Necrostatin-1 Ameliorates Peripheral Nerve Injury-Induced Neuropathic Pain by Inhibiting the RIP1/RIP3 Pathway

Liang, Yingxia; Wang, Nannan; Zhang, Zhiyu; Juan, Zhaodong; Zhang, Can

doi:10.3389/fncel.2019.00211

Cited by 26 publications

(32 citation statements)

References 58 publications

(71 reference statements)

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“…This observation is consistent with other studies showing that chronic inhibition of RIPK1 can lead to reduced expression of RIPK3 and/or MLKL in different inflammatory rodent models [26][27][28][29]. Inhibiting the kinase activity of RIPK1 may result in an increase stability of RIPK1.…”

Section: Discussionsupporting

confidence: 92%

Inhibition of receptor-interacting protein kinase 1 improves experimental non-alcoholic fatty liver disease

Majdi

Aoudjehane

Ratziu

et al. 2020

Journal of Hepatology

116

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Background & Aims: In non-alcoholic fatty liver disease (NAFLD), hepatocytes can undergo necroptosis, a regulated form of necrotic cell death mediated by the receptorinteracting protein kinase (RIPK) 1. We herein assessed the potential of RIPK1 and its downstream effector mixed lineage kinase domain-like protein (MLKL), as therapeutic targets and markers of activity in NAFLD. Methods: C57/BL6J-mice were fed a normal chow diet (NCD) or high fat diet (HFD). The effect of RIPA-56, a highly specific inhibitor of RIPK1, was evaluated in either a prophylactic or a curative treatment of HFD-fed mice, and in primary human steatotic hepatocytes. RIPK1 and MLKL concentrations were measured in the serum of patients with NAFLD. Results: Both prophylactic and curative treatments of HFD-fed mice with RIPA-56, caused a down-regulation of MLKL and a reduction of liver injury, inflammation and fibrosis, characteristic of non-alcoholic steatohepatitis (NASH), as well as of steatosis. This latter effect was reproduced by treating primary human steatotic hepatocytes with RIPA-56 or necrosulfonamide (NSA), a specific inhibitor of human MLKL, and by knocking out (KO) MLKL in fat-loaded AML-12 mouse hepatocytes. MLKL KO in steatotic hepatocytes, caused an activation of the mitochondrial respiration, and an increase in b-oxidation. Along with MLKL decreased activation, RIPK3-KO mice exhibited increased activities of the liver mitochondrial respiratory chain complexes in experimental NASH. In patients with NAFLD, serum concentrations of RIPK1 and MLKL increased in correlation with the activity. Conclusion: The inhibition of RIPK1 improves NASH features in HFD-fed mice and reverses steatosis by an MLKL-dependent mechanism that involves at least partly an increase in mitochondrial respiration. RIPK1 and MLKL are potential serum markers of activity and promising therapeutic targets in NAFLD.

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Section: Discussionsupporting

confidence: 92%

Inhibition of receptor-interacting protein kinase 1 improves experimental non-alcoholic fatty liver disease

Majdi

Aoudjehane

Ratziu

et al. 2020

Journal of Hepatology

116

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“…Western blot was performed on the proteins p-RIPK3 and p-MLKL in PRU-treated cells upon co-treatment with inhibitor Nec-1 at 0.1 mM concentration. Nec-1 is a small effective molecule that inhibits the process of necroptosis by causing reduction in RIPK1/RIPK3 kinase activity leading to the inhibition of several residues of serine-phosphorylation during the formation of the necrosome complex [ 35 , 39 ]. The results as depicted in Figure 5 b show that the elevated expression of p-RIPK3 and p-MLKL in the PRU treated cells were found to be reduced upon co-treatment with the inhibitor Nec-1.…”

Section: Resultsmentioning

confidence: 99%

Compound Prunetin Induces Cell Death in Gastric Cancer Cell with Potent Anti-Proliferative Properties: In Vitro Assay, Molecular Docking, Dynamics, and ADMET Studies

Vetrivel

Kim

et al. 2020

Biomolecules

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Gastric cancer is the common type of malignancy positioned at second in mortality rate causing burden worldwide with increasing treatment options. Prunetin (PRU) is an O-methylated flavonoid that belongs to the group of isoflavone executing beneficial activities. In the present study, we investigated the anti-proliferative and cell death effect of the compound PRU in AGS gastric cancer cell line. The in vitro cytotoxic potential of PRU was evaluated and significant proliferation was observed. We identified that the mechanism of cell death was due to necroptosis through double staining and was confirmed by co-treatment with inhibitor necrostatin (Nec-1). We further elucidated the mechanism of action of necroptosis via receptor interacting protein kinase 3 (RIPK3) protein expression and it has been attributed by ROS generation through JNK activation. Furthermore, through computational analysis by molecular docking and dynamics simulation, the efficiency of compound prunetin against RIPK3 binding was validated. In addition, we also briefed the pharmacokinetic properties of the compound by in silico ADMET analysis.

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“…Therefore, we next sought to attenuate fat graft fibrosis in vivo by reducing necroptotic death of MFCs and demonstrated that Nec-1 treatment reduced fat graft fibrosis. Studies of necroptosis have shown that intraperitoneal injection of Nec-1 protects cellular structures under necroptosis-related pathological conditions in animal models ( Liang et al, 2019 ). This is the first report of the long-term therapeutic application of Nec-1 to reduce fat graft fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…To investigate the effects of necroptosis inhibition in vivo , fat-grafted mice were intravenously injected with 1.65 mg/kg necrostatin-1 (Nec-1; Sigma-Aldrich, St. Louis, MO, United States; Linkermann et al, 2013 ; Caccamo et al, 2017 ; Liang et al, 2019 ) once per day for 30 days from the fourth week after grafting. Control fat-grafted mice were intravenously injected with the same volume of DMSO diluted in saline solution.…”

Section: Methodsmentioning

confidence: 99%

Necroptosis in Macrophage Foam Cells Promotes Fat Graft Fibrosis in Mice

Chen

Deng

Feng

et al. 2021

Front. Cell Dev. Biol.

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Background: Fibrosis is a major grafting-related complication that leads to fat tissue dysfunction. Macrophage-induced inflammation is related to the development of fat tissue fibrosis. Necroptosis is a recently discovered pathway of programmed cell necrosis that results in severe inflammation and subsequent tissue fibrosis. Thus, in this study, we investigated the role of macrophage necroptosis in fat graft fibrosis and the underlying mechanisms.Methods: Fibrosis and necroptosis were investigated in mouse fat tissue before and after grafting. An in vitro “crown-like” structure (CLS) cell culture model was developed by co-culturing RAW 264.7 macrophages with apoptotic adipocytes to reproduce in vivo CLS macrophage-adipocyte interactions. Lipid uptake and necroptosis in CLS macrophages were analyzed using Oil-Red-O staining, western blotting, and immunofluorescence. RAW264.7 macrophages were cultured alone or with apoptotic adipocytes and treated with a necroptosis inhibitor (Nec-1 or GSK872) to explore the paracrine effect of necroptotic CLS macrophages on collagen synthesis in fibroblasts in vitro. Mice were treated with Nec-1 to analyze the effect of blocking necroptosis on fat graft fibrosis.Results: Fibrosis was increased after grafting in fat grafts of mice. Macrophages clustered around apoptotic adipocytes or large oil droplets to form a typical CLS in fibrotic depots. This was accompanied by formation and necroptosis of macrophage foam cells (MFCs) in CLSs. RAW 264.7 macrophages co-cultured with apoptotic adipocytes induced CLS formation in vitro, and lipid accumulation in CLS macrophages resulted in the formation and necroptosis of MFCs. Necroptosis of MFCs altered the expression of collagen I and VI in fibroblasts via a paracrine mechanism involving inflammatory cytokines/chemokines, which was reversed by GSK872 or Nec-1 treatment. Furthermore, treatment with Nec-1 ameliorated fat graft fibrosis in mice.Conclusion: Apoptotic adipocytes induced necroptosis of MFCs, and necroptosis of these cells activated collagen synthesis in fibroblasts via a paracrine mechanism. Inhibition of necroptosis in macrophages is a potential approach to prevent fibrosis in fat grafts.

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Necrostatin-1 Ameliorates Peripheral Nerve Injury-Induced Neuropathic Pain by Inhibiting the RIP1/RIP3 Pathway

Cited by 26 publications

References 58 publications

Inhibition of receptor-interacting protein kinase 1 improves experimental non-alcoholic fatty liver disease

Inhibition of receptor-interacting protein kinase 1 improves experimental non-alcoholic fatty liver disease

Compound Prunetin Induces Cell Death in Gastric Cancer Cell with Potent Anti-Proliferative Properties: In Vitro Assay, Molecular Docking, Dynamics, and ADMET Studies

Necroptosis in Macrophage Foam Cells Promotes Fat Graft Fibrosis in Mice

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