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RATIONALE AND OBJECTIVES: To assess the consistency between ultrasound and dual-energy computed tomography (DECT) for the diagnosis of gout in the knee joint. MATERIALS AND METHODS: The ultrasound and DECT images of 176 knee joints from 167 patients diagnosed with gout at the Gout Specialty Clinic of Qingdao University Affiliated Hospital from February 2022 to December 2023 were retrospectively analyzed. The knee joint was segmented into five anatomical regions: intra-articular, anterior, posterior, medial, and lateral. The location of monosodium urate (MSU) crystal deposition was recorded. Tophi were classified as hypoechogenic, isoechogenic, hyperechogenic, or strongly echogenic. The Kappa test was used to assess the consistency between the two examination methods in different regions of the knee joint. The McNemar chi-square test was utilized to conduct a differential analysis between the DECT and ultrasound results. The chi-square test was used to assess differences in the rate of tophi detection with different echogenicities by DECT. Pearson's correlation coefficient was used to assess the correlation between MSU crystal deposition volume and clinically relevant indicators. RESULTS: Double contour (61.4%) was the most common intra-articular ultrasound sign. In the extra-articular region, MSU crystals were commonly deposited in and around the popliteal groove region (ultrasound: 52.3%; DECT: 60.0%). Corresponding MSU deposits on DECT were found in 7 of 54 joints with aggregates detected on ultrasound, and in 15 of 108 joints with DC. Tophi with hyperechogenicity or strong echogenicity were more likely to be detected on DECT than those with hypoechoic or isoechoic features (84.3% and 90.9% vs. 55.1% and 27.8%, respectively). For the assessment of MSU deposits, ultrasound showed an overall higher positive rate than DECT (81.1% vs. 72.2%), with poor consistency between the two examinations (κ = 0.177). In distinct anatomical regions, ultrasound and DECT showed high consistency in the medial (κ = 0.651) and lateral (κ = 0.705) views, with no significant difference. The intra-articular (κ = 0.316) and anterior (κ = 0.346) regions exhibited only fair consistency, with statistically significant diagnostic differences. When exclusively assessing cases with tophi, ultrasound and DECT demonstrated similar consistency in the medial, lateral and anterior views (κ = 0.633, 0.712, and 0.400, respectively), with statistically significant differences. In the intra-articular region, the consistency was reduced (κ = 0.237), and the differences were statistically significant. CONCLUSION: Ultrasound and DECT are effective methods to detect MSU deposition in gout of the knee. However, the consistency between the two techniques varies in different anatomical locations. Clinical assessment should be tailored based on the specific anatomical position. DECT is advantageous for the evaluation of intra-articular MSU deposits, while ultrasound is more sensitive for the early detection of scattered MSU deposits.
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Objective: The pleiotropic effect of hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) is responsible for potent defense against inflammatory response. This study evaluated the inhibitory effects of HMG-CoA reductase inhibitors on the monosodium urate (MSU)-induced inflammatory response through the regulation of interleukin-37 (IL-37) expression. Methods: Serum was collected from patients with gout (n = 40) and from healthy controls (n = 30). The mRNA and protein expression of the target molecules IL-1ß, IL-37, caspase-1, and Smad3 were measured in THP-1 macrophages stimulated with MSU, atorvastatin, or rosuvastatin using a real-time quantitative polymerase chain reaction and Western blot assay. Transfection with IL-1ß or Smad3 siRNA in THP-1 macrophages was used to verify the pharmaceutical effect of statins in uric-acid-induced inflammation. Results: Serum IL-37 levels in gout patients were significantly higher than in controls (p < 0.001) and was associated with the serum uric acid level (r = 0.382, p = 0.008). THP-1 cells stimulated with MSU markedly induced IL-37 mRNA expression and the transition of IL-37 from the cytoplasm to the nucleus. Recombinant IL-37 treatment dose-dependently inhibited activation of caspase-1 and IL-1ß in MSU-induced inflammation. Atorvastatin and rosuvastatin attenuated caspase-1 activation and mature IL-1ß expression but augmented translocation of IL-37 from the cytoplasm to the nucleus. Atorvastatin and rosuvastatin induced phosphorylation of Smad3 in THP-1 cells treated with MSU crystals. Statins potently attenuated translocation of IL-37 from the cytoplasm to the nucleus in THP-1 macrophages transfected with Smad3 siRNA compared to cells with negative control siRNA. Conclusions: This study revealed that statins inhibit the MSU-induced inflammatory response through phosphorylated Smad3-mediated IL-37 expression in THP-1 macrophages.
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Xanthohumol (XAN) is an isoprenyl flavonoid from Humulus lupulus L. known for beer brewing, and an osteoprotective agent due to its active improvement in bone loss of osteoporosis. This study was first time to investigate its effects on anti-gouty bone injury in rats of gouty arthritis (GA) induced by monosodium urate (MSU). Results showed that XAN could significantly exert anti-inflammatory activity by alleviating swelling degree of joints, reducing serum level of inflammatory factors, improving inflammatory injury and degrading the Markin's score in lesion joint. Meanwhile, XAN could also fight against gouty bone damage by improving pathological changes of bone tissue and parameters of bone micro-structure. Moreover, XAN could even promote bone formation by effectively enhancing expression of Runx2 and OPG, while inhibit bone resorption with depressing matrix metalloproteinase-9 (MMP-9), MMP-13 and CTSK expression, reducing RANKL secretion, and abating the ratio of RANKL/OPG. Therefore, it was the first time to reveal the mechanism of XAN against gouty bone injury via inhibiting RANKL/OPG/RANK signaling pathway. Above all, this study provided potential strategy for the treatment of GA, and further contributed to research and resource development for hops.
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Background: Spinal gout, a rare and often underdiagnosed condition, significantly impacts patients' quality of life. Therefore, the aim of the research is to analyze cases of spinal gout, including clinical features, anatomical location of spinal gout, laboratory studies, imaging studies, treatment choices, and outcomes from various cases of spinal gout. Methods: The author conducted a systematic literature search in the PUBMED and Science Direct databases from 2013 to 2023. We included clinical case presentations of spinal cases in adults, published in English. The three researchers independently reviewed the title and abstract of each article, and any differences in opinions were resolved through consensus. The extracted data were subsequently analyzed descriptively. Results: A total of 88 cases of spinal gout were obtained and studied. Out of the total reviewed cases of spinal gout, 89.77% of the subjects were male, with an average age of 51.9 years (age range 16-87 years). Common symptoms include back/neck pain (78.41%) and lower extremity weakness (37.50%). The lumbar spine is the most frequently affected region (62.50%), diagnosed primarily through magnetic resonance imaging (MRI) scans. Surgery, performed in 61.36% of cases, commonly involves decompressive laminectomy. Posttreatment, symptoms resolve in 87.50% of cases. Conclusion: Cases of spinal gout present with a variety of symptoms, including back pain and weakness. Diagnosis typically involves an MRI examination and synovial fluid analysis for confirmation. Treatment varies and includes medication therapy and surgical interventions. A deeper understanding of these cases can assist healthcare practitioners in the management and diagnosis of spinal gout cases.
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Hyperuricemic patients (≥7.8 mg/dL) can develop polyarticular tophaceous gout from intermittent arthritis if untreated. Acute flares and tophi development can be avoided by lowering blood urate levels with xanthine oxidase inhibitors.
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BACKGROUND: Persistent hyperuricemia can lead to the generation and deposition of monosodium urate (MSU) crystals. This can trigger gouty arthritis (GA), which in turn induces inflammation. Activation of the Nod-like receptor pyrin domain containing 3 (NLRP3) inflammasome plays a critical role in the onset and progression of GA. Autophagy may have a dual effect on GA with regard to the NLRP3 inflammasome. Therefore, the present study aimed to gain a deeper comprehension of the interaction between autophagy and NLRP3 inflammasome activation is imperative for developing more efficacious treatments for GA. METHODS: Peripheral blood monocytes (PBMCs) were first isolated from GA patients and healthy controls and underwent bulk RNA sequencing analysis. Overexpression and knockdown of dual specificity phosphatase 1 (DUSP1) was performed in THP-1 monocytes to investigate its role in the immune response and mitochondrial damage. The luciferase assay and Western blot analysis were used to study the interaction between autophagy and NLRP3 inflammasome activation. RESULTS: Bulk RNA sequencing analysis showed significant upregulation of DUSP1 expression in PBMCs from GA patients compared to healthy controls. This result was subsequently verified by reverse transcription quantitative polymerase chain reaction (RT-qPCR). DUSP1 expression in human THP-1 monocytes was also shown to increase after MSU treatment. Downregulation of DUSP1 expression increased the secretion of inflammatory cytokines after MSU treatment, whereas the overexpression of DUSP1 decreased the secretion levels. Lipopolysaccharides (LPS) combined with adenosine-triphosphate (ATP) led to mitochondrial damage, which was rescued by overexpressing DUSP1. DUSP1 overexpression further increased the level of autophagy following MSU treatment, whereas downregulation of DUSP1 decreased autophagy. Treatment with the autophagy inhibitor 3-Methyladenine (3-MA) restored inflammatory cytokine secretion levels in the DUSP1 overexpression group. MSU caused pronounced pathological ankle swelling in vivo. However, DUSP1 overexpression significantly mitigated this phenotype, accompanied by significant downregulation of inflammatory cytokine secretion levels in the joint tissues. CONCLUSIONS: This study revealed a novel function and mechanism for DUSP1 in promoting autophagy to mitigate the MSU-induced immune response in GA. This finding suggests potential diagnostic biomarkers and anti-inflammatory targets for more effective GA therapy.
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Artritis Gotosa , Autofagia , Fosfatasa 1 de Especificidad Dual , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Ácido Úrico , Humanos , Autofagia/efectos de los fármacos , Fosfatasa 1 de Especificidad Dual/genética , Fosfatasa 1 de Especificidad Dual/metabolismo , Artritis Gotosa/genética , Artritis Gotosa/metabolismo , Artritis Gotosa/inmunología , Artritis Gotosa/inducido químicamente , Ácido Úrico/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Inflamasomas/metabolismo , Inflamasomas/inmunología , Células THP-1 , Masculino , Monocitos/metabolismo , Monocitos/inmunología , Monocitos/efectos de los fármacos , Estudios de Casos y Controles , Femenino , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Persona de Mediana EdadRESUMEN
The aim of this study was to validate the preventive effects of koumine (KM), a monoterpene indole alkaloid, on gouty arthritis (GA) and to explore its possible mechanisms. C57BL/6 mice were intraperitoneally administered KM (0.8, 2.4 or 7.2 mg/kg), colchicine (3.0 mg/kg) or sterile saline. One hour later, a monosodium urate (MSU) suspension was injected into the right hind paws of the mice to establish an acute gout model. Inflammation symptoms were evaluated at 0, 3, 6, 12 and 24 h, and the mechanical withdrawal threshold was evaluated at 0, 6 and 24 h. After 24 h, the mice were euthanized, and the joint tissue, kidney and blood were collected for subsequent experiments. Histological examination and antioxidant enzyme, kidney index and serum uric acid (UA) measurements were taken. The expression levels of the signalling pathway components were determined. KM effectively alleviated the symptoms of redness, swelling and pain; counteracted inflammatory cell infiltration; and increased antioxidant enzyme levels, reduced kidney index and serum UA levels through regulating UA excretion in MSU-induced mice. The expression of toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB)/nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) signalling pathway proteins and mRNA were reduced in the KM group. These results suggest that KM may be effective in alleviating GA through the TLR4/NF-κB/NLRP3 pathway.
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Artritis Gotosa , Ratones Endogámicos C57BL , FN-kappa B , Proteína con Dominio Pirina 3 de la Familia NLR , Transducción de Señal , Receptor Toll-Like 4 , Ácido Úrico , Animales , Artritis Gotosa/inducido químicamente , Artritis Gotosa/tratamiento farmacológico , Artritis Gotosa/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Receptor Toll-Like 4/metabolismo , FN-kappa B/metabolismo , Ácido Úrico/sangre , Transducción de Señal/efectos de los fármacos , Masculino , Ratones , Alcaloides Indólicos/farmacología , Modelos Animales de Enfermedad , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Colchicina/farmacologíaRESUMEN
Objective: This study investigates the MRI features of knee gouty arthritis (KGA), examines its relationship with the extent of tissue involvement, and assesses whether risk factors can predict KGA. Materials and methods: Patients diagnosed with KGA underwent MRI examinations, and two independent observers retrospectively analyzed data from 44 patients (49 knees). These patients were divided into mild and severe groups based on tissue involvement observed during arthroscopy. MRI features were summarized, and the intraclass correlation coefficient evaluated interobserver reproducibility. Single-factor analysis compared clinical indicators and MRI features between groups, while Cramer's V coefficient assessed correlations. Multivariate logistic regression identified predictors of tissue involvement extent, and a ROC curve evaluated diagnostic performance. Results: Among 49 knees, 18 had mild and 31 had severe tissue involvement. Key MRI features included ligament sketch-like changes, meniscal urate deposition, irregularly serrated cartilage changes, low-signal signs within joint effusion, synovial proliferation, Hoffa's fat pad synovitis, gouty tophi, bone erosion, and bone marrow edema. The interobserver reliability of the MRI features was good. Significant differences (P < 0.05) were observed between the groups for anterior cruciate ligament (ACL) sketch-like changes, Hoffa's fat pad synovitis, and gouty tophi. ACL sketch-like changes (r = 0.309), Hoffa's fat pad synovitis (r = 0.309), and gouty tophi (r = 0.408) were positively correlated with the extent of tissue involvement (P < 0.05). ACL sketch-like changes (OR = 9.019, 95 % CI: 1.364-61.880), Hoffa's fat pad synovitis (OR = 6.472, 95 % CI: 1.041-40.229), and gouty tophi (OR = 5.972, 95 % CI: 1.218-29.276) were identified as independent predictors of tissue involvement extent (P < 0.05). The area under the ROC curve was 0.862, with a sensitivity of 67.70 %, specificity of 94.40 %, and accuracy of 79.14 %. Conclusion: This comprehensive analysis of MRI features identifies ligament sketch-like changes, meniscal urate deposition, and low-signal signs within joint effusion as characteristic MRI manifestations of KGA. Irregular cartilage changes are valuable for differential diagnosis in young and middle-aged patients. ACL sketch-like changes, Hoffa's fat pad synovitis, and gouty tophi correlate with tissue involvement severity and are critical in predicting and assessing the extent of tissue involvement in KGA.
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PURPOSE OF REVIEW: To highlight novel findings in the detection of monosodium urate deposits in vessels using dual energy computed tomography, and to discuss the potential clinical implications for gout and hyperuricemia patients. RECENT FINDINGS: Gout is an independent risk factor for cardiovascular disease. However, classical risk calculators do not take into account these hazards, and parameters to identify patients at risk are lacking. Monosodium urate measured by dual energy computed tomography is a well-established technology for the detection and quantification of monosodium urate deposits in peripheral joints and tendons. Recent findings also suggest its applicability to identify vascular urate deposits. Dual energy computed tomography is a promising tool for detection of cardiovascular monosodium urate deposits in gout patients, to better delineate individuals at increased risk for cardiovascular disease.
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Gota , Tomografía Computarizada por Rayos X , Ácido Úrico , Humanos , Ácido Úrico/análisis , Tomografía Computarizada por Rayos X/métodos , Gota/diagnóstico por imagen , Hiperuricemia/diagnóstico por imagen , Enfermedades Cardiovasculares/diagnóstico por imagenRESUMEN
Gout flare-up, commonly resulting from monosodium urate monohydrate (MSUM) crystallization, has led to painful inflammatory arthritis among hundreds of millions of people. Herein, a kind of hydrogel nanoparticles (HNPs) with specific properties was developed, aimed at providing a promising pathway for MSUM crystallization control. The experimental and molecular dynamics simulation results synchronously indicate that the fabricated HNPs achieve efficient inhibition of MSUM crystallization governed by the mechanism of "host-guest interaction" even under very low-dose administration. HNPs as the host dispersed in the hyperuricemic model effectively lift the relative heterogeneous nucleation barrier of the MSUM crystal and hinder solute aggregation with strong electronegativity and hydrophobicity. The initial appearance of MSUM crystals was then delayed from 94 to 334 h. HNPs as the guest on the surface of the formed crystal can decelerate the growth rate by anchoring ions and occupying the active sites on the surface, and the terminal yield of the MSUM crystal declined to less than 1% of the control group. The good biocompatibility of HNPs (cell viability > 94%) renders it possible for future clinical applications. This study can guide the rational design of inhibitory nanomaterials and the development of their application in the control of relevant pathological crystallization.
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Cristalización , Hidrogeles , Simulación de Dinámica Molecular , Nanopartículas , Ácido Úrico , Ácido Úrico/química , Hidrogeles/química , Nanopartículas/química , Animales , Supervivencia Celular/efectos de los fármacos , Ratones , Tamaño de la Partícula , Iones/química , Propiedades de SuperficieRESUMEN
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.
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Acrilamidas , Gota , Histona Desacetilasas , Macrófagos , Ratones Endogámicos C57BL , Ratones Noqueados , Fenilendiaminas , Ácido Úrico , Animales , Ácido Úrico/toxicidad , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genética , Histona Desacetilasas/deficiencia , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Gota/metabolismo , Gota/patología , Ratones , Inflamación/metabolismo , Inflamación/inducido químicamente , Masculino , Artritis Gotosa/inducido químicamente , Artritis Gotosa/metabolismo , Artritis Gotosa/patología , Modelos Animales de Enfermedad , Transducción de Señal/efectos de los fármacosRESUMEN
Background: Ultrasound (US) has a high sensitivity in detecting monosodium urate (MSU) deposition in gout patients. However, the value of US in predicting gout flares has been reported only in a few monocentric studies. Objective: To investigate the association between gout flares in the previous year and US-detected MSU burden using two different US scores. Design: A retrospective study. Methods: Patients with gout were consecutively recruited to undergo musculoskeletal US examinations of their knees, ankles, and feet. The score derived from Outcome Measure in Rheumatology (hereinafter referred to as MSU score) and musculoskeletal US features-based (hereinafter referred to as MSKF score) were used to quantify the MSU burden of gout. Odds ratios for frequent gout flares were calculated. Results: We enrolled 1894 patients with gout (mean age: 45 years; gout duration: 5 years; males: 96.1%), experiencing a median of three flares over the past year. Of these, 428 (22.6%) patients reported frequent (⩾7) gout flares. The MSU and MSKF median scores were 6 and 9, respectively. For each five-point increase in MSU and MSKF score, the odds ratio of frequent gout flares increased 1.13-fold and 1.24-fold, respectively. The area under the curve (AUC) for the MSU and MSKF score was 0.635 [95% confidence interval (CI): 0.604-0.665] and 0.688 (95% CI: 0.659-0.718), respectively, (AUC difference 0.054, p value for AUC difference < 0.001). Conclusion: The MSU and MSKF scores were significantly associated with the number of gout flares in the previous year. The MSKF score outperformed the MSU score in terms of frequent gout flare discrimination.
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Pyroptosis is a programmed cell death process that frequently occurs in many diseases, including hyperuricemic nephropathy (HN). In HN, a range of stimuli mediates inflammation, leading to the activation of inflammasomes and the production of gasdermin D (GSDMD). Baicalin (BA), a natural flavonoid renowned for its antioxidant and anti-inflammatory properties, was investigated for its role in HN in this study. Initially, HN-like inflammation and pyroptosis were induced in HK-2 cells with treatment of monosodium urate (MSU), followed by the BA treatment. The expression of pyroptosis-associated genes, Panx-1 and P2X7, at both mRNA and protein levels was assessed through real-time polymerase chain reaction (RT-qPCR) and Western blotting (WB) without or with BA treatment. The results showed that expression of Panx-1 and P2X7 at mRNA and protein levels was increased in MSU-treated HK-2 cells, which subsequently decreased upon the BA treatment. Further experiments showed that BA could combine NLRP3 inflammasome and GSDMD, destabilizing GSDMD protein. Moreover, BA protected the cell membrane from MSU-induced damage, as evidenced by Hoechst 33342 and PI double staining, lactate dehydrogenase (LDH) assays, and electron microscopy observations. These results suggest that BA is involved in the regulating Panx-1/P2X7 pathways and thus inhibits pyroptosis, highlighting its potential therapeutic effect for HN.
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Piroptosis , Ácido Úrico , Humanos , Simulación del Acoplamiento Molecular , Células Epiteliales , Flavonoides/farmacología , Inflamación , ARN Mensajero/genéticaRESUMEN
OBJECTIVE: To determine the association of cardiovascular atherosclerotic plaque monosodium urate deposits with the occurrence of major cardiovascular events in gout and hyperuricemia patients. METHODS: This retrospective cohort study included patients with clinically suspicion of gout, who performed a dual energy computed tomography of the affected limb and thorax between June 1st, 2012 and December 5th, 2019. Clinical and laboratory parameters were retrieved from patients charts. Established cardiovascular risk factors were evaluated. Medical history review identified the presence of major adverse cardiac events with a median follow up time of 33 months (range 0-108 months) after the performed computed tomography scan. RESULTS: Full data sets were available for 189 patients: 131 (69.3%) gout patients, 40 (21.2%) hyperuricemia patients, and 18 (9.5%) controls. Patients with cardiovascular monosodium urate deposits (n = 85/189, 45%) revealed increased serum acute phase reactants, uric acid levels and calcium scores in computed tomography compared with patients without cardiovascular monosodium urate deposits. Major adverse cardiac events were observed in 35 patients (18.5%) with a higher prevalence in those patients revealing cardiovascular monosodium urate deposits (n = 22/85, 25.9%) compared with those without cardiovascular monosodium urate deposits (n = 13/104, 12.5%, OR 2.4, p= 0.018). CONCLUSION: This is the first study demonstrating the higher hazard of major adverse cardiac events in patients with dual energy computed tomography-verified cardiovascular monosodium urate deposits. The higher prevalence of cardiac events in patients with cardiovascular monosodium urate deposits may facilitate risk stratification of gout patients, as classical cardiovascular risk scores or laboratory markers fail in their proper identification.
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BACKGROUND: Gout is a chronic inflammatory diseases caused by monosodium urate crystal deposition. However, the role of interleukin (IL)-36 in gout has not dbeen elucidated. METHODS: We enrolled 75 subjects, including 20 healthy controls (HC), 30 patients with acute gout attack and 25 patients in remission. Baseline data were obtained through clinical interrogation and laboratory data were obtained through tests of blood samples. Serum levels of IL-36α were detected using enzyme-linked immunosorbent assay. Spearman correlation analysis was used to investigate the correlation of IL-36α with other parameters. The diagnostic value of IL-36α was demonstrated using a receiver operating characteristic curve. RESULTS: The serum IL-36α level of gout patients in acute attack and remission stage was significantly higher than that of HC. Serum IL-36α was positively correlated with alanine transaminase (ALT) and aspartate transaminase (AST). Serum amyloid A (SAA) levels positively correlated with C-reactive protein levels and erythrocyte sedimentation rates. Glutamyl transpeptidase levels positively correlated with AST and ALT levels. CONCLUSION: In conclusion, serum IL-36α levels were elevated in patients with gout and correlated with the clinical markers of inflammation. Our findings suggest that IL-36α may be a novel inflammatory indicator for gout.
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Biomarcadores , Gota , Interleucina-1 , Humanos , Gota/sangre , Gota/diagnóstico , Masculino , Persona de Mediana Edad , Femenino , Interleucina-1/sangre , Biomarcadores/sangre , Adulto , Aspartato Aminotransferasas/sangre , Proteína C-Reactiva/metabolismo , Proteína C-Reactiva/análisis , Alanina Transaminasa/sangre , Curva ROC , Anciano , Proteína Amiloide A Sérica/metabolismo , Sedimentación Sanguínea , Estudios de Casos y Controles , Ácido Úrico/sangre , Relevancia ClínicaRESUMEN
CLEC12A, a member of the C-type lectin receptor family involved in immune homeostasis, recognizes MSU crystals released from dying cells. However, the molecular mechanism underlying the CLEC12A-mediated recognition of MSU crystals remains unclear. Herein, we reported the crystal structure of the human CLEC12A-C-type lectin-like domain (CTLD) and identified a unique "basic patch" site on CLEC12A-CTLD that is necessary for the binding of MSU crystals. Meanwhile, we determined the interaction strength between CLEC12A-CTLD and MSU crystals using single-molecule force spectroscopy. Furthermore, we found that CLEC12A clusters at the cell membrane and seems to serve as an internalizing receptor of MSU crystals. Altogether, these findings provide mechanistic insights for understanding the molecular mechanisms underlying the interplay between CLEC12A and MSU crystals.
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Lectinas Tipo C , Receptores Mitogénicos , Ácido Úrico , Humanos , Gota/metabolismo , Lectinas Tipo C/química , Lectinas Tipo C/inmunología , Receptores Mitogénicos/química , Receptores Mitogénicos/inmunología , Ácido Úrico/química , Ácido Úrico/inmunología , Dominios Proteicos , Cristalografía por Rayos X , Imagen Individual de Molécula , Línea CelularRESUMEN
C-type lectin receptors (CLRs) are a family of pattern recognition receptors, which detect a broad spectrum of ligands via small carbohydrate-recognition domains (CRDs). CLEC12A is an inhibitory CLR that recognizes crystalline structures such as monosodium urate crystals. CLEC12A also recognizes mycolic acid, a major component of mycobacterial cell walls, and suppresses host immune responses. Although CLEC12A could be a therapeutic target for mycobacterial infection, structural information on CLEC12A was not available. We report here the crystal structures of human CLEC12A (hCLEC12A) in ligand-free form and in complex with 50C1, its inhibitory antibody. 50C1 recognizes human-specific residues on the top face of hCLEC12A CRD. A comprehensive alanine scan demonstrated that the ligand-binding sites of mycolic acid and monosodium urate crystals may overlap with each other, suggesting that CLEC12A utilizes a common interface to recognize different types of ligands. Our results provide atomic insights into the blocking and ligand-recognition mechanisms of CLEC12A and leads to the design of CLR-specific inhibitors.
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Lectinas Tipo C , Receptores Mitogénicos , Lectinas Tipo C/inmunología , Lectinas Tipo C/química , Lectinas Tipo C/metabolismo , Humanos , Receptores Mitogénicos/química , Receptores Mitogénicos/inmunología , Receptores Mitogénicos/metabolismo , Cristalografía por Rayos X , Ligandos , Unión Proteica , Sitios de Unión , Modelos Moleculares , Ácido Úrico/química , Ácido Úrico/metabolismo , Ácido Úrico/inmunologíaRESUMEN
OBJECTIVES: To determine the clinical associations and predictive value of two thresholds of negative dual-energy CT (DECT) for MSU crystal deposition in gout patients initiating urate lowering therapy (ULT), and identify which threshold is more clinically relevant. METHODS: Patients from the CRYSTALILLE cohort with a diagnosis of gout naive to ULT with baseline DECT scans of knees and feet were selected. Two thresholds of positivity for DECT detection of MSU crystal deposition were considered (<0.01 cm3 and <0.1 cm3). Baseline characteristics and the prediction of key outcomes after ULT initiation including reaching serum urate (SU) levels <6.0 and 5.0 mg/dl and occurrence of flares at 6, 12 and 24 months, associated with both thresholds of negative DECTs were compared with those of. PATIENT: s having positive DECT scans. RESULTS: 211 patients aged 66.2 years [57; 75.8] with a symptom duration of 3 years [0; 7.8] were included. 38/211 (18%) and 90/211 (43%) had negative DECT scans for the 0.01 and 0.1 cm3 thresholds, respectively. Factors associated with negative DECT scans were younger age, shorter symptom duration, and absence of cardiovascular disease for both volume thresholds. 9/39 (23.1%), 3/26 (11.5%), and 1/18 (5.6%) of patients with <0.1 cm3 MSU crystals had flares at 6, 12 and 24 months, respectively, compared with 18/45 (40.0%), 9/36 (25.0%) and 2/18 (11.1%) patients with ≥0.1 cm3 (p> 0.05).Overall, 95 patients (68.3%) reached SU levels <6.0 mg/dl and 68 (48.9%) <5.0 mg/dl, without any difference between positive and negative DECTs, with ULT dosages which tended to be lower in patients with negative DECT. CONCLUSION: The 0.1 cm3 threshold was better correlated to clinical presentation and evolution than 0.01 cm3. Patients with gout with negative DECTs exhibit milder disease and a lower comorbidity burden. They do not exhibit particularly easy-to-treat hyperuricemia, but may have a lower risk of flares.
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Dual-energy CT (DECT) is an exciting application in CT technology conferring many advantages over conventional single-energy CT at no additional with comparable radiation dose to the patient. Various emerging and increasingly established clinical DECT applications in musculoskeletal (MSK) imaging such as bone marrow oedema detection, metal artefact reduction, monosodium urate analysis, and collagen analysis for ligamentous, meniscal, and disc injuries are made possible through its advanced DECT post-processing capabilities. These provide superior information on tissue composition, artefact reduction and image optimization. Newer DECT applications to evaluate fat fraction for sarcopenia, Rho/Z application for soft tissue calcification differentiation, 3D rendering, and AI integration are being assessed for future use. In this article, we will discuss the established and developing applications of DECT in the setting of MSK radiology as well as the basic principles of DECT which facilitate them.
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Enfermedades de la Médula Ósea , Enfermedades Musculoesqueléticas , Imagen Radiográfica por Emisión de Doble Fotón , Humanos , Tomografía Computarizada por Rayos X/métodos , Imagen Radiográfica por Emisión de Doble Fotón/métodos , Enfermedades Musculoesqueléticas/diagnóstico por imagen , Ácido ÚricoRESUMEN
Objective: Gout is a dangerous metabolic condition related to monosodium urate (MSU). Our aim is to study the molecular mechanisms underlying gout and to identify potential clinical biomarkers by bioinformatics analysis and experimental validation. Methods: In this study, we retrieved the overlapping genes between GSE199950-Differential Expressed Genes (DEGs) dataset and key module in Weighted Gene Co-Expression Network Analysis (WGCNA) on GSE199950. These genes were then analyzed by protein-protein interaction (PPI) network, expression and Gene Set Enrichment Analysis to identify the hub gene related to gout. Then, the gene was investigated by peripheral blood mononuclear cells (PBMCs), immunoassay and cell experiments like western blotting to uncover its underlying mechanism in gout cells. Results: From the turquoise module and 83 DEGs, we identified 62 overlapping genes, only 11 genes had mutual interactions in PPI network and these genes were highly expressed in MSU-treated samples. Then, it was found that the IL1A (interleukin 1 alpha) was the only one gene related to Toll-like receptor signaling pathway that was associated with the occurrence of gout. Thus, IL1A was determined as the hub gene in this study. In immunoassay, IL1A was significantly positively correlated with B cells and negatively correlated with macrophages. Moreover, IL1A is highly expressed in gout patients,it has a good clinical diagnostic value. Finally, the results of in vitro experiments showed that after knocking down IL1A, the expressions of pro-inflammatory cytokines and Toll-like receptor signaling pathway-related proteins (TLR2, TLR4, MyD88) were all reduced. Conclusion: It is confirmed that IL1A is a promoting gene in gout with a good diagnostic value, and specifically it affects the inflammation in gout through Toll-like receptor pathway. Our research offers fresh perspectives on the pathophysiology of gout and valuable directions for future diagnosis and treatment.