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 (HUA), 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 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 NOD-like receptor thermoprotein domain associated protein 3 (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 (TCM), additional research is required to unravel the underlying mechanisms and molecular targets through which THMs alleviate AGA.

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.

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; 22(3): 270-278.

[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.

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.

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.

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.

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.

Mechanism of DaiTongXiao in the treatment of gouty arthritis through the NLRP3 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: DaiTongXiao (DTX) is a traditional Chinese Dai folk formulation utilized for gouty arthritis treatment, with substantial evidence supporting its anti-inflammatory properties. The NLRP3 inflammasome disorder is tightly linked to the development of many inflammatory diseases. AIM OF THE STUDY: To elucidate the therapeutic efficacy of DTX in gouty arthritis and reveal its potential underlying mechanism. MATERIALS AND METHODS: The primary active constituents in DTX were determined through ultraviolet spectrophotometry and gas chromatography. Rats underwent induction with monosodium urate (MSU), followed by treatment of J774A.1 cells with adenosine triphosphate (ATP) activation and lipopolysaccharide (LPS) induction and the subsequent culture in Dulbecco's modified Eagle's medium. The degree of foot joint swelling in rats was assessed, and ankle joints were evaluated through H&E staining. Enzyme-linked immunosorbent assay was performed to measure the levels of interleukin (IL)-1ß, IL-6, IL-8, and tumor necrosis factor (TNF)-α in both serum and cells. Reverse transcription-polymerase chain reaction (RT-PCR) was performed to determine the relative mRNA expression levels of NLRP3, ASC, Caspase-1, and NF-κB in J774A.1 macrophages. The expression of NLRP3, ASC, Caspase-1, and NF-κB was examined by western blotting. RESULTS: DTX could alleviate MSU-induced joint swelling in rats, as evidenced by a reduction in joint inflammation. Moreover, DTX effectively enhanced the survival rate of J774A.1 cells following LPS induction and ATP activation. Furthermore, DTX significantly reduced IL-1ß, IL-6, IL-8, and TNF-α levels in both cell culture medium and rat serum. RT-PCR results revealed that DTX notably downregulated the mRNA expression levels of NLRP3, ASC, Caspase-1, and NF-κB in J774A.1 cells. Additionally, DTX downregulated NLRP3, ASC, NF-κB, and Caspase-1 expression in the joint tissue. CONCLUSIONS: DTX exerts a significant anti-gouty arthritis effect, with its mechanism being tightly linked to the NLRP3 inflammatory signaling pathway. This pathway may be modulated by inhibiting IL-1ß differentiation and maturation by downregulating NLRP3, ASC, Caspase-1, and NF-κB protein expression. This, in turn, leads to a reduction in the release of IL-6, IL-8, and TNF-α, ultimately impeding gouty arthritis progression.

Virtual screening combined with experimental verification reveals the potential mechanism of Fuzitang decoction against Gouty Arthritis.

Background: and Purpose: Fuzitang decoction (FZT), a classic prescription of traditional Chinese medicine (TCM), has excellent efficacy in treating gouty arthritis (GA). However, the underlying molecular mechanism remains obscure. In the present study, we aimed to explore the underlying mechanisms of FZT in treating GA by virtual screening combined with experimental verification. Methods: In this study, the active components of FZT and their corresponding targets were screened from the TCMSP database and TargetNet database. Then, the potential targets of FZT against GA were retrieved from multiple databases to generate a network. Protein-protein interaction, herbal-component-target, Gene Ontology (GO) enrichment, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were applied to identify potential targets and related signaling pathways. Furthermore, molecular docking simulation was applied to identify the interactions between the drug and targets. Finally, in vitro experiments were conducted to validate the potential targets and signaling pathways. Results: In the present study, several crucial components, including kaempferol, luteolin, catechin, deoxyandrographolide, and perlolyrine in FZT, were obtained through network pharmacology, and several potential targets to treat GA were developed, such as PPARG, CYP3A4, PTGS2 (known as COX2), VEGFA, and CYP1A1. Experimental validation suggested that deoxyandrographolide significantly suppressed the expression of IL-1ß, COX2, NLRP3 and IL-6 in inflammatory monocyte cells. Conclusions: Our results identified a novel anti-inflammatory compound, deoxyandrographolide, which helps to explain the potential mechanism of FZT in treating GA and provides evidence to support FZT's clinical use.

Mechanism of ShuiJingDan in Treating Acute Gouty Arthritis Flares Based on Network Pharmacology and Molecular Docking.

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-1ß (IL-1ß), 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-1ß, PTGS2, and CXCL8.

[Immediate analgesic effect of electroacupuncture combined with diclofenac sodium on acute gouty arthritis: a randomized controlled trial].

OBJECTIVE: To observe the immediate analgesic effect of electroacupuncture (EA) combined with diclofenac sodium on acute gouty arthritis (AGA). METHODS: A total of 90 patients with AGA were randomly divided into a low-dose medication (LM) group (30 cases, 1 case was eliminated, 1 case dropped off), a conventional medication (CM) group (30 cases, 1 case dropped off) and a combination of acupuncture and medication (AM) group (30 cases ). The LM group was given oral administration of 50 mg diclofenac sodium sustained-release capsule; the CM group was given oral administration of 100 mg diclofenac sodium sustained-release capsule; on the basis of the treatment of LM group, the AM group was treated with electroacupuncture at ashi points, Dadu (SP 2), Taichong (LR 3), Taibai (SP 3), Neiting (ST 44), Sanyinjiao (SP 6), Zusanli (ST 36) and Yinlingquan (SP 9) on the affected side, and Taichong (LR 3) and Zusanli (ST 36), Sanyinjiao (SP 6) and Yinlingquan (SP 9) were connected to electroacupuncture respectively, continuous wave, 2 Hz in frequency. The visual analogue scale (VAS) scores of pain before treatment and after 10 min, 2 h, 4 h and 6 h of treatment completion, joint tenderness and swelling scores before treatment and after 10 min and 6 h of treatment completion were compared, and the rate of diclofenac sodium addition within 24 h after treatment completion was recorded among the three groups. RESULTS: After 10 min of treatment completion, the scores of VAS, joint tenderness and joint swelling in the AM group were lower than those before treatment (P<0.05), and the VAS score in the AM group was lower than that in the other two groups (P<0.05). After 2, 4 and 6 h of treatment completion, the VAS scores of the three groups were lower than those before treatment (P<0.05), and the scores in the AM group were lower than those in the LM group (P<0.05). After 6 h of treatment completion, the joint tenderness scores of the three groups and the joint swelling scores of the AM group and the CM group were lower than those before treatment (P<0.05), and the joint tenderness and swelling scores of the AM group were lower than those of the LM group (P<0.05). The rate of diclofenac sodium addition was 3.3 % (1/30) and 3.4 % (1/29) in the AM group and the CM group, respectively, which were lower than 17.9% (5/28) in the LM group (P<0.05). CONCLUSION: Electroacupuncture combined with diclofenac sodium have a good immediate analgesic effect in the treatment of AGA, and have the advantages of small dosage of analgesic drugs and less adverse reactions.

Kaempferol Attenuates Gouty Arthritis by Regulating the Balance of Th17/Treg Cells and Secretion of IL-17.

Kaempferol is a common flavonoid aglycone widely found in plants. It exhibits beneficial therapeutic effects in the treatment of arthritis. However, the effects of kaempferol on gouty arthritis (GA) have not been verified. This study aimed to explore the potential mechanisms by which kaempferol regulates GA by network pharmacology and experimental validation. Potential drug targets for GA were identified with a protein-protein interaction network. Then, we performed a KEGG pathway analysis to elucidate the major pathway involved in the kaempferol-mediated treatment of GA. In addition, the molecular docking was performed. A rat model of GA was constructed to verify the results of network pharmacology analysis and investigate the mechanism of kaempferol against GA. The network pharmacology study indicated that there were 275 common targets of kaempferol and GA treatment. Kaempferol exerted therapeutic effects on GA, in part, by regulating the IL-17, AGE-RAGE, p53, TNF, and FoxO signaling pathways. Molecular docking results showed that kaempferol stably docked with the core MMP9, ALB, CASP3, TNF, VEGFA, CCL2, CXCL8, AKT1, JUN, and INS. Experimental validation suggested that kaempferol eased MSU-induced mechanical allodynia, ankle edema, and inflammation. It significantly suppressed the expression of IL-1ß, IL-6, TNF-α, and TGF-ß1 and restored Th17/Treg imbalance in MSU-induced rats and IL-6-induced PBMCs. Kaempferol also affected RORγt and Foxp3 through IL-17 pathway. The present study clarifies the mechanism of kaempferol against GA and provides evidence to support its clinical use.

In vivo anti-hyperuricemia and anti-gouty arthritis effects of the ethanol extract from Amomumvillosum Lour.

The incidence of hyperuricemia and gout has been increasing year by year, and it is showing a younger trend. However, the first-line drugs currently used for hyperuricemia and gouty arthritis have serious side effects that limit their clinical application. Amomum villosum Lour. has been widely used in China for thousands of years as a traditional medical and edible plant, and previous screening showed that the ethanol extract of Amomum villosum Lour. could effectively inhibit the activity of xanthine oxidase. Based on this discovery, this paper had achieved in-depth mechanism research. The results showed that the ethanol extract of Amomum villosum Lour. could treat hyperuricemia by reducing the production of uric acid via inhibition of xanthine oxidase and increasing the excretion of uric acid via regulation of urate transporters. Meanwhile, the extract also showed a certain protective effect on hepatic and renal damage caused by hyperuricemia. With the formation of extensive uric acid, gouty arthritis will be induced by the deposition of monosodium urate in the joint. The extract could also relieve the inflammation by reducing the expression of inflammatory cytokines. In conclusion, the extract deserves focused research and development as a potential medicine, health care product or supplemented food for the prevention and treatment of hyperuricemia and gouty arthritis.

Costunolide covalently targets NACHT domain of NLRP3 to inhibit inflammasome activation and alleviate NLRP3-driven inflammatory diseases.

The NLRP3 inflammasome's core and most specific protein, NLRP3, has a variety of functions in inflammation-driven diseases. Costunolide (COS) is the major active ingredient of the traditional Chinese medicinal herb Saussurea lappa and has anti-inflammatory activity, but the principal mechanism and molecular target of COS remain unclear. Here, we show that COS covalently binds to cysteine 598 in NACHT domain of NLRP3, altering the ATPase activity and assembly of NLRP3 inflammasome. We declare COS's great anti-inflammasome efficacy in macrophages and disease models of gouty arthritis and ulcerative colitis via inhibiting NLRP3 inflammasome activation. We also reveal that the α-methylene-γ-butyrolactone motif in sesquiterpene lactone is the certain active group in inhibiting NLRP3 activation. Taken together, NLRP3 is identified as a direct target of COS for its anti-inflammasome activity. COS, especially the α-methylene-γ-butyrolactone motif in COS structure, might be used to design and produce novel NLRP3 inhibitors as a lead compound.

Component identification of modified sanmiao pills by UPLC-Xevo G2-XS QTOF and its anti-gouty arthritis mechanism based on network pharmacology and experimental verification.

ETHNOPHARMACOLOGICAL RELEVANCE: Modified sanmiao pills (MSMP), a traditional Chinese medicine (TCM) formula, is consisted of rhizome of Smilax glabra Roxb., Cortexes of Phellodendron chinensis Schneid., rhizome of Atractylodes chinensis (DC.) Koidz., and roots of Cyathula officinalis Kuan. in a ratio of 3:3:2:1. This formula has been broadly applied to treat gouty arthritis (GA) in China. AIMS OF THE STUDY: To elaborate the pharmacodynamic material basis and pharmacological mechanism of MSMP against GA. MATERIALS AND METHODS: UPLC-Xevo G2-XS QTOF combined with UNIFI platform was applied to qualitatively assess the chemical compounds of MSMP. Network pharmacology and molecular docking were used to identify the active compounds, core targets and key pathways of MSMP against GA. The GA mice model was established by MSU suspension injecting into ankle joint. The swelling index of ankle joint, expressions of inflammatory cytokines, and histopathological changes in mice ankle joints were determined to validate the therapeutic effect of MSMP against GA. The protein expressions of TLRs/MyD88/NF-κB signaling pathway and NLRP3 inflammasome in vivo was detected by Western blotting. RESULTS: In total, 34 chemical compounds and 302 potential targets of MSMP were ascertained, of which 28 were overlapping targets pertaining to GA. 143 KEGG enrichment pathway were obtained, of which the NOD-like receptor signaling pathway, Toll-like receptor signaling pathway, and NF-κB signaling pathway were strongly associated with GA. In silico study indicated that the active compounds had excellent binding affinity to core targets. In vivo study confirmed that MSMP observably decreased swelling index and alleviated pathological damage to ankle joints in acute GA mice. Besides, MSMP significantly inhibited the secretion of inflammatory cytokines (IL-1ß, IL-6, and TNF-α) induced by MSU, as well as the expression levels of key proteins involved in TLRs/MyD88/NF-κB signaling pathway and NLRP3 inflammasome. CONCLUSION: MSMP possessed a pronounced therapeutic effect on acute GA. Results from network pharmacology and molecular docking showed that obaculactone, oxyberberine, and neoisoastilbin might treat gouty arthritis by down-regulating TLRs/MyD88/NF-κB signaling pathway and NLRP3 inflammasome.

Discovery of alantolactone as a naturally occurring NLRP3 inhibitor to alleviate NLRP3-driven inflammatory diseases in mice.

BACKGROUND AND PURPOSE: The NLR family pyrin domain-containing 3 (NLRP3) inflammasome is activated in many inflammatory conditions. So far, no low MW compounds inhibiting NLRP3 have entered clinical use. Identification of naturally occurring NLRP3 inhibitors may be beneficial to the design and development of compounds targeting NLRP3. Alantolactone is a phytochemical from a traditional Chinese medicinal plant with anti-inflammatory activity, but its precise target remains unclear. EXPERIMENTAL APPROACH: A bank of phytochemicals was screened for inhibitors of NLRP3-driven production of IL-1ß in cultures of bone-marrow-derived macrophages from female C57BL/6 mice. Models of gouty arthritis and acute lung injury in male C57BL/6J mice were used to determine the in vivo effects of the most potent compound. KEY RESULTS: Among the 150 compounds screened in vitro, alantolactone exhibited the highest inhibitory activity against LPS + ATP-induced production of IL-1ß in macrophages, suppressing IL-1ß secretion, caspase-1 activation and pyroptosis. Alantolactone directly bound to the NACHT domain of NLRP3 to inhibit activation and assembly of NLRP3 inflammasomes. Molecular simulation analysis suggested that Arg335 in NLRP3 was a critical residue for alantolactone binding, leading to suppression of NLRP3-NEK7 interaction. In vivo studies confirmed significant alleviation by alantolactone of two NLRP3-driven inflammatory conditions, acute lung injury and gouty arthritis. CONCLUSION AND IMPLICATIONS: The phytochemical alantolactone inhibited activity of NLRP3 inflammasomes by directly targeting the NACHT domain of NLRP3. Alantolactone shows great potential in the treatment of NLRP3-driven diseases and could lead to the development of novel NLRP3 inhibitors.

Relief effects of Laoshan cherry extracts as a dietary supplement against the symptoms of acute gouty arthritis in rats induced by urate crystals.

We evaluated the effects of Laoshan cherry as a food or dietary supplement on relieving the symptoms of acute gouty arthritis in rats induced by urate crystals. Rats in groups of 10 were given Laoshan cherry functional extracts at doses of 5, 10, and 20 mg/kg by oral gavage for 21 days and then injected with a sodium nitrate suspension in the rear ankle area as an induced acute gouty arthritis model. The ankle swelling and inflammations in the model (no treatment) group increased significantly compared with blank group; the ankle inflammations reduced in experimental groups receiving three different doses of the cherry extract and the joint swelling reduced in the high-dose group by 43% compared with the model group. Serum uric acid and xanthine oxidase activities were also elevated in the model group and these parameters were reduced by a maximum of 8% and 33%, respectively, in the rats receiving the cherry extracts. The serum levels of the inflammatory cytokine IL-1ß in the high-dose group decreased by 12% compared with the model group. These results demonstrated that the cherries possess a functional substance that has a significant alleviating effect on the symptoms of gouty arthritis in rats induced by sodium urate injection.

Total Saponin Fraction of Dioscorea Nipponica Makino Improves Gouty Arthritis Symptoms in Rats via M1/M2 Polarization of Monocytes and Macrophages Mediated by Arachidonic Acid Signaling.

OBJECTIVE: To explore the mechanism of effects of total saponin fraction from Dioscorea Nipponica Makino (TSDN) on M1/M2 polarization of monocytes/macrophages and arachidonic acid (AA) pathway in rats with gouty arthritis (GA). METHODS: Seventy-two Sprague Dawley rats were randomly divided into 4 groups (n=18 in each): normal, model, TSDN at 160 mg/kg, and celecoxib at 43.3 mg/kg. Monosodium urate crystal (MSU) was injected into the rats' ankle joints to induce an experimental GA model. Blood and tissue samples were collected on the 3rd, 5th, and 8th days of drug administration. Histopathological changes in the synovium of joints were observed via hematoxylin and eosin (HE) staining. The expression levels of arachidonic acid (AA) signaling pathway were assessed via real-time polymerase chain reaction (qPCR) and Western blot. Flow cytometry was used to determine the proportion of M1 and M2 macrophages in the peripheral blood. An enzyme-linked immunosorbent assay (ELISA) was used to detect interleukine (IL)-1 ß, tumor necrosis factor-alpha (TNF-α), IL-4, IL-10, prostaglandin E2 (PGE2), and leukotriene B4 (LTB4). RESULTS: HE staining showed that TSDN improved the synovial tissue. qPCR and Western blot showed that on the 3rd, 5th and 8th days of drug administration, TSDN reduced the mRNA and protein expressions of cyclooxygenase (COX)2, microsomal prostaglandin E synthase-1 derived eicosanoids (mPGES-1), 5-lipoxygenase (5-LOX), recombinant human mothers against decapentaplegic homolog 3 (Smad3), nucleotide-binding oligomerization domain-like receptor protein 3 (NALP3), and inducible nitric oxide synthase (iNOS) in rats' ankle synovial tissues (P<0.01). TSDN decreased COX1 mRNA and protein expression on 3rd and 5th day of drug administration and raised it on the 8th day (both P<0.01). It lowered CD68 protein expression on days 3 (P<0.01), as well as mRNA and protein expression on days 5 and 8 (P<0.01). On the 3rd, 5th, and 8th days of drug administration, TSDN elevated the mRNA and protein expression of Arg1 and CD163 (P<0.01). Flow cytometry results showed that TSDN decreased the percentage of M1 macrophages while increasing the percentage of M2 in peripheral blood (P<0.05 or P<0.01). ELISA results showed that on the 3rd, 5th, and 8th days of drug administration, TSDN decreased serum levels of IL-1 ß, TNF-α, and LTB4 (P<0.01), as well as PGE2 levels on days 3rd and 8th days (P<0.05 or P<0.01); on day 8 of administration, TSDN increased IL-4 serum levels and enhanced IL-10 contents on days 5 and 8 (P<0.05 or P<0.01). CONCLUSION: The anti-inflammatory effect of TSDN on rats with GA may be achieved by influencing M1/M2 polarization through AA signaling pathway.