Shichao Xing

Hyperuricemia (HUA) has become a worldwide health issue, drawing increasing public attention. This study aimed to elucidate the roles of bile acids (BAs) and their associations with gut microbiota in a HUA rat model. We established normal control (N) and HUA rat groups, then characterized the BA profiles in liver, serum, and ileum contents using a targeted metabolomics approach. Additionally, gut microbiota composition was analyzed through 16S rDNA gene sequencing. The results were that hyperuricemia induced elevated levels of cholic acid (CA) in liver and elevated levels of taurocholic acid (TCA), glycocholic acid (GCA), and taurodeoxycholic acid (TDCA) in the ileum content, particularly the increases in the levels of total 12α-hydroxy bile acid in the ileum content, which were consistent with the increased levels of CA in the liver. These changes are correlated to an increase in the abundance of the genera Allobaculum and Bifidobacterium . Our investigation revealed the fluxes of bile acids and their association with gut microbiota in HUA and provides new ideas for the study of metabolic diseases in hyperuricemia.

This study aimed to investigate the therapeutic effects of Chlorella on ovarian hormone levels, steroidogenic enzymes, ovarian dysfunction, oxidative stress, and gut microbiota composition in a mouse model of polycystic ovary syndrome (PCOS). A PCOS mouse model was established using dehydroepiandrosterone (DHEA) induction. The effects of Chlorella supplementation were evaluated in vivo to determine its potential for alleviating PCOS‐related symptoms. Chlorella treatment effectively reduced testosterone (T) and luteinizing hormone (LH) levels in mice with PCOS. Additionally, Chlorella modulated the expression of oxidative stress‐related genes and improved ovarian morphology and function. Notably, Chlorella also restored the gut microbiota from PCOS‐associated dysbiosis. Chlorella ameliorated PCOS symptoms by rebalancing ovarian steroid hormones, enhancing antioxidant defense, and modulating the gut microbiota. These findings support its potential as a natural therapeutic agent for PCOS management.

Hyperuricemia (HUA) impaires spermatogenesis. This study was carried out, aiming to determine whether butyric acid (NaB) avoids the HUA-induced decline of sperm quality HUA mice were developed through intra-peritoneal injection of the potassium oxalate combined with intragastric uric acid (UA) and by tube feeding 300 mg·kg-1·d-1NaB. The effect of NaB on the reproduction of HUA male mice was determined by measuring sperm count, sperm motility and testosterone content. In addition, TM3 and GC-2 cells were treated with a solution containing 30 mg/dl UA and 1mM NaB. The effects of NaB on the sperm quality were evaluated with the expression level of the genes involving in LH/cAMP/PKA signaling pathway and meiosis, and that encoding OPRL1 receptor protein. Results showed that NaB improved sperm count, sperm motility, testosterone synthesis, and impaired spermatocyte meiosis via HUA. In addition, in vitro analysis showed that NaB activated the LH/cAMP/PKA signaling pathway of TM3 cells, promoted the synthesis of testosterone, up-regulated the content of pain-sensitive peptide receptor (OPRL1) on the surface of GC-2 cells, and promoted meiosis. NaB also promoted the utilization of ATP by GC-2 cells. We illustrated a close relationship between HUA and spermatogenesis defects. NaB-promoted the expression of the genes functioning in testis meiosis, and the testosterone content may aid to improving spermatogenesis quality.

The underlying molecular mechanism of hyperuricemia-induced lipid metabolism disorders is still unclear. The study aimed to investigate the mechanism of lipid disturbance in hyperuricemia mice model. To our knowledge, we proposed for the first time that CXCL-13 may be a key regulator of hyperuricemia and lipid metabolism disorders. These results may provide new insights for the clinical treatment of hyperuricemia.

Background: More than 30–40% of uric acid is excreted via the intestine, and the dysfunction of intestinal epithelium disrupts uric acid excretion. The involvement of gut microbiota in hyperuricemia has been reported in previous studies, but the changes and mechanisms of intestinal immunity in hyperuricemia are still unknown.Methods: This study developed a urate oxidase (Uox)-knockout (Uox–/–) mouse model for hyperuricemia using CRISPR/Cas9 technology. The lipometabolism was assessed by measuring changes in biochemical indicators. Furthermore, 4-kDa fluorescein isothiocyanate–labeled dextran was used to assess gut barrier function. Also, 16S rRNA sequencing was performed to examine the changes in gut microbiota in mouse feces. RNA sequencing, Western blot, Q-PCR, ELISA, and immunohistochemical analysis were used for measuring gene transcription, the number of immune cells, and the levels of cytokines in intestinal tissues, serum, kidney, liver, pancreas, and vascellum.Results: This study showed that the abundance of inflammation-related microbiota increased in hyperuricemic mice. The microbial pattern recognition–associated Toll-like receptor pathway and inflammation-associated TNF and NF-kappa B signaling pathways were significantly enriched. The increased abundance of inflammation-related microbiota resulted in immune disorders and intestinal barrier dysfunction by upregulating TLR2/4/5 and promoting the release of IL-1β and TNF-α. The levels of epithelial tight junction proteins occludin and claudin-1 decreased. The expression of the pro-apoptotic gene Bax increased. The levels of LPS and TNF-α in systemic circulation increased in hyperuricemic mice. A positive correlation was observed between the increase in intestinal permeability and serum levels of uric acid.Conclusion: Hyperuricemia was characterized by dysregulated intestinal immunity, compromised intestinal barrier, and systemic inflammation. These findings might serve as a basis for future novel therapeutic interventions for hyperuricemia.

Background and aim Intestinal epithelial dysfunction is the foundation of various intestinal and extra-intestinal diseases, while the effects and mechanism of uric acid on the intestinal barrier are little known. TSPO has been shown to be related to the generation of ROS and is involved in regulating inflammation, whether uric acid drives intestinal epithelial dysfunction through TSPO-mediated NLRP3 inflammasome activation is unknown. Methods UOX gene knockout mouse (UOX-/-) were used for models of hyperuricemia. Fluorescein isothiocyanate (FITC)-labeled dextran was used to assess in vivo intestinal permeability. Serum lipopolysaccharide (LPS) and culture supernatants IL-1β were measured using ELISA Kit. IEC-6 exposed to different concentrations of uric acid was used for in vitro experiment. Protein content and mRNA were assessed using Western blotting and Q-PCR, respectively. Intracellular ROS was determined using flow cytometry and fluorescence microscope. Mitochondrial membrane potential was detected on an immunofluorescence. Small interfering RNA transfection was used to assess the interaction between translocator protein (TSPO) and NLRP3 inflammasome. N-acetyl-L-cysteine (NAC) was used as ROS scavenger. Results Our results showed that hyperuricemia mice were characteristic by increased intestinal permeability. Hyperuricemia upregulated TSPO, increased production of ROS and activated NLRP3 inflammasome, which resulted in lower expression of occludin and claudin-1. In vitro, we showed that soluble uric acid alone increased the expression of TSPO, depolarized mitochondrial membrane potential, increased ROS release and activated NLRP3 inflammasome, which further reduced the expression of occludin and claudin-1. Silencing TSPO suppressed NLRP3 inflammasome activation and increased expression of claudin-1 and occludin, which was accompanied by lower levels of ROS. Scavenging ROS also significantly inhibited NLRP3 inflammasome activation without change of TSPO, indicating that TSPO-mediated NLRP3 inflammasome activation was dependent on ROS. Conclusions In conclusion, uric acid drives intestinal barrier dysfunction through TSPO-mediated NLRP3 inflammasome.

Objective(s): Hyperuricemia is a risk for cardiovascular and metabolic diseases, but the mechanism is ambiguous. Increased intestinal permeability is correlated with metabolic syndrome risk factors. Intestinal epithelial cells play a pivotal role in maintaining intestinal permeability. Uric acid is directly eliminated into intestinal lumen, however, the mechanism and effect of uric acid on intestinal epithelial cells is poorly explored. Here we carried out an analysis to identify the effect and mechanism of uric acid on intestinal epithelial cells.Materials and Methods: IEC-6 was exposed to different concentrations of uric acid to simulate the effect of uric acid on intestinal epithelial cells. Cell viability was determined by MTS assay. Protein content and mRNA were assessed using Western blotting and Q-PCR, respectively. Intracellular ROS was determined using flow-cytometry and fluorescence microscopy. Mitochondrial membrane potential was detected by immunofluorescence using a mitochondrial membrane potential assay kit with JC-1. Small interfering RNA transfection was used to suppress the expression of TLR4.Results: We found soluble uric acid alone increased the release of ROS, depolarized the mitochondrial membrane potential, up-regulated TSPO, increased the expression of TLR4 and NLRP3, and then activated NLRP3 inflammasome and NF-κB signaling, which further resulted in lower expression of tight junction protein and exerted adverse effects on intestinal epithelial cells. Furthermore, the elevated IL-1β could be restored by silencing of TLR4, indicating soluble uric acid induces inflammation via the TLR4/NLRP3 pathway.Conclusion: Soluble uric acid exerted detrimental effect on intestinal epithelial cells through the TLR4/NLRP3 pathway.

Abstract Aims SLC2A9 is also known as glucose transporter9 (GLUT9) or urate efflux transporter (URAT)v1, which should be involved in the transport of glucose and uric acid. To further verify it, the correlation of the SLC2A9 polymorphisms(rs13129697,rs7442295) with T2DM, Hyperuricemia (HUA) and T2DM compared with HUA will be investigated in male Han Chinese. Methods Two SNPs of the SLC2A9, rs13129697, rs7442295, were genotyped in 285 T2DM patients, 300 HUA patients and 198 T2DM compared with HUA patients respectively through TaqMan-MGB Duplex real-time PCR, and 550 healthy subjects were selected as control group. The total 1333 subjects were all recruited from the Affiliated Hospital of Qingdao University Medical School. Results Compared with control group, the variant SNP of rs13129697 was both significantly associated with HUA group(P0.05). Conclusion The rs13129697 polymorphism of the SLC2A9 gene, but not rs7442295 is associated with impaired glucose tolerance/impaired fasting glucose complicated with hyperuricaemia. And G allele may protect against the risk to develop HUA.