence of low voltage can range from 20-74% and the voltage/mass ratio carries a greater diagnostic accuracy than QRS voltage alone. Patients with cardiac amyloidosis can have conduction system infiltration and this may result in a BBB. Therefore, the ECG or mass/voltage criteria established for patients with a narrow QRS in the diagnosis of cardiac amyloidosis may not be applicable in patients with a BBB. We sought to identify criteria to aid in the diagnosis of cardiac amyloidosis in patients with increased LVWT on echocardiogram and with a BBB on ECG. We calculated the total QRS score/LVWT, limb lead QRS score/LVWT, R in lead aVL/LVWT, R in lead I/LVWT, and Sokolow index/LVWT. In patients with an increase in LVWT and BBB, total QRS voltage that is indexed to wall thickness can help distinguish between patients with increased wall thickness who have cardiac amyloidosis from those who have LVH related to a pressure overload state. A unique index of Total QRS Score/LVWT is the best predictor of cardiac amyloidosis with a cutoff value of 92.5 mV/cm which is 100% sensitive and 83% specific for the diagnosis of cardiac amyloidosis. This may be a useful screening tool in patients with an increased wall thickness to raise diagnostic suspicion for cardiac amyloidosis.


Assuntos
Amiloidose/diagnóstico , Bloqueio de Ramo/complicações , Eletrocardiografia/métodos , Sistema de Condução Cardíaco/fisiopatologia , Cardiopatias/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Amiloidose/etiologia , Amiloidose/fisiopatologia , Bloqueio de Ramo/diagnóstico , Bloqueio de Ramo/fisiopatologia , Seguimentos , Cardiopatias/etiologia , Cardiopatias/fisiopatologia , Humanos , Masculino , Estudos Retrospectivos
15.
Int J Mol Sci ; 22(3)2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33494290

RESUMO

Amyloid A (AA) amyloidosis is a condition in which amyloid fibrils characterized by a linear morphology and a cross-ß structure accumulate and are deposited extracellularly in organs, resulting in chronic inflammatory diseases and infections. The incidence of AA amyloidosis is high in humans and several animal species. Serum amyloid A (SAA) is one of the most important precursor amyloid proteins and plays a vital step in AA amyloidosis. Amyloid enhancing factor (AEF) serves as a seed for fibril formation and shortens the onset of AA amyloidosis sharply. In this study, we examined whether AEFs extracted and purified from five animal species (camel, cat, cattle, goat, and mouse) could promote mouse SAA (mSAA) protein aggregation in vitro using quantum-dot (QD) nanoprobes to visualize the aggregation. The results showed that AEFs shortened and promoted mSAA aggregation. In addition, mouse and cat AEFs showed higher mSAA aggregation-promoting activity than the camel, cattle, and goat AEFs. Interestingly, homology analysis of SAA in these five animal species revealed a more similar amino acid sequence homology between mouse and cat than between other animal species. Furthermore, a detailed comparison of amino acid sequences suggested that it was important to mSAA aggregation-promoting activity that the 48th amino acid was a basic residue (Lys) and the 125th amino acid was an acidic residue (Asp or Glu). These data imply that AA amyloidosis exhibits higher transmission activity among animals carrying genetically homologous SAA gene, and may provide a new understanding of the pathogenesis of amyloidosis.


Assuntos
Amiloide/metabolismo , Amiloidose/metabolismo , Glicoproteínas/metabolismo , Proteína Amiloide A Sérica/metabolismo , Sequência de Aminoácidos , Amiloidose/etiologia , Amiloidose/patologia , Animais , Modelos Animais de Doenças , Fígado/metabolismo , Fígado/patologia , Camundongos , Imagem Molecular , Filogenia , Agregados Proteicos , Agregação Patológica de Proteínas/metabolismo , Proteína Amiloide A Sérica/química , Proteína Amiloide A Sérica/classificação , Proteína Amiloide A Sérica/genética
16.
Commun Biol ; 4(1): 120, 2021 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-33500517

RESUMO

The thermodynamic hypothesis of protein folding, known as the "Anfinsen's dogma" states that the native structure of a protein represents a free energy minimum determined by the amino acid sequence. However, inconsistent with the Anfinsen's dogma, globular proteins can misfold to form amyloid fibrils, which are ordered aggregates associated with diseases such as Alzheimer's and Parkinson's diseases. Here, we present a general concept for the link between folding and misfolding. We tested the accessibility of the amyloid state for various proteins upon heating and agitation. Many of them showed Anfinsen-like reversible unfolding upon heating, but formed amyloid fibrils upon agitation at high temperatures. We show that folding and amyloid formation are separated by the supersaturation barrier of a protein. Its breakdown is required to shift the protein to the amyloid pathway. Thus, the breakdown of supersaturation links the Anfinsen's intramolecular folding universe and the intermolecular misfolding universe.


Assuntos
Amiloide/química , Amiloide/metabolismo , Dobramento de Proteína , Sequência de Aminoácidos/fisiologia , Amiloidose/etiologia , Amiloidose/metabolismo , Precipitação Química , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Humanos , Proteínas Intrinsicamente Desordenadas/química , Proteínas Intrinsicamente Desordenadas/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas/química , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Concentração Osmolar , Agregação Patológica de Proteínas/etiologia , Agregação Patológica de Proteínas/metabolismo , Conformação Proteica , Multimerização Proteica/fisiologia , Termodinâmica , alfa-Sinucleína/química , alfa-Sinucleína/metabolismo , Proteínas tau/química , Proteínas tau/metabolismo
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