Rictor/Mammalian Target of Rapamycin Complex 2 Signaling Protects Colonocytes from Apoptosis and Prevents Epithelial Barrier Breakdown

Castro-Martínez, Felipe; Candelario-Martínez, Aurora; Encarnación-García, María Del Rocío; Piedra-Quintero, Zayda L.; Bonilla-Moreno, Raul; Betanzos, Abigail; Perez-Orozco, Rocio; Hernández-Cueto, María de Los Ángeles; Patiño-López, Genaro; Schnoor, Michael; Villegas‐Sepúlveda, Nicolás; Nava, Porfirio

doi:10.1016/j.ajpath.2021.06.004

Cited by 10 publications

(4 citation statements)

References 42 publications

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“…Moreover, apoptosis analysis and Western blotting results found that DSS exposure increased the expression of ACaps-3 in colonic tissues ( Figures 5E–G ). It indicates that DSS could induce apoptosis of colonic epithelial cells and enhance leaky epithelium ( Castro-Martinez et al, 2021 ). However, HO treatment significantly decreased ACaps-3 levels compared to the DSS group ( p < 0.0001), and was obviously inhibited by NH administration ( p < 0.0001).…”

Section: Resultsmentioning

confidence: 99%

Central administration of human opiorphin alleviates dextran sodium sulfate-induced colitis in mice through activation of the endogenous opioid system

Luo

Gao

et al. 2022

Front. Pharmacol.

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The opioid system plays a crucial role in maintaining gastrointestinal homeostasis. Endogenous opioid peptide enkephalins have anti-inflammatory effect and participate in the treatment of inflammatory bowel diseases (IBDs). Here, we investigated the effect of natural enkephalinase inhibitor human opiorphin (HO) on dextran sodium sulfate (DSS)-induced colitis in mice. Our results showed that central administration of HO attenuated DSS-induced colitis, as indicated by the reduction of disease activity index (DAI) scores, macroscopic scores, histological scores, and the myeloperoxidase (MPO) activity. Moreover, HO alleviated DSS-induced inflammation by decreasing inflammatory cytokines TNF-α, IL-6, and IL-1β, and increasing anti-inflammatory cytokine IL-10 in both serum and colon tissues in DSS-treated mice. The potential anti-inflammatory effect of HO at a dose of 40 μg/kg was observed as evidenced by a decrease in nuclear factor κB (NF-κB) p65, toll-like receptor-4 (TLR-4), iNOS, and COX-2. HO also improved intestinal barrier function by enhancing the expression of tight junction proteins. Furthermore, HO treatment significantly inhibited activities of neutral endopeptidase (NEP) and aminopeptidase N (APN), elevated serum enkephalins concentrations, and increased expressions of mu and delta opioid receptors. In addition, pretreatment with opioid receptor antagonist naloxone hydrochloride (NH) compromised the protective effect of HO and aggravated colitis symptoms, as indicated by inhibited anti-inflammatory effects, disrupted intestinal barrier function, and decreased opioid receptor activity. In conclusion, these data indicate that HO protects against DSS-induced colitis by inhibiting TLR4/NF-κB pathway activation and improving intestinal barrier function through activation of the endogenous opioid system. Therefore, targeting the opioid system with peptidase inhibitors intervention would be a novel strategy in the therapy of IBD.

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Section: Resultsmentioning

confidence: 99%

Central administration of human opiorphin alleviates dextran sodium sulfate-induced colitis in mice through activation of the endogenous opioid system

Luo

Gao

et al. 2022

Front. Pharmacol.

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“…Interestingly, the work by Kuo et al (2019 ) identified that low-dose of TNF could inhibit the activity and transcription of caspase-3, leading to generalized apoptotic resistance, which might be the adaptive mechanism of enhancing epithelial survival in an inflammatory environment. However, most of the literatures reported that inflammatory cytokines partly increase the caspase-3 activity during acute injury and promote intestinal epithelial cell apoptosis by inhibiting anti-apoptotic signals such as mTORC2/AKT in the epithelial cells destroying the mucosal epithelial barrier ( Arab et al, 2021 ; Castro-Martinez et al, 2021 ; Pochard et al, 2021 ). These studies suggest that the crosstalk between apoptosis and intestinal barrier in intestinal epithelial cells depends on the degree of inflammation.…”

Section: Discussionmentioning

confidence: 99%

Shenling Baizhu Powder Alleviates TNBS-Induced Colitis in Rats by Improving Intestinal Epithelial Permeability and Inhibiting Inflammation Through the TLR5/MyD88/NF-κB Pathway

et al. 2022

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Aim of the study: To evaluate the protective effect and mechanism of shenling baizhu powder (SBP) on TNBS-induced colitis.Methods: Rats were given TNBS to establish the model of colitis and subsequently treated with different doses of SBP or mesalamine (MES). In addition, the expression of the TLR5/MyD88/NF-κB signaling pathway and critical targets of the intestinal mucosal barrier was detected by immunochemical analysis techniques.Results: SBP significantly ameliorated the symptoms of TNBS-induced colitis in rats and reduced the secretion of pro-inflammatory cytokines. SBP could effectively strengthen epithelial barrier integrity in TNBS-induced colitis by increasing the secretion of mucin and tight junction and inhibiting apoptosis. Furthermore, we identified the crucial role of the TLR5/MyD88/NF-κB signaling pathway in exerting the therapeutic effect of SBP.Conclusion: The results of our study suggest that SBP has therapeutic effects on TNBS-induced colitis and potential value in treating and maintaining remission of colitis.

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“…Intestinal epithelial barrier dysfunction is the characteristic index of the intestinal pathological process [8]. The intestinal barrier is formed by the intestinal epithelial cells (IECs) network [9].…”

Section: Introductionmentioning

confidence: 99%

PLK1‐activating IFI16–STING–TBK1 pathway induces apoptosis of intestinal epithelial cells in patients with intestinal Behçet's syndrome

Bao,

She,

Hou

et al. 2024

The FEBS Journal

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Inflammatory signals from immunological cells may cause damage to intestinal epithelial cells (IECs), resulting in intestinal inflammation and tissue impairment. Interferon‐γ‐inducible protein 16 (IFI16) was reported to be involved in the pathogenesis of Behçet's syndrome (BS). This study aimed to investigate how inflammatory cytokines released by immunological cells and IFI16 participate in the pathogenesis of intestinal BS. RNA sequencing and real‐time quantitative PCR (qPCR) showed that the positive regulation of tumor necrosis factor‐α (TNF‐α) production in peripheral blood mononuclear cells (PBMCs) of intestinal BS patients may be related to the upregulation of polo like kinase 1 (PLK1) in PBMCs (P = 0.012). The plasma TNF‐α protein level in intestinal BS was significantly higher than in healthy controls (HCs; P = 0.009). PBMCs of intestinal BS patients and HCs were co‐cultured with human normal IECs (NCM460) to explore the interaction between immunological cells and IECs. Using IFI16 knockdown, PBMC‐NCM460 co‐culture, TNF‐α neutralizing monoclonal antibody (mAb), stimulator of interferon genes (STING) agonist 2′3′‐cGAMP, and the PLK1 inhibitor SBE 13 HCL, we found that PLK1 promotes the secretion of TNF‐α from PBMCs of intestinal BS patients, which causes overexpression of IFI16 and induces apoptosis of IECs via the STING–TBK1 pathway. The expressions of IFI16, TNF‐α, cleaved caspase 3, phosphorylated STING (pSTING) and phosphorylated tank binding kinase 1 (pTBK1) in the intestinal ulcer tissue of BS patients were significantly higher than that of HCs (all P < 0.05). PLK1 in PBMCs of intestinal BS patients increased TNF‐α secretion, inducing IEC apoptosis via activation of the IFI16–STING–TBK1 pathway. PLK1 and the IFI16–STING–TBK1 pathway may be new therapeutic targets for intestinal BS.

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Rictor/Mammalian Target of Rapamycin Complex 2 Signaling Protects Colonocytes from Apoptosis and Prevents Epithelial Barrier Breakdown

Cited by 10 publications

References 42 publications

Central administration of human opiorphin alleviates dextran sodium sulfate-induced colitis in mice through activation of the endogenous opioid system

Central administration of human opiorphin alleviates dextran sodium sulfate-induced colitis in mice through activation of the endogenous opioid system

Shenling Baizhu Powder Alleviates TNBS-Induced Colitis in Rats by Improving Intestinal Epithelial Permeability and Inhibiting Inflammation Through the TLR5/MyD88/NF-κB Pathway

PLK1‐activating IFI16–STING–TBK1 pathway induces apoptosis of intestinal epithelial cells in patients with intestinal Behçet's syndrome

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