RESUMO
Parkinson's disease (PD) is a neurodegenerative movement disorder associated with a loss of dopamine neurons in the substantia nigra. The diagnosis of PD is sensitive since it shows clinical features that are common with other neurodegenerative diseases. In addition, most symptoms arise at the late stage of the disease, where most dopaminergic neurons are already damaged. Several studies reported that oxidative stress is a key modulator in the development of PD. This condition occurs due to excess reactive oxygen species (ROS) production in the cellular system and the incapability of antioxidants to neutralize it. In this study, we focused on the pathology of PD by measuring serum xanthine oxidase (XO) activity, which is an enzyme that generates ROS. Interestingly, the serum XO activity of patients with PD was markedly upregulated compared to patients with other neurological diseases (ONDs) as a control. Moreover, serum XO activity in patients with PD showed a significant correlation with the disease severity based on the Hoehn and Yahr (HY) stages. The investigation of antioxidant status also revealed that serum uric acid levels were significantly lower in the severe group (HY ≥ 3) than in the ONDs group. Together, these results suggest that XO activity may contribute to the development of PD and might potentially be a biomarker for determining disease severity in patients with PD.
Assuntos
Antioxidantes , Doença de Parkinson , Ácido Úrico , Xantina Oxidase , Humanos , Doença de Parkinson/sangue , Doença de Parkinson/metabolismo , Xantina Oxidase/sangue , Xantina Oxidase/metabolismo , Masculino , Feminino , Idoso , Antioxidantes/metabolismo , Pessoa de Meia-Idade , Ácido Úrico/sangue , Biomarcadores/sangue , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Oxigênio/sangueRESUMO
Curcumin and artemisinin are commonly used in traditional East Asian medicine. In this study, we investigated the inhibitory effects of these active compounds on xanthine oxidase (XO) using allopurinol as a control. XO was purified from the serum of arthritis patients through ammonium sulfate precipitation (65%) and ion exchange chromatography on diethylaminoethyl (DEAE)-cellulose. The specific activity of the purified enzyme was 32.5 U/mg protein, resulting in a 7-fold purification with a yield of 66.8%. Molecular docking analysis revealed that curcumin had the strongest interaction energy with XO, with a binding energy of -9.28 kcal/mol. The amino acid residues Thr1077, Gln762, Phe914, Ala1078, Val1011, Glu1194, and Ala1079 were located closer to the binding site of curcumin than artemisinin, which had a binding energy of -7.2 kcal/mol. In vitro inhibition assays were performed using nanocurcumin and artemisinin at concentrations of 5, 10, 15, 20, and 25 µg/mL. Curcumin inhibited enzyme activity by 67-91%, while artemisinin had a lower inhibition ratio, which ranged from 40-70% compared to allopurinol as a control.
Assuntos
Artemisininas , Artrite , Curcumina , Xantina Oxidase , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/sangue , Curcumina/química , Curcumina/farmacologia , Artemisininas/química , Artemisininas/farmacologia , Humanos , Artrite/sangue , Artrite/enzimologia , Simulação de Acoplamento Molecular , Alopurinol/química , Alopurinol/farmacologia , Ligação ProteicaRESUMO
BACKGROUND: This study aimed to evaluate the urate-lowering effects of Yi-Suan-Cha and explore its underlying mechanisms in experimental hyperuricemia induced in rats. METHODS: Forty-eight male SD rats were randomly allocated into normal control, model, allopurinol, benzbromarone, low-dose Yi-Suan-Cha (0.2 g/ml), and high-dose Yi-Suan-Cha (0.4 g/ml) groups (n = 8 rats per group). Rat models of hyperuricemia were established through intragastric administration of adenine 25 mg/kg + potassium oxalate 300 mg/kg for 3 weeks. After the last administration, serum uric acid, creatinine, and urea nitrogen levels were measured. Renal histopathology was observed by hematoxylin-eosin staining. Xanthine oxidase level in serum and liver homogenates was measured by ELISA. The protein and mRNA expression of URAT1, ABCG2, OAT1, and GLUT9 in the kidney was detected by Western blotting and RT-PCR, respectively. RESULTS: The serum uric acid levels were significantly lowered in all medication groups than in the model group. The benzbromarone and both Yi-Suan-Cha groups showed clear kidney structures with no obvious abnormalities. Compared with the normal control group, the model group showed increased URAT1/GLUT9 protein expression and decreased ABCG2/OAT1 protein expression. Compared with the model group, both Yi-Suan-Cha groups showed decreased URAT1/GLUT9 protein expression and increased ABCG2/OAT1 protein expression. Compared with that in the normal control group, URAT1/GLUT9 mRNA expression increased in the model group. Compared with the model group, the low-dose and high-dose Yi-Suan-Cha groups showed decreased URAT1/GLUT9 mRNA expression and increased ABCG2/OAT1 mRNA expression. CONCLUSION: Yi-Suan-Cha may lower uric acid level by downregulating URAT1/GLUT9 expression and upregulating ABCG2/OAT1 expression.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Hiperuricemia/tratamento farmacológico , Rim/efeitos dos fármacos , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Proteínas de Transporte de Ânions/genética , Proteínas de Transporte de Ânions/metabolismo , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperuricemia/metabolismo , Hiperuricemia/patologia , Rim/metabolismo , Rim/patologia , Masculino , Proteínas de Transporte de Monossacarídeos/genética , Proteínas de Transporte de Monossacarídeos/metabolismo , Proteína 1 Transportadora de Ânions Orgânicos/genética , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Ratos Sprague-Dawley , Ácido Úrico/sangue , Xantina Oxidase/sangue , Xantina Oxidase/metabolismoRESUMO
Xanthine oxidase (XO) competes with thiopurine S-methyltransferase (TPMT) and hypoxanthine guanine phosphoribosyltransferase (HPRT) to metabolize azathioprine (AZA)/6-mercaptopurine (6-MP) in vivo. A retrospective investigation was performed to detect the activity of XO in thiopurine curative Chinese inflammatory bowel disease (IBD) patients. We also evaluated whether a relationship between XO activity and incidence of thiopurine-induced adverse effects (AEs) existed. Clinical data and blood samples were collected from 140 IBD patients before receiving AZA/6-MP therapy, and the erythrocyte XO activity was measured. The XO activities of all patients were 20.29 ± 4.43 U/g Hb. No sex difference in XO activity was observed (p = .728), and the XO activity showed no difference between the UC and CD patients (p = .082). AEs were observed in 41 (29.3%) patients including leukopenia (26, 18.57%), gastrointestinal intolerance (11, 7.86%), flu-like symptom (5, 3.57%), alopecia (5, 3.57%), and hepatotoxicity (1, 0.71%). XO activity was significantly lower in the patients with AEs than in those without AEs (18.40 ± 3.73 vs. 21.07 ± 4.48 U/g Hb, p = .001), especially in the patients with leukopenia (18.29 ± 3.68 vs. 21.07 ± 4.48 U/g Hb, p = .004). However, no significant difference in XO activity was found between patients with and without other AEs. Decreased XO activity was observed in the patients who developed flu-like symptoms (17.58 ± 3.50 U/g Hb) and alopecia (18.67 ± 2.91 U/g Hb) compared to those who did not, although the differences did not reach statistical significance. These findings suggested that patients with low XO expression might have a high risk of thiopurine-induced toxicity.
Assuntos
Azatioprina/efeitos adversos , Imunossupressores/efeitos adversos , Doenças Inflamatórias Intestinais/sangue , Mercaptopurina/efeitos adversos , Xantina Oxidase/sangue , Adolescente , Adulto , Idoso , Povo Asiático , Azatioprina/farmacologia , Azatioprina/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Leucopenia/induzido quimicamente , Masculino , Mercaptopurina/farmacologia , Mercaptopurina/uso terapêutico , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
Redox balance and methylation are crucial to homeostasis and are linked by the methionine-homocysteine cycle. We examined whether differences in methylation potential, measured as plasma levels of S-adenosyl methionine (SAM) and S-adenosyl homocysteine (SAH), occur at baseline and during anti-oxidant therapy with the xanthine oxidase inhibitor allopurinol in patients with heart failure with reduced ejection fraction. We analyzed plasma samples collected at baseline and 24 weeks in the Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients (EXACT-HF) study, which randomized patients with heart failure with reduced ejection fraction to allopurinol or placebo. Associations between plasma levels of SAM, SAH, SAM/SAH ratio, and outcomes, including laboratory markers and clinical events, were assessed. Despite randomization, median SAM levels were significantly lower at baseline in the allopurinol group. SAH levels at 24 weeks, and change in SAM from baseline to week 24, were significantly higher in the group of patients randomized to allopurinol compared to the placebo group. A significant correlation was observed between change in SAH levels and change in plasma uric acid (baseline to 24-week changes) in the allopurinol group. There were no significant associations between levels of SAM, SAH, and SAM/SAH ratio and clinical outcomes. Our results demonstrate significant biological variability in SAM and SAH levels at baseline and during treatment with an anti-oxidant and suggest a potential mechanism for the lack of efficacy observed in trials of anti-oxidant therapy. These data also highlight the need to explore personalized therapy for heart failure.
Assuntos
Alopurinol/uso terapêutico , Sequestradores de Radicais Livres/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Hiperuricemia/tratamento farmacológico , S-Adenosil-Homocisteína/sangue , S-Adenosilmetionina/sangue , Idoso , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Humanos , Hiperuricemia/sangue , Hiperuricemia/fisiopatologia , Masculino , Metilação/efeitos dos fármacos , Pessoa de Meia-Idade , Oxirredução/efeitos dos fármacos , Medicina de Precisão , Volume Sistólico/efeitos dos fármacos , Resultado do Tratamento , Ácido Úrico/sangue , Xantina Oxidase/sangue , Xantina Oxidase/genéticaRESUMO
Lobetyolin (LBT), a general marker compound mainly found in Codonopsis plants including C. pilosula, C. tubulosa, and C. lanceolata, exhibits antitumor, antiviral, anti-inflammatory, mucosal protective, and antioxidant activities. Xanthine oxidase (XO) catalyzes the formation of uric acid from xanthine, a critical metabolic pathway related to hyperuricemia and gout. The aim of this study was to investigate the effect of LBT on XO activity and its mechanism using in vitro enzyme assay system and in vivo potassium oxonate-induced hyperuricemic mice. LBT was found to weakly inhibit XO activity via a mixed type mechanism. Consistently, the impact of 1-week oral LBT treatment on serum XO activity in vivo is limited in hyperuricemic mice. However, oral LBT at 50 mg/kg significantly reduced hepatic XO activity in vivo. To the best of our knowledge, this is the first study to report effects of LBT on XO activity and its inhibition mechanism.
Assuntos
Inibidores Enzimáticos/farmacologia , Poli-Inos/farmacologia , Xantina Oxidase/metabolismo , Administração Oral , Animais , Relação Dose-Resposta a Droga , Hiperuricemia/induzido quimicamente , Hiperuricemia/tratamento farmacológico , Masculino , Camundongos , Ácido Oxônico/toxicidade , Ácido Úrico/metabolismo , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/sangueRESUMO
Increased levels of the superoxide radical are associated with oxidative damage to healthy tissues and with elimination of malignant cells in a living body. It is desirable that a chemotherapeutic combines pro-oxidant behavior around and inside tumors with antioxidant action near healthy cells. A complex consisting of a pro-oxidant cation and antioxidant ligands could be a potential anticancer agent. Ga(III) salts are known anticancer substances, and 5-aminoorotic acid (HAOA) is a ligand with antioxidant properties. The in vitro effects of HAOA and its complex with Ga(III) (gallium(III) 5-aminoorotate (GaAOA)) on the in vitro accumulation of superoxide and other free radicals were estimated. Model systems such as potassium superoxide (KO2), xanthine/xanthine oxidase (X/XO), and rat blood serum were utilized. Data suggested better antioxidant effect of GaAOA compared to HAOA. Evidently, all three ligands of GaAOA participated in the scavenging of superoxide. The effects in rat blood serum were more nuanced, considering the chemical and biochemical complexity of this model system. It was observed that the free-radical-scavenging action of both compounds investigated may be manifested via both hydrogen donation and electron transfer pathways. It was proposed that the radical-scavenging activities (RSAs) of HAOA and its complex with Ga(III) may be due to a complex process, depending on the concentration, and on the environment, nature, and size of the free radical. The electron transfer pathway was considered as more probable in comparison to hydrogen donation in the scavenging of superoxide by 5-aminoorotic acid and its gallium(III) complex.
Assuntos
Antioxidantes/farmacologia , Complexos de Coordenação/farmacologia , Gálio/farmacologia , Ácido Orótico/análogos & derivados , Animais , Antioxidantes/química , Complexos de Coordenação/química , Sequestradores de Radicais Livres/sangue , Radicais Livres/sangue , Gálio/química , Humanos , Ácido Orótico/química , Ácido Orótico/farmacologia , Ratos , Superóxidos/sangue , Xantina Oxidase/sangueRESUMO
CONTEXT: Lycium barbarum L. (Solanaceae) polysaccharides (LBPs) are important active constituents that have demonstrated kidney protection. OBJECTIVE: This study investigated the effect of LBPs on hyperuricaemia and explored the underlying mechanism in mice. MATERIALS AND METHODS: Thirty-six C57BL/6 mice were randomly divided into the control group, hyperuricaemia group, allopurinol group (5 mg/kg) and three LBP groups (n = 6). The LBP groups were treated orally with LBPs at 50, 100 and 200 mg/kg body weight for 7 days. We examined the levels of serum uric acid (SUA) and urinary uric acid (UUA), as well as xanthine oxidase (XOD) activities. mRNA and protein were quantified by quantitative real-time PCR and Western blotting, respectively. RESULTS: LBPs treatment (100 and 200 mg/kg) significantly reduced the SUA levels to 4.83 and 4.48 mg/dL, and markedly elevated the UUA levels to 4.68 and 5.18 mg/dL (p < 0.05), respectively, while significantly increased the mRNA and protein expression levels of renal organic anti-transporter 1 (OAT1) and organic anti-transporter 3 (OAT3), and markedly decreased the levels of glucose transporter 9 (GLUT9) (p < 0.05). Additionally, the serum XOD activities were reduced to 31.5 and 31.1 mU/mL, and the liver XOD activities were reduced to 80.6 and 75.6 mU/mL after treatment with 100 and 200 mg/kg LBPs (p < 0.01), respectively. DISCUSSION AND CONCLUSIONS: This study demonstrated the potential role of LBPs in reducing the uric acid level in hyperuricemic mice. A border study population should be evaluated. These results are valuable for the development of new anti-hyperuricaemia agents from LBPs.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Hiperuricemia/tratamento farmacológico , Substâncias Protetoras/farmacologia , Ácido Úrico/metabolismo , Xantina Oxidase/metabolismo , Animais , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Hiperuricemia/prevenção & controle , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Lycium/química , Masculino , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos C57BL , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Ácido Úrico/sangue , Xantina Oxidase/sangueRESUMO
Considering the global health threat posed by kidney disease burden, a search for new nephroprotective drugs from our local flora could prove a powerful strategy to respond to this health threat. In this study we investigated the antihyperuricemic and nephroprotective potential of RA-3, a plant-derived lanosteryl triterpene. The antihyperuricemic and nephroprotective effect of RA-3 was investigated using the adenine and gentamicin induced hyperuricemic and nephrotoxicity rat model. Following the induction of hyperuricemia and nephrotoxicity, the experimental model rats (Sprague Dawley) were orally administered with RA-3 at 50 and 100 mg/kg body weight, respectively, daily for 14 days. Treatment of the experimental rats with RA-3, especially at 100 mg/kg, effectively lowered the serum renal dysfunction (blood urea nitrogen and creatinine) and hyperuricemic (uric acid and xanthine oxidase) biomarkers. These were accompanied by increased antioxidant status with decrease in malondialdehyde content. A much improved histomorphological structure of the kidney tissues was also observed in the triterpene treated groups when compared to the model control group. It is evident that RA-3 possesses the antihyperuricemic and nephroprotective properties, which could be vital for prevention and amelioration of kidney disease.
Assuntos
Hiperuricemia/tratamento farmacológico , Rim/patologia , Lanosterol/análogos & derivados , Lanosterol/uso terapêutico , Substâncias Protetoras/uso terapêutico , Triterpenos/uso terapêutico , Animais , Biomarcadores/sangue , Nitrogênio da Ureia Sanguínea , Peso Corporal/efeitos dos fármacos , Creatinina/sangue , Hiperuricemia/sangue , Interleucina-6/sangue , Rim/efeitos dos fármacos , Rim/fisiopatologia , Lanosterol/química , Lanosterol/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Ratos Sprague-Dawley , Triterpenos/química , Triterpenos/farmacologia , Ácido Úrico/sangue , Xantina Oxidase/sangueRESUMO
OBJECTIVE: The etiology of multiple myeloma (MM) is not known. Enzymes such as xanthine oxidase (XO) and NADPH oxidase 1 (NOX1) as relevant sources of reactive oxygen species (ROS) production may play a crucial role in the incidence and progress of MM. Uric acid generated by XO has a controversial dual role in both the prevention and promotion of cancer. We conducted a case-control study and selected patients with stage I MM to investigate the status of XO, NOX1, and uric acid in the patients and controls. METHODS: We used a sample of 33 patients with stage I MM and 30 healthy controls. The enzyme-linked immunosorbent assay (ELISA) measured the enzyme concentration of XO and NOX1, and the colorimetric method measured the serum level of uric acid. RESULTS: Mean serum levels for XO in patients and controls were 6.17±0.83 ng/ml and 4.12±0.57 ng/ml (P<0.001). serum levels of NOX1 were 4.35±1.03 ng/ml in patients and 3.54±0.91 ng/ml in controls (P<0.001). Evaluating the levels of XO and NOX1 in male and female populations showed a significant difference in the male population (NOX1 P=0.002; XO P<0.001) and female population (NOX1 P=0.002; XO P<0.001). Also, a significant correlation was observed between the two enzymes only in the female population (Pearson correlation=0.5; P=0.006). A significant inverse correlation found between albumin and XO (Pearson correlation=-0.7, P<0.001) and NOX1 (Pearson correlation=-0.5, P<0.001). XO was correlated with B2-m (Pearson correlation=0.37, P=0.003). There was no significant difference in uric acid between patients (6.2±1.2 mg/dl) and controls (5.7±1 mg/dl) (P=0.2), and no correlation was found with XO. CONCLUSION: The present study indicates the possible role of XO and NOX 1 in the etiology of MM. Although we found no correlation between uric acid and XO, further studies will help clarify the function of uric acid in the pathogenesis of MM.
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Assuntos
Biomarcadores Tumorais/sangue , Mieloma Múltiplo/patologia , NADPH Oxidase 1/sangue , Ácido Úrico/sangue , Xantina Oxidase/sangue , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Estadiamento de Neoplasias , Espécies Reativas de Oxigênio/metabolismoRESUMO
Aster glehni extracts (AGE) reduced serum uric acid levels in hyperuricemia rats in several previous studies. However, its efficacy in human has not been yet explored. This study aimed at investigating the efficacy and safety of AGE on the anti-hyperuricemia effect in subjects with slightly high serum uric acid. A randomized, double-blinded, placebo-controlled clinical trial was conducted for 12 weeks. Eligible subjects were randomly assigned to either AGE (480 mg/day) or placebo. The primary endpoint was the change in serum uric acid concentrations from baseline to follow-up time points. The secondary endpoints were the change of serum xanthine oxidase activity, and the levels of C-reactive protein (CRP) and tumor necrosis factor alpha (TNF-α) in the blood from baseline to follow-up time points. Safety was assessed by clinical laboratory parameters and adverse events reported by subjects. Six weeks of AGE supplementation significantly reduced serum uric acid level from baseline (P = .0468) but at the end of the intervention the participants did not show the beneficial effect of AGE supplementation. Also, the serum uric acid level in the AGE group was not significantly different at the follow-up time points, when compared with placebo. The mean changes of secondary endpoints from baseline to each time point did not show significant differences within and between the two groups. There were no adverse events reported by subjects or changes in safety parameters after intervention. In conclusion, AGE supplementation for 12 weeks did not show significant benefits for reducing serum uric acid concentrations in subjects with mild hyperuricemia.
Assuntos
Aster/química , Hiperuricemia/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Ácido Úrico/sangue , Adulto , Proteína C-Reativa/análise , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/sangue , Xantina Oxidase/sangue , Adulto JovemRESUMO
BACKGROUND: Hyperuricemia is an abnormal increase in uric acid levels in the blood. It is the cause of gout that manifested by inflammatory arthritis and painful disable. Therefore, current study evaluated the potential ameliorative impact of Lesinurad and Allopurinol on the kidneys of hyperuricemic mice at the biochemical, molecular and cellular levels. METHODS: Lesinurad and allopurinol alone or in combination were orally administered to hyperuricemic and control mice for seven consecutive days. Levels of uric acid and blood urea nitrogen, along with antioxidants and inflammatory cytokines (IL-1ß and TNF-α) were measured in the serum. The mRNA expression of mouse urate anion transporter-1, glucose transporter 9, organic anion transporters, in renal tissues were examined using quantitative real time PCR. Simultaneously, the immunoreactivity of transforming growth factor-beta 1 was examined immunohistochemically. RESULTS: Lesinurad and allopurinol administration resulted in significant decrease in serum levels of uric acid, blood urea nitrogen, xanthine oxidase activity, catalase, glutathione peroxidase and inflammatory cytokines (IL-1ß and TNF-α) reported in hyperuricemic mice. Both partially reversed oxonate-induced alterations in renal mURAT-1, mGLUT-9, mOAT-1 and mOAT-3 expressions, as well as alterations in the immunoreactivity of TGF- ß1, resulting in the increase of renal uric acid secretion and excretion. The combined administration of lesinurad and ALP restored all altered parameters in a synergistic manner, improving renal function in the hyperuricemic mouse model employed. CONCLUSION: This study confirmed synergistic ameliorative hypouricemic impact of both lesinurad and allopurinol in the treatment of hyperuricemia in mice at the biochemical, molecular and cellular levels.
Assuntos
Alopurinol/uso terapêutico , Supressores da Gota/uso terapêutico , Hiperuricemia/tratamento farmacológico , Tioglicolatos/uso terapêutico , Triazóis/uso terapêutico , Alopurinol/farmacologia , Animais , Nitrogênio da Ureia Sanguínea , Catalase/sangue , Sinergismo Farmacológico , Glutationa Peroxidase/sangue , Supressores da Gota/farmacologia , Hiperuricemia/sangue , Hiperuricemia/genética , Hiperuricemia/metabolismo , Interleucina-1beta/sangue , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Tioglicolatos/farmacologia , Triazóis/farmacologia , Fator de Necrose Tumoral alfa/sangue , Ácido Úrico/sangue , Xantina Oxidase/sangue , Xantina Oxidase/metabolismoRESUMO
Fatty liver is the hepatic consequence of chronic insulin resistance (IR) and related syndromes. It is mostly accompanied by inflammatory and oxidative molecules. Increased activity of xanthine oxidase (XO) exerts both inflammatory and oxidative effects and has been implicated in metabolic derangements including non-alcoholic fatty liver disease. Short chain fatty acids (SCFAs) elicit beneficial metabolic alterations in IR and related syndromes. In the present study, we evaluated the preventive effects of a SCFA, acetate, on nicotine-induced dysmetabolism and fatty liver. Twenty-four male Wistar rats (n = 6/group): vehicle-treatment (p.o.), nicotine-treated (1.0 mg/kg; p.o.), sodium acetate-treated (200 mg/kg; p.o.) and nicotine + sodium acetate-treated groups. The treatments lasted for 8 weeks. IR was estimated by oral glucose tolerance test and homeostatic model assessment of IR. Plasma and hepatic free fatty acid, triglyceride (TG), glutathione peroxidase, adenosine deaminase (ADA), XO and uric acid (UA) were measured. Nicotine exposure resulted in reduced body weight, liver weight, visceral adiposity, glycogen content and glycogen synthase activity. Conversely, exposure to nicotine increased fasting plasma glucose, lactate, IR, plasma and hepatic TG, free fatty acid, TG/HDL-cholesterol ratio, lipid peroxidation, liver function enzymes, plasma and hepatic UA, XO and ADA activities. However, plasma and hepatic glucose-6-phosphate dehydrogenase-dependent antioxidant defense was not affected by nicotine. Concomitant treatment with acetate ameliorated nicotine-induced effects. Taken together, these results indicate that nicotine exposure leads to excess deposition of lipid in the liver by enhancing XO activity. The results also imply that acetate confers hepatoprotection and is accompanied by decreased XO activity.
Assuntos
Lipídeos/análise , Fígado/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Acetato de Sódio/farmacologia , Xantina Oxidase/metabolismo , Animais , Área Sob a Curva , Ácidos Graxos não Esterificados/sangue , Teste de Tolerância a Glucose , Resistência à Insulina , Peroxidação de Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Fígado/metabolismo , Fígado/patologia , Masculino , Nicotina/farmacologia , Curva ROC , Ratos , Ratos Wistar , Triglicerídeos/sangue , Xantina Oxidase/sangueRESUMO
This study was aimed at evaluating the prospect of edible chrysanthemum extract as a potential substance for the prevention and treatment of hyperuricemia. Chrysanthemum morifolium Ramat. 'Boju' extract (CBE), which had the strongest xanthine oxidase inhibitory activity, showed a significant hypouricemic effect on potassium oxonate-induced hyperuricemic rats through inhibiting serum xanthine oxidase activity, regulating renal uric acid transport-related protein (ABCG2, URAT1 and GLUT9) expression and blood lipid levels, and protecting renal function. Serum metabolomics based on UPLC-ESI-QTOF/MS was used to illustrate mechanisms underlying the amelioration effect of CBE on hyperuricemia. A total of 35 potential biomarkers were identified. CBE prevented the pathological process of hyperuricemia by regulating 16/17 biomarkers associated with tryptophan, sphingolipid, glycerophospholipid and arachidonic acid metabolisms. CBE could alleviate hyperuricemia-related diseases including chronic kidney disease, hyperlipidemia and inflammation via reducing indoxyl sulfate, lysophosphatidylcholines and arachidonic acid levels, exhibiting its applicability and superiority in the treatment of hyperuricemia.
Assuntos
Chrysanthemum/química , Medicamentos de Ervas Chinesas/administração & dosagem , Hiperuricemia/tratamento farmacológico , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Cromatografia Líquida de Alta Pressão , Proteínas Facilitadoras de Transporte de Glucose/sangue , Proteínas Facilitadoras de Transporte de Glucose/genética , Humanos , Hiperuricemia/sangue , Hiperuricemia/genética , Masculino , Espectrometria de Massas , Metabolômica , Transportadores de Ânions Orgânicos/sangue , Transportadores de Ânions Orgânicos/genética , Ratos , Soro/química , Soro/metabolismo , Xantina Oxidase/sangue , Xantina Oxidase/genéticaAssuntos
Biomarcadores Tumorais/sangue , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/mortalidade , Proteínas de Neoplasias/sangue , Xantina Oxidase/sangue , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Neoplasias Hematológicas/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Taxa de SobrevidaAssuntos
Alopurinol/uso terapêutico , Febuxostat/uso terapêutico , Gota/sangue , Ácido Úrico/sangue , Xantina Oxidase/antagonistas & inibidores , Idoso , Inibidores Enzimáticos/uso terapêutico , Feminino , Gota/tratamento farmacológico , Supressores da Gota/uso terapêutico , Humanos , Masculino , Xantina Oxidase/sangueRESUMO
Head and neck cancer (HNC) is one of the most common malignancies in the world. HNC is a group of cancers that starts in the mouth, nose, throat, larynx, sinuses, or salivary glands. According to this section of the body parts; induction of cancer can be associated with CO2 and oxidative stress. The aim of this study is to assess the activities of carbonic anhydrase (CA), catalase (CAT), paraoxonase1 (PON1), and xanthine oxidase (XO) activities in 89 HNC patients and 115 healthy volunteers. Paraoxonase1 activity was found lower in HNC cancer patients. There is no statistically significant difference between patients and controls for catalase, carbonic anhydrase, and xanthine oxidase enzyme levels. According to this results, paraoxonase1 levels could be a candidate as an oxidative marker in HNC patients, but further studies are needed to investigate the other type of cancer related PON1 and the other enzyme levels.
Assuntos
Arildialquilfosfatase/metabolismo , Biomarcadores Tumorais/metabolismo , Dióxido de Carbono/metabolismo , Anidrases Carbônicas/metabolismo , Catalase/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Xantina Oxidase/metabolismo , Arildialquilfosfatase/sangue , Biomarcadores Tumorais/sangue , Dióxido de Carbono/sangue , Anidrases Carbônicas/sangue , Catalase/sangue , Feminino , Neoplasias de Cabeça e Pescoço/sangue , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Xantina Oxidase/sangueRESUMO
BACKGROUND: The extra-renal effects of aldosterone on left ventricular (LV) structure and function are exacerbated by increased dietary sodium in persons with hypertension. Previous studies demonstrated endothelial dysfunction and increased oxidative stress with high salt diet in normotensive salt-resistant subjects. We hypothesized that increased xanthine oxidase (XO), a product of endothelial cells, is related to 24-h urinary sodium and to LV hypertrophy and function in patients with resistant hypertension (RHTN). METHODS: The study group included persons with RHTN (nâ¯=â¯91), defined as a blood pressureâ¯>â¯140/90â¯mmHg onâ¯≥â¯3 medications at pharmacologically effective doses. Plasma XO activity and 24-h urine were collected, and cardiac magnetic resonance imaging (MRI) was performed to assess LV function and morphology. Sixty-seven normotensive persons on no cardiovascular medications served as controls. A subset of RHTN (nâ¯=â¯19) received spironolactone without salt restriction for six months with follow-up XO activity measurements and MRI analyses. RESULTS: XO activity was increased two-fold in RHTN vs. normal and was positively correlated with LV mass, LV diastolic function, and 24-h urinary sodium. In RHTN patients receiving spironolactone without salt restriction, LV mass decreased, but LV diastolic function and XO activity did not improve. Baseline urinary sodium was positively associated with rate of change of LV mass to volume ratio and the LV E/A ratio. CONCLUSIONS: These results demonstrate a potential role of endothelium-derived oxidative stress and excess dietary salt in the pathophysiology of LV hypertrophy and diastolic dysfunction in persons with RHTN unaffected by the addition of spironolactone.
Assuntos
Hipernatremia/diagnóstico , Hipertensão/complicações , Hipertrofia Ventricular Esquerda/diagnóstico , Sódio/metabolismo , Xantina Oxidase/sangue , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Hipernatremia/sangue , Hipernatremia/enzimologia , Hipernatremia/etiologia , Hipertrofia Ventricular Esquerda/sangue , Hipertrofia Ventricular Esquerda/enzimologia , Hipertrofia Ventricular Esquerda/etiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND: ChondroT, a new herbal medication, consists of the water extracts of Osterici Radix, Lonicerae Folium, Angelicae Gigantis Radix, Clematidis Radix, and Phellodendri Cortex (6:4:4:4:3). We previously reported that ChondroT showed significant anti-arthritis and anti-inflammatory effects. METHODS: This study was designed to evaluate the effect of ChondroT on hyperuricemia. First, the effect of ChondroT was evaluated on xanthine oxidase (XOD) activity in vitro. The anti-hyperuricemic effect of ChondroT was also studied in potassium oxonate (PO)-induced hyperuricemic model mice. Uric acid (UA) and XOD were evaluated in the serum, urine, and liver of the mice. In addition, we measured serum creatinine (Cr) and blood urea nitrogen (BUN) levels as well as mRNA expression of the mouse urate transporter 1 (mURAT1) to evaluate kidney function and urate excretion in hyperuricemic mice. RESULTS: ChondroT showed in vitro XOD inhibitory activity in a dose-dependent manner (P < 0.05). We demonstrated that ChondroT (37.5, 75 and 150 mg/kg) significantly reduced serum UA (P < 0.01 and P < 0.001, respectively), and upregulated urinary UA (P < 0.001, respectively) in PO-induced hyperuricemic mice. In addition, ChondroT (75 and 150 mg/kg) significantly reduced Cr (P < 0.05 and P < 0.01, respectively), BUN (P < 0.05 and P < 0.001, respectively), GOT (P < 0.05 and P < 0.01, respectively), and GPT (P > 0.05 and P < 0.05, respectively) levels in PO-induced hyperuricemic mice. ChondroT (75 and 150 mg/kg) also significantly downregulated serum (P < 0.05) and liver (P < 0.05) XOD activity. Compared to the hyperuricemic mice, the ChondroT (37.5, 75, and 150 mg/kg)-treated mice showed decreased mURAT1 protein expression level. CONCLUSION: ChondroT displayed anti-hyperuricemic effects by regulating XOD activity and kidney mURAT1.
Assuntos
Regulação para Baixo/efeitos dos fármacos , Medicamentos de Ervas Chinesas/administração & dosagem , Hiperuricemia/tratamento farmacológico , Transportadores de Ânions Orgânicos/genética , Ácido Oxônico/efeitos adversos , Xantina Oxidase/genética , Animais , Creatinina/sangue , Avaliação Pré-Clínica de Medicamentos , Humanos , Hiperuricemia/induzido quimicamente , Hiperuricemia/genética , Hiperuricemia/metabolismo , Rim/efeitos dos fármacos , Rim/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Transportadores de Ânions Orgânicos/metabolismo , Ácido Úrico/sangue , Xantina Oxidase/sangueRESUMO
AIMS/INTRODUCTION: There is controversy as to whether hyperuricemia is an independent risk factor for cardiometabolic diseases. The serum level of uric acid is affected by a wide variety of factors involved in its production and excretion. In contrast, evidence has accumulated that locally- and systemically-activated xanthine oxidase (XO), a rate-limiting enzyme for production of uric acid, is linked to metabolic derangement in humans and rodents. We therefore explored the clinical implication of plasma XO activity in patients with type 2 diabetes mellitus and metabolic syndrome (MetS). MATERIALS AND METHODS: We enrolled 60 patients with type 2 diabetes mellitus and MetS. MetS was defined according to the 2005 International Diabetes Federation guidelines. Plasma XO activity was measured by highly-sensitive fluorometric assay measuring the conversion of pterin to isoxanthopterin, and explored associations between the value of plasma XO activity and metabolic parameters. RESULTS: The value of plasma XO activity was correlated with indices of insulin resistance and the level of circulating liver transaminases. In contrast, the level of serum uric acid was not correlated with indices of insulin resistance. The value of plasma XO activity was not correlated with the serum uric acid level. CONCLUSIONS: Plasma XO activity correlates with indices of insulin resistance and liver dysfunction in Japanese patients with type 2 diabetes mellitus and MetS. Through assessing the plasma XO activity, patients showing normal levels of serum uric acid with higher activity of XO can be screened, thereby possibly providing a clue to uncovering metabolic risks in type 2 diabetes mellitus and MetS patients.