Foxo1 transcription factor is an evolutionarily conserved regulator of cell metabolism, oxidative stress, inflammation, and apoptosis. Activation of Hedgehog/Gli signaling is known to regulate cell growth, differentiation, and immune function. However, the molecular mechanisms by which interactive cell signaling networks restrain oxidative stress response and necroptosis are still poorly understood. Here, we report that myeloid-specific Foxo1 knockout (Foxo1M-KO) mice were resistant to oxidative stress-induced hepatocellular damage with reduced macrophage/neutrophil infiltration, and proinflammatory mediators in liver ischemia/reperfusion injury (IRI). Foxo1M-KO enhanced β-catenin-mediated Gli1/Snail activity, and reduced receptor-interacting protein kinase 3 (RIPK3) and NIMA-related kinase 7 (NEK7)/NLRP3 expression in IR-stressed livers. Disruption of Gli1 in Foxo1M-KO livers deteriorated liver function, diminished Snail, and augmented RIPK3 and NEK7/NLRP3. Mechanistically, macrophage Foxo1 and β-catenin colocalized in the nucleus, whereby the Foxo1 competed with T-cell factor (TCF) for interaction with β-catenin under inflammatory conditions. Disruption of the Foxo1–β-catenin axis by Foxo1 deletion enhanced β-catenin/TCF binding, activated Gli1/Snail signaling, leading to inhibited RIPK3 and NEK7/NLRP3. Furthermore, macrophage Gli1 or Snail knockout activated RIPK3 and increased hepatocyte necroptosis, while macrophage RIPK3 ablation diminished NEK7/NLRP3-driven inflammatory response. Our findings underscore a novel molecular mechanism of the myeloid Foxo1–β-catenin axis in regulating Hedgehog/Gli1 function that is key in oxidative stress-induced liver inflammation and necroptosis.
This study evaluated the mitigating effects of dietary chlorogenic acid (CGA) on colon damage and the bacterial profile in a mouse model of dextran sulfate sodium (DSS)-induced colitis. C57BL/6J mice were randomly assigned to receive one of the following treatments: (i) basal diet; (ii) basal diet with 2% CGA; (iii) basal diet with 2.5% DSS or (iv) basal diet with 2% CGA and 2.5% DSS. Following a 2-week pre-treatment period, mice in the DSS and CGA-DSS groups received 2.5% DSS in drinking water for 5 days, while the other two groups received sterile water. Compared to DSS alone, CGA was found to reduce the disease activity index, myeloperoxidase activity and tumor necrosis factor-α levels in colon tissues ( P < 0.05). CGA also ameliorated DSS-induced inflammatory responses, reduced colon shortening and decreased the histological scores ( P < 0.05). In an evaluation of the relative abundances of bacteria in the fecal microbiota, we found that CGA reversed the decrease in diversity caused by DSS and improved the relative abundance of organisms in the genus Lactobacillus ( P < 0.05). These results indicate that CGA maintains intestinal health and reduces DSS-induced colon injury by decreasing the production of pro-inflammatory cytokines and restoring intestinal microbial diversity.
Berberine (BBR) has been demonstrated to protect against renal ischemia/reperfusion injury; however, the underlying molecular mechanism is largely unknown. In the present study, we examined the role of silent information regulator 1 (Sirt1)/p53 in the protective effect of BBR on hypoxia/reoxygenation (H/R)-mediated mitochondrial dysfunction in rat renal tubular epithelial cells (NRK-52E cells). NRK-52E cells were preconditioned with small interfering RNA targeting Sirt1 (Sirt1-siRNA) and BBR before subjected to H/R. Cell damage was assessed by CCK8 assay and detection of oxidative parameters. The apoptotic rate was determined by flow cytometry and Hoechst 33258 staining. The expression of apoptotic markers, Sirt1, p53 and the translocation of p53 were examined by Western blotting assay. Nuclear p53 deacetylation by Sirt1 was detected using immunoprecipitation. Compared with the H/R group, BBR pretreatment increased cell viability and inhibited mitochondrial oxidative stress and apoptosis. Protein expression of Sirt1 was also enhanced along with a reduction of p53. Furthermore, both nuclear translocation of p53 and its acetylation were inhibited in NRK-52E cells pretreated with BBR. However, the knockdown of Sirt1 counteracted the renoprotection of BBR. BBR preconditioning protects rat renal tubular epithelial cells against H/R-induced mitochondrial dysfunction via regulating the Sirt1/p53 pathway.
IRW (Ile-Arg-Trp), a bioactive peptide isolated from egg ovotransferrin, has been shown to exert anti-inflammatory effects. In this study, the effects of IRW on inflammatory cytokines and microbiota were explored in human umbilical vein endothelial cells (HUVECs) and a lipopolysaccharide (LPS)-induced rat model of inflammatory peritonitis. Rats were injected intraperitoneally with LPS to establish peritonitis. HUVECs were exposed to IRW for 12 h before introducing LPS. Notably, IRW exerted beneficial effects against LPS-induced peritonitis, specifically, by reducing the serum levels of tumour necrosis factor (TNF)-α and interleukin (IL)-6 and myeloperoxidase (MPO) activity (P<0.05). A faecal microbiota analysis revealed that IRW significantly increased the Shannon and decreased the Simpson indices (P<0.05). Furthermore, IRW treatment significantly inhibited the LPS-induced enhancement of TNF-α, IL-8, intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) expression in HUVECs (P<0.05). In conclusion, IRW supplementation inhibited the inflammatory mediator synthesis and LPS-induced inflammatory responses and influenced the gut microbiota.
BaCKgRoUND aND aIMS:The cluster of differentiation 47 (CD47)-signal regulatory protein alpha (SIRPα) signaling pathway plays important roles in immune homeostasis and tissue inflammatory response. Activation of the Hedgehog/ smoothened (SMO)/GLI family zinc finger 1 (Gli1) pathway regulates cell growth, differentiation, and immune function. However, it remains unknown whether and how the CD47-SIRPα interaction may regulate Hedgehog/SMO/Gli1 signaling in mesenchymal stem cell (MSC)-mediated immune regulation during sterile inflammatory liver injury. appRoaCH aND ReSUltS: In a mouse model of ischemia/reperfusion (IR)-induced sterile inflammatory liver injury, we found that adoptive transfer of MSCs increased CD47 expression and ameliorated liver IR injury. However, deletion of CD47 in MSCs exacerbated IR-induced liver damage, with increased serum ALT levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators. MSC treatment augmented SIRPα, Hedgehog/SMO/Gli1, and Notch1 intracellular domain (NICD), whereas CD47-deficient MSC treatment reduced these gene expressions in IR-stressed livers. Moreover, disruption of myeloid SMO or Notch1 increased IR-triggered liver inflammation with diminished Gli1 and NICD, but enhanced NIMA related kinase 7 (NEK7) and NLR family pyrin domain containing 3 (NLRP3) activation in MSC-transferred mice. Using a MSC/macrophage co-culture system, we found that MSC CD47 and macrophage SIRPα expression were increased after LPS stimulation. The CD47-SIRPα interaction increased macrophage Gli1 and NICD nuclear translocation, whereby NICD interacted with Gli1 and regulated its target gene Dvl2 (dishevelled segment polarity protein 2), which in turn inhibited NEK7/NLRP3 activity. CoNClUSIoNS:The CD47-SIRPα signaling activates the Hedgehog/SMO/Gli1 pathway, which controls NEK7/NLRP3 activity through a direct interaction between Gli1 and NICD. NICD is a coactivator of Gli1, and the target gene Dvl2 regulated by the NICD-Gli1 complex is crucial for the modulation of NLRP3-driven inflammatory response in MSCmediated immune regulation. Our findings provide potential therapeutic targets in MSC-mediated immunotherapy of sterile inflammatory liver injury. (Hepatology 2021;0:1-18). M esenchymal stem cells (MSCs) are multipotent cells capable of differentiation into mesenchymal lineages. They have become the most frequently used cell type for tissue repair and regeneration because of their remarkable immunoregulatory properties. MSCs exert extensive immunomodulation through interaction with immune cells
Steatotic livers are more susceptible to ischemia/reperfusion injury, and increase the risk of primary graft non-function after liver transplantation. The protective effects of berberine have been described in various liver pathological models. However, it is unknown if berberine exerts its beneficial action in steatotic donors undergoing liver transplantation. In the present study, male Wistar rats were fed with high-fat diet (HFD) for 12 weeks to induce moderate steatotic liver. Then orthotropic liver transplantation was constructed. Berberine (200 mg/kg/d) was given intragastrically one week before liver transplantation. Thapsigargin (TG) (0.2 mg/kg) was administrated intravenously 24 h before liver transplantation. Liver function, oxidative stress, and inflammatory cytokine were detected by biochemical or histopathological analysis. The morphology of autophagosomes and endoplasmic reticulum (ER) was observed by transmission electron microscopy. The expression of CHOP, BIP, the phosphorylation of PERK, LC3-II/I, Beclin-1, and p62 were determined by Western blot assay. The co-localization of endoplasmic reticulum marker (KDEL) and autophagic protein (LC3B) was analyzed by immunofluorescence microscopy. The level of reticulophagy hallmark (FAM134B) was determined by immunohistochemistry. Compared with HFD + LT group, berberine ameliorated hepatocellular damage, decreased the oxidative stress level and inflammatory cytokine release. Simultaneously, berberine inhibited the expression of both endoplasmic reticulum stress parameters and autophagy-related proteins. Additionally, the co-localization of endoplasmic reticulum marker and LC3B was also reduced in HFD + BBR + LT group. berberine down-regulated the level of FAM134B. TG reversed the beneficial effects of berberine. Our study revealed that berberine exerts protective effects on steatotic livers undergoing transplantation by inhibiting endoplasmic reticulum stress-mediated reticulophagy. Impact statement Berberine is isolated from traditional Chinese medicine plants and has dramatically therapeutic potential against inflammation, diarrhea, and diabetes. But the benefits of BBR on steatotic grafts after liver transplantation remain poorly understood. Our findings might help explain the mechanism of berberine in protecting steatotic livers undergoing transplantation and give advantageous insights that berberine has potential as a suitable candidate for preventing hepatic injury after steatotic liver transplantation by inhibiting ER stress-mediated reticulophagy.
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