Current updates for hyperuricemia and gout in age-related macular degeneration.

The escalating prevalence of metabolic syndrome poses a significant public health challenge, particularly among aging populations, with metabolic dysfunctions contributing to pro-inflammatory states. In this review, we delved into the less recognized association between hyperuricemia (HUA), a manifestation of metabolic syndrome and a primary risk factor for gout, and age-related macular degeneration (AMD), a sight-threatening ailment predominantly affecting the elderly. In recent years, inflammation, particularly its involvement in complement pathway dysregulation, has gained prominence in AMD pathophysiology. The contradictory role of uric acid (UA) in intercellular and intracellular environments was discussed, highlighting its antioxidant properties in plasma and its pro-oxidant effects intracellularly. Emerging evidence suggests a potential link between elevated serum uric acid levels and choroid neovascularization in AMD, providing insights into the role of HUA in retinal pathologies. Various pathways, including crystal-induced and non-crystal-induced mechanisms, were proposed to indicate the need for further research into the precise molecular interactions. The implication of HUA in AMD underscores its potential involvement in retinal pathologies, which entails interdisciplinary collaboration for a comprehensive understanding of its impact on retina and related clinical manifestations.

Uric acid en route to gout.

Gout and hyperuricemia (HU) have generated immense attention due to increased prevalence. Gout is a multifactorial metabolic and inflammatory disease that occurs when increased uric acid (UA) induce HU resulting in monosodium urate (MSU) crystal deposition in joints. However, gout pathogenesis does not always involve these events and HU does not always cause a gout flare. Treatment with UA-lowering therapeutics may not prevent or reduce the incidence of gout flare or gout-associated comorbidities. UA exhibits both pro- and anti-inflammation functions in gout pathogenesis. HU and gout share mechanistic and metabolic connections at a systematic level, as shown by studies on associated comorbidities. Recent studies on the interplay between UA, HU, MSU and gout as well as the development of HU and gout in association with metabolic syndromes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular, renal and cerebrovascular diseases are discussed. This review examines current and potential therapeutic regimens and illuminates the journey from disrupted UA to gout.

Spontaneous resolution of acute gout: mechanisms and therapeutic targets.

Gout is a common inflammatory arthritis that has been increasing in both prevalence and incidence. Consequently, management of refractory and chronic gout has been gaining attention. Onset of gout is related to the deposition of monosodium urate crystals under hyperuricaemia. Interestingly, acute gout attacks often resolve spontaneously within 7-10 days, and many studies have confirmed the notion that gout flares can be self-relieved. However, the underlying mechanism for spontaneous remission of gout requires further elucidation. In this article, we summarise the roles and mechanisms related to spontaneous remission of gout, which are essential for understanding its pathogenesis and developing potential targeted therapies.

Sodium-glucose cotransporter-2 inhibitors use and the risk of gout: a systematic review and meta-analysis.

Objective: To assess the relationship between use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and the risk of gout among patients with type 2 diabetes mellitus (T2DM). Methods: A systemic review and meta-analysis were designed by reviewing articles published between 2000 January 1 and 2022 December 31 using PubMed system and Web of Science system based on the PRISMA 2020 guidelines. The end point of interest was gout (including gout flares, gout events, starting uric-acid lowering therapy and starting anti-gout drugs use) among patients with T2DM using SGLT2i versus not using SGLT2i. A random-effects model was utilized to measure the pooled hazard ratio (HR) with 95% confidence interval (CI) for the risk of gout associated with SGLT2i use. Results: Two prospective post-hoc analyses of randomized controlled trials and 5 retrospective electronic medical record-linkage cohort studies met the inclusion criteria. The meta-analysis demonstrated that there was a decreased risk of developing gout for SGLT2i use as comparing with non-use of SGLT2i among patients with T2DM (pooled HR=0.66 and 95%CI=0.57-0.76). Conclusions: This meta-analysis demonstrates that SGLT2i use is associated with a 34% decreased risk of developing gout among patients with T2DM. SGLT2i may be the treatment options for patients with T2DM who are at high risk of gout. More randomized controlled trials and real-world data are needed to confirm whether there is a class effect of SGLT2i for the risk reduction of gout among patients with T2DM.

Risk Factors for Hyperuricemia or Gout in Men and Women: The Circulatory Risk in Communities Study (CIRCS).

AIM: We aimed to examine sex-specific risk factors for hyperuricemia or gout in Japanese cohorts. METHODS: We followed up 3,188 men (mean age, 55.6 years) and 6,346 women (mean age, 54.1 years) without hyperuricemia, gout, or elevated liver enzymes at baseline from 1986 to 1990 for a median of 14.6 years. The participants were considered as having hyperuricemia or gout if their serum uric acid levels were ≥ 7.0 mg/dL or they were receiving treatment for hyperuricemia or gout during annual health checkups. The sex-specific multivariable hazard ratios (HRs) of hyperuricemia or gout incidence were calculated after adjustment for smoking and drinking status, body mass index, hypertension, diabetes, hypercholesterolemia, and hypertriglyceridemia using the Cox proportional-hazard model. RESULTS: During follow-up, 733 men and 355 women had hyperuricemia or gout. Among men, the multivariable HRs (95% confidence intervals) of hyperuricemia or gout were 1.23 (1.00-1.52) and 1.41 (1.13-1.75) for drinkers of ＜46 and ≥ 46 g ethanol/day, respectively, compared with non-drinkers; 1.00 (0.81-1.24) and 1.18 (0.93-1.50) for smokers of 1-19 and ≥ 20 cigarettes/day, respectively, compared with never smokers; and 1.41 (1.20-1.65) for hypertensive compared with non-hypertensive participants. The HRs for women were 1.02 (0.70-1.48), 1.66 (1.05-2.63), and 1.12 (0.88-1.42) for current drinkers, current smokers, and hypertensive participants, respectively. For both men and women, body mass index, diabetes, hypercholesterolemia, and hypertriglyceridemia were not associated with hyperuricemia or gout incidence. CONCLUSIONS: Hypertension and alcohol drinking are risk factors for hyperuricemia or gout among men and smoking among women.

"Dialogue Between Franklin and the Gout" Reexamined.

Benjamin Franklin, one of the founding fathers of the United States, was not just a politician and a political philosopher but an inventor with a scientific temperament. He was overweight and likely suffered from the consequences of metabolic syndrome including gout. He woke up with a gout attack on October 22, 1780 and wrote the "Dialogue Between Franklin and the Gout." His observations on the risk factors for gout are re-examined in the modern context 243 years later.

Modifiable risk factors and incidence of gout: Estimation of population attributable fraction in the US.

OBJECTIVE: The burden of gout is substantial in the United States (US). Most gout cases can be attributed to modifiable risk factors, while systematic evidence-based assessment of gout cases and incidence attributable to the risk factors in the US is limited. METHODS: The estimated cases and incidence of gout in the US was obtained from global burden of disease (GBD) study 2019. We calculated the exposure rate of risk factors from National Health and Nutrition Examination Survey (NHANES) 2009-2010, since we estimated an average induction time of 10 years for risk factors and gout. We also conducted a meta-analysis to evaluate the associations of modifiable risk factors and gout in the US population. Furthermore, the population attributable fraction (PAF) was calculated using based on the prevalence of risk factors and relative risk (RR) from the meta-analysis. RESULTS: The weighted prevalence of hypertension was 14.37%, and the average body mass index (BMI) and alcohol consumption was 28.50 kg/m2 and 7.14 g/d, respectively. Meta-analysis showed that individuals with hypertension had a higher risk of gout (2.12, 95% CI 1.88 to 2.40). For every five units of increase in BMI, the risk of gout increased by 1.48-fold (95% CI 1.26 to 1.75). The pooled RR was 1.21 (95% CI 1.13 to 1.29) for every 10 g/day increment of alcohol consumption. BMI, hypertension and alcohol consumption accounted for 53.58%, 13.85% and 12.66% of gout cases, respectively. Overall, 65.05% of gout incidence was attributable to the joint effects of these three risk factors. CONCLUSION: Hypertension, excess BMI and high alcohol consumption were responsible for approximately 65% of gout incidence in the US in 2019. Reducing the exposure to these factors can effectively reduce the incidence of gout.

Environmental factors and risk of gout.

Gout is a chronic disease with inflammatory arthritis caused by monosodium urate (MSU) crystals deposition, an elevated serum urate level (hyperuricaemia) is the critical factor leading to MSU crystals deposition and promoting the progression of gout. The onset and development of gout is generally the result of multiple factors, such as diet, heredity and environmental factors. Although genetics and diet are thought to play as major factors, a growing body of research evidence has highlighted that environmental factors also play a significant role in the onset and exacerbation of gout. Recent studies have shown that air pollutants such as particulate matter, sulfur dioxide (SO2) and carbon monoxide (CO) may increase the risk of hospitalizations for gout, and that the changes in temperature and humidity may affect uric acid (UA) levels. There is also seasonal trend in gout. It has been demonstrated that environmental factors may induce or accelerate the production and release of pro-inflammatory mediators, causing an unbalance oxidative stress and systemic inflammation, and then participating in the overall process or a certain link of gout. Moreover, several environmental factors have shown the ability to induce the production urate and regulate the innate immune pathways, involving in the pathogenesis of gout. Nevertheless, the role of environmental factors in the etiology of gout remains unclear. In this review, we summarized the recent literatures and aimed to discuss the relationship between environmental factors (such as microclimate, season, ambient/indoor air pollution and extreme weather) and gout. We further discussed the inflammatory mechanisms of environmental factors and gout and the comprehensive effects of environmental factors on gout. We also made a prospect of the management and treatment of gout, with special consideration to environmental factors associated with gout.

The Role of the Intestine in the Development of Hyperuricemia.

Gout is a common inflammatory arthritis caused by the deposition of sodium urate crystals in the joints. Hyperuricemia is the fundamental factor of gout. The onset of hyperuricemia is related to purine metabolism disorders or uric acid excretion disorders. Current studies have shown that the intestine is an important potential organ for the excretion of uric acid outside the kidneys. The excretion of uric acid of gut is mainly achieved through the action of uric acid transporters and the catabolism of intestinal flora, which plays an important role in the body's uric acid balance. Here we reviewed the effects of intestinal uric acid transporters and intestinal flora on uric acid excretion, and provide new ideas for the treatment of hyperuricemia and gout.

Tetrahedral-Framework Nucleic Acids Carry Small Interfering RNA to Downregulate Toll-Like Receptor 2 Gene Expression for the Treatment of Sepsis.

Sepsis is caused by the invasion of pathogenic microorganisms, which can lead to excessive expression of toll-like receptors (TLRs) in cells and uncontrollable amplification of the inflammatory response. TLR2, as an essential part of the TLR family, has a significant feature in the identification of innate immune responses. Therefore, blocking the expression and activation of TLR2 can inhibit the synthesis and release of inflammatory factors and avoid the occurrence of excessive inflammatory reactions. Small interfering RNA (siRNA) can selectively target the silencing or downregulation of pathogenic genes and has the advantages of high specificity, a strong effect, and fewer adverse reactions. However, the application of siRNA is limited by its high molecular weight, poor biostability, and difficulty in passive uptake into cells. Tetrahedral-framework nucleic acid (tFNA) is a new kind of three-dimensional nucleic acid nanomaterial, which has the advantages of good biocompatibility, stable structure, and editability. In this study, we used tFNA as carriers to deliver siRNA-targeting downregulation of TLR2 expression for anti-inflammatory therapy. We show that siRNA can specifically reduce lipopolysaccharide (LPS)-induced TLR2 elevation and reduce release of inflammatory factors in LPS-induced experimental sepsis, which provides a new idea for the prevention and treatment of sepsis.

The role of alcohol consumption in pathogenesis of gout.

Alcohol is recognized a risk factor for increased uric acid and gout flare. The aim of the study was to review the literature in order to find out what is the role of alcohol consumption in pathogenesis of gout. A search in PubMed, Google Scholar, Medline Complete database was performed in January 2021. The databases were searched with the phrases: "uric acid and alcohol," "alcoholic beverages and gout," "hyperuricemia and alcoholic beverages consumption" published between 2000 and 2021. A total of 2642 results were found. The 99 non-duplicate citations were screened. Then 81 articles were excluded after abstract screen. After that 18 articles were retrieved. Eventually 15 articles were included for systematic review. Several authors see the positive correlation between beer or distilled spirits consumption and gout. Some include wine to the list of triggers of gout. Others state that moderate wine consumption protects from gout attacks due to antioxidants and phytoestrogen content. Majority noticed the relationship between episodic alcohol consumption and gout attacks. Episodic alcohol intake triggers gout attacks, regardless of type of alcohol. Thus, individuals with established gout and pre-existing risk factors should limit all types of alcohol intake to prevent gout episodes.

Uric acid extrarenal excretion: the gut microbiome as an evident yet understated factor in gout development.

Humans do not produce uricase, an enzyme responsible for degrading uric acid. However, some bacteria residing in the gut can degrade one-third of the dietary and endogenous uric acid generated daily. New insights based on metagenomic and metabolomic approaches provide a new interest in exploring the involvement of gut microbiota in gout. Nevertheless, the exact mechanisms underlying this association are complex and have not been widely discussed. In this study, we aimed to review the evidence that suggests uric acid extrarenal excretion and gut microbiome are potential risk factors for developing gout. A literature search was performed in PubMed, Web of Science, and Google Scholar using several keywords, including "gut microbiome AND gout". A remarkable intestinal dysbiosis and shifts in abundance of certain bacterial taxa in gout patients have been consistently reported among different studies. Under this condition, bacteria might have developed adaptive mechanisms for de novo biosynthesis and salvage of purines, and thus, a concomitant alteration in uric acid metabolism. Moreover, gut microbiota can produce substrates that might cross the portal vein so the liver can generate de novo purinogenic amino acids, as well as uric acid. Therefore, the extrarenal excretion of uric acid needs to be considered as a factor in gout development. Nevertheless, further studies are needed to fully understand the role of gut microbiome in uric acid production and its extrarenal excretion, and to point out possible bacteria or bacterial enzymes that could be used as probiotic coadjutant treatment in gout patients.

Purinergic Signaling in the Regulation of Gout Flare and Resolution.

Gout flares require monosodium urate (MSU) to activate the NLRP3 inflammasome and secrete sufficient IL-1ß. However, MSU alone is not sufficient to cause a flare. This is supported by the evidence that most patients with hyperuricemia do not develop gout throughout their lives. Recent studies have shown that, besides MSU, various purine metabolites, including adenosine triphosphate, adenosine diphosphate, and adenosine bind to different purine receptors for regulating IL-1ß secretion implicated in the pathogenesis of gout flares. Purine metabolites such as adenosine triphosphate mainly activate the NLRP3 inflammasome through P2X ion channel receptors, which stimulates IL-1ß secretion and induces gout flares, while some purine metabolites such as adenosine diphosphate and adenosine mainly act on the G protein-coupled receptors exerting pro-inflammatory or anti-inflammatory effects to regulate the onset and resolution of a gout flare. Given that the purine signaling pathway exerts different regulatory effects on inflammation and that, during the inflammatory process of a gout flare, an altered expression of purine metabolites and their receptors was observed in response to the changes in the internal environment. Thus, the purine signaling pathway is involved in regulating gout flare and resolution. This study was conducted to review and elucidate the role of various purine metabolites and purinergic receptors during the process.

Role of diet in hyperuricemia and gout.

BACKGROUND: Gout is the most common form of inflammatory arthritis, affecting 41 million adults worldwide. The global burden of gout has been increasing over the last three decades, yet its management remains suboptimal. The primary aim of this manuscript is to review the impact of various diets such as the DASH, Mediterranean, and low purine diets; weight loss; and individual foods, including alcohol, caffeine, cherry, dairy, high-fructose corn syrup, omega-3 fatty acids, and vitamin C on hyperuricemia and clinical gout outcomes such as flares and tophi. CONCLUSION: Few studies to date have specifically evaluated the effect of various dietary approaches on hyperuricemia among people with gout and on gout-specific outcomes. Overall, the dietary factors appear to have a small effect on serum urate levels, and their impact on the long-term clinical course of gout is uncertain. Limited evidence suggests that avoidance of certain foods and beverages may decrease the frequency of gout flares. Weight loss may be beneficial for prevention as well as treatment of gout. Urate-lowering therapy remains the mainstay of therapy, with diet and dietary factors studied to date playing a limited role in the definitive management of gout.

CD38 activation by monosodium urate crystals contributes to inflammatory responses in human and murine macrophages.

Cluster of differentiation (CD) 38, a major enzyme for nicotinamide adenine dinucleotide (NAD+) degradation, plays a key role in inflammation. Meanwhile, intracellular NAD+ decline is also associated with inflammatory responses. However, whether CD38 activation is involved in gouty inflammation has not been elucidated. The present study aimed to clarify the role of CD38 in monosodium urate crystals (MSU)-triggered inflammatory responses. The results showed that MSU crystals increased the protein expression of CD38 in time- and concentration-dependent manner in THP-1 macrophages and mouse bone marrow-derived macrophages (BMDMs). Moreover, intracellular NAD+ levels were reduced by MSU crystals along with the increased IL-1ß release. However, CD38 inhibition by 78c elevated intracellular NAD+ levels and suppressed IL-1ß release in MSU crystals-treated THP-1 macrophages and BMDMs. Interestingly, CD38 inhibition without significant elevation of intracellular NAD+ also decreased IL-1ß release driven by MSU crystals in THP-1 macrophages. In conclusion, the present study revealed that MSU crystals could activate CD38 with the ensuing intracellular NAD+ decline to promote inflammatory responses in THP-1 macrophages and BMDMs, while CD38 inhibition could suppress MSU crystals-triggered inflammatory responses, indicating that CD38 is a potential therapeutic target for gout.

Gout Augments the Risk of Cardiovascular Disease in Patients With Psoriasis: A Population-Based Cohort Study.

Objective: Patients with psoriasis (PsO) have a high frequency of concomitant gout and increased risk of cardiovascular diseases (CVD). We aimed to estimate the synergistic impact of gout on the risk of CVD in patients with PsO. Methods: A population-based cohort of patients registered in the National Health Insurance Research Database of Taiwan between 2000 and 2013 was stratified according to the presence of PsO and gout. Propensity score analysis was used to match age and gender at a ratio of 1:4. Cox proportional hazard models and subgroup analyses were used to estimate the hazard ratios (HRs) for CVD adjusted for traditional risk factors. The Kaplan-Meier method was used to plot the cumulative incidence curves. Results: Patients with combined PsO and gout (n = 97), PsO alone (n = 388), gout alone (matched, n = 388) and matched controls (n = 388) were identified. Compared with the patients with PsO alone, the patients with combined PsO and gout had a significantly higher risk of CVD (relative risk 2.39, 95% CI 1.56 to 3.65). After adjustment for traditional risk factors, the risk of CVD was higher in patients with gout alone (HR 2.16, 95% CI 1.54 to 3.04) and in patients with combined PsO and gout (HR 2.72, 95% CI 1.73 to 4.28). Conclusions: Gout augments the risk of CVD independently of traditional risk factors in patients with PsO.

The Role of ABCG2 in the Pathogenesis of Primary Hyperuricemia and Gout-An Update.

Urate homeostasis in humans is a complex and highly heritable process that involves i.e., metabolic urate biosynthesis, renal urate reabsorption, as well as renal and extrarenal urate excretion. Importantly, disturbances in urate excretion are a common cause of hyperuricemia and gout. The majority of urate is eliminated by glomerular filtration in the kidney followed by an, as yet, not fully elucidated interplay of multiple transporters involved in the reabsorption or excretion of urate in the succeeding segments of the nephron. In this context, genome-wide association studies and subsequent functional analyses have identified the ATP-binding cassette (ABC) transporter ABCG2 as an important urate transporter and have highlighted the role of single nucleotide polymorphisms (SNPs) in the pathogenesis of reduced cellular urate efflux, hyperuricemia, and early-onset gout. Recent publications also suggest that ABCG2 is particularly involved in intestinal urate elimination and thus may represent an interesting new target for pharmacotherapeutic intervention in hyperuricemia and gout. In this review, we specifically address the involvement of ABCG2 in renal and extrarenal urate elimination. In addition, we will shed light on newly identified polymorphisms in ABCG2 associated with early-onset gout.

NLRP3 inflammasome inhibitor cucurbitacin B suppresses gout arthritis in mice.

Gouty arthritis is a common inflammatory disease characterized by monosodium urate (MSU) crystal-induced nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome activation with upregulated caspase 1 protease and IL-1ß in macrophages. Cucurbitacin B (CuB) is a tetracyclic triterpene that possesses a potential anti-inflammatory activity. However, the immunomodulatory and anti-inflammatory effects of CuB on gout have not been well characterized. Therefore, the purpose of the present study was to determine whether CuB exhibits anti-inflammatory effects on gout and to analyze the underlying molecular mechanism. We examined the effects of CuB on various stimuli-activated bone marrow-derived macrophages (BMDMs) and in a mouse model with MSU-induced acute gouty arthritis. Our results demonstrated that CuB effectively suppressed multiple stimuli-activated IL-1ß secretion by interrupting NLRP3 inflammasome complex formation, inhibiting NLRP3 inflammasome activation and suppressing key enzymes of glycolysis in macrophages. Consistent with this, CuB pretreatment also ameliorated MSU-induced arthritis in vivo models of gout arthritis, manifested by reduced foot swelling and inflammatory cell infiltration. Taken together, our data provide the evidence that CuB is an NLRP3 inflammasome inhibitor with therapeutic potential for treating NLRP3 inflammasome-mediated diseases, especially gouty arthritis.

Taxonomic variations in the gut microbiome of gout patients with and without tophi might have a functional impact on urate metabolism.

OBJECTIVE: To evaluate the taxonomic composition of the gut microbiome in gout patients with and without tophi formation, and predict bacterial functions that might have an impact on urate metabolism. METHODS: Hypervariable V3-V4 regions of the bacterial 16S rRNA gene from fecal samples of gout patients with and without tophi (n = 33 and n = 25, respectively) were sequenced and compared to fecal samples from 53 healthy controls. We explored predictive functional profiles using bioinformatics in order to identify differences in taxonomy and metabolic pathways. RESULTS: We identified a microbiome characterized by the lowest richness and a higher abundance of Phascolarctobacterium, Bacteroides, Akkermansia, and Ruminococcus_gnavus_group genera in patients with gout without tophi when compared to controls. The Proteobacteria phylum and the Escherichia-Shigella genus were more abundant in patients with tophaceous gout than in controls. Fold change analysis detected nine genera enriched in healthy controls compared to gout groups (Bifidobacterium, Butyricicoccus, Oscillobacter, Ruminococcaceae_UCG_010, Lachnospiraceae_ND2007_group, Haemophilus, Ruminococcus_1, Clostridium_sensu_stricto_1, and Ruminococcaceae_UGC_013). We found that the core microbiota of both gout groups shared Bacteroides caccae, Bacteroides stercoris ATCC 43183, and Bacteroides coprocola DSM 17136. These bacteria might perform functions linked to one-carbon metabolism, nucleotide binding, amino acid biosynthesis, and purine biosynthesis. Finally, we observed differences in key bacterial enzymes involved in urate synthesis, degradation, and elimination. CONCLUSION: Our findings revealed that taxonomic variations in the gut microbiome of gout patients with and without tophi might have a functional impact on urate metabolism.

Why Does Hyperuricemia Not Necessarily Induce Gout?

Hyperuricemia is a risk factor for gout. It has been well observed that a large proportion of individuals with hyperuricemia have never had a gout flare(s), while some patients with gout can have a normuricemia. This raises a puzzle of the real role of serum uric acid (SUA) in the occurrence of gout flares. As the molecule of uric acid has its dual effects in vivo with antioxidant properties as well as being an inflammatory promoter, it has been placed in a delicate position in balancing metabolisms. Gout seems to be a multifactorial metabolic disease and its pathogenesis should not rely solely on hyperuricemia or monosodium urate (MSU) crystals. This critical review aims to unfold the mechanisms of the SUA role participating in gout development. It also discusses some key elements which are prerequisites for the formation of gout in association with the current therapeutic regime. The compilation should be helpful in precisely fighting for a cure of gout clinically and pharmaceutically.