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− | <p>
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− | Uric acid is a product of purine nucleotide catabolism in nucleic acid constituent units. Most mammals and poultries are
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− | able to produce uricase, which decomposes uric acid into allantoin, then into NH3, CO2 and H2O. However,
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− | humans and apes lack the ability to produce uricase, so in humans uric acid is the end product of purine
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− | metabolism. For humans, increased production or decreased excretion of uric acid can lead to its accumulation
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− | in the body, causing hyperuricemia. Research shows that hyperuricemia is an independent risk factor of arteriosclerosis,
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− | hypertension, heart failure and metabolic syndrome[1].
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− | </p>
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− | <img src="https://static.igem.org/mediawiki/2017/6/68/T--SCU-WestChina--Wiki-Background-image002.png" alt="">
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− | <div class="img-describe">
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− | Figure 1 Purine catabolism. purine bases are converted, first, into xanthine and, then, into urate for excretion[2].
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− | </div>
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− | <p>
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− | As the concentration of uric acid in blood increases, if sodium urate crystals deposit from super-saturated extracellular
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− | fluids to joints, synovium or other tissues and organs, it will cause a syndrome clinically known as "gout",
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− | including features like arthritis, tophi, uric acid kidney stones and gouty nephropathy. At this stage the
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− | patient suffer from acute gouty arthritis, having acute pains in the joint from time to time.
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− | </p>
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− | <img src="https://static.igem.org/mediawiki/2017/7/74/T--SCU-WestChina--Wiki-Background-image004.png" alt="">
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− | <div class="img-describe">
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− | Figure 2 The illustration of the gout formation. Urate deposits in the joint, which causes inflammation, swelling or even
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− | the formation of tophi.
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− | </div>
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− | <p>
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− | Refractory gout is caused by recurrent episodes of acute gouty arthritis for several years, manifested as chronic, multiple,
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− | destructive arthritis with pain and tophi formation and / or uric acid kidney stones. The number of such
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− | patients grows with the increasing prevalence of gout and the younger onset of the incidence, and these patients
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− | have severe illness and low quality of life. 3% of the 3 million gout patients in the United States suffer
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− | from refractory gout. Some patients treated by existing medications get poor result or have intolerance,
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− | and the treatments are time-consuming and difficult, so how to treat the disease effectively is a major clinical
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− | issue faced by physicians.
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− | </p>
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− | <p>
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− | The biochemical basis of refractory gout is hyperuricemia, so the key to the treatment is to control the level of serum uric
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− | acid effectively, the target value of which is
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− | <356μmol / L (<6.0 mg / dl). The daily production of uric acid by a normal adult is 750mg, 80% of which is endogenous, and
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− | 20% of which exogenous. The uric acid gets into the metabolic pool of urate, the daily metabolic rate of
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− | which is about 60%.Of the uric acid metabolized, 1/3 is catabolized in the intestine, and 2/3 is excreted
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− | through the kidneys. This process can maintain a stable level of uric acid in the body, and any problem within
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− | the process can lead to hyperuricemia. </p>
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− | <img src="https://static.igem.org/mediawiki/2017/1/1f/T--SCU-WestChina--Wiki-Background-image006.png" alt="">
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− | <div class="img-describe">
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− | Figure 3 Tophaceous gout with multiple tophi on both hands[3].
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− | </div>
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− | <p>
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− | The mechanism of traditional uric acid–lowering agents is mainly to inhibit xanthine oxidase, reducing uric acid production
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− | and to inhibit renal tubular reabsorption of uric acid, promoting uric acid excretion[4].
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− | </p>
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− | <p>
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− | Controversy still exists on whether to use medications on ordinary patients with hyperuricemia: specialists of rheumatic
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− | and immunologic fields state that hyperuricemia without symptoms of gout does not require drug treatment;
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− | however, in the Cardiology field hyperuricemia is considered as an independent risk factor of atherosclerosis
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− | and need to be controlled by medications[5,6]. And for patients with refractory gout, traditional
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− | drug treatment is slow, taking several years to complete, and for some of them the uric acid level
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− | still cannot get low enough for tophi to dissolve. At the same time, for some patients, age factors
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− | and complications like hypertension, renal insufficiency, diabetes and vascular disease have also
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− | limited drug use on them [7].
| + | |
− | </p>
| + | |
− | <p>
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− | In recent years, Pegloticase, a new type of uric acid–lowering agent, has brought new solutions for patients with refractory
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− | gout and tophi. Pegloticase is a kind of PEG-modified uric acid oxidase which can transform uric
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− | acid into allantoin, which can be easily excreted. It can reduce the level of serum uric acid effectively,
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− | so as to quickly dissolve tophi and treat chronic gout. The PEG modification helps to improve its
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− | antigenicity, and FDA has approved the marketing of the drug (trade name Krystexxa®) in 2010. In
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− | the 2012 American College of Rheumatology Guidelines for Management of Gout, the drugs was recommended
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− | drug for treatment of refractory gout: “Pegloticase is appropriate for patients with severe gout
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− | disease burden and refractoriness to, or intolerance of, conventional and appropriately dosed urate-lowering
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− | therapy”[8]. However, in clinical practice, it is hard to ignore the immune response caused by injections
| + | |
− | (Infusion Reactions). Peter E Lipsky et al. found in 2014 that among the 169 patients treated with
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− | the drug, 41% of them had high-titer anti-uricase antibodies, 40% had high-titer anti-PEG antibodies,
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− | and one patient had high-titer anti-uricase antibodies even after treatment with mere placebo[9].
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− | Because of the presence of high-titer antibodies, the efficacy of Pegloticase is low for one-half
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− | of the patients treated, which means that for the small number of patients, refractory gout is incurable[10].
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− | Furthermore, the price of the medication is high, costing around 3,500 USD per month, which also
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− | limits its clinical application. Moreover, the strong uric acid–lowering effect of the drug can cause
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− | very fast dissolve of tophi, leading to acute gout.
| + | |
− | </p>
| + | |
− | <img src="https://static.igem.org/mediawiki/2017/e/e1/T--SCU-WestChina--Wiki-Background-image008.png" alt="">
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− | <div class="img-describe">Figure 4 The offical website of Pegloticase.</div>
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− | <p>
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− | Based on the reasons above, our project will put forward a new method to control hyperuricemia and treat
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− | refractory gout from the following two aspects:</p>
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− | <p>
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− | 1) Control of ordinary hyperuricemia (in the intestinal tract);
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− | </p>
| + | |
− | <p>
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− | 2) Treatment of refractory gout when Pegloticase treatment is of no avail (with methods of dialysis)
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− | </p>
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− | <p>
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− | 1. Control of ordinary hyperuricemia/gout (in the intestinal tract)</p>
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− | <p>
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− | As mentioned above, current drug targets mainly focus on inhibition of uric acid synthesis and inhibition
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− | of uric acid reabsorption protein, with more attention paid to the latter. The intestinal tract itself,
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− | however, as a place for uric acid production, is a potential new target. The mechanism of uric acid
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− | reabsorption in the intestine is not yet fully elucidated. It is found that the purine metabolism
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− | in the intestine may be an important source of uric acid, and the urate transporter—solute carrier
| + | |
− | protein 2 family member 9 (SLC2A9) expressed by the intestinal epithelial cells plays an important
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− | role in the transport of uric acid to the blood to maintain the homeostasis[11,12]. An analysis of
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− | intestinal microbes in patients with gout carried out in 2016 showed that the compared to heathy
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− | adults, the intestinal microbes in gout patients produce more uric acid and have fewer enzymes to
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− | catabolize uric acid, resulting in its accumulation in the body[13]. In a study of the effect of
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− | montmorillonite on adsorbing uric acid and lowering blood uric acid levels carried out by Juntao
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− | Li et al., the uric acid concentration in the blood and urinary tract of the mice (administrated
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− | uric acid intragastrically) decreased with the increase of the amount of montmorillonite (Figure
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− | 5); for the hyperuricemia model conducted by intraperitoneal injection of uric acid, the mice of
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− | montmorillonite group (administrated intragastrically) had a significantly lower blood uric acid
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− | level than those in the model group. The conclusion is that montmorillonite can adsorb uric acid
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− | significantly and can reduce the serum uric acid level in mice with hyperuricemia[14]. </p>
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− | <img src="https://static.igem.org/mediawiki/2017/2/28/T--SCU-WestChina--Wiki-Background-image010.png" alt="">
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− | <div class="img-describe">Figure 5 Changes of intestinal and serum uric acid concentrations caused by different doses of montmorillonite[14].
| + | |
− | </div>
| + | |
− | <p>
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− | Furthermore, Ming Li et al. fed mice with hyperuricemia with lactobacilli which utilizes uridine and inosine (important components
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− | in purine metabolism) well, and found their serum uric acid concentration significantly lowered (Figure
| + | |
− | 6)[15].
| + | |
− | </p>
| + | |
− | <p>
| + | |
− | Based on the information above, we speculated that the reduction of intestinal uric acid concentration can mean a reduced
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− | serum uric acid concentration, thus treating hyperuricemia. Meanwhile, the use of probiotics offers
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− | a perfect solution for the dispute about whether to use medications to treat hyperuricemia: the blood
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− | uric acid level is lowered through proper application of intestinal microbes without the administration
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− | medications.
| + | |
− | </p>
| + | |
− | <img src="https://static.igem.org/mediawiki/2017/0/0d/T--SCU-WestChina--Wiki-Background-image013.jpg" alt="">
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− | <div class="img-describe"> Figure 6 Changes of serum uric acid concentrations of the mice after being fed with lactobacilli DM9218
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− | which utilizes uridine and inosine (important components in purine metabolism) well[15].
| + | |
− | </div>
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− | <p>We hope to construct a metabolic pathway of uric acid in E. coli Nissle 1917 expressing urate permease
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− | (transporter) on its surface. We try to introduce engineered bacteria into the intestine to consume
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− | intestinal uric acid, thus reducing blood uric acid concentration, so as to treat gout.</p>
| + | |
− | <p>2. Treatment of refractory gout when Pegloticase treatment is of no avail (with methods like dialysis)</p>
| + | |
− | <p>The key to the treatment of refractory gout is to lower the blood uric acid concentration, but direct
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− | protein contact may be blocked immediately by the IgG antibodies (of a long half-life) of the uricase-resistant
| + | |
− | patient, so it is necessary to build a relatively independent immunologically privileged sites. Through
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− | the establishment of a dialysis system, we try to solve the problem of refractory gout. At the same
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− | time, if the efficiency of the device is acceptable, it can be used as an inexpensive treatment regimen
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− | to accelerate the dissolution of gout and may be able to change the principles of treatment for chronic
| + | |
− | tophi.</p>
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− | <p>References: </p>
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− | <p>[1] Billiet L, Doaty S, Katz J D, et al. Review of Hyperuricemia as New Marker for Metabolic Syndrome[J].
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− | Isrn Rheumatology, 2014, 2014(5-6):852954. </p>
| + | |
− | <p>[2] John L. Tymoczko, Jeremy M Berg, Lubert Stryer. Biochemistry: A Short Course (The 3rd Edition), Page
| + | |
− | 598, 2013</p>
| + | |
− | <p>[3] Barajas-Ochoa A, Castaneda-Sanchez J J, Ramos-Remus C. Is gout an easy-to-treat disease? The importance
| + | |
− | of health determinants[J]. Reumatología Clínica, 2017.</p>
| + | |
− | <p>[4] 刘湘源. 难治性痛风石性痛风的治疗[J]. 中华临床医师杂志:电子版, 2008, 2(6):5-7.</p>
| + | |
− | <p>[5] Wakuda H, Uchida S, Ikeda M, et al. Is hyperuricemia a risk factor for arteriosclerosis? Uric Acid
| + | |
− | and arteriosclerosis in apolipoprotein e-deficient mice.[J]. Biological & pharmaceutical bulletin,
| + | |
− | 2014, 37(12):1866-71.</p>
| + | |
− | <p>[6] Krishnan E, Pandya B J, Chung L, et al. Hyperuricemia and the risk for subclinical coronary atherosclerosis--data
| + | |
− | from a prospective observational cohort study.[J]. Arthritis Research & Therapy, 2011, 13(2):1-8.</p>
| + | |
− | <p>[7] Hershfield M S, Ganson N J, Kelly S J, et al. Induced and pre-existing anti-polyethylene glycol antibody
| + | |
− | in a trial of every 3-week dosing of pegloticase for refractory gout, including in organ transplant
| + | |
− | recipients.[J]. Arthritis Research & Therapy, 2014, 16(2):R63.</p>
| + | |
− | <p>[8] Khanna D, Fitzgerald J D, Khanna P P, et al. 2012 American College of Rheumatology guidelines for
| + | |
− | management of gout. Part 1: Systematic nonpharmacologic and pharmacologic therapeutic approaches
| + | |
− | to hyperuricemia[J]. Arthritis Care Res, 2012, 64(10):1431.</p>
| + | |
− | <p>[9] Lipsky P E, Calabrese L H, Kavanaugh A, et al. Pegloticase immunogenicity: the relationship between
| + | |
− | efficacy and antibody development in patients treated for refractory chronic gout[J]. Arthritis Research
| + | |
− | & Therapy, 2014, 16(2):R60.</p>
| + | |
− | <p>[10] Abeles A M. PEG-ing down (and preventing?) the cause of pegloticase failure[J]. Arthritis Research
| + | |
− | & Therapy, 2014, 16(3):1-2.</p>
| + | |
− | <p>[11] Vitart V, Rudan I, Hayward C, et al. SLC2A9 is a newly identified urate transporter influencing
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− | serum urate concentration, urate excretion and gout[J]. Nature Genetics, 2008, 40(4):437-442.</p>
| + | |
− | <p>[12] Ma Z, Long L H, Liu J, et al. Montmorillonite adsorbs uric acid and increases the excretion of uric
| + | |
− | acid from the intestinal tract in mice[J]. Journal of Pharmacy & Pharmacology, 2009, 61(11):1499–1504.</p>
| + | |
− | <p>[13] Guo Z, Zhang J, Wang Z, et al. Intestinal Microbiota Distinguish Gout Patients from Healthy Humans.[J].
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− | Scientific Reports, 2016, 6:20602.</p>
| + | |
− | <p>[14] Ma Z, Long L H, Liu J, et al. Montmorillonite adsorbs uric acid and increases the excretion of uric
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− | acid from the intestinal tract in mice[J]. Journal of Pharmacy & Pharmacology, 2009, 61(11):1499–1504.</p>
| + | |
− | <p>[15] Li M, Yang D, Mei L, et al. Screening and Characterization of Purine Nucleoside Degrading Lactic
| + | |
− | Acid Bacteria Isolated from Chinese Sauerkraut and Evaluation of the Serum Uric Acid Lowering Effect
| + | |
− | in Hyperuricemic Rats[J]. Plos One, 2014, 9(9):e105577-e105577.</p>
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| </div> | | </div> |
| </div> | | </div> |