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ObjectiveTo investigate the effect of alcohol extract of Oroxylum indicum （MHD-80） on reducing uric acid （UA） and protecting the kidney in the hyperuricemia （HUA） model in vivo. MethodPotassium oxazine （350 mg·kg-1） and adenine （80 mg·kg-1） were used to construct an HUA model of mice in vivo to evaluate the mechanism related to UA reduction and the protective effect of renal function of MHD-80. Seventy male ICR mice were randomly divided into seven groups， including the normal group， model group， allopurinol group （5 mg·kg-1）， febusotan group （5 mg·kg-1）， and MHD-80 low-， medium-， and high-dose groups （3， 6， 12 mg·kg-1）， with 10 in each group. Except for the normal group， the other groups were given intragastric administration of potassium oxazine and adenine for 14 consecutive days to establish the HUA model. On the 8th to 14th day after modeling， each group was given corresponding drugs by intragastric administration， once a day. 1 h after the last administration， blood was collected from the eyeballs， and kidney and liver tissues of mice were collected. Serum levels of UA， urea nitrogen （BUN）， and creatinine （Cr） and liver activity of xanthine oxidase （XOD） were determined by enzyme colorimetry. Serum contents of tumor necrosis factor-α （TNF-α） and interleukin-1β （IL-1β） were determined by enzyme-linked immunosorbent assay （ELISA）. Hematoxilin-eosin （HE） staining was used to observe the pathological changes in kidney tissues. The protein expression levels of ATP-binding box transporter G2 （ABCG2） and glucose-facilitating transporter 9 （GLUT9） in kidney tissues were detected by Western blot. ResultIn vivo experiment shows that compared with the normal group， the serum levels of UA， Cr， BUN， inflammatory factors TNF-α， IL-1β， and liver XOD activity in the serum of mice in the model group were significantly increased （P<0.05， P<0.01）， and the expression of GLUT9 in kidney tissues was significantly up-regulated （P<0.05）. ABCG2 protein expression was significantly down-regulated （P<0.05）， and renal injury was obvious. Compared with the model group， the levels of UA， BUN， Cr， TNF-α， IL-1β， and liver XOD activity in the serum of mice in the high-dose group of MHD-80 were decreased to different degrees （P<0.05， P<0.01）， GLUT9 protein expression was significantly down-regulated （P<0.01）， ABCG2 protein expression was significantly up-regulated （P<0.05） in the high-dose group of MHD-80， and the degree of renal injury was reduced. ConclusionMHD-80 has certain uric acid reduction， anti-inflammatory， and anti-renal injury effects， which are related to inhibiting XOD activity and regulating the expression of ABCG2 and GLUT9 uric acid transporter.
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ObjectiveTo explore the pharmacodynamic effects of total flavonoids of Paeonia suffruticosa flower （TFPFs） on rats with hyperuricemia and provide scientific data support for the research and development of therapeutic drugs for hyperuricemia. MethodThe hyperuricemia model was induced by adenine combined with ethambutol in rats. The rats were randomly divided into a blank control group， a model group， two positive control groups （allopurinol at 42 mg·kg-1 and Tongfengshu tablets at 600 mg·kg-1）， and high-， medium-， and low-dose TFPFs groups （260， 130， and 65 mg·kg-1）. The general conditions of rats were observed and recorded， and the body weight was recorded once every 5 days. The 24-hour urine volume， water intake， uric acid （UA）， and urinary protein of rats were determined after the last administration. The kidney index was calculated. The pathological changes in thymus and spleen tissues of rats were observed by hematoxylin-eosin （HE） staining. The serum activities of UA， creatinine （Cr）， blood urea nitrogen （BUN）， malondialdehyde （MDA）， superoxide dismutase （SOD）， and total antioxidant capacity （T-AOC） of rats were determined. The xanthine oxidase （XOD） and adenosine deaminase （ADA） activities in the liver were detected. The content of uric acid transporter 1 （URAT1）， organic anion transporter 1 （OAT1）， and glucose transporter 9 （GLUT9） in the kidney was detected by enzyme-linked immunosorbent assay （ELISA）. ResultCompared with the results in the model group， TFPFs could improve the mental state of rats， increase the body weight（P<0.01）， promote UA excretion（P<0.01）， reduce the content of urinary protein（P<0.05）， relieve renal glomerular atrophy， renal tubular epithelial cell status， and urate crystal deposition in renal tubules， dwindle 24-hour urine volume， water intake， kidney index（P<0.05）， serum levels of UA， Cr， BUN， and MDA（P<0.05，P<0.01）， inhibit the activities of XOD（P<0.05） and ADA（P<0.05，P<0.01）in the liver， diminish the expression of GLUT9 in the renal homogenate（P<0.05）， and increase serum SOD and T-AOC activities as well as OAT1 expression（P<0.01） in the kidney. The pathological changes of thymus and spleen were improved. ConclusionTFPFs possess a protective effect on the kidney of rats with hyperuricemia， which is achieved by promoting uric acid excretion， inhibiting oxidation and the activity of key enzymes in uric acid synthesis， and regulating the expression of uric acid transporters.
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ObjectiveTo explore the pharmacodynamic effects of total flavonoids of Paeonia suffruticosa flower （TFPFs） on rats with hyperuricemia and provide scientific data support for the research and development of therapeutic drugs for hyperuricemia. MethodThe hyperuricemia model was induced by adenine combined with ethambutol in rats. The rats were randomly divided into a blank control group， a model group， two positive control groups （allopurinol at 42 mg·kg-1 and Tongfengshu tablets at 600 mg·kg-1）， and high-， medium-， and low-dose TFPFs groups （260， 130， and 65 mg·kg-1）. The general conditions of rats were observed and recorded， and the body weight was recorded once every 5 days. The 24-hour urine volume， water intake， uric acid （UA）， and urinary protein of rats were determined after the last administration. The kidney index was calculated. The pathological changes in thymus and spleen tissues of rats were observed by hematoxylin-eosin （HE） staining. The serum activities of UA， creatinine （Cr）， blood urea nitrogen （BUN）， malondialdehyde （MDA）， superoxide dismutase （SOD）， and total antioxidant capacity （T-AOC） of rats were determined. The xanthine oxidase （XOD） and adenosine deaminase （ADA） activities in the liver were detected. The content of uric acid transporter 1 （URAT1）， organic anion transporter 1 （OAT1）， and glucose transporter 9 （GLUT9） in the kidney was detected by enzyme-linked immunosorbent assay （ELISA）. ResultCompared with the results in the model group， TFPFs could improve the mental state of rats， increase the body weight（P<0.01）， promote UA excretion（P<0.01）， reduce the content of urinary protein（P<0.05）， relieve renal glomerular atrophy， renal tubular epithelial cell status， and urate crystal deposition in renal tubules， dwindle 24-hour urine volume， water intake， kidney index（P<0.05）， serum levels of UA， Cr， BUN， and MDA（P<0.05，P<0.01）， inhibit the activities of XOD（P<0.05） and ADA（P<0.05，P<0.01）in the liver， diminish the expression of GLUT9 in the renal homogenate（P<0.05）， and increase serum SOD and T-AOC activities as well as OAT1 expression（P<0.01） in the kidney. The pathological changes of thymus and spleen were improved. ConclusionTFPFs possess a protective effect on the kidney of rats with hyperuricemia， which is achieved by promoting uric acid excretion， inhibiting oxidation and the activity of key enzymes in uric acid synthesis， and regulating the expression of uric acid transporters.
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OBJECTIVE To investigat e the effects of water extract （WCS）and ethanol extract （ECS）from the root of Caragana sinica on hyperuricemia （HUA）in mice. METHODS Kunming mice were randomly divided into normal control group ， model group ，allopurinol group （positive control ，5 mg/kg），benzbromarone group （positive control ，7.8 mg/kg），WCS low-dose ， medium-dose and high-dose groups （38，75，150 mg/kg），ECS low-dose ，medium-dose and high-dose groups （50，100，200 mg/kg）， with 10 mice in each group. Except for the normal control group ，the other mice were given potassium oxazinate intraperitoneally and hypoxanthine intragastrically for consecutive 7 d to establish HUA model. On the third day of modeling ，mice in each administration group were given corresponding drugs intragastrically ，and normal control group and model group were given equal volume of normal saline once a day for 5 consecutive days.The body weight of mice were weighted during administration ；one hour after the last administration ，the organ indexes of liver ，kidney and spleen were calculated ；the contents of serum uric acid （SUA）， blood urea nitrogen （BUN）and serum creatinine （SCR）；the activity of xanthine oxidase （XOD）in serum and liver tissue were determined. Relative mRNA and protein expressions of XOD in liver tissue ，relative expre ssions of GLUT9，URAT1 and OAT 1 in renal tissue were all detected ；and the pathological changes of renal tissue were observed. RESULTS There were no significant differences in liver index and spleen index in each group （P＞0.05）. Compared with normal control group ， except for allopurinol group ， there were no significant differences in the body weight and the contents of BUN and SCR in mice of other administration groups （P＞0.05）；the renal index and SUA content of mice in the m odel group and allopurinol group were significantly increased （P＜0.05）；in the model group ，the XOD activity in serum and liver tissue ，the relative mRNA and protein expression of XOD in liver tissue ，the relative expressions of GLUT 9 and URAT 1 protein in renal tissue were significantly increased （P＜0.05），and the relative expression of OAT 1 protein in renal tissue was significantly decreased （P＜ 0.05）. Compared with model group ，renal indexes of mice were decreased significantly in WCS and ECS groups （P＜0.05），and the pathological damage of renal tissue was significantly improved ；SUA content ，XOD activity in serum and liver tissue ，the relative mRNA and protein expression of XOD in liver tissue ，and the relative expression of URAT 1 protein in renal tissue were decreased significantly in administration groups （P＜0.05）. The relative expression of GLUT 9 protein in renal tissue of mice in benzbromarone group and ECS high-dose group decreased significantly （P＜0.05）；relative expression of OAT 1 protein in renal tissue of mice in benzbromarone group ，WCS low-dose and high-dose groups ，ECS low-dose group were increased significantly （P＜0.05）. CONCLUSIONS WCS and ECS can significantly decrease the contents of SUA in HUA model mice ，and improve pathological state of renal tissue ，the mechanism of which may be associated with inhibiting XOD activity and uric acid reabsorption，and down-regulating protein and mRNA expression of XOD.
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With the improvement of people's living standard and the change of dietary structure, the prevalence of gout has increased gradually with the increased intake of protein, sugar and fat. There has been a positive correlation between gout and age, and the age of onset decreased gradually. The inflammation induced by sodium urate crystal is the pathological basis of gout, which activates innate immunity, releases many kinds of inflammatory mediators, such as interleukin(IL)-1β, IL-6 and tumor necrosis factor(TNF)-α, and then causes inflammatory cascade reaction and acute attacks, such as joint redness, swelling and heat pain. There is a spontaneous remission mechanism in gout. For one thing, macrophages reduce the stimulation of monosodium urate(MSU) through phagocytosis of MSU crystals as foreign bodies, for another, differentiated and mature macrophages secrete anti-inflammatory factor transforming growth factor(TGF)-β1, inhibit the expression of inflammatory factors and promote spontaneous relief of acute gout attack. In addition to the activation mechanism of intracellular signaling molecules associated with inflammatory response, the inflammatory mechanism of gout also involves complement activation, cell activation and other pathways. The complications caused by gout, such as cardiovascular system damage and joint destruction, are seriously harmful to human health. At present, western drugs, such as allopurinol and febuxostat, exert an effect in inhibiting xanthine oxidase. Benzimarone has effect in reducing renal absorption of uric acid and promoting uric acid excretion by inhibiting uric acid transporter 1(URAT1) and glucose transporter 9(GLUT9). Even Lesinurad and other medicines in current studies are based on the inhibition of uric acid re-absorption, but with adverse reactions that limit the clinical application. The treatment of gout with traditional Chinese medicine(TCM) has multi-target characteristics, with advantages in reducing uric acid, resisting inflammation and improving joint function and a high safety. It has been gradually popularized and applied in clinical treatment of gout. Therefore, it is a promising research direction to treat gout with TCM and western medicine based on the pathomechanism of gout.
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Gout is a common disease in the elderly men. The prevalence rate of gout is rising worldwide in recent years, and gout has become a serious metabolic disease threatening human health. Moreover, gout is also closely related to incidence of many diseases and symptoms such as hypertension, hyperlipidemia, atherosclerosis, obesity and insulin resistance. Recently, investigation and development of new drugs have attracted increasing attention. This paper summarizes the research advances in new agents for treatment of gout, including the uric acid reduction drugs that target the key enzymes of purine metabolism, the drugs which target the renal tubular urate transporters to lower the uric acid level, the dual inhibitors of xanthine oxidoreductase(XOR) and renal tubular urate transporters, and the uricase.
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Gout is a common disease in the elderly men. The prevalence rate of gout is rising worldwide in recent years,and gout has become a serious metabolic disease threatening human health. Moreover,gout is also closely related to incidence of many dis?eases and symptoms such as hypertension,hyperlipidemia,atherosclerosis,obesity and insulin resistance. Recently,investigation and development of new drugs have attracted increasing attention. This paper summarizes the research advances in new agents for treat?ment of gout,including the uric acid reduction drugs that target the key enzymes of purine metabolism,the drugs which target the re?nal tubular urate transporters to lower the uric acid level,the dual inhibitors of xanthine oxidoreductase(XOR)and renal tubular urate transporters,and the uricase.
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Objective To observe whether high-level insulin increases serum uric acid level and rosiglitazone improves hyperuricemia, and to explore the mechanism. Methods OLETF rats with spontaneous type 2 diabetes complicated with metabolic syndrome and normal control LETO rats were randomly divided into three groups (n=20 each). The animals were fed with standard chow diet in control group, high-purine diet and adenine administered intragastrically in experimental group, and rosiglitazone in interventional group. Body weight, serum levels of uric acid, insulin, triglyceride ( TG ) , and total cholesterol ( TC ) were measured after 3 weeks. Urate transporter 1 ( URAT1 ) and uric acid transporter (UAT) mRNA expressions in renal cortex were examined. HK-2 cells were incubated with various concentrations of insulin for 24 hours. UAT mRNA expression in HK-2 cells was examined. Results ( 1 ) In control group, the insulin level of OLETF rats was significantly higher than that of LETO rats ( P<0. 05 ), and there was no significant difference in serum uric acid level between OLETF and LETO rats. (2)In experimental groups, the insulin level in OLETF rats was significantly higher than that in LETO rats [(61.83±12.13 vs 36.73±12.73 )μIU/ml ,P<0. 05], and the incidence of hyperuricemia (76.92% vs 36.13%,P<0.01 ) and serum uric acid level[( 327.75 ±45.73 vs 264.40±36.32 ) μmol/L, P<0. 01]in OLETF rats were significantly higher than those in LETO rats. (3) Insulin[(41.3± 10.2 vs 61.8±12. 1 )μIU/ml,P<0. 05]and uric acid[( 198.0±45.4 vs 236.9±29.30 ) μmol/L, P<0. 05]levels in OLETF rats in interventional group were significantly lower than those of OLETF rats in experimental group, meanwhile the amount of urinary uric acid excretion was significantly increased[(5 644±371 vs 4 692±278 ) μ mol/L, P<0. 05]. (4) There was no significant difference in insulin level and the expressions of URAT1 and UAT mRNA in renal cortex between OLETF rats in control group and experimental group. URAT1 mRNA expression of OLETF rats in interventional group was significantly decreased, while UAT mRNA expression was significantly increased. (5)With the increase of insulinconcentration in culture medium, the expression of UAT mRNA expression in HK-2 cells was gradually decreased. Conclusions Rosiglitazone may alleviate hyperinsulinemia-induced hyperuricemia via regulating UAT and URAT1 mRNA expression.