Mefunidone ameliorates renal inflammation and tubulointerstitial fibrosis via suppression of IKKβ phosphorylation

Zhang, Jin; Zheng, Linfeng; Yuan, Xiangning; Liu, Chunyan; Yuan, Qiongjing; Xie, Feifei; Qiu, Sisi; Peng, Zhangzhe; Tang, Yiting; Meng, Jian; Qin, Jiao; Hu, Gaoyun; Tao, Ling

doi:10.1016/j.biocel.2016.10.005

Cited by 17 publications

(14 citation statements)

References 37 publications

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“…Renal obstruction caused by UUO leads to increased urinary pressure, decreased renal blood flow, venous drainage obstruction, infiltration of inflammatory cells and proliferation of fibroblasts, thus leading to renal failure. This model has been used in numerous studies regarding renal inflammation ( 11 , 12 ). In addition, LPS may induce a multisystemic inflammatory response; however, the specific renal inflammatory response was reduced in vivo LPS treatment.…”

Section: Introductionmentioning

confidence: 99%

Anti-inflammatory effects of Lefty-1 in renal tubulointerstitial inflammation via regulation of the NF-κB pathway

Zhang

et al. 2017

Int J Mol Med

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Renal tubulointerstitial inflammation has an important role in fibrosis, which is the main pathogenetic alteration associated with chronic kidney disease (CKD). The left-right determination factor 1 (Lefty-1) gene pleiotropically and biologically regulates transforming growth factor, mitogen-activated protein kinase and other signaling pathways, and is considered to have a potential anti-inflammatory function. However, its role in renal tubulointerstitial inflammation, which is often a long-term consequence of renal fibrosis, is currently unknown. In the present study, the effects of adenovirus-mediated overexpression of Lefty-1 (Ad-Lefty-1-flag) on renal tubulointerstitial inflammation were determined using a mouse model of unilateral ureteral obstruction (UUO) and a rat renal tubular duct epithelial cell line (NRK-52E), which was treated with lipopolysaccharide (LPS). In vivo results indicated that the inflammatory response was increased in UUO mice, as evidenced by the increase in inflammatory cytokines and chemokines. Conversely, Lefty-1 significantly reversed the effects of UUO. Furthermore, the results of the in vitro study demonstrated that Lefty-1 significantly inhibited LPS-induced inflammatory marker expression in cultured NRK-52E cells via the nuclear factor (NF)-κB signaling pathway. These results suggested that Lefty-1 may ameliorate renal tubulointerstitial inflammation by suppressing NF-κB signaling. In conclusion, the findings of the present study indicated that Lefty-1 may be considered a potential novel therapeutic agent for inhibiting renal tubulointerstitial inflammation or even reversing the CKD process.

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Section: Introductionmentioning

confidence: 99%

Anti-inflammatory effects of Lefty-1 in renal tubulointerstitial inflammation via regulation of the NF-κB pathway

Zhang

et al. 2017

Int J Mol Med

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“…[9][10][11][12] Mefunidone (MFD), [1-(4-((3-(4-methylpiperazin-1-yl) propyl)amino)benzyl)-5-(trifluoromethyl) pyridin-2(1H)one] (see molecular structure in Supporting Information S1), a novel synthetic compound with high water solubility, shows dramatic antifibrotic and anti-inflammatory effects in obstructive kidney model. 13,14 Nevertheless, whether MFD is potentially renoprotective in DKD remains unclear. In order to clarify whether mefunidone is beneficial to DKD, we studied the effect of mefunidone in diabetic animals, including db/db mice and STZ-treated rats and further explored the mechanism.…”

mentioning

confidence: 99%

Mefunidone ameliorates diabetic kidney disease in STZ and db/db mice

Jiang

Xie

et al. 2020

FASEB j.

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Diabetic kidney disease (DKD) a kind of microvascular complication, is a primary cause of end-stage renal disease (ESRD) worldwide. 1,2 Characteristic pathological features of DKD include glomerular basement membrane (GBM) thickening, mesangial expansion, glomerulosclerosis, and tubulointerstitial fibrosis, owing to high expression of extracellular matrix (ECM), such as collagen, fibronectin, and so on. 3,4 Type 1 diabetes millitus (T1D) and type 2 diabetes millitus (T2D) are the most common cause of DKD. The incidence of DKD complicated by T1D and T2D is about 50%

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“…Mefunidone (MFD, Figure B) is a synthesized derivation of PFD that exhibited greater anti‐fibrosis and anti‐inflammatory effects as compared to PFD in several animal models and cellular experiments . MFD significantly alleviated renal interstitial damage and fibrosis in rat unilateral urethral obstruction (UUO) models, and the anti‐fibrotic effect from 25 mg·kg −1 of MFD and 500 mg·kg −1 of PFD was equivalent, suggesting that the anti‐fibrotic effect of MFD was 20‐fold stronger compared with PFD .…”

Section: Introductionmentioning

confidence: 99%

“…8,9 Mefunidone (MFD, Figure 1B) is a synthesized derivation of PFD that exhibited greater anti-fibrosis and anti-inflammatory effects as compared to PFD in several animal models and cellular experiments. 10 MFD significantly alleviated renal interstitial damage and fibrosis in rat unilateral urethral obstruction (UUO) models, and the anti-fibrotic effect from 25 mg·kg −1 of MFD and 500 mg·kg −1 of PFD was equivalent, suggesting that the anti-fibrotic effect of MFD was 20-fold stronger compared with PFD. [11][12][13] Studies showed that MFD exhibited significant anti-fibrotic activity upon NRK-49F fiberglass cell lines with an IC 50 of 0.059mM, showing 20-fold higher potency compared with PFD (IC 50 = 0.997mM in the NRK-49F).…”

Section: Introductionmentioning

confidence: 99%

LC−MS/MS assay for the determination of a novel anti‐fibrotic candidate mefunidone in monkey plasma and its application to a pharmacokinetics study

Han

Wen

Fan³

et al. 2019

Drug Testing and Analysis

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Mefunidone (MFD) is a promising anti‐fibrotic candidate molecule with greater anti‐fibrotic activity than pirfenidone (PFD). However, there has been no report on the methodology used for the quantification of MFD or on any investigation of its pharmacokinetics. In this study, an efficient and reliable liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed to assay MFD in monkey plasma. This assay method was validated and applied to a pharmacokinetics study in monkeys. The lower limit of quantification of this assay was 0.1 μg·mL−1, and the linear calibration curve was acquired with R2 > 0.99 between 0.1 and 60 μg·mL−1. The intra‐day and inter‐day precision were evaluated with coefficient of variations of 1.5%–5.8%, whereas the mean accuracy ranged from 91.7% to 106.9%. A negligible matrix effect and good recovery were obtained using this assay, with average extraction recoveries of MFD and the internal standard (IS) in the range of 85.5%–124.8% and 84.1%–94.0%, respectively. The precision of the absolute matrix effect of MFD and the IS was 1.2–3.0% and 1.2–7.3%, respectively. The samples were stable under all experimental conditions. Linear pharmacokinetics were observed for MFD in monkeys, where the exposures of MFD increased proportionally with increasing MFD doses at the range of 10–90 mg·kg−1. Moderate elimination of MFD from the body was observed, with t1/2 of 5–7 h, and the elimination rate of MFD was stable during multiple dosing. In conclusion, this method provides an reliable analytical approach for quantification of MFD in plasma and was successfully applied to a pharmacokinetics study in monkeys.

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Mefunidone ameliorates renal inflammation and tubulointerstitial fibrosis via suppression of IKKβ phosphorylation

Cited by 17 publications

References 37 publications

Anti-inflammatory effects of Lefty-1 in renal tubulointerstitial inflammation via regulation of the NF-κB pathway

Anti-inflammatory effects of Lefty-1 in renal tubulointerstitial inflammation via regulation of the NF-κB pathway

Mefunidone ameliorates diabetic kidney disease in STZ and db/db mice

LC−MS/MS assay for the determination of a novel anti‐fibrotic candidate mefunidone in monkey plasma and its application to a pharmacokinetics study

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