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Nephrolithiasis is a systemic metabolic disease with a worldwide incidence that is increasing yearly, as well as a high recurrence rate; however, this disease's pathogenesis has not been thoroughly elucidated to date. Several epidemiological studies have shown that the risk for developing kidney stones increases in people with dyslipidemia. To explore the mechanism of lipid-induced kidney stones, we established a mouse model for renal urolithiasis based on intraperitoneal injections of glyoxylate (120 mg/kg/d). Lipidomics based on ultra high performance liquid chromatography coupled with quadrupole-time of flight mass spectrometry (UPLC-QTOF-MS/MS) was performed to determine the changes in lipid metabolism in serum and kidneys. We screened 179 and 196 different lipid metabolites in the kidneys and serum, respectively, including fatty acyls, glycerophospholipids, sphingolipids, glycerolipids and prenol lipids. We found that polyunsaturated fatty acids, such as arachidonic acid, eicosapentaenoic acid, and docosahexoenoic acid, and ceramides and lysophosphocholines mediated inflammatory responses and that the oxidative stress induced by oleylethanolamine and glycerophosphoethanolamine plasmalogens is closely related to the development of kidney stones. These results provide strong evidence for the relationship between lipid metabolism and the development of kidney stones and suggest a clear direction for future research. [ABSTRACT FROM AUTHOR]

• Development of a sensitive and reliable LC-MS/MS method for the accurate quantification of six α-hydroxyl ceramides in serum. • Strong support for the research of biological function of α-hydroxyl ceramides in the future. • Revealing the α-hydroxyl ceramides associated with sepsis. Alpha-hydroxy ceramides are not only the precursors of many complex sphingolipids, also play a major role in membrane homeostasis and cellular signal transduction. However, current research rarely involved quantitative methods for α-hydroxy ceramides, which greatly restricts the study of its biological function. This work aimed to develop a reliable assay for the accurate quantification of α-hydroxy ceramides in vivo study. LC-MS/MS method was developed for the accurate quantification of six α-hydroxy ceramides of Cer(d18:1/16:0(2OH)), Cer(d18:1/18:0(2OH)), Cer(d18:1/18:1(2OH)), Cer(d18:1/20:0(2OH)), Cer(d18:1/22:0(2OH)) and Cer(d18:1/24:1(2OH)) in mice serum. This assay was validated with low limit of quantitation of 3.125 ng/mL, a dynamic range of 3.125–400 ng/mL (R2 > 0.99), precision (<15 %), and accuracy (88 % to 115 %). Applying the method to the determination of α-hydroxy ceramides in the serum of sepsis mice, the levels of Cer(d18:1/16:0(2OH)), Cer(d18:1/20:0(2OH)), Cer(d18:1/24:1(2OH)) were significantly elevated in LPS-induced septic as compared to the normal control. In conclusion, this LC-MS method was qualified in α-hydroxy ceramides quantification in vivo and a significant association was found between α-hydroxy ceramides and sepsis. [ABSTRACT FROM AUTHOR]

• SA-AKI was effectively alleviated with RCE treatment. • 25 differential metabolites related to the pathological processes of SA-AKI and the effects of RCE were identified. • A compound-metabolite-target-disease network was constructed to explore the mechanisms of RCE against SA-AKI. • RCE may mitigate SA-AKI through regulating these 17 overlapping target proteins in the network. Sepsis remains the most common cause of acute kidney injury (AKI) in critically ill patients, increasing the risk of in-hospital and long-term death. Rhizoma Coptidis (RC), a classical traditional Chinese herb, exhibits anti-inflammatory and antioxidant properties in various diseases including sepsis. This study aimed to investigate the protective effects of RC extracts (RCE) against sepsis-associated acute kidney injury (SA-AKI) and explore the underlying mechanisms with metabolomics-based network pharmacology. The results showed that RCE improved renal function and histological injury and decreased reactive oxygen species (ROS) production in SA-AKI. Using ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF/MS), 25 differential metabolites were identified that had a close connection with the pathological processes of SA-AKI and the effects of RCE. Afterward, a compound-metabolite-target-disease network was constructed and 17 overlapping target proteins of the components of RCE, the differential metabolites, and the disease-related genes were discovered. Among these overlapping target proteins, RCE increased the nuclear translocation of nuclear factor-erythroid 2-related factor-2 (Nrf2), the protein expression of heme oxygenase-1 (HO-1), the mRNA expression of peroxisome proliferator activated receptor α (PPARα) and reduced nitric oxide synthase 2 (NOS2) activity. In addition, molecular docking revealed that both berberine and quercetin could bond with NOS2 and PPARα, respectively. Therefore, RCE demonstrated protective effects for SA-AKI through the regulation of metabolism and different signaling pathways. [ABSTRACT FROM AUTHOR]