Acute kidney injury (AKI) causes severe morbidity and mortality for which new therapeutic strategies are needed. Inhibition of soluble epoxide hydrolase (sEH) has been reported previously to attenuate the kidney injury in cisplatin‐caused AKI. However, the effect of sEH inhibition on ischemia/reperfusion (I/R)‐caused‐AKI remains unknown. In addition, the mechanism underlying the benefit of sEH inhibition to AKI has not been well understood. Here we report that epoxyeicosatrienoic acids (EETs) are the major mediators responsible for the beneficial effect of sEH inhibition in I/R‐caused AKI. Inhibition of sEH resulted in a significant increase in plasma level of 14(15)‐EET. Administration of both 14(15)‐EET alone and TPPU (a potent sEH inhibitor) significantly prolonged the survival of AKI mice. Co‐administration of 14(15)‐EET with TPPU enhanced such effect in survival. Administration of 14(15)‐EET with or without TPPU to AKI mice significantly attenuated the kidney injury, which was supported by the histological analysis of renal tissue, plasma levels of creatinine and urea nitrogen, and renal levels of NGAL. Furthermore, 14(15)‐EET significantly reversed the I/R‐caused reduction in glycogen synthase kinase 3β (GSK3β) phosphorylation in murine kidney, dose‐dependently inhibited the hypoxia/reoxygenation (H/R)‐caused apoptosis of murine renal tubular epithelial cells (mRTECs), and reversed the H/R‐caused reduction in GSK3β phosphorylation in mRTECs. Therefore, inhibition of sEH attenuates kidney injury via, at least partially, 14(15)‐EET modulating the apoptosis of RTECs and GSK3β phosphorylation in mRTECs. This study provides AKI patients with promising therapeutic strategies. Support or Funding Information This study was supported in part by NSFC grants 81470588 and 81100090, as well as NIEHS Grant (R01 ES02710), NIEHS Superfund Grant (P42 ES04699), NIH/NHLBI grant (R01 HL59699‐06A1), and a Translational Technology Grant from the UC Davis Medical Center. K.S.S.L. is supported by NIEHS Grant R00 ES024806. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
Abstract Emerging research has revealed regulation of colorectal cancer metabolism by bacteria. Fusobacterium nucleatum (Fn) plays a crucial role in the development of colorectal cancer, however, whether Fn infection modifies metabolism in patients with colorectal cancer remains unknown. Here, LC-MS/MS-based lipidomics identified the upregulation of cytochrome P450 monooxygenases, primarily CYP2J2, and their mediated product 12,13-EpOME in patients with colorectal cancer tumors and mouse models, which increased the invasive and migratory ability of colorectal cancer cells in vivo and in vitro by regulating the epithelial–mesenchymal transition (EMT). Metagenomic sequencing indicated a positive correlation between increased levels of fecal Fn and serum 12,13-EpOME in patients with colorectal cancer. High levels of CYP2J2 in tumor tissues also correlated with high Fn levels and worse overall survival in patients with stage III/IV colorectal cancer. Moreover, Fn was found to activate TLR4/AKT signaling, downregulating Keap1 and increasing NRF2 to promote transcription of CYP2J2. Collectively, these data identify that Fn promotes EMT and metastasis in colorectal cancer by activating a TLR4/Keap1/NRF2 axis to increase CYP2J2 and 12,13-EpOME, which could serve as clinical biomarkers and therapeutic targets for Fn-infected patients with colorectal cancer. Significance: This study uncovers a mechanism by which Fusobacterium nucleatum regulates colorectal cancer metabolism to drive metastasis, suggesting the potential biomarker and therapeutic utility of the CYP2J2/12,13–EpOME axis in Fn-infected patients.
Purpose: Sumoylation plays a critical role in gene regulation and tumorigenesis, and is hypothesized to correlate with the development of various cancers.So far, there has been no reported association between sumoylation-related genes and the risk of gastric cancer (GC).Methods: A total of 17 tagging single-nucleotide polymorphisms (tag-SNPs) in 5 sumoylationrelated genes were selected and genotyped by SNaPshot in a case-control study, including 1021 GC patients and 1304 controls.Odds ratio (OR) and 95% confidential interval (CI) were computed to evaluate the genetic association of the onset of GC.Results: We demonstrated that CBX4 rs77447679 polymorphism was significantly associated with GC risk (P= 0.017; adjusted OR: 1.71; 95% CI: 1.10-2.66).The patients with CC genotype had a lower risk of GC (CC vs. CA+AA, P= 0.017; adjusted OR: 1.24; 95% CI: 1.04-1.49). Conclusion:This study revealed that CBX4 rs77447679 polymorphism was positively associated with GC, and individuals with CC genotype had less risk of GC.The risky effects and functional effect of this polymorphism in GC require further investigation.
Background and Purpose Chronic kidney disease (CKD) is a global public health problem and one of the leading causes of all‐cause mortality. However, the pathogenic mechanisms and intervention methods for CKD progression are not fully understood. Experimental Approach Plasma from patients with uraemia and from healthy controls ( n = 30 per group) was analysed with LC‐MS/MS‐based non‐targeted metabolomics to identify potential markers of uraemia. These potential markers were validated in the same cohort and a second cohort ( n = 195) by quantitative analysis of the markers, using LC‐MS/MS. The most promising marker was identified by correlation analysis and further validated using HK‐2 cells and mouse models. Key Results Trimethylamine N ‐oxide (TMAO) was identified as a promising marker among the 18 potential markers found in the first cohort, and it was optimally correlated with renal function of CKD patients in the second cohort. Treatment of HK‐2 cells with TMAO decreased cell viability and up‐regulated expression of α‐smooth muscle actin. In mice, a TMAO‐containing diet decreased kidney mass and increased protein expression of α‐smooth muscle actin. Also, control of TMAO production by inhibiting its biosynthetic pathway with 3,3‐dimethyl‐1‐butanol or disrupting gut microbiota function with an antibiotic cocktail, attenuated renal injury in a murine model of CKD. Conclusion and Implications Our data show that decreased TMAO production could be a new strategy to attenuate the progression of renal injury in CKD.
Monosodium urate-induced inflammation plays a vital role in acute gout (AG). Inflammation is a multi-stage process involved in the acute release of arachidonic acid and its metabolites. However, the function of the metabolism of arachidonic acid and other polyunsaturated fatty acids in AG is not well understood. This study aimed to investigate the modification of polyunsaturated fatty acid metabolism by AG. Plasma samples from patients with an AG attack (n = 26) and gender-matched healthy controls (n = 26) were analysed by metabolic profiling of polyunsaturated fatty acids. The findings were further validated with a second cohort (n = 20 each group). The associated mechanisms were investigated in whole blood cells from the second cohort and neutrophils in vitro. Plasma metabolic profiling revealed a significant increase in leukotriene B4 (LTB4) for AG patients in both cohorts. The increase in plasma LTB4 was accounted for by the dynamic balance between the activation of 5-lipoxygenase and CYP4F3, the former mediating the biosynthesis of LTB4 and the latter mediating its metabolism. This was supported by significantly increased transcriptional levels of 5-lipoxygenase and CYP4F3 in whole blood cells from AG patients compared with those of controls, and the uric acid-caused dose-relevant and time-dependent activation of 5-lipoxygenase and CYP4F3 at the transcriptional and molecular levels in vitro. Increased LTB4 in AG patients is mainly due to activation of 5-lipoxygenase. 5-Lipoxygenase inhibition may be of therapeutic value clinically.
Abstract Background Hearing loss is a common sensorineural dysfunction with a high incidence in China. Although genetic factors are important causes of hearing loss, hearing-related gene detection has not been widely adopted in China. Objective Establishing a rapid and efficient method to simultaneously detect hotspot hearing loss gene mutations. Methods A reverse dot blot assay combined with a flow-through hybridization technique was developed for the simultaneous detection of 13 hotspot mutations of 4 hearing loss–related genes including GJB2, GJB3, SLC26A4, and the mitochondrial gene MT-RNR1 . This method involved PCR amplification systems and a hybridization platform. Results The technique can detect 13 hotspot mutations of 4 hearing loss–related genes. And a total of 213 blood samples were used to evaluate the availability of this method. Discussion Our reverse dot blot assay was a simple, rapid, accurate, and cost-effective method to identify hotspot mutations of 4 hearing loss–related genes in a Chinese population.
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