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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. To research the uric acid (UA)-lowering activity and mechanism of AR and the representative compounds through the constructed hyperuricemia mouse and cellular models. 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. 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. 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. [Display omitted] • Astragali Radix (AR) main compounds were terpenoids, flavonoids and alkaloids. • Mice treated with the highest AR dose showed significantly lower serum uric acid (UA). • Reduced creatinine and urea nitrogen indicated that AR could relieve acute hyperuricemia. • The UA reabsorption protein (URAT1 & GLUT9) was down-regulated in AR groups. • AR could promote the excretion of UA by regulating PI3K/Akt signalling pathway. [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]

Scheme 1. Synthesis of nuciferine derivative 1a-1r,2a-2l. Reagents and conditions: (a) 48% HBr solution, glacial acetic acid, 70 °C; (b) Et 3 N, N 2 , CH 2 Cl 2 , 25℃, 1h; (c) NaH, N 2 , DMF, 0 °C, 2h. [Display omitted] • The inhibition effect of compound 1j (104.46 ± 4.07%) was roughly the same as benzbromarone (101.44 ± 6.21%) in UA-induced HK-2 cells model; • Compound 1j inhibited the expression of URAT1 and GLUT9 through repressing PI3K/Akt pathway in HK-2 cells; • Compound 1j can promote the excretion of uric acid and thereby increase the fraction of uric acid excretion in vivo ; • Compound 1j can ameliorate renal inflammation and reduce the level of renal inflammatory factors; • Compound 1j shows nephroprotective effect through regulate TLR4/IκBα/NF-κB signaling pathway; 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. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • 42 novel geniposide derivatives were designed and synthesized for the purpose of discovering an efficient XOD inhibitor. • Compound 6c was the most potent XOD inhibitor in vitro , showing 117.81-fold more active than that of geniposide. • Compound 6c effectively inhibited XOD activity in hyperuricemic mice. • Compound 6c could regulate the TLR4/IκBα/NF-κB signal pathway, thereby reducing the level of inflammatory factors. • Compound 6c could inhibit renal fibrosis by reducing the expression of TGF-β. [ABSTRACT FROM AUTHOR]