Changing a paradigm.

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.

Background and Objective: Despite striking advances in multimodality management, gastric cancer (GC) remains the third cause of cancer mortality globally and identifying novel diagnostic and prognostic biomarkers is urgently demanded. The study aimed to identify potential key genes associated with the pathogenesis and prognosis of GC. Methods: Differentially expressed genes between GC and normal gastric tissue samples were screened by an integrated analysis of multiple gene expression profile datasets. Key genes related to the pathogenesis and prognosis of GC were identified by employing protein-protein interaction network and Cox proportional hazards model analyses. Results: We identified nine hub genes (TOP2A, COL1A1, COL1A2, NDC80, COL3A1, CDKN3, CEP55, TPX2 and TIMP1) which might be tightly correlated with the pathogenesis of GC. A prognostic gene signature consisted of CST2, AADAC, SERPINE1, COL8A1, SMPD3, ASPN, ITGBL1, MAP7D2, and PLEKHS1 was constructed with a good performance in predicting overall survivals. Conclusion: The findings of this study would provide some directive significance for further investigating the diagnostic and prognostic biomarkers to facilitate the molecular targeting therapy of GC. Key words: gastric cancer, bioinformatics, differentially expressed genes, survival, biomarker, GEO, TCGA

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Identification of Potential Key Genes Associated With the Pathogenesis and Prognosis of Gastric Cancer Based on Integrated Bioinformatics Analysis

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

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.

Aims of this study were to determine the normal range of absolute and relative Hertel exophthalmometric values (EVs) in a Chinese Han population. This population-based cross-sectional study consisted of 2010 healthy Han Chinese (1051 females and 959 males) aged between 8–87 years living in Shenyang, Northeast China, including 515 children (aged 8–14 years), 517 teenagers (aged 15–19 years), 582 adults (aged 20–69 years) and 396 elderly (aged 70–87 years). A Hertel exophthalmometer was used by the same physician for the measurement of EV and inter-orbital distance (IOD). For the entire study population, the Hertel EVs ranged from 10 mm to 22 mm; the mean EVs for the left eye (OS) and right eye (OD) were 15.0 ± 1.9 mm and 15.0 ± 2.0 mm, respectively; the upper normal limits of the EVs (mean + 2 SD) for OS and OD were 18.8 mm and 19.0 mm, respectively; the mean relative EV was 0.20 ± 0.43 mm. Age, but not sex, had a significant effect on the EV. We concluded that our study provides normative ophthalmic data in a Chinese Han population. The normal EVs, asymmetry and IOD values have been established for clinical reference.

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Normal Values of Hertel Exophthalmometry in a Chinese Han Population from Shenyang, Northeast China

Cyclin-dependent kinase inhibitor 3 (CDKN3) has been reported to promote tumorigenesis. Since it is unclear whether CDKN3 participates in the development of human gastric cancer, this study assessed the association between CDKN3 expression and cell biological function and demonstrated the clinical significance and prognosis of CDKN3 in human gastric cancer. In this study, we found that CDKN3 showed a high expression in 35 paired human gastric cancer tissues and was correlated with poor patient survival, AJCC clinical staging, and recurrence. Silencing of CDKN3 in human gastric cancer cells can significantly reduce proliferation, migration, invasion, and adhesion abilities. Also, silencing of CDKN3 in human gastric cancer cells can induce G0-G1 cell cycle arrest and apoptosis. Detection of cell cycle marker expression showed that CDKN3 knockdown promotes cell cycle arrest by decreasing the expression of CDK2, CDC25A, CCNB1, and CCNB2 in human gastric cancer cells. The results of this study will help elucidate the oncogene function of CDKN3 in human gastric cancer.

Knockdown of Cyclin-Dependent Kinase Inhibitor 3 Inhibits Proliferation and Invasion in Human Gastric Cancer Cells.

Molecular epidemiologic studies previously reported that 1,25-dihydroxy vitamin D3 (1,25(OH)2 D3) appears to influence cancer risk It exerts its activity through the intracellular vitamin D receptor (VDR), which regulates the transcription of genes This study aimed to investigate the genetic association of VDR polymorphisms with renal cell carcinoma (RCC) risk in the Chinese population The genotypes of five VDR polymorphisms (TaqI, BsmI, Cdx-2, ApaI and FokI) were studied using polymerase chain reaction in 302 RCC patients and 302 healthy controls ApaI variant AA and AC genotypes were found to be associated with a significantly increased risk of RCC compared with the CC genotype (OR = 260, 95% CI = 139–485 for AA vs CC and OR = 152, 95% CI = 108–213 for AC vs CC) The AA genotype was also associated with a higher Fuhrman grade (OR = 287, 95% CI = 115–716 for AA vs CC) No significant difference was found between the other four VDR polymorphisms and RCC risk Our study suggests that VDR ApaI genotypes may be involved in the increased risk and progression of RCC in the Chinese Han population

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The vitamin D receptor gene ApaI polymorphism is associated with increased risk of renal cell carcinoma in Chinese population.

Polyostotic fibrous dysplasia (PFD) is a rare non-inherited genetic disorder characterized by osteolytic lesions in multiple bones causing bone pain, deformity, and pathological fracture. As an anti-osteolytic agent, the new generation bisphosphonate zoledronic acid (ZOL) restricts lesion progression by inhibiting osteoclastic activity. Although ZOL is more effective than pamidronate, its efficacy and safety in long-term therapy in PFD is unknown. We report a case of PFD advanced to extensive bone destruction in the skull and ribs and evaluate the efficacy and long-term safety of early first-line ZOL in PFD with severe bone disease, recommending possible future treatments. The annual infusion of 5 mg ZOL was intravenously administered, cumulatively 20 mg over four courses, with oral supplementation of calcium, vitamin D, and potassium. No long-term use side effect was observed, and mild transient symptoms were easily resolved. Significant radiological improvement was seen in filling of destroyed bone and cortical thickening. ZOL decreased both serum collagen type 1 cross-linked C-telopeptide and type 1 procollagen N-terminal (P1NP) from extremely high baseline levels. An unexpected direct increase in P1NP after long-term therapy could indicate discontinuation of ZOL to observe its prolonged effect. Early first-line ZOL therapy is effective in PFD with severe bone destruction and is safe for long-term therapy. The use of bisphosphonates in FD remains off-label, and regular monitoring is highly advised.

Di Wu

Papers

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

Normal Values of Hertel Exophthalmometry in a Chinese Han Population from Shenyang, Northeast China

Knockdown of Cyclin-Dependent Kinase Inhibitor 3 Inhibits Proliferation and Invasion in Human Gastric Cancer Cells.

The vitamin D receptor gene ApaI polymorphism is associated with increased risk of renal cell carcinoma in Chinese population.

Continuous effect with long-term safety in zoledronic acid therapy for polyostotic fibrous dysplasia with severe bone destruction