OBJECTIVES: To analyze the differentially expressed exosomal miRNAs in patients with chronic heart failure (CHF) complicated by hyperuricemia (HUA) and explore their potential as novel diagnostic molecular markers and their target genes. METHODS: This study was conducted among 30 CHF patients with HUA (observation group) and 30 healthy volunteers (control group) enrolled between September, 2020 and September, 2023. Peripheral blood samples were collected from 6 CHF patients with HUA for analyzing exosomal miRNAs by high-throughput sequencing, and the results were validated in the remaining 24 patients using qRT-PCR. GO and KEGG enrichment analyses were performed to predict the the target genes of the identified differential miRNAs. We also validated the differentially expressed miRNAs by animal experiment. RESULTS: A total of 42 differentially expressed exosomal miRNAs were detected in observation group by high-throughput sequencing; among them, miR-27a-5p was significantly upregulated (P=0.000179), and miR-139-3p was significantly downregulated (P=0.000058). In the 24 patients with both CHF and PUA, qRT-PCR validated significant upregulation of miR-27a-5p (P=0.004) and downregulation of miR-139-3p (P=0.005) in serum exosomes. When combined, miR-27a-5p and miR-139-3p had a maximum area under the curve (AUC) of 0.899 (95% CI: 0812-0.987) for predicting CHF complicated by HUA. GO and KEGG enrichment analyses suggested that the differential expressions of miR-27a-5p and miR-139-3p was associated with the activation of the AMPK-mTOR signaling pathway to activate the autophagic response. We obtained the same conclusion from animal experiment. CONCLUSIONS Upregulated exosomal miR-27a-5p combined with downregulated exosomal miR-139-3p expression can serve as a novel molecular marker for diagnosis of CHF complicated by HUA, and their differential expression may promote autophagy in cardiomyocytes by activating the AMPK-mTOR signaling pathway.
Humans ; Hyperuricemia/diagnosis* ; Heart Failure/genetics* ; MicroRNAs/metabolism* ; Exosomes/metabolism* ; Chronic Disease ; Male ; Female ; Middle Aged ; Animals

Urate oxidase (Uox) plays a pivotal role in uric acid (UA) degradation, and it has been applied in controlling serum UA level in clinical treatment of hyperuricemia (HUA). However, because Uox is a heterogenous protein to the human body, the immune rejections typically occur after intravenous administration, which greatly hampers the application of Uox-based agents. In this study, we used Lactococcus lactis NZ9000, a food-grade bacterium, as a host to express exogenous Uox genes, to generate the Uox-expressing engineered strains to treat HUA. Aspergillus flavus-derived Uox (aUox) and the "resurrected" human-derived Uox (hUox) were cloned into vector and expressed in NZ9000, to generate engineered strains, respectively. The engineered NZ9000 strains were confirmed to express Uox and showed UA-lowering activity in a time-dependent manner in vitro. Next, in an HUA mice model established by oral gavage of yeast paste, the UA levels were increased by 85.4% and 106.2% at day 7 and day 14. By contrast, in mice fed with NZ9000-aUox, the UA levels were increased by 39.5% and 48.3% while in mice fed with NZ9000-hUox were increased by 57.0% and 82.9%, suggesting a UA-lowering activity of both engineered strains. Furthermore, compared with allopurinol, the first-line agent for HUA treatment, mice fed with NZ9000-aUox exhibited comparable liver safety but better kidney safety than allopurinol, indicating that the use of engineered NZ9000 strains not only alleviated kidney injury caused by HUA, but could also avoided the risk of kidney injury elicited by using allopurinol. Collectively, our study offers an effective and safe therapeutic approach for HUA long-term treatment and controlling.
Animals ; Lactococcus lactis/metabolism* ; Urate Oxidase/genetics* ; Mice ; Uric Acid/blood* ; Hyperuricemia ; Humans ; Administration, Oral ; Aspergillus flavus/genetics* ; Male

As the largest ecosystem of human body, intestinal microorganisms participate in the synthesis and metabolism of uric acid. Developing and utilizing intestinal bacteria to degrade uric acid might provide new ideas for the treatment of hyperuricemia. The fecal samples of people with low uric acid were inoculated into uric acid selective medium with the concentration of 1.5 mmol/L for preliminary screening, and the initially screened strains that may have degradation ability were domesticated by concentration gradient method, and the strains with high uric acid degradation rate were identified by 16S rRNA sequencing method. A strain of high-efficiency uric acid degrading bacteria was screened and domesticated from the feces of people with low uric acid. The degradation rate of uric acid could reach 50.2%. It was identified as Escherichia coli. The isolation and domestication of high efficient uric acid degrading strains can not only provide scientific basis for the study of the mechanism of intestinal microbial degradation of uric acid, but also reserve biological strains for the treatment of hyperuricemia and gout in the future.
Bacteria/metabolism* ; Domestication ; Ecosystem ; Escherichia coli/genetics* ; Humans ; Hyperuricemia ; RNA, Ribosomal, 16S/metabolism* ; Uric Acid/metabolism*

Adult ; Genetic Background ; Gout ; diagnosis ; genetics ; urine ; Humans ; Hyperuricemia ; diagnosis ; genetics ; urine ; Kidney Diseases ; diagnosis ; genetics ; urine ; Male ; Uric Acid ; urine ; Young Adult

The present study was designed to examine the anti-hyperuricemic and anti-inflammatory effects and possible mechanisms of vaticaffinol, a resveratrol tetramer isolated from ethanol extracts of Dipterocarpus alatus, in oxonate-induced hyperuricemic mice. At 1 h after 250 mg·kg potassium oxonate was given, vaticaffinol at 20, 40, and 60 mg·kg was intragastrically administered to hyperuricemic mice once daily for seven consecutive days. Vaticaffinol significantly decreased serum uric acid levels and improved kidney function in hyperuricemic mice. It inhibited hepatic activity of xanthine dehydrogenase (XDH) and xanthine oxidase (XOD), regulated renal mRNA and protein levels of urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), organic anion transporter 1 (OAT1), organic cation transporter 1 (OCT1), OCT2, organic cation/carnitine transporter 1 (OCTN1), and OCTN2 in hyperuricemic mice. Moreover, vaticaffinol markedly down-regulated renal protein levels of NOD-like receptor 3 (NLRP3), apoptosis-associated speck-like (ASC), and Caspase-1, resulting in the reduction of interleukin (IL)-1β, IL-18, IL-6 and tumor necrosis factor-α (TNF-α) levels in this animal model. Additionally, HPLC and LC-MS analyses clearly testified the presence of vaticaffinol in the crude extract. These results suggest that vaticaffinol may be useful for the prevention and treatment of hyperuricemia with kidney inflammation.
Animals ; Anti-Inflammatory Agents ; administration & dosage ; Dipterocarpaceae ; chemistry ; Humans ; Hyperuricemia ; blood ; drug therapy ; immunology ; Interleukin-18 ; genetics ; immunology ; Interleukin-1beta ; genetics ; immunology ; Interleukin-6 ; genetics ; immunology ; Kidney ; drug effects ; immunology ; Male ; Mice ; Organic Anion Transport Protein 1 ; genetics ; immunology ; Plant Extracts ; administration & dosage ; Stilbenes ; administration & dosage ; Tumor Necrosis Factor-alpha ; genetics ; immunology ; Uric Acid ; blood

The aim of this study is to evaluate the efficacy of total saponins of Dioscorea (TSD), an extract of the Chinese herbal Bi Xie, on hyperuricemia and to elucidate the underlying mechanisms. The rat hyperuricemia model was established by administration of adenine. Thirty-two rats were randomly allocated into 4 groups: model group, low/high-dose TSD-treated groups, and allopurinol-treated group. Meanwhile, 8 rats were used as normal controls. Serum uric acid (UA), blood urea nitrogen (BUN), serum creatinine (Scr), and organic anion transporting polypeptide 1A1 (OATP1A1) levels were measured. Comparison between the model group and treatment (allopurinol and TSD) groups showed the serum UA levels were significantly decreased in treatment groups. TSD had similar effects to allopurinol. It was found that the OATP1A1 protein expression levels in treatment groups were higher than in model group and normal controls. And different from the allopurinol-treated groups, TSD-treated group had elevated OATP1A1 expression levels in the stomach, liver, small intestine and large intestine tissues. It was suggested that TSD may facilitate the excretion of UA and lower UA levels by up-regulating OATP1A1 expression.
Animals ; Creatinine ; blood ; Dioscorea ; chemistry ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Hyperuricemia ; drug therapy ; Intestines ; drug effects ; metabolism ; Liver ; drug effects ; metabolism ; Male ; Organic Anion Transporters, Sodium-Independent ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley ; Saponins ; pharmacology ; therapeutic use ; Stomach ; drug effects ; metabolism ; Up-Regulation ; Uric Acid ; blood

The aim of the study was to investigate the effects of Siwu decoction on hyperuricemia, kidney inflammation, and dysfunction in hyperuricemic mice. Siwu decoction at 363.8, 727.5, and 1 455 mg·kg(-1) was orally administered to potassium oxonate-induced hyperuricemic mice for 7 days. Serum urate, creatinine, and blood urea nitrogen levels and hepatic xanthine oxidase (XOD) activity were measured. The protein levels of hepatic XOD and renal urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), organic anion transporters 1 (OAT1), ATP-binding cassette subfamily G member 2 (ABCG2), organic cation transporter 1 (OCT1), OCT2, organic cation/carnitine transporter 1 (OCTN1), OCNT2, Nod-like receptor family, pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC), Caspase-1, and interleukin-1β (IL-1β) were determined by Western blotting. Renal histopathology change was obtained following hematoxylin-eosin staining. Our results indicated that Siwu decoction significantly reduced serum urate, creatinine and blood urea nitrogen levels and increased fractional excretion of uric acid in hyperuricemic mice. It effectively reduced hepatic XOD activity and protein levels in this animal model. Furthermore, Siwu decoction down-regulated URAT1 and GLUT9 protein levels, and up-regulated the protein levels of OAT1, ABCG2, OCT1, OCT2, OCTN1, and OCTN2 in the kidney of the hyperuricemic mice. Additionally, Siwu decoction remarkably reduced renal protein levels of NLRP3, ASC, Caspase-1, and IL-1β in the hyperuricemic mice. These results suggested that Siwu decoction exhibited anti-hyperuricemic and anti-inflammatory effects by inhibiting hepatic XOD activity, regulating renal organic ion transporter expression, and suppressing renal NLRP3 inflammasome activation, providing the evidence for its use in the treatment of hyperuricemia and associated kidney inflammation.
Animals ; Blood Urea Nitrogen ; Creatinine ; urine ; Drugs, Chinese Herbal ; administration & dosage ; Humans ; Hyperuricemia ; chemically induced ; drug therapy ; immunology ; urine ; Interleukin-1beta ; genetics ; immunology ; Kidney ; drug effects ; immunology ; Liver ; drug effects ; Male ; Mice ; Organic Anion Transport Protein 1 ; genetics ; immunology ; Sulfuric Acids ; Uric Acid ; urine

OBJECTIVETo investigate the correlation between polymorphisms of uric acid transporter related gene SLC17A1 and hyperuricemia (HUA) among ethnic Uygur patients from Xinjiang.

METHODSA case-control study was carried out, which enrolled 1036 patients with hyperuricemia and 1031 healthy controls. Two single nucleotide polymorphisms (SNPs) of the SLC17A1 gene were determined with Sequenom MassARRAY. Crossover analysis was used to assess the effect of interaction between above SNPs and alcohol drinking on uric acid level.

RESULTSGenotypic and allelic frequencies of the SLC17A1 gene at the two loci in the two groups were compared. The CT genotype of the rs9467596 locus and TC genotype of the rs2096386 locus showed a higher risk for hyperuricemia (OR=1.334, 95%CI:1.082-1.644; OR=1.242, 95%CI:1.015-1.519, respectively). Crossover analysis also revealed that the SLC17A1 rs2096386 polymorphism has a positive interaction with alcohol drinking in a multiplication model (ORint=1.21, P<0.05, OR>1).

CONCLUSIONSNP rs9467596 and rs2096386 of the SLC17A1 gene may have a correlation between hyperuricemia and alcohol drinking among Uygur patients.

Adult ; Aged ; Alcohol Drinking ; ethnology ; genetics ; Alleles ; Asian Continental Ancestry Group ; genetics ; China ; Ethnic Groups ; genetics ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; ethnology ; genetics ; Genotype ; Humans ; Hyperuricemia ; ethnology ; genetics ; Male ; Middle Aged ; Odds Ratio ; Polymorphism, Single Nucleotide ; Risk Factors ; Sodium-Phosphate Cotransporter Proteins, Type I ; genetics ; Young Adult

With the development of the quality of life, the morbidity of hyperuricemia is increasing year by year. At the same time, it appears that this disease attacks the young people currently. As the study of pathogenesis of hyperuricemia advanced, a series of uric acid transporters were found during this process. Meanwhile, the definition of transporterome was proposed. They were divided into three groups according to the functions: reabsorption proteins, excretion proteins and skeleton proteins. At moment, the drugs for hyperuricmia mainly include uric acid composition inhibitors and uric acid excretion promoters. Since the excretion of uric acid plays a leading role during the process of attack of hyperurecimia, it makes sense to explore Chinese medicines with clear mechanism targeting the transporterome. Therefore, this paper would focus on transporterome and summarize the mechanisms of Chinese medicines in treating hyperuricemia.
Animals ; Biological Transport ; Carrier Proteins ; antagonists & inhibitors ; genetics ; metabolism ; Drugs, Chinese Herbal ; therapeutic use ; Humans ; Hyperuricemia ; drug therapy ; metabolism ; Uric Acid ; metabolism

In this study, SD rats were orally administrated with oteracil potassium (300 mg . kg-1 . d-1 ) to prepare the hyperuricemia model, and divided into normal, model, Allopurinol, LE high dosage, middle dosage and low dose (200, 100, 50 mg . kg-1 . d-1) groups. The rats were orally administrated with test drugs 1 hour later after being orally administrated with Oteracil potassium. After 7 days, serum uric acid, serum creatinine, uric acid and expression of relevant transporters in kidney were tested to study the regulatory effect of leonurus extracts on serum uric acid, renal function and relevant transporters in kidney of rats with hyperuricemia. Compared with the model group, the leonurus extract group could significantly down-regulate serum uric acid and creatinine levels of rats with hyperuricemia, and increase the urine uric acid level. Meanwhile, leonurus extracts could notably down-regulate the mRNA expressions of urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9), up-regulate the mRNA expressions of organic cation transportanter (OCT) and Carnitine transporter (OCTN) and promote the excretion of uric acid of kidney.
Allopurinol ; pharmacology ; Animals ; Blood Urea Nitrogen ; Creatinine ; blood ; Disease Models, Animal ; Down-Regulation ; Gene Expression Regulation ; drug effects ; Hyperuricemia ; blood ; drug therapy ; Kidney ; drug effects ; Leonurus ; chemistry ; Male ; Organic Anion Transporters ; genetics ; Oxonic Acid ; administration & dosage ; Plant Extracts ; isolation & purification ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Specific Pathogen-Free Organisms ; Up-Regulation ; Uric Acid ; blood