RESUMO
BACKGROUND: Activation of the NLRP3 inflammasome is critical in the inflammatory response to gout. Potassium ion (K+) efflux mediated by the TWIK2 channel is an important upstream mechanism for NLRP3 inflammasome activation. Therefore, the TWIK2 channel may be a promising therapeutic target for MSU crystal-induced inflammation. In the present study, we investigated the effect of ML335, a known K2P channel modulator, on MSU crystal-induced inflammatory responses and its underlying molecular mechanisms. METHODS: By molecular docking, we calculated the binding energies and inhibition constants of five K2P channel modulators (Hydroxychloroquine, Fluoxetine, DCPIB, ML365 and ML335) with TWIK2. Intracellular potassium ion concentration and mitochondrial function were assessed by flow cytometry. The interaction between MARCH5 and SIRT3 was demonstrated by immunoprecipitation and Western blotting assay. MSU suspensions were injected into mouse paw and peritoneal cavity to induce acute gout model. RESULTS: ML335 has the highest binding energy and the lowest inhibition constant with TWIK2 in the five calculated K2P channel modulators. In comparison, among these five compounds, ML335 efficiently inhibited the release of IL-1ß from MSU crystal-treated BMDMs. ML335 decreased MSU crystal-induced K+ efflux mainly dependent on TWIK2 channel. More importantly, ML335 can effectively inhibit the expression of the mitochondrial E3 ubiquitin ligase MARCH5 induced by MSU crystals, and MARCH5 can interact with the SIRT3 protein. ML335 blocked MSU crystal-induced ubiquitination of SIRT3 protein by MARCH5. In addition, ML335 improved mitochondrial dynamics homeostasis and mitochondrial function by inhibiting MARCH5 protein expression. ML335 attenuated the inflammatory response induced by MSU crystals in vivo and in vitro. CONCLUSION: Inhibition of TWIK2-mediated K+ efflux by ML335 alleviated mitochondrial injury via suppressing March5 expression, suggesting that ML335 may be an effective candidate for the future treatment of gout.
Assuntos
Inflamação , Mitocôndrias , Potássio , Animais , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Inflamação/patologia , Potássio/metabolismo , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Masculino , Gota/metabolismo , Gota/patologia , Gota/tratamento farmacológico , Camundongos , Ubiquitina-Proteína Ligases/metabolismo , Canais de Potássio/metabolismo , Sirtuína 3/metabolismo , Interleucina-1beta/metabolismo , Inflamassomos/metabolismo , HumanosRESUMO
A 64-year-old male with a history of gout was seen with a swelling of het left acromioclavicular joint. Microscopic examination revealed monosodium urate crystals, confirming the diagnosis of tophaceous gout.
Assuntos
Articulação Acromioclavicular , Gota , Humanos , Masculino , Pessoa de Meia-Idade , Articulação Acromioclavicular/patologia , Gota/diagnóstico , Gota/patologia , Ácido Úrico/análiseRESUMO
Crystallization of monosodium urate monohydrate (MSU) leads to painful gouty arthritis. Despite extensive research it is still unknown how this pathological biomineralization occurs, which hampers its prevention. Here we show how inflammatory MSU crystals form after a non-inflammatory amorphous precursor (AMSU) that nucleates heterogeneously on collagen fibrils from damaged articular cartilage of gout patients. This non-classical crystallization route imprints a nanogranular structure to biogenic acicular MSU crystals, which have smaller unit cell volume, lower microstrain, and higher crystallinity than synthetic MSU. These distinctive biosignatures are consistent with the template-promoted crystallization of biotic MSU crystals after AMSU at low supersaturation, and their slow growth over long periods of time (possibly years) in hyperuricemic gout patients. Our results help to better understand gout pathophysiology, underline the role of cartilage damage in promoting MSU crystallization, and suggest that there is a time-window to treat potential gouty patients before a critical amount of MSU has slowly formed as to trigger a gout flare.
Assuntos
Cristalização , Gota , Ácido Úrico , Ácido Úrico/metabolismo , Humanos , Gota/metabolismo , Gota/patologia , Biomineralização , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Artrite Gotosa/metabolismo , Artrite Gotosa/patologiaRESUMO
Euphorbia L. is a traditionally used herb and contains many newly identified compounds with novel chemical structures. Euphorbia factor L2 (EFL2), a diterpenoid derived from Euphorbia seeds, is reported to alleviate acute lung injury and arthritis by exerting anti-inflammatory effects. In this study, we aimed to test the therapeutic benefit and mechanisms of EFL2 in NLRP3 inflammasome-mediated gouty models and identified the potential molecular mechanism. A cell-based system was used to test the specific inhibitory effect of EFL2 on NLRP3-related inflammation. The gouty arthritis model and an air pouch inflammation model induced by monosodium urate monohydrate (MSU) crystals were used for in vivo experiments. Nlrp3-/- mice and in vitro studies were used for mechanistic exploration. Virtual molecular docking and biophysical assays were performed to identify the direct binding and regulatory target of EFL2. The inhibitory effect of EFL2 on inflammatory cell infiltration was determined by flow cytometry in vivo. The mechanism by which EFL2 activates the NLRP3 inflammasome signaling pathway was evaluated by immunological experiment and transmission electron microscopy. In vitro, EFL2 specifically reduced NLRP3 inflammasome-mediated IL-1ß production and alleviated MSU crystal-induced arthritis, as well as inflammatory cell infiltration. EFL2 downregulated NF-κB phosphorylation and NLRP3 inflammasome expression by binding to glucocorticoid receptors. Moreover, EFL2 could specifically suppress the lysosome damage-mediated NLRP3 inflammasome activation process. It is expected that this work may be useful to accelerate the development of anti-inflammatory drugs originated from traditional herbs and improve therapeutics in gout and its complications.
Assuntos
Anti-Inflamatórios , Euphorbia , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Humanos , Masculino , Camundongos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Artrite Gotosa/tratamento farmacológico , Artrite Gotosa/imunologia , Artrite Gotosa/metabolismo , Artrite Gotosa/induzido quimicamente , Modelos Animais de Doenças , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Euphorbia/química , Gota/tratamento farmacológico , Gota/imunologia , Gota/patologia , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ácido ÚricoRESUMO
We report two patients with pancreatic tophaceous gout diagnosed by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of presumed cystic mass lesions. The first case involved a patient who had a recent episode of acute pancreatitis 6 months prior, with subsequent imaging concerning for a pseudocyst or mass lesion. The second case involved a patient with epigastric pain associated with a pancreatic head cystic mass and an erroneous original diagnosis of a mucinous pancreatic neoplasm on EUS-FNA. Diff-Quik stained direct smears on fresh material obtained from EUS-FNA of the lesions showed chalky debris with needle shaped negatively birefringent crystals consistent with gout. For the first case, the chalky material was not present on the H&E stained paraffin embedded formalin fixed cellblock slides. The importance of inclusion of cytologic specimen preparations to examine monosodium urate crystals is emphasized.
Assuntos
Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Gota , Humanos , Gota/patologia , Gota/diagnóstico , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Masculino , Pessoa de Meia-Idade , Idoso , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/diagnóstico , Pâncreas/patologia , Pâncreas/diagnóstico por imagem , Feminino , Pancreatopatias/patologia , Pancreatopatias/diagnósticoRESUMO
BACKGROUND: Gout is caused by monosodium urate (MSU) crystals deposition to trigger immune response. A recent study suggested that inhibition of Class I Histone deacetylases (HDACs) can significantly reduce MSU crystals-induced inflammation. However, which one of HDACs members in response to MSU crystals was still unknown. Here, we investigated the roles of HDAC3 in MSU crystals-induced gouty inflammation. METHODS: Macrophage specific HDAC3 knockout (KO) mice were used to investigate inflammatory profiles of gout in mouse models in vivo, including ankle arthritis, foot pad arthritis and subcutaneous air pouch model. In the in vitro experiments, bone marrow-derived macrophages (BMDMs) from mice were treated with MSU crystals to assess cytokines, potential target gene and protein. RESULTS: Deficiency of HDAC3 in macrophage not only reduced MSU-induced foot pad and ankle joint swelling but also decreased neutrophils trafficking and IL-1ß release in air pouch models. In addition, the levels of inflammatory genes related to TLR2/4/NF-κB/IL-6/STAT3 signaling pathway were significantly decreased in BMDMs from HDAC3 KO mice after MSU treatment. Moreover, RGFP966, selective inhibitor of HDAC3, inhibited IL-6 and TNF-α production in BMDMs treated with MSU crystals. Besides, HDAC3 deficiency shifted gene expression from pro-inflammatory macrophage (M1) to anti-inflammatory macrophage (M2) in BMDMs after MSU challenge. CONCLUSIONS: Deficiency of HDAC3 in macrophage alleviates MSU crystals-induced gouty inflammation through inhibition of TLR2/4 driven IL-6/STAT3 signaling pathway, suggesting that HDAC3 could contribute to a potential therapeutic target of gout.
Assuntos
Acrilamidas , Gota , Histona Desacetilases , Macrófagos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenilenodiaminas , Ácido Úrico , Animais , Ácido Úrico/toxicidade , Histona Desacetilases/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/deficiência , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Gota/metabolismo , Gota/patologia , Camundongos , Inflamação/metabolismo , Inflamação/induzido quimicamente , Masculino , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/metabolismo , Artrite Gotosa/patologia , Modelos Animais de Doenças , Transdução de Sinais/efeitos dos fármacosRESUMO
OBJECTIVE: Tophaceous lesions of the middle ear from calcium pyrophosphate deposition disease (CPPD, or pseudogout) and gout are infrequently reported. Recognizing its characteristic findings will allow clinicians to accurately narrow the differential diagnosis of bony-appearing middle ear lesions and improve management. PATIENTS: Two consecutive cases of tophaceous middle ear lesions presenting to a tertiary care center between January 2021 and December 2021. Neither with previous rheumatologic history. INTERVENTIONS: Surgical excision of tophaceous middle ear lesions. MAIN OUTCOME MEASURE: Improvements in facial weakness and conductive hearing loss. RESULTS: The first case was a 66-year-old gentleman with progressive conductive loss, ipsilateral progressive facial weakness over years, and an opaque, irregular-appearing tympanic membrane anterior to the malleus found to have CPPD on surgical pathology, with immediate postoperative improvement of facial function. The second was a 75-year-old gentleman with progressive conductive loss and similar appearing tympanic membrane as case 1, previously diagnosed with tympanosclerosis, found to have gout on surgical pathology. In both cases, the CT showed a heterogenous, bony-appearing lesion in the middle ear, and both tophaceous lesions were a of gritty, chalky consistency intraoperatively. CONCLUSION: Tophaceous lesions of the middle ear are rare but have similar findings. Notably, the tympanic membrane can appear opaque and irregular, and the CT demonstrates a radiopaque, heterogeneous appearance. Facial weakness is an unusual finding. Specimens of suspected tophi must be sent to pathology without formalin for accurate diagnosis.
Assuntos
Condrocalcinose , Paralisia Facial , Gota , Masculino , Humanos , Idoso , Orelha Média/diagnóstico por imagem , Orelha Média/cirurgia , Orelha Média/patologia , Membrana Timpânica/patologia , Gota/diagnóstico , Gota/patologia , Perda Auditiva Condutiva/etiologia , Perda Auditiva Condutiva/cirurgia , Perda Auditiva Condutiva/diagnóstico , Paralisia Facial/patologiaRESUMO
Monosodium urate (MSU) crystal deposition in joints can lead to the infiltration of neutrophils and macrophages, and their activation plays a critical role in the pathological progress of gout. However, the role of MSU crystal physicochemical properties in inducing cell death in neutrophil and macrophage is still unclear. In this study, MSU crystals of different sizes are synthesized to explore the role of pyroptosis in gout. It is demonstrated that MSU crystals induce size-dependent pyroptotic cell death in bone marrow-derived neutrophils (BMNs) and bone marrow-derived macrophages (BMDMs) by triggering NLRP3 inflammasome-dependent caspase-1 activation and subsequent formation of N-GSDMD. Furthermore, it is demonstrated that the size of MSU crystal also determines the formation of neutrophil extracellular traps (NETs) and aggregated neutrophil extracellular traps (aggNETs), which are promoted by the addition of interleukin-1ß (IL-1ß). Based on these mechanistic understandings, it is shown that N-GSDMD oligomerization inhibitor, dimethyl fumarate (DMF), inhibits MSU crystal-induced pyroptosis in BMNs and J774A.1 cells, and it further alleviates the acute inflammatory response in MSU crystals-induced gout mice model. This study elucidates that MSU crystal-induced pyroptosis in neutrophil and macrophage is critical for the pathological progress of gout, and provides a new therapeutic approach for the treatment of gout.
Assuntos
Gota , Macrófagos , Neutrófilos , Piroptose , Ácido Úrico , Gota/patologia , Gota/metabolismo , Animais , Neutrófilos/metabolismo , Neutrófilos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Piroptose/efeitos dos fármacos , Camundongos , Armadilhas Extracelulares/metabolismo , Armadilhas Extracelulares/efeitos dos fármacos , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Caspase 1/metabolismoRESUMO
Abstract Serum uric acid (UA) is a traditional biomarker in the clinical diagnosis of gout and hyperuricemia. However, serum treatment and storage are cumbersome, and wounds are susceptible to infection. Therefore, in this study, a simple and noninvasive method was developed to detect the UA in human saliva to monitor the gout. An Inertsil ODS-3 column was used for the analysis under the condition of isocratic elution with the mixed solution phosphate buffer (74 mM, pH=2.2): Methanol=98:2 (v:v) and the UV detection at 284 nm. Using salivary UA data from healthy volunteers (HVs) (n=68) and gout patients (GPs) (n=14), we examined the salivary UA difference in their content. The intra-and inter-day accuracy and precision (RSD %) were less than 2.56%, the limit of detection (LOD) of UA was 5.0 ng/mL, the mean recoveries of the corresponding compounds were 102.48%. Saliva levels of UA in HVs and GPs were 35.26±14.06 µg/mL and 91.96±23.90 µg/mL, respectively. The concentrations of salivary UA in GPs were significantly higher than those in HVs ( p < 0.001). This method was also expected to monitor the hyperuricemia and other metabolic disorders in the future
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Saliva , Ácido Úrico/análise , Estudo de Validação , Voluntários Saudáveis/classificação , Gota/patologia , Pacientes/classificação , Cromatografia Líquida de Alta Pressão/métodosRESUMO
ABSTRACT Gout is an inflammatory arthritis characterized by the deposition of monosodium urate crystals in the synovial membrane, articular cartilage and periarticular tissues leading to inflammation. Men are more commonly affected, mainly after the 5th decade of life. Its incidence has been growing with the population aging.In the majority of the cases, the diagnosis is made by clinical criteria and synovial fluid analysis, in search for monosodium urate crystals. Nonetheless, gout may sometimes have atypical presentations, complicating the diagnosis. In these situations, imaging methods have a fundamental role, aiding in the diagnostic confirmation or excluding other possible differential diagnosis. Conventional radiographs are still the most commonly used method in gout patients’ evaluation; nevertheless, this is not a sensitive method, since it detect only late alterations. In the last years, there have been several advances in imaging methods for gout patients. Ultrasound has shown a great accuracy in the diagnosis of gout, identifying monosodium urate deposits in the synovial membrane and articular cartilage, in detecting and characterizing tophi and in identifying tophaceous tendinopathy and enthesopathy. Ultrasound has also been able to show crystal deposition in patients with articular pain in the absence of a classical gout crisis. Computed tomography is an excellent method for detecting bone erosions, being useful in spine involvement. Dual-energy CT is a new method able to provide information about the chemical composition of tissues, with high accuracy in the identification of monosodium urate deposits, even in the early stages of the disease and in cases of difficult characterization. Magnetic resonance imaging is useful in the evaluation of deep tissues not accessible by ultrasound. Besides the diagnosis, with the emergence of new drugs that aim to reduce tophaceous burden, imaging methods have become useful tools in monitoring the treatment of patients with gout.
RESUMO A gota é uma artrite caracterizada pela deposição de cristais de monourato sódico na membrana sinovial, na cartilagem articular e nos tecidos periarticulares que leva a um processo inflamatório. Na maioria dos casos o diagnóstico é estabelecido por critérios clínicos e pela análise do líquido sinovial, em busca dos cristais de MSU. Porém, a gota pode se manifestar de maneiras atípicas e dificultar o diagnóstico. Nessas situações, os exames de imagem têm papel fundamental, auxiliam na confirmação diagnóstica ou ainda excluem outros diagnósticos diferenciais. A radiografia convencional ainda é o método mais usado no acompanhamento desses pacientes, porém é um exame pouco sensível, por detectar somente alterações tardias. Nos últimos anos, surgiram avanços nos métodos de imagem em relação à gota. O ultrassom se mostra um exame de grande acurácia no diagnóstico de gota, identifica depósitos de MSU na cartilagem articular e nos tecidos periarticulares e detecta e caracteriza tofos, tendinopatias e entesopatias por tofos. A tomografia computadorizada é um ótimo exame para a detecção de erosões ósseas e avaliação do acometimento na coluna. A tomografia computadorizada de dupla-energia, um método novo, fornece informações sobre a composição química dos tecidos, permite a identificação dos depósitos de MSU com elevada acurácia. A ressonância magnética pode ser útil na avalição dos tecidos profundos, não acessíveis ao ultrassom. Além do diagnóstico, com o surgimento de drogas que visam reduzir a carga tofácea, os exames de imagem se tornam uma ferramenta útil no acompanhamento do tratamento dos pacientes com gota.
Assuntos
Humanos , Imageamento por Ressonância Magnética , Imagem Radiográfica a Partir de Emissão de Duplo Fóton , Gota/terapia , Gota/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Gota/patologiaRESUMO
Abstract: Psoriasis is a chronic inflammatory disease of multifactorial etiology influenced by genetic, immunological, and environmental factors. We report the case of a patient with psoriasis for more than 25 years who developed hyperuricemia and chronic tophaceous gout with unusual appearance. In psoriasis, hyperuricemia may occur by increased epidermal cell turnover, which accelerates purine metabolism and has uric acid as the product of its catabolism. The association of psoriasis with hyperuricemia can trigger the onset of gouty arthritis, and pose a greater risk of developing other inflammatory comorbidities. Therefore, it is important to periodically investigate uric acid levels in order to treat changes triggered by hyperuricemia.
Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/complicações , Hiperuricemia/etiologia , Gota/etiologia , Doença Crônica , Gota/patologiaAssuntos
Humanos , Masculino , Idoso , Dedos/patologia , Gota/patologia , Dermatoses da Mão/patologia , Biópsia , Derme/patologiaAssuntos
Pessoa de Meia-Idade , Hiperuricemia , Pé , Gota/diagnóstico , Gota/patologia , Diagnóstico DiferencialRESUMO
La monoartritis es un reto diagnóstico para el clínico, ya que es extensa la lista de patologías asociadas. En pacientes con diagnóstico establecido de enfermedad articular inflamatoria, se acepta que la monoartritis corresponde a la exacerbación de la enfermedad de base; sin embargo, ignorar el abordaje sistematizado de las monoartritis puede generar omisiones e implicaciones diagnósticas erróneas. En este reporte se analiza el abordaje de un caso de artritis seudoséptica, simulando un ataque agudo de artritis por urato monosódico recurrente en un paciente con retención de cuerpo extraño intraarticular.
Monoarthritis is a diagnostic challenge for the clinician, as the list of associated conditions is quite long. It is accepted that in patients with a diagnosis of inflammatory joint disease monoarthritis represents exacerbation of the underlying disease. However, ignoring the systematized approach to monoarthritides may lead to omissions and mistaken diagnostic implications. This report describes the approach to a case of pseudoseptic arthritis that mimicked an acute episode of recurrent arthritis due to monosodium urate in a patient with retention of an intraarticular foreign body.
Assuntos
Adulto , Humanos , Masculino , Artrite Infecciosa/diagnóstico , Corpos Estranhos/diagnóstico , Gota/patologia , Sinovite/diagnóstico , Artrite Infecciosa/patologia , Corpos Estranhos/patologia , Sinovite/patologia , Ácido Úrico/metabolismoRESUMO
La lesión articular por microcristales de urato monosódico es la artritis mas frecuente en el sexo masculino entre los 40 y 60 años. Su presentación clínica clásica esta precedida por un estado morbido de hiperuricemia que debe ser adecuadamente reconocido y manejado. Una vez la gota se presenta clínicamente el papel del médico consiste no solo en tratar el episodio agudo sino en realizar un enfoque diagnóstico y terapéutico acorde con los parámetros internacionales, buscando un control sintomático rápido y seguro. Esta revisiàn incluye conceptos sobre la etiopatogenia, presentación clínica, criterios de diagnóstico y las diferentes opciones terapéuticas disponibles hoy en dia.
Assuntos
Ácido Úrico/análise , Ácido Úrico/efeitos adversos , Gota/diagnóstico , Gota/tratamento farmacológico , Gota/etiologia , Gota/patologiaRESUMO
Gouty tenosynovitis may present as infection, tendon rupture, nerve compression and/or digital stiffness. We report a case of tophaceous gout which presented as bilateral carpal tunnel syndrome.
Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Gota/complicações , Síndrome do Túnel Carpal/etiologia , Articulação do Punho/patologia , Articulação do Punho , Gota/patologia , GotaRESUMO
Part II of the cutaneous deposition disorders focuses on cutaneous calcification and ossification, alkaptonuria and ochronosis, and gout. These disorders have in common the deposition of materials in the dermis or subcutis and often involve metabolic defects in hormonal and enzymatic regulation. The pathogenesis, clinical findings, and treatment of these diseases are discussed. Both the histologic and ultrastructural findings are reviewed.
Assuntos
Humanos , Alcaptonúria/patologia , Calcinose/patologia , Dermatopatias/patologia , Gota/patologia , Ocronose/patologia , Ossificação Heterotópica/patologiaRESUMO
Se presenta un caso anátomo-clínico de Gota en un paciente de 1 mes y medio de edad, cuyo diagnóstico, confirmado por la autopsia, no fue sospechado durante su evolución. Son muy pocos los casos publicados a tan corta edad y puede concluirse que se trata de un caso excepcional de interés pediátrico