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1.
Heart Fail Clin ; 20(3): 307-316, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38844301

RESUMO

Cardiac amyloidosis (CA) is caused by the myocardial deposition of misfolded proteins, either amyloid transthyretin (ATTR) or immunoglobulin light chains (AL). The paradigm of this condition has transformed, since CA is increasingly recognized as a relatively prevalent cause of heart failure. Cardiac scintigraphy with bone tracers is the unique noninvasive technique able to confirm CA without performing tissue biopsy or advanced imaging tests. A moderate-to-intense myocardial uptake (Perugini grade ≥2) associated with the absence of a monoclonal component is greater than 99% specific for ATTR-CA, while AL-CA confirmation requires tissue biopsy.


Assuntos
Amiloidose , Cardiomiopatias , Compostos Radiofarmacêuticos , Humanos , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/metabolismo , Amiloidose/diagnóstico por imagem , Amiloidose/metabolismo , Amiloidose/patologia , Cintilografia/métodos , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Miocárdio/patologia , Miocárdio/metabolismo , Neuropatias Amiloides Familiares/diagnóstico por imagem , Neuropatias Amiloides Familiares/metabolismo , Neuropatias Amiloides Familiares/patologia , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/metabolismo , Pré-Albumina/metabolismo
2.
Heart Fail Clin ; 20(3): 249-260, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38844296

RESUMO

Amyloidosis is a heterogenous group of disorders, caused by the deposition of insoluble fibrils derived from misfolded proteins in the extracellular space of various organs. These proteins have an unstable structure that causes them to misfold, aggregate, and deposit as amyloid fibrils with the pathognomonic histologic property of green birefringence when viewed under cross-polarized light after staining with Congo red. Amyloid fibrils are insoluble and degradation-resistant; resistance to catabolism results in progressive tissue amyloid accumulation. The outcome of this process is organ disfunction independently from the type of deposited protein, however there can be organ that are specifically targeted from certain proteins.


Assuntos
Amiloide , Amiloidose , Humanos , Amiloidose/metabolismo , Amiloidose/patologia , Amiloide/metabolismo
3.
Res Vet Sci ; 175: 105315, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38838511

RESUMO

Systemic amyloid light-chain (AL) amyloidosis is an infrequent disease in which amyloid fibrils derived from the immunoglobulin light chain are deposited in systemic organs, resulting in functional impairment. This disease has been notably uncommon in animals, and nonhuman primates have not been reported to develop it. In this study, we identified the systemic AL kappa chain amyloidosis in a captive Bornean orangutan (Pongo pygmaeus) and analyzed its pathogenesis. Amyloid deposits were found severely in the submucosa of the large intestine, lung, mandibular lymph nodes, and mediastinal lymph nodes, with milder lesions in the liver and kidney. Mass spectrometry-based proteomic analysis revealed an abundant constant domain of the immunoglobulin kappa chain in the amyloid deposits. Immunohistochemistry further confirmed that the amyloid deposits were positive for immunoglobulin kappa chains. In this animal, AL amyloidosis resulted in severe involvement of the gastrointestinal submucosa and lymph nodes, which is consistent with the characteristics of AL amyloidosis in humans, suggesting that AL amyloid may have a similar deposition mechanism across species. This report enhances the pathological understanding of systemic AL amyloidosis in animals by providing a detailed characterization of this disease based on proteomic analysis.


Assuntos
Amiloidose , Doenças dos Símios Antropoides , Pongo pygmaeus , Animais , Doenças dos Símios Antropoides/patologia , Amiloidose/veterinária , Amiloidose/patologia , Cadeias kappa de Imunoglobulina , Amiloidose de Cadeia Leve de Imunoglobulina/veterinária , Amiloidose de Cadeia Leve de Imunoglobulina/patologia , Linfonodos/patologia , Masculino , Proteômica , Feminino
4.
Mol Cell Biol ; 44(5): 165-177, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38758542

RESUMO

Systemic amyloid A (AA) amyloidosis, which is considered the second most common form of systemic amyloidosis usually takes place several years prior to the occurrence of chronic inflammation, generally involving the kidney. Activated HSF1, which alleviated unfolded protein response (UPR) or enhanced HSR, is the potential therapeutic target of many diseases. However, the effect of HSF1 on AA amyloidosis remains unclear. This study focused on evaluating effect of HSF1 on AA amyloidosis based on HSF1 knockout mice. As a result, aggravated amyloid deposits and renal dysfunction have been found in HSF1 knockout mice. In progressive AA amyloidosis, HSF1 deficiency enhances serum amyloid A production might to lead to severe AA amyloid deposition in mice, which may be related to deactivated unfolded protein response as well as enhanced inflammation. Thus, HSF1 plays a significant role on UPR related pathway impacting AA amyloid deposition, which can mitigate amyloidogenic proteins from aggregation pathologically and is the possible way for intervening with the pathology of systemic amyloid disorder. In conclusion, HSF1 could not only serve as a new target for AA amyloidosis treatment in the future, but HSF1 knockout mice also can be considered as a valuable novel animal model for renal AA amyloidosis.


Assuntos
Amiloidose , Fatores de Transcrição de Choque Térmico , Rim , Camundongos Knockout , Resposta a Proteínas não Dobradas , Animais , Amiloidose/metabolismo , Amiloidose/genética , Amiloidose/patologia , Fatores de Transcrição de Choque Térmico/metabolismo , Fatores de Transcrição de Choque Térmico/genética , Camundongos , Rim/patologia , Rim/metabolismo , Proteína Amiloide A Sérica/metabolismo , Proteína Amiloide A Sérica/genética , Modelos Animais de Doenças , Nefropatias/metabolismo , Nefropatias/patologia , Nefropatias/genética , Nefropatias/etiologia , Camundongos Endogâmicos C57BL
5.
Anal Chem ; 96(23): 9460-9467, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38820243

RESUMO

Pathological cardiac hypertrophy is a complex process that often leads to heart failure. Label-free proteomics has emerged as an important platform to reveal protein variations and to elucidate the mechanisms of cardiac hypertrophy. Endomyocardial biopsy is a minimally invasive technique for sampling cardiac tissue, but it yields only limited amounts of an ethically permissible specimen. After regular pathological examination, the remaining trace samples pose significant challenges for effective protein extraction and mass spectrometry analysis. Herein, we developed trace cardiac tissue proteomics based on the anchor-nanoparticles (TCPA) method. We identified an average of 6666 protein groups using ∼50 µg of myocardial interventricular septum samples by TCPA. We then applied TCPA to acquire proteomics from patients' cardiac samples both diagnosed as hypertrophic hearts and myocarditis controls and identified significant alterations in pathways such as regulation of actin cytoskeleton, oxidative phosphorylation, and cGMP-PKG signaling pathway. Moreover, we found multiple lipid metabolic pathways to be dysregulated in transthyretin cardiac amyloidosis compared to other types of cardiac hypertrophy. TCPA offers a new technique for studying pathological cardiac hypertrophy and can serve as a platform toolbox for proteomic research in other cardiac diseases.


Assuntos
Miocárdio , Nanopartículas , Proteômica , Proteômica/métodos , Humanos , Miocárdio/metabolismo , Miocárdio/patologia , Miocárdio/química , Nanopartículas/química , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/diagnóstico , Amiloidose/metabolismo , Amiloidose/patologia , Neuropatias Amiloides Familiares
6.
Prog Mol Biol Transl Sci ; 206: 265-290, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38811083

RESUMO

Misfolded proteins assemble into fibril structures that are called amyloids. Unlike usually folded proteins, misfolded fibrils are insoluble and deposit extracellularly or intracellularly. Misfolded proteins interrupt the function and structure of cells and cause amyloid disease. There is increasing evidence that the most pernicious species are oligomers. Misfolded proteins disrupt cell function and cause cytotoxicity by calcium imbalance, mitochondrial dysfunction, and intracellular reactive oxygen species. Despite profound impacts on health, social, and economic factors, amyloid diseases remain untreatable. To develop new therapeutics and to understand the pathological manifestations of amyloidosis, research into the origin and pathology of amyloidosis is urgently needed. This chapter describes the basic concept of amyloid disease and the function of atypical amyloid deposits in them.


Assuntos
Amiloide , Humanos , Amiloide/metabolismo , Animais , Amiloidose/patologia , Amiloidose/metabolismo
7.
Prog Mol Biol Transl Sci ; 206: 341-388, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38811085

RESUMO

A family of maladies known as amyloid disorders, proteinopathy, or amyloidosis, are characterized by the accumulation of abnormal protein aggregates containing cross-ß-sheet amyloid fibrils in many organs and tissues. Often, proteins that have been improperly formed or folded make up these fibrils. Nowadays, most treatments for amyloid illness focus on managing symptoms rather than curing or preventing the underlying disease process. However, recent advances in our understanding of the biology of amyloid diseases have led to the development of innovative therapies that target the emergence and accumulation of amyloid fibrils. Examples of these treatments include the use of small compounds, monoclonal antibodies, gene therapy, and others. In the end, even if the majority of therapies for amyloid diseases are symptomatic, greater research into the biology behind these disorders is identifying new targets for potential therapy and paving the way for the development of more effective treatments in the future.


Assuntos
Amiloidose , Humanos , Animais , Amiloidose/terapia , Amiloidose/patologia , Amiloide/metabolismo , Deficiências na Proteostase/terapia , Terapia Genética
9.
Scand J Clin Lab Invest ; 84(3): 193-201, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38709651

RESUMO

Amyloidosis is a disease characterized by the deposition of protein fibrils. Cardiac involvement is a significant factor in determining prognosis. This study aimed to examine the clinical profile, outcomes, and long-term mortality rates in patients with transthyretin (ATTR) and amyloid light-chain (AL) amyloidosis. The retrospective cohort study included 94 patients with amyloidosis (69 with AL and 25 with ATTR amyloidosis) diagnosed between 2010 and 2022. The study involved multimodality imaging (ECG, echocardiography and cardiac magnetic resonance (CMR) data and survival analyses. Patients with ATTR amyloidosis were older and had a higher proportion of males compared to those with AL amyloidosis. Cardiac involvement was more prevalent in the ATTR group, including atrial fibrillation (AF), while pleural and pericardial effusion were more frequent in the AL group. Biomarkers such as NT-proBNP and troponin T were significantly elevated in both groups and were associated with all-cause mortality only in univariate analyses. CMR data, especially typical late gadolinium enhancement (LGE) was not associated with increased mortality, while pleural effusion and left atrial dilatation on echocardiography were identified as powerful predictors of mortality. In conclusion, both AL and ATTR amyloidosis exhibited poor outcomes. Cardiac involvement, particularly dilated left atrium and pleural effusion on echocardiography were associated with an increased risk of mortality, while typical LGE on CMR was not.


Assuntos
Ecocardiografia , Peptídeo Natriurético Encefálico , Humanos , Masculino , Feminino , Idoso , Estudos Retrospectivos , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Imageamento por Ressonância Magnética , Neuropatias Amiloides Familiares/diagnóstico por imagem , Neuropatias Amiloides Familiares/mortalidade , Neuropatias Amiloides Familiares/patologia , Amiloidose de Cadeia Leve de Imunoglobulina/diagnóstico por imagem , Amiloidose de Cadeia Leve de Imunoglobulina/mortalidade , Amiloidose de Cadeia Leve de Imunoglobulina/patologia , Amiloidose/diagnóstico por imagem , Amiloidose/patologia , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Troponina T/sangue , Eletrocardiografia , Fibrilação Atrial/diagnóstico por imagem , Derrame Pericárdico/diagnóstico por imagem , Prognóstico , Cardiomiopatias/diagnóstico por imagem
11.
J Neuroinflammation ; 21(1): 129, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38745337

RESUMO

Diet-induced increase in body weight is a growing health concern worldwide. Often accompanied by a low-grade metabolic inflammation that changes systemic functions, diet-induced alterations may contribute to neurodegenerative disorder progression as well. This study aims to non-invasively investigate diet-induced metabolic and inflammatory effects in the brain of an APPPS1 mouse model of Alzheimer's disease. [18F]FDG, [18F]FTHA, and [18F]GE-180 were used for in vivo PET imaging in wild-type and APPPS1 mice. Ex vivo flow cytometry and histology in brains complemented the in vivo findings. 1H- magnetic resonance spectroscopy in the liver, plasma metabolomics and flow cytometry of the white adipose tissue were used to confirm metaflammatory condition in the periphery. We found disrupted glucose and fatty acid metabolism after Western diet consumption, with only small regional changes in glial-dependent neuroinflammation in the brains of APPPS1 mice. Further ex vivo investigations revealed cytotoxic T cell involvement in the brains of Western diet-fed mice and a disrupted plasma metabolome. 1H-magentic resonance spectroscopy and immunological results revealed diet-dependent inflammatory-like misbalance in livers and fatty tissue. Our multimodal imaging study highlights the role of the brain-liver-fat axis and the adaptive immune system in the disruption of brain homeostasis in amyloid models of Alzheimer's disease.


Assuntos
Imunidade Adaptativa , Amiloidose , Encéfalo , Dieta Ocidental , Modelos Animais de Doenças , Camundongos Transgênicos , Animais , Camundongos , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/imunologia , Amiloidose/metabolismo , Amiloidose/patologia , Amiloidose/imunologia , Dieta Ocidental/efeitos adversos , Camundongos Endogâmicos C57BL , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/imunologia
12.
Nat Commun ; 15(1): 3996, 2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38734693

RESUMO

SPI1 was recently reported as a genetic risk factor for Alzheimer's disease (AD) in large-scale genome-wide association studies. However, it is unknown whether SPI1 should be downregulated or increased to have therapeutic benefits. To investigate the effect of modulating SPI1 levels on AD pathogenesis, we performed extensive biochemical, histological, and transcriptomic analyses using both Spi1-knockdown and Spi1-overexpression mouse models. Here, we show that the knockdown of Spi1 expression significantly exacerbates insoluble amyloid-ß (Aß) levels, amyloid plaque deposition, and gliosis. Conversely, overexpression of Spi1 significantly ameliorates these phenotypes and dystrophic neurites. Further mechanistic studies using targeted and single-cell transcriptomics approaches demonstrate that altered Spi1 expression modulates several pathways, such as immune response pathways and complement system. Our data suggest that transcriptional reprogramming by targeting transcription factors, like Spi1, might hold promise as a therapeutic strategy. This approach could potentially expand the current landscape of druggable targets for AD.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Amiloidose , Modelos Animais de Doenças , Proteínas Proto-Oncogênicas , Transcriptoma , Animais , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Camundongos , Amiloidose/genética , Amiloidose/metabolismo , Amiloidose/patologia , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Fenótipo , Camundongos Transgênicos , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Placa Amiloide/genética , Humanos , Masculino , Camundongos Endogâmicos C57BL , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Transativadores
14.
Analyst ; 149(11): 3152-3160, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38630503

RESUMO

Cholesterol plays an important biological role in the body, and its disruption in homeostasis and synthesis has been implicated in several diseases. Mapping the locations of cholesterol is crucial for gaining a better understanding of these conditions. Silver deposition has proven to be an effective method for analyzing cholesterol using mass spectrometry imaging (MSI). We optimized and evaluated thermal evaporation as an alternative deposition technique to sputtering for silver deposition in MSI of cholesterol. A silver layer with a thickness of 6 nm provided an optimal combination of cholesterol signal intensity and mass resolution. The deposition of an ultrathin nanofilm of silver enabled high-resolution MSI with a pixel size of 10 µm. We used this optimized method to visualize the distribution of cholesterol in the senile plaques in the brains of APP/PS1 mice, a model that resembles Alzheimer's disease pathology. We found that cholesterol was evenly distributed across the frontal cortex tissue, with no evidence of plaque-like accumulation. Additionally, we investigated the presence and distribution of cholesterol in myocardial sections of a human heart affected by wild-type ATTR amyloidosis. We identified the presence of cholesterol in areas with amyloid deposition, but complete colocalization was not observed.


Assuntos
Colesterol , Prata , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Animais , Colesterol/análise , Colesterol/química , Prata/química , Humanos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Camundongos , Camundongos Transgênicos , Placa Amiloide , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagem , Miocárdio/metabolismo , Miocárdio/química , Miocárdio/patologia , Amiloidose/metabolismo , Amiloidose/patologia , Volatilização , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Temperatura
15.
J Biochem ; 175(6): 575-585, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38430131

RESUMO

Amyloidosis is characterized by the abnormal accumulation of amyloid proteins. The causative proteins aggregate from monomers to oligomers and fibrils, among which some intermediate oligomers are considered as major toxins. Cytotoxic oligomers are generated not only by aggregation but also via fibril disaggregation. However, little is known about the structural characteristics and generation conditions of cytotoxic oligomers produced during disaggregation. Herein, we summarized the structural commonalities of cytotoxic oligomers formed under various disaggregation conditions, including the addition of heat shock proteins or small compounds. In vitro experimental data demonstrated the presence of high-molecular-weight oligomers (protofibrils or protofilaments) that exhibited a fibrous morphology and ß-sheet structure. Molecular dynamics simulations indicated that the distorted ß-sheet structure contributed to their metastability. The tendency of these cytotoxic oligomers to appear under mild disaggregation conditions, implied formation during the early stages of disaggregation. This review will aid researchers in exploring the characteristics of highly cytotoxic oligomers and developing drugs that target amyloid aggregates.


Assuntos
Amiloide , Humanos , Amiloide/química , Amiloide/metabolismo , Simulação de Dinâmica Molecular , Agregados Proteicos , Amiloidose/metabolismo , Amiloidose/patologia , Agregação Patológica de Proteínas/metabolismo
16.
J Investig Med High Impact Case Rep ; 12: 23247096241237759, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38462925

RESUMO

Gastrointestinal amyloidosis is a rare condition commonly found in the setting of systemic AL amyloidosis. Amyloid can deposit throughout the gastrointestinal tract and the resulting symptoms vary depending on the site of deposition. Gastrointestinal (GI) manifestations can range from weight loss or abdominal pain, to more serious complications like gastrointestinal bleeding, malabsorption, dysmotility, and obstruction. This case describes a patient with known history of IgG lambda AL amyloidosis, presenting with epigastric pain and unintentional weight loss found to have gastroduodenal amyloidosis. The definitive diagnosis of GI amyloidosis requires endoscopic biopsy with Congo red staining and visualization under polarized light microscopy. There are currently no specific guidelines for the management of GI amyloidosis. Generally, the goal is to treat the underlying cause of the amyloidosis along with symptom management. Our patient is being treated with cyclophosphamide, bortezomib, and dexamethasone (CyBorD) and started on hemodialysis due to progression of renal disease.


Assuntos
Amiloidose , Amiloidose de Cadeia Leve de Imunoglobulina , Humanos , Dor Abdominal , Amiloidose/complicações , Amiloidose/diagnóstico , Amiloidose/patologia , Biópsia , Hemorragia Gastrointestinal/etiologia , Amiloidose de Cadeia Leve de Imunoglobulina/complicações , Amiloidose de Cadeia Leve de Imunoglobulina/diagnóstico , Redução de Peso
18.
J Transl Med ; 22(1): 291, 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38500108

RESUMO

BACKGROUND: Biologic TNF-α inhibitors (bTNFIs) can block cerebral TNF-α in Alzheimer's disease (AD) if these macromolecules can cross the blood-brain barrier (BBB). Thus, a model bTNFI, the extracellular domain of type II TNF-α receptor (TNFR), which can bind to and sequester TNF-α, was fused with a mouse transferrin receptor antibody (TfRMAb) to enable brain delivery via BBB TfR-mediated transcytosis. Previously, we found TfRMAb-TNFR to be protective in a mouse model of amyloidosis (APP/PS1) and tauopathy (PS19), and herein we investigated its effects in mice that combine both amyloidosis and tauopathy (3xTg-AD). METHODS: Eight-month-old female 3xTg-AD mice were injected intraperitoneally with saline (n = 11) or TfRMAb-TNFR (3 mg/kg; n = 11) three days per week for 12 weeks. Age-matched wild-type (WT) mice (n = 9) were treated similarly with saline. Brains were processed for immunostaining and high-resolution multiplex NanoString GeoMx spatial proteomics. RESULTS: We observed regional differences in proteins relevant to Aß, tau, and neuroinflammation in the hippocampus of 3xTg-AD mice compared with WT mice. From 64 target proteins studied using spatial proteomics, a comparison of the Aß-plaque bearing vs. plaque-free regions in the 3xTg-AD mice yielded 39 differentially expressed proteins (DEP) largely related to neuroinflammation (39% of DEP) and Aß and tau pathology combined (31% of DEP). Hippocampal spatial proteomics revealed that the majority of the proteins modulated by TfRMAb-TNFR in the 3xTg-AD mice were relevant to microglial function (⁓ 33%). TfRMAb-TNFR significantly reduced mature Aß plaques and increased Aß-associated microglia around larger Aß deposits in the 3xTg-AD mice. Further, TfRMAb-TNFR increased mature Aß plaque-associated microglial TREM2 in 3xTg-AD mice. CONCLUSION: Overall, despite the low visual Aß load in the 11-month-old female 3xTg-AD mice, our results highlight region-specific AD-relevant DEP in the hippocampus of these mice. Chronic TfRMAb-TNFR dosing modulated several DEP involved in AD pathology and showed a largely microglia-centric mechanism of action in the 3xTg-AD mice.


Assuntos
Doença de Alzheimer , Amiloidose , Produtos Biológicos , Camundongos , Feminino , Animais , Doença de Alzheimer/tratamento farmacológico , Fator de Necrose Tumoral alfa/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Doenças Neuroinflamatórias , Camundongos Transgênicos , Encéfalo/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Amiloidose/metabolismo , Amiloidose/patologia , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Anticorpos/metabolismo , Produtos Biológicos/metabolismo , Modelos Animais de Doenças
19.
Exp Dermatol ; 33(3): e15040, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38429888

RESUMO

The effect of persistent skin inflammation on extracutaneous organs and blood is not well studied. Patients with recessive dystrophic epidermolysis bullosa (RDEB), a severe form of the inherited blistering skin disorder, have widespread and persistent skin ulcers, and they develop various complications including anaemia, hyperglobulinaemia, hypoalbuminaemia and secondary amyloidosis. These complications are associated with the bioactivities of IL-6, and the development of secondary amyloidosis requires the persistent elevation of serum amyloid A (SAA) level. We found that patients with RDEB had significantly higher serum levels of IL-6 and SAA compared to healthy volunteers and patients with psoriasis or atopic dermatitis. Both IL-6 and SAA were highly expressed in epidermal keratinocytes and dermal fibroblasts of the skin ulcer lesions. Keratinocytes and fibroblasts surrounding the ulcer lesions are continuously exposed to Toll-like receptor (TLR) ligands, pathogen-associated and damage-associated molecular pattern molecules. In vitro, TLR ligands induced IL-6 expression via NF-κB in normal human epidermal keratinocytes (NHEKs) and dermal fibroblasts (NHDFs). SAA further induced the expression of IL-6 via TLR1/2 and NF-κB in NHEKs and NHDFs. The limitation of this study is that NHEKs and NHDFs were not derived from RDEB patients. These observations suggest that TLR-mediated persistent skin inflammation might increase the risk of IL-6-related systemic complications, including RDEB.


Assuntos
Amiloidose , Epidermólise Bolhosa Distrófica , Interleucina-6 , Humanos , Amiloidose/metabolismo , Amiloidose/patologia , Colágeno Tipo VII/metabolismo , Epidermólise Bolhosa Distrófica/metabolismo , Epidermólise Bolhosa Distrófica/patologia , Fibroblastos/metabolismo , Inflamação/metabolismo , Interleucina-6/metabolismo , Queratinócitos/metabolismo , NF-kappa B/metabolismo , Proteína Amiloide A Sérica/metabolismo , Receptores Toll-Like/metabolismo
20.
J Am Coll Cardiol ; 83(11): 1085-1099, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38479957

RESUMO

Cardiac amyloidosis is increasingly recognized as a treatable form of heart failure. Highly effective specific therapies have recently become available for the 2 most frequent forms of cardiac amyloidosis: immunoglobulin light chain amyloidosis and transthyretin (ATTR) amyloidosis. Nevertheless, initiation of specific therapies requires recognition of cardiac amyloidosis and appropriate characterization of the amyloid type. Although noninvasive diagnosis is possible for ATTR cardiac amyloidosis, histological demonstration and typing of amyloid deposits is still required for a substantial number of patients with ATTR and in all patients with light chain amyloidosis and other rarer forms of cardiac amyloidosis. Amyloid histological typing can be performed using different techniques: mass spectrometry, immunohistochemistry, and immunoelectron microscopy. This review describes which patients require histological confirmation of cardiac amyloidosis along with when and how to type amyloid deposits in histologic specimens. Furthermore, it covers the characteristics and limitations of the different typing methods that are available in clinical practice.


Assuntos
Neuropatias Amiloides Familiares , Amiloidose , Cardiomiopatias , Insuficiência Cardíaca , Humanos , Placa Amiloide , Amiloidose/patologia , Amiloide , Insuficiência Cardíaca/diagnóstico , Imuno-Histoquímica , Proteínas Amiloidogênicas , Pré-Albumina , Neuropatias Amiloides Familiares/diagnóstico , Cardiomiopatias/diagnóstico , Cardiomiopatias/terapia
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