Silencing lncRNA Lfar1 alleviates the classical activation and pyoptosis of macrophage in hepatic fibrosis

Zhang, Kun; Shi, Zhemin; Zhang, Mengxia; Dong, Xueyi; Zheng, Lemin; Li, Guantong; Han, Xiaohui; Yao, Zhi; Han, Tao; Wang, Hong

doi:10.1038/s41419-020-2323-5

Cited by 74 publications

(46 citation statements)

References 32 publications

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“…Therefore, researchers began to focus on the role of inflammation and immune response caused by cholestasis on liver injury [24,25]. The literature reported that 24 h after bile duct ligation, a large number of inflammatory cells infiltrated around the injured liver tissue [26,27]. Our study also showed the necrosis of diseased hepatocytes accompanied by inflammatory cell infiltration in mice 48 h after ANIT administration.…”

Section: Discussionmentioning

confidence: 52%

Protective effects of PAMAM dendrimers against ANIT-induced cholestatic liver injury in mice

Zhang¹,

Liu²,

Ren³

et al. 2020

Preprint

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Background:Cholestatic liver disease (CLD) is a common disease of infancy, threatening infants’ health seriously. However, there is no effective drug to treat this disease.It is urgently to develop a new drug to overcome it. Polyamide-amine (PAMAM) dendrimer is a hyperbranched nano polymer, which has been found that has an anti-inflammatory effect recently. For this study, we aim to explore the protective effect and mechanism of PAMAM on CLD.Methods:In this study, a mouse model of cholestatic liver injury was created using ANIT,and TNF-α was utilized to stimulate human hepatocytes to investigate the protective effect and mechanism of 4.5th generation carboxyl-terminated PAMAM dendrimers (G4.5-COOH) in vivo and in vitro.Liver serum biochemistry, inflammatory, oxidative stress(OxS), endoplasmic reticulum(ER) stress and apoptosis indicators were determined.In addition, the eﬀects of G4.5-COOH on PPAR-γ and PI3K/AKT/mTOR signaling pathway were studied. Data were analyzed by using one-way ANOVA. Results:We find the G4.5-COOH may inhibit TNF-α to damage hepatocytes and ameliorate the cholestatic liver injury. We also find that the protective effect of G4.5-COOH might be due to inhibition of P-Akt、P-mTOR expression by a mechanism that might be partly dependent on up-regulated functional expression of PPAR-γ.Conclusions:G4.5-COOH PAMAM dendrimer has a protective effect on CLD.

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Section: Discussionmentioning

confidence: 52%

Protective effects of PAMAM dendrimers against ANIT-induced cholestatic liver injury in mice

Zhang¹,

Liu²,

Ren³

et al. 2020

Preprint

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“…Pyroptosis has been implicated in various diseases, such as inflammation, nonalcoholic fatty liver disease, and liver fibrosis 28 – 31 . Bacteria, toxins and so on can elicit a strong immune response in macrophages, resulting in pyroptosis 29 , 32 . However, the molecular basis of Kupffer cells pyroptosis is incompletely understood, which has limited the identification of therapeutic targets.…”

Section: Discussionmentioning

confidence: 99%

DHA/AA alleviates LPS-induced Kupffer cells pyroptosis via GPR120 interaction with NLRP3 to inhibit inflammasome complexes assembly

Fan

Chen

et al. 2021

Cell Death Dis

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Pyroptosis is a novel type of programmed cell death associated with the pathogenesis of many inflammatory diseases. Docosahexaenoic acid (DHA) and Arachidonic acid (AA) is widely involved in inflammatory pathological processes. However, the effect and mechanism of DHA and AA on pyroptosis in Kupffer cells are poorly understood. The present study demonstrated that DHA and AA ameliorated lipopolysaccharide (LPS)-induced Kupffer cells pyroptosis by reversing the increased expression of NLRP3 inflammasome complex, GSDMD, IL-1β, IL-18, and PI-stained positive rate. Next, the study revealed that GPR120 silencing eliminated the anti-pyroptosis of DHA and AA in LPS-induced Kupffer cells, suggesting that DHA and AA exerted their effect through GPR120 signaling. Importantly, GPR120 endocytose and binds to NLRP3 under LPS stimulation. Furthermore, co-immunoprecipitation showed that DHA and AA promoted the interaction between GPR120 and NLRP3 in LPS-exposed Kupffer cells, thus inhibiting the self-assembly of NLRP3 inflammasome complex. Finally, the study verified that DHA and AA alleviated hepatic injury through inhibiting Kupffer cells pyroptosis in vivo. The findings indicated that DHA and AA alleviated LPS-induced Kupffer cells pyroptosis via GPR120 interaction with NLRP3, it might become a potential therapeutic approach hepatic injury.

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“… 16 LPS are involved in activating caspase-11 in mice and caspase-4 and -5 in humans, 17 – 19 and LPS and ATP have been shown to markedly upregulate the expression levels of pyroptosis-related genes that activate the NLRP3 inflammasome. 20 Additionally, LPS induces caspase-11 in mice to activate the GSDMD protein and trigger non-canonical pyroptosis, while caspase-4 and -5 in humans have similar functions and stimulate the innate cellular immune response. 21 – 23 In mice with sepsis, the continuity of the neural nuclear and mitochondrial membrane suffers from injury, suggesting that neurons undergo pyroptosis.…”

Section: Discussionmentioning

confidence: 99%

Roles of the pyroptosis signaling pathway in a sepsis-associated encephalopathy cell model

et al. 2020

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Objectives The inhibition of pyroptosis has a protective effect in sepsis-associated encephalopathy (SAE). However, the mechanisms underlying pyroptosis in SAE remain to be elucidated. Methods Here, we investigated the effects of the caspase inhibitors, Belnacasan (Beln) and Wedelolactone (Wede), on an induced model of SAE in P12 cells, using immunofluorescence, ELISA, western blotting, and flow cytometry. Results The cell viability decreased, IL-1β and IL-18 secretion increased, and the levels of the caspase cleavage products, N-terminal gasdermin D, cleaved caspase-1, and cleaved caspase-11, increased in P12 cells following combined treatment with lipopolysaccharides (LPS) and adenosine triphosphate (ATP). However, treatment with Beln or Wede ameliorated the effects induced by LPS and ATP. Neither Beln nor Wede notably affected the levels of cell apoptosis-associated proteins but these inhibitors regulated the levels of cell pyroptosis-associated proteins. Further, the combination of Beln and Wede exerted greater inhibitory effects on cell pyroptosis than either Beln or Wede alone. Conclusions The results demonstrated that both the canonical and non-canonical signaling pathways of cell pyroptosis are involved in LPS-induced cell damage and that the non-canonical signaling pathway may be involved to a greater extent. This suggests that the inhibition of pyroptosis may exert potential therapeutic effects on SAE.

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Silencing lncRNA Lfar1 alleviates the classical activation and pyoptosis of macrophage in hepatic fibrosis

Cited by 74 publications

References 32 publications

Protective effects of PAMAM dendrimers against ANIT-induced cholestatic liver injury in mice

Protective effects of PAMAM dendrimers against ANIT-induced cholestatic liver injury in mice

DHA/AA alleviates LPS-induced Kupffer cells pyroptosis via GPR120 interaction with NLRP3 to inhibit inflammasome complexes assembly

Roles of the pyroptosis signaling pathway in a sepsis-associated encephalopathy cell model

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