Renal tubular secretion mediated by organic anion transporters(OATs)and the multidrug resistance-associated protein 4(MRP4)is an important means of drug and toxin excretion.Unfortunately,there are no biomarkers to evaluate their function.The aim of this study was to identify and characterize an endogenous biomarker of the renal tubular OATs-MRP4 channel.Twenty-six uremic toxins were selected as candidate compounds,of which kynurenic acid was identified as a potential biomarker by assessing the protein-binding ratio and the uptake in OAT1-,OAT3-,and MRP4-overexpressing cell lines.OAT1/3 and MRP4 mediated the transcellular vectorial transport of kynurenic acid in vitro.Serum kynurenic acid concentration was dramatically increased in rats treated with a rat OAT1/3(rOAT1/3)inhibitor and in rOAT1/3 double knockout(rOAT1/3-/-)rats,and the renal concentrations were markedly elevated by the rat MRP4(rMRP4)inhibitor.Kynurenic acid was not filtered at the glomerulus(99％of albumin binding),and was specifically secreted in renal tubules through the OAT1/3-MRP4 channel with an appropriate affinity(Km)(496.7 μM and 382.2 μM for OAT1 and OAT3,respectively)and renal clearance half-life(ti/2)in vivo(3.7±0.7 h).There is a strong correlation in area under the plasma drug concentration-time curve(AUC0-t)between cefmetazole and kynurenic acid,but not with creatinine,after inhibition of rOATs.In addition,the phase of increased kynurenic acid level is earlier than that of creatinine in acute kidney injury process.These results suggest that albumin-bound kynurenic acid is an appropriate endogenous biomarker for adjusting the dosage of drugs secreted by this channel or predicting kidney injury.

Objective To observe the value of multiparametric quantitative MRI for diagnosis of thyroid-associated ophthalmopathy(TAO)complicated with dysthyroid optic neuropathy(DON).Methods Fifty-five TAO patients with 109 affected eyes were retrospectively enrolled and divided into DON group(22 cases with 44 affected eyes)and non DON group(33 cases with 65 affected eyes)based on complicated with DON or not.Clinical data and multiparametric quantitative MRI indicators were compared between groups.The influencing factors of TAO complicated with DON were screened with logistic regression to establish a model,and the diagnostic efficacy of the model was observed.Results Significant differences of the course of disease,degree of eyeball protrusion,muscle index,as well as the number,thickness,T1 value,T2 value,fat fraction and orbital fat water fraction of thickened extraocular muscle were found between groups(all P＜0.05).T1 value and orbital fat water fraction of thickened extraocular muscle were both independent influencing factors of TAO complicated with DON,with the area under the curve(AUC)for diagnosing TAO complicated with DON of 0.859 and 0.868,respectively,and AUC of the combined diagnosis of the two was 0.922,significantly higher than orbital fat water fraction alone(P=0.034)but not significantly different with that of T1 value alone(P=0.851).Conclusion T1 value and orbital fat water fraction of thickened extraocular muscle based on multiparametric quantitative MRI were helpful for diagnosing TAO complicated with DON.

Inflammatory bowel disease (IBD) is a formidable disease due to its complex pathogenesis. Macrophages, as a major immune cell population in IBD, are crucial for gut homeostasis. However, it is still unveiled how macrophages modulate IBD. Here, we found that LIM domain only 7 (LMO7) was downregulated in pro-inflammatory macrophages, and that LMO7 directly degraded 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) through K48-mediated ubiquitination in macrophages. As an enzyme that regulates glycolysis, PFKFB3 degradation led to the glycolytic process inhibition in macrophages, which in turn inhibited macrophage activation and ultimately attenuated murine colitis. Moreover, we demonstrated that PFKFB3 was required for histone demethylase Jumonji domain-containing protein 3 (JMJD3) expression, thereby inhibiting the protein level of trimethylation of histone H3 on lysine 27 (H3K27me3). Overall, our results indicated the LMO7/PFKFB3/JMJD3 axis is essential for modulating macrophage function and IBD pathogenesis. Targeting LMO7 or macrophage metabolism could potentially be an effective strategy for treating inflammatory diseases.