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1.
J Agric Food Chem ; 71(3): 1620-1627, 2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36625439

RESUMO

The xanthine oxidase (XO) inhibitory peptides from pacific white shrimp or swimming crab were identified by molecular docking, and the anti-hyperuricemic activity of the peptides was confirmed in hyperuricemic cells. In our study, 17 novel XO inhibitory peptides were purified from pacific white shrimp or swimming crab, and Ala-Glu-Ala-Gln-Met-Trp-Arg (AEAQMWR, 891.01 Da, IC50 = 8.85 ± 0.05 mM) exhibited the greatest XO inhibitory activity in vitro. Molecular docking results indicated that attractive charge, salt bridge, and hydrogen bond showed a crucial effect on the interactions of XO inhibitory peptides with the pivotal residues of Arg880, Glu802, and Glu1261. In addition, XO inhibitory peptides alleviated hyperuricemia by inhibiting inflammation and preventing increased uric acid transporter expression levels in hyperuricemia cells. Overall, these results further confirmed that screening of XO inhibitory peptides rapidly via molecular docking was feasible.


Assuntos
Braquiúros , Hiperuricemia , Animais , Simulação de Acoplamento Molecular , Xantina Oxidase/metabolismo , Inibidores Enzimáticos/química , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Natação , Peptídeos
2.
J Nat Prod ; 86(1): 24-33, 2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36634312

RESUMO

Hyperuricemia is the result of overproduction and/or underexcretion of uric acid, and it is a well-known risk factor for gout, hypertension, and diabetes. However, available drugs for hyperuricemia in the clinic are limited. Recently, a lot of research has been conducted in order to discover new uric acid-lowering agents from plants and foods. We found that the extracts from the pericarp of mangosteen reduced urate. Bioactivity-guided study showed that α-mangostin was the principal constituent. Herein, we reported for the first time the hypouricemic activities and underling mechanism of α-mangostin. The α-mangostin dose- and time-dependently decreased the levels of serum urate in hyperuricemic mice and markedly increased the clearance of urate in hyperuricemic rats, exhibiting a promotion of urate excretion in the kidney. Further evidence showed that α-mangostin significantly decreased the protein levels of GLUT9 in the kidneys. The change in the expression of URAT1 was not observed. Moreover, α-mangostin did not inhibit the activities of xanthine oxidoreductase and uricase in vitro or in vivo. Taken together, these findings suggest that α-mangostin has potential to be developed as a new anti-hyperuricemic agent with promoting uric acid excretion.


Assuntos
Garcinia mangostana , Hiperuricemia , Ratos , Camundongos , Animais , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Ácido Úrico/metabolismo , Xantina Oxidase , Rim/metabolismo
3.
J Agric Food Chem ; 71(3): 1434-1446, 2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36525382

RESUMO

Hyperuricemia characterized by high serum levels of uric acid (UA, >6.8 mg/dL) is regarded as a common chronic metabolic disease. When used as a food supplement, naringenin might have various pharmacological activities, including antioxidant, free-radical-scavenging, and inflammation-suppressing activities. However, the effects of naringenin on hyperuricemia and renal inflammation and the underlying mechanisms remain to be elucidated. Here, we comprehensively examined the effects of naringenin on hyperuricemia and the attenuation of renal impairment. Mice were injected with 250 mg/kg of potassium oxonate (PO) and given 5% fructose water to induce hyperuricemia. The pharmacological effects of naringenin (10 and 50 mg/kg) and benzbromarone (positive control group, 20 mg/kg) on hyperuricemic mice were evaluated in vivo. The disordered expression of urate transporters in HK-2 cells was stimulated by 8 mg/dL UA, which was used to determine the mechanisms underlying the effects of naringenin in vitro. Naringenin markedly reduced the serum UA level in a dose-dependent manner and improved renal dysfunction. Moreover, the increased elimination of UA in urine showed that the effects of naringenin were associated with the regulation of renal excretion. Further examination indicated that naringenin reduced the expression of GLUT9 by inhibiting the PI3K/AKT signaling pathway and reinforced the expression of ABCG2 by increasing the abundance of PDZK1 in vivo and in vitro. Furthermore, sirius red staining and western blotting indicated that naringenin plays a protective role in renal injury by suppressing increases in the levels of pro-inflammatory cytokines, including IL-6 and TNF-α, which contribute to the inhibition of the TLR4/NF-κB signaling pathway in vivo and in vitro. Naringenin supplementation might be a potential therapeutic strategy to ameliorate hyperuricemia by promoting UA excretion in the kidney and attenuating the inflammatory response by decreasing the release of inflammatory cytokines. This study shows that naringenin could be used as a functional food or dietary supplement for hyperuricemia prevention and treatment.


Assuntos
Hiperuricemia , Camundongos , Animais , Hiperuricemia/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Ácido Úrico/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Eliminação Renal , Rim/metabolismo , Transdução de Sinais , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Citocinas/metabolismo , Ácido Oxônico
4.
Bioorg Chem ; 131: 106320, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36527991

RESUMO

Xanthine oxidase (XO) is a crucial target for the treatment of hyperuricemia and gout. A series of derivatives based on natural 3,4-dihydroxychalcone, obtained from Carthamus tinctorious and Licorice, were designed and synthesized. Nine derivatives (9a-e, 10b,c, and 15a,b) exhibited apparent XO inhibitory activity in vitro (IC50 values varied from 0.121 to 7.086 µM), 15b presented the most potent inhibitory activity (IC50 = 0.121 µM), which was 27.47-fold higher than that of allopurinol (IC50 = 3.324 µM). The SAR analysis indicated that introducing hydroxyl groups at 3'/4'/5'-position on ring A was more beneficial to the inhibition of XO than at 2'/6'-position; the removal of 3­hydroxyl group on ring B could weaken the inhibitory potency of hydroxychalcones on XO, but it was beneficial to the XO inhibitory potency of methoxychalcones. Molecule modeling studies afforded insights into the binding mode of 15b with XO and supported the findings of SAR analysis. Additionally, kinetics studies demonstrated that 15b presented a reversible and competitive XO inhibitor, which spontaneously combined with XO through hydrophobic force, and finally changed the secondary conformation of XO. Furthermore, the acute hyperuricemia model was employed to investigate the hypouricemic effect of 15b, which could effectively reduce the serum uric acid levels of rats at an oral dose of 10 mg/kg. ADMET prediction suggested that compound 15b possessed good pharmacokinetic properties. Briefly, compound 15b emerges as an interesting XO inhibitor for the treatment of hyperuricemia and gout with beneficial effects on serum uric acid levels regulating. Meanwhile, the XO inhibitors with chalcone skeleton will deserve further attention and discussion.


Assuntos
Chalcona , Chalconas , Gota , Hiperuricemia , Ratos , Animais , Relação Estrutura-Atividade , Ácido Úrico , Chalconas/farmacologia , Chalconas/uso terapêutico , Xantina Oxidase , Chalcona/farmacologia , Chalcona/uso terapêutico , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Inibidores Enzimáticos/química , Gota/tratamento farmacológico
5.
J Agric Food Chem ; 70(50): 15647-15664, 2022 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-36482671

RESUMO

Hyperuricemia is a metabolic disease caused by the accumulation of uric acid in the body. Allopurinol, benzbromarone, and febuxostat, which are available in the market, have reduced the circulating urate levels; however, they exhibit serious side effects. Therefore, it is reasonable to develop a new active antihyperuricemia drug with few side effects. With the deepening of research, numerous kinds of literature have shown that natural active substances are effective in the treatment of hyperuricemia with a variety of sources and few side effects, which have become the focus of research in recent years. This review focuses on natural active substances with uric-acid-reducing activity and discusses their pharmacological effects. More specifically, the bioactive compounds of natural active substances are divided into five categories: natural extracts, monomer compounds extracted from plants, natural protease hydrolysates, peptides, and probiotic bacteria. In addition, the mechanisms by which these bioactive compounds exhibit hypouricemic effects can be divided into four classes: inhibition of key enzyme activities, promotion of uric acid excretion and inhibition of reabsorption in the kidney, promotion of decomposing uric acid precursors, and promotion of decomposing uric acid. Overall, this current and comprehensive review examines the role of natural active substances in the treatment of hyperuricemia.


Assuntos
Hiperuricemia , Humanos , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Ácido Úrico/metabolismo , Febuxostat/metabolismo , Febuxostat/farmacologia , Febuxostat/uso terapêutico , Rim/metabolismo , Alopurinol , Xantina Oxidase/metabolismo
6.
Food Funct ; 13(23): 12412-12425, 2022 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-36374311

RESUMO

Akkermansia muciniphila (A. muciniphila) has been demonstrated to exhibit beneficial effects against various metabolic diseases, but whether A. muciniphila has an anti-hyperuricemia effect remains unexplored. In this study, live and pasteurized A. muciniphila were examined for their efficacy in alleviating hyperuricemia in mice. Live and pasteurized A. muciniphila (approximately 2 × 108 CFU) were given to a hyperuricemic mice model via oral gavage for three weeks. Both forms of A. muciniphila decreased serum urate and inhibited xanthine oxidase in the liver. In addition, fecal and urinal urate was increased in both treatment groups, which corresponds to the changes in the mRNA and protein expression levels of renal uric acid-related transporters (URAT1, GLUT9, and ABCG2) and intestinal ABCG2. Both forms of bacteria reduced the mRNA expression of inflammatory factors in the liver, kidneys and colon. Live A. muciniphila enhanced the expression of tight junction proteins and improved the dysbiosis of intestinal flora. These findings suggest that both live or pasteurized A. muciniphila could effectively attenuate hyperuricemia by moderating uric acid metabolism and inflammation, and live bacteria exhibit additional beneficial effects on the gut microbiota. These findings highlight that A. muciniphila could be potentially developed as a probiotic or postbiotic to combat hyperuricemia.


Assuntos
Microbioma Gastrointestinal , Hiperuricemia , Camundongos , Animais , Ácido Úrico , Hiperuricemia/metabolismo , Verrucomicrobia , Inflamação , RNA Mensageiro
7.
J Food Sci ; 87(11): 5118-5127, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36250495

RESUMO

Hyperuricemia is a well-known cause of gout and also a risk factor for various comorbidities. Current agents like xanthine oxidase inhibitors prevent hyperuricemia, but usually induce severe side effects. Alternative strategies, such as novel dietary supplementations, are necessary for the management of hyperuricemia. Lactic acid bacteria (LAB) have been used in human diet for a long time with a good safety record. In this study, 345 LAB strains isolated from traditional fermented dairy products were tested for assimilating abilities of guanosine. Two LAB strains, Lacticaseibacillus rhamnosus 1155 (LR1155) and Limosilactobacillus fermentum 2644 (LF2644), showing great capacities of guanosine transformation and degradation were selected. Compared to LR1155, LF2644 showed a better effect with 100.00% transforming rate and 55.10% degrading rate. In an in vivo test, a hyperuricemic rat model was established and the results showed that administration of LR1155 (p < 0.01) or LF2644 (p < 0.01) prevented the rise of serum uric acid with more than 20% decrease when compared with the hyperuricemia rats. In addition, an increased fecal uric acid level was observed in LF2644 or LR1155 treated rats (LR1155-M p < 0.05, others p < 0.01). This study proved that LR1155 and LF2644 can be promising candidates of dietary supplements for prevention or improvement of hyperuricemia. PRACTICAL APPLICATION: The LAB strains tested in this study could be considered as good potential probiotic candidates for dietary supplements because of their urate-lowering effects, which provide a novel antihyperuricemic strategy with advantages of safety and sustainability.


Assuntos
Produtos Fermentados do Leite , Hiperuricemia , Lactobacillales , Humanos , Ratos , Animais , Ácido Úrico/metabolismo , Ácido Úrico/uso terapêutico , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Lactobacillales/metabolismo , Xantina Oxidase , Guanosina/uso terapêutico
8.
J Ethnopharmacol ; 298: 115679, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36058481

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Shi Wei Ru Xiang powder (SWR) is a traditional Tibetan medicinal formula with the effect of dispelling dampness and dispersing cold. In clinical practice, SWR is generally used for the treatment of hyperuricemia (HUA). However, its exact pharmacological mechanism remains unclear. AIMS OF THE STUDY: To preliminarily elucidate the regulatory effects and possible mechanisms of SWR on hyperuricemia using network pharmacology and experimental validation. MATERIALS AND METHODS: A mouse model of hyperuricemia was used to evaluate the alleviating effect of SWR on hyperuricemia. The major components of SWR were acquired by UPLC-Q/TOF-MS. The potential molecular targets and associated signaling pathways were predicted through network pharmacology. The mechanism of action of SWR in ameliorating hyperuricemia was further investigated by pharmacological evaluation. RESULTS: Mice with hyperuricemia and renal dysfunction were ameliorated by SWR. The 36 components of SWR included phenolic acids, terpenoids, alkaloids and flavonoids were identified. Network pharmacological analysis showed the involvement of the above compounds, and 115 targets were involved to treat hyperuricemia, involving multiple biological processes and different signaling pathways. Pharmacological experiments validated that SWR ameliorated hyperuricemic nephropathy in mice by modulating the mitogen-activated protein kinase (MAPK) signaling pathway, nuclear factor kappaB (NF-κB) signaling pathway and NOD-like receptor signaling pathway. CONCLUSION: MAPK signaling pathway, NF-κB signaling pathway and NOD-like receptor signaling pathway play important roles in the therapeutic effects of SWR on hyperuricemia.


Assuntos
Medicamentos de Ervas Chinesas , Hiperuricemia , Animais , Medicamentos de Ervas Chinesas/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Medicina Tradicional Tibetana , Camundongos , NF-kappa B , Proteínas NLR , Farmacologia em Rede , Pós/uso terapêutico
9.
Basic Clin Pharmacol Toxicol ; 131(6): 474-486, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36126111

RESUMO

Elevated levels of circulating fibroblast growth factor 21 (FGF21) have been reported in patients with hyperuricemia. However, the effect of FGF21 in hyperuricemic nephropathy (HN) remains unexplored. Here, we investigated the effect and mechanism of action of FGF21 on HN. HN model was induced with adenine and potassium oxysalt in wild-type C57BL/6 mice and FGF21-/- mice. For in vitro studies, human renal tubular epithelial (HK-2) cells were exposed to uric acid with/without FGF21 or ß-Klotho-siRNA. Here, we reported aggravated renal dysfunction and structural damage in the FGF21-/- mice compared to the wild-type mice. These were evident in the upsurge of inflammatory factors IL-1ß, TNF-α, IL-6, and IL-18; fibrotic markers Collagen I and α-SMA; and oxidation products ROS and MDA. However, exogenous administration of FGF21 to wild-type HN mice significantly reversed these negative effects. In terms of mechanism, FGF21 significantly inhibited NF-κB/NLRP3 and TGF-ß1/Smad3 pathways and promoted nuclear translocation of Nrf2 both in vivo and in vitro. Furthermore, the silencing of ß-Klotho was marked by the attenuation of the improved effect of FGF21 on cell damage. In conclusion, our studies revealed that exogenous FGF21 treatment significantly improved HN, which was achieved by the inhibition of inflammation, fibrosis, and oxidative stress.


Assuntos
Hiperuricemia , Humanos , Camundongos , Animais , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Ácido Úrico , Transdução de Sinais , Camundongos Endogâmicos C57BL , Fibrose , Estresse Oxidativo , Inflamação/tratamento farmacológico
10.
Eur J Pharmacol ; 932: 175237, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36063871

RESUMO

Increasing evidence indicates that hyperuricaemia (HUA) is not only a result of decreased renal urate excretion but also a contributor to kidney disease. Na+-K+-ATPase (NKA), which establishes the sodium gradient for urate transport in proximal tubular epithelial cells (PTECs), its impairment leads to HUA-induced nephropathy. However, the specific mechanism underlying NKA impairment-mediated renal tubular injury and increased urate reabsorption in HUA is not well understood. In this study, we investigated whether autophagy plays a key role in the NKA impairment signalling and increased urate reabsorption in HUA-induced renal tubular injury. Protein spectrum analysis of exosomes from the urine of HUA patients revealed the activation of lysosomal processes, and exosomal expression of lysosomal-associated membrane protein-2 was associated with increased serum levels and decreased renal urate excretion in patients. We demonstrated that high uric acid (UA) induced lysosome dysfunction, autophagy and inflammation in a time- and dose-dependent manner and that high UA and/or NKA α1 siRNA significantly increased mitochondrial abnormalities, such as reductions in mitochondrial respiratory complexes and cellular ATP levels, accompanied by increased apoptosis in cultured PTECs. The autophagy inhibitor hydroxychloroquine (HCQ) ameliorated NKA impairment-mediated mitochondrial dysfunction, Nod-like receptor pyrin domain-containing protein 3 (NLRP3)-interleukin-1ß (IL-1ß) production, and abnormal urate reabsorption in PTECs stimulated with high UA and in rats with oxonic acid (OA)-induced HUA. Our findings suggest that autophagy plays a pivotal role in NKA impairment-mediated signalling and abnormal urate reabsorption in HUA-induced renal tubular injury and that inhibition of autophagy by HCQ could be a promising treatment for HUA.


Assuntos
Hiperuricemia , Adenosina Trifosfatases , Trifosfato de Adenosina , Animais , Autofagia , Hidroxicloroquina , Hiperuricemia/complicações , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Interleucina-1beta , Glicoproteínas de Membrana Associadas ao Lisossomo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ácido Oxônico , RNA Interferente Pequeno , Ratos , Ratos Sprague-Dawley , Sódio , ATPase Trocadora de Sódio-Potássio , Ácido Úrico/metabolismo
11.
Front Immunol ; 13: 931087, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36177037

RESUMO

Aim: Numerous reports have demonstrated the key importance of macrophage-elicited metabolic inflammation in insulin resistance (IR). Our previous studies confirmed that hyperuricemia or high uric acid (HUA) treatment induced an IR state in several peripheral tissues to promote the development of type 2 diabetes mellitus (T2DM). However, the effect of HUA on glucose uptake and the insulin sensitivity of macrophages and its mechanism is unclear. Methods: To assess systemic IR, we generated hyperuricemic mice by urate oxidase knockout (UOX-KO). Then, glucose/insulin tolerance, the tissue uptake of 18F-fluorodeoxyglucose, body composition, and energy balance were assessed. Glucose uptake of circulating infiltrated macrophages in the liver was evaluated by glucose transporter type 4 (GLUT-4) staining. Insulin sensitivity and the insulin signaling pathway of macrophages were demonstrated using the 2-NBDG kit, immunoblotting, and immunofluorescence assays. The immunoprecipitation assay and LC-MS analysis were used to determine insulin receptor substrate 2 (IRS2) levels and its interacting protein enrichment under HUA conditions. Results: Compared to WT mice (10 weeks old), serum uric acid levels were higher in UOX-KO mice (WT, 182.3 ± 5.091 µM versus KO, 421.9 ± 45.47 µM). Hyperuricemic mice with metabolic disorders and systemic IR showed inflammatory macrophage recruitment and increased levels of circulating proinflammatory cytokines. HUA inhibited the nuclear translocation of GLUT-4 in hepatic macrophages, restrained insulin-induced glucose uptake and glucose tolerance, and blocked insulin IRS2/PI3K/AKT signaling. Meanwhile, HUA mediated the IRS2 protein degradation pathway and activated AMPK/mTOR in macrophages. LC-MS analysis showed that ubiquitination degradation could be involved in IRS2 and its interacting proteins to contribute to IR under HUA conditions. Conclusion: The data suggest that HUA-induced glucose intolerance in hepatic macrophages contributed to insulin resistance and impaired the insulin signaling pathway via IRS2-proteasome degradation.


Assuntos
Diabetes Mellitus Tipo 2 , Intolerância à Glucose , Hiperuricemia , Resistência à Insulina , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Citocinas/metabolismo , Fluordesoxiglucose F18 , Glucose/metabolismo , Intolerância à Glucose/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Hiperuricemia/metabolismo , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Células de Kupffer/metabolismo , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Urato Oxidase , Ácido Úrico/farmacologia
12.
Food Funct ; 13(20): 10546-10557, 2022 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-36155703

RESUMO

Hyperuricemia is a purine metabolism disorder, with increasing prevalence worldwide. Here, a high throughput cell model for screening of antihyperuricemic compounds was set up. Human kidney cells (HK2 cells) were stimulated with adenosine and the resulting supernatant and lysate were then analyzed using high performance liquid chromatography (HPLC). The results showed that hypoxanthine content was increased in both HK2 cells supernatant and xanthine oxidase (XO)-overexpressing HK2 cells lysate, but no uric acid was detected due to lower endogenous XO content in these cells. Exogenous XO was added to the supernatant, and then used to evaluate the antihyperuricemic activity of Febuxostat and two the previously identified peptides, Pro-Gly-Ala-Cys-Ser-Asn (PGACSN) and Trp-Met-Leu (WML). By adding exogenous XO, this combined-adenosine-XO-induced hyperuricemia model was optimized and established, and the Febuxostat and peptides were confirmed to significantly reduce uric acid production in the HK2 cells supernatant (p < 0.05). Therefore, this cell model could be recommended for screening potential bioactive antihyperuricemic compounds.


Assuntos
Hiperuricemia , Xantina Oxidase , Adenosina/uso terapêutico , Febuxostat/efeitos adversos , Supressores da Gota , Humanos , Hiperuricemia/metabolismo , Hipoxantinas/uso terapêutico , Peptídeos/química , Ácido Úrico/efeitos adversos , Xantina Oxidase/metabolismo
13.
Pak J Pharm Sci ; 35(4): 1015-1021, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36008897

RESUMO

As a popular medicinal plant traditionally used in Tibet of China, Nepeta angustifolia C. Y. Wu is mainly administered to treat apoplexia, cerebral haemorrhage, fainting and epilepsy and other symptoms, while its effect on hyperuricemia is still unclear. In the present study, we evaluated the improvement of the 70% ethanol extract of Nepeta angustifolia C. Y. Wu in fructose-induced hyperuricemic mice. The results revealed that Nepeta angustifolia C. Y. Wu significantly decreased blood glucose and blood lipid levels, as well as lowering the urinary levels of uric acid, creatinine and urea nitrogen. Meanwhile, it effectively restored the serum levels of uric acid, creatinine and urea nitrogen and inhibited serum and hepatic XOD activities and renal oxidative stress, while suppressing the secretions of TNF-α, IL-1ß and IL-6 in kidney. Nepeta angustifolia C. Y. Wu also attenuated the infiltration of inflammatory cells and reduced the production and accumulation of glycogen and collagen, while restoring the dysregulated protein expressions of renal URAT1, GLUT9, OAT1 and OAT3. In summary, our results support the idea that Nepeta angustifolia C. Y. Wu is a promising agent for treating hyperuricemia.


Assuntos
Medicamentos de Ervas Chinesas , Hiperuricemia , Nepeta , Animais , Creatinina/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Etanol/farmacologia , Frutose/efeitos adversos , Hiperuricemia/induzido quimicamente , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Rim , Camundongos , Nitrogênio/metabolismo , Ureia/metabolismo , Ácido Úrico
14.
Food Funct ; 13(18): 9434-9442, 2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-35972268

RESUMO

This study aims to investigate the anti-hyperuricemia effect and mechanism of anserine in hyperuricemic rats. Hyperuricemic rats were induced with a combination of 750 mg per kg bw d potassium oxazinate (PO) and 200 mg per kg bw d hypoxanthine for a week, and the rats were separately orally administered anserine (20, 40, 80 mg kg-1) and allopurinol (10 mg kg-1) for three weeks. The results show that the content of serum uric acid (SUA) decreased by approximately 40% and 60% after the intervention of anserine and allopurinol, respectively. The activity of superoxide dismutase (SOD) was increased and the levels of malondialdehyde (MDA), alkaline phosphatase (ALP) and alanine aminotransferase (ALT) were significantly decreased in the anserine groups. After the administration of anserine, the contents of blood urea nitrogen (BUN) and creatinine (Cr) were reduced in the kidney, and the levels of the proinflammatory cytokines IL-1ß, IL-6ß, TNF-α and TGF-ß and inflammatory cell infiltration were reduced in both the liver and kidney. Moreover, the gene expressions of xanthine oxidase (XOD), renal urate transporter 1 (URAT1) and glucose transporter type 9 (GLUT9) were downregulated by anserine administration, and the gene expressions of ATP-binding cassette transporter G2 (ABCG2), organic anion transporter 1 (OAT1) and organic anion transporter 3 (OAT3) were upregulated at the same time. These findings suggest that hepatorenal injury was repaired by anserine, which further regulated the expression of hepatic XOD and renal URAT1, GLUT9, ABCG2, OAT1 and OAT3 to relieve hyperuricemia in rats.


Assuntos
Hiperuricemia , Transportadores de Ânions Orgânicos , Transportadores de Cassetes de Ligação de ATP/metabolismo , Alanina Transaminase/metabolismo , Fosfatase Alcalina/metabolismo , Alopurinol/metabolismo , Alopurinol/farmacologia , Animais , Anserina/metabolismo , Anserina/farmacologia , Creatinina , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Hiperuricemia/metabolismo , Hipoxantinas/metabolismo , Hipoxantinas/farmacologia , Rim , Fígado/metabolismo , Malondialdeído/metabolismo , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Potássio/metabolismo , Potássio/farmacologia , Ratos , Superóxido Dismutase/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ácido Úrico , Xantina Oxidase/metabolismo
15.
J Food Biochem ; 46(10): e14286, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35929489

RESUMO

Abnormal uric acid level result in the development of hyperuricemia and hallmark of various diseases, including renal injury, gout, cardiovascular disorders, and non-alcoholic fatty liver. This study was designed to explore the anti-inflammatory potential of stevia residue extract (STR) against hyperuricemia-associated renal injury in mice. The results revealed that STR at dosages of 150 and 300 mg/kg bw and allopurinol markedly modulated serum uric acid, blood urea nitrogen, and creatinine in hyperuricemic mice. Serum and renal cytokine levels (IL-18, IL-6, IL-1Β, and TNF-α) were also restored by STR treatments. Furthermore, mRNA and immunohistochemistry (IHC) analysis revealed that STR ameliorates UA (uric acid)-associated renal inflammation, fibrosis, and EMT (epithelial-mesenchymal transition) via MMPS (matrix metalloproteinases), inhibiting NF-κB/NLRP3 activation by the AMPK/SIRT1 pathway and modulating the JAK2-STAT3 and Nrf2 signaling pathways. In summary, the present study provided experimental evidence that STR is an ideal candidate for the treatment of hyperuricemia-mediated renal inflammation. PRACTICAL APPLICATIONS: The higher uric acid results in hyperuricemia and gout. The available options for the treatment of hyperuricemia and gout are the use of allopurinol, and colchicine drugs, etc. These drugs possess several undesirable side effect. The polyphenolic compounds are abundantly present in plants, for example, stevia residue extract (STR) exert a positive effect on human health. From this study results, we can recommend that polyphenolic compounds enrich STR could be applied to develop treatment options for the treatment of hyperuricemia and gout.


Assuntos
Medicamentos de Ervas Chinesas , Gota , Hiperuricemia , Stevia , Proteínas Quinases Ativadas por AMP/farmacologia , Alopurinol/metabolismo , Alopurinol/farmacologia , Alopurinol/uso terapêutico , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Colchicina/metabolismo , Colchicina/farmacologia , Colchicina/uso terapêutico , Creatinina/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Gota/tratamento farmacológico , Gota/metabolismo , Humanos , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Inflamação/metabolismo , Interleucina-18/metabolismo , Interleucina-18/farmacologia , Interleucina-18/uso terapêutico , Interleucina-6/metabolismo , Rim , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR , RNA Mensageiro/metabolismo , Sirtuína 1/metabolismo , Stevia/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ácido Úrico
16.
Front Immunol ; 13: 940228, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35874662

RESUMO

Hyperuricemia (HUA) is the presence of excessive uric acid (UA) in blood, which leads to an increased risk of chronic kidney disease and gout. Probiotics have the potential effect of alleviating HUA. The purpose of this study was to screen probiotics with UA-lowering activity and explore the underlying mechanism. The UA-lowering activity of 20 lactic acid bacteria strains was investigated in vitro, and the effect of candidate probiotics on UA metabolism was evaluated using the HUA Balb/c mouse model. The results showed that Lactobacillus paracasei X11 had excellent UA-lowering activity in vitro, which could degrade nucleotides and nucleosides completely within 30 min, and the degradation rates of purine and trioxypurine could reach 83.25% and 80.42%, respectively. In addition, oral administration of L. paracasei X11 could reduce serum UA by 52.45% and inhibit renal proinflammatory cytokine IL-1ß by 50.69%, regulating adenosine deaminase (ADA), xanthine oxidase (XOD), and transporter expression (GLUT9, NPT1, and URAT1) to a normal level. Moreover, it could restore the ratio of Bacteroidetes to Firmicutes (Bac/Firm ratio) and showed a positive effect on the recovery of the intestinal microbiota. These findings provided fundamental information about the UA-lowering properties of probiotics, which suggested that L. paracasei X11 had the potential to be developed as a novel probiotic strain to ameliorate HUA.


Assuntos
Microbioma Gastrointestinal , Hiperuricemia , Animais , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Ácido Úrico
17.
Phytomedicine ; 103: 154256, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35714456

RESUMO

BACKGROUND: Hyperuricemia is characterized with high serum uric acids (SUAs) and directly causes suffering gout. Caffeic acid phenethyl ester (CAPE) is widely included in dietary plants and especially propolis of honey hives. HYPOTHESIS/PURPOSE: Since CAPE exerts a property resembling a redox shuttle, the hypothesis is that it may suppress xanthine oxidase (XOD) and alleviate hyperuricemia. The aim is to unveil the hypouricemic effect of CAPE and the underlying mechanisms. METHODS: By establishing a hyperuricemic model with potassium oxonate (PO) and hypoxanthine (HX) together, we investigated the hypouricecmic effect of CAPE. On this model, the expressions of key mRNAs and proteins, including glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1), and the activity of XOD were assayed in vivo. Also, the inhibitory effect of CAPE against XOD was assayed in vitro through enzymatic activity tests and by molecular docking. RESULTS: CAPE demonstrated a remarkable hypouricemic effect, which reduced the SUAs of hyperuricemic mice (401 ± 111 µmol/l) to 209 ± 56, 204 ± 65 and 154 ± 40 µmol/l (p < 0.01) at the doses of 15, 30 and 60 mg/kg respectively, depicting efficacies between 48 and 62% and approaching allopurinol's efficacy (52%). Serum parameters, body weights, inner organ coefficients, and H&E staining suggested that CAPE displayed no general toxicity and it alleviated the liver and kidney injuries caused by hyperuricemia. Mechanistically, CAPE decreased XOD activities significantly in vivo, presented an IC50 at 214.57 µM in vitro and depicted a favorable binding to XOD in molecular simulation, indicating that inhibiting XOD may be an underlying mechanism of CAPE against hyperuricemia. CAPE did decreased GLUT9 protein and down-regulated URAT1 mRNA and protein. In addition, CAPE up-regulated ATP binding cassette subfamily G member 2 (ABCG2) and organic anion transporter 3 (OAT3) mRNA and proteins in comparison with that of the hyperuricemic control. All above, CAPE may alleviate hyperuricmia through inhibiting XOD, decreasing GLUT9 and URAT1 and increasing ABCG2 and OAT3. CONCLUSION: CAPE presented potent hypouricemic effect in hyperuricemic mice through inhibiting XOD activity and up-regulating OAT3. CAPE may be a promising treatment against hyperuricemia.


Assuntos
Hiperuricemia , Transportadores de Ânions Orgânicos , Animais , Ácidos Cafeicos , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Rim , Camundongos , Simulação de Acoplamento Molecular , Transportadores de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Ácido Oxônico , Álcool Feniletílico/análogos & derivados , RNA Mensageiro/metabolismo , Ácido Úrico , Xantina Oxidase/metabolismo
18.
Biochem Biophys Res Commun ; 617(Pt 2): 55-61, 2022 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-35696777

RESUMO

The molecular mechanisms of uric acid (UA)-induced liver injury has not been clearly elucidated. In this study, we aimed to investigate the effect and action mechanisms of UA in liver injury. We analyzed the damaging effect of UA on mouse liver and L02 cells and subsequently performed metabolomics studies on L02 cells to identify abnormal metabolic pathways. Finally, we verified transcription factors that regulate related metabolic enzymes. UA directly activated the hepatic NLRP3 inflammasome and Bax apoptosis pathway invivo and invitro. Related metabolites in the arginine biosynthesis pathway (or urea cycle), l-arginine and l-argininosuccinate were decreased, and ammonia was increased in UA-stimulated L02 cells, which was mediated by carbamoyl phosphate synthase 1 (CPS1), argininosuccinate synthase (ASS) and argininosuccinate lyase (ASL) downregulation. UA upregulated hypoxia inducible factor-1alpha (HIF-1α) invivo and invitro, and HIF-1α inhibition alleviated the UA-induced ASS downregulation and hepatocyte injury. In conclusion, UA upregulates HIF-1α and inhibits urea cycle enzymes (UCEs). This leads to liver injury, with evidence of hepatocyte inflammation, apoptosis and oxidative stress.


Assuntos
Hiperuricemia , Animais , Arginina/metabolismo , Argininossuccinato Sintase , Hepatócitos/metabolismo , Humanos , Hiperuricemia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fígado/metabolismo , Camundongos , Ureia/metabolismo
19.
J Agric Food Chem ; 70(22): 6679-6687, 2022 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-35608514

RESUMO

Plant-derived peptides are a treasure trove for new-generation anti-hyperuricemia drugs. In the current study, we optimized a short hexapeptide rice-derived peptide 1 (RDP1)-M3 (AAAAGA) according to the anti-hyperuricemia RDP1 peptide identified from rice in our previous research. Results showed that RDP1-M3 exerted better hyperuricemia-alleviating and xanthine oxidase (XOD)-inhibiting potency in mice than RDP1. The biodistribution of RDP1-M3 was also analyzed. RDP1-M3 directly decreased XOD and uric acid levels in vivo and in vitro. In addition, RDP1-M3 reduced the expression of urate transporter 1 and glucose transporter 9, increased the level of organic anion transporter 1, reduced the expression of NOD-like receptor superfamily pyrin 3 inflammasomes, and reduced the levels of interleukin-1ß and tumor necrosis factor-α of hyperuricemic mice. Thus, our results indicated that the optimized short hexapeptide RDP1-M3 may be a candidate drug for anti-hyperuricemia.


Assuntos
Hiperuricemia , Oryza , Proteínas de Plantas/farmacologia , Animais , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Rim/metabolismo , Camundongos , Oryza/metabolismo , Peptídeos/metabolismo , Proteínas de Plantas/metabolismo , Distribuição Tecidual , Ácido Úrico/metabolismo , Xantina Oxidase/metabolismo
20.
Eur J Med Chem ; 237: 114379, 2022 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-35468514

RESUMO

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 IC50 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-ß, TNF-α and IL-1ß, 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-ß. 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.


Assuntos
Hiperuricemia , Nefropatias , Animais , Fibrose , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Inflamação/tratamento farmacológico , Iridoides , Camundongos , Simulação de Acoplamento Molecular , Fator de Crescimento Transformador beta , Ácido Úrico , Xantina Oxidase
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