Fluorofenidone Alleviates Renal Fibrosis by Inhibiting Necroptosis Through RIPK3/MLKL Pathway

Dai, Qing; Zhang, Yan; Liao, Xiali; Jiang, Yupeng; Lv, Xin; Yuan, Xiangning; Meng, Jian; Xie, Yanyun; Peng, Zhangzhe; Yuan, Qiongjing; Tao, Ling; Huang, Ling

doi:10.3389/fphar.2020.534775

Cited by 23 publications

(10 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hence, fluorofenidone (AKFPD), a novel pyridone agent with similar chemical structure to PFD, was screened by our group. According to previous studies, AKFPD and PFD showed similar capacity in the aspects of anti-inflammation, anti-oxidation, and anti-fibrosis (Dai et al, 2020;Jiang et al, 2019;Meng et al, 2012;Song et al, 2016;Tang et al, 2015;Zheng et al, 2018).…”

Section: Introductionmentioning

confidence: 62%

Mefunidone Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Mice

Han

Jiang

et al. 2021

Front. Pharmacol.

Self Cite

View full text Add to dashboard Cite

Idiopathic pulmonary fibrosis (IPF) is one of the most common and devastating interstitial lung diseases with poor prognosis. Currently, few effective drugs are available for IPF. Hence, we sought to explore the role of mefunidone (MFD), a newly synthesized drug developed by our team, in lung fibrosis. In this study, MFD was found to attenuate bleomycin (BLM) -induced lung fibrosis and inflammation in mice according to Ashcroft and alveolitis scoring. The protein contents and total cell counts in bronchoalveolar lavage fluids of BLM-treated mice were also lowered by MFD. Moreover, the elevation of TGF-β/Smad2 and phosphorylation of MAPK pathways was repressed by MFD. Additionally, MFD attenuated the swelling and vacuolization of mitochondria, lowered the ratio of apoptotic cells, restored the mitochondrial membrane potential, and reversed the expression of cleaved-caspase 3, Bcl-2 and Bax. Meanwhile, the level of epithelial marker, E-cadherin, was restored by MFD, while the levels of mesenchymal markers such as Snail and vimentin were down-regulated by MFD. Besides, MFD inhibited the expression of fibronectin and α-smooth muscle actin in TGF-β treated normal human lung fibroblasts. Thus, our findings suggested that MFD could ameliorate lung fibrosis, cell apoptosis and EMT potentially via suppression of TGF-β/Smad2 and MAPK pathways.

show abstract

Section: Introductionmentioning

confidence: 62%

Mefunidone Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Mice

Han

Jiang

et al. 2021

Front. Pharmacol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Thus, Wnt/β-catenin/GSK signaling is involved in the development of renal fibrosis in acute kidney injury (Pan et al, 2021) and diabetic nephropathy (Chang et al, 2018). In our model of UUO, the pathogenesis of renal fibrosis involves a complex network orchestrated by necroptosis, oxidative stress, inflammation, TGF-β1, and activation of Wnt/catenin signaling (Jiang et al, 2015;Dai et al, 2020;Jin et al, 2020). Inhibition of necroptosis or Wnt/catenin signaling alleviates UUO-induced renal fibrosis (Xiao et al, 2017;Gong et al, 2021), implying a relationship between necroptosis and Wnt/ β-catenin signaling.…”

Section: Discussionmentioning

confidence: 90%

Dapagliflozin Alleviates Renal Fibrosis by Inhibiting RIP1-RIP3-MLKL-Mediated Necroinflammation in Unilateral Ureteral Obstruction

et al. 2022

View full text Add to dashboard Cite

Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, offers renoprotection in diabetes. However, potential for use in nondiabetic kidney disease remains unknown. Herein, we assessed whether dapagliflozin alleviates renal fibrosis by interfering with necroinflammation in a rat model of unilateral ureteral obstruction (UUO) and in vitro. After induction of UUO, rats were administered dapagliflozin daily for seven consecutive days. UUO induced significant renal tubular necrosis and overexpression of RIP1-RIP3-MLKL axis proteins; these coincided with NLRP3 inflammasome activation, and subsequent development of renal fibrosis. Oxidative stress caused by UUO is tightly associated with endoplasmic reticulum stress and mitochondrial dysfunction, leading to apoptotic cell death through Wnt3α/β-catenin/GSK-3β signaling; all of which were abolished by both dapagliflozin and specific RIP inhibitors (necrostatin-1 and GSK872). In H2O2-treated HK-2 cells, dapagliflozin and RIP inhibitors suppressed overexpression of RIP1-RIP3-MLKL proteins and pyroptosis-related cytokines, decreased intracellular reactive oxygen species production and apoptotic cell death, whereas cell viability was improved. Moreover, activated Wnt3α/β-catenin/GSK-3β signaling was inhibited by dapagliflozin and Wnt/β-catenin inhibitor ICG-001. Our findings suggest that dapagliflozin ameliorates renal fibrosis by inhibiting RIP1-RIP3-MLKL-mediated necroinflammation via Wnt3α/β-catenin/GSK-3β signaling in UUO.

show abstract

“…Unfortunately, there is still lack of effective therapeutic medicine. As the me-better drug of pirfenidone, fluorofenidone has a higher no observed adverse effect level (NOAEL) and longer half-time period than pirfenidone and has shown obviously anti-fibrosis effects ( Song et al, 2016 ; Dai et al, 2020 ; Tu et al, 2021 ). In the present study, we not only proved that fluorofenidone could efficiently protect ALI for the first time but also demonstrated that fluorofenidone could provide preventive and therapeutic effects for ALI.…”

Section: Discussionmentioning

confidence: 99%

“…Fluorofenidone [1-(3-fluorophenyl)-5-methyl-2-([1H])-pyridone; AKFPD] is a novel pyridone anti-fibrosis compound which has demonstrated a remarkable therapeutic effect on organ fibrosis, including the kidney, liver, and lungs ( Song et al, 2016 ; Dai et al, 2020 ; Tu et al, 2021 ). Currently, fluorofenidone is undergoing phase II clinical trial for liver fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Protective Effect of Fluorofenidone Against Acute Lung Injury Through Suppressing the MAPK/NF-κB Pathway

Lv¹,

Yao²,

He³

et al. 2021

Front. Pharmacol.

Self Cite

View full text Add to dashboard Cite

Acute lung injury (ALI) is a severe disease that presents serious damage and excessive inflammation in lungs with high mortality without effective pharmacological therapy. Fluorofenidone (AKFPD) is a novel pyridone agent that has anti-fibrosis, anti-inflammation, and other pharmacological activities, while the effect of fluorofenidone on ALI is unclarified. Here, we elucidated the protective effects and underlying mechanism of fluorofenidone on lipopolysaccharide (LPS)-induced ALI. In this study, fluorofenidone alleviated lung tissue structure injury and reduced mortality, decreased the pulmonary inflammatory cell accumulation and level of inflammatory cytokines IL-1β, IL-6, and TNF-α in the bronchoalveolar lavage fluid, and attenuated pulmonary apoptosis in LPS-induced ALI mice. Moreover, fluorofenidone could block LPS-activated phosphorylation of ERK, JNK, and P38 and further inhibited the phosphorylation of IκB and P65. These results suggested that fluorofenidone can significantly contrast LPS-induced ALI through suppressing the activation of the MAPK/NF-κB signaling pathway, which indicates that fluorofenidone could be considered as a novel therapeutic candidate for ALI.

show abstract

Fluorofenidone Alleviates Renal Fibrosis by Inhibiting Necroptosis Through RIPK3/MLKL Pathway

Cited by 23 publications

References 46 publications

Mefunidone Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Mice

Mefunidone Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Mice

Dapagliflozin Alleviates Renal Fibrosis by Inhibiting RIP1-RIP3-MLKL-Mediated Necroinflammation in Unilateral Ureteral Obstruction

Protective Effect of Fluorofenidone Against Acute Lung Injury Through Suppressing the MAPK/NF-κB Pathway

Contact Info

Product

Resources

About