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1.
Front Immunol ; 13: 888306, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35464445

RESUMO

Gout, a chronic inflammatory arthritis disease, is characterized by hyperuricemia and caused by interactions between genetic, epigenetic, and metabolic factors. Acute gout symptoms are triggered by the inflammatory response to monosodium urate crystals, which is mediated by the innate immune system and immune cells (e.g., macrophages and neutrophils), the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome activation, and pro-inflammatory cytokine (e.g., IL-1ß) release. Recent studies have indicated that the multiple programmed cell death pathways involved in the inflammatory response include pyroptosis, NETosis, necroptosis, and apoptosis, which initiate inflammatory reactions. In this review, we explore the correlation and interactions among these factors and their roles in the pathogenesis of gout to provide future research directions and possibilities for identifying potential novel therapeutic targets and enhancing our understanding of gout pathogenesis.


Assuntos
Artrite Gotosa , Gota , Artrite Gotosa/metabolismo , Gota/metabolismo , Humanos , Inflamassomos/metabolismo , Macrófagos , Piroptose
2.
Cell Cycle ; 21(8): 805-819, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35239453

RESUMO

Gouty arthritis (GA) is caused by monosodium urate (MSU) crystal accumulation in the joints. MSU-mediated inflammation is an important inducing factor in gouty arthritis (GA). Recent studies have demonstrated that microRNAs can influence GA progression. Herein, the role and mechanism of miRNA-142-3p in GA were explored. To establish the in vitro and in vivo GA models, MSU was used to induce inflammatory response in human monocyte cell line THP-1 and male C57BL/6 mice. Protein levels, gene expression and proinflammatory cytokine secretion were respectively tested by Western blotting, RT-qPCR, and enzyme-linked immunosorbent assay (ELISA). Pathological changes in sagittal sections of ankle tissues were exhibited by hematoxylin-eosin (HE) staining. Binding relationship between miRNA-142-3p and zinc finger E-box binding homeobox 2 (ZEB2) was predicted and confirmed by bioinformatics analysis and luciferase reporter assay. In this study, MSU induced inflammatory response and upregulated miRNA-142-3p in THP-1 cells. Functionally, miRNA-142-3p knockdown inhibited inflammatory response in MSU-stimulated THP-1 cells and alleviated pathological symptoms of GA mice. Mechanically, miRNA-142-3p targeted ZEB2 in THP-1 cells. ZEB2 expression was elevated in MSU-administrated THP-1 cells and GA mice. ZEB2 downregulation reserved the inhibitory effect of miRNA-142-3p deficiency on inflammatory response in MSU-treated THP-1 cells. In addition, miRNA-142-3p activated NF-κB signaling by binding with ZEB2 in THP-1 cells upon MSU stimulation. Overall, miRNA-142-3p facilitates inflammatory response by targeting ZEB2 and activating NF-κB signaling in GA.


Assuntos
Artrite Gotosa , MicroRNAs , Animais , Artrite Gotosa/genética , Artrite Gotosa/metabolismo , Artrite Gotosa/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Ácido Úrico
3.
Cell Rep ; 38(10): 110489, 2022 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-35263587

RESUMO

Monosodium urate crystals (MSUc) induce inflammation in vivo without prior priming, raising the possibility of an initial cell-autonomous phase. Here, using genome-wide transcriptomic analysis and biochemical assays, we demonstrate that MSUc alone induce a metabolic-inflammatory transcriptional program in non-primed human and murine macrophages that is markedly distinct to that induced by LPS. Genes uniquely upregulated in response to MSUc belong to lipid and amino acid metabolism, glycolysis, and SLC transporters. This upregulation leads to a metabolic rewiring in sera from individuals and mice with acute gouty arthritis. Mechanistically, the initiating inflammatory-metabolic changes in acute gout flares are regulated through a persistent expression and increased binding of JUN to the promoter of target genes through JNK signaling-but not P38-in a process that is different than after LPS stimulation and independent of inflammasome activation. Finally, pharmacological JNK inhibition limits MSUc-induced inflammation in animal models of acute gouty inflammation.


Assuntos
Artrite Gotosa , Ácido Úrico , Animais , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/metabolismo , Inflamação/metabolismo , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Camundongos , Ácido Úrico/metabolismo
4.
Immunol Lett ; 244: 28-39, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35288207

RESUMO

Caspase-1 is an integral regulator of innate immunity, which plays a key role in inflammasome activation and the release of pro-inflammatory cytokines. The development of novel non-peptidic small molecule caspase-1 inhibitors is an important strategy for antagonizing excessively activated caspase-1 induced by inflammatory diseases, including gouty arthritis. In the present study, we identified 63 caspase-1 inhibitors, with different structures and potencies, from bioactive compound libraries. Among them, NSC697923 potently inhibited the enzymatic activity of caspase-1, with an IC50 value of 1.737 µM. This compound adopted a favorable conformation in the active pocket of caspase-1. Furthermore, NSC697923 potently decreased mature interleukin (IL)-1ß secretion in macrophages stimulated by lipopolysaccharide plus nigericin, ATP, and monosodium urate crystal. NSC697923 also inhibited NLRP3 protein expression by suppressing the NF-κB signaling pathway and the interaction between receptor interacting protein-2 (RIP2) and pro-caspase-1, thereby blocking the priming of the NLRP3 inflammasome. In addition, NSC697923 significantly inhibited caspase-1 mediated gasdermin D cleavage and pyroptosis in macrophages. In an animal model of gouty arthritis, NSC697923 effectively inhibited joint swelling, IL-1ß release, and NLRP3 inflammasome activation. Our results indicate that NSC697923 can effectively suppress NLRP3 inflammasome activation by inhibiting caspase-1, thus warranting further investigation as a potential therapeutic for treating NLRP3 inflammasome-related diseases.


Assuntos
Artrite Gotosa , Gota , Animais , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/tratamento farmacológico , Artrite Gotosa/metabolismo , Caspase 1/metabolismo , Inflamassomos/metabolismo , Inflamação/tratamento farmacológico , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose
5.
Sci Rep ; 12(1): 157, 2022 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-34997110

RESUMO

The objective of this work was to assess the consequences of repeated intra-articular injection of monosodium urate (MSU) crystals with inflammasome priming by lipopolysaccharide (LPS) in order to simulate recurrent bouts of gout in rats. Translational imaging was applied to simultaneously detect and quantify injury in different areas of the knee joint. MSU/LPS induced joint swelling, synovial membrane thickening, fibrosis of the infrapatellar fat pad, tidemark breaching, and cartilage invasion by inflammatory cells. A higher sensitivity to mechanical stimulus was detected in paws of limbs receiving MSU/LPS compared to saline-injected limbs. In MSU/LPS-challenged joints, magnetic resonance imaging (MRI) revealed increased synovial fluid volume in the posterior region of the joint, alterations in the infrapatellar fat pad reflecting a progressive decrease of fat volume and fibrosis formation, and a significant increase in the relaxation time T2 in femoral cartilage, consistent with a reduction of proteoglycan content. MRI also showed cyst formation in the tibia, femur remodeling, and T2 reductions in extensor muscles consistent with fibrosis development. Repeated intra-articular MSU/LPS injections in the rat knee joint induced pathology in multiple tissues and may be a useful means to investigate the relationship between urate crystal deposition and the development of degenerative joint disease.


Assuntos
Artrite Gotosa/diagnóstico por imagem , Articulações/diagnóstico por imagem , Imageamento por Ressonância Magnética , Ácido Úrico , Animais , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/metabolismo , Artrite Gotosa/patologia , Biópsia , Cristalização , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Feminino , Mediadores da Inflamação/metabolismo , Injeções Intra-Articulares , Articulações/metabolismo , Articulações/patologia , Lipopolissacarídeos , Valor Preditivo dos Testes , Ratos , Ratos Endogâmicos Lew , Líquido Sinovial/metabolismo , Fatores de Tempo , Microtomografia por Raio-X
6.
J Food Biochem ; 46(2): e14072, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34997623

RESUMO

Gouty arthritis, one of the most severe and common forms of arthritis, is characterized by monosodium urate crystal deposition in joints and surrounding tissues. Epidemiological evidence indicates that gouty arthritis incidence is sharply rising globally. Polyphenols are found in many foods and are secondary metabolites in plant foods. The anti-inflammatory and antioxidant effects of food polyphenols have been extensively studied in many inflammatory chronic diseases. Research has suggested that many food polyphenols have excellent anti-gouty arthritis effects. The mechanisms mainly include (a) inhibiting xanthine oxidase activity; (b) reducing the levels of inflammatory cytokines and chemokines; (c) inhibiting the activation of signaling pathways and the NLRP3 inflammasome; and (d) reducing oxidative stress. This paper reviews the research progress and pathogenesis of gouty arthritis and introduces the mechanisms of food polyphenols in treating gouty arthritis, which aims to explore the potential of functional foods in the treatment of gouty arthritis. PRACTICAL APPLICATIONS: The incidence rate of gouty arthritis has increased sharply worldwide, which has seriously affected people's quality of life. According to the current research progress, food polyphenols alleviate gouty arthritis through anti-inflammatory and antioxidant effects. This paper reviews the research progress and molecular pathogenesis of gouty arthritis and introduces the mechanisms of food-derived polyphenols in the treatment of gouty arthritis, which is helpful to the prevention and treatment of gouty arthritis.


Assuntos
Artrite Gotosa , Polifenóis , Artrite Gotosa/tratamento farmacológico , Artrite Gotosa/metabolismo , Artrite Gotosa/patologia , Ingestão de Alimentos , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Qualidade de Vida , Ácido Úrico
7.
Bioengineered ; 13(1): 345-356, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34965184

RESUMO

Gout is a common and complex form of arthritis that has brought great inconveniences to the normal lives of patients. It is reported that oxidative stress and nod-like receptor family protein 3 (NLRP3) inflammasome-mediated inflammatory reactions are involved in the pathogenesis of gout arthritis. S14G-humanin (S14G-HNG) is a modified peptide of HNG with higher inhibitory activity on the accumulation and deposition of Aß. Recently, S14G-HNG has been reported to exert great anti-inflammatory effects. The present study proposed to explore the possible therapeutic property of S14G-HNG against gout arthritis. An animal model was established by stimulation with mono-sodium urate (MSU) crystals, followed by treatment with colchicine and S14G-HNG, respectively. The elevated Gait score promoted synovitis score and activated myeloperoxidase (MPO) observed in MSU crystals-treated mice were significantly reversed by colchicine and S14G-HNG. Bone marrow-derived macrophages (BMDMs) were isolated from mice and stimulated with MSU crystals, followed by being treated with 25 and 50 µM S14G-HNG. The increased mitochondrial reactive oxygen species (ROS) and Malondialdehyde (MDA) levels, upregulated NADPH oxidase-4 (NOX-4), activated NLRP3 inflammasome, and elevated production of inflammatory factors in MSU crystals-treated BMDMs were dramatically reversed by S14G-HNG, accompanied by the upregulation of sirtuin type-1 (SIRT1). Lastly, the protective effects of S14G-HNG against MSU crystals-induced NLRP3 inflammasome activation were significantly abolished by the knockdown of SIRT1. In conclusion, our data reveal that S14G-HNG could possess potential benefits against MSU crystals-induced gout arthritis, with colchicine displaying a better effect.


Assuntos
Artrite Gotosa/tratamento farmacológico , Colchicina/administração & dosagem , Macrófagos/citologia , Peptídeos/administração & dosagem , Ácido Úrico/efeitos adversos , Animais , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/metabolismo , Células Cultivadas , Colchicina/farmacologia , Modelos Animais de Doenças , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Malondialdeído/metabolismo , Camundongos , NADPH Oxidase 4/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Peptídeos/farmacologia , Peroxidase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Resultado do Tratamento
8.
Bioengineered ; 12(2): 9803-9815, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34874227

RESUMO

Gout can affect the quality of life of patients due to monosodium urate monohydrate (MSU) crystals. Numerous studies have proposed that long noncoding RNAs (lncRNAs) regulate gout. We aimed to reveal the function of lncRNA small nucleolar RNA host gene 8 (SNHG8) in acute gouty arthritis (GA). A GA mouse model was established by injection of MSU into footpads. The levels of SNHG8, miR-542-3p and adaptor-related protein complex 3 subunit delta 1 (AP3D1) in footpads were detected via polymerase chain reaction analysis. Hematoxylin-eosin staining revealed the paw swelling in mice. Enzyme-linked immunosorbent assay and western blot analysis were applied to determine the concentrations of proinflammatory cytokines. SNHG8 expression was identified to be upregulated after MSU treatment. Ablation of SNHG8 decreased the MSU-induced enhancement of paw swelling and foot thickness. In addition, SNHG8 depletion decreased the protein levels of proinflammatory factors in GA mice. Mechanically, SNHG8 was verified to be a sponge of miR-542-3p, and miR-542-3p targeted AP3D1 3' untranslated region. SNHG8 competitively bound with miR-542-3p to upregulate AP3D1 expression. Finally, results of rescue assays illustrated that AP3D1 upregulation offset the SNHG8-mediated inhibition on paw swelling and protein levels of proinflammatory factors in GA mice. In conclusion, SNHG8 accelerates acute GA development by upregulating AP3D1 in an miR-542-3p-dependent way in mice, providing an effective therapeutic approach to treat acute GA.


Assuntos
Complexo 3 de Proteínas Adaptadoras/biossíntese , Subunidades beta do Complexo de Proteínas Adaptadoras/biossíntese , Artrite Gotosa/metabolismo , RNA Longo não Codificante/metabolismo , Regulação para Cima , Doença Aguda , Complexo 3 de Proteínas Adaptadoras/genética , Subunidades beta do Complexo de Proteínas Adaptadoras/genética , Animais , Artrite Gotosa/genética , Humanos , Masculino , Camundongos , RNA Longo não Codificante/genética , Células THP-1
9.
Front Immunol ; 12: 739953, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34745110

RESUMO

Erianin (Eri) is the extract of Dendrobium chrysotoxum Lindl. The NLRP3 inflammasome is a multiprotein complex that plays key roles in a wide variety of chronic inflammation-driven human diseases. Nevertheless, little is known about the protection of Eri against NLRP3 inflammasome-related diseases. In this study, we demonstrated that Eri inhibited NLRP3 inflammasome activation in vitro and in vivo. Mechanistically, Eri directly interacted with NLRP3, leading to inhibition of NLRP3 inflammasome assembly. Eri associated with the Walker A motif in the NACHT domain and suppressed NLRP3 ATPase activity. In mouse models, Eri had therapeutic effects on peritonitis, gouty arthritis and type 2 diabetes, via NLRP3. More importantly, Eri was active ex vivo for synovial fluid cells and monocytes from patients with IAV infection and gout. Eri may serve as a potential novel therapeutic compound against NLRP3-driven diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Gotosa/tratamento farmacológico , Bibenzilas/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inflamassomos/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Peritonite/tratamento farmacológico , Fenol/farmacologia , Animais , Artrite Gotosa/genética , Artrite Gotosa/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Cães , Células HEK293 , Humanos , Inflamassomos/genética , Inflamassomos/metabolismo , Células Madin Darby de Rim Canino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Peritonite/genética , Peritonite/metabolismo , Domínios e Motivos de Interação entre Proteínas , Células THP-1
10.
J Mater Chem B ; 9(48): 9923-9931, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34842263

RESUMO

As an incurable metabolic disease, gouty arthritis (GA) requires long-term treatment with frequent drug administration several times per day. Compared to non-specific small organic medications, interleukin-1ß (IL-1ß) blocking therapies, such as IL-1 receptor antagonist (IL-1Ra), show great therapeutic potential in clinical trials of GA. However, IL-1Ra application is starkly limited due to its short half-life and poor bioavailability. Herein, we demonstrate a new type of nanotherapeutic formulation via noncovalent assembly of an engineered IL-1Ra chimera protein. PEGylation was employed to induce such assembly by exploiting electrostatic complexation and hydrophobic interactions. The engineered protein nanoparticles had a combination of biocompatibility, improved bioavailability and therapeutic performance. It showed extraordinary long-term anti-inflammatory effect and robust bio-efficacy for GA therapy in acute GA rat models. Strikingly, this nanoprotein system possesses an ultralong half-life of 27 hours and a bioavailability 7 times higher than that of pristine IL-1Ra, thus extending the dosing interval from several hours to more than 3 days. Therefore, our noncovalent assembly strategy via an engineered chimeric protein empowers the construction of potent delivery nanosystems for efficient GA treatment, and this might be adapted for other therapeutics to form long-acting formulations.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Gotosa/tratamento farmacológico , Materiais Biocompatíveis/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Nanopartículas/química , Engenharia de Proteínas , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Artrite Gotosa/metabolismo , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Proteína Antagonista do Receptor de Interleucina 1/química , Masculino , Teste de Materiais , Ratos , Ratos Sprague-Dawley
11.
Ann Rheum Dis ; 80(12): 1604-1614, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34663597

RESUMO

Crystal structures activate innate immune cells, especially macrophages and initiate inflammatory responses. We aimed to understand the role of the mechanosensitive TRPV4 channel in crystal-induced inflammation. Real-time RT-PCR, RNAscope in situ hybridisation, and Trpv4eGFP mice were used to examine TRPV4 expression and whole-cell patch-clamp recording and live-cell Ca2+ imaging were used to study TRPV4 function in mouse synovial macrophages and human peripheral blood mononuclear cells (PBMCs). Both genetic deletion and pharmacological inhibition approaches were used to investigate the role of TRPV4 in NLRP3 inflammasome activation induced by diverse crystals in vitro and in mouse models of crystal-induced pain and inflammation in vivo. TRPV4 was functionally expressed by synovial macrophages and human PBMCs and TRPV4 expression was upregulated by stimulation with monosodium urate (MSU) crystals and in human PBMCs from patients with acute gout flares. MSU crystal-induced gouty arthritis were significantly reduced by either genetic ablation or pharmacological inhibition of TRPV4 function. Mechanistically, TRPV4 mediated the activation of NLRP3 inflammasome by diverse crystalline materials but not non-crystalline NLRP3 inflammasome activators, driving the production of inflammatory cytokine interleukin-1ß which elicited TRPV4-dependent inflammatory responses in vivo. Moreover, chemical ablation of the TRPV1-expressing nociceptors significantly attenuated the MSU crystal-induced gouty arthritis. In conclusion, TRPV4 is a common mediator of inflammatory responses induced by diverse crystals through NLRP3 inflammasome activation in macrophages. TRPV4-expressing resident macrophages are critically involved in MSU crystal-induced gouty arthritis. A neuroimmune interaction between the TRPV1-expressing nociceptors and the TRPV4-expressing synovial macrophages contributes to the generation of acute gout flares.


Assuntos
Artralgia/metabolismo , Artrite/metabolismo , Artropatias por Cristais/metabolismo , Leucócitos Mononucleares/metabolismo , Macrófagos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Nociceptores/metabolismo , Canais de Cátion TRPV/genética , Adulto , Animais , Artralgia/imunologia , Artrite/imunologia , Artrite Gotosa/imunologia , Artrite Gotosa/metabolismo , Artropatias por Cristais/imunologia , Gota/imunologia , Gota/metabolismo , Humanos , Inflamassomos/imunologia , Inflamação , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Leucócitos Mononucleares/imunologia , Macrófagos/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Imagem Óptica , Técnicas de Patch-Clamp , Membrana Sinovial/citologia , Células THP-1 , Canais de Cátion TRPV/agonistas , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo , Ácido Úrico
12.
Int Immunopharmacol ; 100: 108107, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34482265

RESUMO

Activation of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome plays a crucial role in the inflammatory responses of monosodium urate (MSU) crystal-induced gouty arthritis. Therefore, the molecular basis of NLRP3 inflammasome is very valuable in developing potential therapeutic drugs for gout. Tetrahydropalmatine (THP), the main active component of the traditional Chinese medicinal herb Corydalis yanhusuo, has shown prominent anti-inflammatory and analgesic activities, but to date, these effects have not been investigated exhaustively on gout. This study indicated that THP attenuated pain and swelling in an MSU-induced acute gout model by decreasing pro-inflammatory cytokine production and inflammatory cell infiltration. THP exerted its actions by suppressing NLRP3 inflammasome activation and subsequent formation of caspase-1. Furthermore, results showed that THP alleviated MSU-induced reactive oxygen species (ROS) generation, upstream of NLRP3 inflammasome activation, by an increase in the activities of antioxidant enzymes both in vitro and in vivo. In conclusion, our study suggests that THP suppressed ROS-mediated NLRP3 inflammasome activation in MSU-induced inflammatory responses, which highlights its therapeutic potential in gouty arthritis.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Artrite Gotosa/prevenção & controle , Alcaloides de Berberina/farmacologia , Inflamassomos/metabolismo , Articulações/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Analgésicos/farmacologia , Animais , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/imunologia , Artrite Gotosa/metabolismo , Caspase 1/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Articulações/imunologia , Articulações/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Células RAW 264.7 , Transdução de Sinais , Ácido Úrico
13.
Biomed Res Int ; 2021: 6641701, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34212036

RESUMO

INTRODUCTION: Animal models are valid for in vivo research on the pathophysiological process and drug screening of gout arthritis. Intra-articular injection of monosodium urate (MSU) is the most common method, while stable MSU deposition enveloped by inflammatory cells was rarely reported. OBJECTIVE: To develop a modified gouty arthritis rat model characterized by intra-articular MSU deposition and continuous joint pain with a minimally invasive method. METHOD: A total of twenty-four rats were randomly allocated into six groups. Three intervention groups of rats received intra-articular MSU embedment. Sham groups received pseudosurgeries with equal normal saline (NS). Gross parameters and pathological features of synovium harvested from anterior capsule were estimated. Mechanical pain threshold tests were conducted over a 96-hour period postoperatively. Moreover, quantitative immunofluorescence was conducted to assess tissue inflammation. RESULT: After MSU embedding, rats got more persistent arthritic symptoms as well as tissue MSU deposition. More significant synovial swelling was detected in the MSU group compared to sham groups (P < 0.025). Behavioral tests showed that the embedding of MSU resulted in prolonged mechanical hyperalgesia during 2 hours to 96 hours postoperatively (P < 0.05). MSU depositions enveloped by inflammatory cells that express IL-1ß and TNF-α were detected in embedding groups. Quantitative immunofluorescence suggested that the frequencies of MSU interventions upregulated expression of proinflammatory factors including IL-1ß and TNF-α (P < 0.05). CONCLUSION: A minimally invasive method was developed to establish modified rat model of intra-articular MSU deposition. This model was proved to be a simple reproducible method to mimic the pathological characteristics of persistent gouty arthritis.


Assuntos
Artrite Gotosa/induzido quimicamente , Artrite Gotosa/patologia , Ácido Úrico/farmacologia , Animais , Artrite Gotosa/metabolismo , Modelos Animais de Doenças , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Inflamação/metabolismo , Inflamação/patologia , Injeções Intra-Articulares/métodos , Interleucina-1beta/metabolismo , Masculino , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
14.
Inflammation ; 44(5): 2065-2077, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34085163

RESUMO

Increasing evidences indicate that circular RNAs (circRNAs) play important roles in regulating gene expressions in various diseases. However, the role of circRNAs in inflammatory response of gouty arthritis remains unknown. This study aims to investigate the role and underlying mechanism of circHIPK3 in inflammatory response of gouty arthritis. Quantitative real-time PCR was used to detect the expressions of circHIPK3, miR-192 and miR-561. Western blot was used to detect the protein levels of TLR4, NLRP3, nuclear factor-κB (NF-κB) related proteins, and Caspase-1. Dual luciferase reporter assay, RNA pull-down assay, and FISH assay were used to confirm the interaction between circHIPK3 and miR-192/miR-561. ELISA was used to detect interleukin (IL)-1ß and tumor necrosis factor (TNF)-α levels. circHIPK3 was elevated in synovial fluid mononuclear cells (SFMCs) from patients with gouty arthritis and monosodium urate (MSU)-stimulated THP-1 cells. circHIPK3 overexpression promoted the inflammatory cytokines levels in MSU-stimulated THP-1 cells, and circHIPK3 silencing obtained the opposite effect. Mechanistically, circHIPK3 sponged miR-192 and miR-561, and subsequently promoted the expressions of miR-192 and miR-561 target gene TLR4 and NLRP3. In vivo experiments confirmed circHIPK3 knockdown suppressed gouty arthritis. circHIPK3 sponges miR-192 and miR-561 to promote TLR4 and NLRP3 expressions, thereby promoting inflammatory response in gouty arthritis.


Assuntos
Artrite Gotosa/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , MicroRNAs/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Artrite Gotosa/patologia , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Circular/metabolismo , Transdução de Sinais/fisiologia , Células THP-1/metabolismo , Células THP-1/patologia
15.
J Ethnopharmacol ; 278: 114322, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34118343

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Duan Teng Yimu decoction is a Chinese herbal medicine compound with proven therapeutic effects on inflammasome-related diseases, such as rheumatoid arthritis. This decoction consists of three Chinese herbal medicines, including Leonurus japonicus (L. japonicus), which promotes the blood circulation and exhibits detumescence activity, traditionally curing gynecologic and inflammasome diseases. AIM OF THE STUDY: To explore the anti-inflammasome activity and the underlying mechanisms of action of the compounds from L. japonicus. MATERIALS AND METHODS: A series of compounds were isolated from L. japonicus. Their anti-inflammasome activities were evaluated in macrophages that were co-stimulated by lipopolysaccharide (LPS) and NLRP3 inflammasome inducers. NLRP3 inflammasome formation and apoptosis speck like containing a CARD (ASC) oligomerization were evaluated by immunofluorescent microscopy and Western blot analysis. The regulation of autophagy after treatment of this compound was also evaluated. Lastly, in vivo activity of Leojaponin was analyzed in a mouse acute gouty arthritis model. RESULTS: Here we show that Leojaponin, a diterpenoid compound from L. japonicus, suppressed lactate dehydrogenase and IL-1ß release in Nigericin-stimulated macrophages in a pyroptosis model. Leojaponin inhibits NLRP3 inflammasome activation in both J774A.1 cells and bone marrow-derived macrophages in a dose dependent manner. Moreover, Leojaponin suppressed NLRP3-mediated ASC specks formation and ASC oligomerization. These activities of Leojaponin depend on restoration of autophagy via promoting RAPTOR phosphorylation. Furthermore, Leojaponin ameliorated monosodium urate (MSU)-induced acute gouty arthritis in vivo. CONCLUSION: Our findings suggest that Leojaponin inhibits NLRP3 inflammasome activation through enhancing autophagy via RAPTOR phosphorylation, thereby highlighting Leojaponin as a potent drug for inflammasome-related diseases.


Assuntos
Artrite Gotosa/tratamento farmacológico , Autofagia/efeitos dos fármacos , Diterpenos/uso terapêutico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína Regulatória Associada a mTOR/metabolismo , Animais , Artrite Gotosa/metabolismo , Linhagem Celular , Diterpenos/química , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamassomos/genética , Inflamassomos/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , L-Lactato Desidrogenase/antagonistas & inibidores , Leonurus/química , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Nigericina/toxicidade , Fosforilação , Proteína Regulatória Associada a mTOR/genética , Regulação para Cima
16.
J Mol Endocrinol ; 67(2): 27-40, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34047713

RESUMO

Gouty arthritis is a common inflammatory disease characterized by monosodium urate (MSU) crystal-induced nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome activation with upregulated caspase 1 protease and IL-1ß in macrophages. Cucurbitacin B (CuB) is a tetracyclic triterpene that possesses a potential anti-inflammatory activity. However, the immunomodulatory and anti-inflammatory effects of CuB on gout have not been well characterized. Therefore, the purpose of the present study was to determine whether CuB exhibits anti-inflammatory effects on gout and to analyze the underlying molecular mechanism. We examined the effects of CuB on various stimuli-activated bone marrow-derived macrophages (BMDMs) and in a mouse model with MSU-induced acute gouty arthritis. Our results demonstrated that CuB effectively suppressed multiple stimuli-activated IL-1ß secretion by interrupting NLRP3 inflammasome complex formation, inhibiting NLRP3 inflammasome activation and suppressing key enzymes of glycolysis in macrophages. Consistent with this, CuB pretreatment also ameliorated MSU-induced arthritis in vivo models of gout arthritis, manifested by reduced foot swelling and inflammatory cell infiltration. Taken together, our data provide the evidence that CuB is an NLRP3 inflammasome inhibitor with therapeutic potential for treating NLRP3 inflammasome-mediated diseases, especially gouty arthritis.


Assuntos
Artrite Gotosa/metabolismo , Inflamassomos/antagonistas & inibidores , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Triterpenos/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Artrite Gotosa/tratamento farmacológico , Artrite Gotosa/etiologia , Artrite Gotosa/patologia , Biomarcadores , Modelos Animais de Doenças , Suscetibilidade a Doenças , Glicólise , Gota/tratamento farmacológico , Gota/etiologia , Gota/metabolismo , Gota/patologia , Interleucina-1beta/metabolismo , Lipopolissacarídeos/efeitos adversos , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Receptor 4 Toll-Like/metabolismo
17.
Int J Rheum Dis ; 24(4): 599-607, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33650318

RESUMO

BACKGROUND: MicroRNAs (miRNAs) have been shown to play a crucial role in inflammation regulation; however, their relationship with inflammation in acute gouty arthritis has not been fully elucidated. Herein, we conducted a study to explore the regulatory roles of miR-223-3p and miR-22-3p in gouty-associated inflammation. METHODS: In vitro and in vivo experiments were conducted to examine the molecular mechanisms of miRNA regulation in gouty inflammation. Dual-luciferase reporter assay was used to verify the direct target of miR-223-3p and miR-22-3p. RESULTS: We found that miR-223-3p and miR-22-3p interacted with the 3' untranslated region segment of NLRP3 (nucleotide-binding domain leucine-rich repeat [NLR] and pyrin domain containing receptor 3) and inhibited its expression. A decreased expression of miR-223-3p and miR-22-3p was observed in both mice air pouch synovium and phorbol myristrate acetate-treated THP-1 cells stimulated with monosodium urate (P < .05). Compared with the negative control group, NLRP3 expression at the transcript and protein level in miR-223-3p and miR-22-3p overexpression group significantly decreased after 6 hours of monosodium urate treatment in vivo and in vitro (P < .05). The results of the dual-luciferase reporter assay demonstrated that miR-223-3p and miR-22-3p directly targeted NLRP3. CONCLUSION: The findings of the present study show that miR-223-3p and miR-22-3p can reduce the inflammatory effects of gout by inhibiting the expression of NLRP3.


Assuntos
Artrite Gotosa/metabolismo , Inflamassomos/metabolismo , Inflamação/metabolismo , MicroRNAs/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Regiões 3' não Traduzidas , Animais , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/imunologia , Artrite Gotosa/prevenção & controle , Sítios de Ligação , Modelos Animais de Doenças , Regulação para Baixo , Humanos , Inflamassomos/genética , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/prevenção & controle , Masculino , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Transdução de Sinais , Células THP-1 , Ácido Úrico
18.
Biomed Pharmacother ; 138: 111413, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33677310

RESUMO

BACKGROUND: Monosodium urate (MSU)-mediated inflammatory response is a crucial inducing factor in gouty arthritis. Here, we explored the underlying mechanism of total glucosides of paeony (TGP) in MSU-induced inflammation of THP-1 macrophages in gouty arthritis. METHODS: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to detect cell viability. Enzyme-linked immunosorbent assay (ELISA) was utilized to measure the production of interleukin 1ß (IL-1ß) and tumor necrosis factor α (TNF-α). Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot assay were conducted to determine RNA and protein expression. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and RNA pull down assay were used to confirm the interaction between miR-876-5p and MALAT1 or NLR family pyrin domain containing 3 (NLRP3). RESULTS: MSU-induced damage and inflammatory response in THP-1 macrophages were alleviated by the treatment of TGP in a dose-dependent manner. Overexpression of NLRP3 or MALAT1 reversed the protective effects of TGP in MSU-induced THP-1 macrophages. The binding relation between miR-876-5p and MALAT1 or NLRP3 was identified in THP-1 macrophages. MALAT1 up-regulated the expression of NLRP3 by sponging miR-876-5p in THP-1 macrophages. TGP suppressed MSU-induced inflammation in THP-1 macrophages through regulating MALAT1/miR-876-5p/NLRP3 axis. TGP suppressed MSU-induced activation of TLR4/MyD88/NF-κB pathway through regulating MALAT1/miR-876-5p/NLRP3 axis. CONCLUSION: In conclusion, TGP suppressed MSU-induced inflammation in THP-1 macrophages through regulating MALAT1/miR-876-5p/NLRP3 axis and TLR4/MyD88/NF-κB pathway, suggesting that TGP was a promising active ingredient for gouty arthritis treatment.


Assuntos
Artrite Gotosa/metabolismo , Glucosídeos/uso terapêutico , MicroRNAs/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Paeonia , RNA Longo não Codificante/metabolismo , Ácido Úrico/toxicidade , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/prevenção & controle , Glucosídeos/isolamento & purificação , Glucosídeos/farmacologia , Humanos , Mediadores da Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Células THP-1/efeitos dos fármacos , Células THP-1/metabolismo
20.
Biomed Pharmacother ; 135: 111194, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33395608

RESUMO

The increasing incidence of gout poses a very challenging management problem. However, the currently available drugs often have various toxic side effects. As a traditional edible and medicinal macrofungus, Sanghuangporus vaninii presents high medical research value. Therefore, to improve fermentation efficiency and identify novel anti-gout drugs, we optimized the culture medium of S. vaninii with lignin and further investigated its anti-gout effects. The results indicated that 0.06 g/L of lignin was most favorable for S. vaninii growth. In the hyperuricemia cell model, we found that S. vaninii could significantly induce the downregulation of xanthine oxidoreductase and the upregulation of hypoxanthine-guanine phosphoribosyltransferase. Furthermore, following oral administration of the extracts, the serum uric acid levels of mice with hyperuricemia were effectively reduced. In a gouty arthritis rat model, S. vaninii also achieved strong suppression of synovial swelling, indicating its anti-inflammatory activity. In addition, the antioxidant assays suggested that S. vaninii shows a strong free radical scavenging capacity and can effectively alleviate cellular oxidative stress. This activity further enhances its anti-inflammatory activity and reduces the incidence of comorbidities. In summary, our results provide the basis for the utilization of S. vaninii to develop anti-gout drugs.


Assuntos
Artrite Gotosa/tratamento farmacológico , Técnicas Bacteriológicas , Basidiomycota/metabolismo , Meios de Cultura/metabolismo , Supressores da Gota/farmacologia , Hiperuricemia/tratamento farmacológico , Lignina/metabolismo , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Artrite Gotosa/metabolismo , Artrite Gotosa/microbiologia , Basidiomycota/crescimento & desenvolvimento , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Supressores da Gota/isolamento & purificação , Humanos , Hiperuricemia/genética , Hiperuricemia/metabolismo , Hipoxantina Fosforribosiltransferase/genética , Hipoxantina Fosforribosiltransferase/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Xantina Desidrogenase/genética , Xantina Desidrogenase/metabolismo
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