Comparison of efficacy of acupuncture-related therapies in treating Acute Gouty Arthritis: A Network Meta-Analysis of Randomized Controlled Trials.

Background: and purpose: Acupuncture and moxibustion, as a complementary and alternative therapy, has been widely used in the treatment of acute gouty arthritis (AGA). However, there are various forms of acupuncture and moxibustion, and the curative effect of different forms is different. This study evaluated the clinical efficacy of different acupuncture therapies in treating AGA by network meta-analysis. Methods: Computer searches of English databases (including PubMed, The Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, Embase) and Chinese databases (including China National Knowledge Infrastructure (CNKI), VIP Database, Wanfang Database and China Biomedical Literature Database) were conducted for randomized controlled trials (RCTs) of acupuncture therapies in treating AGA. We set the search time from the database establishment to May 2022. Data analysis was performed using Stata14.2 software. Results: Thirty-two RCTs involving 2434 patients with AGA were screened out. The results showed that in terms of the improvement of pain visual analogue scale (VAS) scores, the top ones were acupoint application (100%), electroacupuncture + Western medicine (73.5%) and acupuncture + Western medicine (69.2%); In terms of total effective rate, acupoint application (85.2%), acupuncture (75.2%) and acupuncture + Western medicine (63%) ranked the top; In terms of reducing serum uric acid (SUA) levels, the top ones were acupoint application (95%), acupuncture + Western medicine (87.5%) and acupuncture (66.2%); In terms of the reduction of erythrocyte sedimentation rate (ESR), acupuncture (95%), acupoint application (84.7%), and electroacupuncture + Western medicine (52.8%) were the most prominent. Conclusion: The existing evidence shows that acupoint application has more advantages in improving the total effective rate, improving pain and reduce SUA levels, and acupuncture has an advantage in reducing ESR levels and adverse events. However, due to the low qualities of the original studies, the quality of this evidence is poor. Therefore, it is recommended that more scientific research be performed to confirm the efficacy of acupuncture.

Upadacitinib sustained-release tablets for the treatment of chronic refractory gouty arthritis: a case report and literature review.

Background: Gouty arthritis (GA) is a crystal-related joint disease caused by the deposition of monosodium urate (MSU) crystals, directly associated with hyperuricemia resulting from purine metabolism disorder and/or reduced uric acid excretion. Acute attacks of typical gouty arthritis are generally relieved through the clinical use of NSAIDs, colchicine, or glucocorticoids. However, managing patients with chronic refractory gout poses challenges due to complications such as multiple tophi, gouty nephropathy, diabetes, and gastrointestinal bleeding. While there have been numerous studies on gout in recent years, research specifically regarding chronic refractory gout remains limited. The management of such cases still faces several unresolved issues, including recurrent disease flare-ups and poor patient compliance leading to inadequate drug utilization and increased risk of side effects. In this report, we present a case of successful improvement in chronic refractory gouty arthritis using the biologic agent upadacitinib sustained-release tablets. Case presentation: Our case report involves a 53 years-old Asian patient with recurrent gouty arthritis who had a history of over 20 years without regular treatment, presenting with tophi and an increasing number of painful episodes. During hospitalization, various analgesics and anti-inflammatory drugs provided inadequate relief, requiring the use of steroids to alleviate symptoms. However, tapering off steroids proved challenging. We decided to add upadacitinib sustained-release tablets to the treatment regimen, which ultimately improved the patient's condition. After 6 months of follow-up, the patient has not experienced any further acute pain episodes. Conclusion: This case highlights the potential therapeutic effect of upadacitinib sustained-release tablets during the acute phase of chronic refractory gouty arthritis.

Traditional Herbal Medicine: Therapeutic Potential in Acute Gouty Arthritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Acute Gouty Arthritis (AGA) is characterized by a rapid inflammatory reaction caused by the build-up of monosodium urate (MSU) crystals in the tissues surrounding the joints. This condition often associated with hyperuricemia, is distinguished by its symptoms of intense pain, active inflammation, and swelling of the joints. Traditional approaches in AGA management often fall short of desired outcomes in clinical settings. However, recent ethnopharmacological investigations have been focusing on the potential of Traditional Herbal Medicine (THM) in various forms, exploring their therapeutic impact and targets in AGA treatment. AIM OF THE REVIEW: This review briefly summarizes the current potential pharmacological mechanisms of THMs - including active ingredients, extracts, and prescriptions -in the treatment of AGA, and discusses the relevant potential mechanisms and molecular targets in depth. The objective of this study is to offer extensive information and a reference point for the exploration of targeted AGA treatment using THMs. MATERIALS AND METHODS: This review obtained scientific publications focused on in vitro and in vivo studies of anti-AGA Traditional Herbal Medicines (THMs) conducted between 2013 and 2023. The literature was collected from various journals and electronic databases, including PubMed, Elsevier, ScienceDirect, Web of Science, and Google Scholar. The retrieval and analysis of relevant articles were guided by keywords such as "acute gouty arthritis and Chinese herbal medicine," "acute gouty arthritis herbal prescription," "acute gouty arthritis and immune cells," "acute gouty arthritis and inflammation," "acute gouty arthritis and NLRP3," "acute gouty arthritis and miRNA," and "acute gouty arthritis and oxidative stress." RESULTS: We found that AGA has a large number of therapeutic targets, highlighting the effectiveness the potential of THMs in AGA treatment through in vitro and in vivo studies. THMs and their active ingredients can mitigate AGA symptoms through a variety of therapeutic targets, such as influencing macrophage polarization, neutrophils, T cells, natural killer (NK) cells, and addressing factors like inflammation, NLRP3 inflammasome, signaling pathways, oxidative stress, and miRNA multi-target interactions. The anti-AGA properties of THMs, including their active components and prescriptions, were systematically summarized and categorized based on their respective therapeutic targets. CONCLUSION: phenolic, flavonoid, terpenoid and alkaloid compounds in THMs are considered the key ingredients to improve AGA. THMs and their active ingredients achieve enhanced efficacy through interactions with multiple targets, of which NLRP3 is a main therapeutic target. Nonetheless, given the intricate composition of traditional Chinese medicine, additional research is required to unravel the underlying mechanisms and molecular targets through which THMs alleviate AGA.

Gut-immunity-joint axis: a new therapeutic target for gouty arthritis.

Gouty arthritis (GA) is an inflammatory disease characterized by pain. The primary goal of current treatment strategies during GA flares remains the reduction of inflammation and pain. Research suggests that the gut microbiota and microbial metabolites contribute to the modulation of the inflammatory mechanism associated with GA, particularly through their effect on macrophage polarization. The increasing understanding of the gut-joint axis emphasizes the importance of this interaction. The primary objective of this review is to summarize existing research on the gut-immune-joint axis in GA, aiming to enhance understanding of the intricate processes and pathogenic pathways associated with pain and inflammation in GA, as documented in the published literature. The refined comprehension of the gut-joint axis may potentially contribute to the future development of analgesic drugs targeting gut microbes for GA.

Efficacy and safety of Huzhang Granule, a compound Chinese herbal medicine, for acute gouty arthritis: A double-blind, randomized controlled trial.

BACKGROUND: Acute gouty arthritis (AGA) is an inflammatory joint disease with a high prevalence. Typical medical interventions, including nonsteroidal anti-inflammatory drugs, colchicine and glucocorticoids, can have serious adverse reactions. Huzhang Granule (HZG), a compound Chinese herbal medicine, has been used to treat AGA for more than 30 years with satisfactory effects and no significant adverse reactions. However, the efficacy and safety of HZG in AGA patients remains unknown. OBJECTIVE: The present investigation was designed to examine the efficacy and safety profile of HZG in managing AGA patients. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: The current study was conducted as a noninferiority, randomized controlled clinical trial on 180 eligible enrolled participants. Participants were randomly assigned into the HZG and etoricoxib groups. Treatments were administered for 5 d, during which the HZG group received HZG and placebo etoricoxib, while the etoricoxib group received etoricoxib and placebo HZG in the same ratio (1:1). MAIN OUTCOME MEASURES: The primary outcome was pain experienced by the patient in the gout-afflicted joint from days 2 to 5 of the treatment window. The pain level was measured via a visual analogue scale, ranging from 0 mm to 100 mm. The secondary outcomes comprised joint tenderness and swelling, reduction of inflammatory biomarkers, and the patient's and investigator's global evaluations of therapeutic response. RESULTS: The mean reduction in pain was -51.22 mm (95% confidence interval [CI], [-53.42, -49.03] mm) for the HZG and -52.00 mm (95% CI, [-54.06, -49.94] mm) for the etoricoxib groups. The mean difference between the two groups was 0.78 mm (95% CI, [-2.25, 3.81] mm). All additional efficacy endpoints, covering decreased inflammation and pain relief, yielded compelling proof of noninferiority. Patients in the HZG group exhibited a comparatively lower rate of adverse events compared to those in the etoricoxib group (4.44% vs 13.33%; P ≤ 0.05). CONCLUSION: HZG and etoricoxib groups demonstrated similar levels of analgesic effectiveness. The safety and efficacy of HZG indicates that it can be used as a potential therapeutic option for treating AGA. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2000036970). Please cite this article as: Wang H, Chen ST, Ding XJ, Kuai L, Hua L, Li X, Wang YF, Zhang M, Li B, Wang RP, Zhou M. Efficacy and safety of Huzhang Granule, a compound Chinese herbal medicine, for acute gouty arthritis: A double-blind, randomized controlled trial. J Integr Med. 2024; Epub ahead of print.

A case report of multicentric reticulohistiocytosis with atypical cutaneous presentation.

Multicentric reticulohistiocytosis (MRH) is a rare systemic disorder characterized by histiocytic hyperplasia that mainly involves the skin, mucous membranes, and joints. The typical clinical features include papules, nodules, and arthritis. MRH lesions are relatively extensive but small and scattered. Joint inflammation is characterized by diffuse symmetric polyarthritis as the first symptom, which can be severe and disabling due to destructive joint changes. MRH is easily misdiagnosed in clinical practice. Here, we report the case of an elderly male patient who presented with polyarticular pain in the hip and interphalangeal joints as the first manifestation, followed by the development of large, isolated, bulging skin nodules, which are atypical MRH lesions. This is rare in all MRH case reports, and we made the correct diagnosis by combining skin histopathology, immunohistochemistry, and other clinical examinations. We performed surgical treatment on the local skin lesions of this patient. This case suggests that clinicians should actively correlate the condition and accurately diagnose MRH when encountering atypical skin changes or other diseases as the first symptom and explore the mechanisms of MRH and other clinical manifestations.

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.

Targeting Neutrophil Extracellular Traps in Gouty Arthritis: Insights into Pathogenesis and Therapeutic Potential.

Gouty arthritis (GA) is an immune-mediated disorder characterized by severe inflammation due to the deposition of monosodium urate (MSU) crystals in the joints. The pathophysiological mechanisms of GA are not yet fully understood, and therefore, the identification of effective therapeutic targets is of paramount importance. Neutrophil extracellular traps (NETs), an intricate structure of DNA scaffold, encompassing myeloperoxidase, histones, and elastases - have gained significant attention as a prospective therapeutic target for gouty arthritis, due to their innate antimicrobial and immunomodulatory properties. Hence, exploring the therapeutic potential of NETs in gouty arthritis remains an enticing avenue for further investigation. During the process of gouty arthritis, the formation of NETs triggers the release of inflammatory cytokines, thereby contributing to the inflammatory response, while MSU crystals and cytokines are sequestered and degraded by the aggregation of NETs. Here, we provide a concise summary of the inflammatory processes underlying the initiation and resolution of gouty arthritis mediated by NETs. Furthermore, this review presents an overview of the current pharmacological approaches for treating gouty arthritis and summarizes the potential of natural and synthetic product-based inhibitors that target NET formation as novel therapeutic options, alongside elucidating the intrinsic challenges of these inhibitors in NETs research. Lastly, the limitations of HL-60 cell as a suitable substitute of neutrophils in NETs research are summarized and discussed. Series of recommendations are provided, strategically oriented towards guiding future investigations to effectively address these concerns. These findings will contribute to an enhanced comprehension of the interplay between NETs and GA, facilitating the proposition of innovative therapeutic strategies and novel approaches for the management of GA.

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.

Role of Chemotaxis of Vδ2 T Cells to the Synovium in the Pathogenesis of Acute Gouty Arthritis.

Background: This study aimed to explore the potential roles of Vδ2 T cells in the pathogenesis of acute gouty arthritis. Methods: Patients with gout (n=86), rheumatoid arthritis (n=7), osteoarthritis (n=9), and healthy controls (n=40) were enrolled. γδT cell frequency, chemokine receptor expression and production of pro-inflammatory cytokines in cells from peripheral blood and synovial fluid samples were quantified by flow cytometry. The chemotaxis ability of Vδ2 T cells was determined by transwell migration assay. The levels of chemokines were also detected by enzyme-linked immunosorbent assay. Results: Peripheral Vδ2 T cells had significantly lower frequencies in acute gout patients than that in healthy controls (P<0.001). These peripheral Vδ2 T cells were negatively correlated with inflammatory markers. Vδ2 T cells from acute gout patients accumulated in synovial fluid, as evidenced by a higher abundance of Vδ2 T cells in it than that in the serum (P<0.01). And Vδ2 T cells expressed a high level of C-X-C chemokine receptor 3 (P=0.035), and its corresponding chemokine C-X-C motif chemokine ligand 10 showed a high concentration in synovial fluid (P<0.05). Vδ2 T cells from synovial fluid of acute gout patients produced a high level of interleukin-17 (P=0.033). Conclusion: The up-regulated expression of C-X-C chemokine receptor 3 on Vδ2 T cells potentially facilitates their infiltration into synovial fluid during acute gouty arthritis. Further production of interleukin-17 by Vδ2 T cells may contribute to the pathogenesis of gout. This study sheds new light on developing novel Vδ2 T cells-based therapeutic strategies for gout treatment.

[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.

Lipidomics Analysis Deepen Understanding the Molecular Mechanisms in a Gouty Model Induced by Combination of MSU Crystals Injection and High-Fat Diet Feeding and the Intervention Mechanisms of Allopurinol.

Background: Gouty arthritis (GA) is a common inflammatory disease caused by deposition of monosodium urate (MSU) crystals in diarthrodial joints. GA attacks commonly involved in joint with red, swollen, heat and pain, and often happened in unilateral foot-first metatarsophalangeal. Accumulated studies have proved that lipids play critical roles in biological processes and lipids biomarkers can substitute for the diagnosis of various diseases. Methods: Herein, shotgun lipidomics was used to quantitatively analyze serum lipidomes of a gouty model which was induced by injecting MSU crystals and feeding high-fat diet with/without treatment with allopurinol. Meanwhile, ELISA kit was used to detect mouse serum levels of inflammatory cytokines (eg, tumor necrosis factor-α, interleukin 1 beta) and HE staining was used to observe the infiltration of inflammatory cells in the foot pad. Results: A total of 9 types of serum lipids were detected in lipidomics by shotguns, and the result of NMDS' analysis demonstrated significant differences in lipids profiles between the control and model group. It is worth noting that lipid abnormality in GA (such as Ceramide (Cer), sphingomyelin (SM), 4-hydroxyalkenals (HNE), phosphatidylinositol (PI), ethanolamine glycerophospholipid (PE), etc.) is related with phospholipid and energy metabolism, and allopurinol treatment could correct the aberrant metabolism of lipid to some extent. Conclusion: Our results indicated that various aberrant lipid metabolisms were present in the established gouty model, and allopurinol treatment could relief this aberrant metabolism of lipids to some degree.

Traditional Chinese Medicine is Associated with the Reduction in Endpoint Events in Patients with Gouty Arthritis: Cohort Study and Association Rule Analysis.

Objective: This study aimed to evaluate the effect of traditional Chinese medicine (TCM) on endpoint events in patients with gouty arthritis (GA). Methods and Materials: A total of 2091 hospitalized GA patients were followed up by telephone, and propensity score matching (PSM) was used to reduce potential bias in the study design. Cox proportional risk model and Kaplan-Meier survival curve were utilized to analyze the impact and time effect of factors on the readmission of GA patients. The differences of laboratory indexes before and after treatment between the low and high exposure groups were compared, and the types and frequencies of medicines in all patients were counted. Association rule analysis was performed to investigate the association between TCM and test indexes or endpoint events. Results: After 1:1 PSM, 187 patients were enrolled in the TCM group and 187 patients in the non-TCM group. The incidence of readmission, new tophus, and all-cause death was lower in the TCM group than that in the non-TCM group (P < 0.05). Cox proportional risk regression analysis showed that TCM, NSAIDs and uric acid lowering drug were independent protective factors for GA readmission. The protective effect was enhanced by the prolongation of TCM treatment and the drug combinations. Kaplan-Meier survival curves indicated a significantly lower readmission rate in the high exposure group than in the low exposure group (P < 0.01). Compared with before treatment, NLR, hs-CRP, UA, TC and other laboratory indexes of the low and high exposure groups were improved after treatment (P < 0.01); The improvement of TG and TC in the high exposure group was more significant than the low exposure group (P < 0.01). The analysis of medicines used by all patients identified the top 20 Chinese herbal medicines and the top 2 Chinese patent medicines. The core drugs identified through association rule analysis that can improve test index and reduce the incidence of endpoint events include Yiyiren, Danshen, and HQC, among others. The network diagram of association rule analysis intuitively shows the relationship between core drugs and "improvement of indicators" and "the absence of endpoint events". Conclusion: TCM is associated with a reduced incidence of endpoint events in patients with GA.

Geraniin restricts inflammasome activation and macrophage pyroptosis by preventing the interaction between ASC and NLRP3 to exert anti-inflammatory effects.

Geraniin, a chemical component of the traditional Chinese medicine geranii herba, possesses anti-inflammatory and anti-oxidative activities. However, its anti-inflammatory role in managing NLRP3 inflammasome and pyroptosis remains to be elucidated. To investigate the anti-inflammation mechanism of geraniin, LPS-primed macrophages were incubated with classical activators of NLRP3 inflammasome (such as ATP, Nigericin, or MSU crystals), and MSU crystals were injected into the ankle joints of mice to establish an acute gouty arthritis model. The propidium iodide (PI) staining results showed that geraniin could restrain cell death in the ATP- or nigericin-stimulated bone marrow-derived macrophages (BMDMs). Geraniin decreased the release of lactate dehydrogenase (LDH) and interleukin (IL)-1ß from cytoplasm to cell supernatant. Geraniin also inhibited the expression of caspase-1 p20, IL-1ß in cell supernatant and N-terminal of gasdermin D (GSDMD-NT) while blocking the oligomerization of ASC to form speck. The inhibitory effects of geraniin on caspase-1 p20, IL-1ß, GSDMD-NT, and ASC speck were not observed in NLRP3 knockout (NLRP3-/-) BMDMs. Hence, the resistance of geraniin to inflammasome and pyroptosis was contingent upon NLRP3 presence. Geraniin reduced reactive oxygen species (ROS) production and maintained mitochondrial membrane potential while preventing interaction between ASC and NLRP3 protein. Additionally, geraniin diminished MSU crystal-induced mouse ankle joint swelling and IL-1ß expression. Geraniin blocked the recruitment of neutrophils and macrophages to the synovium of joints. Our results demonstrate that geraniin prevents the assembly of ASC and NLRP3 through its antioxidant effect, thereby inhibiting inflammasome activation, pyroptosis, and IL-1ß release to provide potential insights for gouty arthritis targeted therapy.

Nuclear receptor coactivator 6 is a critical regulator of NLRP3 inflammasome activation and gouty arthritis.

Transcriptional coactivators regulate the rate of gene expression in the nucleus. Nuclear receptor coactivator 6 (NCOA6), a coactivator, has been implicated in embryonic development, metabolism, and cancer pathogenesis, but its role in innate immunity and inflammatory diseases remains unclear. Here, we demonstrated that NCOA6 was expressed in monocytes and macrophages and that its level was increased under proinflammatory conditions. Unexpectedly, nuclear NCOA6 was found to translocate to the cytoplasm in activated monocytes and then become incorporated into the inflammasome with NLRP3 and ASC, forming cytoplasmic specks. Mechanistically, NCOA6 associated with the ATP hydrolysis motifs in the NACHT domain of NLRP3, promoting the oligomerization of NLRP3 and ASC and thereby instigating the production of IL-1ß and active caspase-1. Of note, Ncoa6 deficiency markedly inhibited NLRP3 hyperactivation caused by the Nlrp3R258W gain-of-function mutation in macrophages. Genetic ablation of Ncoa6 substantially attenuated the severity of two NLRP3-dependent diseases, folic-induced acute tubular necrosis and crystal-induced arthritis, in mice. Consistent with these findings, NCOA6 was highly expressed in macrophages derived from gout patients, and NCOA6-positive macrophages were significantly enriched in gout macrophages according to the transcriptome profiling results. Conclusively, NCOA6 is a critical regulator of NLRP3 inflammasome activation and is therefore a promising target for NLRP3-dependent diseases, including gout.

Sanmiao wan alleviates inflammation and exhibits hypouricemic effect in an acute gouty arthritis rat model.

ETHNOPHARMACOLOGICAL RELEVANCE: Sanmiao wan (SMW), a classical traditional Chinese medicine (TCM) formula, has been employed to treat gouty diseases in clinic as early as Yuan dynasty. It shows remarkably therapeutic effects in acute gouty arthritis (GA). However, the potential mechanisms of SMW are still not fully revealed. AIM OF THE STUDY: The objective of this project is to evaluate the pharmacological effects and possible mechanisms of SMW in a rat model of acute GA. MATERIALS AND METHODS: Monosodium urate (MSU) suspension was injected into the ankle joint of rats to establish acute GA model. The inflammation was evaluated by measuring the posterior ankle diameter. The pathological status of synovial tissue was assessed by hematoxylin eosin (HE), Masson, and picrosirius red staining. The level of IL-6 was measured using ELISA kit. The levels of blood urea nitrogen (BUN), creatinine (CR), UA (uric acid), and xanthine oxidase (XOD) in the serum were measured using standard diagnostic kits. The percentage of Th17 cells in blood samples was performed using flow cytometry. Moreover, RT-qPCR was performed to examine the mRNA level of RANK, RORγt, RANKL, and STAT3 in the synovial tissue. Furthermore, immunofluorescence was carried out to assess the expression of STAT3 in the synovial tissue. RESULTS: SMW effectively alleviated the inflammation and improved the pathological status of the ankle joint in rats with acute GA. It significantly suppressed the release of proinflammatory cytokine (IL-6). Meanwhile, the levels of UA, BUN, and CR were markedly reduced after SMW treatment. A remarkable reduction of XOD activity was observed in the study. Importantly, SMW treatment significantly reduced the frequency of Th17 cells, decreased the mRNA levels of RANK, RORγt, RANKL, and STAT3 in the synovial tissue. Furthermore, the suppression of STAT3 was also demonstrated using immunofluorescence in SMW-treated group. CONCLUSION: SMW showed significant anti-inflammatory and hypouricemic effects in a rat model of GA. It is an effective TCM formula for GA therapy.

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.

Efficacy of Qingpeng ointment (a Tibetan medicine) for acute gouty arthritis: a multi-center, randomized, double-blind, placebo-controlled trial.

BACKGROUND: This study aims to assess the efficacy and safety of Qingpeng ointment (QPO), a Tibetan medicine for alleviating symptoms in individuals with acute gouty arthritis (AGA). METHODS: This study was a randomized, double-blind, placebo-controlled trial that involved individuals with AGA whose joint pain, as measured on a visual analog scale (VAS) from 0 to 10, was equal to or greater than 3. The participants were randomly assigned to either the QPO or the placebo group and received their respective treatments twice daily for seven consecutive days. In case of intolerable pain, the participants were allowed to use diclofenac sodium sustained-release tablets as a rescue medicine. The primary outcomes measured were joint pain and swelling, while the secondary outcomes included joint mobility, redness, serum uric acid levels, C-reactive protein levels, and the amount of remaining rescue medicine. Any adverse events that occurred during the trial were also recorded. RESULTS: A total of 203 cases were divided into two groups, with balanced baselines: 102 in the QPO group and 101 in the placebo group. For joint pain, differences between the groups were notable in the VAS scores [1.75 (0, 3.00) versus 2.00 (1.00, 3.50); P = 0.038], changes in VAS [5.00 (3.00, 6.00) versus 4.00 (2.00, 6.00); P = 0.036], and disappearance rate [26.47% compared to 15.84%; P = 0.046] after treatment. Concerning joint swelling, significant between-group differences were observed in the VAS scores [1.00 (0, 2.30) versus 2.00 (0.70, 3.00); P = 0.032] and disappearance rate [33.33% compared to 21.78%; P = 0.046] at treatment completion. The QPO group exhibited a statistically significant mobility improvement compared to the placebo group (P = 0.004). No significant differences were found in other secondary outcomes. Five patients, four from the QPO group and one from the other, encountered mild adverse events, primarily skin irritation. All of these cases were resolved after dosage reduction or discontinuation of the medication. CONCLUSIONS: Compared to the placebo, QPO exhibits positive effects on AGA by alleviating pain, reducing swelling, and enhancing joint mobility, without causing significant adverse effects. TRIAL REGISTRATION: ISRCTN34355813. Registered on 25/01/2021.

Stefin B alleviates the gouty arthritis in mice by inducing the M2 polarization of macrophages.

The present study aims to explore the therapeutic effect of Stefin B on gouty arthritis (GA) and the polarization of macrophages in mice. Stefin B-overexpressed or knockdown M0 macrophages were constructed. The GA model was established in mice by injecting 25 mg/mL MSU, followed by a single injecting of Stefin B-overexpressing adenovirus vector (GA model + Stefin B OE) or an empty vector (GA model + Stefin B OE NC). Stefin B was found lowly expressed in M1 macrophages. CD206 was markedly upregulated and IL-10 release was signally increased in Stefin B-overexpressed macrophages. In gouty arthritis mice, marked redness and swelling were observed in the ankle joint. Dramatical infiltration of inflammatory cells was observed in the GA model and GA model + Stefin B OE NC groups, which was suppressed in the Stefin B OE group. Increased proportion of F4/80+CD86+ cells observed in GA mice was markedly repressed by Stefin B overexpression, accompanied by the declined level of Caspase-1 and IL-17. Collectively, Stefin B alleviated the GA in mice by inducing the M2 polarization of macrophages.

Effect and mechanism of aqueous extract of Chinese herbal prescription (TFK) in treating gout arthritis.

ETHNOPHARMACOLOGICAL RELEVANCE: With the rapid development of China's economic level, great changes have taken place in people's diet structure, gout has become a common disease that puzzles people's health, seriously affects the realization of China's "Healthy China" strategic goal. Gouty arthritis (GA) is a common joint disease caused by chronic purine metabolism disorder. Currently, drugs used to treat GA are allopurinol and colchicine. However, these drugs can only temporarily relieve the clinical symptoms of GA with significant side effects. More and more basic and clinical studies have confirmed that Traditional Chinese medicine has definite curative effect on GA. AIM OF THE STUDY: To elucidate the potential molecular mechanism of Tongfengkang (TFK) in the treatment of GA, and to provide experimental basis for the search and development of efficient and low-toxicity Chinese medicine for GA treatment. MATERIALS AND METHODS: Aqueous extract of TFK (AETFK) were determined by liquid phase high resolution mass spectrometry and the possible effective constituents were screened out. Acute GA model rats were established to detect the anti-inflammatory and detumification effects of AETFK on GA and explore the potential mechanism. The effect of AETFK on serum uric acid and urinary uric acid levels in acute GA rats was determined by automatic biochemical analyzer, and the effect of AETFK on the expression of acute GA-related immunoinflammatory factors were determined by protein thermal fluorescence chip. The effect of AETFK on the concentration of neutrophils in the joint fluid of acute GA rats were determined by Reichs-Giemsa staining. The effect of AETFK on macrophage activation was detected by ELISA. In order to further investigate the mechanism of AETFK in the treatment of GA, a rat model of hyperuricemia was established to detect the effect of AETFK on the level of uric acid in hyperuricemia model rats. Biochemical indexes of liver and kidney and hematoxylin-eosin staining (HE) were used to evaluate the effects of AETFK on the organs, and to preliminatively evaluate the safety of ventilation confufang. RESULTS: Compared with the model group, the joint swelling degree of GA rats in AETFK treatment group were significantly reduced, and the levels of blood uric acid and urine uric acid were also significantly decreased. Protein thermal fluorescence microarray results showed that the levels of gout - related inflammatory factors in GA rats in AETFK treatment group were significantly lower than those in control group. Reichsen-giemsa staining and ELISA showed that AETFK could reduce the activation of macrophages and the accumulation of neutrophils in the joint fluid. The results of liver and kidney biochemical indexes and HE staining showed that no obvious tissue damage was observed in the organs of rats treated with AETFK. CONCLUSIONS: AETFK not only has significant anti-inflammatory effects on GA, but also can significantly reduce the level of blood uric acid in GA rats, without obvious toxic and side effects. These effects may be related to AETFK's inhibition of neutrophil enrichment and macrophage activation during early inflammation.