RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Ilex cornuta is a valuable species of the Holly genus (Aquifoliaceae), and mainly distributed in eastern China. It is not only made into tea, namely Kudingcha, but also used as traditional medicine to relieve cough, headache, gout, and nourish liver and kidney. AIM OF THE STUDY: The purpose of this study was to explore the exact efficacy of different extracts from Ilex cornuta in the treatment of hyperuricemia in vitro and in vivo, and to explore its pharmacological mechanism, so as to bring new ideas for the development of new drugs for reducing uric acid (UA) and anti-gout. MATERIALS AND METHODS: Five crude extracts from Ilex cornuta leaves were extracted by different methods. Then, the xanthine oxidase inhibitory activity and antioxidant capacity of 5 extracts in vitro were compared to screen the extract with the most UA regulating potential. In vivo experiment, hyperuricemia model of mice was established by intragastric administration of potassium oxonate and feeding high yeast diet. Biochemical indexes such as serum UA level, xanthine oxidase activity, liver and kidney index of mice in each group were detected. The pathological sections of kidney and liver tissues were also observed and compared. The mechanism of Ilex cornuta leaves (western blotting, and RT-qPCR) in the treatment of hyperuricemia was further explored by targeting UA transporters ABCG2, GLUT9, and URAT1. RESULTS: The in vitro results of inhibitory activity of xanthine oxidase showed that the crude saponin extract was the best, followed by crude flavonoids extract. Then, the in vivo results reflected that both crude saponins and crude flavonoids extracts could significantly reduce the serum UA level, inhibit the activity of xanthine oxidase in serum and liver, and maintain serum urea nitrogen and creatinine at normal level. Meanwhile, there was no liver and kidney injury in mice. Through the comparison of the mechanism results, it was found that both extracts could up-regulate the expression of ABCG2 protein and mRNA related to UA excretion, and down-regulate the expression of GLUT9 and URAT1 protein and mRNA. CONCLUSION: The crude flavonoids and saponins of Ilex cornuta leaves not only inhibited XOD activity in vitro, but also significantly controlled XOD activity and reduced UA level in hyperuricemia mice in vivo. One of the potential mechanisms was to regulate UA level in vivo by regulating ABCG2, GLUT9, and URAT1 transporters directly related to UA transport, thus achieving the effect of intervening hyperuricemia. This study provided a preliminary experimental basis for the development of new drugs of Ilex cornuta leaves for treating hyperuricemia.

Asunto(s)

Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Hiperuricemia , Ilex , Transportadores de Anión Orgánico , Extractos Vegetales , Hojas de la Planta , Ácido Úrico , Xantina Oxidasa , Animales , Hiperuricemia/tratamiento farmacológico , Extractos Vegetales/farmacología , Extractos Vegetales/química , Hojas de la Planta/química , Ácido Úrico/sangre , Xantina Oxidasa/metabolismo , Xantina Oxidasa/antagonistas & inhibidores , Transportadores de Anión Orgánico/metabolismo , Masculino , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Ilex/química , Ratones , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Antioxidantes/farmacología , Antioxidantes/aislamiento & purificación , Modelos Animales de Enfermedad , Proteína 1 de Transporte de Anión Orgánico

RESUMEN

Long-term hyperuricemia can induce kidney damage, clinically referred to as hyperuricemic nephropathy (HN), which is characterized by renal fibrosis, inflammation, and oxidative stress. However, currently used uric acid-lowering drugs are not capable of protecting the kidneys from damage. Therefore, uric acid-lowering drugs that can also protect the kidneys are urgently needed. In this study, we first discovered that salinomycin, an antibiotic, can regulate uric acid homeostasis and ameliorate kidney damage in mice with HN. Mechanistically, salinomycin inhibited serum and hepatic xanthine oxidase (XOD) activities and downregulated renal urate transporter 1 (URAT1) expression and transport activity, thus exerting uric acid-lowering effects in mice with HN. Furthermore, we found that salinomycin promoted p-NRF2 Ser40 expression, resulting in increased nuclear translocation of NRF2 and activation of NRF2. More importantly, salinomycin affected the gut microbiota and promoted the generation of short-chain fatty acids (SCFAs) in mice with HN. In conclusion, our results revealed that salinomycin maintains uric acid homeostasis and alleviates kidney injury in mice with HN by multiple mechanisms, suggesting that salinomycin might be a desirable candidate for HN treatment in the clinic.

RESUMEN

PURPOSE: Preeclampsia (PE) is a common complication of pregnancy that carries significant risks for both the mother and the fetus, and is frequently accompanied by hyperuricemia, yet the exact source of elevated uric acid (UA) levels remains partially elucidated. Several potential origins for increased UA levels include abnormal renal function, increased tissue breakdown, and increased activity of the enzyme Xanthine Oxidase (XO). The aim of the study was to determine serum levels of UA and XO not only in maternal serum, but also in umbilical vein (UV) and umbilical artery (UA) and explore their possible role in PE development. METHODS: A prospective case-control pilot study was conducted in women who were found positive for PE with severe features, and had elevated UA levels above 6 mg/dL, with normotensive pregnant women serving as controls. Renal function, UA and XO levels were measured in maternal, UV and UA serums immediately after delivery. They were then compared between PE (n = 21) and control (n = 18) groups, as well as across all mediums (maternal, UV and UA) among the total study sample (N = 39). Diastolic blood pressure (DBP) was also measured immediately following delivery. RESULTS: The mean serum maternal creatinine levels did not differ significantly between groups (0.65 ± 0.03 vs 0.6 ± 0.07, p = 0.13). Both mean maternal serum UA and XO concentrations were higher in PE group than in control (7.3 ± 1.2 vs 4.2 ± 0.9, p < 0.01 and 3.6 ± 3.5 Vs 1.7 ± 0.8, p < 0.01, respectively). The mean UV and UA serum XO concentrations were significantly higher in PE group compared to control (4.2 ± 3.6 vs 2.2 ± 1.4, p < 0.01 and 4.2 ± 3.6 vs 2.1 ± 1.5, p < 0.01, respectively). Polynomial fit correlation test demonstrated a significant association between maternal DBP and UV XO concentration for all the total study participants (p = 0.03). CONCLUSION: Despite preserved renal functions, UA and XO levels were elevated in women with PE. Importantly, this pattern was found to be applied to the feto-placental unit as well, which may indicate an active involvement of the fetus in the hypoxic process. Further study is needed to clarify the possible role of the feto-placental unit in pregnancies complicated by PE.

Asunto(s)

Preeclampsia , Ácido Úrico , Xantina Oxidasa , Humanos , Femenino , Embarazo , Preeclampsia/sangre , Ácido Úrico/sangre , Estudios de Casos y Controles , Proyectos Piloto , Adulto , Estudios Prospectivos , Xantina Oxidasa/sangre , Venas Umbilicales , Arterias Umbilicales , Adulto Joven

RESUMEN

Acute pancreatitis (AP) is a potentially fatal condition with no targeted treatment options. Although inhibiting xanthine oxidase (XO) in the treatment of AP has been studied in several experimental models and clinical trials, whether XO is a target of AP and what its the main mechanism of action is remains unclear. Here, we aimed to re-evaluate whether XO is a target aggravating AP other than merely generating reactive oxygen species that trigger AP. We first revealed that XO expression and enzyme activity were significantly elevated in the serum and pancreas of necrotizing AP models. We also found that allopurinol and febuxostat, as purine-like and non-purine XO inhibitors, respectively, exhibited protective effects against pancreatic acinar cell death in vitro and pancreatic damage in vivo at different doses and treatment time points. Moreover, we observed that conditional Xdh overexpression aggravated pancreatic necrosis and severity. Further mechanism analysis showed that XO inhibition restored the hypoxia-inducible factor 1-alpha (HIF-1α)-regulated lactate dehydrogenase A (LDHA) and NOD-like receptor family pyrin domain containing 3 (NLRP3) signaling pathways and reduced the enrichment of 13C6-glucose to 13C3-lactate. Lastly, we observed that clinical circulatory XO activity was significantly elevated in severe cases and correlated with C-reactive protein levels, while pancreatic XO and urate were also increased in severe AP patients. These results together indicated that proper inhibition of XO might be a promising therapeutic strategy for alleviating pancreatic necrosis and preventing progression of severe AP by downregulating HIF-1α-mediated LDHA and NLRP3 signaling pathways.

RESUMEN

BACKGROUND: Geranyl acetate, a compound found in plant oils, has been studied for its potential effects on renal and cardiovascular ailments. OBJECTIVE: This study aimed to investigate the diuretic and anti-hyperuricemic properties of geranyl acetate in male Wistar rats using a hyperuricemia-induced rat model. METHODS: Molecular docking studies were conducted to assess geranyl acetate's interactions with various targets. in vitro studies were performed to evaluate its scavenging ability and inhibition of xanthine oxidase, urease, and acetylcholinesterase. Subsequently, we administered different doses of geranyl acetate (25, 50, and 100 mg/kg) and a reference drug (furosemide) to the rats to assess their acute and repeated dose diuretic effects over seven days. To understand the diuretic mechanism, we used inhibitors, such as L-- NAME, indomethacin, and atropine, prior to administering geranyl acetate. We also tested the anti-hyperuricemic potential of geranyl acetate on hyperuricemic rats. RESULTS: Molecular docking suggested strong binding between geranyl acetate and nitric oxide synthase. in vitro studies showed significant free radical scavenging activity and and inhibition of acetylcholinesterase, xanthine oxidase, and urease. The 100 mg/kg dose exhibited the most promising diuretic effects, with nitric oxide appearing to influence its action. Uric acid excretion increased at this dose, resembling allopurinol effects. CONCLUSION: Geranyl acetate has demonstrated significant diuretic and anti-hyperuricemic effects, likely influenced by nitric oxide release and inhibition of enzymes, like xanthine oxidase and urease. The findings have suggested potential benefits for individuals with kidney ailments, hypertension, and gout.

RESUMEN

Guanine deaminase (GD)plays important roles in the diagnosis of liver function. However, there is no totally rapid and simple for the eatimation of GD activity in clinical application. Herein, we have constructed an enzymatic assay system with highly sensitive and strong stability for quantification of GD activity by highly double enzyme-coupling (xanthine oxidase and uric acid oxidase) and adding compound stabilizer in GD kit. In this study, we validated parameters, including reagent blank, sensitivity, accuracy, inter-batch difference, intra-batch difference, linear range. Furthermore, composite stabilizers, containing gentamicin sulfate, bovine serum albumin, and mannitol, were selected to improve stability of GD kit during long-term storage. The experimental results showed that the absorbance of the reagent blank was <0.2, the mean recovery rate was 103 %, the inter-batch and intra-batch diffeerence were <15 %, The linearity range was 0 U/L-50 U/L (R2 > 0.99). All indicators met the kit requirements for clinical applications. When gentamicin sulfate, bovine serum albumin, and mannitol were used as a stabilizer, the kit remained stable for 12 months without significant loss of enzymatic activity. These results indicated that GD kit possesses high sensitivity and strong stability, which can be used for routine biochemical applications and is of great significance for the diagnosis and differential diagnosis of liver diseases.

RESUMEN

Xanthine oxidase (XO) is an enzyme that converts hypoxanthine into xanthine and xanthine into uric acid, which is then eliminated by the kidneys. Serum XO has been linked to diabetes, hypertension, liver dysfunction, and cardiovascular diseases. However, limited information exists on the relationship between serum XO activity and MetS. This study aimed to analyze the relationship between XO activity and metabolic syndrome (MetS) and its components in an adult population group in Bangladesh A total of 601 participants aged ≥18 years were included in the study. MetS was defined based on the criteria set by the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III). Serum XO activity was measured using the enzyme-linked immunosorbent assay (ELISA), while other biochemical parameters were measured using colorimetric methods. The relationship between serum XO and MetS levels was determined through multivariate logistic regression analysis. Serum XO activity was found to be significantly higher in females (6.17 ± 3.77 U/L) as compared to males (4.00 ± 2.77 U/L) (p < 0.001). Furthermore, participants with MetS had significantly higher mean levels of serum XO (5.34 ± 3.39 U/L) than those without MetS (3.86 ± 2.90 U/L) (p < 0.001). The prevalence of MetS and its components, such as blood pressure and blood glucose increased across the XO quartiles (p < 0.001). Regression analysis indicated that XO activity was significantly and independently associated with the prevalence of MetS (at least p < 0.05 for all cases) and its components, including elevated blood pressure, high blood glucose, and low HDL-C (at least p < 0.05 for all cases). In conclusion, individuals with MetS had significantly higher XO levels than those without MetS. Serum XO activity showed an independent association with MetS and some of its components. Therefore, XO might serve as a useful marker of MetS. Prospective studies are needed to determine the underlying mechanisms linking XO and MetS.

Asunto(s)

Síndrome Metabólico , Xantina Oxidasa , Humanos , Síndrome Metabólico/sangre , Síndrome Metabólico/epidemiología , Masculino , Femenino , Bangladesh/epidemiología , Adulto , Persona de Mediana Edad , Xantina Oxidasa/sangre , Xantina Oxidasa/metabolismo

RESUMEN

The difference on inhibitory effects of bioflavonoids inhibiting XOD activity assayed by varying test methods cause of us to be further in consideration. The reported test method creating a micro-environment surrounding XOD in the absence of ⋅O2 -, which is seemly different from the assay in vivo. So, the vitro test method for assaying XOD activity is necessary to be improved for selection of potential inhibitors in the presence of ⋅O2 -. The inhibitory results demonstrated that bioflavonoids of MY, DMY, QUE and LUT are capable to be on effective IC50 values, but others are not. As well, their resulting inhibitions determined by the improved test method are much less than that reported in the literature, indicating that their chemical affinities with XOD become weaker. Moreover, DMY assayed on the inhibitions of XOD in the improved test method performs to be a better inhibitor, as compared to the assay of the reported test methods. Abasing on the transformation of DMY into MY in the presence of ⋅O2 -, the good inhibition of DMY on XOD activity can be explained by the synergistic effect of MY.

RESUMEN

In miso, due to the substantial presence of genistein, flazin is often overlapped and masked by genistein in HPLC analysis. Flazin in the miso extracts could be resolved with genistein through medium-pressure liquid chromatography run under a nonacidified methanol-water system and subsequently fractionated by semipreparative HPLC and identified by NMR spectroscopic analysis. As referenced, flazin was detected in all 11 locally marketed miso products, with contents ranging from 3.5 to 124.8 µg/g. In lab-made miso fermented at 28 and 37 °C for 8 weeks, flazin formed faster at 37 °C than at 28 °C. Based on the time-dependent HPLC chromatographic changes of the miso extracts during fermentation, the presence of tryptophan-derived ß-carboline intermediates was deduced. Tryptophan was then supplemented for miso fermentation, and four peak substances were targeted for isolation by sophisticated approaches. Four ß-carbolines were purified and instrumentally identified, i.e., P1: 1-(1,3,4,5-tetrahydroxypentyl)-9H- pyrido[3,4-b]indole, P2 (diastereomer of P1): 1-(1*,3,4,5-tetrahydroxypentyl)- 9H-pyrido[3,4-b]indole, and Miso 101: 1-(1,3,4,5-tetrahydroxypentyl)-9H- pyrido[3,4-b]indole 3-carboxylic acid, and Miso 111 (diastereomer of Miso 101): 1-(1*,3,4,5-tetrahydroxypentyl)-9H-pyrido[3,4-b]indole 3-carboxylic acid. Each of the purified ß-carbolines along with tryptophan and flazin exhibited varied ABTS·+ scavenging and xanthine oxidase inhibitory activities.

RESUMEN

Background & Aims: There are no studies investigating the direct effects of elevated xanthine oxidase (XO) on lipid metabolism disorders. Here, we aimed to clarify the role of XO in lipid metabolism in a prospective cohort study and elucidate the underlying mechanisms. Methods: The association between serum XO activity and metabolic associated steatotic liver disease (MASLD) was examined in Cox proportional hazard models in a population-based cohort of 3,358 participants (20-75 years) at baseline. In addition, mouse models were used to investigate the underlying mechanism for the association between overexpression of XO and the lipid metabolism disorders. Results: After an average 5.8 years of follow up, we found elevated serum XO activity was associated with an increased risk of developing MASLD (hazard ratio [HR]: 2.08; 95% CI: 1.44-3.01; p-trend <0.001). Moreover, serum XO activity was significantly associated with serum triglyceride levels (r = 0.68, p <0.001). We demonstrated that hepatic XO expression increased in liver samples from patients with MASLD. Using tissue-specific Xdh knockin mice, we observed rapid lipid metabolism disorders under a high-fat diet rather than a normal chow diet. We found that XO overexpression promotes the absorption of excess dietary fat in the small intestine. Inhibition of XO also significantly reduced the absorption of fat in mice fed a high-fat diet. Conclusions: Our study clarified the association between serum XO activity levels and the development of MASLD in a large population-based prospective cohort study. Furthermore, our mouse models demonstrated that XO overexpression promotes lipid accumulation through mechanisms involving excessive fat absorption by the small intestine. Impact and implications: Using a prospective population-based cohort and various animal models, we have identified novel mechanisms by which xanthine oxidase regulates lipid metabolism. Our findings indicate that xanthine oxidase overexpression promotes lipid accumulation by increasing the absorption of excess dietary fat and possibly facilitating lipid transport in vivo. These results could be important for the development of therapies to treat diseases associated with lipid metabolism disorders.

RESUMEN

Hyperuricemia (HUA) is a metabolic disorder characterized by an imbalance in uric acid production and excretion, frequently leading to gout and various chronic conditions. Novel bioactive compounds offer effective alternatives for managing HUA, reducing side effects of traditional medications. Recent studies have highlighted the therapeutic potential of protein hydrolysates and peptides in managing HUA. This review focuses on preparing and applying protein hydrolysates to treat HUA and explores peptides for xanthine oxidase inhibition. Particularly, we discuss their origins, enzymatic approaches, and mechanisms of action in detail. The review provides an updated understanding of HUA pathogenesis, current pharmacological interventions, and methodologies for the preparation, purification, identification, and assessment of these compounds. Furthermore, to explore the application of protein hydrolysates and peptides in the food industry, we also address challenges and propose solutions related to the safety, bitterness, oral delivery, and the integration of artificial intelligence in peptide discovery. Bridging traditional pharmacological approaches and innovative dietary interventions, this study paves the way for future research and development in HUA management, contributing to the utilization of proteins from different food sources. In conclusion, protein hydrolysates and peptides show significant promise as safe agents and dietary interventions for preventing and treating HUA.

Asunto(s)

Hiperuricemia , Péptidos , Hidrolisados de Proteína , Hidrolisados de Proteína/química , Hiperuricemia/tratamiento farmacológico , Hiperuricemia/metabolismo , Humanos , Péptidos/química , Animales , Ácido Úrico/metabolismo , Xantina Oxidasa/metabolismo

RESUMEN

Hyperuricemia is an independent predictor of mortality in patients with chronic heart failure (CHF). To determine whether febuxostat, a urate-lowering agent, may improve clinical outcomes in CHF patients, we conducted a multicenter, prospective, randomized, open-label, blinded endpoint study with a treatment period of 24 weeks. We randomly assigned Japanese outpatients diagnosed with both CHF with reduced left ventricular ejection fraction (LVEF < 40%) and asymptomatic hyperuricemia (serum uric acid [UA] levels > 7.0 mg/dl and < 10.0 mg/dl) to either a febuxostat group (n = 51) or a control group (n = 50). The primary efficacy endpoint was the change in log-transformed plasma B-type natriuretic peptide (BNP) levels from baseline to week 24 (or at discontinuation). The secondary efficacy endpoints were the changes in LV systolic or diastolic function evaluated by echocardiography, New York Heart Association (NYHA) class, hemoglobin, and estimated glomerular filtration rate from baseline to week 24, and the change in log-transformed plasma BNP levels or serum UA levels from baseline to weeks 4, 8, 12, 16 and 20 (BNP) or weeks 4, 8, 12, 16, 20 and 24 (serum UA). The primary safety endpoints were occurrence of all-cause death or major cardiovascular events. The mean age of participants was 70 years; 14% were female. The febuxostat group and the control group did not differ with respect to the primary efficacy endpoint (p = 0.13), although the decrease in log-transformed plasma BNP levels from baseline to each of weeks 4, 8, 12, 16 and 20 was greater in the febuxostat group. There were no significant differences between the two groups in the primary safety endpoints or the secondary efficacy endpoints except reduced serum UA levels in the febuxostat group. Febuxostat did not reduce plasma BNP levels at week 24 in patients with CHF, but it appeared safe with no increase in major cardiovascular events and all-cause or cardiovascular mortality.

RESUMEN

Xanthine oxidase (XO) inhibitors, both synthetic and semisynthetic, have been developed extensively over the past few decades. The increased level of XO is not only the major cause of gout but is also responsible for various conditions associated with hyperuricemia, such as cardiovascular disorders, chronic kidney disorders, diabetes, Alzheimer's disease and chronic wounds. Marketed available XO inhibitors (allopurinol, febuxostat, and topiroxostat) are used to treat hyperuricemia but they are associated with fatal side effects, which pose serious problems for the healthcare system, rising the need for new, more potent, safer compounds. This review summarizes recent findings on XO and describes their design, synthesis, biological significance in the development of anti-hyperuricemic drugs with ADME profile, structure activity relationship (SAR) and molecular docking studies. The results might help medicinal chemists to develop more efficacious XO inhibitors.

RESUMEN

Hyperuricemia (HUA) has attained a considerable global health concern, related to the development of other metabolic syndromes. Xanthine oxidase (XO), the main enzyme that catalyzes xanthine and hypoxanthine into uric acid (UA), is a key target for drug development against HUA and gout. Available XO inhibitors are effective, but they come with side effects. Recent, research has identified new XO inhibitors from dietary sources such as flavonoids, phenolic acids, stilbenes, alkaloids, polysaccharides, and polypeptides, effectively reducing UA levels. Structural activity studies revealed that -OH groups and their substitutions on the benzene ring of flavonoids, polyphenols, and stilbenes, cyclic rings in alkaloids, and the helical structure of polysaccharides are crucial for XO inhibition. Polypeptide molecular weight, amino acid sequence, hydrophobicity, and binding mode, also play a significant role in XO inhibition. Molecular docking studies show these bioactive components prevent UA formation by interacting with XO substrates via hydrophobic, hydrogen bonds, and π-π interactions. This review explores the potential bioactive substances from dietary resources with XO inhibitory, and UA lowering potentials detailing the molecular mechanisms involved. It also discusses strategies for designing XO inhibitors and assisting pharmaceutical companies in developing safe and effective treatments for HUA and gout.

Asunto(s)

Inhibidores Enzimáticos , Gota , Hiperuricemia , Xantina Oxidasa , Xantina Oxidasa/antagonistas & inhibidores , Xantina Oxidasa/metabolismo , Xantina Oxidasa/química , Gota/tratamiento farmacológico , Hiperuricemia/tratamiento farmacológico , Humanos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Simulación del Acoplamiento Molecular , Animales , Ácido Úrico/metabolismo

RESUMEN

Gout is the second largest metabolic disease worldwide after diabetes, with acute gouty arthritis as most common symptom. Xanthine oxidase (XOD) and the NOD like receptor-3 (NLRP3) inflammasome are the key targets for acute gout treatment. Chlorogenic acid has been reported with a good anti-inflammatory activity, and Apigenin showed an excellent potential in XOD inhibition. Therefore, a series of chlorogenic acid-apigenin (CA) conjugates with varying linkers were designed and synthesized as dual XOD/NLRP3 inhibitors, and their activities both in XOD and NLRP3 inhibition were evaluated. An in vitro study of XOD inhibitory activity revealed that the majority of CA conjugates exhibited favorable XOD inhibitory activity. Particularly, the effects of compounds 10c and 10d, with an alkyl linker on the apigenin moiety, were stronger than that of allopurinol. The selected CA conjugates also demonstrated a favorable anti-inflammatory activity in RAW264.7 cells. Furthermore, compound 10d, which showed the optimal activity both in XOD inhibition and anti-inflammatory, was chosen and its inhibitory ability on NLRP3 and related proinflammatory cytokines was further tested. Compound 10d effectively reduced NLRP3 expression and the secretion of interluekin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) with an activity stronger than the positive control isoliquiritigenin (ISL). Based on these findings, compound 10d exhibits dual XOD/NLRP3 inhibitory activity and, therefore, the therapeutic effects on acute gout is worthy of further study.

Asunto(s)

Apigenina , Ácido Clorogénico , Supresores de la Gota , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Ratones , Apigenina/farmacología , Apigenina/química , Apigenina/síntesis química , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Células RAW 264.7 , Ácido Clorogénico/farmacología , Ácido Clorogénico/química , Ácido Clorogénico/síntesis química , Supresores de la Gota/farmacología , Supresores de la Gota/síntesis química , Supresores de la Gota/química , Supresores de la Gota/uso terapéutico , Relación Estructura-Actividad , Xantina Oxidasa/antagonistas & inhibidores , Xantina Oxidasa/metabolismo , Estructura Molecular , Gota/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacología , Antiinflamatorios/química

RESUMEN

Kaempferia subglobosa is a perennial medicinal plant in the Zingiberaceae family, identified as a new species in January 2024. To uncover the biological benefits of K. subglobosa and its compounds, investigation of the metabolites of the roots and rhizomes, yielded three new monoterpene-chalcone conjugates, the globosones A-C, representing a rare metabolite group within the Zingiberaceae, along with six known compounds. The biogenetic pathway for the globosones involves an oxidative [3+2] cycloaddition between α-phellandrene and 4'-methoxy-4,2',6'-trihydroxychalcone. Biological testing revealed potent xanthine oxidase (XO) inhibition by globosones A and B, with IC50 values of 7.0 ± 1.0 and 3.0 ± 0.2 µM, respectively, surpassing the positive control drug allopurinol (IC50 7.2 ± 0.1 µM). Globosones A-C also showed good aromatase inhibition (IC50 3.0-3.5 µM). Molecular docking studies indicated that globosones A and B may inhibit xanthine oxidase through binding at the FAD domain site. The physicochemical properties of these isolates suggest that they possess characteristics suitable for additional biological assessment in more advanced test systems. This study enhances an understanding of monoterpene-chalcone conjugate inhibitors of XO, and offers preliminary insights into the metabolites and bioactivities of K. subglobosa, uncovering potent biological activities associated with this newly discovered plant species.

RESUMEN

Urolithiasis, characterized by the formation of solid crystalline structures within the urinary tract, presents a significant global health burden with high recurrence rates and limited treatment efficacy. Recent research has identified various protein receptors and enzymes implicated in the pathogenesis of urolithiasis, offering potential targets for therapeutic intervention. Protein receptors such as the calcium-sensing receptor and vasopressin V2 receptor play crucial roles in regulating urinary calcium excretion and water reabsorption, respectively, influencing stone formation. Additionally, modulation of receptors like the angiotensin II receptor and aldosterone receptor can impact renal function and electrolyte balance, contributing to stone prevention. Furthermore, enzymes such as urease inhibitors and xanthine oxidase inhibitors offer targeted approaches to prevent the formation of specific stone types. This review discusses the potential of targeting these receptors and enzymes for the treatment of urolithiasis, exploring associated drugs and their mechanisms of action. Despite promising avenues for personalized and precision medicine approaches, challenges such as the need for robust clinical evidence and ensuring cost-effectiveness must be addressed for the translation of these interventions into clinical practice. By overcoming these challenges, receptor-targeted therapies and enzyme inhibitors hold promise for revolutionizing the management of urolithiasis and reducing its global burden.

Asunto(s)

Terapia Molecular Dirigida , Medicina de Precisión , Urolitiasis , Humanos , Urolitiasis/tratamiento farmacológico , Urolitiasis/metabolismo , Medicina de Precisión/métodos , Animales , Inhibidores Enzimáticos/uso terapéutico , Inhibidores Enzimáticos/farmacología , Ureasa/antagonistas & inhibidores , Ureasa/metabolismo , Receptores Sensibles al Calcio/metabolismo , Receptores Sensibles al Calcio/antagonistas & inhibidores , Xantina Oxidasa/antagonistas & inhibidores , Xantina Oxidasa/metabolismo , Receptores de Vasopresinas/metabolismo

RESUMEN

Young shoots of cereals are widely regarded as superfoods with health benefits attributed to their potential antioxidant activity and antioxidant-related effects (e.g. anticancer). The current study aimed to examine the chemical characteristics of Hordeum vulgare methanolic and aqueous extracts and assess their antioxidant activity using the DDPH and ORAC. Furthermore, the inhibitory effect of xanthine oxidase was screened. TLC bioautography was employed to determine the polarity of the compounds present in the extracts that exhibited the most potent free radical scavenging activity. Total flavonoid content of the methanolic and aqueous extracts was 0.14 mg QE/g and 0.012 mg QE/g, respectively. The antioxidant activity of the methanolic extract was found to be more potent, with a value of 0.97 ± 0.13 mmol TE/g than the aqueous extract which had no activity. This study presents novel findings on the xanthine inhibitory activity of H. vulgare. The methanolic extract demonstrated moderate inhibition of xanthine oxidase with a value of 23.24%. The results of our study were compared with the phytochemical and pharmacological analysis of Triticum aestivum, and further comparison was made with the data reported in the literature. Inconsistencies were observed in the chemical and pharmacological properties of H. vulgare, which could be a result of using herbal material harvested in different vegetative phases and various methods used for extraction. The findings of our study indicate that the timing of the harvest and extraction method may play crucial role in attaining the optimal phytochemical composition of H. vulgare, hence enhancing its pharmacological activity.

RESUMEN

In our previous study, we reported a series of N-(9,10-anthraquinone-2-carbonyl) amino acid derivatives as novel inhibitors of xanthine oxidase (XO). Recognizing the suboptimal drug-like properties associated with the anthraquinone moiety, we embarked on a nonanthraquinone medicinal chemistry exploration in the current investigation. Through systematic structure-activity relationship (SAR) studies, we identified a series of 4-(isopentyloxy)-3-nitrobenzamide derivatives exhibiting excellent in vitro potency against XO. The optimized compound, 4-isopentyloxy-N-(1H-pyrazol-3-yl)-3-nitrobenzamide (6k), demonstrated exceptional in vitro potency with an IC50 value of 0.13 µM. Compound 6k showed favorable drug-like characteristics with ligand efficiency (LE) and lipophilic ligand efficiency (LLE) values of 0.41 and 3.73, respectively. In comparison to the initial compound 1d, 6k exhibited a substantial 24-fold improvement in IC50, along with a 1.6-fold enhancement in LE and a 3.7-fold increase in LLE. Molecular modeling studies provided insights into the strong interactions of 6k with critical amino acid residues within the active site. Furthermore, in vivo hypouricemic investigations convincingly demonstrated that 6k significantly reduced serum uric acid levels in rats. The MTT results revealed that compound 6k is nontoxic to healthy cells. The gastric and intestinal stability assay demonstrated that compound 6k exhibits good stability in the gastric and intestinal environments. In conclusion, compound 6k emerges as a promising lead compound, showcasing both exceptional in vitro potency and favorable drug-like characteristics, thereby warranting further exploration.