Hyperuricemia (HC) was one of the important risk factors for gout, arteriosclerosis, and cardiovascular disease. Animal studies have shown that Lactobacillus plantarum can improve the microbiota, immune regulation, and inhibit the uric acid production. However, it was not clear whether L. plantarum can improve HC and intestinal microbiota. We used potassium oxonate (PO) to induce HC in male SD rats, and then treated L. plantarum TCI227 in a dose dependent (HC+LD, HC+MD, HC+HD) for 4 weeks, and examined weight organs, biochemical examination of blood and urine, and analyzed the intestinal microbiota in feces by 16s rDNA sequence analysis. In this study, TCI227 improved body weight, decreased creatinine, serum uric acid, and increased urine uric acid compared to the HC group. Furthermore, TCI227 increased short-chain fatty acids (SCFAs). In fecal microbiota (family), TCI227 increased the level of Lactobacillaceae, and then decreased the level of Deferribacteres and Prevotellaceae compared to the HC group. Finally, in fecal microbiota (genus), TCI227 decreased the level of Prevotella, and then increased the level of Lactobacillus and Ruminococcus compared to the HC group. This study suggested that TCI227 can improve HC and change the compositions of the intestinal microbiota in PO induced male HC SD rats.

Abstract: Hyperuricemia is commonly diagnosed in subjects with abnormal purine metabolism. Prolonged hyperuricemia often associated with gout, which is a vital risk factor for joint dysfunction. The current study was designed to determine the efficacy of vitamin C supplements for treatment of high serum uric acid (UA) among hyperuricemic and gouty patients, and finding-out the effect of supplementation on serum creatinine (Cr) level and glomerular filtration rate (GFR). This intervention study was started in April, 2013, till two months. A convenient sample of 30 adults aged between 24-75 years of both genders was assigned into two study groups: hyperuricemic (n=15) and gouty (n=15) groups. Each participant supplemented with 500 mg/day vitamin C chewable tablets for 2 months. Serum UA, Cr, and GFR were measured before and after treatment. At the end of this study, Cr and GFR enhanced insignificantly in both groups. UA increased insignificantly in gouty group after 2 months by about 0.31 mg/dl. On the other hand, hyperuricemic group showed significant (P ≤0.05) decrease in UA (-0.78 mg/dl) after 2 months duration. In conclusion, supplementation with 500 mg/day vitamin C for 2 months significantly attenuated serum UA for hyperuricemic patients and insignificantly affected serum UA in gouty patients. The uselessness of vitamin C supplements on gouty patients could be associated to a number of possible reasons.

The ATP-binding cassette (ABC) transporter ABCG2 is a significant urate transporter with a high capacity, and it plays a crucial role in the development of hyperuricemia and gout. Therefore, it has the potential to be targeted for therapeutic interventions. Cortex Fraxini, a traditional Chinese medicine (TCM), has been found to possess anti-hyperuricemia properties. However, the specific constituents of Cortex Fraxini responsible for this effect are still unknown, particularly the compound that is responsible for reducing uric acid levels in vivo. In this study, we propose a target screening protocol utilizing bio-affinity ultrafiltration mass spectrometry (BA-UF-MS) to expediently ascertain ABCG2 ligands from the plasma of rats administered with Cortex Fraxini. Our screening protocol successfully identified fraxin as a potential ligand that interacts with ABCG2 when it functions as the targeted protein. Subsequent investigations substantiated fraxin as an activator of ABCG2. These findings imply that fraxin exhibits promise as a drug candidate for the treatment of hyperuricemia. Furthermore, the utilization of BA-UF-MS demonstrates its efficacy as a valuable methodology for identifying hit compounds that exhibit binding affinity towards ABCG2 within TCMs.

Gout is not only associated with obstructive sleep apnea (OSA), but the intermittent episodes of hypoxia that occur with OSA may also have a role in causing gout. Epidemiological studies have documented a higher incidence and prevalence of gout in individuals diagnosed with OSA than in individuals never diagnosed with OSA. The pathophysiology of OSA’s chronic episodes of hypoxia leading to hyperuricemia and gout involves boththe overproduction and underexcretion of uric acid. Treating OSA may be an additional way to control gout and its life-threatening comorbidities. Clinicians are urged to evaluate their patients with hyperuricemia/gout for OSA as it may lead to alternative ways to control gout with superior outcomes that simply pharmacologic treatment alone.

Hyperuricemia is a risk factor for gout. It has been well observed that a large proportion of hyperuricemia individuals have never had a gout attack(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 attacks. As the molecule of uric acid has its dual effects in vivo with antioxidant property 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 MSU crystal. This critical review aims to unfold the mechanisms of the SUA role participating in gout development. It also discusses some key elements which are prerequisite 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.

Gout is the most common form of inflammatory arthritis. Hyperuricaemia is the pre-requisite for gout and is influenced by variable modifiable and non-modifiable risk factors. Clinical features unique for gout are due to deposition of monosodium urate (MSU) crystal in articular and extra articular tissues. Among various treating agents, anti-inflammatory drugs and urate lowering therapies (ULT) are used widely and successfully, however, non-medicinal means are also effective in the disorder. In their updated guidelines, ACR (2012) and EULAR (2016) recommended both medicinal and non-medicinal approaches that could be used in treating gout, though some of the recommendations are based on lower level of evidence. Moreover, researchers’ continued effort in finding new gout managing agents appear promising, for example, role of Lesinurad in gout management (CLEAR1, CLEAR2). In this new synthesis the author is aimed to provide updated information on gout management based on a systematic review including published work within last ten years between 2008 and 2018 and for this purpose, using ‘clinical trials in gout management’ string, published worked searched in PubMed database from 1st September 2018 to 30 October 2018. Besides the recent ACR and EULAR evidence based management guidelines, the author reviewed another 91 (total 93) articles to make this new draft – 39 articles describe role of pharmacological agents and 54 describe different gout risks, pharmacokinetics/pharmacodynamics of ULT, association between raised sUA level and renal impairment, efficacy of non-pharmacological agents in reducing sUA. According to published work, anti-inflammatory agent is the most appropriate drug group in mitigating inflammatory symptoms of gout, though they often adversely affect over other vital 2 organs with impaired function. Besides ULT, uricase analogues are also found useful in non refractory gout. Since anti-inflammatory agents and ULT contraindicate in some clinical conditions, intra-articular steroid and or adrenocorticotropic hormone (ACTH) are appropriate alternatives instead. However, head-to-head comparison between different NSAIDs, NSAID and prednisolone, NSAID and colchicine are yet to perform. Use of combined anti-inflammatory preparations in gout is also based on lower level of evidence. Regarding effective maximum dose and long-standing impact of ULT on vital organs we are yet to reach a conclusion. Likewise, non-medicinal approaches are widely using in achieving target sUA level, though some of them are based on biased study outcomes and or study with inadequate power, requiring further analysis. Among non-pharmacological approaches, life-style modification, restriction of purine rich diets, avoidance of gout inciting agents are important, but inconclusive. Educating patients’ about diseases, risk factors, available treatment options and side effects from them are also important in terms of achieving sUA level, nevertheless too much counseling sometimes could be worthless.

The accumulation of loss of function mutations in the uricase gene well explains the high urate levels in hominoids (apes and humans) compared to other mammals. The loss of human uricase activity may have allowed humans to survive environmental stressors, evolution bottlenecks, and life-threatening pathogens. While high urate levels may contribute to developing cardiometabolic disorders such as hypertension and insulin resistance, low urate levels may increase the risk for neurodegenerative diseases. The double-edged sword effect of uric acid has resurrected a growing interest in the antioxidant role of urate and the role of the uricase gene in modulating the risk of obesity. Characterizing both the effect of uric acid levels and the uricase gene in different animal models may provide new insights into the potential therapeutic benefits of uric acid and novel uricase-based therapy.

Gout is at least 3 times more prevalent in men than in women. However, concurrent with rising total gout prevalence, complex factors, including comorbidities, diet and lifestyle, and aging, have promoted higher gout prevalence in females. This narrative review focuses on summarizing recent developments in the landscape of gout in women, and mechanisms involved. New knowledge on sex hormone effects on both urate-excreting and urate-reabsorbing transporters, and higher hypertension and chronic kidney disease prevalence in women compared to men, may help explain why gout incidence rises robustly after menopause in women to approach that in men. Racial and ethnic factors, risk profiles based on heritable genetic polymorphisms of urate transporters, and diet, body mass index, and lifestyle factors differ according to sex. In addition, sex differences in clinical phenotypes and outcomes of gout and non-gout illnesses include more frequent comorbidities, more pain and disability during gout flare, different perceptions of disease burden, and more frequent severe cutaneous hypersensitivity reaction to allopurinol in women. Significantly, women with gout also have poorer COVID-19 outcomes than do men. Collectively, such findings support the potential clinical benefits of tailoring gout and hyperuricemia treatment according to sex.

Renal uric acid (UA) reabsorption is mainly mediated by urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9). Dotinurad selectively inhibits URAT1 and do not inhibit other UA transporters such as GLUT9, ATP-binding cassette transporter G2 (ABCG2) and organic anion transporter1/3 (OAT1/3). We discovered that dotinurad improved metabolic parameters and renal function in hyperuricemic patients. We consider a significance of high selectivity in inhibiting URAT1 by dotinurad for metabolic syndrome, chronic kidney disease (CKD), and cardiovascular disease (CVD). Dotinurad inhibits selectively URAT1 and increases UA in the proximal tubules, and UA may compete with glucose for GLUT9, reducing glucose reabsorption. The inhibition of UA entry via URAT1 to liver and adipose tissues by dotinurad increased energy expenditure and decrease lipid synthesis and inflammation in rats. The inhibition of URAT1 in kidney, liver and adipose tissues improve metabolic parameters. CKD patients accumulate uremic toxins such as indoxyl sulfate (IS) in the body. ABCG2 regulates renal and intestinal excretion of IS which strongly affects CKD. OAT1/3 inhibitors suppress IS uptake into kidney, increasing plasma IS, which produces oxidative stress, inducing vascular endothelial dysfunction in CKD patients. The high-selective inhibition of URAT1 by dotinurad may be beneficial for metabolic syndrome, CKD and CVD.

Vitamin D plays an important role in maintaining healthy mineralized skeleton. It is also consid-ered an immunomodulatory agent that regulate the innate and adaptive immune systems. Multi-ple observational studies have demonstrated the association between low level of serum 25-hydroxyvitamin D [25(OH)D] and presence and severity of several rheumatic diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), spondyloarthropathies and oste-oarthritis (OA). Nevertheless, the specific benefits of vitamin D supplement for treatment and prevention of rheumatic diseases are less accepted as the results from randomized clinical trials are inconsistent, although some conceivable benefits of vitamin D for improvement of disease ac-tivity of RA, SLE and OA have been demonstrated in meta-analyses. It is also possible that some individuals might benefit from vitamin D differently from others since inter-individual difference in responsiveness to vitamin D supplementation has been observed in genomic studies. Although the optimal level of serum 25(OH)D is still debatable, it is advisable it is advisable that patients with rheumatic diseases should maintain serum 25(OH)D level at least 30 ng/mL (75 nmol/L) to prevent osteomalacia, secondary osteoporosis and fracture, and possibly 40 – 60 ng/mL (100 – 150 nmol/L) to achieve maximal benefit from vitamin D for immune health and overall health.