A widely distributed gene cluster compensates for uricase loss in hominids

Liu, Yuanyuan; Jarman, John B.; Low, Yen; Augustijn, Hannah E.; Huang, Steven Kuan-Hua; Chen, Haoqing; DeFeo, Mary E.; Sekiba, Kazuma; Hou, Bi-Huei; Meng, Xiangru; Weakley, Allison M.; Cabrera, Alvin R.; Zhou, Zhiwei; Wezel, Gilles P. van; Medema, Marnix H.; Ganesan, Calyani; Pao, Alan C.; Gombar, Saurabh; Dodd, Dylan

doi:10.1016/j.cell.2023.06.010

Cited by 46 publications

(23 citation statements)

References 50 publications

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“…Endogenous purines constitute the primary source of uric acid production within the body, with dietary intake accounting for the remaining portion. 6 Under normal physiological conditions, the human body maintains a dynamic equilibrium between uric acid production and excretion. Approximately two-thirds of uric acid is excreted through renal elimination, while the remaining one-third is expelled via gut excretion.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Endogenous purines constitute the primary source of uric acid production within the body, with dietary intake accounting for the remaining portion . Under normal physiological conditions, the human body maintains a dynamic equilibrium between uric acid production and excretion.…”

Section: Introductionmentioning

confidence: 99%

“…J = 7 6. Hz, 1H, Naph-H), 1.39 (s, 6H, CH 3 CH 3 ), 1.24− 1.14 (m, 1H, CH), 1.13−1.07 (m, 2H, CH 2 ), 0.79 (t, J = 4.7 Hz, 2H, CH 2 ).13 C NMR (100 MHz, DMSO-d 6 ) δ 175.12, 166 30,.…”

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confidence: 99%

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Discovery of a Novel Thienopyrimidine Compound as a Urate Transporter 1 and Glucose Transporter 9 Dual Inhibitor with Improved Efficacy and Favorable Druggability

Shi,

Zhao,

Wang

et al. 2024

J. Med. Chem.

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Gout and hyperuricemia are metabolic diseases characterized with high serum uric acid (SUA) levels that significantly impact human health. Lesinurad, a uricosuric agent, is limited to concurrent use with xanthine oxidase inhibitors (XOIs) in clinical practice due to its restricted efficacy and potential nephrotoxicity. Herein, extensive structural modifications of lesinurad were conducted through scaffold hopping and substituent modification strategies, affording 54 novel derivatives containing pyrimidine-fused cyclic structures. Notably, the thienopyrimidine compound 29 demonstrated a remarkable 2fold increase in SUA-lowering in vivo activity compared to lesinurad, while exhibiting potent inhibitory activity against the urate transporter 1 (URAT1, IC 50 = 2.01 μM) and glucose transporter 9 (GLUT9, IC 50 = 18.21 μM). Furthermore, it possessed a lower effective dosage of 0.5 mg/kg, favorable safety profile without any apparent acute toxicity at doses of 1000 mg/kg, and improved pharmacokinetic properties. Overall, we have discovered an efficacious URAT1/GLUT9 dual inhibitor for inhibiting urate reabsorption with favorable pharmacokinetic profiles.

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Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Discovery of a Novel Thienopyrimidine Compound as a Urate Transporter 1 and Glucose Transporter 9 Dual Inhibitor with Improved Efficacy and Favorable Druggability

Shi,

Zhao,

Wang

et al. 2024

J. Med. Chem.

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“…Consequently, there is an urgent need for alternative approaches that offer improved efficacy and safety. Accumulating evidence suggests that changes in intestinal flora often accompany the development of hyperuricemia [17]. For instance, a high-purine diet in mice can alter the intestinal flora, increasing the prevalence of Gram-negative bacteria, which leads to inflammation and hyperuricemia [18].…”

Section: Introductionmentioning

confidence: 99%

“…Lactobacillus can absorb and utilize purine, reducing the absorption of dietary purine in the intestinal tract [ 23 ]. Additionally, short-chain fatty acids produced by specific intestinal flora can reduce intestinal inflammation and influence purine metabolism [ 17 , 24 , 25 ]. For instance, probiotic treatment of hyperuricemia mice using Clostridium butyricum not only lowered blood UA levels but also led to the release of intestinal lipopolysaccharides, tumor necrosis factor-α (TNF-α), and inflammatory factors such as interleukin-6.…”

Section: Introductionmentioning

confidence: 99%

Ethanol Extracts from Torreya grandis Seed Have Potential to Reduce Hyperuricemia in Mouse Models by Influencing Purine Metabolism

Yao,

Bai,

Duan

et al. 2024

Foods

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The purpose of this study was to evaluate the efficacy of ethanol extracts from Torreya grandis seed (EST) as a functional food in hyperuricemia mice. We investigated EST by analyzing its chemical composition. Using a mouse model of hyperuricemia induced by potassium oxonate (PO), we evaluated the effects of EST on uric acid (UA) production, inflammation-related cytokines, and gut microbiota diversity. The primary constituents of EST consist of various flavonoids and phenolic compounds known for their antioxidant and anti-inflammatory properties in vitro. Notably, our findings demonstrate that EST significantly reduced UA levels in hyperuricemia mice by 71.9%, which is comparable to the effects observed with xanthine treatment. Moreover, EST exhibited an inhibitory effect on xanthine oxidase activity in mouse liver, with an IC50 value of 20.90 μg/mL (36%). EST also provided protective effects to the mouse kidneys by modulating oxidative stress and inflammation in damaged tissues, while also enhancing UA excretion. Finally, EST influenced the composition of the intestinal microbiota, increasing the relative abundance of beneficial bacteria such as Akkermansia muciniphila, Corynebacterium parvum, Enterorhabdus, Muribaculaceae, Marvinbryantia, and Blautia. In summary, our research unveils additional functions of Torreya grandis and offers new insights into the future of managing hyperuricemia.

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Emerging Urate-Lowering Drugs and Pharmacologic Treatment Strategies for Gout: A Narrative Review

Terkeltaub

2023

Drugs

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A widely distributed gene cluster compensates for uricase loss in hominids

Cited by 46 publications

References 50 publications

Discovery of a Novel Thienopyrimidine Compound as a Urate Transporter 1 and Glucose Transporter 9 Dual Inhibitor with Improved Efficacy and Favorable Druggability

Discovery of a Novel Thienopyrimidine Compound as a Urate Transporter 1 and Glucose Transporter 9 Dual Inhibitor with Improved Efficacy and Favorable Druggability

Ethanol Extracts from Torreya grandis Seed Have Potential to Reduce Hyperuricemia in Mouse Models by Influencing Purine Metabolism

Emerging Urate-Lowering Drugs and Pharmacologic Treatment Strategies for Gout: A Narrative Review

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