Uric acid and oxidative stress Relative impact on cardiovascular risk

a Department of Clinical and Experimental Medicine, Federico II University Medical School, Via S. Pansini 5, 80131 Naples, Italy

b Vascular Risk Unit, Division of Internal Medicine, La Paz University Hospital, Madrid, Spain

 Available online 20 July 2007.


Post-hoc analyses of the GREACE and the LIFE trials have renewed the interest in elevated serum uric acid (SUA) as a factor contributing to atherosclerotic cardiovascular disease (CVD) and in the possible benefit derived from its pharmacological reduction. The results of these trials are consistent with reports indicating favourable effects of SUA lowering treatment with allopurinol on the rate of cardiovascular complications in patients with coronary heart disease, congestive heart failure and dilated cardiomyopathy.


Two recent overviews have concluded that, while in population samples at relatively low risk of CVD, SUA is at best a very weak predictor of CVD, by contrast it is a significant independent predictor among subjects at high or very high risk. This raises the question of a different meaning of excess SUA levels under different circumstances. Whereas in uncomplicated obese, insulin-resistant and hypertensive patients SUA levels increase mainly as a consequence of impaired renal excretion, in conditions of local ischemia an increased production of uric acid occurs in parallel with that of reactive oxygen species (ROS). Thus, although clinical and experimental evidence suggest that uric acid has actually antioxidant properties, it is conceivable that under these conditions its antioxidant activity is overcome by the pro-oxidant and pro-inflammatory effects of ROS accumulation.


At present, there is no solid evidence to recommend treatment of the mild asymptomatic hyperuricemia associated with obesity, diabetes and/or hypertension (up to 10 mg/dL). By contrast, similar SUA elevations in patients at higher cardiovascular risk should be taken more seriously. A controlled trial to investigate the effects of SUA reduction in these patients, while monitoring concomitant changes in parameters of oxidative stress and inflammation, is warranted.


Nutrition, Metabolism and Cardiovascular Diseases

Volume 17, Issue 6, July 2007, Pages 409-414

Nutrition, Metabolism and Cardiovascular Diseases

Uric acid and oxidative stress: Relative impact on cardiovascular risk - ScienceDirect

Rapid Crystal Dissolution in Gout - Medscape

May 14, 2020. Monosodium urate crystals dissolve and are eliminated from joints and soft tissues as serum uric acid levels drop below its saturating point (400 μmol/l). Time to crystal clearance relates to disease duration and to the serum uric acid level achieved with therapy. The current recommended target level by most guidelines is 360 µmol/l (6 mg/dl), but evidence supporting this target is scant. Lower targets warrant a faster crystal clearance – and therefore a faster disease cure – and might be appropriate in the general gouty population but most especially in selected patients such as those with significant cardiovascular risk, poor renal function or tophaceous gout.


Biochem Biophys Res Communication. 2018 Sep 18
High-mobility group box 1 is responsible for monosodium urate crystal-induced inflammation in human U937 macrophages

Division of Rheumatology, Department of Internal Medicine, Arthritis & Autoimmunity Research Center, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea.
2Department of Orthopedic Surgery, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea.
3Arthritis & Autoimmunity Research Center, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea.
4Division of Rheumatology, Department of Internal Medicine, Arthritis & Autoimmunity Research Center, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea. Electronic address:

High-mobility group box 1 (HMGB1) was originally identified as a highly conserved non-histone DNA-binding factor and demonstrated to be a potent mediator in inflammatory diseases. We performed this study to investigate the role of HMGB1 in the pathogenesis of uric acid-induced inflammation in human U937 macrophages. To simulate uric acid-induced inflammation, human U937 macrophages were treated with monosodium urate (MSU) crystals. In addition to determining the effects of MSU crystal treatment on expression of various genes and proteins, cells were transfected with interfering RNA (siRNA) for HMGB1, or caspase-1 and then treated with MSU. Expression of interleukin-1β (IL-1β), IL-18, HMGB1, and caspase-1 was detected in human U937 cells and peripheral blood mononuclear cells (PBMCs) in gout patients and healthy controls by western blot analysis or quantitative real-time polymerase chain reaction. Transcript expression of IL-1β, IL-18, caspase-1, HMGB1 in PBMCs was significantly higher in active gout patients than inactive gout patients and healthy controls. The protein levels of these molecules were significantly increased by stimulation of U937 cells with 0.2 mg/ml MSU crystals. Stimulation of U937 cells with MSU crystals induced translocation of HMGB1 from the nucleus to the cytoplasm and its extracellular release. U937 cells transfected with caspase-1 siRNA had significantly lower HMGB1 expression in the cytoplasm and supernatant than non-transfected cells. Antioxidants, such as N-acetyl-l-cysteine and quercetin, markedly inhibited the nuclear-to-cytoplasmic translocation of HMGB1 and its release into the extracellular milieu. In conclusion, HMGB1, regulated by the enzymatic activity of caspase-1, is a crucial mediator in uric acid-induced inflammation.

High-mobility group box 1 is responsible for monosodium urate crystal-induced inflammation in human U937 macrophages - PubMed


Recent advances in crystal-induced acute inflammation
Department of General Medicine, Kitasato University School of Medicine, Kitasato, Sagamihara, Kanagawa, Japan.

Purpose of review: The aim of this article is to highlight recent advances suggesting essential involvement of the innate immune system in crystal-induced acute inflammation.

Recent findings: Gout is a disease caused by the deposition of monosodium urate monohydrate crystals. Precise mechanisms underlying the initiation of monosodium urate monohydrate crystal-induced acute inflammation, however, are not known. Recent investigations provided novel evidence in the pathology of acute gout. Immunological study indicated that monosodium urate monohydrate crystals can act as a 'danger signal' that resembles exogenous adjuvants. Two laboratories have documented interesting findings that Toll-like receptor-mediated pathways or MyD88-dependent pathways are involved in monosodium urate monohydrate crystal-induced acute inflammation. Upregulation of the triggering receptor expressed on myeloid cells 1 (TREM-1) in phagocytes by the stimulation with monosodium urate monohydrate crystals has been demonstrated. Furthermore, pathological significance of NALP 3 inflammasome in gout has been shown. These findings provide a new concept that the innate immune system may play a crucial role on the triggering of crystal-induced acute inflammation. Spontaneous resolution is a characteristic feature of acute gout. Involvement of nuclear hormone receptors, peroxisome proliferator-activated receptor gamma and liver X receptor alpha, during the termination of acute gout has been also shown.

Summary: These studies provided a new insight into the mechanisms underlying the initiation and the termination of monosodium urate monohydrate crystal-induced acute inflammation.

Recent advances in crystal-induced acute inflammation - PubMed


Cytokine. 2014 Sep;
How is inflammation initiated? Individual influences of IL-1, IL-18 and HMGB1

1Department of Biological Sciences, Texas Tech University, Biology Rm 108, Box 43131, Lubbock, TX 79409-3131, United States.

Pro-inflammatory cytokines are crucial for fighting infection and establishing immunity. Recently, other proteins, such as danger-associated molecular patterns (DAMPs), have also been appreciated for their role in inflammation and immunity. Following the formation and activation of multiprotein complexes, termed inflammasomes, two cytokines, IL-1β and IL-18, along with the DAMP High Mobility Group Box 1 (HMGB1), are released from cells. Although these proteins all lack classical secretion signals and are released by inflammasome activation, they each lead to different downstream consequences. This review examines how various inflammasomes promote the release of IL-1β, IL-18 and HMGB1 to combat pathogenic situations. Each of these effector molecules plays distinct roles during sterile inflammation, responding to viral, bacterial and parasite infection, and tailoring the innate immune response to specific threats.

How is inflammation initiated? Individual influences of IL-1, IL-18 and HMGB1 - PubMed


Inflammation Research. 2017 Mar;
Macrophage-derived IL-1β enhances monosodium urate crystal-triggered NET formation
Department of Infectious Diseases, College of Veterinary Medicine, The University of Georgia, 501 D.W. Brooks Drive, Athens, GA, 30602, USA.

Objective and design: Arthritic gout is caused by joint inflammation triggered by the damaging effects of monosodium uric acid (MSU) crystal accumulation in the synovial space. Neutrophils play a major role in mediating joint inflammation in gout. Along with neutrophils, other immune cells, such as macrophages, are present in inflamed joints and contribute to gout pathogenesis. Neutrophils form neutrophil extracellular traps (NETs) in response to MSU crystals. In the presence of MSU crystals, macrophages release IL-1β, a cytokine crucial to initiate gout pathogenesis and neutrophil recruitment. Our research investigated interactions between human macrophages and neutrophils in an in vitro model system and asked how macrophages affect NET formation stimulated by MSU crystals.

Materials or subjects: Human neutrophils and PBMCs were isolated from peripheral blood of healthy volunteers. PBMCs were differentiated into macrophages in vitro using human M-CSF.

Treatment: Human neutrophils were pretreated with macrophage-conditioned media, neutrophil-conditioned media, recombinant human IL-1β or anakinra prior to stimulation by MSU crystals.

Method: Interaction of neutrophils with MSU crystals was evaluated by live imaging using confocal microscopy. The presence of myeloperoxidase (MPO) and neutrophil elastase (NE) was measured by ELISA. NET formation was quantitated by Sytox Orange-based extracellular DNA release assay and NE-DNA ELISA. AggNET formation was assessed by macroscopic evaluation.

Results: We found that crystal- and cell-free supernatants of macrophages stimulated with MSU crystals promote MSU crystal-stimulated NET formation in human neutrophils. This observation was confirmed by additional assays measuring the release of MPO, NE, and the enzymatic activity of NE. MSU crystal-induced NET formation remained unchanged when neutrophil supernatants were tested. IL-1β is a crucial cytokine orchestrating the onset of inflammation in gout and is known to be released in large amounts from macrophages following MSU crystal stimulation. We found that recombinant IL-1β strongly promoted MSU crystal-induced NET formation in human neutrophils. Interestingly, IL-1β alone did not induce any NET release. We also found that clinical grade anakinra, an IL-1 receptor blocker, strongly reduced the NETosis-enhancing effect of macrophage supernatants indicating that IL-1β is mainly responsible for this effect.

Conclusions: Macrophage-derived IL-1β enhances MSU crystal-induced NET release in neutrophils. We identified a new mechanism by which macrophages and IL-1β affect neutrophil functions, and could contribute to the inflammatory conditions present in gout. Our results also revealed a new anti-inflammatory mechanism of anakinra.

Macrophage-derived IL-1β enhances monosodium urate crystal-triggered NET formation - PubMed


J Urology.1989 Oct;
Solubility of uric acid and supersaturation of monosodium urate: why is uric acid so highly soluble in urine?

1Department of Urology, Ehime University School of Medicine, Japan.

The solubility of uric acid and the stability of supersaturation of monosodium urate (NaU) were studied in buffer solutions containing 150 mM sodium in the physiological urinary pH range at 37C. The solubility of uric acid increased with the rise in pH, and the total dissolved urate (undissociated uric acid + urate anion) concentration did not change during seven-day incubation in the pH range below 6.6. In this pH range, the calculated concentration of undissociated uric acid was constant (about six mg./dl.). Consequently, the increasing solubility of uric acid with the rise in pH depended solely on the increase of urate anion. As much as 220 mg./dl. of uric acid could be dissolved for 24 hours at pH 7.0. But following seven-day incubation the total dissolved urate concentration decreased to 16 mg./dl. due to NaU crystallization. The stability of NaU supersaturation depended not only on the concentration of sodium and urate anion but also on time and pH. When monopotassium urate crystals were incubated for seven days, the total dissolved urate concentration decreased according to NaU crystallization; the higher the pH, the more marked the decrease. However, at least some 80 mg./dl. of total dissolved urate was stable up to pH 8.2 within 24 hours. These findings can well explain why NaU crystals are seldom formed in the normal urine. Urinary stasis and/or pathological high urinary pH may cause NaU crystallization.



在生理尿液pH值为37C的条件下,在含有150 mM钠的缓冲溶液中研究了尿酸的溶解度和尿酸钠(NaU)的过饱和稳定性。尿酸的溶解度随着pH的升高而增加,并且在低于6.6的pH范围内培养7天后,总溶解尿酸盐(未解离的尿酸+尿酸盐阴离子)的浓度没有变化。在该pH范围内,未离解的尿酸的计算浓度是恒定的(约6mg./dl。)。因此,随着pH值的升高,尿酸的溶解度增加仅取决于尿酸根阴离子的增加。高达220 mg./dl。 pH 7.0下,尿酸可以溶解24小时。但是在孵育7天后,总溶解尿酸盐浓度降低到16 mg./dl。由于NaU结晶。 NaU过饱和的稳定性不仅取决于钠和尿酸根阴离子的浓度,还取决于时间和pH。将尿酸一钾晶体培养7天后,总溶解尿酸盐浓度会根据NaU结晶而降低; pH越高,下降越明显。但是,至少约80mg./dl。在24小时内,总溶解尿酸盐的总含量稳定到pH 8.2。这些发现可以很好地解释为什么在正常尿液中很少形成NaU晶体。尿路淤滞和/或病理性尿液pH高可能会导致NaU结晶。

Solubility of uric acid and supersaturation of monosodium urate: why is uric acid so highly soluble in urine? - PubMed


Scand J Rheumatology. 2016 Oct;

Synovial fluid proteins are required for the induction of interleukin-1β production by monosodium urate crystals

1a Rheumatology Unit, Department of Medicine , University of Padova , Italy.
2b Division of Immunology and Allergy, Inflammation and Allergy Research Group, Hans Wilsdorf Laboratory, University Hospital and Faculty of Medicine , University of Geneva , Switzerland.
3c Department of Surgery, Oncology and Gastroenterology , University of Padova , Italy.

Objectives: Monosodium urate (MSU) crystal deposition in gouty joints promotes the release of inflammatory mediators, in particular interleukin (IL)-1β. The induction of IL-1β production by MSU crystals requires a co-stimulus. The objective of this study was to determine which part of the synovial fluid (SF) provides co-stimulation to MSU crystals to induce IL-1β in macrophages.

Method: The lipidic fraction (LF) and the protein fraction (PF) were isolated from the SF of patients with arthropathies. The PF was subfractionated according to different molecular weight (MW) ranges. THP-1 cells or human primary monocytes were stimulated with MSU crystals in the presence or absence of SF or SF fractions. IL-1β and IL-8 production and IL-1β mRNA expression were assessed by an enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qPCR).

Results: Exposure of monocytes/macrophages to MSU crystals alone induced the moderate release of IL-8 but not of IL-1β. The production of IL-1β required the presence of both SF from patients with inflammatory arthritis (SFi) and MSU crystals. SF from patients with non-inflammatory arthritis, that is patients with osteoarthritis (OA), did not affect the IL-1β production but slightly enhanced the secretion of IL-8. Both MSU crystals and SFi were required for the induction of the IL-1β transcript, which was not expressed in the presence of either stimulus alone. SFi fractionation demonstrated that the MSU crystal co-stimulus was contained in the PF of SFi with MW > 50 kDa but not in the LF.

Conclusions: This study shows that the SF of inflammatory arthritis patients, including gout patients, contains proteins required for the induction of IL-1β by MSU crystals in macrophages whereas lipids are not involved.

Synovial fluid proteins are required for the induction of interleukin-1β production by monosodium urate crystals - PubMed


Natural Products and Extracts as Xantine Oxidase Inhibitors - A Hope for Gout Disease?

Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey

Xanthine oxidase (EC (XO) is one of the main enzymatic sources that create reactive oxygen species (ROS) in the living system. It is a dehydrogenase enzyme that performs electron transfer to nicotinamide adenine dinucleotide (NAD+ ), while oxidizing hypoxanthin, which is an intermediate compound in purine catabolism, first to xanthine and then to uric acid. XO turns into an oxidant enzyme that oxidizes thiol groups under certain stress conditions in the tissue. The last metabolic step, in which hypoxanthin turns into uric acid, is catalyzed by XO. Uric acid, considered a waste product, can cause kidney stones and gouty-type arthritis as it is crystallized, when present in high concentrations. Thus, XO inhibitors are one of the drug classes used against gout, a purine metabolism disease that causes urate crystal storage in the joint and its surroundings caused by hyperuricemia. Urate-lowering therapy include XO inhibitors that reduce uric acid production as well as uricosuric drugs that increase urea excretion. Current drugs that obstruct uric acid synthesis through XO inhibition are allopurinol, febuxostat, and uricase. However, since the side effects, safety and tolerability problems of some current gout medications still exist; intensive research is ongoing to look for new, effective, and safer XO inhibitors of natural or synthetic origins for the treatment of the disease. In the present review, we aimed to assess in detail XO inhibitory capacities of pure natural compounds along with the extracts from plants and other natural sources via screening Pubmed, Web of Science (WoS), Scopus, and Google Academic. The data pointed out to the fact that natural products, particularly phenolics such as flavonoids (quercetin, apigenin, and scutellarein), tannins (agrimoniin and ellagitannin), chalcones (melanoxethin), triterpenes (ginsenoside Rd and ursolic acid), stilbenes (resveratrol and piceatannol), alkaloids (berberin and palmatin) have a great potential for new XO inhibitors capable of use against gout disease. In addition, not only plants but other biological sources such as microfungi, macrofungi, lichens, insects (silk worms, ants, etc) seem to be the promising sources of novel XO inhibitors.

Natural Products and Extracts as Xantine Oxidase Inhibitors - A Hope for Gout Disease? | Bentham Science


Xanthine oxidase inhibitory activity of constituents of Cinnamomum cassia twigs

a National Institute of Medicinal Materials, Hanoi, Viet Nam
b College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea
c Vietnam Military Medical University, Hanoi, Viet Nam
d National Institute of Drug Quality Control, Hanoi, Viet Nam

A methanol extract of the twigs of Cinnamomum cassia was found to inhibit xanthine oxidase. Purification of the methanol extract afforded three new phenolic glycosides, cinnacasolide A–C (11–13), together with 10 known compounds (1–10). The structures of the three new compounds were determined by interpretation of spectroscopic data. Cinnamaldehyde derivatives 1−5 and 7 were significant inhibitors of xanthine oxidase, with IC50 values ranging from 7.8 to 36.3 μg/mL. The results indicate that the acyl group of these cinnamaldehyde derivatives plays an important role in the inhibition of xanthine oxidase.


发现肉桂肉桂的甲醇提取物抑制了黄嘌呤氧化酶。 甲醇提取物的纯化提供了三种新的酚类糖苷,肉桂酸酯固体A–C(11–13),以及10种已知化合物(1–10)。 这三种新化合物的结构是通过光谱数据的解释来确定的。 肉桂醛衍生物1-5和7是黄嘌呤氧化酶的重要抑制剂,IC50值在7.8至36.3μg/ mL之间。 结果表明,这些肉桂醛衍生物的酰基在抑制黄嘌呤氧化酶中起重要作用。

Xanthine oxidase inhibitory activity of constituents of Cinnamomum cassia twigs - ScienceDirect