Uric acid is the final oxidation product of purine metabolism in humans. Xanthine oxidoreductase (XOR) catalyzes oxidative hydroxylation of hypoxanthine to xanthine to uric acid, accompanying the production of reactive oxygen species (ROS). Uric acid usually forms ions and salts known as urates and acid urates in serum. Clinically, overproduction or under-excretion of uric acid results in the elevated level of serum uric acid (SUA), termed hyperuricemia, which has long been established as the major etiologic factor in gout. Accordingly, urate-lowering drugs such as allopurinol, an XOR-inhibitor, are extensively used for the treatment of gout. In recent years, the prevalence of hyperuricemia has significantly increased and more clinical investigations have confirmed that hyperuricemia is an independent risk factor for cardiovascular disease, hypertension, diabetes, and many other diseases. Urate-lowering therapy may also play a critical role in the management of these diseases. However, current XOR-inhibitor drugs such as allopurinol and febuxostat may have significant adverse effects. Therefore, there has been great effort to develop new XOR-inhibitor drugs with less or no toxicity for the long-term treatment or prevention of these hyperuricemia-related diseases. In this review, we discuss the mechanism of uric acid homeostasis and alterations, updated prevalence, therapeutic outcomes, and molecular pathophysiology of hyperuricemia-related diseases. We also summarize current discoveries in the development of new XOR inhibitors.

Hyperuricemia-Related Diseases and Xanthine Oxidoreductase (XOR) Inhibitors: An Overview

Background and objectives 
Recent studies have shown that hyperuricemia is commonly associated with dyslipidemia, cardiovascular diseases, hypertension and metabolic syndrome. Elevated serum uric acid has been demonstrated to be associated with obesity in the adult population in many countries; however, there is still a lack of evidence for the Bangladeshi population. The aims of this study were to evaluate the prevalence of hyperuricemia and determine the relationship between serum uric acid (SUA) and obesity among the Bangladeshi adults.


Methods 
In this cross-sectional study, blood samples were collected from 260 adults (142 males and 118 females) and analyzed for SUA and lipid profile. All participants were categorized as underweight (n = 11), normal (n = 66), overweight (n = 120) and obese (n = 63) according to the body mass index (BMI) scale for the Asian population. Based on SUA concentration the participants were stratified into four quartiles (Q1: 345 μmol/L).


Results 
The mean age and BMI of the participants were 32.5 ± 13.3 years and 24.9 ± 3.8 kg/m2, respectively. The average level of SUA was 294 ± 90 μmol/L with a significant difference between males and females (p < 0.001). Overall, the estimated prevalence of hyperuricemia was 9.3% with 8.4% in male and 10.2% in female participants. There were significant increases in the prevalence of obesity (17.4%, 22.2%, 28.6% and 31.8%, respectively, p < 0.01 for trend) across the SUA quartiles. A multiple logistic regression analysis revealed that SUA quartiles were independently associated with the presence of obesity (p < 0.01).


Conclusion 
Present study indicates a significant positive relationship between SUA and obesity among the Bangladeshi adults. Therefore, routine measurement of SUA is recommended in obese individuals to prevent hyperuricemia and its related complications.

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Prevalence of hyperuricemia and the relationship between serum uric acid and obesity: A study on Bangladeshi adults.

Hyperuricemia, the physiological prerequisite for gout, is linked to the presence and severity of multiple comorbidities that affect longevity and well-being. By using the baseline data from the China Health and Retirement Longitudinal Study, a nationally representative survey, the prevalence of hyperuricemia in general middle-aged and older Chinese was estimated. The potential effects of health behaviours and comorbidities on hyperuricemia were also explored. In 2010, the prevalence of hyperuricemia among middle-aged and older Chinese was 6.4%. Hyperuricemia was more prevalent in males than in females (7.9% vs. 4.9%). The risk of hyperuricemia increased with advanced age in both sexes. In males, current drinking, obesity and dyslipidemia were positively associated with hyperuricemia, whereas singles males and males living in North China were with lower odds of having hyperuricemia. For females, being single, at a higher economic level, living in the Southwest China, smoking, obesity, diabetes, hypertension and dyslipidemia were all significant risk factors for hyperuricemia, but females living in North China and Northwest China were with a lower hyperuricemia prevalence than females in East China. Therefore, hyperuricemia in China was not as prevalent as in developed countries, its prevalence varied greatly according to demographic, socioeconomic, and geographic factors.

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Prevalence and correlates of hyperuricemia in the middle-aged and older adults in China

Purines and their derivatives, most notably adenosine and ATP, are the key molecules controlling intracellular energy homoeostasis and nucleotide synthesis. Besides, these purines support, as chemical messengers, purinergic transmission throughout tissues and species. Purines act as endogenous ligands that bind to and activate plasmalemmal purinoceptors, which mediate extracellular communication referred to as “purinergic signalling”. Purinergic signalling is cross-linked with other transmitter networks to coordinate numerous aspects of cell behaviour such as proliferation, differentiation, migration, apoptosis and other physiological processes critical for the proper function of organisms. Pathological deregulation of purinergic signalling contributes to various diseases including neurodegeneration, rheumatic immune diseases, inflammation, and cancer. Particularly, gout is one of the most prevalent purine-related disease caused by purine metabolism disorder and consequent hyperuricemia. Compelling evidence indicates that purinoceptors are potential therapeutic targets, with specific purinergic agonists and antagonists demonstrating prominent therapeutic potential. Furthermore, dietary and herbal interventions help to restore and balance purine metabolism, thus addressing the importance of a healthy lifestyle in the prevention and relief of human disorders. Profound understanding of molecular mechanisms of purinergic signalling provides new and exciting insights into the treatment of human diseases.

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From purines to purinergic signalling: molecular functions and human diseases.

Hyperuricemia, a condition due to high serum uric acid level and is notorious to health. It is considered to be a potent risk factor for gout and dramatically associated in the development of many chronic diseases such as malignant tumor, cardiovascular disorders and renal failure. Modern innovative medicinal and therapeutic interventions are underlying these days to combat hyperuricemia. Previously reported studies revealed the significant impact of dietary polyphenols (e.g. anthocyanins, phenolic acids, flavonoids etc.) against hyperurecemia disorder. Dietary plant polyphenols, unlike anti- hyperuricemic agents, are not reported to have any side effects in curing hyperuricemia. The current comprehensive review figure outs the use of dietary polyphenols as a natural remedy for the management of hyperuricemia. The sources, affiliated pathways, mode of actions and factors affecting their efficiency to prevent hyperuricemia are deeply discussed in this article. Additionally, limitations and suggestions regarding previously reported studies are also highlighted.

Management of hyperuricemia through dietary polyphenols as a natural medicament: A comprehensive review

We systematically identified the prevalence of hyperuricemia and gout in mainland China and provided informative data that can be used to create appropriate local public health policies. Relevant articles from 2000 to 2014 were identified by searching 5 electronic databases: PubMed, Google Scholar, Chinese Wanfang, CNKI, and Chongqing VIP. All of the calculations were performed using the Stata 11.0 and SPSS 20.0 software. The eligible articles (n = 36; 3 in English and 33 in Chinese) included 44 studies (38 regarding hyperuricemia and 6 regarding gout). The pooled prevalence of hyperuricemia and gout was 13.3% (95% CI: 11.9%, 14.6%) and 1.1% (95% CI: 0.7%, 1.5%), respectively. Although publication bias was observed, the results did not change after a trim and fill test, indicating that that impact of this bias was likely insignificant. The prevalence of hyperuricemia and gout was high in mainland China. The subgroup analysis suggested that the geographical region, whether the residents dwell in urban or rural and coastal or inland areas, the economic level, and sex may be associated with prevalence.

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Prevalence of Hyperuricemia and Gout in Mainland China from 2000 to 2014: A Systematic Review and Meta-Analysis.

Pycnogenol (PYC) is an extract from French maritime pine bark. Its antioxidative and anti-inflammatory effects have been shown to be beneficial for atherosclerosis. Here, we tested whether PYC could suppress high cholesterol and fat diet (HCD)-induced atherosclerosis formation in apolipoprotein E (apoE)-deficient mice. In our study, PYC suppressed oxidized low-density lipoprotein (ox-LDL)-induced lipid accumulation in peritoneal macrophages. Apolipoprotein E-deficient mice were orally administered PYC or a control solvent for ten weeks, and these mice were fed a standard diet or high cholesterol and fat diet during the latter eight weeks. Pycnogenol markedly decreased the size of atherosclerotic lesions induced by high cholesterol and fat diet compared with the nontreated controls. In addition, TLR4 expression in aortic sinus was stimulated by high cholesterol and fat diet feeding and was significantly reduced by PYC. A mechanistic analysis indicated that lipopolysaccharide (LPS) significantly increased expression of fatty acid binding protein (aP2) and macrophage scavenger receptor class A (SR-A), which were blocked by a JNK inhibitor. Furthermore, PYC inhibited the lipopolysaccharide-induced upregulation of aP2 and scavenger receptor class A via the JNK pathway. In conclusion, PYC administration effectively attenuates atherosclerosis through the TLR4-JNK pathway. Our results suggest that PYC could be a potential prophylaxis or treatment for atherosclerosis in humans.

Pycnogenol Reduces Toll-Like Receptor 4 Signaling Pathway-Mediated Atherosclerosis Formation in Apolipoprotein E-Deficient Mice.

Background: A study had reported that a low TSH level is associated with elevated plasma fibrinogen (FIB) levels. Our purpose was to investigate the role of FIB in the differential diagnosis of thyrotoxicosis. Methods: The data of 104 patients with primary thyrotoxicosis at the First Hospital of China Medical University from July 2010 to March 2011 were analyzed and divided into three groups: 45 cases of subacute thyroiditis, 50 cases of Graves’ disease, and 9 cases of toxic multinodular goiter. The patients with subacute thyroiditis were followed up before and after the treatment. FIB levels of the three groups were compared. Results: There was no significant difference in serum TSH, FT3 and FT4 between the patients with three different causes of thyrotoxicosis (P > 0.05). The proportion of hyperfibrinogenemia in patients with subacute thyroiditis was 98%. The FIB levels of patients with subacute thyroiditis were significantly higher than those with Graves’ disease and toxic multinodular goiter (P < 0.05). Levels of ESR show a similar tendency. The FIB levels returned to normal with the remission of subacute thyroiditis. Conclusions: Elevated plasma fibrinogen is a common manifestation of the active phase of subacute thyroiditis. A FIB test can be used for the differential diagnosis of thyrotoxicosis. We can anticipate the outcome of subacute thyroiditis through the dynamic changes of FIB.

Rui Liu

Papers

Prevalence of Hyperuricemia and Gout in Mainland China from 2000 to 2014: A Systematic Review and Meta-Analysis.

Pycnogenol Reduces Toll-Like Receptor 4 Signaling Pathway-Mediated Atherosclerosis Formation in Apolipoprotein E-Deficient Mice.

Utility of plasma fibrinogen in the differential diagnosis of thyrotoxicosis