Reduction In Uric Acid Levels Research Articles

#2549 Real world data of dapagliflozin effect on proteinuria in primary glomerulopathies in Croatia

Abstract Background and Aims SGLT2 inhibitors, namely dapagliflozin, proved to slow progression of kidney disease in randomized clinical trials. Our aim was to assess real world efficacy of dapagliflozin on proteinuria level in primary glomerulopathies (GN). Method adult patients with biopsy proven glomerulonephritis from all university hospitals in Croatia who started dapagliflozin as a standard of care were enrolled. Data were analyzed if patients had at least six months of follow up. None of the patients were on immunosuppression. Data are shown as N (%) or median with interquartile range (IQR) and accompanied p levels. Results Overall 118 patients, predominantly male 84 (71.8%) of average age of 52 years (min–max 20–76), were enrolled. Most of the patients had IgA nephropathy (IgAN) (N = 55;46.6%), followed by membranous nephropathy (N = 27;22.9%), FSGS (N = 19;16.1%), membranoproliferative GN (N = 8;6.8%), Alport syndrome (N = 8;6.8%). 95.8% of patients were on ACE inhibitors or angiotensin receptor blockers and 10.7% were on mineralocorticoid receptor inhibitors and RAAS blockage was not significantly upscaled during follow up. During the median follow up of 12.2 (7.5-18.6) months, proteinuria was significantly reduced from 1139 (534–2265) to 701 (305-1543) mg/dU; p < 0.001. When divided by glomerulonephritis type, statistically significant reduction of proteinuria was observed in patients with IgAN and Alport syndrome, while trend of reduction of proteinuria was observed in all types of GN. There was a slight reduction in eGFR levels (54 (43-78) vs. 52 (39–73) ml/min/1,73 m²; p < 0.001) and rise in creatinine values (122 (89–149) vs. 128 (91–159) μmol/l; p < 0.001). There was a significant reduction in systolic (130 (120-140) vs.125 (115-134) mmHg; p < 0.001) and diastolic blood pressure (80 (75-90) vs. 80 (70-85) mmHg; p < 0.001). Reduction of uric acid level was noticed (377 (313–460) vs.343 (294–422); p < 0.001), while there was no effect on LDL levels (2.6 (2.12–3.53) vs.2.3 (1.9–3.30); p = 0.073). Dapagliflozin was well tolerated, one patient discontinued the therapy due to intolerance, one due to urinary infection and two due to relapse of GN which needed immunosuppressive therapy. One patient was excluded from analysis due to non-adherence. Conclusion SGLT2 inhibitor dapagliflozin has significant effect on reduction of proteinuria in patients with primary glomerulonephritis. Our data support a growing body of evidence that SGLT2 inhibitors should be used as a standard of care in patients with glomerular kidney diseases, especially IgAN. Future research should address earlier use of SGLT2 inhibitors during the treatment of glomerulonephritis alongside immunosuppressive therapy as well as look into the effect of SGLT2 inhibitors on mesangial cells.

Priestia megaterium ASC-1 Isolated from Pickled Cabbage Ameliorates Hyperuricemia by Degrading Uric Acid in Rats.

Pickled cabbage, a traditional fermented food rich in functional microorganisms, can effectively control hyperuricemia and gout. In this study, a Priestia megaterium ASC-1 strain with strong uric acid (UA) degradation ability was isolated from pickled cabbage. After oral administration for 15 days, ASC-1 was stably colonized in the rats in this study. ASC-1 significantly reduced UA levels (67.24%) in hyperuricemic rats. Additionally, ASC-1 alleviated hyperuricemia-related inflammatory response, oxidative stress, and blood urea nitrogen. Intestinal microbial diversity results showed that ASC-1 restored intestinal injury and gut flora dysbiosis caused by hyperuricemia. These findings suggest that P. megaterium ASC-1 may be used as a therapeutic adjuvant for the treatment of hyperuricemia.

Ethanol Extracts from Torreya grandis Seed Have Potential to Reduce Hyperuricemia in Mouse Models by Influencing Purine Metabolism.

The purpose of this study was to evaluate the efficacy of ethanol extracts from Torreya grandis seed (EST) as a functional food in hyperuricemia mice. We investigated EST by analyzing its chemical composition. Using a mouse model of hyperuricemia induced by potassium oxonate (PO), we evaluated the effects of EST on uric acid (UA) production, inflammation-related cytokines, and gut microbiota diversity. The primary constituents of EST consist of various flavonoids and phenolic compounds known for their antioxidant and anti-inflammatory properties in vitro. Notably, our findings demonstrate that EST significantly reduced UA levels in hyperuricemia mice by 71.9%, which is comparable to the effects observed with xanthine treatment. Moreover, EST exhibited an inhibitory effect on xanthine oxidase activity in mouse liver, with an IC50 value of 20.90 μg/mL (36%). EST also provided protective effects to the mouse kidneys by modulating oxidative stress and inflammation in damaged tissues, while also enhancing UA excretion. Finally, EST influenced the composition of the intestinal microbiota, increasing the relative abundance of beneficial bacteria such as Akkermansia muciniphila, Corynebacterium parvum, Enterorhabdus, Muribaculaceae, Marvinbryantia, and Blautia. In summary, our research unveils additional functions of Torreya grandis and offers new insights into the future of managing hyperuricemia.

Anti-Hyperuricemic Effects of Extracts from Chaenomeles speciosa (Sweet) Nakai Fruits on Hyperuricemic Rats.

Chaenomeles speciosa (Sweet) Nakai (C. speciosa) fruit has medicinal and food applications and exhibits beneficial pharmacological properties. This study aimed to explore the hypouricemic effect of C. speciosa fruit extracts on hyperuricemic rats and uncover potential protective mechanisms. The rats were given hypoxanthine (HX, 100 mg/kg) and potassium oxonate (PO, 300 mg/kg) for 14 days to induce hyperuricemia. Subsequently, the rats were orally administered C. speciosa fruits total extract (CSFTE, 250, 500, and 1000 mg/kg) and allopurinol (AP, 10 mg/kg) one hour after exposure to HX and PO. The results showed that CSFTE had significant xanthine oxidase (XOD) inhibitory activity in vitro (IC50 value of 334.2 μg/mL) and exhibited hypouricemic effects in vivo, reducing uric acid (UA), creatinine (CRE), and blood urea nitrogen (BUN) levels in serum. CSFTE increased UA excretion through the regulation of URAT1, GLUT9, OAT1, and OAT3 protein expression in the kidneys of hyperuricemic rats. Additionally, CSFTE (500 and 1000 mg/kg) was more effective than AP in improving renal injury and protecting kidney function in hyperuricemic rats. Our study demonstrated that CSFTE effectively reduced UA levels and protected the kidneys by inhibiting XOD expression in vitro and regulating UA, CRE, BUN, URAT1, GLUT9, OAT1, and OAT3 proteins in vivo.

Uric acid-lowering effects of sodium-glucose cotransporter 2 inhibitors for preventing cardiovascular events and mortality: A systematic review and meta-analysis.

To evaluate the effect of a 1 mg/dl reduction in uric acid (UA) on cardiovascular events and mortality in patients treated with sodium-glucose cotransporter 2 (SGLT2) inhibitors. We performed a systematic review of the MEDLINE and EMBASE databases searched up to 30 June 2023 (PROSPERO, CRD42022355479) to identify large-scale SGLT2 inhibitor trials. Random-effects meta-analyses were used to pool the estimates. In total, five SGLT2 inhibitor trials (31 535 patients, 54% with heart failure) were analysed. Over a median follow-up of 2.2 years, the mean reduction in UA was -0.79 mg/dl (95% confidence interval (CI), -1.03 to -0.54). Every 1 mg/dl reduction in UA was associated with a significantly lower risk of a composite of cardiovascular death and hospitalization for heart failure [hazard ratio, 0.64 (95% CI, 0.46-0.88)] and hospitalization for heart failure (0.68; 95% CI, 0.62-0.74), with a similar risk of mortality. SGLT2 inhibitors reduced UA levels and cardiovascular events independently of heart failure status.

Chinese Sumac (Rhus chinensis Mill.) Fruits Prevent Hyperuricemia and Uric Acid Nephropathy in Mice Fed a High-Purine Yeast Diet.

Hyperuricemia (HUA) is a prevalent chronic disease, characterized by excessive blood uric acid levels, that poses a significant health risk. In this study, the preventive effects and potential mechanisms of ethanol extracts from Chinese sumac (Rhus chinensis Mill.) fruits on HUA and uric acid nephropathy were comprehensively investigated. The results demonstrated a significant reduction in uric acid levels in hyperuricemia mice after treatment with Chinese sumac fruit extract, especially in the high-dose group, where the blood uric acid level decreased by 39.56%. Visual diagrams of the kidneys and hematoxylin and eosin (H&E)-stained sections showed the extract's effectiveness in protecting against kidney damage caused by excessive uric acid. Further investigation into its mechanism revealed that the extract prevents and treats hyperuricemia by decreasing uric acid production, enhancing uric acid excretion, and mitigating the oxidative stress and inflammatory reactions induced by excessive uric acid in the kidneys. Specifically, the extract markedly decreased xanthine oxidase (XOD) levels and expression in the liver, elevated the expression of uric acid transporters ABCG2, and lowered the expression of uric acid reabsorption proteins URAT1 and SLC2A9. Simultaneously, it significantly elevated the levels of endogenous antioxidant enzymes (SOD and GSH) while reducing the level of malondialdehyde (MDA). Furthermore, the expression of uric-acid-related proteins NLRP3, ACS, and Caspase-3 and the levels of IL-1β and IL-6 were significantly reduced. The experimental results confirm that Chinese sumac fruit extract can improve HUA and uric acid nephropathy in mice fed a high-purine yeast diet. This finding establishes a theoretical foundation for developing Chinese sumac fruit as a functional food or medicine for preventing and treating HUA.

Watermelon (Citrullus lanatus (Thunb.) Matsum. & Nakai) Exocarp Extract Effectivity Against Blood Uric Acid Levels in Male Mice (Mus musculus)

Uric acid is the product of the body from foods that contain high purines. Watermelon (Citrullus lanatus (Thunb.) Matsum. & Nakai) exocarp contains active compounds such as lycopene and flavonoids, which can inhibit the formation of free radicals and inhibit xanthine oxidation. This study aims to determine the activity of watermelon exocarp extract on uric acid levels in male mice. Twenty-five mice were divided into five experimental groups, with each treatment consisting of five replicate male mice. Treatment groups consisted of a solvent control (CMC Na 0.5%), a positive control (Allopurinol 0.26 mg/20gBB), dose I (Watermelon exocarp extract 50 mg/kgBB), dose II (Watermelon exocarp extract 100 mg/kgBB), dose III (Watermelon exocarp extract 200 mg/kgBB). Then the test animals were measured for uric acid levels, and each treatment was carried out with induction of chicken liver suspension 25 mg/kgBB until it showed that the mice had hyperuricemia. Mice were treated similarly to the treatment group for 15 days until their uric acid levels became normal. Blood uric acid levels were measured on days 5, 10, and 15. The results showed that all treatment doses had activity as a reduction in uric acid levels, and dose III of watermelon exocarp extract 200 mg/kgBB with a duration of 15 days was the most effective dose as a reduction in uric acid levels with a percentage reduction of 53,16 %.

Anti-gout and urate-lowering potentials of curcumin: A review from bench to beside.

Gouty arthritis is a complex form of inflammatory arthritis, triggered by the sedimentation of monosodium urate crystals in periarticular tissues, synovial joints, and other sites in the body. Curcumin is a natural polyphenol compound, isolated from the rhizome of the plant Curcuma longa, possessing countless physiological features, including antioxidant, anti-inflammatory, and anti-rheumatic qualities. This study aimed to discuss the beneficial impacts of curcumin and its mechanism in treating gout disease. Ten English and Persian databases were used to conduct a thorough literature search. Studies examining the anti-gouty arthritis effects of curcumin and meeting the inclusion criteria were included. According to the studies, curcumin has shown xanthine oxidase and urate transporter-1 inhibitory properties, uric acid inhibitory characteristics, and antioxidant and anti-inflammatory effects. However, some articles found no prominent reduction in uric acid levels. In this review, we emphasized the potency of curcumin and its compounds against gouty arthritis. Despite the potency, we suggest an additional well-designed evaluation of curcumin, before its therapeutic effectiveness is completely approved as an anti-gouty arthritis agent.

#6674 SAFETY AND EFFICACY OF SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITORS IN KIDNEY TRANSPLANT PATIENTS WITH TYPE 2 OR POST-TRANSPLANT DIABETES

Abstract Background and Aims Diabetes mellitus (DM) is a complication in kidney transplant (KT) patients, leading to a higher cardiovascular mortality and graft loss. Therapies such as sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown a cardioprotective and nephroprotective effect and may offer benefits in KT. The aim of our study is to describe the effectiveness and safety of SGLT2i in KT patients. Method Retrospective cohort study of KT with DM who started SGLT2i in three Spanish hospitals (Puerta del Mar University Hospital, Jerez de la Frontera University Hospital and Puerto Real University Hospital) between May 2018 and December 2022. Clinical and demographic variables were analyzed. We collected SGLT2i type and dose. Glomerular filtration rate (eGFR), proteinuria, and weight were collected at the start of treatment and after 6 and 12 months. We analyze glycemic control, blood pressure, lipid profile and magnesium, uric acid and hemoglobin levels. We document adverse effects. Parametric and non-parametric tests were performed according to the normality of the sample. Results In this period, 57 KT with DM were treated with SGLT2i, of which thirty-five (61%) patients had developed post-transplant diabetes mellitus (PTDM). Fifty-one patients completed a minimum follow-up of 6 months and thirty-six patients 1 year. At the start of the treatment the mean age was 62 years and 65% were men. Mean baseline estimated glomerular filtration rate (eGFR) was 54.5 ml/min/1.73 m2 and the time post-KT was 44 months. The median proteinuria measured by the albumin-creatinine ratio in isolated urine was 83.2 mg/g. The mean weight was 91 kg. The SGLT2i mostly prescribed was empagliflozin (58%). The maintenance immunosuppressive therapy included steroids (94%), tacrolimus (96%), mycophenolate (84%), everolimus (19%) and cyclosporine (2%). Glomerular filtration rate and proteinuria remained unchanged during all the follow-up. In our cohort, body weight significantly reduced (−2.6 Kg at 6 months, p = .007 and −2.1 Kg at 12 months, p = .073). Furthermore, HbA1c (−1.2 mmol/L at 6 months) and faster blood sugar levels (−21.7 mg/dl at 6 months, p = .006 and 14.3 mg/dl at 12 months) decreased. On the other hand, we observed a reduction in LDL-cholesterol (−6 mg/dl at 6 months, p = 0.033 and −11.5 mg/dl at 12 months, p = 0.012). Finally, we observe a reduction in uric acid levels (−0.4 mg/dl at 6 months, p = 0.081) and an improvement in magnesium (+0.07 mg/dl at 6 months, p = 0.021) and haemoglobin levels (+0.3 g/dl at 6 months, p = 0.001). We found no differences in antihypertensive, diuretics, antidiabetic, lipid-lowering drugs and doses of epoetin alfa during the follow-up. Regarding adverse effects, 8 patients suffered urinary tract infections (UTIs) after starting the drug and one of them required hospital admission. Three patients had to discontinue the drug due to impaired renal function. Conclusion SGLT2i may be an option for the management of DM in KT patients, improving glycemic control and cardiovascular risk factors. An adequate selection, hygienic recommendations and surveillance of urinary infections are important.

In Vivo Antihyperuricemic Activities of 3,4,5-Tri-O-caffeoylquinic acid, 4,4',6'-Trihydroxy-2'-Methoxychalcone, and Caffeic Acid from the Aerial Parts of Gnaphalium Affine

The extract of Gnaphalium affine has been reported to have antihyperuricemic and renal protective effects in vivo. The plant could alleviate acute hyperuricemia by inhibiting the activity of xanthine oxidase (XOD). 3,4,5-Tri-O-caffeoylquinic acid (3,4,5-triCQA), 4,4',6'-trihydroxy-2'-methoxychalcone (Chal), and caffeic acid (CA) were identified as the main ingredients of the plant attributed to the potential to retard XOD activity. However, whether the compounds were the effective ingredient of the plant exerting antihyperuricemic activity remained largely unknown. In this study, an experimental mouse model of hyperuricemia was induced by potassium oxonate and hypoxanthine, and orally administered with 3,4,5-triCQA (10 and 20 mg/kg/d), Chal (20 and 40 mg/kg/d), and CA (40 and 80 mg/kg/d) for 6 consecutive days, respectively. Then, serum urate levels and liver XOD activities were assessed. The liver- or kidney-to body weight ratio was calculated. Allopurinol (AP, 50 mg/kg/d) and benzbromarone (BBR, 10 mg/kg/d) were used as controls. Our data showed that there were 52.7 to 81.0% inhibitions in XOD activities in mice treated with 3,4,5-TriCQA (10 and 20 mg/kg/d), Chal (20 and 40 mg/kg/d), and CA (80 mg/kg/d), and 38.8 to 72.5% reduction in uric acid levels in mice treated with 3,4,5-TriCQA (20 mg/kg/d), Chal (20 and 40 mg/kg/d), and CA (40 and 80 mg/kg/d). A larger kidney-to-body weight ratio was observed in hyperuricemic mice and further enhanced by AP treatment. However, the increasing trend was significantly reversed by additional treatment of 3,4,5-triCQA (10 and 20 mg/kg/d) and CA (40 mg/kg/d). Given the above fundings, 3,4,5-triCQA, Chal, and CA may be the key component responsible for the in vivo activities of G. affine for urate-lowering therapy and even promising agents for the treatment of hyperuricemia.

Investigating the Effect of Cigarette Smoking on Serum Uric Acid Levels in Multiple Sclerosis Patients: A Cross Sectional Study.

The present study is aimed at determining the effect of cigarette smoking (CS) on serum uric acid (UA) levels quantitatively before and after smoking cessation among people with MS (pwMS). Additionally, a possible correlation between UA levels and both disability progression and disease severity was also investigated. A retrospective cross-sectional study was conducted using the Nottingham University Hospitals MS Clinics database. It involves 127 people with definite MS recorded when reporting the latest smoking status and the clinical diagnosis. All necessary demographics and clinical characteristics were collected. We found that smoker pwMS had significantly lower serum UA levels than non-smoker pwMS (p-value = 0.0475), and this reduction was recovered after smoking cessation (p-value = 0.0216). However, the levels of disability or disease severity were not correlated with the levels of serum UA in current smoker pwMS, measured by the expanded disability status scale (EDSS; r = -0.24; p-value = 0.38), multiple sclerosis impact scale 29 (MSIS-29; r = 0.01; p-value = 0.97) and MS severity score (MSSS; r = -0.16; p-value = 0.58), respectively. Our result suggests that the reduction in UA levels is more likely a consequence of oxidative stress triggered by many risk factors, including CS, and could be considered a potential indicator of smoking cessation. In addition, the absence of a correlation between UA levels and disease severity and disability suggests that UA is not an optimal biomarker for disease severity and disability prediction among current smoker, ex-smoker or non-smoker pwMS.

Design, synthesis and structure-activity relationship of N-phenyl aromatic amide derivatives as novel xanthine oxidase inhibitors

Our previous studies suggested that N-phenyl aromatic amides are a class of promising xanthine oxidase (XO) inhibitor chemotypes. In this effort, several series of N-phenyl aromatic amide derivatives (4a-h, 5–9, 12i-w, 13n, 13o, 13r, 13s, 13t and 13u) were designed and synthesized to carry out an extensive structure–activity relationship (SAR). The investigation provided some valuable SAR information and identified N-(3-(1H-imidazol-1-yl)-4-((2-methylbenzyl)oxy)phenyl)-1H-imidazole-4-carboxamide (12r, IC50 = 0.028 µM) as the most potent XO inhibitor with close in vitro potency to that of topiroxostat (IC50 = 0.017 µM). Molecular docking and molecular dynamics simulation rationalized the binding affinity through a series of strong interactions with the residues Glu1261, Asn768, Thr1010, Arg880, Glu802, etc. In vivo hypouricemic studies also suggested that the uric acid lowering effect of compound 12r was improved compared with the lead g25 (30.61 % vs 22.4 % reduction in uric acid levels at 1 h; 25.91 % vs 21.7 % reduction in AUC of uric acid) . Pharmacokinetic studies revealed that compound 12r presented a short t1/2 of 0.25 h after oral administration. In addition, 12r has non-cytotoxicity against normal cell HK-2. This work may provide some insights for further development of novel amide-based XO inhibitors.

Ethanol extract of Sophora japonica flower bud, an effective potential dietary supplement for the treatment of hyperuricemia

Hyperuricemia (HUA) is a common metabolic condition associated with a variety of diseases, mainly manifested by the increase in uric acid (UA) levels. As xanthine oxidase (XOD) is the key enzyme in UA production, it has become a target for treating HUA. In this study, an extract named EESJ was extracted from Sophora japonica using 80% ethanol solution and administered to HUA mice to verify its UA-lowering effect. The results confirmed that administering EESJ could reduce the UA levels in vivo by inhibiting XOD activity, and ameliorating renal injury in a dose-dependent manner. To further study the active components in EESJ, 243 chemical components and 32 blood components were identified by the UHPLC-Q-TOF-MS/MS technology, of which flavonoids were the main constituents. The molecular docking results showed that the following six compounds, namely hydroxygenkwanin, genistein, tectorigenin, kaempferol, sophoricoside, and quercetin, had strong binding properties with XOD; among which hydroxygenkwanin had the best binding capacity. In conclusion, this study confirmed that EESJ could effectively reduce UA levels, and speculated the active compounds playing a role in lowering UA levels, which has certain guiding significance for Sophora japonica and natural compounds as potentially effective treatment options for HUA.

Evaluating the effects of uric acid level reduction on serum vitamin D level in hemodialysis patients

Introduction: The role of vitamin D in metabolism, bone-mineral regulation, and anti-oxidation effect has drawn researchers’ attention toward its exact role in hemodialysis. Objectives: In this study, the effect of uric acid level reduction on serum 25-hydroxy vitamin D levels in hemodialysis patients was assessed. Patients and Methods: This study is a triple-blind clinical trial conducted on 81 hemodialysis patients suffering from asymptomatic hyperuricemia. Serum uric acid levels were assessed at the start of the study. Then patients were divided randomly into two groups of intervention and control. The intervention group received 100 mg of allopurinol tablets daily for two months. The control group received placebo tablets for the same duration. At the end of the study, 25-hydroxyvitamin D and uric acid levels were assessed. Data were analyzed using SPSS software and chi-square, independent t test, Mann–Whitney U, and Spearman’s rank correlation tests. Results: In our study, two groups of control and intervention were similar in terms of patients’ demographic and hemodialysis characteristics. After the intervention, compared to the control group, the serum uric acid levels were significantly lower in the intervention group, while the level of 25-hydroxyvitamin D showed no significant difference between the two groups. Conclusion: In this study, no significant effect of uric acid lowering therapy with vitamin D elevation in hemodialysis patients was detected. Trial Registration: The trial protocol was approved by the Iranian Registry of Clinical Trials (identifier: IRCT2015041721803N1; https:// en.irct.ir/trial/18996, ethical code#IR.SKUMS.1395.231).

Comparison of Febuxostat and Allopurinol in the Treatment of Patients with Chronic Kidney Disease Stage 3∼5 with Hyperuricemia

Objective To compare the efficacy of febuxostat and allopurinol in the treatment of chronic kidney disease (CKD) at stages 3∼5 with hyperuricemia. Methods A total of 100 patients with stage 3 to 5 CKD with hyperuricemia in our hospital from July 2018 to December 2019 were selected and divided into the control group (n = 50) and the experimental group (n = 50) according to the random number expression method, the control group on the basis of conventional treatment with allopurinol treatment, the experimental group based on conventional treatment using the febuxostat be treatment. The clinical efficacy, incidence of adverse reactions, and renal function indexes, blood urea nitrogen (BUN), serum creatinine (Scr), serum sodium (Na), serum potassium (K), and serum uric acid (UA) before and after treatment were compared between the two groups. Results The total effective rate of the experimental group and the control group was 82.00% and 78.00%, respectively, with little difference (P > 0.05); compared with before treatment, BUN, Scr, and UA of the two groups were decreased (P < 0.05); and the degree of decline in the experimental group was significantly greater than that in the control group (P < 0.05); the incidence of adverse reactions in the control group was 22.00%, which was significantly higher than that in the experimental group (10.00%) (P < 0.05). Conclusion Compared with allopurinol, febuxostat can improve renal function, reduce UA levels, and reduce the occurrence of complications, with high safety, which is worthy of further clinical promotion.

ETHANOL EXTRACT ON BLACK GARLIC (Allium sativum L.) REDUCES URIC ACID LEVELS IN MALE MICE HYPERURISEMIA MODEL

Black garlic is garlic that goes through a heating process and has a higher bioactivity of substances. The purpose of this study was to determine the effect of black garlic extract on the reduction of uric acid in male mice with hperuricemia induced by 25 ml / kg of chicken liver juice and 250 mg / kg of potassium oxonate. The mice used were male mice with uric acid levels above 3.3 mg / dL or 6.3-6.8 mg / dL. This research is an experimental study with the method of Pre Test - Post Test Control Group Design. The treatment group was K +: Giving allopurinol suspension 10 mg / kg BW, K-: Giving aquabides to the negative control group of mice, P1: Giving black garlic ethanol extract 4.2 mg / 20gr bb, P2: Giving black garlic ethanol extract 8.4 mg / 20gr bb, P3: Provision of black garlic ethanol extract 12.4 mg / 20gr bb. Measurement of uric acid levels was carried out at D-10 after induction of a high uric acid diet, as well as D-26 after treatment of each group. Data were analyzed by One Way Anova test and post hoc LSD test. The results showed that the ethanol extract of black garlic was able to reduce uric acid levels in the blood of mice with the highest percentage reduction in the P3 group (12.4 mg / 20gr bb) by 31,2%, followed by P2 (8.4 mg / 20gr. bb) of 18,03%. The lowest percentage reduction in uric acid levels was in the P1 group (4.2 mg / 20gr bb) by 10,2%. Black garlic ethanol extract has an effect on reducing total uric acid levels in mice due to its antioxidant content such as flavonoids, polyphenols, 5-hydroxymethylfurfural (5-HMF), leucine, and isoleucine.&#x0D; Key words: Black garlic, hyperuricemia, antioxidants, flavonoids.

Excess Uric Acid Induces Gouty Nephropathy Through Crystal Formation: A Review of Recent Insights

Uric acid (UA) is the final product of purine metabolism in the human body, and impaired purine metabolism can increase the uric acid in serum, finally resulting in hyperuricemia (HUA). Current evidences suggest that urates might have antioxidant properties under certain circumstances, but most evidences suggest that urates promote inflammation. Hyperuricemia leads to the formation of urate crystals, which might be recognized as a red flag by the immune system. Such a response stimulates macrophage activation, leads to the activation of NOD-like receptor protein 3 (NLRP3) inflammasome vesicles, and ultimately the production and liberation of interleukin-1b (IL-1b) and interleukin-18 (IL-18), which can mediate inflammation, apoptosis and necroinflammation and cause an inflammatory cascade response. The kidney is one of the most commonly affected organs in HUA, which promotes the development of chronic kidney disease (CKD) by damaging endothelial cells, activating the renin-angiotensin system (RAS), and promoting inflammatory responses. Pharmacological interventions and lifestyle modifications are the primary means for controlling gout and lowering UA. The febuxostat is safe for CKD patients in the UA lowering therapy. Although dialysis can reduce UA levels, the application of drug is also necessary for dialysis patients. This article reviews the synthesis and metabolism of UA, etiology of HUA, the relationship between HUA and kidney disease, the treatment of gout and gouty nephropathy (GN).

Tea and its components reduce the production of uric acid by inhibiting xanthine oxidase.

BackgroundThe health benefits of tea are as diverse including the reduction of uric acid levels. Xanthine oxidase is the most directly mediated enzyme in the production of uric acid.ObjectiveTo explore the inhibitory effects of different teas and its main bioactive components on the production of uric acid.DesignExperimental study. The experiments were conducted in vitro using human immortalized normal liver cell line HL-7702 (L-02).ResultsThe inhibition of the xanthine oxidase activities and the expression level of xanthine dehydrogenase mRNA stimulated in the hyperuric hepatocyte cell model showed that the unfermented green tea and th1e lightly fermented yellow tea, white tea, and oolong tea significantly stronger than the highly fermented black tea and dark tea. The main bioactive compound, gallic acid, showed the strongest inhibitory effect on uric acid production, followed by tea polyphenols and theaflavins.DiscussionAll teas exhibited significant inhibition of xanthine oxidase activities, and the degree of fermentation of tea may be inversely proportional to its ability to inhibit the production of uric acid. Compared with tea polyphenols rich in tea, gallic acid may be a more potential uric acid-lowering component.ConclusionIn this article, we first compared the effects of six traditional Chinese tea made from a single variety in stabilizing the synthesis of uric acid and found that the lighter the fermentation, the greater the potential for inhibiting the production of uric acid. Furthermore, we analyzed the inhibitory effects of its main biochemical active ingredients and found that the inhibitory effects of polyphenols rich in lightly fermented tea were significantly stronger than caffeine rich in highly fermented tea. Our findings will be helpful for people to choose a proper tea for alleviating hyperuricemia and provide a scientific basis for uric acid-lowering tea processing.

Uricase sensitizes hepatocellular carcinoma cells to 5-fluorouracil through uricase-uric acid-UMP synthase axis.

Conventional chemotherapy plays a key role in hepatocellular carcinoma (HCC) treatment, however, with intrinsic or acquired chemoresistance being a major constraint. Here, we aimed to identify potential target to reverse such chemoresistance. In the present study, we found significant difference in uridine monophosphate synthetase (UMPS) expression between 5-FU resistant and sensitive HCC cell lines and the overexpression or downregulation of UMPS impacted 5-FU response in HCC cells. We further found that inhibition of UMPS activity with uric acid at concentration present in human plasma decreased the 5-FU sensitivity of HCC cells, while reduction of uric acid levels with uricase improved the 5-FU sensitivity of HCC cells as well as colorectal cancer cells. In vivo studies also suggested that modulation of uric acid levels did affect 5-FU sensitivity of tumors. These data indicated that UMPS was correlated with the 5-FU resistance in HCC cells and uricase sensitized cancer cells to 5-FU through uricase-uric acid-UMP synthase axis, which provided a potential strategy to improve the efficacy of 5-FU-based chemotherapy for human cancers.

Beneficial herb-drug interaction of Gnaphalium affine extract on benzbromarone: A pharmacokinetic and pharmacodynamic study in rats

BackgroundGnaphalium affine D. Don extract (GAD) enhanced efficacy and reduced toxicity of benzbromarone (BBR) in combination use. However, little is known about effects of GAD on the pharmacokinetics (PKs) and metabolic enzymes of BBR. PurposeTo investigate the pharmacokinetic (PK) and pharmacodynamic (PD) mechanism of the herb-drug interactions (HDIs) between GAD and BBR. Study design and methodsIntragastric single BBR (4.5 or 50 mg/kg), single BBR (4.5 or 50 mg/kg) + single GAD (450 mg/kg, 2 h after BBR-administration), or single BBR (4.5 or 50 mg/kg) + multiple GAD (450 mg/kg/day, once daily for 7 days) were administered to both sexes for BBR PK studies in normal rats. Intragastric multiple BBR (4.5 mg/kg/day), or multiple BBR (4.5 mg/kg/day) + multiple GAD (450 mg/kg/day, 2 h after BBR-administration) were administered for BBR PK and PD studies in male rats with hyperuricemic nephropathy (HN). The cumulative anti-hyperuricemic effects of BBR and BBR+GAD were determined by plasma uric acid (UA) concentration-time curve and area under curve (AUCUA). An in vivo cocktail approach was employed to determine the effects of GAD on cytochrome P450 (CYP) 2C11(9) and 1A2 – mediated drug metabolism. ResultsIn normal rats, the repeated dose administration of GAD induced a significant increase of BBR AUC and prolonged the mean residence time (MRT) (p < 0.05). systemic exposure to BBR and metabolically derived hydroxybenzbromarones was significantly greater in female compared with male rats (p < 0.05). In HN rats, post-administration of GAD resulted in significantly higher bioavailability and enterohepatic recycling (ER) of BBR relative to the BBR alone administrated group from the prolongation of terminal elimination half-life (T1/2) and MRT of BBR (p < 0.05). Significantly higher urate-lowering effect of BBR+GAD compared with BBR alone was generally observed at post-dosing most time points with a maximal effect of 84.3% (acute treatment), 71.4% (7-day subchronic treatment) and 82.5% (14-day subchronic treatment) reduction in UA levels. Additionally, GAD showed a significant inhibitory effect on CYP2C11(9)-mediated tolbutamide (probe substrate) metabolism with ≥ 1.25 but < 2-fold increase in AUCtolbutamide. ConclusionsPD synergism demonstrated with the BBR+GAD combination could be explained by the PK interaction observed partially from CYP2C11(9)-mediation and enterohepatic recycling.