BRD4 promotes gouty arthritis through MDM2-mediated PPARγ degradation and pyroptosis.

BACKGROUND: Gouty arthritis (GA) is characterized by monosodium urate (MSU) crystal accumulation that instigates NLRP3-mediated pyroptosis; however, the underlying regulatory mechanisms have yet to be fully elucidated. The present research endeavors to elucidate the regulatory mechanisms underpinning this MSU-induced pyroptotic cascade in GA. METHODS: J774 cells were exposed to lipopolysaccharide and MSU crystals to establish in vitro GA models, whereas C57BL/6 J male mice received MSU crystal injections to mimic in vivo GA conditions. Gene and protein expression levels were evaluated using real-time quantitative PCR, Western blotting, and immunohistochemical assays. Inflammatory markers were quantified via enzyme-linked immunosorbent assays. Pyroptosis was evaluated using immunofluorescence staining for caspase-1 and flow cytometry with caspase-1/propidium iodide staining. The interaction between MDM2 and PPARγ was analyzed through co-immunoprecipitation assays, whereas the interaction between BRD4 and the MDM2 promoter was examined using chromatin immunoprecipitation and dual-luciferase reporter assays. Mouse joint tissues were histopathologically evaluated using hematoxylin and eosin staining. RESULTS: In GA, PPARγ was downregulated, whereas its overexpression mitigated NLRP3 inflammasome activation and pyroptosis. MDM2, which was upregulated in GA, destabilized PPARγ through the ubiquitin-proteasome degradation pathway, whereas its silencing attenuated NLRP3 activation by elevating PPARγ levels. Concurrently, BRD4 was elevated in GA and exacerbated NLRP3 activation and pyroptosis by transcriptionally upregulating MDM2, thereby promoting PPARγ degradation. In vivo experiments showed that BRD4 silencing ameliorated GA through this MDM2-PPARγ-pyroptosis axis. CONCLUSION: BRD4 promotes inflammation and pyroptosis in GA through MDM2-mediated PPARγ degradation, underscoring the therapeutic potential of targeting this pathway in GA management.

Distinct characteristics of the gut virome in patients with osteoarthritis and gouty arthritis.

BACKGROUND/PURPOSE(S): The gut microbiota and its metabolites play crucial roles in pathogenesis of arthritis, highlighting gut microbiota as a promising avenue for modulating autoimmunity. However, the characterization of the gut virome in arthritis patients, including osteoarthritis (OA) and gouty arthritis (GA), requires further investigation. METHODS: We employed virus-like particle (VLP)-based metagenomic sequencing to analyze gut viral community in 20 OA patients, 26 GA patients, and 31 healthy controls, encompassing a total of 77 fecal samples. RESULTS: Our analysis generated 6819 vOTUs, with a considerable proportion of viral genomes differing from existing catalogs. The gut virome in OA and GA patients differed significantly from healthy controls, showing variations in diversity and viral family abundances. We identified 157 OA-associated and 94 GA-associated vOTUs, achieving high accuracy in patient-control discrimination with random forest models. OA-associated viruses were predicted to infect pro-inflammatory bacteria or bacteria associated with immunoglobulin A production, while GA-associated viruses were linked to Bacteroidaceae or Lachnospiraceae phages. Furthermore, several viral functional orthologs displayed significant differences in frequency between OA-enriched and GA-enriched vOTUs, suggesting potential functional roles of these viruses. Additionally, we trained classification models based on gut viral signatures to effectively discriminate OA or GA patients from healthy controls, yielding AUC values up to 0.97, indicating the clinical utility of the gut virome in diagnosing OA or GA. CONCLUSION: Our study highlights distinctive alterations in viral diversity and taxonomy within gut virome of OA and GA patients, offering insights into arthritis etiology and potential treatment and prevention strategies.

Sirt1 inhibits macrophage polarization and inflammation in gouty arthritis by inhibiting the MAPK/NF-κB/AP-1 pathway and activating the Nrf2/HO-1 pathway.

OBJECTIVE AND DESIGN: To elucidate Sirt1's role in gouty arthritis inflammation and its potential mechanisms. MATERIAL: Constructed murine models of gouty arthritis and conducted THP-1 cell experiments. TREATMENT: 1 mg of MSU crystals injected into mice ankle joints for a 72-h intervention. After a 3-h pre-treatment with Sirt1-specific inhibitor (EX527) and agonist (SRT2104), inflammation was induced for 21 h using lipopolysaccharide (LPS) plus MSU crystals. METHODS: We assessed gouty arthritis severity through joint inflammation index, swelling, and hematoxylin and eosin (H&E) staining, and measured CD68 mononuclear macrophages and Sirt1 expression in synovial tissue via immunohistochemistry. ELISA, NO assay, RT-qPCR, Flow cytometry, and Western blot were utilized to examine macrophage inflammatory factors, polarization, reactive oxygen species(ROS), MAPK/NF-κB/AP-1 and Nrf2/HO-1 pathways proteins. RESULTS: Significant joint swelling, synovial tissue edema, and inflammatory cell infiltration were observed. CD68 mononuclear macrophages and Sirt1 expression were elevated in synovium. Sirt1 activation decreased inflammatory factors, M1 polarization, and ROS generation. Sirt1 activation reduced p38/JNK phosphorylation, thereby inhibiting downstream NF-κB p65/AP-1 and enhancing Nrf2/HO-1, thus suppressing inflammation. CONCLUSIONS: Sirt1 alleviates M1 macrophage polarization and inflammation in gouty arthritis by inhibiting the MAPK/NF-κB/AP-1 pathway and activating the Nrf2/HO-1 pathway. Thus, activating Sirt1 may provide a new therapeutic target for gouty arthritis.

Britannin as a novel NLRP3 inhibitor, suppresses inflammasome activation in macrophages and alleviates NLRP3-related diseases in mice.

Overactivation of the NLRP3 inflammasomes induces production of pro-inflammatory cytokines and drives pathological processes. Pharmacological inhibition of NLRP3 is an explicit strategy for the treatment of inflammatory diseases. Thus far no drug specifically targeting NLRP3 has been approved by the FDA for clinical use. This study was aimed to discover novel NLRP3 inhibitors that could suppress NLRP3-mediated pyroptosis. We screened 95 natural products from our in-house library for their inhibitory activity on IL-1ß secretion in LPS + ATP-challenged BMDMs, found that Britannin exerted the most potent inhibitory effect with an IC50 value of 3.630 µM. We showed that Britannin (1, 5, 10 µM) dose-dependently inhibited secretion of the cleaved Caspase-1 (p20) and the mature IL-1ß, and suppressed NLRP3-mediated pyroptosis in both murine and human macrophages. We demonstrated that Britannin specifically inhibited the activation step of NLRP3 inflammasome in BMDMs via interrupting the assembly step, especially the interaction between NLRP3 and NEK7. We revealed that Britannin directly bound to NLRP3 NACHT domain at Arg335 and Gly271. Moreover, Britannin suppressed NLRP3 activation in an ATPase-independent way, suggesting it as a lead compound for design and development of novel NLRP3 inhibitors. In mouse models of MSU-induced gouty arthritis and LPS-induced acute lung injury (ALI), administration of Britannin (20 mg/kg, i.p.) significantly alleviated NLRP3-mediated inflammation; the therapeutic effects of Britannin were dismissed by NLRP3 knockout. In conclusion, Britannin is an effective natural NLRP3 inhibitor and a potential lead compound for the development of drugs targeting NLRP3.

Chondroitin sulfate-modified tragacanth gum-gelatin composite nanocapsules loaded with curcumin nanocrystals for the treatment of arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease of yet undetermined etiology that is accompanied by significant oxidative stress, inflammatory responses,  and damage to joint tissues. In this study, we designed chondroitin sulfate (CS)-modified tragacanth gum-gelatin composite nanocapsules (CS-Cur-TGNCs) loaded with curcumin nanocrystals (Cur-NCs), which rely on the ability of CS to target CD44 to accumulate drugs in inflamed joints. Cur was encapsulated in the form of nanocrystals into tragacanth gum-gelatin composite nanocapsules (TGNCs) by using an inborn microcrystallization method, which produced CS-Cur-TGNCs with a particle size of approximately 80 ± 11.54 nm and a drug loading capacity of 54.18 ± 5.17%. In an in vitro drug release assay, CS-Cur-TGNCs showed MMP-2-responsive properties. During the treatment of RA, CS-Cur-TGNCs significantly inhibited oxidative stress, promoted the polarization of M2-type macrophages to M1-type macrophages, and decreased the expression of inflammatory factors (TNF-α, IL-1ß, and IL-6). In addition, it also exerted excellent anti-inflammatory effects, and significantly alleviated the swelling of joints during the treatment of gouty arthritis (GA). Therefore, CS-Cur-TGNCs, as a novel drug delivery system, could lead to new ideas for clinical therapeutic regimens for RA and GA.

Potential Anti-Gouty Arthritis of Citronella Essential Oil and Nutmeg Essential Oil through Reducing Oxidative Stress and Inhibiting PI3K/Akt/mTOR Activation-Induced NLRP3 Activity.

Citronella and Nutmeg are two common spices used for seasoning and medicinal purposes, both of which have significant economic value. This study aimed to investigate whether Citronella essential oil and Nutmeg essential oil (NEO) can ameliorate monosodium urate (MSU)-induced gouty arthritis in rats and the potential mechanisms. The results showed that CEO and NEO reduced swelling and redness at joint sites, inhibited neutrophil infiltration, and limited proinflammatory mediator secretion in mice with MSU-induced gouty arthritis. Based on the results of network pharmacology, molecular docking, and western blotting, CEO and NEO may exert anti-gouty arthritis effects by reducing the expression of reactive oxygen species and oxidative stress and downregulating the phosphorylation of the PI3K/AKT/mTOR signaling pathway, thereby inhibiting the production of the NLRP3 inflammasome and inhibiting the production of inflammatory cytokines. Therefore, these two essential oils show potential for use as adjuvant treatments for gouty arthritis in specific aromatherapy products or food seasonings.

Knowledge, attitudes, and practices of gouty arthritis in the general population aged > 30.

BACKGROUND: A knowledge of gouty arthritis could help in the primary prevention of the disease development and lead to an early diagnosis if it occurs. This study investigated the knowledge, attitudes, and practices (KAP) toward gouty arthritis in the general population > 30 years old. METHODS: This web-based cross-sectional study was conducted among the general population > 30 years old between January and March 2023 in Chengdu, Sichuan. The questionnaire was designed by the investigators based on the available guidelines (Cronbach's α = 0.846). A score above 70% indicated good knowledge, a positive attitude, and proactive practice. Multivariable and structural equation modeling (SEM) analyses were performed to analyze the factors influencing KAP. RESULTS: A total of 537 questionnaires were included. The knowledge, attitudes, and practices scores were 13.12 ± 6.41, 25.28 ± 3.97, and 45.25 ± 5.77, respectively. Female (OR = 0.47, 95%CI: 0.31-0.71, P < 0.001), suburban living (OR = 0.18, 95%CI: 0.04-0.78, P = 0.022), heads of institution/organization and professional and technical staff (OR = 2.04, 95%CI: 1.23-3.39, P = 0.006), and an income of < 2,000 yuan (OR = 0.35, 95%CI: 0.14-0.85, P = 0.021) were independently associated with knowledge. Female (OR = 2.17, 95%CI: 1.43-3.30, P < 0.001), age (OR = 1.03, 95%CI: 1.01-1.05, P = 0.001), college and above education (OR = 2.26, 95%CI: 1.16-4.41, P = 0.017), an income of 5,000-10,000 yuan (OR = 2.05, 95%CI: 1.27-3.31, P = 0.003), and an income of > 10,000 yuan (OR = 2.07, 95%CI: 1.12-3.81, P = 0.020) were independently associated with attitudes. Attitude (OR = 1.31, 95%CI: 1.23-1.40, P < 0.001), female (OR = 1.62, 95%CI: 1.01-2.58, P = 0.044), and age (OR = 1.02, 95%CI: 1.00-1.04, P = 0.016) were independently associated with practices. The structural equation modeling analysis showed that knowledge directly influenced attitude (ß=-0.10, P < 0.001) and indirectly influenced practice (ß=-0.07, P < 0.001), and attitude directly influenced practice (ß = 0.68, P < 0.001). CONCLUSION: The general population over 30 years old had inadequate knowledge, unfavorable attitudes, and less proactive practices toward gouty arthritis. Targeted interventions should focus on enhancing knowledge about gout and promoting positive attitudes toward its management.

Arthroscopic surgery for ankle gouty arthritis: a retrospective analysis of clinical outcomes at six month follow-up based on a novel classification system.

PURPOSE: This study aimed to evaluate the clinical outcomes, patient-reported outcomes, and recurrence rate of patients diagnosed with ankle gouty arthritis who underwent arthroscopic surgery based on the new classification. METHODS: A total of 51 patients diagnosed with ankle gouty arthritis were included in this retrospective study. A new classification was proposed based on the location and extent of MSU crystal deposition under an arthroscopy view. Patients are classified into different types and underwent arthroscopic surgery accordingly. The primary outcome measure was the American Orthopaedic Foot & Ankle Society (AOFAS) ankle-hindfoot score. The secondary outcomes included the visual analog pain scale (VAS), serum uric acid levels, and the recurrence rate of ankle gouty arthritis at one year postoperatively. RESULTS: Based on the new classification, five patients were Type I, 24 patients were Type II, five were Type III A, six were Type III B, and 11 were Type IV. The average follow-up time was 23.5 ± 10.9 months. The AOFAS hindfoot-ankle score improved significantly from 70.3 ± 15.9 to 85.6 ± 13.0 (p < 0.01). The mean serum uric acid level was significantly decreased from 442.0 ± 109.2 to 540.5 ± 132.4 (p < 0.01). The average VAS scale decreased from 3.8 ± 1.9 to 1.4 ± 1.7 (p < 0.01). The median of recurrences in one year postoperatively was significantly decreased from 1.5 (1, 3.75) to 0 (0, 0.75) (p < 0.01). CONCLUSION: A new classification strategy for ankle gouty arthritis based on arthroscopic view was proposed. Patients with ankle gouty arthritis showed significant improvement in ankle function and pain relief after undergoing arthroscopic surgery driven by the new classification.

Osteostatin Mitigates Gouty Arthritis through the Inhibition of Caspase-1 Activation and Upregulation of Nrf2 Expression.

Gouty arthritis results from monosodium urate (MSU) crystal deposition in joints, initiating (pro)-interleukin (IL)-1ß maturation, inflammatory mediator release, and neutrophil infiltration, leading to joint swelling and pain. Parathyroid hormone-related protein (107-111) C-terminal peptide (osteostatin) has shown anti-inflammatory properties in osteoblasts and collagen-induced arthritis in mice, but its impact in gouty arthritis models remains unexplored. We investigated the effect of osteostatin on pyroptosis, inflammation, and oxidation in macrophages, as well as its role in the formation of calcium pyrophosphate dihydrate crystals and MSU-induced gouty arthritis in mice models. Osteostatin ameliorated pyroptosis induced by lipopolysaccharide and adenosine 5'-triphosphate (LPS + ATP) in mice peritoneal macrophages by reducing the expression of caspase-1, lactate dehydrogenase release, and IL-1ß and IL-18 secretion. Additionally, IL-6 and tumor necrosis factor-α (TNF-α) were also decreased due to the reduced activation of the NF-κB pathway. Furthermore, osteostatin displayed antioxidant properties in LPS + ATP-stimulated macrophages, resulting in reduced production of mitochondrial and extracellular reactive oxygen species and enhanced Nrf2 translocation to the nuclei. In both models of gouty arthritis, osteostatin administration resulted in reduced pro-inflammatory cytokine production, decreased leukocyte migration, and reduced caspase-1 and NF-κB activation. These results highlight the potential of osteostatin as a therapeutic option for gouty arthritis.

Advances in Gouty Arthritis Management: Integration of Established Therapies, Emerging Treatments, and Lifestyle Interventions.

Gouty arthritis, a prevalent inflammatory condition characterized by the deposition of monosodium urate crystals within joints, often results in debilitating pain and inflammation. Conventional therapeutic approaches, including nonsteroidal anti-inflammatory drugs, corticosteroids, and urate-lowering agents such as allopurinol and febuxostat, often have limitations such as adverse effects, drug interactions, and suboptimal patient compliance. This review presents a comprehensive overview of both established and emerging therapeutic strategies, developed between 2019 and 2024, for gouty arthritis; the review focuses on their mechanisms of action, efficacy, and safety profiles. Novel therapeutic approaches include pharmaceutical plant additives (e.g., Citrullus colocynthis, Atractylodes lancea), anti-inflammatory agents such as canakinumab and ozone therapy, and complementary therapies such as warm ginger compresses, Qingpeng ointment, and various lifestyle modifications. These strategies offer promising alternatives to conventional treatments by targeting uric acid metabolism, inflammatory pathways, and crystal formation, potentially reducing reliance on standard medications and minimizing adverse effects. Although therapies such as canakinumab have demonstrated significant efficacy in reducing gout flares, others such as polyphenol-rich foods offer favorable safety profiles. Further research, including large-scale clinical trials, is warranted to validate these findings and integrate these strategies into clinical practice to improve patient outcomes and quality of life.

Honokiol alleviates monosodium urate-induced gouty pain by inhibiting voltage-gated proton channels in mice.

OBJECTIVE: To investigate whether honokiol (HNK) acted as an analgesic in connection with inhibiting the voltage-gated proton channel (Hv1). METHODS: The model of gouty arthritis was induced by injecting monosodium urate (MSU) crystals into the hind ankle joint of mice. HNK was given by intragastric administration. Ankle swelling degree and mechanical allodynia were evaluated using ankle joint circumference measurement and von Frey filaments, respectively. Hv1 current, tail current, and action potential in dorsal root ganglion (DRG) neurons were recorded with patch-clamp techniques. RESULTS: HNK (10, 20, 40 mg/kg) alleviated inflammatory response and mechanical allodynia in a dose-dependent manner. In normal DRG neurons, 50 µM Zn2+ or 2-GBI significantly inhibited the Hv1 current and the current density of Hv1 increased with increasing pH gradient. The amplitude of Hv1 current significantly increased on the 3rd after MSU treatment, and HNK dose-dependently reversed the upregulation of Hv1 current. Compared with MSU group, 40 mg/kg HNK shifted the activation curve to the direction of more positive voltage and increased reversal potential to the normal level. In addition, 40 mg/kg HNK reversed the down-regulation of tail current deactivation time constant (τtail) but did not alter the neuronal excitability of DRG neurons in gouty mice. CONCLUSION: HNK may be a potential analgesic by inhibiting Hv1 current.

Preparing a novel baicalin-loaded microemulsion-based gel for transdermal delivery and testing its anti-gout effect.

We previously demonstrated that baicalin had efficacy against gouty arthritis (GA) by oral administration. In this paper, a novel baicalin-loaded microemulsion-based gel (B-MEG) was prepared and assessed for the transdermal delivery of baicalin against GA. The preparation method and transdermal capability of B-MEG was screened and optimized using the central composite design, Franz diffusion cell experiments, and the split-split plot design. Skin irritation tests were performed in guinea pigs. The anti-gout effects were evaluated using mice. The optimized B-MEG comprised of 50 % pH 7.4 phosphate buffered saline, 4.48 % ethyl oleate, 31.64 % tween 80, 13.88 % glycerin, 2 % borneol, 0.5 % clove oil and 0.5 % xanthan gum, with a baicalin content of (10.42 ± 0.08) mg/g and particle size of (15.71 ± 0.41) nm. After 12 h, the cumulative amount of baicalin permeated from B-MEG was (672.14 ± 44.11) µg·cm-2. No significant skin irritation was observed following B-MEG application. Compared to the model group, B-MEG groups significantly decreased the rate of auricular swelling (P < 0.01) and number of twists observed in mice (P < 0.01); and also reduced the rate of paw swelling (P < 0.01) and inflammatory cell infiltration in a mouse model of GA. In conclusion, B-MEG represents a promising transdermal carrier for baicalin delivery and can be used as a potential therapy for GA.

[Mechanism of acteoside in prevention and treatment of gouty arthritis based on liver metabolomics].

This study aims to reveal the effect of acteoside on gouty arthritis(GA) in rats based on liver metabolomics. The ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS) was employed to search for the potential biomarkers and metabolic pathways. SD rats were randomly assigned into blank, model, colchicine(0.3 mg·kg~(-1)), and high-, medium-, low-dose(200, 100, and 50 mg·kg~(-1), respectively) acteoside groups(n=7). The rats were administrated once a day for 7 continuous days. Monosodium urate(MSU) was used to induce GA model in rats during administration. The degree of joint swelling and pathological changes of synovial tissue in rats were observed, and the levels of interleukin(IL)-1ß, IL-18 and tumor necrosis factor(TNF)-α in the synovial tissue of rats were measured. UPLC-Q-TOF-MS was employed to collect rat liver data, and Progenesis QI and EZ info were used for data analysis. Human Metabolomics Database(HMDB) and Kyoto Encyclopedia of Genes and Genomes(KEGG) were employed to predict the potential biomarkers and metabolic pathways. The results showed that acteoside alleviated joint swelling, reduced synovial tissue damage, and lowered the levels of inflammatory cytokines in GA rats. A total of 19 common biomarkers were identified, 17 of which can be regulated by acteoside. Seven metabolic pathways were enriched, such as glycerophospholipid metabolism, linoleic acid metabolism, and taurine and hypotaurine metabolism, among which glycerophospholipid metabolism was strongly disturbed. The metabolomics analysis suggested that acteoside may down-regulate the expression of inflammatory cytokines and alleviate the symptoms of GA rats by regulating glycerophospholipid metabolism, linoleic acid metabolism, and taurine and hypotaurine metabolism. The findings provide a reference for future research and development of acteoside.

[Modern understanding of uric acid metabolism disorders and progress in traditional Chinese medicine prevention and treatment].

The abnormal production and/or excretion of uric acid can lead to a disorder in uric acid metabolism, resulting in hyperuricemia, uric acid nephropathy, gouty arthritis, and other diseases related to uric acid metabolism disorder. The clinical incidence of these diseases is increasing year after year, posing a significant threat to public health. In the past, hyperuricemia and gouty arthritis were often considered different diseases, with uric acid nephropathy being a complication of hyperuricemia. However, recent research has challenged this perspective, suggesting that hyperuricemia, uric acid nephropathy, and gouty arthritis are different stages of the same disease, with urate deposition as the common pathological feature. This article offered a comprehensive overview of the current understanding of hyperuricemia, uric acid nephropathy, and gouty arthritis in both traditional Chinese medicine(TCM) and western medicine. It delved into the most up-to-date insights into the involvement of urate deposition in the pathogenesis of uric acid metabolism disorders and highlighted the dominant role of TCM in the prevention and treatment of uric acid metabolism disorders, so as to provide a reference for effective intervention strategies and drug development in uric acid metabolism disorder-related diseases.

Spirodalesol analog 8A inhibits NLRP3 inflammasome activation and attenuates inflammatory disease by directly targeting adaptor protein ASC.

Pharmacological inhibition of the Nod-like receptor family protein 3 (NLRP3) inflammasome contributes to the treatment of numerous inflammation-related diseases, making it a desirable drug target. Spirodalesol, derived from the ascomycete fungus Daldinia eschscholzii, has been reported to inhibit NLRP3 inflammasome activation. Based on the structure of spirodalesol, we synthesized and screened a series of analogs to find a more potent inhibitor. Analog compound 8A was identified as the most potent selective inhibitor for NLRP3 inflammasome assembly, but 8A did not inhibit the priming phase of the inflammasome. Specifically, while 8A did not reduce NLRP3 oligomerization, we found that it inhibited the oligomerization of adaptor protein apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), as ASC speck formation was significantly reduced. Also, 8A interrupted the assembly of the NLRP3 inflammasome complex and inhibited the activation of caspase-1. Subsequently, we used a cellular thermal shift assay and microscale thermophoresis assay to demonstrate that 8A interacts directly with ASC, both in vitro and ex vivo. Further, 8A alleviated lipopolysaccharide-induced endotoxemia, as well as monosodium urate-induced peritonitis and gouty arthritis in mice by suppressing NLRP3 inflammasome activation. Thus, 8A was identified as a promising ASC inhibitor to treat inflammasome-driven diseases.

Phospholipase A2 regulates autophagy in gouty arthritis: proteomic and metabolomic studies.

BACKGROUND: Acute gouty arthritis is inflammatory joint arthritis. Gouty arthritis (GA) involves multiple pathological processes. Deposition of joints by monosodium urate (MSU) crystals has been shown to play a critical role in the injury process. Due to the different effects of MSU stimulation on the joints, the exact changes in the synovial fluid are unknown. We want to explore the changes in proteins and metabolites in the joints of gouty arthritis. Regulating various functional substances in the joint can reduce inflammation and pain symptoms. METHODS: 10 patients with gouty knee arthritis and 10 normal controls were selected from clinical, surgical cases. The biological function of the metabolome was assessed by co-expression network analysis. A molecular network based on metabolomic and proteomic data was constructed to study critical molecules. The fundamental molecular changes in the relevant pathways were then verified by western blot. RESULTS: Proteomic analysis showed that the expressions of proteases Cathepsin B, Cathepsin D, Cathepsin G, and Cathepsin S in synovial fluid patients with gouty arthritis were significantly increased. Enrichment analysis showed a positive correlation between lysosomal and clinical inflammatory cell shape changes. Untargeted metabolomic analysis revealed that lipids and lipoids accumulate, inhibit autophagic flux, and modulate inflammation and immunity in gouty arthritis patients. It was determined that the accumulation of lipid substances such as phospholipase A2 led to the imbalanced state of the autophagy-lysosome complex, and the differentially expressed metabolites of Stearoylcarnitine, Tetradecanoylcarnitine, Palmitoylcarnitine were identified (|log2 fold change|> 1.5, adjusted P value < 0.05 and variable importance in prediction (VIP) > 1.5). The autophagy-lysosomal pathway was found to be associated with gouty knee arthritis. Essential molecular alterations of multi-omics networks in gouty knee arthritis patients compared with normal controls involve acute inflammatory response, exosomes, immune responses, lysosomes, linoleic acid metabolism, and synthesis. CONCLUSIONS: Comprehensive analysis of proteomic and untargeted metabolomics revealed protein and characteristic metabolite alterations in gouty arthritis, it mainly involves lipids and lipid like molecules, phospholipase A2 and autophagic lysosomes. This study describes the pathological characteristics, pathways, potential predictors and treatment goals of gouty knee arthritis.

Characterizations of the multi-kingdom gut microbiota in Chinese patients with gouty arthritis.

OBJECTIVE: The gut microbial composition has been linked to metabolic and autoimmune diseases, including arthritis. However, there is a dearth of knowledge on the gut bacteriome, mycobiome, and virome in patients with gouty arthritis (GA). METHODS: We conducted a comprehensive analysis of the multi-kingdom gut microbiome of 26 GA patients and 28 healthy controls, using whole-metagenome shotgun sequencing of their stool samples. RESULTS: Profound alterations were observed in the gut bacteriome, mycobiome, and virome of GA patients. We identified 1,117 differentially abundant bacterial species, 23 fungal species, and 4,115 viral operational taxonomic units (vOTUs). GA-enriched bacteria included Escherichia coli_D GENOME144544, Bifidobacterium infantis GENOME095938, Blautia_A wexlerae GENOME096067, and Klebsiella pneumoniae GENOME147598, while control-enriched bacteria comprised Faecalibacterium prausnitzii_G GENOME147678, Agathobacter rectalis GENOME143712, and Bacteroides_A plebeius_A GENOME239725. GA-enriched fungi included opportunistic pathogens like Cryptococcus neoformans GCA_011057565, Candida parapsilosis GCA_000182765, and Malassezia spp., while control-enriched fungi featured several Hortaea werneckii subclades and Aspergillus fumigatus GCA_000002655. GA-enriched vOTUs mainly attributed to Siphoviridae, Myoviridae, Podoviridae, and Microviridae, whereas control-enriched vOTUs spanned 13 families, including Siphoviridae, Myoviridae, Podoviridae, Quimbyviridae, Phycodnaviridae, and crAss-like. A co-abundance network revealed intricate interactions among these multi-kingdom signatures, signifying their collective influence on the disease. Furthermore, these microbial signatures demonstrated the potential to effectively discriminate between patients and controls, highlighting their diagnostic utility. CONCLUSIONS: This study yields crucial insights into the characteristics of the GA microbiota that may inform future mechanistic and therapeutic investigations.

Atranorin inhibits NLRP3 inflammasome activation by targeting ASC and protects NLRP3 inflammasome-driven diseases.

Aberrant NLRP3 activation has been implicated in the pathogenesis of numerous inflammation-associated diseases. However, no small molecular inhibitor that directly targets NLRP3 inflammasome has been approved so far. In this study, we show that Atranorin (C19H18O8), the secondary metabolites of lichen family, effectively prevents NLRP3 inflammasome activation in macrophages and dendritic cells. Mechanistically, Atranorin inhibits NLRP3 activation induced cytokine secretion and cell pyroptosis through binding to ASC protein directly and therefore restraining ASC oligomerization. The pharmacological effect of Atranorin is evaluated in NLRP3 inflammasome-driven disease models. Atranorin lowers serum IL-1ß and IL-18 levels in LPS induced mice acute inflammation model. Also, Atranorin protects against MSU crystal induced mice gouty arthritis model and lowers ankle IL-1ß level. Moreover, Atranorin ameliorates intestinal inflammation and epithelial barrier dysfunction in DSS induced mice ulcerative colitis and inhibits NLRP3 inflammasome activation in colon. Altogether, our study identifies Atranorin as a novel NLRP3 inhibitor that targets ASC protein and highlights the potential therapeutic effects of Atranorin in NLRP3 inflammasome-driven diseases including acute inflammation, gouty arthritis and ulcerative colitis.

Association between vegetarian diet and gouty arthritis: A retrospective cohort study.

BACKGROUND AND AIMS: A vegetarian diet is rich in vegetables, fruits, and soy products. Although vegetarian diet is beneficial for improving the health outcomes such as body mass index, metabolic syndrome, cardiovascular disease, and mortality rate, the association between a vegetarian diet and gout incidence is not well known. METHODS AND RESULTS: We linked the MJ Health Survey Data and MJ Biodata 2000 with the National Health Insurance Research Database (NHIRD) and the National Registration of Death (2000-2018). Information on the diet was collected from the MJ Health Survey Data, and the incidence of gouty arthritis was confirmed using the NHIRD. The Kaplan-Meier survival curve and log-rank test were used to compare the differences between vegetarian and non-vegetarian participants. Cox regression models were used to estimate the risk of the incidence of gouty arthritis. Among 76,972 participants, 37,297 (48.46%) were men, 2488 (3.23%) were vegetarians and the mean age was 41.65 ± 14.13 years. The mean baseline uric acid level was 6.14 ± 1.65 mg/dL. A total of 16,897 participants developed gouty arthritis, including 16,447 (22.08%) non-vegetarians and 450 (18.9%) vegetarians over a mean follow-up of 19 years. Significant differences were observed in the Kaplan-Meier survival curves between vegetarians and non-vegetarians (log-rank p < 0.001). Vegetarians had a significantly decreased incidence of gouty arthritis compared with non-vegetarians (hazard ratio = 0.87, 95% confidence interval = 0.78-0.98, p = 0.02) after adjusting for potential confounders. CONCLUSION: People with a vegetarian diet had a significantly decreased risk of developing gouty arthritis compared with non-vegetarians in Taiwan.

A liquid chromatography-tandem mass spectrometry method for comprehensive determination of metabolites in the purine pathway of rat plasma and its application in anti-gout effects of Lycium ruthenicum Murr.

It has been proved that purine metabolites are implicated in various biological syndromes and disorders. Therefore, the realization of panoramic detection of purine metabolites will be of great significance to the pathogenesis of purine metabolic disorders. In the present study, an ultra-high performance liquid chromatography with tandem mass spectrometry method was developed for the comprehensive quantification of purine metabolites in rat plasma. The 17 purine metabolites were separated and quantified in the short running time of 15 min. The proposed method was strictly validated by applying SeraSub solution as a matrix and proved to be linear (R2 ≥ 0.9944), accurate (the recoveries of all analytes ranged from 85.3% to 103.0%, with relative standard deviation values ≤ 9.3%), and precise (the intra- and inter-day precisions were less than 10.8% and 12.4%, respectively). The method was then successfully applied to the qualification of the endogenous purine metabolites in acute gouty arthritis rats, as well as colchicine and anthocyanin-intervened rats. Results showed that uric acid, xanthine, hypoxanthine, and xanthine were considered the key factors of acute gouty arthritis. The established method and measurement of purines in rat plasma might help the investigation of the action mechanisms between purine disorders and related diseases.