Uric acid (UA) is a purine metabolite that in most mammals is degraded by the hepatic enzyme uricase to allantoin. Epidemiological studies have shown that an elevated UA level predicts the development of cognition and memory deficits; however, there is no direct evidence of this relationship, and the underlying mechanism is largely undefined. Here, we show that a high-UA diet triggers the expression of proinflammatory cytokines, activates the Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB pathway, and increases gliosis in the hippocampus of Wistar rats. We, subsequently, identify a specific inhibitor of NF-κB, BAY11-7085, and show that stereotactic injections of the inhibitor markedly ameliorate UA-induced hippocampal inflammation and memory deficits in C57BL/6 mice. We also found that NF-κB is activated in the primary cultured hippocampal cells after UA administration. Additionally, C57BL/6 mice that lack TLR4 are substantially protected against UA-induced cognitive dysfunction, possibly due to a decrease in inflammatory gene expression in the hippocampus. Importantly, magnetic resonance imaging confirms that hyperuricemia in rats and humans is associated with gliosis in the hippocampus. Together, these results suggest that UA can cause hippocampal inflammation via the TLR4/NF-κB pathway, resulting in cognitive dysfunction. Our findings provide a potential therapeutic strategy for counteracting UA-induced neurodegeneration.SIGNIFICANCE STATEMENTThis work demonstrates that a high-uric acid (UA) diet triggers the expression of proinflammatory cytokines, activates the Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB pathway, and increases gliosis in the hippocampus of Wistar rats. Inhibition of the NF-κB signaling pathway markedly ameliorates UA-induced hippocampal inflammation and cognitive dysfunction in C57BL/6 mice. TLR4-knock-out mice are substantially protected against UA-induced cognitive dysfunction, possibly due to a decrease in inflammatory gene expression in the hippocampus. Moreover, magnetic resonance imaging confirms that hyperuricemia in rats and humans are associated with gliosis in the hippocampus. Together, this study suggests that there is an important link between UA-induced cognitive dysfunction and hippocampal inflammation in rodents and humans, which may have remarkable implications in the treatment of UA-induced neurodegeneration.

Background: Cichorium intybus L. formula (CILF) is a traditional Chinese medicine (TCM) widely used in the treatment of gout and hyperuricemic nephropathy (HN). The aim of this research was to investigate the potential protective effect of CILF against HN and elucidated the underlying mechanism. Methods: CILF water extract was administered to an HN rat model established by adenine combined with ethambutol. The levels of uric acid (UA), serum urea nitrogen (UREA), and creatinine (CREA) were detected. Changes in the pathology and histology of the kidney were observed by hematoxylin-eosin staining. The 16S rRNA of the gut microbiota was sequenced. The binding ability of the main ingredients of CILF to key targets was analyzed by network pharmacology and molecular docking. The expression levels of the related mRNAs and proteins in the kidney were evaluated by RT-qPCR and immunohistochemistry analysis. Results: CILF administration significantly alleviated increases in UA, UREA, and CREA, structural damage, and kidney dysfunction. Gut microbiota analysis was applied to explore the pharmacological mechanism of the effects of CILF on bacterial diversity and microbiota structure in HN. CILF decreased the abundance of Bacteroides. In addition, it increased the abundance of Lactobacillaceae, Erysipelotrichaceae, Lachnospiraceae, Ruminococcaceae, and Bifidobacterium. Based on network pharmacology and molecular docking analysis, CILF profoundly influenced the IL17, TNF and AGE-RAGE signaling pathway. Additionally, CILF inhibited the expression of STAT3, VEGFA and SIRT1 to improve the symptoms of nephropathy. Our research suggested that CILF protects against kidney dysfunction in rats with HN induced by adenine combined with ethambutol. Conclusion: Our findings on the anti-HN effects of CILF and its mechanism of action, from the viewpoint of systems biology, and elaborated that CILF can alter the diversity and community structure of the gut microbiota in HN, providing new approaches for the prevention and treatment of HN.

Cichorium intybus L. (Asteraceae) formula (CF) has been applied as a folk medicine to treat hyperuricemic nephropathy (HN). However, the exact mechanism remains unclear.To explore the therapeutic e...

Lung metastasis is an important cause for the low 5-year survival rate of colorectal cancer patients. Understanding the metabolic profile of lung metastasis of colorectal cancer is important for developing molecular diagnostic and therapeutic approaches. We carried out the metabonomic profiling of lung tissue samples on a mouse lung metastasis model of colorectal cancer using 1H-nuclear magnetic resonance (1H-NMR). The lung tissues of mice were collected at different intervals after marine colon cancer cell line CT-26 was intravenously injected into BALB/c mice. The distinguishing metabolites of lung tissue were investigated using 1H-NMR-based metabonomic assay, which is a highly sensitive and non-destructive method for biomarker identification. Principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were applied to analyze 1H-NMR profiling data to seek potential biomarkers. All of the 3 analyses achieved excellent separations between the normal and metastasis groups. A total of 42 metabolites were identified, ~12 of which were closely correlated with the process of metastasis from colon to lung. These altered metabolites indicated the disturbance of metabolism in metastatic tumors including glycolysis, TCA cycle, glutaminolysis, choline metabolism and serine biosynthesis. Our findings firstly identified the distinguishing metabolites in mouse colorectal cancer lung metastasis models, and indicated that the metabolite disturbance may be associated with the progression of lung metastasis from colon cancer. The altered metabolites may be potential biomarkers that provide a promising molecular approach for clinical diagnosis and mechanistic study of colorectal cancer with lung metastasis.

Background: Gut microbiota play a critical role in developing hyperuricemic nephropathy (HN). We previously found that sulfur-containing amino acid taurine (T) has nephroprotective effects in hyperuricemia (HUA) rats. However, the mechanism is still unclear. To investigate the underlying mechanism of T, rats were fed adenine and ethambutol hydrochloride for the introduction of HN.Methods: Pathological changes in the kidney were assessed using hematoxylin and eosin staining. 16S rRNA sequencing and metabolomics analyzed changes in the gut microbiota and fecal metabolism, and in vitro experiments were conducted to investigate the potential action and mechanism of T against HN.Results: In vitro results demonstrated that T could inhibit NF-κB, IL-1β, IL-6, TNF-α, and ROS in UA-induced HK-2 cells. It also improved renal function, ameliorated renal fibrosis, and reversed enteric dysbacteriosis in HN rats. These results showed that T protects against HN through the modulation of metabolites mediated by the gut microbiota. Meanwhile, gut microbiota included Lactobacillus and Lachnospiraceae NK4A136 group showed correlations with nephroprotective profiles of T. The combined analysis of 16S rRNA gene sequencing and untargeted metabolomics indicated that the anti-HN effects of T could be achieved through phenylalanine metabolism, caffeine metabolism, nicotinate and nicotinamide metabolism, retinol metabolism, and tryptophan metabolism.Conclusion: These findings suggest that the potential protective mechanism of T for HN is not only related to altered metabolic pathways and downregulation of inflammatory cytokines but also to the reciprocal regulation of microbiota structure and metabolism.

Histone lactylation, as a common post-translational modification (PTM), is crucial in diseases. Aberrant histone lactylation has been linked to disease pathogenesis, thus positioning it as a therapeutic target. This review summarizes the bidirectional relationship between histone lactylation and diseases, emphasizing how Traditional Chinese medicine (TCM) regulates lactate levels to restore histone lactylation homeostasis. Mechanistically, TCM modulates histone lactylation through dual regulation of lactyltransferases and lactate metabolism, thereby influencing disease progression in inflammatory, metabolic, and neoplastic disorders. Notably, TCM is characterized by unique advantages of cost-effectiveness, high efficacy, and minimal adverse effects. For diseases with established drug resistance, TCM offers a promising therapeutic alternative in managing drug-resistant illness by regulating histone lactylation. This review is conducive to understanding the relationship between histone lactylation and disease. TCM effectively treats diseases through the regulation of histone lactylation, thereby highlighting its potential for disease treatment application.