Symbiotic Antidiabetic Effect of Lactobacillus casei and the Bioactive Extract of Cleome droserifolia (Forssk.) Del. on Mice with Type 2 Diabetes Induced by Alloxan.

The consumption of probiotics protects pancreatic ß-cells from oxidative damage, delaying the onset of type 2 diabetes mellitus (T2DM) and preventing microvascular and macrovascular complications. This study aimed to evaluate the antidiabetic activity of CDE fermented by Lactobacillus casei (ATCC 39539) (LC) in alloxan-induced diabetic rats. The oxidative stress identified by catalase (CAT), serum AST, ALT, ALP, creatinine, urea, and uric acid were measured. The chemical profiles of the plant extract and the fermented extract were studied using HPLC/MS. The potential of the compounds towards the binding pockets of aldose reductase and PPAR was discovered by molecular docking. A significant reduction in fasting blood glucose in alloxan-treated rats. The CAT showed a significant decrease in diabetic rats. Also, serum AST, ALT, ALP, creatinine, urea, and uric acid were significantly decreased in the mixture group. Mild histological changes of pancreatic and kidney tissues suggested that the mixture of probiotics and cleome possesses a marked anti-diabetic effect. Overall, the study suggests that the combination of Cleome droserifolia fermented by Lactobacillus casei exhibits significant antidiabetic activity (p-value=0.05), reduces oxidative stress, improves lipid profiles, and shows potential for the treatment of diabetes.

Pre-treatment risk factors to predict early cisplatin-related nephrotoxicity in locally advanced head and neck cancer patients treated with chemoradiation: A single Institution experience.

OBJECTIVES: Cisplatin is essential in the curative treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC) patients. The assessment of risk factors to predict an early cisplatin-induced nephrotoxicity could help in better managing one of the most relevant cisplatin-related dose-limiting factors. MATERIAL AND METHODS: We retrospectively collected data of LA-HNSCC patients treated at our Institution from 2008 to 2019. Patients received cisplatin in a curative setting concurrently with radiation. Acute Kidney Injury (AKI) was assessed as a dichotomous variable (CreaIncr) based on pre-treatment values, and values recorded at days 6-20 post-first cycle of cisplatin. Univariable logistic regression models were performed to investigate associations between CreaIncr and clinical characteristics. A multivariable logistic model on a priori selected putative covariates was performed. RESULTS: Of the 350 LA-HNSCC treated patients, 204 were analyzed. Ninety (44 %) suffered from any grade AKI (grade I 51.1 %): out of them, 84.4 % received high-dose cisplatin (100 mg/m2 q21). On the univariable logistic regression model, male sex, age, serum uric acid, creatinine, concomitant drugs, and cisplatin schedule were significantly associated with a higher rate of AKI. At multivariable model, age (p = 0.034), baseline creatinine (p = 0.027), concomitant drugs (p = 0.043), and cisplatin schedule (one-day bolus or fractionated high-dose vs. weekly; p = 0.001) maintained their significant association. CONCLUSIONS: Identifying pre-treatment risk factors in LA-HNSCC patients may improve decision-making in a setting where cisplatin has a curative significance. A strict monitoring of AKI could avoid cisplatin dose adjustments, interruptions, and treatment delays, thus limiting a negative impact on outcomes.

Lactobacillus plantarum LLY-606 supplementation ameliorates hyperuricemia via modulating intestinal homeostasis and relieving inflammation.

Gut microbiota is associated with hyperuricemia progression and can be regulated by Lactobacillus plantarum. However, the role of Lactobacillus plantarum in hyperuricemia is still unknown. Thus, we constructed the mouse model of hyperuricemia using potassium oxonate and hypoxanthine treatment to explore the effects of Lactobacillus plantarum LLY-606 supplementation on the development of hyperuricemia. The results showed that Lactobacillus plantarum LLY-606 significantly reduced the level of serum uric acid through inhibiting uric acid secretion and regulating uric acid transport. We also found that Lactobacillus plantarum LLY-606 supplementation inhibited the inflammatory response and the activation of the TLR4/MyD88/NF-κB signaling pathway in mice. Microbiome sequencing and analysis suggested the successful colonization of probiotics, which could regulate intestinal flora dysbiosis induced by hyperuricemia. The abundance of Lactobacillus plantarum was significantly negatively correlated with hyperuricemia-related indicators. Notably, the functional abundance prediction of microbiota indicated that lipopolysaccharide biosynthesis protein pathways and lipopolysaccharide biosynthesis pathways were inhibited after the probiotic intervention. In conclusion, Lactobacillus plantarum LLY-606 can serve as a potential functional probiotic to affect the development of hyperuricemia through modulating gut microbiota, downregulating renal inflammation, and regulating uric acid metabolism.

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.

Pectic polysaccharides from Aconitum carmichaelii leaves protects against DSS-induced ulcerative colitis in mice through modulations of metabolism and microbiota composition.

The industrial processing of Aconitum carmichaelii roots for use in Traditional Chinese Medicine generates a high amount of waste material, especially leaves. An acidic polysaccharide fraction isolated from these unutilized leaves, AL-I, was in our previous work shown to contain pectic polysaccharides. This study aimed to investigate the protective effect of AL-I on ulcerative colitis for the possible application of A. carmichaelii leaves in the treatment of intestinal inflammatory diseases. AL-I was found to alleviate symptoms and colonic pathological injury in colitis mice, and ameliorate the levels of inflammatory indices in serum and colon. The production of short- and branched-chain fatty acids was also restored by AL-I. The observed protective effect could be due to the inhibition of NOD1 and TLR4 activation, the promotion of gene transcription of tight-junction proteins, and the modulation of gut microbiota composition like Bacteroides, Dubosiella, Alistipes and Prevotella,. A regulation of serum metabolomic profiles being relevant to the bacterial change, such as D-mannose 6-phosphate, D-erythrose 4-phosphate and uric acid, was also observed.

Berberine Attenuates Hyperuricemia by Regulating Urate Transporters and Gut Microbiota.

Hyperuricemia (HUA) and its associated metabolic diseases seriously threaten human health, and commensal microbiota has been identified as one of the environmental triggers of HUA. The role of berberine (BBR) in the treatment of HUA has begun to receive attention in recent years. However, how BBR modulates the microbiota to slow HUA progression is unclear. In this study, we showed that BBR alleviated potassium oxonate (PO)-induced HUA in mice by suppressing the expression of xanthine oxidase (XOD) in the liver and urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in the kidney. The BBR also improved renal inflammation by inhibiting the expression of TNF-[Formula: see text], IL-1[Formula: see text], and caspase-1. Subsequently, we evaluated whether the observed anti-HUA effects of BBR were associated with changes in gut microbial structure in mice. 16S rRNA sequencing data showed that BBR significantly altered the community compositional structure of the gut microbiota. Specifically, BBR enriched the abundance of Coprococcus, Bacteroides, Akkermansia, and Prevotella. Antibiotic treatment can reverse the anti-HUA effects of BBR that further supports the role of the gut microbiota. In conclusion, our study provides evidence that BBR ameliorates PO-induced HUA by modulating the gut microbiota.

Protective effects of corni fructus extract in mice with potassium oxonate-induced hyperuricemia.

Corni fructus is consumed as food and herbal medicine in Chinese culture. Studies have revealed that corni fructus exhibits potent antioxidant activity; however, few studies have investigated the ability of corni fructus to lower uric acid concentrations. In this study, the xanthine oxidase (XO) inhibition and uric acid-lowering effect of corni fructus extract (CFE) were evaluated in mice with potassium oxonate-induced hyperuricemia. Hyperuricemia is a chronic disease prevalent worldwide and is associated with high recurrence rates. In addition, drugs used to treat hyperuricemia induce side effects that discourage patient compliance. Hyperuricemia induces metabolic imbalances resulting in accumulative uric acid deposition in the joints and soft tissues. Hyperuricemia not only induces gout but also interrupts hepatic and renal function, thereby trigging severe inflammation and various complications, including obesity, nonalcoholic fatty liver disease, diabetes, and metabolic diseases. In this study, the ethyl acetate fraction (EAF) of CFE resulted in yields of antioxidant photochemical components significantly higher than those of CFEs formed using other substances. The EAF of CFE exhibited high free radical scavenging activity and XO inhibition and effectively lowered uric acid concentrations in the animal model of chemically induced hyperuricemia. The results of this study can serve as a reference for the prevention of preclinical gout as well as for functional food research.

Research on the effect and underlying molecular mechanism of Cangzhu in the treatment of gouty arthritis.

OBJECTIVE: We aimed to identify the active ingredients and elucidate the underlying mechanism of action of Atractylodes lancea (Thunb.) DC (namely, Cangzhu) for the treatment of gouty arthritis (GA) based on network pharmacology methods. These findings are expected to provide a theoretical basis for the clinical treatment of GA. METHODS: We used monosodium urate (MSU)-induced GA rats as a model to test the overall efficacy of Cangzhu in vivo. Then, the components of the Cangzhu decoction were analyzed and identified, and we screened the active ingredients and their targets. The GA disease targets were predicted by GeneCards and Disgenet databases and found to overlap in both databases. The STRING database was used to construct a protein-protein interaction network, followed by identification of the hub genes using Network Analyzer. Thereafter, Cytoscape software (version 3.8.2) was applied to construct a network for drug-active ingredient-key targets. Next, we applied cluego, a plug-in of Cytoscape, to perform gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) signal pathway enrichment analyses. Additionally, molecular docking was used to verify the characteristics of the key candidate components interacting with the hub therapeutic targets. Finally, we established an inflammatory injury model of LPS using RAW264.7 macrophages and used it to experimentally validate the critical active ingredients. RESULTS: Cangzhu effectively protected against gouty arthritis in vivo, and network pharmacology results revealed various active ingredients in Cangzhu, such as wogonin, atractylenolide I and atractylenolide II. These compounds were found to act on 16 hub targets, including tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), interleukin-1ß (IL-1ß), prostaglandin-endoperoxide synthase 2 (PTGS2), recombinant mitogen-activated protein kinase 14 (MAPK14) and transcription factor p65 (RELA), which have significant effects on regulating inflammatory factors and apoptosis-related pathways to improve the proinflammatory or anti-inflammatory imbalance in the body, and this may be one of the underlying mechanisms of Cangzhu in anti-GA. CONCLUSION: Our findings revealed that Cangzhu comprises multiple active components that exert various targeted effects during GA treatment. These findings provide relevant insights to illuminate the mechanism of Cangzhu in the treatment of GA and provide a reference for further experimental research.

Effects of Salvia miltiorrhiza Bunge extract and its single components on monosodium urate-induced pain in vivo and lipopolysaccharide-induced inflammation in vitro.

OBJECTIVE: To investigate the possible antinociceptive effects of Salvia (S.) miltiorrhiza Bunge and its single components in monosodium urate (MSU)-induced pain model in mice and lipopolysaccharide (LPS)-induced inflammation model in RAW264.7 cells. METHODS: Pretreatment of S. miltiorrhiza Bunge extract (from 1 to 50 µg/mL) concentration-dependently attenuated LPS-induced nitric oxide (NO) release. The extract of S. miltiorrhiza Bunge (50 or 100 mg/kg) also caused reversals of decreased threshold for pain in the MSU-treated group as measured by Von-Frey test. Furthermore, we assessed the antinociceptive and anti-inflammatory properties of the active single components from S. miltiorrhiza Bunge such as 15, 16-dihydrotanshinone Ⅰ tanshinone Ⅱ cryptotanshinone, miltirone, tanshinone ⅡA, and salvianolic acid B. Some of them showed an anti-inflammatory effect in LPS-induced NO release model and an antinociceptive effect in MSU-treated pain model. RESULTS: Our results suggest that S. miltiorrhiza Bunge extract may exert anti-inflammatory effect by reducing LPS-induced NO release and an antinociceptive property in MSU-treated pain model. Especially, tanshinoneⅡA, miltirone, cryptotanshinone, and 15,16-dihydrotanshinone Ⅰ not only appear to be responsible for LPS-induced NO release induced by S. miltiorrhiza Bunge, but also in the production of S. miltiorrhiza Bunge extract-induced antinociception in MSU-treated pain model. CONCLUSION: Therefore, the analgesic and anti-inflammatory property of S. miltiorrhiza Bunge indicate it as a therapeutic potential candidate for the treatment of pain and inflammation.

Preventive effect of dioscin against monosodium urate-mediated gouty arthritis through inhibiting inflammasome NLRP3 and TLR4/NF-κB signaling pathway activation: an in vivo and in vitro study.

Monosodium urate (MSU)-mediated inflammation is closely related to gouty arthritis (GA). Dioscin, an active ingredient, has been reported to possess anti-inflammatory property. Nevertheless, the role of dioscin in GA and the underlying mechanism have not been fully understood. In the present study, we investigated the anti-inflammatory effect of dioscin on MSU-induced GA through in vivo and in vitro experiments. Histopathological analysis showed that dioscin alleviated the severity of GA concomitant with the lowered uric acid and creatinine levels. Moreover, the increasing IL-1ß, IL-6, and TNF-α levels induced by MSU were decreased via administration of dioscin in mice and human synoviocytes. Western blotting results suggested that dioscin inhibited the activation of NLRP3 through down-regulating the protein expressions of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), cleaved-caspase-1, as well as IL-1ß. In addition, TLR4, myeloid differentiation primary response gene 88 (MyD88), p-IKKß, p-p65, and NF-κB p65 in nuclei levels were significantly reduced by dioscin. Importantly, dioscin remarkably lowered the NF-κB p65-DNA activity in MSU-treated mice utilizing electrophoretic mobility shift assay (EMSA) analysis. Taken together, dioscin had a protective effect against MSU-initiated inflammatory response via repressing the production of inflammatory cytokines and the activation of inflammasome NLRP3 and TLR4/NF-κB signaling pathway. The above findings revealed that dioscin could be a potential drug for the treatment of GA.

Efficacy of Xixiancao (Herba Siegesbeckiae Orientalis) on interactions between nuclear factor kappa-B and inflammatory cytokines in inflammatory reactions of rat synovial cells induced by sodium urate.

OBJECTIVE: To investigate the interaction between nuclear factor kappa-B (NF-κB) and inflammatory cytokines in synovial cell inflammatory responses induced by sodium urate, and to evaluate the efficacy of Xixiancao (Herba Siegesbeckiae Orientalis) on these interactions. METHODS: The interactions between NF-κB and inflammatory cytokines/mediators in synovial cells in acute gouty arthritis were investigated. We observed the expressions of NF-κB, interleukin (IL)-1ß, IL-8, and tumor necrosis factor alpha (TNF-α) in synovial cells at different timepoints in an in vitro model of synovial cell inflammatory responses induced by sodium urate and in an in vivo model of gouty arthritis. Changes in the expressions of NF-κB, IL-1ß, IL-8, and TNF- in synovial cells of all experimental groups were compared and observed after treatment with different doses of Xixiancao (Herba Siegesbeckiae Orientalis) and colchicine. The interactions between NF-κB and IL-1ß, IL-8, and TNF-α were analyzed. Pathological changes in synovial tissues were observed in rats with acute gouty arthritis. RESULTS: Compared with the blank group, the expression levels of NF-κB, IL-1ß, IL-8, and TNF-α were increased significantly at different timepoints in the in vitro model of synovial cell inflammatory responses induced by sodium urate, and in the in vivo model of gouty arthritis. Compared with the model group, the expressions of NF-κB, IL-1ß, IL-8, and TNF-α in synovial cells induced by sodium urate were decreased in the different Xixiancao (Herba Siegesbeckiae Orientalis) dose groups and the colchicine group. The effect was more obvious in the high dose Xixiancao (Herba Siegesbeckiae Orientalis) group. The expression of NF-κB in synovial cells was positively correlated with the expressions of IL-1ß, IL-8, and TNF-. Histopathological examination of synovial tissues in the high dose Xixiancao (Herba Siegesbeckiae Orientalis) group and Colchicine group showed that the characteristics of acute gouty arthritis were reduced, and there was a trend towards a positive correlation between NF-κB and inflammatory cytokine expressions. CONCLUSION: The activation of NF-κB is associated with the activation of IL-1ß, IL-8, and TNF-α during the pathogenesis of acute gouty arthritis, leading to the continuation and enhancement of the inflammatory response. Expressions of IL-1ß, IL-8, and TNF-α in synoviocytes during acute gouty arthritis effectively inhibit local inflammation.

Total saponin of Dioscorea collettii attenuates MSU crystal­induced inflammation via inhibiting the activation of the NALP3 inflammasome and caspase­1 in THP­1 macrophages.

Total saponins extracted from Dioscorea collettii (TSD), extracts of the Chinese herb Dioscorea, are thought to exhibit therapeutic benefit in gouty arthritis. However, its exact mechanism remains unclear. The current study aimed to elucidate the underlying mechanisms by investigating the effects of TSD on the inflammation induced by monosodium urate (MSU) crystals in THP­1 macrophages. The viability of THP­1 macrophages was examined using the MTT assay and the levels of inflammatory cytokines, including interleukin (IL)­1ß, IL­18 and tumor necrosis factor (TNF)­α, released by the cells were quantitatively measured using ELISA kits. The results revealed that the protein level of cluster of differentiation 11b increased in THP­1 cells treated with 100 ng/ml phorbol ester, suggesting that monocytic THP­1 cells were successfully differentiated into macrophages. TSD decreased the levels of inflammatory cytokines, including TNF­α, IL­18 and IL­1ß, secreted by THP­1 macrophages. As the release of IL­1ß and IL­18 is dependent on the NLR family pyrin domain containing 3 (NALP3) inflammasome and caspase­1, the current study investigated the effect of TSD on the aforementioned proteins. The results revealed that TSD decreased the protein levels of NALP3 and apoptosis­associated speck­like, which serve important roles in the assembly of the NALP3 inflammasome. Furthermore, NALP3 inflammasome­related proteins were also decreased by TSD in rotenone induced THP­1 macrophages, TSD inhibited the activation of caspase­1 and rotenone­induced NALP3 inflammasome activation in THP­1 macrophages. The results obtained in the current study revealed that TSD attenuated MSU crystal­induced inflammation by inhibiting rotenone­induced activation of the NALP3 inflammasome and caspase­1, suggesting that these two proteins may be novel targets for the treatment of gouty arthritis.

[Gout]. / La maladie goutteuse.

Gout is a chronic disease due to the deposition of monosodium urate microcrystals in joints and tissues. Its incidence and prevalence are increasing worldwide in close relation with the epidemic of obesity and metabolic syndrome. Gout is related to chronic hyperuricemia that should be treated to ensure the reduction or even the disappearance of acute attacks ("gout flares") and to reduce the size and number of tophi. If arthritis of the first metatarsophalangeal joint is the most typical form, other joints may be affected, including the spine. Demonstration of urate microcrystals arthritis allows diagnosis of gout but, in the absence of possibility of performing joint puncture, imaging may be useful for providing complementary diagnostic elements. Appropriate care is essential to reduce the number of flares and the evolution towards gouty arthropathy but also in terms of public health in order to reduce costs related to this pathology.

Safety of Short-Term Supplementation with Methylliberine (Dynamine®) Alone and in Combination with TeaCrine® in Young Adults.

Methylliberine (Dynamine®; DYM) and theacrine (Teacrine®; TCR) are purine alkaloids purported to have similar neuro-energetic effects as caffeine. There are no published human safety data on DYM, and research on TCR is limited. The purpose of this study was to examine the effect of four weeks of DYM supplementation with and without TCR on cardiovascular function and blood biomarkers. One-hundred twenty-five men and women (mean age 23.0 yrs, height 169.7 cm, body mass 72.1 kg; n = 25/group) were randomly assigned to one of five groups: low-dose DYM (100 mg), high-dose DYM (150 mg), low-dose DYM with TCR (100 mg + 50 mg), high-dose DYM with TCR (150 mg + 25 mg) , and placebo. Regardless of group and sex, significant main effects for time were noted for heart rate, systolic blood pressure, and QTc (p < 0.001), high-density lipoproteins (p = 0.002), mean corpuscular hemoglobin (p = 0.018), basophils (p = 0.006), absolute eosinophils (p = 0.010), creatinine (p = 0.004), estimated glomerular filtration rate (p = 0.037), chloride (p = 0.030), carbon dioxide (p = 0.023), bilirubin (p = 0.027), and alanine aminotransferase (p = 0.043), among others. While small changes were found in some cardiovascular and blood biomarkers, no clinically significant changes occurred. This suggests that DYM alone or in combination with TCR consumed at the dosages used in this study does not appear to negatively affect markers of health over four weeks of continuous use.

A mouse model of MSU-induced acute inflammation in vivo suggests imiquimod-dependent targeting of Il-1ß as relevant therapy for gout patients.

Rationale: The role of Monosodium Urate (MSU) crystals in gout pathophysiology is well described, as is the major impact of IL-1ß in the inflammatory reaction that constitutes the hallmark of the disease. However, despite the discovery of the NLRP3 inflammasome and its role as a Pattern Recognition Receptor linking the detection of a danger signal (MSU) to IL-1ß secretion in vitro, the precise mechanisms leading to joint inflammation in gout patients are still poorly understood. Methods: Acute urate crystal inflammation was obtained by subcutaneous injections of MSU crystals in mice. Symptoms were followed by scoring, cytokine quantification by ELISA and western blot, gene expression by RT-qPCR and RNAseq; Magnetic Resonance Imaging was also used to assess inflammation. Results: We provide an extensive clinical, biological and molecular characterization of an acute uratic inflammation mouse model which accurately mimics human gout. We report the efficacy of topical imiquimod treatment and its impact on Interferon-dependent down modulation of Il-1ß gene expression in this experimental model. Conclusion: Our work reveals several key features of MSU-dependent inflammation and identifies novel therapeutic opportunities for gout patients.

Maternal hyperuricemia as a marker of post-spinal hypotension and uterine tone during cesarean delivery: a prospective observational study.

PURPOSE: Raised serum uric acid, a marker of oxidative stress, is known to increase vascular tone and depress myometrial contractility. A rise in serum uric acid levels has also been reported during labor, warranting its correlation with post-spinal hypotension and uterine tone. METHODS: Serum UA sample was drawn from enrolled healthy, laboring parturients. Of these, 100 women who required emergency cesarean delivery were re-sampled prior to surgery. Following spinal anesthesia we recorded episodes of hypotension (MAP < 80% of baseline), use of vasopressors and supplemental uterotonics. The primary outcome was maternal hyperuricemia (1SD > appropriate for gestation age) and its correlation with post-spinal hypotension. Secondary outcomes were total vasopressors used, duration of labor and its effect on uric acid levels, uterine tone and neonatal outcome. RESULTS: Hyperuricemia was observed in 33% of parturients. On comparing with women showing normal uric acid levels, hyperuricemic parturients experienced significantly lower incidence of post-spinal hypotension (45.5% vs. 67.2%; p value = 0.04) and lower vasopressor usage (p value = 0.06). Clinically, an increased use of supplemental uterotonics in these parturients was noted (p = 0.20). The duration of labor had no impact on uric acid levels. Neonatal outcome was unaffected. CONCLUSIONS: In healthy, normotensive parturients undergoing emergency cesarean delivery, maternal hyperuricemia is associated with lower incidence of post-spinal hypotension and reduced need of vasopressors. Elevated serum uric acid levels may also be associated with decreased uterine tone, necessitating greater requirement of supplemental uterotonics. However, further prospective trials are needed to strongly establish this association.

Protective effects of Rhizoma smilacis glabrae extracts on potassium oxonate- and monosodium urate-induced hyperuricemia and gout in mice.

BACKGROUND: Rhizoma smilacis glabrae (RSG, tufuling) has been widely used in traditional Chinese medicine for deoxidation, dampness relief, and easing joint movement. The chemical composition of RSG has been systematically confirmed, and some of its compounds have been revealed to possess antioxidant, anti-inflammatory, immunomodulatory, hypouricemic, and hepatoprotective effects. PURPOSE: We aimed to clarify whether a RSG extract attenuates hyperuricemia, paw edema, and renal injury in mice with potassium oxonate (PO)- and monosodium urate (MSU)-induced chronic hyperuricemia and gout. METHODS: RSG water extract was obtained and analyzed by HPLC-DAD-MS/MS. To establish a murine model with chronic hyperuricemia and gout, PO was orally administered daily from day 0 to day 24, whereas MSU was injected into the tibiotarsal joint on day 21. The mice in the drug intervention groups were treated once daily with doses of allopurinol or RSG extract from day 21 to day 24. The diameter of the ankle joints was measured with calipers. Serum TNF-α and IL-1ß concentrations, hepatic XOD activity, and uric acid, creatinine, and blood urea nitrogen (BUN) levels were also determined. The right kidney and articular cavities were fixed, cut into sections, and stained with hematoxylin and eosin. RESULTS: Nine compounds in the RSG water extract were unambiguously identified as 5-O-caffeoylshikimic acid, neoastilbin, astilbin, taxifolin, neoisoastilbin, isoastilbin, engeletin, isoengeletin, and trans-resveratrol. The RSGE treatment dose-dependently reduced PO- and MSU-induced paw edema, serum TNF-α, IL-1ß, IL-6, IL-12, uric acid, and BUN, while significantly elevated serum IL-10, urinary uric acid and creatinine levels as compared with the respective values in the hyperuricemic and gouty mice group (vehicle group). Moreover, the hepatic XOD activity was dose-dependently reduced by the RSGE treatment. In addition, RSGE treatment not only ameliorated the infiltration of inflammatory cells, tubular dilation and vacuole formation in renal tubular, but also improved the synovial hyperplasia, reduced inflammatory cells infiltration into the synovium, and diminished the erosive damage in the cartilage. CONCLUSION: The murine model with chronic hyperuricemia and gout be built in present study is consistent with the clinical symptoms of patients with long-standing hyperuricemia and acute gouty arthritis. RSG water extract has potent efficacy in ameliorating murine hyperuricemia and gout induced by PO and MSU.

Rhein, An Anthraquinone Drug, Suppresses the NLRP3 Inflammasome and Macrophage Activation in Urate Crystal-Induced Gouty Inflammation.

Rhein, an anthraquinone drug, is a widely used traditional Chinese medicine. Rhein is a major bioactive metabolite of diacerein which has been approved for treating osteoarthritis with a good safety profile in humans. Gouty arthritis is an inflammatory disease characterized by urate crystal-induced NLRP3 inflammasome activation with up-regulated caspase-1 protease and IL-1 ß in macrophages. Inhibition of the NLRP3 inflammasome formation has been considered as a potential therapeutic avenue for treating or preventing many inflammatory diseases. This study aimed to evaluate the anti-inflammatory effects of rhein on gouty arthritis. Rhein within the physiological levels of humans showed no toxicity on the cell viability and differentiation, but significantly decreased the production of IL-1 ß , TNF- α and caspase-1 protease in urate crystal-activated macrophages. Compared to medium controls, rhein at the therapeutic concentration (2.5 µ g/mL) effectively inhibited IL-1 ß production by 47% ( P=0.002 ). Rhein did not affect the mRNA levels of CASP1, NLRP3 and ASC, but suppressed the protein expression and enzyme activity of caspase-1. Immunofluorescence confocal microscopy further revealed that rhein suppressed the aggregation of ASC speck and inhibited the formation of NLRP3 inflammasome. Rhein of 5 µ g/mL significantly decreased the ASC speck to 36% ( P=0.0011 ), and reduced the NLRP3 aggregates to 37.5% ( P=0.014 ). Our data demonstrate that rhein possesses pharmacological activity to suppress caspase-1 protease activity and IL-1 ß production by interfering with the formation of NLRP3 multiprotein complex. These results suggest that rhein has therapeutic potential for treating NLRP3 inflammasome-mediated diseases such as gouty arthritis.

Disease-Associated Particulates and Joint Inflammation; Mechanistic Insights and Potential Therapeutic Targets.

It is now well established that intra-articular deposition of endogenous particulates, such as osteoarthritis-associated basic calcium phosphate crystals, gout-associated monosodium urate crystals, and calcium deposition disease-associated calcium pyrophosphate crystals, contributes to joint destruction through the production of cartilage-degrading enzymes and pro-inflammatory cytokines. Furthermore, exogenous wear-debris particles, generated from prosthetic implants, drive periprosthetic osteolysis which impacts on the longevity of total joint replacements. Over the last few years, significant insight has been gained into the mechanisms through which these particulates exert their effects. Not only has this increased our understanding of the pathological processes associated with crystal deposition but it has also led to the identification of a number of therapeutic targets to treat particulate-associated disease. In this review, we discuss recent developments regarding the cellular events triggered by joint-associated particulates, as well as future directions in therapy for particulate-related arthropathies.

Eucalyptus globulus Inhibits Inflammasome-Activated Pro-Inflammatory Responses and Ameliorate Monosodium Urate-Induced Peritonitis in Murine Experimental Model.

Eucalyptus globulus Labill. (E. globulus, Myrtaceae) is used in Europe as a traditional folk remedy for inflammation-related disorders such as arthritis, diabetes, asthma, and gout. We investigated this study to evaluate the protective effects of E. globulus extract (EG) on inflammatory responses, and provide scientific and mechanistic evidence in in vitro and in vivo experimental models. LPS-stimulated murine bone marrow-derived macrophages (BMDMs) were used to study the regulatory effect of EG on inflammasome activation in vitro. Monosodium urate (MSU)-induced peritonitis was used to study the effect of EG in an in vivo murine model. EG suppressed IL-[Formula: see text] secretion via the regulation of apoptosis-associated speck-like proteins containing a CARD (ASC) oligomerization and caspase-1 maturation, leading to the inhibition of inflammasome activation. In the in vivo study, EG suppressed the MSU-induced peritonitis by attenuating interleukin (IL)-1[Formula: see text], providing scientific support for its traditional use in the treatment of inflammation-related disorders.