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Ethnopharmacological Relevance: Astragali Radix (AR) is the dry root of the leguminous plants Astragalus membranaceus (Fisch) Beg. var. mongholicus (Beg) Hsiao, and Astragalus membranaceus (Fisch) Bge., being used as a medicinal and edible resource. AR is used in traditional Chinese medicine prescriptions to treat hyperuricemia, but this particular effect is rarely reported, and the associated mechanism of action is still need to be elucidated., Aim of the Study: To research the uric acid (UA)-lowering activity and mechanism of AR and the representative compounds through the constructed hyperuricemia mouse and cellular models., Materials and Methods: In our study, the chemical profile of AR was analysed by UHPLC-QE-MS, as well as the mechanism of action of AR and the representative compounds on hyperuricemia was studied through the constructed hyperuricemia mouse and cellular models., Results: The main compounds in AR were terpenoids, flavonoids and alkaloids. Mice group treated with the highest AR dosage showed significantly lower (p < 0.0001) serum uric acid (208 ± 9 μmol/L) than the control group (317 ± 11 μmol/L). Furthermore, UA increased in a dose-dependence manner in urine and faeces. Serum creatinine and blood urea nitrogen standards, as well as xanthine oxidase in mice liver, decreased (p < 0.05) in all cases, indicating that AR could relieve acute hyperuricemia. UA reabsorption protein (URAT1 and GLUT9) was down-regulated in AR administration groups, while the secretory protein (ABCG2) was up-regulated, indicating that AR could promote the excretion of UA by regulating UA transporters via PI3K/Akt signalling pathway., Conclusion: This study validated the activity, and revealed the mechanism of AR in reducing UA, which provided experimental and clinical basis for the treatment of hyperuricemia with it., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Hyperuricemia is a common metabolic disease with a series of complications. Nuciferine, a typical aporphine alkaloid natural compound extracted from the leaves of Nelumbo nucifera Gaertn., was confirmed to have an antihyperuricemia effect. In the present study, 30 novel nuciferine derivatives were designed and synthesized. The effects of all derivatives on the regulation of URAT1 were studied in a uric acid-induced HK-2 cell model with benzbromarone as a positive control. The results indicated that Compound 1j showed the optimal URAT1 inhibitory activity through repressing PI3K/Akt pathway in HK-2 cells and the inhibitory effect was similar to that of benzbromarone. In addition, in vivo experiments demonstrated that Compound 1j could reduce uric acid levels and ameliorate kidney damage in hyperuricemic mice. On the one hand, Compound 1j could inhibit the expression of URAT1 and GLUT9 to increase the uric acid excretion index. On the other hand, Compound 1j could regulate the TLR4/IκBα/NF-κB signaling pathway to reduce the levels of inflammatory cytokines, thereby alleviating kidney damage. Meanwhile, a molecular docking assay revealed the potential molecular binding power (-9.79 kcal/mol) between Compound 1j and URAT1, which was more tightly bound than the lead compound nuciferine (-7.44 kcal/mol). Based on these results, Compound 1j may be a future drug for the development of new potential antihyperuricemia and nephroprotective drug candidates., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Hyperuricemia is a metabolic disease caused by abnormal purine metabolism in the body. Long-term high levels of uric acid in the body will lead to gout and kidney disease. Xanthine oxidase (XOD) is a key enzyme in the pathogenesis of hyperuricemia. In this context, a series of geniposide derivatives were designed, synthesized and evaluated as xanthine oxidase inhibitors. Most of these compounds exhibited potent XOD inhibitory activities in vitro, and representatives 6a, 6c, 6g and 6j were found to be the most potent inhibitors against the enzyme with IC 50 values of 2.15 ± 1.03, 1.37± 0.26, 4.14± 0.79 and 1.86± 0.13 μM, which were 33.03-158.37 fold more active than geniposide, respectively. Compounds 6a, 6c, 6g and 6j were evaluated in hyperuricemia mice, and the results demonstrated that compound 6c showed the strongest anti-hyperuricemia and renal protective activity in vivo. Subsequently, the molecular mechanism of compound 6c was studied in this investigation. In vitro cell experiments showed that compound 6c inhibited the inflammation of HK-2 cells under high uric acid conditions by inhibiting the expressions of TGF-β, TNF-α and IL-1β, and reduced the cell fibrosis by decreasing the expressions of α-SMA and Collagen I. The results of the mice experiments indicated that compound 6c efficiently decreased the level of serum uric acid (SUA) in hyperuricemia mice by inhibiting the XOD activity. Moreover, compound 6c effectively reduced the urate accumulation in the kidney and simultaneously decreased inflammation by regulating the expression of the TLR4/IκBα/NF-κB signaling pathway. In addition, consistent with cell experiments, compound 6c also reduced renal fibrosis in hyperuricemia mice, which may be due to compound 6c inhibiting the expression of inflammatory factor TGF-β. Furthermore, a molecular docking study was performed to gain insight into the binding mode of compound 6c with XOD. These results suggest that compound 6c has the potential to be developed into a novel medicine to reduce blood uric acid and treat renal diseases caused by hyperuricemia., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Xanthine oxidase (XO) is a key enzyme in the generation and development of hyperuricemia. Thiazolidine-2-thione, a typical heterocyclic compound, have been widely used in the field of drug synthesis. In this study, a series of novel thiazolidine-2-thione derivatives were synthesized as XO inhibitors, and the XO inhibitory potencies of obtained compounds were evaluated by in vitro enzyme catalysis. The result shown that compound 6k behaved the strongest XO inhibitory activity with an IC50 value of 3.56 μmol/L, which was approximately 2.5-fold more potent than allopurinol. The structure-activity relationship revealed that the phenyl-sulfonamide group was indispensable for thiazolidine-2-thione derivatives to produce XO inhibitory activity. The enzyme inhibition kinetics analyses confirmed that compound 6k exerted a mixed-type XO inhibition. Additionally, the molecular docking results suggested that the 4-fluorophenyl-sulfonyl moiety could interact with Gly260 and Ile264 in the innermost part of the active pocket through 2 hydrogen bonds, while the thiazolidinethione moiety could form two hydrogen bonds with Glu263 and Ser347 in hydrophobic pockets. In summary, the results described above suggested that compound 6k could be a valuable lead compound for the treatment of hyperuricemia as a novel XO inhibitor., Competing Interests: The authors have declared that no competing interests exist.

• The technological route for preparation of high-purity geniposide was obtained. • Geniposide significantly decreased SUA levels via inhibiting the XOD activity. • Geniposide can increase the excretion of urinary uric acid. • Gardenoside can protect the kidney by reducing the release of inflammatory factors. • Gardenoside can suppress TLR4/MyD88 signaling and NLRP3 inflammasome activation. Hyperuricemia is a key risk factor for kidney disease. Geniposide possesses various pharmacological activities, however, to our knowledge, no previous work investigated the therapeutic effect of geniposide on urate nephropathy. The present study established a chronic hyperuricemia model using a combination of adenine and ethambutol administration. The potential beneficial effects and mechanisms of geniposide on hyperuricemia and nephropathy were also investigated. The results demonstrated that geniposide significantly decreased SUA levels via inhibition of the XOD activity and increasing the excretion of urinary uric acid. Geniposide also markedly improved kidney damage related to hyperuricemia. Further investigation indicated that geniposide improved the symptoms of nephropathy via decreasing the production of proinflammatory cytokines, including IL-1β, PG-E 2 , and TNF-α, and inhibiting the expression of TGF-β1. The molecular mechanism of action may be associated with suppression of TLR4/MyD88 signaling and NLRP3 inflammasome activation to reduce IL-1β and TNF-α production respectively in hyperuricemic mice. [ABSTRACT FROM AUTHOR]

Hyperuricemia is a common metabolic disease and is one of the factors that could induce chronic kidney disease (CKD). Geniposide (GEN) is a typical natural iridoid glucoside compound with a series of biological activities, but the poor bioavailability of GEN limits its clinical application. In this context, the pharmacological activity of the geniposide-phospholipid complex (GEN-PLC) in ameliorating posthyperuricemia CKD was evaluated by in vitro and in vivo experiments in this study. In vitro cell experiments showed that GEN-PLC treatment markedly decreased inflammatory cytokine levels and reactive oxygen species levels compared with those of GEN in uric acid-treated HKC cells. In vivo research results confirmed that a high concentration of uric acid could cause CKD by increasing inflammatory cytokines and reactive oxygen species in hyperuricemic mice. At the same time, GEN-PLC could regulate the PI3K/AKT/NF-κB and Keap1/Nrf2/HO-1 signaling pathways to effectively inhibit the inflammatory response and oxidative stress, thereby ameliorating posthyperuricemia CKD, and the therapeutic effect was better than that of GEN. In addition, the preparation technology of GEN-PLC was optimized, and the physiochemical analysis explained the intermolecular interactions of the two components. Based on the research results, GEN-PLC could enhance the bioavailability of GEN and become a promising candidate for clinical drug development. [Display omitted] [ABSTRACT FROM AUTHOR]