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1.
Trials ; 23(1): 248, 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35365187

RESUMO

BACKGROUND: Acute gouty arthritis (GA) is the main clinical manifestation and the most common initial symptom of gout. The treatment of acute GA involves the use of colchicine, non-steroidal anti-inflammatory drugs, and corticosteroids. Because of the side effects of these drugs, their clinical applications are limited. The use of traditional Chinese medicine for the treatment of acute GA has unique advantages. The aim of this trial is to clarify the treatment efficacy, safety, and recurrence control efficacy of Huzhang granules (HZG) in patients with GA showing dampness-heat syndrome. METHODS/DESIGN: This double-blind, randomized, controlled trial was planned to be conducted between July 1, 2020, and December 31, 2022. A sample size of 267 participants (89 per group) with GA will be randomly assigned to three treatment groups in the ratio of 1:1:1: HZG, etoricoxib, and placebo groups. The study duration is 13 days, including a 1-day screening period, 5-day intervention period, and 1-week follow-up period. The primary outcome is analgesic effectiveness, assessed as pain in the worst-affected joint, which will be measured using the visual analog scale. Secondary outcomes include the patient's assessment of pain in the primary study joint, patient's global assessment of response to therapy, investigator's global assessment of response to therapy, investigator's assessment of tenderness and swelling of the study joint, and TCM syndromes. Furthermore, the number, nature, and severity of adverse events will be recorded. DISCUSSION: This study will provide evidence regarding the clinical efficacy and safety of Chinese medicine treatment for acute gouty arthritis. This study will provide noteworthy findings. TRIAL REGISTRATION: ClinicalTrials.gov NCT04462666 . Registered on July 05, 2020 (first version).


Assuntos
Artrite Gotosa , Medicamentos de Ervas Chinesas , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/diagnóstico , Artrite Gotosa/tratamento farmacológico , Método Duplo-Cego , Medicamentos de Ervas Chinesas/efeitos adversos , Humanos , Medicina Tradicional Chinesa , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
2.
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
3.
Inflamm Res ; 71(4): 485-495, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35298670

RESUMO

OBJECTIVE: The transient receptor potential vanilloid subtype 1 (TRPV1) channel is considered to play an important regulatory role in the process of pain. The purpose of this study is to observe the change characteristics of TRPV1 channel in MSU-induced gouty arthritis and to find a new target for clinical treatment of gout pain. METHODS: Acute gouty arthritis was induced by injection of monosodium urate (MSU) crystals into the ankle joint of mice. The swelling degree was evaluated by measuring the circumference of the ankle joint. Mechanical hyperalgesia was conducted using the electronic von Frey. Calcium fluorescence and TRPV1 current were recorded by applying laser scanning confocal microscope and patch clamp in dorsal root ganglion (DRG) neurons, respectively. RESULTS: MSU treatment resulted in significant inflammatory response and mechanical hyperalgesia. The peak swelling degree appeared at 12 h, and the minimum pain threshold appeared at 8 h after MSU treatment. The fluorescence intensity of capsaicin-induced calcium response and TRPV1 current were increased in DRG cells from MSU-treated mice. The number of cells that increased calcium response after MSU treatment was mainly distributed in small-diameter DRG cells. However, the action potential was not significantly changed in small-diameter DRG cells after MSU treatment. CONCLUSIONS: These findings identified an important role of TRPV1 in mediating mechanical hyperalgesia in MSU-induced gouty arthritis and further suggest that TRPV1 can be regarded as a potential new target for the clinical treatment of gouty arthritis.


Assuntos
Artrite Gotosa , Canais de Potencial de Receptor Transitório , Animais , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/tratamento farmacológico , Cálcio , Edema , Hiperalgesia/induzido quimicamente , Camundongos , Dor , Canais de Cátion TRPV , Canais de Potencial de Receptor Transitório/uso terapêutico , Ácido Úrico
4.
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
5.
Inflammation ; 45(3): 1332-1347, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35039996

RESUMO

Gout is an inflammatory arthritis characterized by the deposition of monosodium urate (MSU) crystals in the joints or soft tissue. MSU crystals are potent inflammation inducers. Melatonin (MLT) is a powerful endogenous anti-inflammatory agent and effective in reducing cellular damage. In the present study, possible underlying mechanisms associated with anti-inflammatory and antioxidative effects were investigated in rats with gouty arthritis and melatonin deprivation treated with MLT. Fifty-six rats were divided into seven groups: control, sham control, pinealectomy (PNX), MSU (on the 30th day, single-dose 20 mg/ml, intraperitoneal), MSU + MLT (10 mg/kg/day for 30 days, intraperitoneal), MSU + PINX and MSU + PINX + MLT. PNX procedure was performed on the first day of the study. As compared to the controls, the results showed that MSU administration caused significant increases in oxidative stress parameters (malondialdehyde and total oxidant status). Besides, significant decreases in antioxidant defense systems (glutathione, superoxide dismutase and total antioxidant status) were observed. A statistically significant increase was found in the mean histopathological damage score in the groups that received MSU injection. It was found that histopathological changes were significantly reduced in the MSU + MLT group given MLT. In our study, it was determined that many histopathological changes, as well as swelling and temperature increase in the joint, which are markers of inflammation, were significantly reduced with MLT supplementation. These results suggest that melatonin ameliorates MSU-induced gout in the rat through inhibition of oxidative stress and proinflammatory cytokine production.


Assuntos
Artrite Gotosa , Gota , Melatonina , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/tratamento farmacológico , Artrite Gotosa/patologia , Inflamação/tratamento farmacológico , Inflamação/patologia , Melatonina/farmacologia , Melatonina/uso terapêutico , Estresse Oxidativo , Pinealectomia , Ratos , Ácido Úrico
6.
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
7.
J Nat Med ; 76(1): 178-187, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34586567

RESUMO

Acute gouty arthritis is a self-limiting inflammatory disease resulting from the deposition of monosodium urate (MSU) crystals. It has been shown that Gentiopicroside (GPS) possesses anti-inflammatory and analgesic functions. The aim of this study was to parse out whether GPS has an effect on acute gouty arthritis. We established an acute gouty arthritis model by the injection of MSU into the paw, and found that GPS relieves MSU-induced mechanical, thermal hyperalgesia, and paw swelling. Furthermore, GPS down-regulated the release of pro-inflammatory cytokines in paw tissues, including IL-1ß, IL-6, IL-18, and TNF-α. The results of H&E staining and MPO activity measurement showed that GPS inhibits neutrophil infiltration. And the over-expressions of NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and Caspase-1 induced by MSU were inhibited by treatment with GPS. These results revealed that GPS can treat acute gouty arthritis based on anti-inflammatory and analgesic properties in vivo, which might be ascribed to the inhibition on NLRP3 inflammasome. Furthermore, we performed in vitro study to confirm the results of in vivo study. Consistently, the results proved that GPS could inhibit the activation of NLRP3 inflammasome in RAW264.7 macrophages stimulated by LPS-MSU. In conclusion, this study provides an experimental basis for the application of GPS and expands the potential value of GPS in the therapy of acute gouty arthritis.


Assuntos
Artrite Gotosa , Inflamassomos , Animais , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/tratamento farmacológico , Glucosídeos Iridoides , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteínas NLR , Ácido Úrico
8.
Biol Trace Elem Res ; 200(4): 1659-1666, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34196880

RESUMO

Iron oxide nanoparticles (FeO-NPs) exhibit exceptional properties which can be utilized in various aspects of biological sciences. In this experiment we investigated the anti-gout effectiveness of FeO-NPs in mice. BALB/c mice were induced gouty arthritis by administering monosodium urate (MSU) crystals. These gout induced mice were treated with three different concentrations of FeO-NPs (5 ppm, 10 ppm and 20 ppm). Precipitation method was utilized for the synthesis of FeO-NPs, these synthesized NPs were of average 54 nm in size and were characterized using XRD, SEM and EDS. FeO-NPs is given orally three weeks by using FeO-NPs solution to substitute drinking water. Blood biochemical parameters including liver function tests (LFTs), renal function tests (RFTs), lipid profile and blood count have been tested. It has been found that uric acid, blood urea and creatinine have decreased significantly after three weeks of FeO-NP administration (P Value < 0.001) thus suppressing hyperuricemia and gouty arthritis. Additionally, the liver enzymes analysis showed a slight increase in AST, ALT and alkaline phosphatase levels (P Value < 0.001). Histopathological research revealed no significant abnormal changes in the liver, muscle and kidney muscles of the test groups. The findings showed that FeO-NPs can be used for the successful treatment of hyperuricemic condition and gouty arthritis in the coming future in place of commercially available medicines.


Assuntos
Artrite Gotosa , Hiperuricemia , Animais , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/tratamento farmacológico , Hiperuricemia/induzido quimicamente , Hiperuricemia/tratamento farmacológico , Nanopartículas Magnéticas de Óxido de Ferro , Camundongos , Camundongos Endogâmicos BALB C , Ácido Úrico
9.
Drug Des Devel Ther ; 16: 1159-1170, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35496367

RESUMO

Purpose: Gouty arthritis is generally induced by the accumulation of monosodium urate (MSU) crystals in the joints due to elevated serum uric acid levels, potentially leading to serious pathological disorders such as nephrolithiasis, renal failure, and acute gouty arthritis. In this study, we aimed to validate the anti-gout effects of carvacrol, a phenolic monoterpene. Materials and Methods: Male Sprague-Dawley rats were divided into normal saline, disease group by injecting potassium mono-oxonate (PO) at a dose of 250 mg/kg, and three treatment groups, either with carvacrol 20 mg/kg or 50 mg/kg and 10 mg/kg allopurinol. The blood and tissue samples were subsequently collected and analyzed using different biochemical and histopathological techniques. Results: Our results revealed a significant increase in the serum levels of oxidative stress-related markers, namely, uric acid and C-reactive protein (CRP), and NLRP3 inflammasome-dependent inflammatory mediators, including nuclear factor kappa B (NF-κB) and tumor necrosis factor-alpha (TNF-α). Carvacrol administration for seven consecutive days exhibited significant anti-hyperuricemic and anti-inflammatory effects in a dose-dependent manner. Notably, the 50 mg/kg carvacrol treatment was observed to produce results similar to the allopurinol treatment. Furthermore, the renal safety of carvacrol was confirmed by the renal function test. Conclusion: Carvacrol potentially alleviates hyperuricemia-induced oxidative stress and inflammation by regulating the ROS/NRLP3/NF-κB pathway, thereby exerting protective effects against joint degeneration.


Assuntos
Artrite Gotosa , Hiperuricemia , Alopurinol/efeitos adversos , Animais , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/tratamento farmacológico , Cimenos , Hiperuricemia/induzido quimicamente , Hiperuricemia/tratamento farmacológico , Inflamação/tratamento farmacológico , Inflamação/patologia , Masculino , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Ácido Úrico
10.
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
11.
J Biomed Nanotechnol ; 17(10): 2071-2084, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34706807

RESUMO

Uric acid is the final product of purine metabolism, and excessive serum uric acid can cause gouty arthritis and uric acid nephropathy. Therefore, lowering the uric acid level and alleviating inflammation in the body are the key points to treating these diseases. A stable nanosuspension of peptide BmK9 was prepared by the precipitation-ultrasonication method. By combining uricase on the surface of a positively charged carrier, a complex consisting of neutral rod-shaped BmK9 and uricase nanoparticles (Nplex) was formed to achieve the delivery of BmK9 and uricase, respectively. The formulation of Nplex has a diameter of 180 nm and drug loading up to 200%, which releases BmK9 and uricase slowly and steadily in drug release tests in vitro. There was significantly improved pharmacokinetic behavior of the two drugs because Nplex prolonged the half-life and increased tissue accumulation. Histological assessments showed that the dual drug Nplex can reduce the inflammation response in acute gouty arthritis and chronic uric acid nephropathy in vivo. In the macrophage system, there was lower toxicity and increased beneficial effect on inflammation with Nplex than free BmK9 or uricase. Collectively, this novel formulation provides a dual drug delivery system that can treat gouty arthritis and uric acid nephropathy.


Assuntos
Artrite Gotosa , Nefropatias , Nanopartículas , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/tratamento farmacológico , Humanos , Urato Oxidase , Ácido Úrico
12.
Medicina (Kaunas) ; 57(9)2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34577821

RESUMO

Background and Objectives: Gouty arthritis is an acute inflammatory response caused by the precipitation of monosodium urate (MSU) crystals in joints. The triggering of MSU leads to increased production of inflammatory cytokines, such as interleukin-1ß, which in turn lead to the formation of macromolecular complexes, referred to as inflammasomes. Thorough characterization of the NLRP3 inflammasome can be used as an indicator of an immune response against harmful stimuli. Cardamonin is a chalcone, mainly found in the seeds of Alpinia katsumadai, and exhibits anti-inflammatory activity by inhibiting the release of pro-inflammatory cytokines in vitro. However, the mechanism by which cardamonin treatment alleviates gouty arthritis has yet to be fully elucidated. Materials and Methods: In vitro or in vivo models were used to study whether cardamonimn inhibited NLRP3 inflammasome activation or suppressed gouty inflammation. Results: In the current study, we determined that most NLRP3 was released passively after MSU stimulation, and this release of NLRP3 promoted caspase-1 activation and IL-1ß secretion. Cardamonin was shown to decrease both the activity of caspase-1 and secretion of IL-1ß in J774A.1 macrophage cells subjected to MSU stimulation. Cardamonin was also shown to attenuate the production of COX-2 in MSU-stimulated J774A.1 macrophage cells. Finally, cardamonin reduced the thickness of the synovial lining and the infiltration of gouty arthritis in a rat model. Conclusions: Overall, cardamonin significantly attenuated IL-1ß secretion, caspase-1 activity, and COX-2 production stimulated by MSU. These findings provide new insights into the molecular mechanisms underlying the effects of cardamonin treatment for gouty arthritis.


Assuntos
Artrite Gotosa , Chalconas , Animais , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/tratamento farmacológico , Chalconas/farmacologia , Chalconas/uso terapêutico , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ratos , Ácido Úrico
13.
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
14.
Toxins (Basel) ; 13(9)2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34564665

RESUMO

Bee venom (BV) acupuncture has anti-inflammatory and analgesic effects; therefore, it was used as a traditional Korean medicine for various musculoskeletal disorders, especially arthritis. In this study, we investigated the effect of BV on monosodium urate (MSU) crystal-induced acute gouty rats. An intra-articular injection of MSU crystal suspension (1.25 mg/site) was administered to the tibiotarsal joint of the hind paw of Sprague Dawley rats to induce MSU crystal-induced gouty arthritis. Colchicine (30 mg/kg) was orally administered 1 h before MSU crystal injection as a positive control, and BV (0.5 mg/kg) was injected into the tibiotarsal joint immediately after MSU crystal injection. The ankle thickness, mechanical allodynia, and expression of proinflammatory cytokines (TNF-α, IL-1ß, IL6, COX2 and iNOS) and chemokines (MIP-1α, MIP-1ß, MCP-1, GRO-α, MIP-2α) were then evaluated. BV reduced the expression of proinflammatory cytokines and chemokines, which are important mediators of MSU crystal-induced inflammatory responses. This anti-inflammatory effect was also confirmed histologically to attenuate synovitis and neutrophil infiltration. We demonstrated that BV markedly ameliorated ankle edema and mechanical allodynia in gouty rats. These results suggest that BV acupuncture is a potential clinical therapy for acute gouty management.


Assuntos
Artrite Gotosa/induzido quimicamente , Artrite Gotosa/tratamento farmacológico , Venenos de Abelha/uso terapêutico , Edema/tratamento farmacológico , Inflamação/tratamento farmacológico , Dor/tratamento farmacológico , Ácido Úrico/toxicidade , Animais , Modelos Animais de Doenças , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento
15.
Beijing Da Xue Xue Bao Yi Xue Ban ; 53(4): 716-720, 2021 Aug 18.
Artigo em Chinês | MEDLINE | ID: mdl-34393234

RESUMO

OBJECTIVE: To investigate the role of rebamipide in the treatment of acute gout arthritis rats induced by monosodium urate (MSU) crystal. METHODS: Forty-two male rats were randomly divided into three groups (n=14). Group A was treated with oral rebamipide, group B with oral colchicine, and group C with oral placebo. The rats were monitored for the induction of arthritis with clinical manifestations and pathological changes, and the levels of interleukin (IL)-1ß、IL-6、IL-10, and tumor necrosis factor (TNF)-α in serum were measured. RESULTS: In group C, the clinical score and swelling index reached the maximum in 24 h, and then gradually decreased to 72 h. After 24 h of model induced, the clinical scores in group C were significantly higher than those in group A and group B [2 (1-3) vs. 0 (0-1) vs. 1 (0-2), P < 0.01], the swelling indexes in group C were significantly higher than those in group A and group B [0.36 (0.16-0.52) vs. 0.11 (0-0.20) vs. 0.12 (0-0.16), P < 0.01]. Histologically, after 24 h of model induced, there was a large number of neutrophil infiltration in the synovium of group C [scale score: 4 (2-4)], and there was no significant inflammatory cell infiltration in group A [1 (0-2)] and group B [1 (0-2)], the difference was statistically significant (P < 0.001). After 24 h of model induced, the levels of IL-1ß, IL-6, IL-10, and TNF-α in serum of group C were significantly higher than those in group A and B [IL-1ß: (41.86±5.72) vs. (27.35±7.47) vs. (27.76±5.28) ng/L, IL-6: (1 575.55±167.11) vs. (963.53±90.22) vs. (964.08±99.31) ng/L, IL-10: (37.96±3.76) vs. (21.68±4.83) vs. (16.20±2.49) ng/L, TNF-α: (21.32±1.34) vs. (15.82±2.54) vs. (17.35±7.47) µg/L, P < 0.001]. CONCLUSION: Rebamipide has a protective effect on acute gout arthritis rats induced by MUS crystals.


Assuntos
Artrite Gotosa , Quinolonas , Alanina/análogos & derivados , Animais , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/tratamento farmacológico , Interleucina-1beta , Masculino , Ratos , Ácido Úrico
16.
BMC Complement Med Ther ; 21(1): 202, 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34284768

RESUMO

BACKGROUND: Gout is initiated by the precipitation of monosodium urate (MSU) crystals within the joints and soft tissues, and it can eventually cause acute or chronic arthritis. MSU crystals trigger, amplify, and maintain a strong inflammatory response through promoting proinflammatory activity. In this study, the therapeutic effects of Stephania hainanensis (S. hainanensis) total alkaloid (SHA) were tested and evaluated on MSU-induced acute gouty arthritis in a mouse model. METHODS: After oral administration of SHA (10 or 20 mg/kg) or the antigout medicine colchicine (0.5 mg/kg) once daily for 3 consecutive days, MSU crystals suspended in saline (2.5 mg/50 µl) were intradermally injected into the right paw of the mice. Then, SHA and colchicine were administered for another 2 days. During this period, swelling of the ankle and clinical scores were measured at 12, 24, and 48 h postinjection. After the mice were euthanized, inflammatory cytokine expression and paw tissue inflammation-related gene and protein expression, and a histopathological analysis was performed. RESULTS: SHA had obvious therapeutic effects on MSU-induced acute gouty arthritis in mice. SHA alleviated ankle swelling and inhibited the production of cytokines, such as IL-1ß and TNF-α. In addition, NLRP3, Caspase-1 and IL-1ß, which are activated by MSU were also suppressed by SHA. The histological evaluation showed that SHA relieved the infiltration of inflammation around the ankle. CONCLUSIONS: These results suggest that SHA is capable of anti-inflammatory activities and may be useful for treating gouty arthritis.


Assuntos
Alcaloides/farmacologia , Anti-Inflamatórios/farmacologia , Antioxidantes/toxicidade , Artrite Gotosa/induzido quimicamente , Stephania/metabolismo , Ácido Úrico/toxicidade , Animais , Antioxidantes/farmacologia , Camundongos
17.
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
18.
Curr Med Sci ; 41(4): 757-763, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34047943

RESUMO

The aim of this study was to identify the effects of melatonin on acute gouty inflammation and to investigate the underlying mechanisms. We found significantly lower serum melatonin levels in gout patients in the acute phase than in those in the remission phase or in normal individuals. The mRNA expression of melatonin receptor 2 (MT2) was also lower in gout patients than in normal individuals. To verify the in-vivo role of melatonin, a gouty arthritis model was established by intraarticular injection of monosodium urate (MSU, 1 mg) crystals into the paws of C57BL/6 mice. Joint inflammation in the mouse model was evaluated by measuring the thickness of the right paw/left paw, and the inflammation index was determined by examining infiltrating neutrophils with haematoxylin and eosin (H&E) staining. Melatonin was found to reduce both paw thickness and the inflammation index in the mouse model, and melatonin also reduced the mRNA levels of interleukin-1 beta (IL-1ß), IL-6 and NLR family pyrin domain containing 3 (NLRP3) inflammasome. To mimic gouty inflammation in vitro, mouse peritoneal macrophages were stimulated with lipopolysaccharides (LPS) plus MSU. Melatonin was revealed to reduce IL-1ß secretion by stimulated macrophages. The mRNA expression levels of IL-1ß and IL-6 were also inhibited by melatonin. Western blot analysis showed that the expression of NLRP3, caspase-1 and pro-IL-1ß was also inhibited by melatonin. In conclusion, our study demonstrated that melatonin alleviated gouty inflammation in vivo and in vitro, and the underlying mechanism may involve inhibiting the assembly of the NLRP3 inflammasome.


Assuntos
Artrite Gotosa/tratamento farmacológico , Gota/tratamento farmacológico , Inflamação/tratamento farmacológico , Melatonina/farmacologia , Receptor MT2 de Melatonina/sangue , Doença Aguda/epidemiologia , Animais , Artrite Gotosa/sangue , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/genética , Modelos Animais de Doenças , Gota/metabolismo , Gota/patologia , Humanos , Inflamação/sangue , Inflamação/induzido quimicamente , Inflamação/genética , Interleucina-1beta/genética , Interleucina-6/genética , Articulações/efeitos dos fármacos , Articulações/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Melatonina/sangue , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , RNA Mensageiro/sangue , Ácido Úrico/toxicidade
19.
Phytomedicine ; 84: 153521, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33667838

RESUMO

BACKGROUND: Baeckein E (BF-2) was isolated from the aerial parts of Baeckea frutescens L., which has a long history of use in traditional medicine in Southeast Asia to treat inflammatory disease. PURPOSE: BF-2 was identified to have inhibitory activity on nucleotide oligomerization domain (NOD)-like receptor protein-3 inflammasome (NLRP3) activation. This study aimed to investigate the related signaling cascade of BF-2 in both lipopolysaccharides (LPS)/ATP induced pyroptosis in J774A.1 macrophages and its application in a mouse model of gout induced by monosodium urate crystal (MSU). METHODS: The effect of BF-2 on NLRP3 inflammasome activation and gouty arthritis was studied in J774A.1 macrophages and male C57BL/6 mice. The J774A.1 macrophages were primed with LPS and stained by propidium iodide (PI) for cell pyroptosis detection. A gout mouse model was established by subcutaneous injection of MSU crystals into the hind paw of C57BL/6 mice. Mice were then randomly divided into different groups. The concentrations of IL-1ß and IL-18 in both J774A.1 macrophage and gout mouse model were analyzed by ELISA. The NLRP3 inflammasome related protein expression was detected by western blot analysis. The inhibitory effects of BF-2 on NLRP3 inflammasome assembly were analyzed by immunoprecipitation assay. The roles of BF-2 in mitochondrial damage were imaged by Mito Tracker Green and Mito Tracker Red probes. The inhibitory effects of BF-2 on ROS production were imaged by DCF (2',7'-dichlorofluorescein diacetate) probe. RESULTS: The results demonstrated BF-2 could significantly suppress the cell pyroptosis and IL-1ß secretion in macrophages. Furthermore, BF-2 significantly inhibited NLRP3 inflammasome activation and reduced ankle swelling in the gout mouse model. In detail, it alleviated mitochondrial damage mediated oxidative stress and inhibited the assembly of NLRP3 inflammasome by affecting the binding of pro-Caspase 1 and ASC. Moreover, BF-2 blocked NLRP3 activation by inhibiting the MAPK/NF-κB signaling pathways. CONCLUSIONS: Results demonstrated BF-2 inhibited NLRP3 inflammasome activation in both LPS primed macrophages and mouse model of gout through blocking MAPK/NF-κB signaling pathway and mitochondrial damage mediated oxidative stress. This study strongly suggests BF-2 could be a promising drug candidate against inflammatory diseases associated with NLRP3 inflammasome activation.


Assuntos
Artrite Gotosa/tratamento farmacológico , Flavonoides/farmacologia , Inflamassomos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Trifosfato de Adenosina/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/patologia , Células Cultivadas , Modelos Animais de Doenças , Inflamassomos/metabolismo , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
20.
Eur J Med Chem ; 216: 113313, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33667846

RESUMO

P2Y14 nucleotide receptor plays important roles in series of physiological and pathologic events especially associated with immune and inflammation. Based on the 3-amide benzoic acid scaffold reported by our group previously, a series of 5-aryl-3-amide benzoic acid derivatives were designed as novel P2Y14 antagonists with improved pharmacokinetic properties. Among which compound 11m showed most potent P2Y14 antagonizing activity with an IC50 value of 2.18 nM, furnishing greatly improved water solubility and bioavailability compared with PPTN. In MSU-induced acute gouty arthritis model in mice, 11m exerted promising in vivo efficacy in alleviating mice paw swelling and inflammatory infiltration. Mechanistically, compound 11m notably blocked pyroptosis of macrophages through inhibiting NLRP3 inflammasome activation. This work may contribute to the identification of potential therapeutic agents to intervene in acute gouty arthritis.


Assuntos
Ácido Benzoico/química , Desenho de Fármacos , Antagonistas do Receptor Purinérgico P2/síntese química , Receptores Purinérgicos P2Y/química , Amidas/química , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/tratamento farmacológico , Artrite Gotosa/patologia , Ácido Benzoico/metabolismo , Ácido Benzoico/farmacologia , Ácido Benzoico/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Meia-Vida , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Antagonistas do Receptor Purinérgico P2/metabolismo , Antagonistas do Receptor Purinérgico P2/farmacologia , Antagonistas do Receptor Purinérgico P2/uso terapêutico , Piroptose/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2Y/metabolismo , Solubilidade , Relação Estrutura-Atividade
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