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Uremic toxins are a class of toxins that accumulate in patients with chronic kidney disease (CKD). Indoxyl sulfate (IS), a typical uremic toxin, is not efficiently removed by hemodialysis. Modulation of IS production in the gut microbiota may be a promising strategy for decreasing IS concentration, thus, delaying CKD progression. In the present study, we identified isoquercitrin (ISO) as a natural product that can perturb microbiota-mediated indole production without directly inhibiting the growth of microbes or the indole-synthesizing enzyme TnaA. ISO inhibits the establishment of H proton potential by regulating the gut bacteria electron transport chain, thereby inhibiting the transport of tryptophan and further reducing indole biosynthesis. This non-microbiocidal mechanism may enable ISO to be used as a therapeutic tool, specifically against pathologies triggered by the accumulation of the microbial-produced toxin IS, as in CKD. Herein, we have shown that it is possible to inhibit gut microbial indole production using natural components. Therefore, targeting the uremic toxin metabolic pathway in gut bacteria may be a promising strategy to control host uremic toxin production.

The mixture of Salvia miltiorrhiza and Carthamus tinctorius (Danhong injection, DHI) is widely prescribed in China for the treatment of cardiovascular and cerebrovascular diseases. In most cases, DHI is used in combination with acetylsalicylic acid (aspirin, ASA). However, the interaction between DHI and ASA remains largely undefined. The purpose of this study is to explore the interaction profile and mechanism between DHI and ASA. The frequency of drug combination of DHI and ASA was analyzed based on 5,183 clinical cases. The interaction characteristics were evaluated by analyzing the pharmacokinetics and disposition profile of salicylic acid (SA, the primary metabolite of ASA) in rats. The interaction mechanisms were explored through evaluating the hydrolysis of ASA regulated by ASA esterase, the tubular secretion of SA mediated by influx and efflux transporters, and the tubular reabsorption of SA regulated by urinary acidity-alkalinity. The inhibitory potential of DHI on organic anion transporters (OATs) was further verified in aristolochic acid I (AAI) induced nephropathy. Clinical cases analysis showed that DHI and ASA were used in combination with high frequency of 70.73%. In drug combination of DHI and ASA, the maximum plasma concentration of SA was significantly increased by 1.37 times, while the renal excretion of SA was significantly decreased by 32.54%. The mechanism study showed that DHI significantly inhibited the transport function, gene transcription and protein expression of OATs. In OATs mediated AAI nephropathy, DHI significantly reduced the renal accumulation of AAI by 55.27%, and alleviated renal damage such as glomerulus swelling, tubular blockage and lymphocyte filtration. In drug combination of DHI and ASA, DHI increased the plasma concentration of SA not through enhancing the hydrolysis of ASA, and the tubular reabsorption of SA was not significantly affected. Inhibition of tubular secretion of SA mediated by OATs might be the reason that contributes to the decrease of SA renal excretion.

Epilepsy is a common clinical syndrome characterized by sudden and recurrent attacks and temporary central nervous system dysfunction caused by excessive discharge of neurons in the brain. Amber, a fossilized organic substance formed by the resins of conifers and leguminous plants, was prescribed to tranquilize the mind in China. In this paper, the antiepileptic effect of amber was evaluated by a pentylenetetrazole (PTZ)-induced epileptic model. An untargeted metabolomics approach was applied to investigate metabolic changes in the epileptic model, which was based on HILIC-UHPLC-MS/MS multivariate statistical analysis and metabolism network analysis. The outcome of this study suggested that 35 endogenous metabolites showed marked perturbations. Moreover, four metabolism pathways were mainly involved in epilepsy. After treatment by amber, the endogenous metabolites had a marked tendency to revert back to the situation of the control group which was consistent with phenobarbital. This study characterized the pentylenetetrazole-induced epileptic model and provided new evidence for the sedative effect of amber.