Synergistic Impacts of Alpinia oxyphylla Seed Extract and Allopurinol against Experimental Hyperuricemia.

In traditional medicine, Alpinia oxyphylla Miquel seed has been used to treat gout and hyperuricemia-related symptoms by enhancing kidney functions. Allopurinol is the most commonly used drug to treat hyperuricemia; however, the drug has many adverse effects. Combining allopurinol with another compound could reduce the need for high doses and result in improved safety. We investigated the possible synergistic effects of Alpinia oxyphylla seed extract (AE) and allopurinol in decreasing urate concentrations in rats with potassium oxonate-induced hyperuricemia. This study evaluated the effects of allopurinol combined with AE on levels of serum urate, blood urea nitrogen (BUN), and creatinine in a hyperuricemic rat model. The effects of allopurinol plus AE on xanthine oxidase (XOD) activity and urate uptake were measured. The concomitant administration of allopurinol and AE normalized serum urate and reduced BUN and creatinine. The attenuation of hyperuricemia-induced impaired kidney function was related to downregulation of renal urate transporter 1 and upregulation of renal organic anion transporter 1, with inhibition of serum and hepatic XOD activities. The antihyperuricemic effects of allopurinol were enhanced when combined with AE. These results suggested that the combined use of allopurinol and AE may have clinical efficacy in treating hyperuricemia.

Acupuncture-Moxibustion Combined with Rehabilitation Training Is Conducive to Improving the Curative Effect, Cognitive Function, and Daily Activities of Patients with Cerebral Infarction.

Objective: To elucidate the effect of acupuncture-moxibustion combined with rehabilitation training (RHT) on the curative effect, cognitive function (CF), and activities of daily living (ADL) of patients with cerebral infarction (CI). Methods: This study enrolled 150 patients with CI admitted to the Wuhan Sixth Hospital, Affiliated Hospital of Jianghan University from June 2020 to July 2021. Among them, 80 patients who were treated with acupuncture-moxibustion combined with RHT were included in the research group, and 70 patients who received acupuncture-moxibustion alone were included in the control group. The efficacy, CF, and ADL were observed in both groups, and the influences of the two therapies on serum uric acid (UA), high-sensitivity C-reactive protein (hs-CRP), and cystatin C (Cys-C) were compared. Among the various indexes, the CF of patients was assessed by the Montreal Cognitive Assessment (MoCA), and the ADL was evaluated by the Barthel index. Results: After treatment, the research group presented significantly better efficacy, CF, and ADL than the control group, with lower levels of serum UA, hs-CRP, and Cys-C than the control group and before treatment. Conclusion: Acupuncture-moxibustion combined with RHT can inhibit serum UA, hs-CRP, and Cys-C levels of patients with CI while improving the curative effect, CF, and ADL, which is worthy of clinical promotion.

Influence of intervention treatment by "heat-clearing and diuresis-promoting" prescription on NALP3, an inflammatory factor in acute gouty arthritis.

BACKGROUND: To investigate the efficacy of Qingre Lishi Decoction(QLRD), in the treatment of acute gouty arthritis, and its influence on the expression levels of inflammatory factor nucleotide-binding oligomerization domain-like receptor(NALP 3) in patients. METHODS: A total of 78 patients with acute gouty arthritis admitted to our hospital were randomly divided into the control group and the observation group, with 39 cases in each group. The control group was given basic treatment and colchicine tablets, and the observation group was given "heat-clearing and diuresis-promoting" prescription for intervention treatment. The main symptom score, treatment effective rate and laboratory indexes of the two groups were compared 7 days after treatment. RESULTS: After treatment, the scores of joint redness, hot pain, joint flexion and extension disorder, oliguria and constipation were improved in both groups, and the improvement degree in observation group was higher than that in control group (P < 0.05); the clinical effective rate in the observation group (94.87%) was higher than that in the control group (76.92%). The serum uric acid (UA), erythrocyte sedimentation rate (ESR), interleukin-1ß (IL-1ß) and NALP3 showed a decreasing trend, and the decrease degree of each index in observation group was higher than that in control group (P < 0.05). CONCLUSION: The "heat-clearing and diuresis-promoting" prescription for intervention treatment can effectively improve the clinical symptoms of patients with acute gouty arthritis and reduce the level of inflammatory factor NALP3, maintaining remarkable effect.

Anti-hyperuricemic bioactivity of Alstonia scholaris and its bioactive triterpenoids in vivo and in vitro.

ETHNOPHARMACOLOGY RELEVANCE: One folk use of Alstonia scholaris (L.) R. Br. in "Dai" ethno-medicine system is to treat gouty arthritis, which might be caused by hyperuricemia, but anti-hyperuricemic investigation of A. scholaris were rarely reported. AIM OF THE STUDY: To verify anti-hyperuricemic property of A. scholaris, and explore its bioactive compounds in vivo and in vitro. MATERIALS AND METHODS: The anti-hyperuricemic bioactivity of the non-alkaloids fraction and compounds were evaluated with potassium oxonate (PO) induced hyperuricemia mice model in vivo, and monosodium urate (MSU) induced human renal tubular epithelial cells (HK-2) was selected to test in vitro, respectively, with benzobromarone as the positive control. 11 triterpenoids were isolated by phytochemical methods and their structures were elucidated by spectroscopic analysis and ECD calculation. RESULTS: The non-alkaloids fraction of A. scholaris decreased the serum uric acid (UA) level in mice model significantly at the doses of 100 mg/kg and 200 mg/kg, and then nine ursane- and two oleanane-triterpenoids including four new compounds (1-3 and 10) were isolated from the bioactive fraction, in which compounds 1, 4, 5, 6 and 10 exhibited better anti-hyperuricemic tendency in vitro by promoting the excretion of UA in MSU-induced HK-2 cell model at a concentration of 5 µM. Furthermore, compounds 1 and 4 were proved to reduce the serum UA level in mice significantly at 5 mg/kg in vivo. CONCLUSIONS: The results supported the traditional use of A. scholaris in treating gouty arthritis, and also provided new bioactive triterpenoids for further chemical and pharmacological investigation.

Protective role of melatonin against adipose-hepatic metabolic comorbidities in experimentally induced obese rat model.

BACKGROUND: Adipose and hepatic metabolic dysfunctions are critical comorbidities that also aggravate insulin resistance in obese individuals. Melatonin is a low-cost agent and previous studies suggest that its use may promote metabolic health. However, its effects on some comorbidities associated with obesity are unknown. Herein, we investigated the hypothesis that melatonin supplementation would attenuate adipose-hepatic metabolic dysfunction in high fat diet (HFD)-induced obesity in male Wistar rats. MATERIALS AND METHODS: Twenty-four adult male Wistar rats (n = 6/group) were used: Control group received vehicle (normal saline), obese group received 40% high fat diet, melatonin-treated group received 4 mg/kg of melatonin, and obese plus melatonin group received 40% HFD and melatonin. The treatment lasted for 12 weeks. RESULTS: HFD caused increased food intake, body weight, insulin level, insulin resistance and plasma and liver lipid but decreased adipose lipid. In addition, HFD also increased plasma, adipose and liver malondialdehyde, IL-6, uric acid and decreased Glucose-6-phosphate dehydrogenase, glutathione, nitric oxide and circulating obestatin concentration. However, these deleterious effects except food intake were attenuated when supplemented with melatonin. CONCLUSION: Taken together, the present results indicate that HFD exposure causes adipose-hepatic metabolic disturbance in obese animals, which are accompanied by oxidative stress and inflammation. In addition, the present results suggest that melatonin supplementation attenuates adipose-hepatic metabolic dysfunction, accompanying obesity by suppression of oxidative stress/inflammation-dependent mechanism and increasing circulating obestatin.

Isorhamnetin, the xanthine oxidase inhibitor from Sophora japonica, ameliorates uric acid levels and renal function in hyperuricemic mice.

Hyperuricemia is a metabolic condition closely linked to xanthine oxidase (XOD) function, which is involved in the production of uric acid (UA). In this study, XOD was used as a target to construct an in vitro and in vivo activity screening and verification system. The XOD inhibition ability of the main components from the water extract of Sophorae Flos (WSF), an unopened dry flower bud of Sophora japonica, was screened by HPLC. Isorhamnetin (IRh) was identified as a major flavonoid XOD inhibitor from WSF, and we characterized its effects and potential mechanism in ameliorating UA levels and renal function in hyperuricemia model mice. Hyperuricemia was induced by oral administration of potassium oxonate (PO) and hypoxanthine to mice for 7 days. The biochemical index results showed that treatments with low, medium, and high doses of IRh (50, 100, and 150 mg kg-1) significantly reduced serum UA levels and inhibited XOD activity in serum and in the liver. Additionally, IRh effectively decreased the levels of serum creatinine and blood urea nitrogen, suggesting that it possessed nephroprotective effects in hyperuricemic mice. Furthermore, histopathological results showed that nuclear lesions and renal tubule dilatation in the kidneys of IRh-treated hyperuricemic mice were reduced, suggesting that IRh may alleviate renal injury. Molecular docking results showed that IRh combined well with XOD and is an effective XOD inhibitor. In conclusion, IRh from Sophora japonica may reduce the UA levels and alleviate renal injury by inhibiting XOD activity. It potentially functions as a therapeutic drug and dietary supplement to treat hyperuricemia.

Hypouricemic, hepatoprotective and nephroprotective roles of oligopeptides derived from Auxis thazard protein in hyperuricemic mice.

The oligopeptides derived from Auxis thazard protein (ATO) are a class of small peptides with molecular weight <1 kDa and good bioactivity. This paper aimed to explore the hypouricemic, hepatoprotective, and nephroprotective effects of ATO and its potential mechanisms in hyperuricemia in mice induced by potassium oxonate. The results showed that ATO significantly reduced serum UA, serum creatinine levels, inhibited XOD and ADA activities in the liver (p < 0.05), and accelerated UA excretion by downregulating the gene expression of renal mURAT1 and mGLUT9 and upregulating the gene expression of mABCG2 and mOAT1. ATO could also reduce the levels of liver MDA, increase the activities of SOD and CAT, and reduce the levels of IL-1ß, MCP-1 and TNF-α. Histological analysis also showed that ATO possessed hepatoprotective and nephroprotective activities in hyperuricemic mice. Thus, ATO could reduce the serum UA level in hyperuricemic mice by decreasing UA production and promoting UA excretion from the kidney, suggesting that ATO could be developed as a dietary supplement for hyperuricemia treatment.

Sesamol supplementation alleviates nonalcoholic steatohepatitis and atherosclerosis in high-fat, high carbohydrate and high-cholesterol diet-fed rats.

Sesamol, a major ingredient in sesame seeds (Sesamum indicum L.) and its oil, is considered a powerful functional food ingredient. However, few studies have investigated its effects on high-fat, high carbohydrate and high-cholesterol (HF-HCC) diet-induced nonalcoholic steatohepatitis (NASH) complicated with atherosclerosis. The present study elucidates the protective effects of sesamol against NASH and atherosclerosis in HF-HCC diet-fed rats. Sprague-Dawley rats were supplemented with or without sesamol in drinking water (0.05 mg mL-1, 0.1 mg mL-1 and 0.2 mg mL-1) from the beginning to end. At the end of the experiment, sesamol supplementation suppressed HF-HCC diet-induced body weight gain and increased absolute liver and adipose tissue weights in rats. Serum biochemical analyses showed that sesamol supplementation improved HF-HCC diet-induced metabolism disorders and damaged vascular endothelial function. Histological examinations displayed that dietary sesamol not only alleviated hepatic balloon degeneration, steatosis, inflammation and fibrosis, but also mitigated lipid accumulation and fibrous elements in the aorta arch in HF-HCC diet-fed rats. In addition, sesamol supplementation inhibited hepatic NOD-like receptor protein 3 (NLRP3) expression and ERS-IRE1 signaling pathway activation. Moreover, sesamol treatment decreased uric acid levels both in serum and the liver by its effect on the inhibition of xanthine oxidase (XO) activity and/or its expression, which might be closely associated with the inhibitions of NLRP3 expression and ERS-IRE1 signaling pathway activation in HF-HCC diet-fed rats. These findings demonstrated that sesamol alleviated NASH and atherosclerosis in HF-HCC diet-fed rats, and may be a potent dietary supplement for protection against these diseases.

Sonneratia apetala seed oil attenuates potassium oxonate/hypoxanthine-induced hyperuricemia and renal injury in mice.

Sonneratia apetala seeds are considered as prospective nutraceuticals with a high content of unsaturated fatty acids (UFAs) which are mainly distributed in the oil. It is well-known that UFAs could exhibit urate-lowering potency and protect against renal injury, indicating that S. apetala seed oil (SSO) may possess hypouricemic and nephroprotective effects. Consequently, the present work attempted to probe into the effects and mechanisms of SSO on potassium oxonate/hypoxanthine-induced hyperuricemia and associated renal injury. The results indicated that SSO treatment prominently inhibited the increase of serum uric acid (UA), creatinine (CRE), and urea nitrogen (BUN) levels and hepatic xanthine oxidase (XOD) activity in hyperuricemia mice. Kidney indexes and histopathological lesions were also remarkably ameliorated. Additionally, SSO treatment improved the renal anti-oxidant status in hyperuricemia mice by significantly reversing the increase in ROS and MDA levels as well as the decline in SOD, CAT and GSH-Px activities. SSO dramatically downregulated the expression and secretion of pro-inflammatory factors involving MCP-1, IL-1ß, IL-6, IL-18 and TNF-α elicited by hyperuricemia. Furthermore, after SSO treatment, increased protein expressions of GLUT9, URAT1 and OAT1 in the hyperuricemia mice were obviously reversed. SSO treatment enormously restored Nrf2 activation and subsequent translation of related anti-oxidative enzymes in the kidneys. TXNIP/NLRP3 inflammasome activation was also obviously suppressed by SSO. In conclusion, SSO exerted favorable hypouricemic effects owing to its dual functions of downregulating the XOD activity and modulating the expressions of renal urate transport-associated proteins, and it also could alleviate hyperuricemia-induced renal injury by restoring the Keap1-Nrf2 pathway and blocking the TXNIP/NLRP3 inflammasome activation.

Effect of Fermented Soymilk-Honey from Different Probiotics on Osteocalcin Level in Menopausal Women.

Osteoporosis has been discovered to be a risk factor for menopausal women. Although synbiotics (probiotics and prebiotics) are found in fermented soymilk-honey made using local probiotics, their effect on osteocalcin levels is still unknown. Therefore, this study's objective was to determine the influence of fermented soymilk-honey from different probiotics on osteocalcin levels. A 90-day pre-post quasi-experimental study with a control design was conducted on 54 postmenopausal women divided into three intervention groups namely, the soymilk (SM) group, the soymilk-honey fermented with Lactobacillus casei subsp. casei R-68 (SMH Lc) group, and the soymilk-honey fermented with Lactobacillus plantarum 1 R 1.3.2 (SMH Lp) group. Participants consumed 100 mL of soymilk (SM) or fermented soymilk with honey (SMH Lc or SMH Lp) for 90 days. At the beginning and end of the study, the blood serum osteocalcin level was measured and subjects' health status was assessed, such as cholesterol total, random blood glucose, and uric acid levels. Our results presented that in the SMH Lp group, 90 days supplementation of soy-honey milk fermented with Lactobacillus plantarum 1 R 1.3.2 significantly reduced the level of blood serum osteocalcin. Based on these results it is justified to perform more detailed studies on the effect of fermented soy-honey milk on bone health.

Eggshell Membrane Ameliorates Hyperuricemia by Increasing Urate Excretion in Potassium Oxonate-Injected Rats.

Hyperuricemia is the primary cause of gouty arthritis and other metabolic disorders. Eggshell membrane (EM) is an effective and safe supplement for curing pain and stiffness connected with osteoarthritis. However, the effect of EM on hyperuricemia is unclear. This study determines the effects of EM on potassium oxonate-injected hyperuricemia. Uric acid, creatinine, blood urea nitrogen concentrations in the serum, and xanthine oxidase activity in the liver are measured. Protein levels of renal urate transporter 1 (URAT1), organic anion transporters 1 (OAT1), glucose transporter 9 (GLUT9), and ATP-binding cassette transporter G2 (ABCG2) in the kidney are determined with renal histopathology. The results demonstrate that EM reduces serum uric acid levels and increases urine uric acid levels in hyperuricemic rats. Moreover, EM downregulates renal URAT1 protein expression, upregulates OAT1 and ABCG2, but does not change GLUT9 expression. Additionally, EM does not change xanthine oxidase activity in the liver or the serum. EM also decreases uric acid uptake into oocytes expressing hURAT1. Finally, EM markedly reduces renal inflammation and serum interleukin-1ß levels. These findings suggest that EM exhibits antihyperuricemic effects by promoting renal urate excretion and regulating renal urate transporters. Therefore, EM may be useful in the prevention and treatment of gout and hyperuricemia.

Protective role of salicylic acid in gentamicin induced nephrotoxicity.

Salicylic acid, a phenolic compound, found in plants, possesses free radical scavenging and iron chelation properties. The present study is designed to study the antioxidant effect of salicylic acid in gentamicin induced nephrotoxicity in rabbits. For this purpose twenty four male albino rabbits were divided into 4 groups (n=6); control group, healthy untreated rabbits, gentamicin group, received only gentamicin (80mg/kg), gentamicin + salicylic acid group, received gentamicin (80mg/kg) + salicylic acid (80mg/kg) and salicylic acid group, received only salicylic acid (80mg/kg) via intra peritoneal route for 21 consecutive days. Biochemical evaluation was carried out by assessment of body weights and by estimating renal function tests (plasma urea, plasma creatinine and plasma uric acid), tissue antioxidant enzymes (catalase, SOD) and MDA level. Gentamicin induction resulted in decreased body weights, increased plasma urea, plasma creatinine, plasma uric acid, tissue MDA level and decreased tissue SOD and tissue catalase activity in gentamicin treated group which was restored by supplementation with salicylic acid in gentamicin + salicylic acid group. Our data suggests that supplementation of salicylic acid can be useful in reducing gentamicin induced nephrotoxicity in rabbits.

Effect of Berberine on Hyperuricemia and Kidney Injury: A Network Pharmacology Analysis and Experimental Validation in a Mouse Model.

PURPOSE: Berberine (BBR) is an active component of Phellodendri Cortex (PC), which is a traditional Chinese medicine that has been prescribed clinically for hyperuricemia (HUA) for hundreds of years. Many studies reported the anti-inflammatory and nephroprotective properties of BBR and PC; however, the therapeutic effects of BBR on HUA have not been explored. This study aims to investigate the efficacy and mechanism of BBR for treating HUA. METHODS: The mechanism of BBR in the treatment of HUA were predicted by network pharmacology. A mouse model of HUA established by potassium oxonate and hypoxanthine was used to verify the prediction. The levels of serum uric acid (UA), urea nitrogen (BUN) and creatinine (CRE) were determined by biochemical test kits. Hematoxylin and eosin staining of kidney tissues was used to observe the kidney damage. ELISA kits were applied to detect the levels of interleukin (IL)-1ß and IL-18 in serum and kidney tissues. Quantitative real-time PCR and Western blotting were adopted to analyze the expression of NLRP3, ASC, Caspase1, IL-1ß and URAT1. The expressions of URAT1 in the kidney tubules were visualized by immunohistochemical staining. Molecular docking was used to assess the interaction between URAT1 and BBR. RESULTS: The network pharmacology screened out 82 genes and several inflammation-related signaling pathways related to the anti-hyperuricemia effect of BBR. In the in vivo experiment, BBR substantially decreased the level of UA, BUN and CRE, and alleviated the kidney damage in mice with HUA. BBR reduced IL-1ß and IL-18, and downregulated expressions of NLRP3, ASC, Caspase1 and IL-1ß. BBR also inhibited expression of URAT1 and exhibited strong affinity with this target in silico docking. CONCLUSION: BBR exerts anti-HUA and nephroprotective effects via inhibiting activation of NLRP3 inflammasome and correcting the aberrant expression of URAT1 in kidney. BBR might be a novel therapeutic agent for treating HUA.

The gut microbiota mediates the protective effects of anserine supplementation on hyperuricaemia and associated renal inflammation.

Hyperuricaemia is a disease associated with elevated serum uric acid content, which has emerged rapidly in recent decades. The drugs used to treat clinical hyperuricaemia have side effects, and their safety is poor. However, anserine is a natural carnosine derivative that shows an anti-hyperuricaemic effect. A previous study demonstrated that anserine inhibits uric acid synthesis and promotes uric acid excretion, but there is no evidence regarding the effect of anserine from the perspective of the gut microbiota. In this study, the anti-hyperuricaemic and anti-inflammatory effects of anserine were explored in a diet-induced hyperuricaemic mouse model. Anserine alleviated hyperuricaemia and renal inflammation phenotypes, inhibited uric acid biosynthesis, promoted uric acid excretion, and inhibited NLRP3 inflammasome and TLR4/MyD88/NF-κB signalling pathway activation. The results showed that the anti-hyperuricaemic effect of anserine was dependent on the gut microbiota in the germ-free mice experiment. Furthermore, anserine treatment reversed gut microbiota dysbiosis, repaired the intestinal epithelial barrier and increased short-chain fatty acid production. Moreover, the anti-hyperuricaemic effect of anserine was transmissible by transplanting the faecal microbiota from anserine-treated mice, indicating that the protective effects were at least partially mediated by the gut microbiota. Thus, we identified a new and safe prebiotic material to alleviate hyperuricaemia and provided ideas for the development of oligopeptides.

Health properties of the Italian San Martino® mineral-rich water: A self-controlled pilot study.

The effect of hyper-mineral waters on human health has long been debated. This pilot study evaluated the influence of San Martino® water (Sardinia, Italy), on clinical and biological parameters, following the treatment of 10 hospitalized patients. Crenotherapy consisted of 1-2 L of the water daily for 10 days. A complete blood count, serum electrolytes, liver and kidney function tests, fasting lipid profile and plasma glucose, and abdominal ultrasound imaging were assessed before and at the end of treatment. In addition, body weight, dyspeptic symptoms, bowel movements, diuresis, uricuria and blood pressure were evaluated daily. According to its physico-chemical properties, the water is hyper-mineral (TDS 2808 mg/L) with a high content of bicarbonate and iron. At the end of the study, diuresis increased by 60% (850 vs 1295 ml/24 h, P = 0.009) and uricuria by 41% (362 vs 490 mg/24 h, P = 0.022) respectively, whereas plasma uric acid level decreased by 7% (4.7 vs 4.3 mg/dL, P = 0.043). Compared to the basal values, serum gamma-glutamyl transferase, alkaline phosphatase and total bilirubin levels, showed a reduction of 65% (31 vs 18 U/L, P = 0.022), 15% (96 vs 90 U/L, P = 0.041), and 11% (0.53 vs 0.45 g/dL, P = 0.041), respectively. Bowel movements improved in 62.5% of patients with constipation, and 80% of dyspeptic patients experienced symptoms relief. Compliance to the treatment reached 100%. Mild differences were observed in body weight and blood pressure, although not in ultrasound imaging during crenotherapy. These findings suggest that the San Martino® hyper-mineral water may have some benefits to human health. Additional studies with a larger-sized cohort and for a longer period are needed to confirm these preliminary results.

The nephroprotective properties of taurine-amikacin treatment in rats are mediated through HSP25 and TLR-4 regulation.

Amikacin (AMK) is one of the most effective aminoglycoside antibiotics. However, nephrotoxicity is a major deleterious and dose-limiting side effect associated with its clinical use especially in high dose AMK-treated patients. The present study assessed the ability of taurine (TAU) to alleviate or prevent AMK-induced nephrotoxicity if co-administrated with AMK focusing on inflammation, apoptosis, and fibrosis. Male Sprague Dawley rats were assigned to six equal groups. Group 1: rats received saline (normal control), group 2: normal rats received 50 mg kg-1 TAU intraperitoneally (i.p.). Groups 3 and 4: received AMK (25 or 50 mg kg-1; i.p.). Groups 5 and 6: received TAU (50 mg kg-1; i.p.) concurrently with AMK (25 or 50 mg kg-1; i.p.) for 3 weeks. AMK-induced nephrotoxicity is evidenced by elevated levels of serum creatinine (CRE), blood urea nitrogen (BUN), and uric acid (UA). Histopathological investigations provoked damaging changes in the renal tissues. Heat shock proteins (HSP)25 and Toll-like receptor-4 (TLR-4) elevated levels were involved in the induction of inflammatory reactions and focal fibrosis. The improved activation of TLR-4 may stimulate monocytes to upgrade Interleukin (IL)-18 production rather than IL-10. TAU proved therapeutic effectiveness against AMK-induced renal toxicity through downregulation of HSP25, TLR-4, caspase-3, and IL-18 with up-regulation of IL-10 levels.

Ameliorative effect and mechanism of Yi-Suan-Cha against hyperuricemia in rats.

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.

Curcumin modulates gut microbiota and improves renal function in rats with uric acid nephropathy.

It is well known that the progression of hyperuricemia disease often contributes to renal dysfunction. However, there have been few studies on uric acid nephropathy (UAN), especially its relationship with gut microbiota. UAN is usually accompanied by disordered intestinal flora, and damaged gut barrier, which are closely related to tubulointerstitial fibrosis, and systemic inflammation. In previous studies, it has been confirmed that curcumin could alleviate tubulointerstitial fibrosis, and improve renal function through its antioxidant, anti-apoptotic, and anti-inflammatory efficacies. However, the effects curcumin exerts on intestinal flora in uric acid nephropathy are still unknown. Therefore, we used next-generation sequencing technology to investigate the effects of curcumin on gut microbiota in a rat model of UAN induced by adenine and potassium oxonate, and rats were randomly divided into control, model or curcumin treatment groups. The results demonstrated that, compared to the model group, the treatment group showed decreased serum uric acid (156.80 ± 11.90 µmol/L vs. 325.60 ± 18.65 µmol/L, p < 0.001), serum creatinine (66.20 ± 11.88 µmol/L vs. 182.20 ± 8.87 µmol/L, p < 0.001) and BUN level (13.33 ± 3.16 mmol/L vs. 36.04 ± 6.60 mmol/L, p < 0.001). The treatment group also displayed attenuated renal pathological lesions and metabolic endotoxemia (25.60 ± 5.90 ng/mL vs. 38.40 ± 4.98 ng/mL, p < 0.01), and improved tightly linked proteins expression. Besides, curcumin altered the gut microbiota structure in UAN rats. More specifically, curcumin treatment protected against the overgrowth of opportunistic pathogens in UAN, including Escherichia-Shigella and Bacteroides, and increased the relative abundance of bacteria producing short-chain fatty acids (SCFAs), such as Lactobacillus and Ruminococcaceae. These results suggest that curcumin could modulate gut microbiota, fortify the intestinal barrier, attenuate metabolic endotoxemia, and consequently protect the renal function in UAN rats.

Lipidomics study of the therapeutic mechanism of Plantaginis Semen in potassium oxonate-induced hyperuricemia rat.

BACKGROUND: Plantaginis Semen has been widely used as folk medicine and health care food against hyperuricemia (HUA) and gout, but its pharmacological mechanism remains unclear. This study investigated the therapeutic mechanism of Plantaginis Semen extract on potassium oxonate -induced HUA rats based on a lipidomics approach. METHODS: A model of HUA was established by potassium oxonate intragastric administration. 42 Sprague-Dawley (SD) male rats were randomly divided into the control group, model group, benzbromarone group (10 mg/kg) and three Plantaginis Semen groups (n = 7). The Plantaginis Semen groups were treated orally with Plantaginis Semen, 0.9375, 1.875  or 3.75 g/kg for 28 days. The levels of serum uric acid (UA), creatinine (Cr), triacylglycerol (TG) and tumor necrosis factor-α (TNF-α) were  measured using enzyme-linked immunosorbent assay kits. Ultra performance liquid chromatography quadrupole time of flight mass spectrometry (UPLC-Q-TOF/MS) was used for the serum lipidomics analysis, multivariate statistical analysis and independent samples t-test were carried out for the pattern recognition and characteristic metabolites identification. The relative levels of critical regulatory factors were determined by quantitative real-time polymerase chain reaction (RT-qPCR). RESULTS: Compared with the model group, the levels of serum UA, Cr, TG and TNF-α were significantly (p < 0.05) decreased in benzbromarone and three Plantaginis Semen groups. With lipidomics analysis, significant lipid metabolic perturbations were observed in HUA rats, 13 metabolites were identified as potential biomarkers and glycerophospholipid metabolism pathway was  most affected. These perturbations  were partially restored via treatment of benzbromarone and Plantaginis Semen. Additionally, the mRNA expression levels of urate anion transporter 1 (URAT1) and phosphatidylinositol 3-kinase/protein kinases B (PI3K/Akt) were significantly decreased (p < 0.01) after treatment with benzbromarone and high dose of Plantaginis Semen. CONCLUSIONS: Plantaginis Semen had significant effects on anti-HUA, anti-inflammatory and renal protection. It attenuated potassium oxonate-induced HUA through regulation of lipid metabolism disorder.

Apigenin ameliorates hyperuricemic nephropathy by inhibiting URAT1 and GLUT9 and relieving renal fibrosis via the Wnt/ß-catenin pathway.

BACKGROUND: Hyperuricemia (HUA) is characterized by abnormal serum uric acid (UA) levels and demonstrated to be involved in renal injury leading to hyperuricemic nephropathy (HN). Apigenin (API), a flavonoid naturally present in tea, berries, fruits, and vegetables, exhibits various biological functions, such as antioxidant and anti-inflammatory activity. PURPOSE: To investigate the effect of API treatment in HN and to reveal its underlying mechanisms. METHODS: The mice with HN were induced by potassium oxonate intraperitoneally and orally administered for two weeks. The effects of API on renal function, inflammation, fibrosis, and uric acid (UA) metabolism in mice with HN were evaluated. The effects of API on urate transporters were further examined in vitro. RESULTS: The mice with HN exhibited abnormal renal urate excretion and renal dysfunction accompanied by increased renal inflammation and fibrosis. In contrast, API reduced the levels of serum UA, serum creatinine (CRE), blood urea nitrogen (BUN) and renal inflammatory factors in mice with HN. Besides, API ameliorated the renal fibrosis via Wnt/ß-catenin pathway suppression. Furthermore, API potently promoted urinary UA excretion and inhibited renal urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in mice with HN. In vitro, API competitively inhibited URAT1 and GLUT9 in a dose-dependent manner, with IC50 values of 0.64 ± 0.14 µM and 2.63 ± 0.69 µM, respectively. CONCLUSIONS: API could effectively attenuate HN through co-inhibiting UA reabsorption and Wnt/ß-catenin pathway, and thus it might be a potential therapy to HN.