|
1
|
Huang YJ, Wang LC, Wang CP, Yu KH, Kuo CF. Non-inflammatory macrophages phagocytose and hydrolyse monosodium urate crystals in different stages of gout. Scand J Rheumatol 2025:1-10. [PMID: 40338022 DOI: 10.1080/03009742.2025.2491176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 04/07/2025] [Indexed: 05/09/2025]
Abstract
OBJECTIVE Macrophages play a crucial role in gouty arthritis; however, the relationship between non-inflammatory macrophages (M0) and different stages of gout remains unclear. This study aimed to investigate the phagocytosis, hydrolysis, and subsequent cytokine secretion of monosodium urate (MSU) by non-inflammatory macrophages in patients in different stages of gout. METHOD Non-inflammatory macrophages were derived from monocytes through stimulation with macrophage colony-stimulating factor (M-CSF) for a duration of 10 days. The study included patients with asymptomatic hyperuricaemia, intercritical gout, tophaceous gout, and a normal control group. The phagocytic and hydrolytic capabilities of non-inflammatory macrophages were measured using flow cytometry based on the increase in side-scatter area. In addition, to evaluate the relationship between the hydrolysis capability of non-inflammatory macrophages and subsequent inflammation, we cultured them with lipopolysaccharide (LPS) and/or MSU. RESULTS We discovered that M0 macrophages were capable of phagocytosing and hydrolysing MSU crystals in various stages of gout, including the control group. Patients with asymptomatic hyperuricaemia exhibited the most pronounced phagocytic and hydrolytic capabilities, surpassing even those of the normal control group. The presence of MSU alone did not induce the secretion of pro-inflammatory cytokines. However, in experiments where M0 macrophages were stimulated with LPS and/or MSU, the phagocytic and hydrolytic abilities of M0 macrophages were correlated with inflammatory cytokine elevation. CONCLUSION The efficient phagocytosis and hydrolysis of MSU crystals by M0 macrophages suggest their role in maintaining the non-inflammatory stage of gout. Our findings suggest that non-inflammatory macrophages play a role in gout.
Collapse
Affiliation(s)
- Y-J Huang
- School of Medicine, Chang Gung University, Taoyuan, Taiwan
- Division of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - L-C Wang
- Division of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - C-P Wang
- Division of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - K-H Yu
- Division of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - C-F Kuo
- School of Medicine, Chang Gung University, Taoyuan, Taiwan
- Division of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Center for Artificial Intelligence in Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| |
Collapse
|
|
2
|
Fernandes DDO, Machado JR, Beltrami VA, Santos ACPMD, Queiroz-Junior CM, Vago JP, Soriani FM, Amaral FA, Teixeira MM, Felix FB, Pinho V. Disruption of survivin protein expression by treatment with YM155 accelerates the resolution of neutrophilic inflammation. Br J Pharmacol 2025; 182:1206-1222. [PMID: 39568085 DOI: 10.1111/bph.17375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 09/03/2024] [Accepted: 09/20/2024] [Indexed: 11/22/2024] Open
Abstract
BACKGROUND AND PURPOSE Prolonged survival of neutrophils is essential for determining the progression and severity of inflammatory and immune-mediated disorders, including gouty arthritis. Survivin, an anti-apoptotic molecule, has been described as a regulator of cell survival. This study aims to examine the effects of YM155 treatment, a survivin selective suppressant, in maintaining neutrophil survival in vitro and in vivo experimental settings of neutrophilic inflammation. EXPERIMENTAL APPROACH BALB/c mice were injected with monosodium urate (MSU) crystals and treated with YM155 (intra-articularly) at the peak of inflammatory response. Leukocyte recruitment, apoptosis neutrophil and efferocytosis were determined by knee joint wash cell morphology counting and flow cytometry. Resolution interval (Ri) was quantified by neutrophil infiltration, monitoring the amplitude and duration of the inflammation. Cytokine production was measured by ELISA. Mechanical hypernociception was assessed using an electronic von Frey aesthesiometer. Efferocytosis was evaluated in zymosan-induced neutrophilic peritonitis. Survivin and cleaved caspase-3 expression was determined in human neutrophils by flow cytometry. KEY RESULTS Survivin was expressed in neutrophils during MSU-induced gout, and the treatment with YM155 reduced survivin expression and shortened Ri from ∼8 h observed in vehicle-treated mice to ∼5.5 h, effect accompanied by increased neutrophil apoptosis and efferocytosis, both crucial for the inflammation resolution. Reduced IL-1β and CXCL1 levels were also observed in periarticular tissue. YM155 reduced histopathological score and hypernociceptive response. In human neutrophils, lipopolysaccharide (LPS) increased survivin expression, whereas survivin inhibition with YM155 induced neutrophil apoptosis, with activation of caspase-3. CONCLUSIONS AND IMPLICATIONS Survivin may be a promising therapeutic target to control neutrophilic inflammation.
Collapse
Affiliation(s)
- Débora de Oliveira Fernandes
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Jessica Rayssa Machado
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Vinicius Amorim Beltrami
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | | | - Celso Martins Queiroz-Junior
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Juliana Priscila Vago
- Experimental Rheumatology, Department of Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Frederico Marianetti Soriani
- Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Flávio Almeida Amaral
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Mauro Martins Teixeira
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Franciel Batista Felix
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Vanessa Pinho
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| |
Collapse
|
|
3
|
Liu C, Liu W, Lu H, Fan Y, Wang A. Effects of Baicalin on Gout Based on Network Pharmacology, Molecular Docking, and in vitro Experiments. J Inflamm Res 2025; 18:1543-1556. [PMID: 39925939 PMCID: PMC11806711 DOI: 10.2147/jir.s480911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 12/31/2024] [Indexed: 02/11/2025] Open
Abstract
Purpose Baicalin is a flavonoid of Scutellaria baicalensis Georgi. It possesses antipyretic, analgesic, and anti-inflammatory effects. It has great potential to treat gout. A network pharmacology approach, molecular docking and experimental validation were applied to investigate the pharmacological mechanisms of baicalin in treating gout. Methods The potential targets of baicalin were retrieved from the TCMSP, PharmMapper, STITCH, and Swiss Target Prediction databases. The gout-related targets were retrieved from the DrugBank, TTD, and Genecards databases. Then, the potential targets and signaling pathways were acquired via protein-protein interaction (PPI), as well as the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Subsequently, the key targets were selected to dock with baicalin based on molecular docking. Finally, in vitro experiments were conducted to further validate the predictions. Results A total of 318 potential targets of baicalin and 752 gout-related targets were screened. TNF, VEGFA, MMP9, PTGS2, and TLR4 might be the hub therapeutic target genes. The TLR4/NF-κB signaling pathway might be the foremost pathway in baicalin against gout. Moreover, molecular docking showed that baicalin combined well with TNF, VEGFA, MMP9, COX-2, and TLR4, respectively. The results of cell experiments suggested that baicalin could reduce the levels of inflammatory cytokines by inhibiting the TLR4/NF-κB signaling pathway in MSU-stimulated THP-1 cells and regulate the expression of these hub targets. Conclusion These results revealed that baicalin possesses "multitarget, multipathway, multilevel" regulatory effects. From a therapeutic standpoint, baicalin may be a promising anti-inflammatory agent for alleviating gout.
Collapse
Affiliation(s)
- Chunliu Liu
- Department of Rheumatism and Immunity, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, People’s Republic of China
- Department of Respiratory Medicine, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, People’s Republic of China
| | - Wei Liu
- Department of Rheumatism and Immunity, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, People’s Republic of China
| | - Hang Lu
- Department of Rheumatism and Immunity, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, People’s Republic of China
| | - Yihua Fan
- Department of Rheumatism and Immunity, Hospital of Chengdu University of Traditional Chinese Medicine, Sichuan Chengdu, People’s Republic of China
| | - Aihua Wang
- Department of Rheumatism and Immunity, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, People’s Republic of China
| |
Collapse
|
|
4
|
Zhang F, Xia Y, Su J, Quan F, Zhou H, Li Q, Feng Q, Lin C, Wang D, Jiang Z. Neutrophil diversity and function in health and disease. Signal Transduct Target Ther 2024; 9:343. [PMID: 39638788 PMCID: PMC11627463 DOI: 10.1038/s41392-024-02049-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 09/21/2024] [Accepted: 10/31/2024] [Indexed: 12/07/2024] Open
Abstract
Neutrophils, the most abundant type of granulocyte, are widely recognized as one of the pivotal contributors to the acute inflammatory response. Initially, neutrophils were considered the mobile infantry of the innate immune system, tasked with the immediate response to invading pathogens. However, recent studies have demonstrated that neutrophils are versatile cells, capable of regulating various biological processes and impacting both human health and disease. Cytokines and other active mediators regulate the functional activity of neutrophils by activating multiple receptors on these cells, thereby initiating downstream signal transduction pathways. Dysfunctions in neutrophils and disruptions in neutrophil homeostasis have been implicated in the pathogenesis of numerous diseases, including cancer and inflammatory disorders, often due to aberrant intracellular signaling. This review provides a comprehensive synthesis of neutrophil biological functions, integrating recent advancements in this field. Moreover, it examines the biological roles of receptors on neutrophils and downstream signaling pathways involved in the regulation of neutrophil activity. The pathophysiology of neutrophils in numerous human diseases and emerging therapeutic approaches targeting them are also elaborated. This review also addresses the current limitations within the field of neutrophil research, highlighting critical gaps in knowledge that warrant further investigation. In summary, this review seeks to establish a comprehensive and multidimensional model of neutrophil regulation, providing new perspectives for potential clinical applications and further research.
Collapse
Affiliation(s)
- Fengyuan Zhang
- Department of Hand and Foot Surgery, Orthopedics Center, The First Hospital of Jilin University, Changchun, People's Republic of China
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China
| | - Yidan Xia
- Department of Hand and Foot Surgery, Orthopedics Center, The First Hospital of Jilin University, Changchun, People's Republic of China
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China
| | - Jiayang Su
- Department of Hand and Foot Surgery, Orthopedics Center, The First Hospital of Jilin University, Changchun, People's Republic of China
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China
| | - Fushi Quan
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Hengzong Zhou
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Qirong Li
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Qiang Feng
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Chao Lin
- School of Grain Science and Technology, Jilin Business and Technology College, Changchun, China
| | - Dongxu Wang
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China.
| | - Ziping Jiang
- Department of Hand and Foot Surgery, Orthopedics Center, The First Hospital of Jilin University, Changchun, People's Republic of China.
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China.
| |
Collapse
|
|
5
|
Wei H, Zhan L, Lv X, Lin Y, Zheng J, Yang W, Liu J, Sun J, Chen S. Gut commensal Parabacteroides distasonis exerts neuroprotective effects in acute ischemic stroke with hyperuricemia via regulating gut microbiota-gut-brain axis. J Transl Med 2024; 22:999. [PMID: 39501312 PMCID: PMC11539330 DOI: 10.1186/s12967-024-05800-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 10/23/2024] [Indexed: 11/08/2024] Open
Abstract
BACKGROUND Hyperuricemia is considered as an independent risk factor for acute ischemic stroke (AIS), and some AIS patients are accompanied by an increase in serum uric acid. Recent studies have highlighted the important role of gut microbiota in both hyperuricemia and AIS, but there is little available data on the relationship between gut microbiota and the pathogenesis of AIS with hyperuricemia (HAS). METHODS Here we profiled the gut microbiota composition in 63 HAS patients and 269 non-HAS patients through 16s rRNA sequencing. Male rat with hyperuricemia were subjected to middle cerebral artery occlusion (MCAO) to establish HAS model and were then treated with Parabacteroides distasonis. Subsequently, the neurological deficit, pathological damages and blood-brain barrier disruption were evaluated. Moreover, the levels of ROS, inflammatory cytokines, NF-𝜿B pathway related protein, and vascular density markers were determined. RESULTS There were significant differences of gut microbiota composition between HAS patients and non-HAS patients, and a significant decrease in the abundance of Parabacteroides in HAS patients compared to non-HAS patients. Animal experiments showed that supplementation with P. distasonis increased beneficial commensal bacteria, significantly improved neurological deficits, pathological damages and BBB disruption, as well as reduced the level of serum uric acid in HAS rats. We further demonstrated that P. distasonis treatment decreased ROS level and increased SOD2 level, thereby reducing oxidative stress. Meanwhile, P. distasonis effectively inhibited NF-𝜿B signal pathway and reduced the production of inflammatory cytokines, including TNF-α and IL-1β, alleviating the inflammatory response. Notably, P. distasonis treatment increased the levels of vascular density markers including cluster of differentiation 31 (CD31) and alpha-smooth muscle actin (α-SMA), ameliorating vascular damage in HAS rats. CONCLUSIONS Together, these findings highlighted the important role of P. distasonis in the pathogenesis of HAS, and its mechanism was involved in the regulation of gut microbiota-gut-brain axis, which implied a novel strategy against HAS.
Collapse
Affiliation(s)
- Hongming Wei
- Department of Geriatrics, the Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China
| | - Lu Zhan
- Department of Preventive Medicine, School of Public Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Xinhuang Lv
- Department of Geriatrics, the Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China
| | - Yan Lin
- Department of Geriatrics, the Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China
| | - Jie Zheng
- Department of Preventive Medicine, School of Public Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Wenwen Yang
- Department of Preventive Medicine, School of Public Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Jiaming Liu
- Department of Preventive Medicine, School of Public Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Jing Sun
- Department of Geriatrics, the Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China.
| | - Songfang Chen
- Department of Neurology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China.
| |
Collapse
|
|
6
|
Patente TA, Gasan TA, Scheenstra M, Ozir-Fazalalikhan A, Obieglo K, Schetters S, Verwaerde S, Vergote K, Otto F, Wilbers RHP, van Bloois E, Wijck YV, Taube C, Hammad H, Schots A, Everts B, Yazdanbakhsh M, Guigas B, Hokke CH, Smits HH. S. mansoni -derived omega-1 prevents OVA-specific allergic airway inflammation via hampering of cDC2 migration. PLoS Pathog 2024; 20:e1012457. [PMID: 39186814 PMCID: PMC11379383 DOI: 10.1371/journal.ppat.1012457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 09/06/2024] [Accepted: 07/27/2024] [Indexed: 08/28/2024] Open
Abstract
Chronic infection with Schistosoma mansoni parasites is associated with reduced allergic sensitization in humans, while schistosome eggs protects against allergic airway inflammation (AAI) in mice. One of the main secretory/excretory molecules from schistosome eggs is the glycosylated T2-RNAse Omega-1 (ω1). We hypothesized that ω1 induces protection against AAI during infection. Peritoneal administration of ω1 prior to sensitization with Ovalbumin (OVA) reduced airway eosinophilia and pathology, and OVA-specific Th2 responses upon challenge, independent from changes in regulatory T cells. ω1 was taken up by monocyte-derived dendritic cells, mannose receptor (CD206)-positive conventional type 2 dendritic cells (CD206+ cDC2), and by recruited peritoneal macrophages. Additionally, ω1 impaired CCR7, F-actin, and costimulatory molecule expression on myeloid cells and cDC2 migration in and ex vivo, as evidenced by reduced OVA+ CD206+ cDC2 in the draining mediastinal lymph nodes (medLn) and retainment in the peritoneal cavity, while antigen processing and presentation in cDC2 were not affected by ω1 treatment. Importantly, RNAse mutant ω1 was unable to reduce AAI or affect DC migration, indicating that ω1 effects are dependent on its RNAse activity. Altogether, ω1 hampers migration of OVA+ cDC2 to the draining medLn in mice, elucidating how ω1 prevents allergic airway inflammation in the OVA/alum mouse model.
Collapse
Affiliation(s)
- Thiago A Patente
- Department of Parasitology, Leiden University Center of Infectious Disease (LU-CID), Leiden University Medical Center (LUMC), Leiden, Netherlands
| | - Thomas A Gasan
- Department of Parasitology, Leiden University Center of Infectious Disease (LU-CID), Leiden University Medical Center (LUMC), Leiden, Netherlands
| | - Maaike Scheenstra
- Department of Parasitology, Leiden University Center of Infectious Disease (LU-CID), Leiden University Medical Center (LUMC), Leiden, Netherlands
| | - Arifa Ozir-Fazalalikhan
- Department of Parasitology, Leiden University Center of Infectious Disease (LU-CID), Leiden University Medical Center (LUMC), Leiden, Netherlands
| | - Katja Obieglo
- Department of Parasitology, Leiden University Center of Infectious Disease (LU-CID), Leiden University Medical Center (LUMC), Leiden, Netherlands
| | - Sjoerd Schetters
- Laboratory of Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
| | - Stijn Verwaerde
- Laboratory of Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
| | - Karl Vergote
- Laboratory of Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
| | - Frank Otto
- Department of Parasitology, Leiden University Center of Infectious Disease (LU-CID), Leiden University Medical Center (LUMC), Leiden, Netherlands
| | - Ruud H P Wilbers
- Laboratory of Nematology, Plant Sciences Group, Wageningen University and Research, Wageningen, Netherlands
| | - Eline van Bloois
- Department of Parasitology, Leiden University Center of Infectious Disease (LU-CID), Leiden University Medical Center (LUMC), Leiden, Netherlands
| | | | - Christian Taube
- Department of Parasitology, Leiden University Center of Infectious Disease (LU-CID), Leiden University Medical Center (LUMC), Leiden, Netherlands
| | - Hamida Hammad
- Laboratory of Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
- Department of Internal Medicine, Ghent University, Ghent, Belgium
| | - Arjen Schots
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
| | - Bart Everts
- Department of Parasitology, Leiden University Center of Infectious Disease (LU-CID), Leiden University Medical Center (LUMC), Leiden, Netherlands
| | - Maria Yazdanbakhsh
- Department of Parasitology, Leiden University Center of Infectious Disease (LU-CID), Leiden University Medical Center (LUMC), Leiden, Netherlands
| | - Bruno Guigas
- Department of Parasitology, Leiden University Center of Infectious Disease (LU-CID), Leiden University Medical Center (LUMC), Leiden, Netherlands
| | - Cornelis H Hokke
- Department of Parasitology, Leiden University Center of Infectious Disease (LU-CID), Leiden University Medical Center (LUMC), Leiden, Netherlands
| | - Hermelijn H Smits
- Department of Parasitology, Leiden University Center of Infectious Disease (LU-CID), Leiden University Medical Center (LUMC), Leiden, Netherlands
| |
Collapse
|
|
7
|
Chen G, Tong L, Ye Q. Association between the serum uric acid/serum creatinine ratio and cognitive function in older adults: NHANES in the United States. Sci Rep 2024; 14:16312. [PMID: 39009809 PMCID: PMC11251062 DOI: 10.1038/s41598-024-67580-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 07/12/2024] [Indexed: 07/17/2024] Open
Abstract
Cognitive impairment can potentially become a significant health concern in older adults. However, early effective diagnostic methods are still lacking. Therefore, we utilized the NHANES database in the US to investigate the relationship between serum uric acid to serum creatinine (SUA/SCR) ratio and cognitive impairment. In our study, a total of 3874 participants were included (2001-2002, 2011-2014). Weighted t tests or chi-square tests were utilized to analyze the basic characteristics of the population. Weighted logistic regression analysis, smooth-fit curves, threshold effects, and subgroup analysis were conducted to investigate the correlation between the SUA/SCR and cognitive impairment. In this study, the SUA/SCR was significantly lower in individuals with cognitive impairment. The logistic regression model, after adjusting for all covariates, revealed that the Q2-Q4 were 0.65 (95% CI 0.49, 0.86), 0.60 (95% CI 0.40, 0.90), 0.55 (95% CI 0.39, 0.77) respectively. This indicates that participants in the Q4 had a 45% reduced risk of cognitive impairment. Smooth-fit curves and threshold effect analysis revealed a nonlinear relationship between SUA/SCR and cognitive impairment, with a turning point at 4.13. Subgroup analysis showed no statistically significant differences in the relationship between SUA/SCR and cognitive impairment among different subgroups (P > 0.05). Our findings indicate a negative correlation between the SUA/SCR and the risk of cognitive impairment in the population of adults aged 60 and above in the US. This suggests that the SUA/SCR holds promise as a potential indicator for cognitive impairment.
Collapse
Affiliation(s)
- Gang Chen
- Department of Laboratory Medicine, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children's Regional Medical Center, Hangzhou, 310052, China
| | - Ling Tong
- Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qing Ye
- Department of Laboratory Medicine, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children's Regional Medical Center, Hangzhou, 310052, China.
| |
Collapse
|
|
8
|
Yang S, Liu H, Fang XM, Yan F, Zhang Y. Signaling pathways in uric acid homeostasis and gout: From pathogenesis to therapeutic interventions. Int Immunopharmacol 2024; 132:111932. [PMID: 38560961 DOI: 10.1016/j.intimp.2024.111932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Revised: 03/20/2024] [Accepted: 03/24/2024] [Indexed: 04/04/2024]
Abstract
Uric acid is a product of purine degradation, and uric acid may have multiple physiologic roles, including the beneficial effects as an antioxidant and neuroprotector, maintenance of blood pressure during low salt ingestion, and modulation of immunity. However, overproduction of metabolic uric acid, and/or imbalance of renal uric acid secretion and reabsorption, and/or underexcretion of extrarenal uric acid, e.g. gut, will contribute to hyperuricemia, which is a common metabolic disease. Long-lasting hyperuricemia can induce the formation and deposition of monosodium urate (MSU) crystals within the joints and periarticular structures. MSU crystals further induce an acute, intensely painful, and sterile inflammation conditions named as gout by NLRP3 inflammasome-mediated cleavage of pro-IL-1β to bioactive IL-1β. Moreover, hyperuricemia and gout are associated with multiple cardiovascular and renal disorders, e.g., hypertension, myocardial infarction, stroke, obesity, hyperlipidemia, type 2 diabetes mellitus and chronic kidney disease. Although great efforts have been made by scientists of modern medicine, however, modern therapeutic strategies with a single target are difficult to exert long-term positive effects, and even some of these agents have severe adverse effects. The Chinese have used the ancient classic prescriptions of traditional Chinese medicine (TCM) to treat metabolic diseases, including gout, by multiple targets, for more than 2200 years. In this review, we discuss the current understanding of urate homeostasis, the pathogenesis of hyperuricemia and gout, and both modern medicine and TCM strategies for this commonly metabolic disorder. We hope these will provide the good references for treating hyperuricemia and gout.
Collapse
Affiliation(s)
- Shuangling Yang
- School of Health Sciences, Guangzhou Xinhua University, Guangzhou, Guangdong 510520, China
| | - Haimei Liu
- Department of Physiology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China
| | - Xian-Ming Fang
- Department of Cardiology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Guangxi University of Chinese Medicine, Nanning, Guangxi 530011, China.
| | - Fuman Yan
- Department of Physiology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China.
| | - Yaxing Zhang
- Department of Physiology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China; Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China; Issue 12(th) of Guangxi Apprenticeship Education of Traditional Chinese Medicine (Shi‑Cheng Class of Guangxi University of Chinese Medicine), College of Continuing Education, Guangxi University of Chinese Medicine, Nanning, Guangxi 530001, China.
| |
Collapse
|
|
9
|
Yang QB, Zhang MY, Yang L, Wang J, Mi QS, Zhou JG. Deficiency of histone deacetylases 3 in macrophage alleviates monosodium urate crystals-induced gouty inflammation in mice. Arthritis Res Ther 2024; 26:96. [PMID: 38711064 PMCID: PMC11071232 DOI: 10.1186/s13075-024-03335-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 05/01/2024] [Indexed: 05/08/2024] Open
Abstract
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-1β 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.
Collapse
Affiliation(s)
- Qi-Bin Yang
- Department of Rheumatology and Immunology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan Province, 637000, People's Republic of China.
- Henry Ford Immunology Program, Departments of Dermatology and Internal Medicine, Henry Ford Health System, 1 Ford Place, Detroit, MI, 48202, USA.
| | - Meng-Yun Zhang
- Department of Rheumatology and Immunology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan Province, 637000, People's Republic of China
- Department of Integrated TCM and Western Medicine, General Hospital of Central Theater, PLA, Wuhan, Hubei Province, 430070, China
- Henry Ford Immunology Program, Departments of Dermatology and Internal Medicine, Henry Ford Health System, 1 Ford Place, Detroit, MI, 48202, USA
| | - Liu Yang
- Department of Rheumatology and Immunology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan Province, 637000, People's Republic of China
| | - Jie Wang
- Henry Ford Immunology Program, Departments of Dermatology and Internal Medicine, Henry Ford Health System, 1 Ford Place, Detroit, MI, 48202, USA
| | - Qing-Sheng Mi
- Henry Ford Immunology Program, Departments of Dermatology and Internal Medicine, Henry Ford Health System, 1 Ford Place, Detroit, MI, 48202, USA.
| | - Jing-Guo Zhou
- Department of Rheumatology and Immunology, Clinical Medical College, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan Province, 610500, People's Republic of China.
| |
Collapse
|
|
10
|
Chen L, Zhu Y, Huang Y, Shen K, Chen L. The association between Helicobacter pylori infection and the risk for gout in hyperuricemia patients in China - A cross-sectional study. Gut Pathog 2024; 16:24. [PMID: 38678252 PMCID: PMC11056053 DOI: 10.1186/s13099-024-00615-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 04/09/2024] [Indexed: 04/29/2024] Open
Abstract
PURPOSE Helicobacter pylori (H. pylori) infection has been reported to be associated with multiple metabolic diseases. However, the connection between H. pylori infection and gout has not been explored previously. Our study aimed to investigate the association of gout and H. pylori infection in hyperuricemia population in China. PATIENTS AND METHODS This cross-sectional study was performed among the subjects who underwent health checkup in our health promotion center from January 1, 2020 to December 31, 2021. A total of 53,629 subjects with a mean age of 44.2 years were included in this study. H. pylori infection was defined as a positive [13]C-urea breath test. The effect of H. pylori infection on gout was assessed by multiple logistic regression analysis. RESULTS 720 subjects with gout and 15,077 subjects with asymptomatic hyperuricemia (> 420 µmol/L in male and > 360 µmol/L in female) were enrolled. The prevalence rates of H. pylori infection, hyperuricemia and gout were 26.3%, 29.5%, 1.3%, respectively. The prevalence rate of H. pylori infection was significantly higher in subjects with gout than in those with asymptomatic hyperuricemia (35.0% vs. 27.2%; P<0.001). Multiple logistic regression analysis showed that H. pylori infection was associated with an increased risk of gout independent of serum uric acid level in hyperuricemia population (odds ratio [OR]: 1.320, 95% confidence interval [CI]: 1.124-1.550, P = 0.001). CONCLUSION H. pylori infection is positively associated with higher risk of gout in hyperuricemia population. The causal relationship and potential mechanism between H. pylori infection and gout warrants further investigation.
Collapse
Affiliation(s)
- Lin Chen
- Department of General Practice, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou Zhejiang, China
| | - Yue Zhu
- Department of General Practice, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou Zhejiang, China
| | - Yilin Huang
- Department of General Practice, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou Zhejiang, China
| | - Keqing Shen
- Department of General Practice, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou Zhejiang, China
| | - Liying Chen
- Department of General Practice, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou Zhejiang, China.
| |
Collapse
|
|
11
|
Rao B, Xie D, Deng Y, Ye J, Zeng X, Lin A, Chen J, Huang D, Xie C, Chen C, Luo Y, Lu X, Wang X, Lu J. Robust positive association between serum urate and the risk of chronic obstructive pulmonary disease: hospital-based cohort and Mendelian randomisation study. BMJ Open Respir Res 2024; 11:e002203. [PMID: 38479817 PMCID: PMC10941131 DOI: 10.1136/bmjresp-2023-002203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 02/29/2024] [Indexed: 03/17/2024] Open
Abstract
BACKGROUND Chronic obstructive pulmonary disease (COPD) and hyperuricaemia are both characterised by systemic inflammation. Preventing chronic diseases among the population with common metabolic abnormality is an effective strategy. However, the association of hyperuricaemia with the higher incidence and risk of COPD remains controversial. Therefore, replicated researches in populations with distinct characteristics or demographics are compellingly warranted. METHODS This cohort study adopted a design of ambispective hospital-based cohort. We used propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) to minimise the effects of potential confounding factors. A Cox regression model and restricted cubic spline (RCS) model were applied further to assess the effect of serum urate on the risk of developing COPD. Finally, we conducted a two-sample Mendelian randomisation (MR) analysis to explore evidence of causal association. RESULTS There is a higher incidence in the population with hyperuricaemia compared with the population with normal serum urate (22.29/1000 person-years vs 8.89/1000 person-years, p=0.009). This result is robust after performing PSM (p=0.013) and IPTW (p<0.001). The Cox model confirms that hyperuricaemia is associated with higher risk of developing COPD (adjusted HR=3.35 and 95% CI=1.61 to 6.96). Moreover, RCS shows that the risk of developing COPD rapidly increases with the concentration of serum urate when it is higher than the reference (420 µmol/L). Finally, in MR analysis, the inverse variance weighted method evidences that a significant causal effect of serum urate on COPD (OR=1.153, 95% CI=1.034 to 1.289) is likely to be true. The finding of MR is robust in the repeated analysis using different methods and sensitivity analysis. CONCLUSIONS Our study provides convincing evidence suggesting a robust positive association between serum urate and the risk of developing COPD, and indicates that the population with hyperuricaemia is at high risk of COPD in the Chinese population who seek medical advice or treatment in the hospital.
Collapse
Affiliation(s)
- Boqi Rao
- Emergency Department, The Second Affiliated Hospital, The State Key Lab of Respiratory Disease, Institute of Public Health, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Dongming Xie
- The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital, The Institute for Chemical Carcinogenesis, School of Public Health, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yibin Deng
- Centre for Medical Laboratory Science, the Afliated Hospital of Youjiang Medical University for Nationalities, Youjiang Medical University for Nationalities, Baise, Guangxi, China
- Key Laboratory of Research on Clinical Molecular Diagnosis for High Incidence Diseases in Western Guangxi, Baise, Guangxi, China
| | - Junyi Ye
- The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital, The Institute for Chemical Carcinogenesis, School of Public Health, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Xiaobin Zeng
- The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital, The Institute for Chemical Carcinogenesis, School of Public Health, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Ao Lin
- The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital, The Institute for Chemical Carcinogenesis, School of Public Health, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jinbin Chen
- KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Dongsheng Huang
- Department of Respiratory and Critical Care Medicine, Shenzhen Longhua District Central Hospital, Shenzhen, Guangdong, China
| | - Chenli Xie
- Department of Respiratory and Critical Care Medicine, Binhaiwan Central Hospital of Dongguan, Dongguan, Guangdong, China
- Dongguan Key Laboratory of Precision, Dongguan, Guangdong, China
| | - Cuiyi Chen
- Department of Respiratory and Critical Care Medicine, Songshan Lake Central Hospital of Dongguan, Dongguan, Guangdong, China
| | - Yixuan Luo
- Guangzhou Panyu District Central Hospital, Guangzhou, Guangdong, China
| | - Xiaoxiao Lu
- Department of English and American Studies, Ludwig Maximilian University of Munich Faculty of Languages and Literatures, Munich, Germany
| | - Xinhua Wang
- Institute of Basic Medicine, Institute of Public Health, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Jiachun Lu
- The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital, The Institute for Chemical Carcinogenesis, School of Public Health, Guangzhou Medical University, Guangzhou, Guangdong, China
| |
Collapse
|
|
12
|
Ma Q, Lim CS. Molecular Activation of NLRP3 Inflammasome by Particles and Crystals: A Continuing Challenge of Immunology and Toxicology. Annu Rev Pharmacol Toxicol 2024; 64:417-433. [PMID: 37708431 PMCID: PMC10842595 DOI: 10.1146/annurev-pharmtox-031023-125300] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/16/2023]
Abstract
Particles and crystals constitute a unique class of toxic agents that humans are constantly exposed to both endogenously and from the environment. Deposition of particulates in the body is associated with a range of diseases and toxicity. The mechanism by which particulates cause disease remains poorly understood due to the lack of mechanistic insights into particle-biological interactions. Recent research has revealed that many particles and crystals activate the NLRP3 inflammasome, an intracellular pattern-recognition receptor. Activated NLRP3 forms a supramolecular complex with an adaptor protein to activate caspase 1, which in turn activates IL-1β and IL-18 to instigate inflammation. Genetic ablation and pharmacological inhibition of the NLRP3 inflammasome dampen inflammatory responses to particulates. Nonetheless, how particulates activate NLRP3 remains a challenging question. From this perspective, we discuss our current understanding of and progress on revealing the function and mode of action of the NLRP3 inflammasome in mediating adaptive and pathologic responses to particulates in health and disease.
Collapse
Affiliation(s)
- Qiang Ma
- Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, West Virginia, USA;
| | - Chol Seung Lim
- Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, West Virginia, USA;
| |
Collapse
|
|
13
|
Ni Z, Xiao Q, Xia Z, Kuang K, Yin B, Peng D. Electroacupuncture for acute gouty arthritis: a systematic review and meta-analysis of randomized controlled trials. Front Immunol 2024; 14:1295154. [PMID: 38239361 PMCID: PMC10794621 DOI: 10.3389/fimmu.2023.1295154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 12/11/2023] [Indexed: 01/22/2024] Open
Abstract
Acute gouty arthritis (AGA) is a metabolic disorder in which recurrent pain episodes can severely affect the quality of life of gout sufferers. Electroacupuncture (EA) is a non-pharmacologic therapy. This systematic review aimed to assess the efficacy and safety of electroacupuncture in treating acute gouty arthritis. We searched eight Chinese and English databases from inception to July 30, 2023, and 242 studies were retrieved. Finally, 15 randomized controlled trials (n=1076) were included in a meta-analysis using Review Manager V.5.4.1. meta-analysis results included efficacy rate, visual rating scale (VAS) for pain, serum uric acid level (SUA), immediate analgesic effect, and incidence of adverse events. Electroacupuncture (or combined non-pharmacologic) treatment of AGA was significantly different from treatment with conventional medications (RR = 1.14, 95% confidence interval CI = 1.10 to 1.19, P < 0.00001). The analgesic effect of the electroacupuncture group was superior to that of conventional Western drug treatment (MD = -2.26, 95% CI = -2.71 to -1.81, P < 0.00001). The electroacupuncture group was better at lowering serum uric acid than the conventional western drug group (MD =-31.60, CI -44.24 to -18.96], P < 0.00001). In addition, electroacupuncture combined with Western drugs had better immediate analgesic effects than conventional Western drug treatment (MD = -1.85, CI -2.65 to -1.05, P < 0.00001). Five studies reported adverse events in the electroacupuncture group versus the drug group, including 19 cases of gastrointestinal symptoms and 6 cases of neurological symptoms (RR = 0.20, 95% CI = 0.04 to 0.88, P = 0.03). Systematic review registration https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=450037, identifier CRD42023450037.
Collapse
Affiliation(s)
- Zhichao Ni
- College of Acupuncture-Moxibustion and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qinwen Xiao
- West China Second University Hospital, Sichuan University, Chengdu, China
| | - Zihao Xia
- College of Acupuncture-Moxibustion and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Kunlin Kuang
- College of Acupuncture-Moxibustion and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Bingzun Yin
- College of Acupuncture-Moxibustion and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Dezhong Peng
- College of Acupuncture-Moxibustion and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| |
Collapse
|
|
14
|
Jafari-Nozad AM, Jafari A, Yousefi S, Bakhshi H, Farkhondeh T, Samarghandian S. Anti-gout and Urate-lowering Potentials of Curcumin: A Review from Bench to Beside. Curr Med Chem 2024; 31:3715-3732. [PMID: 37488765 DOI: 10.2174/0929867331666230721154653] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 05/23/2023] [Accepted: 06/01/2023] [Indexed: 07/26/2023]
Abstract
BACKGROUND Gouty arthritis is a complex form of inflammatory arthritis, triggered by the sedimentation of monosodium urate crystals in periarticular tissues, synovial joints, and other sites in the body. Curcumin is a natural polyphenol compound, isolated from the rhizome of the plant Curcuma longa, possessing countless physiological features, including antioxidant, anti-inflammatory, and anti-rheumatic qualities. OBJECTIVE This study aimed to discuss the beneficial impacts of curcumin and its mechanism in treating gout disease. METHODS Ten English and Persian databases were used to conduct a thorough literature search. Studies examining the anti-gouty arthritis effects of curcumin and meeting the inclusion criteria were included. RESULTS According to the studies, curcumin has shown xanthine oxidase and urate transporter- 1 inhibitory properties, uric acid inhibitory characteristics, and antioxidant and anti- inflammatory effects. However, some articles found no prominent reduction in uric acid levels. CONCLUSION In this review, we emphasized the potency of curcumin and its compounds against gouty arthritis. Despite the potency, we suggest an additional well-designed evaluation of curcumin, before its therapeutic effectiveness is completely approved as an antigouty arthritis agent.
Collapse
Affiliation(s)
| | - Amirsajad Jafari
- Department of Basic Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
| | - Saman Yousefi
- Faculty of Veterinary Medicine, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Hasan Bakhshi
- Vector-borne Diseases Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Tahereh Farkhondeh
- Department of Toxicology and Pharmacology, School of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran
| | - Saeed Samarghandian
- Healthy Ageing Research Centre, Neyshabur University of Medical Sciences, Neyshabur 9318614139, Iran
| |
Collapse
|
|
15
|
Ling M, Gan J, Hu M, Pan F, Liu M. IL1A regulates the inflammation in gout through the Toll-like receptors pathway. Int J Med Sci 2024; 21:188-199. [PMID: 38164346 PMCID: PMC10750337 DOI: 10.7150/ijms.88447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 10/21/2023] [Indexed: 01/03/2024] Open
Abstract
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.
Collapse
Affiliation(s)
- Meirong Ling
- Emergency Medical Department, Minhang Hospital, Fudan University, 170 Xinsong Road, 201199, Shanghai, China
| | - Jiaqi Gan
- Department of General Medicine, Minhang Hospital, Fudan University, 170 Xinsong Road, 201199, Shanghai, China
| | - Mengting Hu
- Department of General Medicine, Minhang Hospital, Fudan University, 170 Xinsong Road, 201199, Shanghai, China
| | - Fei Pan
- Department of General Medicine, Minhang Hospital, Fudan University, 170 Xinsong Road, 201199, Shanghai, China
| | - Mei Liu
- Department of General Medicine, Minhang Hospital, Fudan University, 170 Xinsong Road, 201199, Shanghai, China
| |
Collapse
|
|
16
|
Oleszycka E, O’Brien EC, Freeley M, Lavelle EC, Long A. Bile acids induce IL-1α and drive NLRP3 inflammasome-independent production of IL-1β in murine dendritic cells. Front Immunol 2023; 14:1285357. [PMID: 38090554 PMCID: PMC10711081 DOI: 10.3389/fimmu.2023.1285357] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 11/01/2023] [Indexed: 12/18/2023] Open
Abstract
Bile acids are amphipathic molecules that are synthesized from cholesterol in the liver and facilitate intestinal absorption of lipids and nutrients. They are released into the small intestine upon ingestion of a meal where intestinal bacteria can modify primary into secondary bile acids. Bile acids are cytotoxic at high concentrations and have been associated with inflammatory diseases such as liver inflammation and Barrett's Oesophagus. Although bile acids induce pro-inflammatory signalling, their role in inducing innate immune cytokines and inflammation has not been fully explored to date. Here we demonstrate that the bile acids, deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA) induce IL-1α and IL-1β secretion in vitro in primed bone marrow derived dendritic cells (BMDCs). The secretion of IL-1β was found not to require expression of NLRP3, ASC or caspase-1 activity; we can't rule out all inflammasomes. Furthermore, DCA and CDCA were shown to induce the recruitment of neutrophils and monocytes to the site of injection an intraperitoneal model of inflammation. This study further underlines a mechanistic role for bile acids in the pathogenesis of inflammatory diseases through stimulating the production of pro-inflammatory cytokines and recruitment of innate immune cells.
Collapse
Affiliation(s)
- Ewa Oleszycka
- Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
- Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
| | - Eoin C. O’Brien
- Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Michael Freeley
- School of Biotechnology, Dublin City University, Dublin, Ireland
| | - Ed C. Lavelle
- Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Aideen Long
- Department of Clinical Medicine, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| |
Collapse
|
|
17
|
Liu Q, Li L, Zheng D, Jin S, Guan X, Fu Z, Xiong Z, Ding H. Mechanism of ShuiJingDan in Treating Acute Gouty Arthritis Flares Based on Network Pharmacology and Molecular Docking. Drug Des Devel Ther 2023; 17:3493-3505. [PMID: 38034481 PMCID: PMC10683514 DOI: 10.2147/dddt.s436360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 11/09/2023] [Indexed: 12/02/2023] Open
Abstract
Purpose This study examined the underlying mechanisms of SJD's anti-inflammatory and analgesic effects on acute GA flares. Methods This study used pharmacology network and molecular docking methods. The active ingredients of ShuiJingDan (SJD) were obtained from the Traditional Chinese Medicine Systems Pharmacology Analysis Platform (TCMSP), and the relevant targets of GA were obtained from the Online Mendelian Inheritance in Man (OMIM) database and Therapeutic Target Database (TTD). The core drug group-target-disease Venn diagram was formed by crossing the active ingredients of SJD and the relevant targets. Gene Ontology (GO) analysis was conducted for functional annotation, DAVID was used for Kyoto Encyclopedia of Genes, and Genomes pathway enrichment analysis, and R was used to find the core targets. The accuracy of SJD network pharmacology analysis in GA treatment was verified by molecular docking simulations. Finally, a rat GA model was used to further verify the anti-inflammatory mechanism of SJD in the treatment of GA. Results SJD mainly acted on target genes including IL1B, PTGS2, CXCL8, EGF, and JUN, as well as signal pathways including NF-κB, Toll-like receptor (TLR), IL-17, and MAPK. The rat experiments showed that SJD could significantly relieve ankle swelling, reduce the local skin temperature, and increased the paw withdrawal threshold. SJD could also reduce synovial inflammation, reduced the concentrations of interleukin-1β (IL-1β), IL-8, and COX-2 in the synovial fluid, and suppressed the expression of IL1B, CXCL8, and PTGS2 mRNA in the synovial tissue. Conclusion SJD has a good anti-inflammatory effect to treat GA attacks, by acting on target genes such as IL-1β, PTGS2, and CXCL8.
Collapse
Affiliation(s)
- Qingsong Liu
- Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China
- School of Sports Medicine and Health, Chengdu Sport University, Chengdu, People’s Republic of China
| | - Lunyu Li
- School of Sports Medicine and Health, Chengdu Sport University, Chengdu, People’s Republic of China
| | - Dan Zheng
- Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China
| | - Songlin Jin
- School of Sports Medicine and Health, Chengdu Sport University, Chengdu, People’s Republic of China
| | - Xiaotian Guan
- School of Sports Medicine and Health, Chengdu Sport University, Chengdu, People’s Republic of China
| | - Zeting Fu
- School of Sports Medicine and Health, Chengdu Sport University, Chengdu, People’s Republic of China
| | - Zhigang Xiong
- Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China
| | - Haili Ding
- Insititute of Sports Medicine and Health, Chengdu Sport University, Chengdu, People’s Republic of China
| |
Collapse
|
|
18
|
Li D, Yuan S, Deng Y, Wang X, Wu S, Chen X, Li Y, Ouyang J, Lin D, Quan H, Fu X, Li C, Mao W. The dysregulation of immune cells induced by uric acid: mechanisms of inflammation associated with hyperuricemia and its complications. Front Immunol 2023; 14:1282890. [PMID: 38053999 PMCID: PMC10694226 DOI: 10.3389/fimmu.2023.1282890] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 10/26/2023] [Indexed: 12/07/2023] Open
Abstract
Changes in lifestyle induce an increase in patients with hyperuricemia (HUA), leading to gout, gouty arthritis, renal damage, and cardiovascular injury. There is a strong inflammatory response in the process of HUA, while dysregulation of immune cells, including monocytes, macrophages, and T cells, plays a crucial role in the inflammatory response. Recent studies have indicated that urate has a direct impact on immune cell populations, changes in cytokine expression, modifications in chemotaxis and differentiation, and the provocation of immune cells by intrinsic cells to cause the aforementioned conditions. Here we conducted a detailed review of the relationship among uric acid, immune response, and inflammatory status in hyperuricemia and its complications, providing new therapeutic targets and strategies.
Collapse
Affiliation(s)
- Delun Li
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Nephrology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China
- Nephrology Institute of Guangdong Provincial Academy of Chinese Medical Sciences (NIGH-CM), Guangzhou, China
| | - Siyu Yuan
- Ministry of Education Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yiyao Deng
- Department of Nephrology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, China
| | - Xiaowan Wang
- Department of Nephrology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China
| | - Shouhai Wu
- The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Nephrology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China
| | - Xuesheng Chen
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Nephrology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China
- Nephrology Institute of Guangdong Provincial Academy of Chinese Medical Sciences (NIGH-CM), Guangzhou, China
| | - Yimeng Li
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Nephrology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China
- Nephrology Institute of Guangdong Provincial Academy of Chinese Medical Sciences (NIGH-CM), Guangzhou, China
| | - Jianting Ouyang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Nephrology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China
- Nephrology Institute of Guangdong Provincial Academy of Chinese Medical Sciences (NIGH-CM), Guangzhou, China
| | - Danyao Lin
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Nephrology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China
- Nephrology Institute of Guangdong Provincial Academy of Chinese Medical Sciences (NIGH-CM), Guangzhou, China
| | - Haohao Quan
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Nephrology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China
- Nephrology Institute of Guangdong Provincial Academy of Chinese Medical Sciences (NIGH-CM), Guangzhou, China
| | - Xinwen Fu
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Nephrology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China
- Nephrology Institute of Guangdong Provincial Academy of Chinese Medical Sciences (NIGH-CM), Guangzhou, China
| | - Chuang Li
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Nephrology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China
- Nephrology Institute of Guangdong Provincial Academy of Chinese Medical Sciences (NIGH-CM), Guangzhou, China
| | - Wei Mao
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Nephrology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China
- Nephrology Institute of Guangdong Provincial Academy of Chinese Medical Sciences (NIGH-CM), Guangzhou, China
| |
Collapse
|
|
19
|
Xu L, Ouyang QR, Xiong Q, Huang LW, Yu M. Elevated serum uric acid is associated with cognitive impairment in acute minor ischemic stroke patients. Heliyon 2023; 9:e21072. [PMID: 37886747 PMCID: PMC10597847 DOI: 10.1016/j.heliyon.2023.e21072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 07/26/2023] [Accepted: 10/13/2023] [Indexed: 10/28/2023] Open
Abstract
Background Acute minor ischemic stroke (AMIS) has been proven to be strongly associated with post-stroke cognitive impairment (PSCI). Few studies have reported that uric acid (UA) levels are linked to PSCI in patients with AMIS, and those results are debatable. We investigated the relationship between serum UA levels and cognitive impairment in patients with AMIS. Methods A total of 318 patients who were diagnosed with AMIS were recruited from Suining Central Hospital. Fasting serum samples were collected the day after admission for UA measurement. Cognitive function was evaluated at admission and 3 months after stroke using the Montreal Cognitive Assessment (MoCA). The relationship between UA and PSCI was examined using a multivariate binary logistic regression model. The optimal cut-off point for UA levels to predict PSCI was determined using the receiver operating characteristic (ROC) curve. Results A total of 197 (61.9 %) of the 318 participants in this study exhibited cognitive impairment at 3 months. Serum UA was strongly linked with PSCI after adjusting for confounding factors (OR = 1.82, 95 % CI: 1.56 to 2.11, P < 0.0001). The ROC curve revealed a cut-off of 363.58 μmol/L serum UA, and the predicted sensitivity and specificity for PSCI were 67.5 % and 83.5 %, respectively. Subgroup analysis showed that confounding factors had no impact on the association between serum UA and PSCI risk. Conclusions Higher baseline serum UA levels might be an independent risk factor for cognitive impairment in AMIS patients. Serum UA levels above 363.58 μmol/L may have clinical implications in predicting PSCI.
Collapse
Affiliation(s)
- Lei Xu
- Department of Neurology, Suining Central Hospital, Suining, 629000, China
| | - Qing-rong Ouyang
- Department of Neurology, Suining Central Hospital, Suining, 629000, China
| | - Qin Xiong
- Department of Internal Medicine, The Third People's Hospital of Suining, Suining, 629099, China
| | - Lu-wen Huang
- Department of Neurology, Suining Central Hospital, Suining, 629000, China
| | - Ming Yu
- Department of Neurology, Suining Central Hospital, Suining, 629000, China
| |
Collapse
|
|
20
|
Xu Y, Song D, Wang W, Li S, Yue T, Xia T, Shi Y. Clec12a inhibits MSU-induced immune activation through lipid raft expulsion. Life Sci Alliance 2023; 6:e202301938. [PMID: 37339805 PMCID: PMC10282328 DOI: 10.26508/lsa.202301938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 06/12/2023] [Accepted: 06/13/2023] [Indexed: 06/22/2023] Open
Abstract
Monosodium uric acid (MSU) crystal, the etiological agent of gout, has been shown to trigger innate immune responses via multiple pathways. It is known that MSU-induced lipid sorting on plasma membrane promotes the phosphorylation of Syk and eventually leads to the activation of phagocytes. However, whether this membrane lipid-centric mechanism is regulated by other processes is unclear. Previous studies showed that Clec12a, a member of the C-type lectin receptor family, is reported to recognize MSU and suppresses this crystalline structure-induced immune activation. How this scenario is integrated into the lipid sorting-mediated inflammatory responses by MSU, and particularly, how Clec12a intercepts lipid raft-originated signaling cascade remains to be elucidated. Here, we found that the ITIM motif of Clec12a is dispensable for its inhibition of MSU-mediated signaling; instead, the transmembrane domain of Clec12a disrupts MSU-induced lipid raft recruitment and thus attenuates downstream signals. Single amino acid mutagenesis study showed the critical role of phenylalanine in the transmembrane region for the interactions between C-type lectin receptors and lipid rafts, which is critical for the regulation of MSU-mediated lipid sorting and phagocyte activation. Overall, our study provides new insights for the molecular mechanisms of solid particle-induced immune activation and may lead to new strategies in inflammation control.
Collapse
Affiliation(s)
- Ying Xu
- Institute for Immunology, School of Medicine, Tsinghua University, Beijing, China
| | - Dingka Song
- Institute for Immunology, School of Medicine, Tsinghua University, Beijing, China
- State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei Wang
- Institute of Coastal Environmental Pollution Control, Key Laboratory of Marine Environment and Ecology, Ministry of Education, Ocean University of China, Qingdao, China
| | - Shixin Li
- Joint International Research Laboratory of Agriculture and Agri-product Safety of the Ministry of Education, Yangzhou University, Yangzhou, China
| | - Tongtao Yue
- Institute of Coastal Environmental Pollution Control, Key Laboratory of Marine Environment and Ecology, Ministry of Education, Ocean University of China, Qingdao, China
| | - Tie Xia
- Institute for Immunology, School of Medicine, Tsinghua University, Beijing, China
| | - Yan Shi
- Institute for Immunology, School of Medicine, Tsinghua University, Beijing, China
- Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute, University of Calgary, Calgary, Canada
| |
Collapse
|
|
21
|
Wang Q, Qiu H. Deubiquitinase USP16 induces gouty arthritis via Drp1-dependent mitochondrial fission and NLRP3 inflammasome activation. Arthritis Res Ther 2023; 25:126. [PMID: 37488647 PMCID: PMC10367261 DOI: 10.1186/s13075-023-03095-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 06/21/2023] [Indexed: 07/26/2023] Open
Abstract
BACKGROUND Gouty arthritis is the most frequently diagnosed inflammatory arthritis worldwide. Dynamin-related protein 1 (Drp1), a regulator of mitochondrial fission, contributes to various inflammatory disorders via activating NLRP3 inflammasome. However, the biological role of Drp1 in gouty arthritis remains undefined. METHODS A mouse model of monosodium urate (MSU)-induced gouty arthritis and MSU-stimulated macrophages were established as in vivo and in vitro models, respectively. Histological changes were assessed by H&E and IHC analysis. RT-qPCR and western blot were used to detect the expression of Drp1 and the key molecules in joint tissues and macrophages. Cytokine secretion was measured by ELISA assay, and antioxidant enzymes activities and LDH release were monitored using commercial kits. Mitochondrial structure and functions were assessed by transmission electron microscopy (TEM) and MitoSOX staining. Co-IP and GST pull-down assay were used to detect the direct interaction between USP16 and Drp1, as well as the ubiquitination of Drp1. RESULTS Drp1 was elevated in MSU-induced gouty arthritis model, and it induced gouty arthritis via NF-κB pathway and NLRP3 inflammasome activation. In addition, Drp1 activated NF-κB/NLRP3 signaling via modulating mitochondrial fission. Mechanistically, USP16 mediated deubiquitination and stabilization of Drp1 through its direct interaction with Drp1. Functional studies further showed that USP16 was highly expressed in MSU-stimulated macrophages and induced gouty arthritis via Drp1-dependent NLRP3 inflammasome activation. CONCLUSION Deubiquitinase USP16 induced gouty arthritis via Drp1-dependent mitochondrial fission and NF-κB/NLRP3 signaling.
Collapse
Affiliation(s)
- Qingdong Wang
- Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi University, Heilongjiang Province, Jiamusi, 154000, People's Republic of China
| | - Hongbin Qiu
- Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi University, Heilongjiang Province, Jiamusi, 154000, People's Republic of China.
| |
Collapse
|
|
22
|
Popov D, Jain L, Alhilali M, Dalbeth N, Poulsen RC. Monosodium urate crystals alter the circadian clock in macrophages leading to loss of NLRP3 inflammasome repression: Implications for timing of the gout flare. FASEB J 2023; 37:e22940. [PMID: 37243314 DOI: 10.1096/fj.202202035r] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 03/21/2023] [Accepted: 04/17/2023] [Indexed: 05/28/2023]
Abstract
Gout is caused by monosodium urate (MSU) crystal deposition within joints. This leads to acute episodes of inflammation ("gout flares") driven by NLRP3 inflammasome activation in macrophages. Gout flares are frequently present during late night/early morning. The reason for this timing is unclear. Recent evidence suggests the NLRP3 inflammasome is under circadian control. The purpose of this study was to determine whether MSU crystals cause changes in the circadian clock in macrophages leading to time-of-day differences in NLRP3 inflammasome activation. Levels of circadian clock components were measured in undifferentiated "monocytic" and PMA-differentiated "macrophagic" THP-1 cells cultured with/without MSU crystals. Caspase-1 activity was measured to assess NLRP3 inflammasome activity. MSU crystal exposure resulted in minimal effects on clock genes in THP-1 monocytes but BMAL1, CRY1, PER2, and REV-ERBα showed altered expression with reduced protein levels of BMAL1 and REV-ERBα in THP-1 macrophages. REV-ERBα activation or BMAL1 over-expression resulted in reduced MSU crystal-induced caspase-1 activity. BMAL1 knockdown resulted in a further increase in MSU crystal-induced caspase-1 activity, but only at times of day when BMAL1 levels were naturally high. MSU crystal-induced NLRP3 inflammasome activation was greatest at the time of day when BMAL1 levels were naturally low. MSU crystals alter the expression of circadian clock components in THP-1 macrophages leading to loss of BMAL1 and REV-ERBα-mediated repression of NLRP3 inflammasome activity and time-of-day differences in susceptibility to inflammasome activation. Our findings suggest that the nocturnal risk of gout flare is at least partially a consequence of altered circadian control of immune cell function.
Collapse
Affiliation(s)
- Dmitry Popov
- Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand
| | - Lekha Jain
- Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand
| | - Mariam Alhilali
- Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand
| | - Nicola Dalbeth
- Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Raewyn C Poulsen
- Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand
| |
Collapse
|
|
23
|
Tanshinone IIA Improves Acute Gouty Arthritis in Rats through Regulating Neutrophil Activation and the NLRP3 Inflammasome. DISEASE MARKERS 2022; 2022:5851412. [PMID: 36578443 PMCID: PMC9792249 DOI: 10.1155/2022/5851412] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 11/13/2022] [Accepted: 12/07/2022] [Indexed: 12/24/2022]
Abstract
Objectives To investigate the prevention and treatment effect of tanshinone IIA (TIIA) on acute gouty arthritis (AGA) and its mechanism. Methods The anti-AGA effect of TIIA was observed in vivo and in vitro. Neutrophils were isolated from the abdominal cavity of mice, and the anti-AGA effect of TIIA was investigated in a rat model of MSU-induced AGA. The pathological changes of the ankle joint tissues were assessed by H&E. Cytokine and chemokine expression were determined by ELISA and RT-qPCR. The NLRP3 inflammasome pathway protein levels in the ankle joint tissues were evaluated via western blotting. Neutrophil migration was evaluated in air pouch and transwell assays. Immunohistochemistry and immunofluorescence analysis evaluate the release of myeloperoxidase (MPO), neutrophil elastase (NE), and citrullination of histone H3 (CitH3). Beclin-1 and LC3B expressions were determined using western blotting and immunofluorescence. Key Findings. Treatment with TIIA alleviated synovial hyperplasia and neutrophil infiltration, regulated cytokine and chemokine expressions, and inhibited NLRP3 activation in AGA rats, neutrophil migration, MPO, NE, and CitH3 expression, and LC3B and Beclin-1 protein expression. Conclusions These results demonstrate that TIIA can effectively enhance AGA by focusing on the neutrophils and NLRP3 inflammasome, demonstrating that TIIA may act as a potential helpful agent for AGA.
Collapse
|
|
24
|
Wu H, Wang Y, Ren Z, Li Y, Huang J, Lin Z, Zhang B. Overnutrition-induced gout: An immune response to NLRP3 inflammasome dysregulation by XOD activity increased in quail. Front Immunol 2022; 13:1074867. [PMID: 36569836 PMCID: PMC9771704 DOI: 10.3389/fimmu.2022.1074867] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 11/24/2022] [Indexed: 12/12/2022] Open
Abstract
Background Gout is a progressive metabolic disease closely related to hyperuricemia and urate deposition, with an increasing prevalence and incidence across the globe. Recent studies have shown that the pathological process of gout includes two stages: asymptomatic hyperuricemia and MSU crystal deposition. However, the immune response during the development of hyperuricemia to gouty arthritis is not fully elucidated. Methods Thus, an overnutrition-induced whole-course gout model was established to clarify the immune response and pathological changes in the development from hyperuricemia to gouty arthritis. The quails without urate oxidase were used as experimental animals. And we confirmed that uric acid metabolic targets were changed when quails were in the asymptomatic hyperuricemia stage. Results When the quail showed gout symptoms, the NLRP3 inflammasome was activated, and the expressions of IL-1β, TNF-α, IL-6, IL-8, and IL-18 were significantly increased. The relationship between the uric acid metabolism target and the NLRP3 inflammasome may be the critical immune response between hyperuricemia and gouty arthritis. Our data showed that, in the process of gout disease, the expression of xanthine oxidase (XOD) has been increasing, which increases the level of uric acid, disrupts the balance of oxidative stress, generates a large amount of ROS, activates the NLRP3 inflammasome, and release IL-1β. Treatment with the XOD inhibitor can reduce uric acid, restore the body's degree of peroxidative damage and antioxidant capacity, and inhibit NLRP3 inflammasome and IL-1β. In vitro, we extracted and identified primary fibroblast-like synoviocytes (FLS) from quail for the first time. Stimulating FLS with uric acid also caused ROS release and NLRP3 inflammasome activation. However, treatment with an XOD inhibitor prevented all these responses in FLS. Conclusion Our results indicate that the immune response between the uric acid metabolism target XOD and NLRP3 inflammasomes plays a crucial role in developing hyperuricemia to gouty arthritis, and inhibition of both XOD and NLRP3 inflammasomes may be an effective treatment for avoiding the development of asymptomatic hyperuricemia to MSU crystal deposition. Meanwhile, this study also provides an advantageous animal model for pathological mechanisms and research and development drugs for gout.
Collapse
Affiliation(s)
- Hao Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Yu Wang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Zhixin Ren
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Yaolei Li
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jingjian Huang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Zhijian Lin
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China,Center for Pharmacovigilance and Rational Use of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Bing Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China,Center for Pharmacovigilance and Rational Use of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China,*Correspondence: Bing Zhang,
| |
Collapse
|
|
25
|
Luo W, Wu G, Chen X, Zhang Q, Zou C, Wang J, Liu J, Chattipakorn N, Wang Y, Liang G. Blockage of MyD88 in cardiomyocytes alleviates cardiac inflammation and cardiomyopathy in experimental diabetic mice. Biochem Pharmacol 2022; 206:115292. [DOI: 10.1016/j.bcp.2022.115292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 10/03/2022] [Accepted: 10/03/2022] [Indexed: 12/15/2022]
|
|
26
|
Hu J, Jin C, Fang L, Lu Y, Wu Y, Xu X, Sun S. MicroRNA-486-5p suppresses inflammatory response by targeting FOXO1 in MSU-treated macrophages. Autoimmunity 2022; 55:661-669. [PMID: 36226520 DOI: 10.1080/08916934.2022.2128780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Gouty arthritis (GA) is mainly caused by the precipitation of monosodium urate (MSU) crystals in the joint. Recently, different regulatory roles of microRNAs (miRNAs) in arthritis have been widely verified. Nevertheless, the specific function of microRNA-486-5p (miR-486-5p) in GA is still unclear. GA cell models in vitro were established by the treatment of 250 μg/mL MSU crystals into THP-1 cells or J774A.1 cells. Then, the accumulation of tumor necrosis factor (TNF)-α, interleukin (IL)-8, and IL-β was estimated by ELISA. The mRNA levels of TNF-α, IL-8, and IL-β were measured through RT-qPCR. The protein level of forkhead box protein O1 (FOXO1) was tested via western blot. Furthermore, the interplay of miR-486-5p and FOXO1 was evaluated via the luciferase reporter assay. In this study, MSU treatment successfully stimulated the inflammatory response in macrophage cells. MiR-486-5p downregulation was observed in THP-1 and J774A.1 cells treated with MSU, and its upregulation markedly decreased the concentration and mRNA levels of TNF-α, IL-8, and IL-β. Furthermore, FOXO1 was demonstrated to be negatively modulated by miR-486-5p. The rescue assay indicated that overexpressing FOXO1 reversed the effects of overexpressing miR-486-5p on inflammatory cytokines. Overall, this study proves that miR-486-5p inhibits GA inflammatory response via modulating FOXO1.
Collapse
Affiliation(s)
- Jianguo Hu
- Department of Rheumatology and Immunology, Xinyu People's Hospital, Xinyu, Jiangxi, China
| | - Cheng Jin
- Department of Orthopedics, Zhoushan Hospital of Zhejiang Province, Zhoushan, Zhejiang, China
| | - Li Fang
- Department of Rheumatology and Immunology, Zhoushan Hospital of Zhejiang Province, Zhoushan, Zhejiang, China
| | - Yao Lu
- Department of Rheumatology and Immunology, Zhoushan Hospital of Zhejiang Province, Zhoushan, Zhejiang, China
| | - Yanying Wu
- Department of Rheumatology and Immunology, Zhoushan Hospital of Zhejiang Province, Zhoushan, Zhejiang, China
| | - Xiangfeng Xu
- Department of Rheumatology and Immunology, Zhoushan Hospital of Zhejiang Province, Zhoushan, Zhejiang, China
| | - Simei Sun
- Department of Rheumatology and Immunology, Zhoushan Hospital of Zhejiang Province, Zhoushan, Zhejiang, China
| |
Collapse
|
|
27
|
Distinct macrophage polarization in acute and chronic gout. J Transl Med 2022; 102:1054-1063. [PMID: 36775346 DOI: 10.1038/s41374-022-00798-4] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 04/14/2022] [Accepted: 04/17/2022] [Indexed: 12/15/2022] Open
Abstract
Macrophage polarization mediates the development of inflammatory diseases. However, the polarization status at various stages of gout is not fully understood. Our study aimed to define the evolution of macrophage polarization in acute and chronic gout. Normal human synovium and synovium with tophi were collected for immunofluorescence (IF). Rat gouty joints were collected for joint thickness assessment and pathological evaluation. Tissue mRNA expression of inducible nitric oxide synthase (iNOS) and arginase-1 (Arg-1) were evaluated. Mouse peritoneal macrophages and THP-1 derived macrophages were stimulated by monosodium urate (MSU) crystals and were collected for detection of interleukin (IL) -1β and IL-37 levels and iNOS/Arg-1 ratio. Arg-1 and IL-37 were highly expressed in normal synovium and synovium with tophi. In rat gouty joints, the inflammatory cell counts and ankle thickness began to increase at 2 h, peaked at 24 h, and was decreased spontaneously. An increase in macrophages preceded the neutrophils infiltration. Infiltration of M1 was positively related with the severity of arthritis. M2 appeared in an early stage (at 2 h) of inflammation. The number of M1 macrophages was comparable to that of M2 from 2 to 12 h and exceeded M2 number at 18 h and 24 h. The ratios of M2/M1 reversed at 48 h and remained reversed until 120 h. In mice gouty joints, iNOS/Arg-1 mRNA ratio was significantly higher than the that in control group at 8 h. The proportion of neutrophils and M1-macrophages reached peak at 4 h in mice model with peritoneal gout. Concentration of IL-1β and ratio of iNOS/Arg-1 were increased at 6 h, peaked at 48 h, and were then decreased at 72 h in vitro, while the concentration of IL-37 peaked at 2 h and then decreased. In summary, altered macrophage polarization was observed in various stages of gouty inflammation. Macrophages in acute gout were polarized into M1 at early stage and into M2 at later stage while the macrophages in chronic gout mainly were only polarized towards M2. The number of M1 rose with the progression of inflammation. Early increase of M2 was observed, which might be generated directly from M0.
Collapse
|
|
28
|
Huang CM, Chen YC, Lai IL, Chen HD, Huang PH, Tu SJ, Lee YT, Yen JC, Lin CL, Liu TY, Chang JG. Exploring RNA modifications, editing, and splicing changes in hyperuricemia and gout. Front Med (Lausanne) 2022; 9:889464. [PMID: 36148448 PMCID: PMC9487523 DOI: 10.3389/fmed.2022.889464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 08/03/2022] [Indexed: 11/13/2022] Open
Abstract
Hyperuricemia and gout are two of the most common metabolic disorders worldwide; their incidence is increasing with changes in lifestyle, and they are correlated with many diseases, including renal and cardiovascular diseases. The majority of studies on hyperuricemia and gout have focused on the discovery of the associated genes and their functions and on the roles of monocytes and neutrophils in the development of gout. Virtually no studies investigating the epigenomics of gout disease or exploring the clinical significance of such research have been conducted. In this study, we observed that the expression of enzymes involved in RNA modifications or RNA editing was affected in uric acid (UA)- or monosodium urate (MSU)-treated cell lines. RNA alternative splicing and splicing factors were also affected by UA or MSU treatment. We used transcriptome sequencing to analyze genome-wide RNA splicing and RNA editing and found significant changes in RNA splicing and RNA editing in MSU- or UA-treated THP-1 and HEK293 cells. We further found significant changes of RNA modifications, editing, and splicing in patients with gout. The data indicate that RNA modifications, editing, and splicing play roles in gout. The findings of this study may help to understand the mechanism of RNA splicing and modifications in gout, facilitating the development of new diagnostic and therapeutic strategies.
Collapse
Affiliation(s)
- Chung-Ming Huang
- Center for Precision Medicine, China Medical University Hospital, Taichung, Taiwan
- Division of Immunology and Rheumatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
- Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Yu-Chia Chen
- Center for Precision Medicine, China Medical University Hospital, Taichung, Taiwan
- Epigenome Research Center, China Medical University Hospital, Taichung, Taiwan
- Million-Person Precision Medicine Initiative, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - I-Lu Lai
- Center for Precision Medicine, China Medical University Hospital, Taichung, Taiwan
- Epigenome Research Center, China Medical University Hospital, Taichung, Taiwan
| | - Hong-Da Chen
- Center for Precision Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Po-Hao Huang
- Division of Immunology and Rheumatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Siang-Jyun Tu
- Center for Precision Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Ya-Ting Lee
- Center for Precision Medicine, China Medical University Hospital, Taichung, Taiwan
- Epigenome Research Center, China Medical University Hospital, Taichung, Taiwan
| | - Ju-Chen Yen
- Center for Precision Medicine, China Medical University Hospital, Taichung, Taiwan
- Epigenome Research Center, China Medical University Hospital, Taichung, Taiwan
| | - Chia-Li Lin
- Center for Precision Medicine, China Medical University Hospital, Taichung, Taiwan
- Epigenome Research Center, China Medical University Hospital, Taichung, Taiwan
| | - Ting-Yuan Liu
- Center for Precision Medicine, China Medical University Hospital, Taichung, Taiwan
- Epigenome Research Center, China Medical University Hospital, Taichung, Taiwan
- Million-Person Precision Medicine Initiative, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Jan-Gowth Chang
- Center for Precision Medicine, China Medical University Hospital, Taichung, Taiwan
- Epigenome Research Center, China Medical University Hospital, Taichung, Taiwan
- *Correspondence: Jan-Gowth Chang,
| |
Collapse
|
|
29
|
Kim SK. The Mechanism of the NLRP3 Inflammasome Activation and Pathogenic Implication in the Pathogenesis of Gout. JOURNAL OF RHEUMATIC DISEASES 2022; 29:140-153. [PMID: 37475970 PMCID: PMC10324924 DOI: 10.4078/jrd.2022.29.3.140] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 02/16/2022] [Accepted: 02/22/2022] [Indexed: 07/22/2023]
Abstract
The NACHT, LRR, and PYD-domains-containing protein 3 (NLRP3) inflammasome is an intracellular multi-protein signaling platform that is activated by cytosolic pattern-recognition receptors such as NLRs against endogenous and exogenous pathogens. Once it is activated by a variety of danger signals, recruitment and assembly of NLRP3, ASC, and pro-caspase-1 trigger the processing and release of pro-inflammatory cytokines including interleukin-1β (IL-1β) and IL-18. Multiple intracellular and extracellular structures and molecular mechanisms are involved in NLRP3 inflammasome activation. Gout is an autoinflammatory disease induced by inflammatory response through production of NLRP3 inflammasome-mediated proinflammatory cytokines such as IL-1β by deposition of monosodium urate (MSU) crystals in the articular joints and periarticular structures. NLRP3 inflammasome is considered a main therapeutic target in MSU crystal-induced inflammation in gout. Novel therapeutic strategies have been proposed to control acute flares of gouty arthritis and prophylaxis for gout flares through modulation of the NLRP3/IL-1 axis pathway. This review discusses the basic mechanism of NLRP3 inflammasome activation and the IL-1-induced inflammatory cascade and explains the NLRP3 inflammasome-induced pathogenic role in the pathogenesis of gout.
Collapse
Affiliation(s)
- Seong-Kyu Kim
- Division of Rheumatology, Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, Korea
| |
Collapse
|
|
30
|
Martin SJ, Frezza V, Davidovich P, Najda Z, Clancy DM. IL-1 family cytokines serve as 'activity recognition receptors' for aberrant protease activity indicative of danger. Cytokine 2022; 157:155935. [PMID: 35759924 DOI: 10.1016/j.cyto.2022.155935] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 05/31/2022] [Accepted: 06/04/2022] [Indexed: 11/03/2022]
Abstract
Members of the extended IL-1 cytokine family play key roles as instigators of inflammation in numerous infectious and sterile injury contexts and are highly enriched at barrier surfaces such as the skin, lungs and intestinal mucosa. Because IL-1 family cytokines do not possess conventional ER-golgi trafficking and secretory signals, these cytokines are typically released into the extracellular space due to tissue damage resulting in necrosis, or pathogen detection resulting in pyroptosis. The latter feature, in combination with other factors, suggests that IL-1 family cytokines serve as canonical damage-associated molecular patterns (DAMPs), which instigate inflammation in response to tissue damage. However, IL-1 family cytokines also require a proteolytic activation step and diverse intracellular, extracellular and non-self proteases have been identified that are capable of processing and activating members of this family. This suggests that IL-1 family members function as sentinels for aberrant protease activity, which is frequently associated with infection or tissue damage. Here, we overview the diversity of proteases implicated in the activation of IL-1 family cytokines and suggest that this ancient cytokine family may have evolved to complement 'pattern recognition receptors', by serving as 'activity recognition receptors' enabling the detection of aberrant enzyme activity indicative of 'danger'.
Collapse
Affiliation(s)
- Seamus J Martin
- Molecular Cell Biology Laboratory, Dept. of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.
| | - Valentina Frezza
- Molecular Cell Biology Laboratory, Dept. of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland
| | - Pavel Davidovich
- Molecular Cell Biology Laboratory, Dept. of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland
| | - Zaneta Najda
- Molecular Cell Biology Laboratory, Dept. of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland
| | - Danielle M Clancy
- Molecular Cell Biology Laboratory, Dept. of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland
| |
Collapse
|
|
31
|
Murakami T, Nakaminami Y, Takahata Y, Hata K, Nishimura R. Activation and Function of NLRP3 Inflammasome in Bone and Joint-Related Diseases. Int J Mol Sci 2022; 23:ijms23105365. [PMID: 35628185 PMCID: PMC9141484 DOI: 10.3390/ijms23105365] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 05/09/2022] [Accepted: 05/10/2022] [Indexed: 12/12/2022] Open
Abstract
Inflammation is a pivotal response to a variety of stimuli, and inflammatory molecules such as cytokines have central roles in the pathogenesis of various diseases, including bone and joint diseases. Proinflammatory cytokines are mainly produced by immune cells and mediate inflammatory and innate immune responses. Additionally, proinflammatory cytokines accelerate bone resorption and cartilage destruction, resulting in the destruction of bone and joint tissues. Thus, proinflammatory cytokines are involved in regulating the pathogenesis of bone and joint diseases. Interleukin (IL)-1 is a representative inflammatory cytokine that strongly promotes bone and cartilage destruction, and elucidating the regulation of IL-1 will advance our understanding of the onset and progression of bone and joint diseases. IL-1 has two isoforms, IL-1α and IL-1β. Both isoforms signal through the same IL-1 receptor type 1, but the activation mechanisms are completely different. In particular, IL-1β is tightly regulated by protein complexes termed inflammasomes. Recent research using innovative technologies has led to a series of discoveries about inflammasomes. This review highlights the current understanding of the activation and function of the NLRP3 (NOD-like receptor family, pyrin domain-containing 3) inflammasome in bone and joint diseases.
Collapse
|
|
32
|
Mijailovic NR, Vesic K, Borovcanin MM. The Influence of Serum Uric Acid on the Brain and Cognitive Dysfunction. Front Psychiatry 2022; 13:828476. [PMID: 35530021 PMCID: PMC9072620 DOI: 10.3389/fpsyt.2022.828476] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 03/17/2022] [Indexed: 12/12/2022] Open
Abstract
Uric acid is commonly known for its bad reputation. However, it has been shown that uric acid may be actively involved in neurotoxicity and/or neuroprotection. These effects could be caused by oxidative stress or inflammatory processes localized in the central nervous system, but also by other somatic diseases or systemic conditions. Our interest was to summarize and link the current data on the possible role of uric acid in cognitive functioning. We also focused on the two putative molecular mechanisms related to the pathological effects of uric acid-oxidative stress and inflammatory processes. The hippocampus is a prominent anatomic localization included in expressing uric acid's potential impact on cognitive functioning. In neurodegenerative and mental disorders, uric acid could be involved in a variety of ways in etiopathogenesis and clinical presentation. Hyperuricemia is non-specifically observed more frequently in the general population and after various somatic illnesses. There is increasing evidence to support the hypothesis that hyperuricemia may be beneficial for cognitive functioning because of its antioxidant effects but may also be a potential risk factor for cognitive dysfunction, in part because of increased inflammatory activity. In this context, gender specificities must also be considered.
Collapse
Affiliation(s)
- Natasa R. Mijailovic
- Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Katarina Vesic
- Department of Neurology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Milica M. Borovcanin
- Department of Psychiatry, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| |
Collapse
|
|
33
|
Suzuki K, Tsuchiya M, Yoshida S, Ogawa K, Chen W, Kanzaki M, Takahashi T, Fujita R, Li Y, Yabe Y, Aizawa T, Hagiwara Y. Tissue accumulation of neutrophil extracellular traps mediates muscle hyperalgesia in a mouse model. Sci Rep 2022; 12:4136. [PMID: 35264677 PMCID: PMC8907237 DOI: 10.1038/s41598-022-07916-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 02/14/2022] [Indexed: 11/24/2022] Open
Abstract
Accumulation of uric acid (UA) during muscular trauma is a factor involved in the development of muscle hyperalgesia. Neutrophil extracellular traps (NETs), DNA-based reticular structures to capture UA, play a central role in the pain onset of gout attacks; however, the involvement of NETs via the elevation of local UA level in muscle hyperalgesia due to injuries from muscle overuse remains unknown. The triceps surae muscles (TSMs) in the unilateral hindlimb of mice were electrically stimulated to induce excessive muscle contraction. Mechanical withdrawal thresholds, tissue UA levels, neutrophil recruitment, and protein amount of citrullinated histone 3 (citH3), a major marker of NETs, were investigated. Furthermore, whether neutrophil depletion, extracellular DNA cleavage, and administration of the urate-lowering agent febuxostat improved muscle hyperalgesia caused by NET formation was examined. CitH3 expression upon neutrophil recruitment was significantly increased in the stimulated TSMs with increased tissue UA levels, whereas febuxostat administration improved muscle hyperalgesia with decreased citH3 and tissue UA levels, as observed in neutrophil depletion and extracellular DNA digestion. The underlying mechanism of muscle hyperalgesia associated with locally recruited neutrophils forming NETs due to increased tissue UA levels potentially plays a significant role in creating a vicious circle of muscle pain.
Collapse
Affiliation(s)
- Kazuaki Suzuki
- Department of Orthopaedic Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan.,Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan
| | - Masahiro Tsuchiya
- Department of Nursing, Tohoku Fukushi University, 6-149-1 Kunimi-ga-oka, Sendai, 981-3201, Japan.
| | - Shinichirou Yoshida
- Department of Orthopaedic Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Kazumi Ogawa
- Department of Orthopaedic Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan.,Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan
| | - Weijian Chen
- Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan
| | - Makoto Kanzaki
- Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan
| | - Tadahisa Takahashi
- Department of Orthopaedic Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan.,Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan
| | - Ryo Fujita
- Department of Orthopaedic Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan.,Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan
| | - Yuqing Li
- Department of Orthopaedic Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan.,Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan
| | - Yutaka Yabe
- Department of Orthopaedic Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Toshimi Aizawa
- Department of Orthopaedic Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Yoshihiro Hagiwara
- Department of Orthopaedic Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan
| |
Collapse
|
|
34
|
A small molecule inhibitor of caspase-1 inhibits NLRP3 inflammasome activation and pyroptosis to alleviate gouty inflammation. Immunol Lett 2022; 244:28-39. [DOI: 10.1016/j.imlet.2022.03.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 03/07/2022] [Accepted: 03/10/2022] [Indexed: 12/11/2022]
|
|
35
|
Borovcanin MM, Janicijevic SM, Mijailovic NR, Jovanovic IP, Arsenijevic NN, Vesic K. Uric Acid Potential Role in Systemic Inflammation and Negative Symptoms After Acute Antipsychotic Treatment in Schizophrenia. Front Psychiatry 2022; 12:822579. [PMID: 35237183 PMCID: PMC8882684 DOI: 10.3389/fpsyt.2021.822579] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 12/27/2021] [Indexed: 12/12/2022] Open
Abstract
Uric acid (UA) has been shown to have neuroprotective or neurotoxic properties, in relation to specific tissues and diseases that have been studied. Previous studies provided contradictory results on the role of UA in schizophrenia as a neurodegenerative disorder. The aim of this brief report was an additional analysis of UA sera levels in different phases of schizophrenia. Here, 86 patients with first-episode psychosis (FEP) vs. 45 patients with schizophrenia in relapse (SC in relapse) vs. 35 healthy control subjects (HC) were studied before and 1 month after antipsychotic therapy. Further, we aimed to explore the possible correlation of UA with scores presenting clinical features and with serum concentrations of the proinflammatory cytokines interleukin (IL)-6 and IL-17. When comparing the data between all three groups, we did not find significant differences in UA levels, either before or after the applied therapy. Also, comparing sera concentrations of UA in every single group, the analysis did not reveal statistically significant differences between FEP patients, but statistically, a significant difference was found in SC in relapse before and after treatment (334.71 ± 116.84 vs. 289.37 ± 109.15 μmol/L, p = 0.05). Uric acid serum levels correlated with negative sub-score (p = 0.001, r = 0.306), general sub-score (p = 0.015, r = 0.236), and total PANSS score (p = 0.009, r = 0.3) after 1 month of therapy. We have established a statistically significant positive correlation between serum concentrations of UA and IL-6 in exacerbation (p = 0.01, r = 0.220) and with IL-17 after treatment and in the stabilization of psychosis (p = 0.01, r = 0.34), suggesting potential cascades in different phases of schizophrenia that potentiate inflammation.
Collapse
Affiliation(s)
- Milica M. Borovcanin
- Department of Psychiatry, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Slavica Minic Janicijevic
- Doctor of Philosophy Studies, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Natasa R. Mijailovic
- Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Ivan P. Jovanovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Nebojsa N. Arsenijevic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Katarina Vesic
- Department of Neurology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| |
Collapse
|
|
36
|
Zhou GQ, Chen G, Yang J, Qin WY, Ping J. Guizhi-Shaoyao-Zhimu decoction attenuates monosodium urate crystal-induced inflammation through inactivation of NF-κB and NLRP3 inflammasome. JOURNAL OF ETHNOPHARMACOLOGY 2022; 283:114707. [PMID: 34619319 DOI: 10.1016/j.jep.2021.114707] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 09/18/2021] [Accepted: 10/01/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Guizhi-Shaoyao-Zhimu decoction (GSZD), a classical traditional Chinese medicine (TCM) prescription, is used empirically to treat various types of arthritis in TCM clinical practice. However, the underlying mechanisms of GSZD on gouty inflammation are not totally elucidated. AIM OF STUDY The purpose of this study is to investigate the effects of GSZD on peritoneal recruitment of neutrophils, production of proinflammatory mediators, activations of nuclear factor (NF)-κB and nucleotide oligomerization domain-like receptor protein-3 (NLRP3) inflammasome in mice with monosodium urate crystal (MSU)-induced peritonitis (MIP). MATERIALS AND METHODS Mice were intragastrically administered with GSZD for 7 days. After the last administration, mice were intraperitoneally injected with MSU. Peritoneal exudates of mice were harvested, and total peritoneal cells were calculated. Levels of interleukin (IL)-1β, IL-6 and monocyte chemotactic protein (MCP)-1 in peritoneal exudates were tested by enzyme-linked immunosorbent assay. Expressions of IL-1β, NLRP3, cysteinyl aspartate specific proteinase (caspase)-1, apoptosis-associated speck-like protein containing the caspase activation and recruitment domain (ASC), phosphorylated (p)-p65, inhibitor of NF-κB (IκB)α, p-IκB kinase (IKK)β, nuclear p65, p-mitogen-activated protein kinases (MAPKs) in peritoneal cells were analyzed by Western blot. Binding activity of NF-κB to DNA was measured by a Trans AM™ kit for p65. Interaction between ASC and pro-caspase-1 was assessed by co-immunoprecipitation assay. RESULTS Total peritoneal cells, levels of IL-1β, IL-6 and MCP-1 were significantly reduced by GSZD treatment in peritoneal exudates of MIP mice. As for the activation of NF-κB, GSZD treatment significantly reduced the levels of p-p65, p-IKKβ, nuclear p65 and p-MAPKs, enhanced the level of IκBα and abated the binding ability of NF-κB to DNA in peritoneal cells of MIP mice. As for the activation of NLRP3 inflammasome, GSZD treatment significantly reduced the levels of IL-1β, NLRP3 and caspase-1, and alleviated the interaction between ASC and pro-caspase-1 in peritoneal cells of MIP mice. Nevertheless, GSZD didn't remarkably change the level of ASC. CONCLUSIONS These results suggest that GSZD attenuates the MSU-induced inflammation through inhibiting the activations of NF-κB and NLRP3 inflammasome.
Collapse
Affiliation(s)
- Guo-Qing Zhou
- Department of Combination of Chinese and Western Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
| | - Gang Chen
- Key Laboratory of Natural Medicine Research of Chongqing Education Commission, College of Environment and Resources, Chongqing Technology and Business University, Chongqing, 400067, China.
| | - Juan Yang
- Department of Combination of Chinese and Western Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
| | - Wen-Yi Qin
- Department of Combination of Chinese and Western Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
| | - Jia Ping
- Department of Combination of Chinese and Western Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
| |
Collapse
|
|
37
|
Accart N, Dawson J, Obrecht M, Lambert C, Flueckiger M, Kreider J, Hatakeyama S, Richards PJ, Beckmann N. Degenerative joint disease induced by repeated intra-articular injections of monosodium urate crystals in rats as investigated by translational imaging. Sci Rep 2022; 12:157. [PMID: 34997110 PMCID: PMC8742129 DOI: 10.1038/s41598-021-04125-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 12/09/2021] [Indexed: 11/09/2022] Open
Abstract
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.
Collapse
Affiliation(s)
- Nathalie Accart
- Musculoskeletal Diseases Department, Novartis Institutes for BioMedical Research, Fabrikstr. 28.3.04, CH-4056, Basel, Switzerland
| | - Janet Dawson
- Autoimmunity, Transplantation & Inflammation Department, Novartis Institutes for BioMedical Research, Lichtstr. 35, WSJ-386.6.08.18, CH-4056, Basel, Switzerland
| | - Michael Obrecht
- Musculoskeletal Diseases Department, Novartis Institutes for BioMedical Research, Fabrikstr. 28.3.04, CH-4056, Basel, Switzerland
| | - Christian Lambert
- Musculoskeletal Diseases Department, Novartis Institutes for BioMedical Research, Fabrikstr. 28.3.04, CH-4056, Basel, Switzerland
| | - Manuela Flueckiger
- Musculoskeletal Diseases Department, Novartis Institutes for BioMedical Research, Fabrikstr. 28.3.04, CH-4056, Basel, Switzerland
| | - Julie Kreider
- Musculoskeletal Diseases Department, Novartis Institutes for BioMedical Research, Fabrikstr. 28.3.04, CH-4056, Basel, Switzerland
| | - Shinji Hatakeyama
- Musculoskeletal Diseases Department, Novartis Institutes for BioMedical Research, Fabrikstr. 28.3.04, CH-4056, Basel, Switzerland
| | - Peter J Richards
- Musculoskeletal Diseases Department, Novartis Institutes for BioMedical Research, Fabrikstr. 28.3.04, CH-4056, Basel, Switzerland
| | - Nicolau Beckmann
- Musculoskeletal Diseases Department, Novartis Institutes for BioMedical Research, Fabrikstr. 28.3.04, CH-4056, Basel, Switzerland.
| |
Collapse
|
|
38
|
Wan Y, Wang D, Shen Y, Chen Y, Qian J, Fu G. Effect of Lactobacillus acidophilus fermentation on the composition of chlorogenic acids and anti-hyperuricemia activity of Artemisia selengensis Turcz. Food Funct 2022; 13:11780-11793. [DOI: 10.1039/d2fo01854c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
FASTE can relieve hyperuricemia by inhibiting the production of uric acid, alleviating oxidative stress damage and inflammation, promoting uric acid excretion and improving the abundance of intestinal flora.
Collapse
Affiliation(s)
- Yin Wan
- State Key Laboratory of Food Science and Technology, College of Food Science and Technology, Nanchang University, Nanchang 330047, China
| | - Dengxiao Wang
- State Key Laboratory of Food Science and Technology, College of Food Science and Technology, Nanchang University, Nanchang 330047, China
| | - Yuefeng Shen
- State Key Laboratory of Food Science and Technology, College of Food Science and Technology, Nanchang University, Nanchang 330047, China
| | - Yanru Chen
- State Key Laboratory of Food Science and Technology, College of Food Science and Technology, Nanchang University, Nanchang 330047, China
| | - Jin Qian
- State Key Laboratory of Food Science and Technology, College of Food Science and Technology, Nanchang University, Nanchang 330047, China
| | - Guiming Fu
- State Key Laboratory of Food Science and Technology, College of Food Science and Technology, Nanchang University, Nanchang 330047, China
- International Institute of Food Innovation, Nanchang University, Nanchang, 330299, P. R. China
| |
Collapse
|
|
39
|
Zhang CL, Zhang JJ, Zhu QF, Guan HY, Yang YX, He X, Fu Y, Chen TX, Dong L, Yang XS, Tang KF, Xu GB, Liao SG. Antihyperuricemia and antigouty arthritis effects of Persicaria capitata herba in mice. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 93:153765. [PMID: 34610527 DOI: 10.1016/j.phymed.2021.153765] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 09/14/2021] [Accepted: 09/16/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Hyperuricemia (HUA) is an important risk factor for gout, renal dysfunction and cardiovascular diseases. The whole plant of Persicaria capitata (Buch.-Ham. ex D. Don) H. Gross, namely Persicaria capitata herba, is a well-known ethnic herb with potent therapeutic effects on urinary tract infections and urinary calculus, yet previous reports have only focused on its effect on urinary tract infections. PURPOSE To evaluate the therapeutic potential of P. capitata herba against gout by investigating its antihyperuricemia and antigouty arthritis effects and possible mechanisms. METHODS The ethanol extract (EP) and water extract (WP) of P. capitata herba were prepared by extracting dried and ground whole plants of P. capitata with 75% ethanol and water, respectively, followed by removal of solvents and characterization by UHPLC-Q-TOF/MS. The antihyperuricemia and antigouty arthritis effects of the two extracts were evaluated in a potassium oxonate- and hypoxanthine-induced hyperuricemia mouse model and a monosodium urate crystal (MSUC)-induced acute gouty arthritis mouse model, respectively. The mechanisms were investigated by testing their effects on the expression of correlated proteins (by Western blot) and mRNAs (by RT-PCR). RESULTS UHPLC-HRMS fingerprinting and two chemical markers (i.e., quercetin and quercitrin) determination were used for the characterization of the WP and EP extracts. Both WP and EP extracts showed pronounced antihyperuricemia activities, with a remarkable decline in serum uric acid and a marked increase in urine uric acid in hyperuricemic mice. Unlike the clinical xanthine oxidase (XOD) inhibitor allopurinol, WP and EP did not show any distinct renal toxicities. The underlying antihyperuricemia mechanism involves the inhibition of the activity and expression of XOD and the downregulation of the mRNA and protein expression of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1). The extracts of P. capitata herba also demonstrated remarkable anti-inflammatory activity in MSUC-induced acute gouty arthritis mice. The mechanism might involve inhibitory effects on the expression of proinflammatory factors. CONCLUSIONS The extracts of P. capitata herba possessed pronounced antihyperuricemia and antigouty arthritis effects and were, therefore, promising natural medicines for hyperuricemia-related disorders and gouty arthritis. The use of P. capitata herba for the treatment of urinary calculus may be, at least to some degree, related to its potential as an antihyperuricemia and antigouty arthritis drug.
Collapse
Affiliation(s)
- Chun-Lei Zhang
- State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmacy, Guizhou Medical University, Guian New Area, 550025, Guizhou, China.
| | - Jin-Juan Zhang
- School of Basic Medical Sciences, Guizhou Medical University, Guizhou 550025, China.
| | - Qin-Feng Zhu
- State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmacy, Guizhou Medical University, Guian New Area, 550025, Guizhou, China.
| | - Huan-Yu Guan
- State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmacy, Guizhou Medical University, Guian New Area, 550025, Guizhou, China.
| | - Ya-Xin Yang
- State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmacy, Guizhou Medical University, Guian New Area, 550025, Guizhou, China.
| | - Xun He
- State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmacy, Guizhou Medical University, Guian New Area, 550025, Guizhou, China.
| | - Yao Fu
- State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmacy, Guizhou Medical University, Guian New Area, 550025, Guizhou, China.
| | - Teng-Xiang Chen
- Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China.
| | - Li Dong
- State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmacy, Guizhou Medical University, Guian New Area, 550025, Guizhou, China.
| | - Xiao-Sheng Yang
- Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang, 550014, Guizhou, China.
| | - Kai-Fa Tang
- Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China.
| | - Guo-Bo Xu
- State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmacy, Guizhou Medical University, Guian New Area, 550025, Guizhou, China; National Engineering Research Center of Miao's Medicines & Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Ministry of Education & Guizhou Provincial Key Laboratory of Pharmaceutics, Guiyang, 550004, Guizhou, China.
| | - Shang-Gao Liao
- State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmacy, Guizhou Medical University, Guian New Area, 550025, Guizhou, China; National Engineering Research Center of Miao's Medicines & Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Ministry of Education & Guizhou Provincial Key Laboratory of Pharmaceutics, Guiyang, 550004, Guizhou, China.
| |
Collapse
|
|
40
|
Ouyang X, Li NZ, Guo MX, Zhang MM, Cheng J, Yi LT, Zhu JX. Active Flavonoids From Lagotis brachystachya Attenuate Monosodium Urate-Induced Gouty Arthritis via Inhibiting TLR4/MyD88/NF-κB Pathway and NLRP3 Expression. Front Pharmacol 2021; 12:760331. [PMID: 34803702 PMCID: PMC8602055 DOI: 10.3389/fphar.2021.760331] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 10/11/2021] [Indexed: 01/05/2023] Open
Abstract
Lagotis brachystachya Maxim is a characteristic herb commonly used in Tibetan medicine. Tibetan medicine records it as an important medicine for the clinical treatment of "Yellow Water Disease," the symptoms of which are similar to that of arthritis. Our previous study showed that the flavonoid fraction extracted from L. brachystachya could attenuate hyperuricemia. However, the effects of the active flavonoids on gouty arthritis remain elusive, and the underlying mechanism is not understood. In the present study, the effects of the active flavonoids were evaluated in rats or Raw264.7 cells with gouty arthritis induced by monosodium urate (MSU) crystal, followed by the detection of TLR4, MyD88, pNF-κB, and NLR family pyrin domain-containing 3 (NLRP3) expression. The swelling of the ankle joint induced by MSU crystal began to be relieved 6 h post the administration with the active flavonoids. In addition, the active flavonoids not only alleviated MSU crystal-induced inflammation in synovial tissues by histopathological examination but also reduced tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) levels in the joint tissue fluid of MSU crystal-induced rats. Furthermore, Western blot analysis indicated that the active flavonoids reduced the production of these cytokines by inhibiting the TLR4/MyD88/NF-κB pathway and decreasing NLRP3 expression in synovial tissues of rats. More importantly, the inhibition of TLR4/MyD88/NF-κB pathway and NLRP3 expression was also confirmed in MSU-induced Raw264.7 cells. In conclusion, these results indicated that the active flavonoids from L. brachystachya could effectively attenuate gouty arthritis induced by MSU crystal through the TLR4/MyD88/NF-κB pathway and NLRP3 expression in vivo and in vitro, suggesting several potential candidates for the treatment of gouty arthritis.
Collapse
Affiliation(s)
- Xiang Ouyang
- Research Center of Natural Resources of Chinese Medicinal Materials and Ethnic Medicine, Jiangxi University of Chinese Medicine, Nanchang, China
| | - Na-Zhi Li
- Research Center of Natural Resources of Chinese Medicinal Materials and Ethnic Medicine, Jiangxi University of Chinese Medicine, Nanchang, China
| | - Min-Xia Guo
- Research Center of Natural Resources of Chinese Medicinal Materials and Ethnic Medicine, Jiangxi University of Chinese Medicine, Nanchang, China
| | - Man-Man Zhang
- Department of Chemical and Pharmaceutical Engineering, Huaqiao University, Xiamen, China
| | - Jie Cheng
- Department of Chemical and Pharmaceutical Engineering, Huaqiao University, Xiamen, China
| | - Li-Tao Yi
- Department of Chemical and Pharmaceutical Engineering, Huaqiao University, Xiamen, China
| | - Ji-Xiao Zhu
- Research Center of Natural Resources of Chinese Medicinal Materials and Ethnic Medicine, Jiangxi University of Chinese Medicine, Nanchang, China
| |
Collapse
|
|
41
|
Kim SK, Park KY, Choe JY. Toll-Like Receptor 9 Is Involved in NLRP3 Inflammasome Activation and IL-1β Production Through Monosodium Urate-Induced Mitochondrial DNA. Inflammation 2021; 43:2301-2311. [PMID: 32700178 DOI: 10.1007/s10753-020-01299-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The NLR family pyrin domain-containing 3 (NLRP3) inflammasome is a cytoplasmic multimolecular complex that generates interleukin (IL)-1β and is considered a main pathogenic mechanism for uric acid-induced inflammation. Whether toll-like receptor 9 (TLR9) is responsible for uric acid-induced NLRP3 inflammasome activation remains unclear. Thus, the aim of this study was to identify the role of TLR9 in NLRP3 inflammasome activation through monosodium urate (MSU) crystal-induced mitochondrial DNA. RAW 264.7 cells treated with MSU crystals, CpG oligonucleotides (ODNs), or a combination of both were used to assess nuclear factor (NF)-κB signaling, NLRP3 inflammasome components such as NLRP3, ASC, and caspase-1, and IL-1β. Real-time polymerase chain reaction (RT-PCR), Western blotting, DNA fragmentation assay, mitochondrial DNA copy number assay, and immunofluorescence were used in the in vitro study. RAW 264.7 cells treated with CpG-ODN stimulated the activation of NF-κB signaling, the NLRP3 inflammasome components NLRP3, ASC, and caspase-1, and IL-1β gene and protein expression. DNA fragmentation assay showed that MSU crystals induced cellular apoptosis. Fragmented DNA prompted by MSU crystals induced TLR9 expression. RAW 264.7 cells treated with CpG-ODN or MSU crystals and both increased expression of mitochondrial DNA relative to nuclear DNA. CpG-ODN and MSU crystals augmented the activation of NLRP3 inflammasome components and IL-1β expression, which was significantly suppressed in RAW 264.7 cells transfected with TLR9 siRNA. This study suggests that TLR9 activated by MSU crystal-mediated mitochondrial DNA contributes to the activation of NLRP3 inflammasomes and IL-1β production.
Collapse
Affiliation(s)
- Seong-Kyu Kim
- Department of Internal Medicine, Division of Rheumatology, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea. .,Arthritis and Autoimmunity Research Center, Catholic University of Daegu, Daegu, Republic of Korea.
| | - Ki-Yeun Park
- Arthritis and Autoimmunity Research Center, Catholic University of Daegu, Daegu, Republic of Korea
| | - Jung-Yoon Choe
- Department of Internal Medicine, Division of Rheumatology, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea.,Arthritis and Autoimmunity Research Center, Catholic University of Daegu, Daegu, Republic of Korea
| |
Collapse
|
|
42
|
Wu Y, Wang S, Xu X. Correlation of Serum Cystatin C with Renal Function in Gout Patients with Renal Injury. J Interferon Cytokine Res 2021; 41:329-335. [PMID: 34435875 DOI: 10.1089/jir.2021.0034] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
The gout-induced continuous deposition of urate in the kidney tissues is the main cause of renal injury, for which cystatin C (Cys C) is an important indicator. This research analyzed the correlation between general renal injury indicators and serum Cys C level, and further investigated the potential of Cys C in renal injury diagnosis. A total of 140 gout patients with renal injury (GRI) were recruited and grouped by their glomerular filtration rate (GFR). Urea nitrogen, uric acid, creatinine, and Cys C levels in the serum were evaluated. The diagnostic efficacy of serum Cys C was evaluated by the nonparametric receiver operating characteristic analysis. Serum Cys C level was increased with decreased GFR in GRI. Urea nitrogen, uric acid, and creatinine levels in the serum showed positive correlations with Cys C level. The area under the curve for serum Cys C was 0.8589 (P < 0.001). In conclusion, this research demonstrated that the serum Cys C level was a precise diagnostic marker for GFR and renal damage evaluation, and showed a significant diagnostic value for renal injury in patients with gout.
Collapse
Affiliation(s)
- Yanqun Wu
- Department of Immune Rheumatology, Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao, Shandong, China
| | - Shunhua Wang
- Department of Immune Rheumatology, Qingdao Municipal Hospital, Qingdao, Shandong, China
| | - Xiaoqing Xu
- Surgery Department Consulting Area, Qingdao Municipal Hospital, Qingdao, Shandong, China
| |
Collapse
|
|
43
|
Wang C, Jiang S, Zhang S, Ouyang Z, Wang G, Wang F. Research Progress of Metabolomics in Asthma. Metabolites 2021; 11:567. [PMID: 34564383 PMCID: PMC8466166 DOI: 10.3390/metabo11090567] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 08/10/2021] [Accepted: 08/19/2021] [Indexed: 12/25/2022] Open
Abstract
Asthma is a highly heterogeneous disease, but the pathogenesis of asthma is still unclear. It is well known that the airway inflammatory immune response is the pathological basis of asthma. Metabolomics is a systems biology method to analyze the difference of low molecular weight metabolites (<1.5 kDa) and explore the relationship between metabolic small molecules and pathophysiological changes of the organisms. The functional interdependence between immune response and metabolic regulation is one of the cores of the body's steady-state regulation, and its dysfunction will lead to a series of metabolic disorders. The signal transduction effect of specific metabolites may affect the occurrence of the airway inflammatory immune response, which may be closely related to the pathogenesis of asthma. Emerging metabolomic analysis may provide insights into the pathogenesis and diagnosis of asthma. The review aims to analyze the changes of metabolites in blood/serum/plasma, urine, lung tissue, and exhaled breath condensate (EBC) samples, and further reveals the potential pathogenesis of asthma according to the disordered metabolic pathways.
Collapse
Affiliation(s)
- Chao Wang
- Department of Pathogen Biology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (C.W.); (S.J.); (S.Z.)
| | - Shengyu Jiang
- Department of Pathogen Biology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (C.W.); (S.J.); (S.Z.)
| | - Siyu Zhang
- Department of Pathogen Biology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (C.W.); (S.J.); (S.Z.)
| | - Zhuoer Ouyang
- Department of Cellular Biology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China;
| | - Guoqiang Wang
- Department of Pathogen Biology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (C.W.); (S.J.); (S.Z.)
| | - Fang Wang
- Department of Pathogen Biology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (C.W.); (S.J.); (S.Z.)
| |
Collapse
|
|
44
|
Xanthine Oxidase-Induced Inflammatory Responses in Respiratory Epithelial Cells: A Review in Immunopathology of COVID-19. Int J Inflam 2021; 2021:1653392. [PMID: 34367545 PMCID: PMC8346299 DOI: 10.1155/2021/1653392] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 07/09/2021] [Accepted: 07/19/2021] [Indexed: 01/16/2023] Open
Abstract
Xanthine oxidase (XO) is an enzyme that catalyzes the production of uric acid and superoxide radicals from purine bases: hypoxanthine and xanthine and is also expressed in respiratory epithelial cells. Uric acid, which is also considered a danger associated molecule pattern (DAMP), could trigger a series of inflammatory responses by activating the inflammasome complex path and NF-κB within the endothelial cells and by inducing proinflammatory cytokine release. Concurrently, XO also converts the superoxide radicals into hydroxyl radicals that further induce inflammatory responses. These conditions will ultimately sum up a hyperinflammation condition commonly dubbed as cytokine storm syndrome (CSS). The expression of proinflammatory cytokines and neutrophil chemokines may be reduced by XO inhibitor, as observed in human respiratory syncytial virus (HRSV)-infected A549 cells. Our review emphasizes that XO may have an essential role as an anti-inflammation therapy for respiratory viral infection, including coronavirus disease 2019 (COVID-19).
Collapse
|
|
45
|
Galozzi P, Bindoli S, Luisetto R, Sfriso P, Ramonda R, Scanu A, Oliviero F. Regulation of crystal induced inflammation: current understandings and clinical implications. Expert Rev Clin Immunol 2021; 17:773-787. [PMID: 34053376 DOI: 10.1080/1744666x.2021.1937129] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Introduction: Accumulation of abnormal crystals in the body, derived from endogenous or exogenous materials can drive a wide spectrum of inflammatory disease states. It is well established that intra-articular deposition of monosodium urate (MSU) and calcium pyrophoshate (CPP) crystals contributes to joint destruction through pro-inflammatory processes.Areas covered: This review will focus on current understanding and recent novelty about the mechanisms and the clinical implications of the inflammation induced by MSU and CPP crystals.Expert opinion: Advances in molecular biology reveal that at the base of the inflammatory cascade, stimulated by MSU or CPP crystals, there are many complex cellular mechanisms mainly involving the NLRP3 inflammasome, the hallmark of autoinflammatory syndromes. The extensive studies carried out through in vitro and in vivo models along with a better clinical definition of the disease has led to an optimized use of existing drugs and the introduction of novel therapeutic strategies. In particular, the identification of IL-1 as the most important target in gout and pseudogout has made it possible to expand the pharmacological indications of anti-IL-1 biological drugs, opening new therapeutic perspectives for patients.
Collapse
Affiliation(s)
- Paola Galozzi
- Rheumatology Unit, Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Sara Bindoli
- Rheumatology Unit, Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Roberto Luisetto
- Department of Surgery, Oncology and Gastroenterology-DISCOG, University of Padova, Padova, Italy
| | - Paolo Sfriso
- Rheumatology Unit, Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Roberta Ramonda
- Rheumatology Unit, Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Anna Scanu
- Rheumatology Unit, Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Francesca Oliviero
- Rheumatology Unit, Department of Medicine - DIMED, University of Padova, Padova, Italy
| |
Collapse
|
|
46
|
The role of Interleukin-1 receptor antagonist as a treatment option in calcium pyrophosphate crystal deposition disease. Mol Biol Rep 2021; 48:4789-4796. [PMID: 34075537 PMCID: PMC8260411 DOI: 10.1007/s11033-021-06457-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 05/27/2021] [Indexed: 12/30/2022]
Abstract
Calcium Pyrophosphate Crystal Deposition (CPPD) disease is characterized by the deposition of calcium pyrophosphate crystals in the cartilage. In most cases, it can manifest as a subclinical condition named chondrocalcinosis, often revealed by joint x-ray examination. In other cases, deposition can cause flares of arthritis, known as acute CPP crystal arthritis. In the last few years, many pathogenic pathways have been discovered. Interleukin-1 (IL-1) plays a key role in the pathogenesis of CPPD disease, both as a mediator of inflammatory response to crystals and as a promoter of damage to articular cartilage. In this review, we investigated the role of IL-1R inhibitor, such as Anakinra, as an alternative to the various therapeutic strategies for CPPD disease, especially among patients resistant to traditional treatment with NSAIDs, corticosteroids and colchicine.
Collapse
|
|
47
|
Nash WT, Okusa MD. Chess Not Checkers: Complexities Within the Myeloid Response to the Acute Kidney Injury Syndrome. Front Med (Lausanne) 2021; 8:676688. [PMID: 34124107 PMCID: PMC8187556 DOI: 10.3389/fmed.2021.676688] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 04/26/2021] [Indexed: 12/23/2022] Open
Abstract
Immune dysregulation in acute kidney injury (AKI) is an area of intense interest which promises to enhance our understanding of the disease and how to manage it. Macrophages are a heterogeneous and dynamic population of immune cells that carry out multiple functions in tissue, ranging from maintenance to inflammation. As key sentinels of their environment and the major immune population in the uninjured kidney, macrophages are poised to play an important role in the establishment and pathogenesis of AKI. These cells have a profound capacity to orchestrate downstream immune responses and likely participate in skewing the kidney environment toward either pathogenic inflammation or injury resolution. A clear understanding of macrophage and myeloid cell dynamics in the development of AKI will provide valuable insight into disease pathogenesis and options for intervention. This review considers evidence in the literature that speaks to the role and regulation of macrophages and myeloid cells in AKI. We also highlight barriers or knowledge gaps that need to be addressed as the field advances.
Collapse
Affiliation(s)
- William T Nash
- Division of Nephrology, Department of Medicine, Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia, Charlottesville, VA, United States
| | - Mark D Okusa
- Division of Nephrology, Department of Medicine, Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia, Charlottesville, VA, United States
| |
Collapse
|
|
48
|
Valiate BVS, Queiroz-Junior CM, Levi-Schaffer F, Galvão I, Teixeira MM. CD300a contributes to the resolution of articular inflammation triggered by MSU crystals by controlling neutrophil apoptosis. Immunology 2021; 164:305-317. [PMID: 34002852 DOI: 10.1111/imm.13371] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 04/26/2021] [Accepted: 04/29/2021] [Indexed: 12/27/2022] Open
Abstract
Gout is an inflammatory disease triggered by deposition of monosodium urate (MSU) crystals in the joints, resulting in high neutrophil influx and pain. Here, we studied the role of the inhibitory receptor CD300a in the resolution process in a murine model of gout. We found increased CD300a expression on neutrophils emigrated to the joint. When compared to WT mice, CD300a-/- mice had persistent neutrophil influx till 24 hr after MSU injection. This was associated with increased concentration of IL-1β and greater tissue damage in the joints of CD300a-/- mice. There was an increase in the percentage of apoptotic neutrophils in the synovial lavage of WT mice, as compared to CD300a-/- mice. This difference was reflected in the decline of efferocytic events in the synovial cavity of CD300a-/- mice 24 hr after MSU injection. A CD300a agonistic antibody was shown, for the first time, to increase apoptosis of human neutrophils, and this was associated with cleavage of caspase-8. In conclusion, our results reveal an important role of CD300a in the control of leucocyte infiltration, IL-1β production and caspase-8 cleavage in neutrophils, contributing to the resolution of inflammation triggered by MSU injection.
Collapse
Affiliation(s)
- Bruno V S Valiate
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Celso M Queiroz-Junior
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Francesca Levi-Schaffer
- Pharmacology and Experimental Therapeutics Unit, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Izabela Galvão
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Mauro M Teixeira
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| |
Collapse
|
|
49
|
Yang QB, Li LQ, Zhang QB, He YL, Mi QS, Zhou JG. microRNA-223 Deficiency Exacerbates Acute Inflammatory Response to Monosodium Urate Crystals by Targeting NLRP3. J Inflamm Res 2021; 14:1845-1858. [PMID: 34007200 PMCID: PMC8123978 DOI: 10.2147/jir.s307796] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 04/14/2021] [Indexed: 01/13/2023] Open
Abstract
Objective MicroRNAs were identified as master-switch molecules limiting acute inflammatory response. This study investigated the potential role of microRNA (miR)-223 in the mechanism of gout. Methods Wild-type (WT) and miR-223 knock-out (KO) mice were used to evaluate the phenotypes of gout models. Inflammatory cytokines were measured in air pouch and peritoneal cavity lavage fluid. In addition to miR-223 level in gout patients, miR-223 and pro-inflammatory genes were examined in bone marrow-derived macrophages (BMDMs) from mice as well as peripheral blood mononuclear cells from healthy controls (HC) treated with monosodium urate (MSU) crystals in vitro. Results MiR-223 was up-regulated in the early phase in BMDMs from WT mice after MSU challenge and decreased rapidly, and this was not observed in miR-223 KO mice in vitro. In addition, miR-223 was required for macrophages homeostasis. In comparison with WT mice in vivo, miR-223 deficiency exacerbated swelling index of MSU-induced inflammation in foot pad and ankle joint models. MiR-223 deficiency also markedly aggravated inflammatory cells infiltration and cytokines release including interleukin (IL)-1β, IL-6 and monocyte chemotactic protein-1 (MCP-1) in the air pouch and peritonitis models. In the in vitro experiments, miR-223 deficiency promoted the inflammatory response by targeting NLR family pyrin domain containing protein 3 (NLRP3). Besides, miR-223 level was down-regulated in gout patients and in HC exposed to MSU in vitro. Conclusion MiR-223 was down-regulated in gout patients and miR-223 deficiency exacerbated inflammatory response in diverse murine models, suggesting that up-regulation of miR-223 could be a potential therapeutic strategy for alleviating gouty inflammation.
Collapse
Affiliation(s)
- Qi-Bin Yang
- Department of Rheumatology and Immunology, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, Sichuan Province, People's Republic of China.,Henry Ford Immunology Program, Departments of Dermatology and Internal Medicine, Henry Ford Health System, Detroit, MI, 48202, USA
| | - Ling-Qin Li
- Department of Rheumatology and Immunology, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, Sichuan Province, People's Republic of China
| | - Quan-Bo Zhang
- Henry Ford Immunology Program, Departments of Dermatology and Internal Medicine, Henry Ford Health System, Detroit, MI, 48202, USA.,Department of Gerontology, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, Sichuan Province, People's Republic of China
| | - Yong-Long He
- Department of Rheumatology and Immunology, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, Sichuan Province, People's Republic of China
| | - Qing-Sheng Mi
- Henry Ford Immunology Program, Departments of Dermatology and Internal Medicine, Henry Ford Health System, Detroit, MI, 48202, USA
| | - Jing-Guo Zhou
- Department of Rheumatology and Immunology, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, Sichuan Province, People's Republic of China
| |
Collapse
|
|
50
|
Shi L, Yuan Z, Liu J, Cai R, Hasnat M, Yu H, Feng J, Wang Z, Zhao Q, Wu M, Huang X, Shen F, Yin L, Yu Y, Liang T. Modified Simiaowan prevents articular cartilage injury in experimental gouty arthritis by negative regulation of STAT3 pathway. JOURNAL OF ETHNOPHARMACOLOGY 2021; 270:113825. [PMID: 33460754 DOI: 10.1016/j.jep.2021.113825] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 01/08/2021] [Accepted: 01/11/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Modified Simiaowan (MSW) is a traditional Chinese medicine formula that is composed of six herbs. It has been widely used in the treatment of gouty arthritis. AIM OF THE STUDY This study was designed to investigate the effect of MSW on gouty arthritis and explore the possible mechanisms. MATERIAL AND METHODS The rat gouty arthritis model was established by intra-articular injection of Monosodium Urate (MSU) crystal, and then treated with MSW for 5 days. The perimeter of the knee joints was measured in a time-dependent manner and serum samples were collected for the detection of TNF-α, IL-1β, and IL-6 protein levels by ELISA. The protein expressions of MMP-3, TIMP-3, STAT3, and p-STAT3 in cartilage tissues and C28/I2 cells were detected by Western blot, and the levels of proteoglycan in primary chondrocytes and cartilage tissues were determined by toluidine blue staining. In addition, AG490 and IL-6 were used in vitro to explore the function of IL-6/STAT3 pathway in the protective effect of MSU. RESULTS MSW reduced the joint swelling rate in gouty arthritis model and inhibited MSU induced up-regulation of IL-1β, TNF-α, and IL-6 protein levels in serum and synovial fluid. IL-1β induced an increase in p-STAT3 and MMP-3 protein expression in C28/I2 cells, as well as a decrease in TIMP-3. MSW serum inhibited the protein expression changes induced by IL-1β in vitro. Furthermore, inhibition of STAT3 signaling negated the effect of MSW serum on p-STAT3, MMP-3, and TIMP-3 protein levels in C28/I2 cells. MSW also increased the content of proteoglycan significantly both in vivo and in vitro. CONCLUSION Our data indicated that MSW protected rats from MSU-induced experimental gouty arthritis and IL-1β/IL-6/STAT3 pathway played an essential role in the protective effect of MSU against GA.
Collapse
Affiliation(s)
- Le Shi
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Ziqiao Yuan
- China Pharmaceutical University, Nanjing, 210009, China.
| | - Jing Liu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Rui Cai
- Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, 210029, China.
| | - Muhammad Hasnat
- Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences, Outfall Road, Lahore, 54600, Pakistan
| | - Hui Yu
- Nanjing Xinbai Pharmaceutical Co., Ltd, Nanjing, 210023, China.
| | - Jing Feng
- Nanjing Xinbai Pharmaceutical Co., Ltd, Nanjing, 210023, China.
| | - Zhanglian Wang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Qianqian Zhao
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Min Wu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Xinxin Huang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Fei Shen
- Nanjing Xinbai Pharmaceutical Co., Ltd, Nanjing, 210023, China.
| | - Lian Yin
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Yun Yu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Tao Liang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| |
Collapse
|