Tetrandrine alleviates inflammation and promotes macrophage M2 polarization in gouty arthritis by NF-κB-mediated Lcp1.

Gouty arthritis (GA) is an inflammatory disease caused by the deposition of monosodium urate (MSU) crystals into joints. Tetrandrine (TET) is a bisbenzylisoquinoline alkaloid extracted from the root of Stephania tetrandra and can exert an anti-inflammatory function in different diseases. Nevertheless, the specific function of TET in GA remains unclear. We established the GA mouse model by MSU injection into joints of mice. Paw volume and gait score were detected for measuring the degree of joint swelling and the situation of joint dysfunction. Western blot were utilized to test the alterations of M1-related factors (IL-6, IL-1ß, TNF-α, IL-12, and iNOS) and M2-related factors (Mgl1, Mgl2, Pgc1-ß, Arg-1, and IL-10). The activity of NF-κB p65 in tissues was determined. The interaction of NF-κB p65 and Lcp1 was measured by ChIP and luciferase reporter assay. Lcp1 KO mice were utilized to detect the effect of Lcp1 depletion on GA process. TET treatment markedly suppressed MSU-induced joint swelling, joint dysfunction, and joint injury in GA mice. TET can also reduce inflammatory reactions in MUS-induced mice. Furthermore, we proved that TET facilitated M2 macrophage polarization and inhibited M1 macrophage polarization in GA mice. In addition, TET was found to inhibit NF-κB activity and NF-κB-mediated Lcp1 expression. Lcp1 knockdown can improve joint injury and promote M2 macrophage polarization in GA mice, while this effect was further enhanced by TET. TET alleviates inflammation and facilitates macrophage M2 polarization in GA by NF-κB-mediated Lcp1.

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.

Glycine protects against doxorubicin-induced heart toxicity in mice.

Doxorubicin (DOXO) is a well-known cancer chemotherapeutic. However, its toxic effect on the heart limits its clinical application. This study aimed to assess the effectiveness of glycine administration to counteract the DOXO-induction of cardiomyopathy in mice. Fifty male albino mice were divided into five groups (n = 10/group) as follows: control, DOXO, Gp100, Gp150, and Gp200. Histopathological examination of the heart, and biochemical examinations for heart function (creatine phosphokinase (CPK), lactate dehydrogenase (LDH), and aspartate aminotransferase (AST)), inflammation (tumor necrosis factor-alpha (TNF-α) and interleukin 10 (IL-10)), oxidative stress (malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase, nitric oxide (NO), and uric acid), kidney function (urea and creatinine), and minerals (calcium, phosphorus, sodium, and potassium) were carried out. Cardiomyopathy induced by DOXO treatment (15 mg/kg total dose) was ascertained via pathological alterations seen in heart tissue and verified biochemically via increases (P < 0.001) in CPK, LDH, AST, TNF-α, IL-10, MDA, NO, Na, and K levels along with decreases (P < 0.001) in GSH, SOD, catalase, and uric acid. Glycine co-treatment, using doses of 100, 150, and 200 mg/kg, in a dose-dependent manner, displayed ameliorated heart architecture, significantly (P < 0.001) improved biochemical heart function tests, reduced oxidative stress and inflammation, and controlled mineral levels. The positive actions of glycine in DOXO-induced cardiotoxicity amelioration via modulating oxidative stress, inflammation, and immunity are confirmed. Glycine antioxidative properties may be behind its positive outcomes. Finally, we present glycine as a worthy possible option against DOXO-induced heart damage after more validation.

Discovery and Characterization of Moracin C as an Anti-Gouty Arthritis/Hyperuricemia Candidate by Docking-Based Virtual Screening and Pharmacological Evaluation.

In the present study, a natural product database of compounds associated with herbs traditionally verified to treat gout/hyperuricemia/arthritis was constructed. 3D-shape and docking-based virtual screening was conducted. To identify potential xanthine oxidase (XOD) inhibitors in the database, eight compounds with commercial availability were identified as high 3D-shape similarity with febuxostat (1), a known XOD inhibitor. Docking was used to further predict the possible interactions between XOD and these compounds. Moracin C (2), moracin D (3), and isoformononetin (8) exhibited higher docking scores and binding energies than other compounds. In vitro, 2 inhibited XOD with an IC50 value of 0.25 ± 0.14 µM, which is similar to that of 1 (0.16 ± 0.08 µM). In a hyperuricemic mouse model, 5-20 mg/kg 2 exhibited satisfying urate-lowering and XOD inhibitory effects. Compound 2 also exhibited antiarthritis activities. In RAW264.7 cells, 2 at 1-10 µM inhibited the expression of IL-1ß and TNF-α induced by MSU. In an acute gouty arthritis model in SD rats, 5-20 mg/kg 2 significantly alleviated the toe swelling, inflammatory response, and dysfunction disorder caused by monosodium urate (MSU). Compound 2 inhibited serum IL-1ß and TNF-α cytokines as well as reduced the expression of the NLRP3/ASC/caspase-1 inflammasome in joints. In summary, 2 was an effective compound for the treatment of hyperuricemia/gouty arthritis.

Gout-induced endothelial impairment: The role of SREBP2 transactivation of YAP.

Gout is a multifaceted inflammatory disease involving vascular impairments induced by hyperuricemia. Experiments using human umbilical vein endothelial cells treated with uric acid (UA), monosodium urate (MSU), or serum from gout patients showed increased expression of pro-inflammatory genes (ie, VCAM1, ICAM1, CYR61, CCNA1, and E2F1) with attendant increase in monocyte adhesion. Mechanistically, UA- or MSU-induced SREBP2 expression and its transcriptional activity. RNA sequencing analysis and real-time PCR showed the induction of YAP signaling and pro-inflammatory pathways in HUVECs transfected with adenovirus-SREBP2. The SREBP2 knockdown by siRNA partially abolished UA- or MSU-induced YAP activity, pro-inflammatory gene expression, and monocytes adhesion. Vascular intima from transgenic mice overexpressing SREBP2 in endothelium or mice with hyperuricemia exhibited activated YAP signaling and increased expression of pro-inflammatory genes. Betulin, an SREBP pharmacological inhibitor, attenuated the UA-, MSU-, or gout serum-induced endothelial cell inflammation and dysfunction. In the human study, endothelial cell function, assessed by EndoPAT, was negatively correlated with serum UA level among gouty patients and healthy controls. Collectively, UA or MSU causes endothelial dysfunction via SREBP2 transactivation of YAP. Betulin inhibition of SREBP2 may restrain gout-induced endothelial dysfunction.

Anethole ameliorates inflammation induced by monosodium urate in an acute gouty arthritis model via inhibiting TLRs/MyD88 pathway.

OBJECTIVE: To assess the effects of anethole on monosodium urate (MSU)-induced inflammatory response, investigate its role in acute gouty arthritis (AGA), and verify its molecular mechanism. METHODS: Hematoxylin and eosin staining assay and time-dependent detection of degree of ankle swelling were performed to assess the effects of anethole on joint injury in MSU-induced AGA mice. Enzyme-linked-immunosorbent serologic assay was performed to demonstrate the production levels of inflammatory factors (interleukin 1ß [IL-1ß], interleukin 6 [IL-6], interleukin 8 [IL-8], tumor necrosis factor α [TNF-α], and monocyte chemo-attractant protein-1 [MCP-1]) in MSU-induced AGA mice. Western blot assays were used to confirm the effects of anethole on oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activity and the activation of toll-like receptors (TLRs)-myeloid differentiation factor 88 (MyD88) pathway in MSU-induced AGA mice. RESULTS: We observed that a significant joint injury occurred in MSU-induced AGA mice. Anethole could alleviate the pathological injury of the synovium in MSU-induced AGA mice and suppressed ankle swelling. In addition, we observed that anethole could inhibit MSU-induced inflammatory response and inflammasome activation in MSU-induced AGA mice. Moreover, we discovered that anethole enabled to inhibit the activation of TLRs/MyD88 pathway in MSU-induced AGA mice. Our findings further confirmed that anethole contributed to the inhibitory effects on progression in MSU-induced AGA mice. CONCLUSION: It confirmed that anethole ameliorated the MSU-induced inflammatory response in AGA mice in vivo via inhibiting TLRs-MyD88 pathway.

Relevance of Collaterals for the Success of Neuroprotective Therapies in Acute Ischemic Stroke: Insights from the Randomized URICO-ICTUS Trial.

BACKGROUND: Collateral circulation may modify the effect of neuroprotective therapies. We report a post hoc analysis of the URICO-ICTUS trial (NCT00860366) assessing the modifying treatment effect of pretreatment collaterals on clinical and radiological outcomes in patients with large-vessel acute ischemic stroke receiving uric acid therapy or placebo. METHODS: URICO-ICTUS was a randomized clinical trial where 411 alteplase-treated patients also received uric acid 1,000 mg (n = 211) or placebo (n = 200) before the end of alteplase infusion. Herein, we included a nested study of 84 patients (placebo = 40, uric acid = 44) who had a pretreatment CT-angiography (CTA) showing a proximal arterial occlusion in the carotid territory. Excellent collaterals were defined as 100% collateral supply on pretreatment CTA. Regression models assessed the interaction between therapy (uric acid/placebo) and collaterals on the main outcome (ordinal modified Rankin Scale [mRS] shift at 90 days). RESULTS: Overall, excellent collaterals were associated with improved outcome. There was a significant interaction between therapy and pretreatment collaterals (p interaction = 0.02) for the prediction of improved mRS shift. The largest treatment contrast in favor of uric acid was found in patients with excellent collaterals (adjusted OR 9.2; 95% CI 1.23-68.6; p = 0.03). CONCLUSIONS: Collectively, the study found that collaterals were associated with the neuroprotective effect of uric acid therapy highlighting the importance of assessing collateral status in neuroprotection trials.

Threshold Effects of Serum Uric Acid on Chronic Kidney Disease in US Women without Hypertension and Diabetes: A Cross-Sectional Study.

BACKGROUND: Serum uric acid (SUA) has been associated with increased risk of chronic kidney disease (CKD) in observational studies; however, data in women without hypertension and diabetes are sparse. PURPOSE: To examine the association between SUA and CKD among women without hypertension and diabetes. METHODS: In this cross-sectional study of 6,776 US women without hypertension and diabetes from the National Health and Nutrition Examination Survey (1999-2006), we investigated the relationship between SUA and CKD using multivariable logistic regression models. Moreover, a generalized additive model and smooth curve fitting (penalized spline method) and a 2 piecewise logistic regression models were conducted to address for nonlinearity. RESULTS: The prevalence of CKD was 8.3%. Multiple logistic analyses showed that per 1 mg/dL increase in SUA was associated with 39% increased prevalence of CKD. Analyses using restricted cubic spline confirmed that the association between SUA and CKD was nonlinear. Further, threshold and saturation effect analysis showed that the inflection point of SUA was 4.5 mg/dL. The ORs (95% CIs) were 0.84 (0.66-1.08) on the left side of inflection point and 1.87 (1.56-2.24) on the right side of inflection point, respectively. Subgroup analysis showed that the stronger association between SUA and CKD was observed in elder women with never/former smoking and higher fasting blood glucose levels (all p values for interaction <0.05). CONCLUSION: Our study suggested threshold effects of SUA on the prevalence of CKD among US women without hypertension and diabetes. SUA levels >4.5 mg/dL were positively and independently associated with CKD.

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.

Uric acid and cognitive decline: a double-edge sword?

PURPOSE OF REVIEW: This narrative review aims to highlight recent findings on the relation between uric acid level and cognitive decline or dementia. RECENT FINDINGS: The antioxidant properties of uric acid, which have supported the hypothesis that uric acid may be neuroprotective, have been questioned by preclinical data. Studies investigating the relation between serum uric acid (SUA) level and Alzheimer disease are mostly cross-sectional, and results are often inconclusive. Similarly, data for an association between uric acid level and cognitive performance are inconsistent. There is some evidence that low SUA level might be associated with Parkinson disease, but studies are limited by methodological heterogeneity and risk of bias. Patients with gout may have decreased risk for Alzheimer disease, but the impact of treatment is unclear. Recent data suggest an increased risk of vascular dementia with high SUA level via increased cerebrovascular burden in older patients. The relation between SUA level and neurologic disorders may be U-shaped. SUMMARY: We lack strong evidence for an association between low SUA level and cognitive decline over time. Conversely, high SUA level might increase the cerebrovascular burden and the risk of vascular dementia; physicians should continue to treat hyperuricemia when appropriate.

Transmembrane TNF-α is sufficient for articular inflammation and hypernociception in a mouse model of gout.

Gout manifests as recurrent episodes of acute joint inflammation and pain due to the deposition of monosodium urate (MSU) crystals within the affected tissue in a process dependent on NLRP3 inflammasome activation. The synthesis, activation, and release of IL-1ß are crucial for MSU-induced inflammation. The current study evaluated the mechanism by which TNF-α contributed to MSU-induced inflammation. Male C57BL/6J or transgenic mice were used in this study and inflammation was induced by the injection of MSU crystals into the joint. TNF-α was markedly increased in the joint after the injection of MSU. There was inhibition in the infiltration of neutrophils, production of CXCL1 and IL-1ß, and decreased hypernociception in mice deficient for TNF-α or its receptors. Pharmacological blockade of TNF-α with Etanercept or pentoxyfylline produced similar results. Mechanistically, TNF-α blockade resulted in lower amounts of IL-1ß protein and pro-IL-1ß mRNA transcripts in joints. Gene-modified mice that express only transmembrane TNF-α had an inflammatory response similar to that of WT mice and blockade of soluble TNF-α (XPro™1595) did not decrease MSU-induced inflammation. In conclusion, TNF-α drives expression of pro-IL-1ß mRNA and IL-1ß protein in experimental gout and that its transmembrane form is sufficient to trigger MSU-induced inflammation in mice.

Uric Acid, Vascular Stiffness, and Chronic Kidney Disease: Is There a Link?

Controversy exists with regard to the causal role of hyperuricemia in chronic kidney disease. Vascular stiffness may be the link that explains the relation between hyperuricemia and kidney disease. Hyperuricemia is associated with a number of effects on the vascular endothelium and vascular smooth muscle cells, including an increase in oxidative stress, production of vasoconstrictors, and changes on the structural properties of the large artery wall. Observational evidence in large epidemiological cross-sectional studies suggests that there is an independent association between uric acid and arterial stiffness. The limited evidence from cohort studies or clinical trials does not support treatment of hyperuricemia to reduce vascular stiffness in order to prevent kidney disease. Nevertheless, vascular stiffness may be a valid, reproducible, and useful surrogate endpoint. At this point there seems to be sufficient evidence to warrant larger clinical trials to determine whether lowering uric acid concentrations would be useful for prevention or treatment of vascular stiffness and, subsequently, of cardiovascular and kidney diseases. Video Journal Club 'Cappuccino with Claudio Ronco' at http://www.karger.com/?doi=452726.

Effects of Mollugo pentaphylla extract on monosodium urate crystal-induced gouty arthritis in mice.

BACKGROUND: Gout is an inflammatory condition induced by the deposition of monosodium urate (MSU) crystals in joints and soft tissues, and it can lead to acute or chronic arthritis. MSU are pro-inflammatory stimuli that can initiate, amplify and sustain an intense inflammatory response. In this study, we evaluated the anti-inflammatory effect of an extract of Mollugo pentaphylla (MPE) on MSU-induced gouty arthritis in a mouse model. METHOD: An MSU crystal suspension (4 mg/50 µL) was injected intradermally into the right paw. The mice were orally administered MPE (150 mg/kg or 300 mg/kg) or the positive control drug colchicine (1 mg/kg) 1 h before the MSU crystals were injected and then once daily for 3 days. The effects of MPE included inflammatory paw edema and pain upon weight-bearing activity, and we evaluated the inflammatory cytokine expression and paw tissue inflammation-related gene expression. RESULTS: MPE suppressed inflammatory paw edema and pain in the MSU-induced mice. MPE showed anti-inflammatory activity by inhibiting the production of TNF-α, interleukin (IL)-1ß, NLRP3 inflammasome and NF-κB. CONCLUSION: These results suggest that MPE has potent anti-inflammatory activities and may be useful as a therapeutic agent against gouty arthritis.

Complement C5a potentiates uric acid crystal-induced IL-1ß production.

Anaphylatoxin C5a released upon complement activation is associated with both acute and chronic inflammations such as gout. The pathogenesis of gout was identified as uric acid crystal deposition in the joints that activates inflammasome, leading to IL-1ß release. However, little is known about the interaction between complement activation and monosodium urate/uric acid (MSU) crystal-induced inflammasome activation or IL-1ß production. Here, we report that MSU crystal-induced proinflammatory cytokines/chemokines in human whole blood is predominantly regulated by C5a through its interaction with C5a receptor. C5a induces pro-IL-1ß and IL-1ß production in human primary monocytes, and potentiates MSU or cholesterol crystals in IL-1ß production. This potentiation is caspase-1 dependent and requires intracellular Ca(2+) mobilization, K(+) efflux, and cathepsin B activity. Our results provide insight into the role of C5a as an endogenous priming signal that is required for the initiation of uric acid crystal-induced IL-1ß production. C5a could potentially be a therapeutic target together with IL-1ß antagonists for the treatment of complement-dependent and inflammasome-associated diseases.

ALDR enhanced endothelial injury in hyperuricemia screened using SILAC.

BACKGROUND: The exact etiology of hyperuricemia-induced endothelial injury remains ill-defined. To elucidate the mechanism that leads to endothelial injury in hyperuricemia, we investigated proteins expressed in human umbilical vein endothelial cells (HUVECs) cultured with high concentrations of uric acid (HUA) in vitro. METHODS: We used stable isotope labeling with amino acids in cell culture (SILAC) combined with LC-MS/MS analysis to compare proteins expressed in HUVECs cultured in media with or without HUA. The results were confirmed by Western blotting. Reactive oxygen species (ROS) were detected using a confocal microscope. RESULTS: Thirty-nine proteins with various cellular functions were differentially expressed. Among them, aldose reductase (ALDR) protein expression was enhanced significantly, indicating increased aldehyde reductase and oxidoreductase activities. ROS levels decreased when ALDR protein activity was inhibited by siALDR. CONCLUSIONS: ALDR protein may play an important role in endothelial injury induced by hyperuricemia, and activity of the ALDR protein is associated with oxidative stress.

Participation of the TRPV1 receptor in the development of acute gout attacks.

OBJECTIVE: The aim of the present study was to investigate the participation of TRPV1 in an acute gout attack model. METHODS: Experiments were conducted to evaluate the participation of TRPV1 in the nociceptive and inflammatory responses (oedema, plasma extravasation, leucocyte infiltration and also IL-1ß production) triggered by IA (ankle) administration of monosodium urate (MSU) in rats using selective antagonist TRPV1 receptor, defunctionalization of sensory fibres and increased immunoreactivity. We have also analysed the inflammatory response. The participation of mast cells in the MSU-induced nociception and inflammation was evaluated using a mast cell stabilizer and a mast cell degranulator compound. RESULTS: We observed that MSU (1.25 mg/site) injected into the rat ankle joint elicited ongoing pain-like behaviour, hyperalgesia, allodynia and articular oedema as well as plasma extravasation, leucocyte infiltration and IL-1ß production in lavage fluid. All of these events were inhibited by the co-administration of the selective TRPV1 receptor antagonist SB366791 (10 nmol/site). MSU crystals also increased the immunoreactivity of the TRPV1 receptor in the articular tissue of injected animals. Furthermore, the defunctionalization of TRPV1-positive sensory neurons also significantly reduced MSU-induced ongoing pain-like behaviour, hyperalgesia and oedema. CONCLUSION: Thus we demonstrate that TRPV1 acts on sensory neurons and plays a relevant role in the nociception and inflammation induced by IA MSU, indicating it as a potential target to treat acute gout attacks.

Fructose and uric acid: is there a role in endothelial function?

Population level data support that consumption of fructose and fructose-based sweeteners has dramatically increased and suggest that high dietary intake of fructose is an important factor in the development of the cardiorenal metabolic syndrome (CRS). The CRS is a constellation of cardiac, kidney and metabolic disorders including insulin resistance, obesity, metabolic dyslipidemia, high blood pressure, and evidence of early cardiac and kidney disease. The consequences of fructose metabolism may result in intracellular ATP depletion, increased uric acid production, oxidative stress, inflammation, and increased lipogenesis, which are associated with endothelial dysfunction. Endothelial dysfunction is an early manifestation of vascular disease and a driver for the development of CRS. A better understanding of fructose overconsumption in the development of CRS may provide new insights into pathogenesis and future therapeutic strategies.

P2Y6 receptor signaling pathway mediates inflammatory responses induced by monosodium urate crystals.

Gout occurs in individuals with hyperuricemia when monosodium urate (MSU) crystals precipitate in tissues and induce acute inflammation via phagocytic cells such as monocytes. MSU crystals have been demonstrated in skin diseases such as tophaceous gout or psoriasis; however, the importance of MSU crystals in the skin is totally unknown. In this study, we found that MSU crystals, through P2Y(6) receptors, stimulated normal human keratinocytes (NHK) to produce IL-1α, IL-8/CXCL8, and IL-6. P2Y(6) receptor expression increased in MSU-stimulated NHK. Both P2Y(6)-specific antagonist and P2Y(6) antisense oligonucleotides significantly inhibited the production of IL-1α, IL-8/CXCL8, and IL-6 by NHK. Similarly, the P2Y(6)-specific antagonist completely inhibited the MSU-induced production of IL-1ß by THP-1 cells, a human monocytic cell line. Remarkably, the P2Y(6)-specific antagonist significantly reduced neutrophil influx in both mouse air pouch and peritonitis models. Thus, these results indicate that the P2Y(6) receptor signaling pathway may be a potential therapeutic target for MSU-associated inflammatory diseases, such as tophaceous gout.

Uric acid and the kidney.

Uric acid, the end product of purine metabolism, is excreted predominantly by the proximal tubules. Abnormal serum levels of uric acid are due to alterations in production or excretion. Fractional excretion of uric acid is helpful in determining the underlying etiology of hypouricemia or hyperuricemia in children. Abnormalities in the molecular mechanisms that control renal uric acid tubular transport are implicated in various disorders associated with abnormal uric acid levels. Gout is rare in children; yet its presence necessitates evaluation for enzymatic defects in purine metabolism. Well-known effects of uric acid on the kidney include nephrolithiasis and acute kidney injury (AKI) in the setting of tumor lysis. However, recent data suggest that uric acid may be an important factor in the pathogenesis of AKI in general, as well as of chronic kidney disease (CKD) and hypertension. Hence, uric acid may not only be a marker but also a potential therapeutic target in kidney disease. Nonetheless, because of confounders, more studies are needed to clarify the association between uric acid and multifactorial disorders of the kidney.

Is hyperuricemia a risk factor for arteriosclerosis? Uric acid and arteriosclerosis in apolipoprotein e-deficient mice.

Although hyperlipidemia, high blood pressure, and diabetes increase the risk of arteriosclerosis, it is not clear whether hyperuricemia increases the risk of arteriosclerosis or not. We examined the effects of uric acid and curative drugs for hyperuricemia on atherosclerosis-susceptible C57BL/6J apolipoprotein E-deficient (apoE(-/-)) mice. Male apoE(-/-) mice (age: 6 weeks) were fed a normal diet (normal diet group) or a uric acid-enriched diet. Mice fed the uric acid-enriched diet were divided into three groups and administered a drinking vehicle (high uric acid diet group), allopurinol (20 mg·kg(-1)·d(-1)), or benzbromarone (20 mg·kg(-1)·d(-1)) for 10 weeks. Serum uric acid concentrations were higher in the high uric acid diet group than in the normal diet group, and concentrations in the allopurinol and benzbromarone groups were lower than in the high uric acid diet group. Serum total cholesterol and triglyceride levels were lower in the allopurinol group than in the high uric acid diet group. Oxidative stress was lower in the benzbromarone group than in the high uric acid diet group. Atherosclerotic lesion areas were smaller in the allopurinol and benzbromarone groups than in the high uric acid diet group. Thus, hyperuricemia may not be an independent risk factor for arteriosclerosis; however, the administration of allopurinol and benzbromarone prevented the development of atherosclerosis in apoE(-/-) mice fed a uric acid-enriched diet. The anti-atherosclerotic effect was in part due to lower total cholesterol and oxidative stress in the serum. Other possible mechanisms underlying this effect should be investigated.