The metabolic mechanisms underlying aristolochic acid (AA)-induced nephrotoxicity are inconclusive. A Gas Chromatography-Mass Spectrometer (GC-MS)-based metabolomic study was performed to analyze urinary metabolites in AA-treated rats at different dosages (10, 20, and 40 mg/kg) and time points (2, 4, and 6 days). Serum blood urea nitrogen (BUN), creatinine, and kidney injury were significantly changed only on the 6th day in 40 mg/kg AA group, whereas metabolic alternation appeared even on the 2nd day in 10 mg/kg AA group. A total of 84 differential metabolites were identified in 40 mg/kg AA groups time-dependently and 81 in 10, 20, and 40 mg/kg AA groups dose-dependently (6 days) compared with control group. Eight metabolites were selected as potential metabolic biomarkers including methylsuccinic acid, nicotinamide, 3-hydroxyphenylacetic acid, citric acid, creatinine, uric acid, glycolic acid, and gluconic acid. Four of them were dose-dependently altered including methylsuccinic acid, citric acid, creatinine, and 3-hydroxyphenylacetic acid, which were defined as "early metabolic biomarker." The alteration of nicotinamide, uric acid, and gluconic acid was time- and dose-dependent, whereas the change of glycolic acid was time- or dose-independent. The latter 4 metabolites were defined as "late metabolic biomarker" because of the obvious reduction on the 6th day in 40 mg/kg AA group. In summary, the urinary metabolic alterations were more sensitive than conventional biomarkers of renal injury. The identified metabolites suggested pathways of energy metabolism, gut microbiota, and purine metabolism were associated with AA-induced nephrotoxicity time- or dose-dependently. Further investigation was warranted to determine the roles of the 8 potential metabolic biomarkers in AA-induced nephrotoxicity.

No abstract

No abstract

Aristolochic acid I (AAI) derived from a natural herbal alkaloid is a nephrotoxicant. AAI-induced acute kidney injury (AKI), a devastating clinical disease associated with high mortality rates, is difficult for early diagnosis. To address this issue, we identified and validated early-detection biomarkers for AAI-induced acute kidney injury via profiling microRNA expression in rats. Global miRNA expression profile analysis found that 21 miRNAs were significantly dysregulated in kidney of rats treated by 40 mg/kg AAI on day 2, day 4, or day 6, among which 5 miRNAs were upregulated at all three time points. Quantitative RT-PCR confirmed that miR-21-3p on day 4 and day 6 was obviously upregulated in kidney of rats treated by 40 mg/kg AAI. Further examination found that miR-21-3p was increased in plasma early on day 2 in 10 mg/kg AAI-treated rats, but not in non-target organs. Importantly, the elevation of plasma miR-21-3p preceded the increase in blood urea nitrogen and creatinine, and the presence of renal tubular injury, characterized by differential increase before and after the presence of renal tubular lesions. Our findings thus show that miRNA expression is upregulated in kidney and plasma of AKI rat induced by AAI, and plasma miR-21-3p may be served as a new potential biomarker for early diagnosing AAI-induced acute kidney injury in rats, and possibly in humans.

Background The prevalence rates of gout worldwide have increased annually. Acute gouty arthritis (AGA) accounts for a large proportion of gout patients and causes severe physical and mental pain in patients. Controlling the occurrence and development of gout inflammation is the first step in the treatment of gout. The main treatment drugs in gout are Non-Steroid Anti-Inflammatory Drugs (NSAIDS), colchicine and glucocorticoids, but these treatments have many adverse reactions which limit their clinical application. Baihu and Guizhi decoction (BHGZ) is one of the classic prescriptions in the Synopsis of the Golden Chamber, and is a good prescription for AGA. Previous clinical studies have shown that BHGZ confers a strong benefit for treating AGA. However, the literature shows a lack of high-quality RCT research on BHGZ with respect to AGA. Therefore, in this study, we use a randomized, double-blind, controlled study with a placebo to evaluate the clinical efficacy and safety of BHGZ on the AGA of moist heat arthralgia spasm syndrome. Methods This study is a randomized, double-blind, controlled clinical trial. A total of 102 adult participants with AGA of moist heat arthralgia spasm syndrome will be enrolled, with balanced treatment allocation (1:1). The experimental intervention will be BHGZ plus the low-dose colchicine and the control intervention will be placebo plus the low-dose colchicine for 10 days. To study the clinical efficacy (including VAS score; joint tenderness, joint swelling, joint movement disorder; TCM evidence efficacy score) and the changes of inflammatory indexes. At the same time, the improvement of joint inflammation in patients with AGA will be observed from musculoskeletal ultrasound imaging, and the safety evaluation will be carried out. Discussion This study will be the first placebo-controlled RCT to assess whether BHGZ plus low-dose colchicine have beneficial effects on changing reducing inflammation of joints for patients with AGA of moist heat arthralgia spasm syndrome. The results of this trial will help to provide evidence-based recommendations for clinicians. Trial registration: Chinese Clinical Trials Register, ChiCTR1900024974. Registered on 5 August 2019.