Limonin ameliorates cisplatin-induced acute liver injury by inhibiting 11ß-hydroxysteroid dehydrogenase type 1.

BACKGROUND: Acute liver injury (ALI) is a common side effect of cisplatin treatment in the clinic and can lead to liver failure if not treated promptly. Previous studies have revealed that Limonin, a critical bioactive substance in citrus fruits, can protect multiple organs from various medical conditions. However, whether Limonin could ameliorate cisplatin-induced ALI remains unclear. METHODS: In vivo and in vitro models were induced by cisplatin in the present study. Non-targeted metabolomics was employed to analyze the metabolic changes in the liver after ALI. In addition, molecular docking was utilized to predict the potential targets of Limonin. RESULTS: Limonin attenuated hepatic histopathological injury by reducing hepatocyte apoptosis, lipid peroxidation, and inflammation in cisplatin-challenged mice. Employing metabolomics, we revealed that Limonin mediated the balance of various disturbed metabolic pathways in the liver after cisplatin-induced ALI. Integrating public data mining, molecular docking studies, and in vitro experiments demonstrated that Limonin suppressed the expression and activity of its direct target, 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), in the liver, thus reducing the production of corticosterone (CORT), a key metabolite promoted hepatocyte apoptosis. CONCLUSIONS: Limonin improves the liver metabolic microenvironment by inhibiting 11ß-HSD1 to protect against cisplatin-induced ALI.

Limonin mitigates cisplatin-induced acute kidney injury through metabolic reprogramming.

BACKGROUND: Acute kidney injury (AKI) is a known complication of cisplatin administration; currently, there are no effective ways to prevent it. Therefore, it largely limited the use of cisplatin in chemotherapy in the clinic. In this study, we reported that Limonin, a triterpenoid compound extracted from citrus, alleviated cisplatin-induced AKI through metabolic reprogramming in the diseased kidneys. METHODS: Cisplatin was employed to induce AKI in mice. Three groups were set up: Sham, cisplatin + vehicle, and cisplatin + Limonin. Using UHPLC-TOF/MS, we conducted metabolomics to profile the kidneys' endogenous metabolites and metabolic pathways. A network pharmacological method was performed to identify the targets of Limonin on AKI. The human proximal tubular epithelial cell line (HK-2) was applied for in vitro studies. RESULTS: Limonin preserved serum creatinine and blood urea nitrogen levels after cisplatin-induced AKI. Employing metabolomics, we identified 33 endogenous differentially expressed metabolites and 7 significantly disturbed metabolic pathways in the diseased kidneys within three groups. After AKI, Limonin significantly reduced linoleic acid and its downstream product, arachidonic acid, thus exerting a protective effect on the kidney. The network pharmacological method identified CYP3A4 as a key target of Limonin in treating AKI, while CYP3A4 also serve as a mediator of arachidonic acid metabolism. In vitro, Limonin markedly reduced the level of arachidonic acid and HK-2 cell apoptosis triggered by cisplatin, mainly related to the targeted inhibition of CYP3A4-mediated arachidonic acid metabolism. CONCLUSION: Limonin ameliorates cisplatin-induced AKI by inhibiting CYP3A4 activity to regulate arachidonic acid metabolism, ultimately preserving kidney function.

The Efficacy of Triptolide in Preventing Diabetic Kidney Diseases: A Systematic Review and Meta-Analysis.

Ethnopharmacological Relevance: Triptolide (TP), the primary biologically active ingredient of Tripterygium wilfordii Hook F (TWHF), possesses the potential to solve the shortcomings of TWHF in treating diabetic kidney disease (DKD) in the clinic. Aim of the Study: We conducted a meta-analysis to evaluate the efficacy of TP in treating DKD and offer solid evidence for further clinical applications of TP. Materials and Methods: Eight databases (CNKI, VIP, CBM, WanFang, PubMed, Web of Science, EMBASE, and Cochrane library) were electronically searched for eligible studies until October 17, 2020. We selected animal experimental studies using TP versus renin-angiotensin system inhibitors or nonfunctional liquids to treat DKD by following the inclusion and exclusion criteria. Two researchers independently extracted data from the included studies and assessed the risk of bias with the Systematic Review Centre for Laboratory Animal Experimentation Risk of Bias tool. Fixed-effects meta-analyses, subgroup analyses, and meta-regression were conducted using RevMan 5.3 software. Inplasy registration number: INPLASY2020100042. Results: Twenty-six studies were included. Meta-analysis showed that TP significantly reduced albuminuria (14 studies; standardized mean difference SMD: -1.44 [-1.65, -1.23], I2 = 87%), urine albumin/urine creatinine ratio (UACR) (8 studies; SMD: -5.03 [-5.74, -4.33], I2 = 84%), total proteinuria (4 studies; SMD: -3.12 [-3.75, -2.49], I2 = 0%), serum creatinine (18 studies; SMD: -0.30 [-0.49, -0.12], I2 = 76%), and blood urea nitrogen (12 studies; SMD: -0.40 [-0.60, -0.20], I2 value = 55%) in DKD animals, compared to the vehicle control. However, on comparing TP to the renin-angiotensin system (RAS) inhibitors in DKD treatment, there was no marked difference in ameliorating albuminuria (3 studies; SMD: -0.35 [-0.72, 0.02], I2 = 41%), serum creatinine (3 studies; SMD: -0.07 [-0.62, 0.48], I2 = 10%), and blood urea nitrogen (2 studies; SMD: -0.35 [-0.97, 0.28], I2 = 0%). Of note, TP exhibited higher capacities in reducing UACR (2 studies; SMD: -0.66 [-1.31, -0.01], I2 = 0%) and total proteinuria (2 studies; SMD: -1.18 [-1.86, -2049], I2 = 0%). Meta-regression implicated that the efficacy of TP in reducing DKD albuminuria was associated with applied dosages. In addition, publication bias has not been detected on attenuating albuminuria between TP and RAS inhibitors after the diagnosis of DKD. Systematic Review Registration: https://clinicaltrials.gov/, identifier INPLASY2020100042.