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Peng S, Zhao Y, Jiang W, Long Y, Hu T, Li M, Hu J, Shen Y. MAPK signaling mediated intestinal inflammation induced by endoplasmic reticulum stress and NOD2. Mol Cell Biochem 2025; 480:3709-3717. [PMID: 39806198 DOI: 10.1007/s11010-025-05212-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Accepted: 01/06/2025] [Indexed: 01/16/2025]
Abstract
Endoplasmic reticulum (ER) stress is crucially involved in inflammatory bowel disease (IBD), but the mechanisms remain incompletely understood. This study aimed to elucidate how ER stress promotes inflammation in IBD. ER stress marker Grp78 and NOD2 in colon tissues of Crohn's disease (CD) patients and IBD model mice were detected by immunohistochemical analysis. THP-1 cells were exposed to ER stress and the expression of NOD2 and inflammatory cytokines was detected by PCR. We found that ER stress markers Grp78 and NOD2 were upregulated in intestinal tissues of CD patients and in THP-1 cells exposed to ER stress. ER stress inhibitor reduced Grp78 and NOD2 expression in colitis model mice and alleviated colitis. ER stress inducer cooperated with NOD2 ligand MDP to upregulate TNF-α, IL-8 and IL-1β, and activate MAPK signaling in THP-1 cells. Moreover, inhibitors of MAPK signaling led to the downregulation of IL-1β, IL-8 and TNF-α in THP-1 cells stimulated by ER stress inducer and MDP. In conclusion, ER stress upregulates NOD2 and promotes inflammation in IBD, at least partially due to the activation of MAPK pathway.
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Affiliation(s)
- Siyuan Peng
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, No.161 Shaoshan Nanlu, Changsha, Hunan, China
| | - Yan Zhao
- Department of Pathology, Changsha Central Hospital Affiliated to University of South China, No.161 Shaoshan Nanlu, Changsha, Hunan, China
| | - Wang Jiang
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, No.161 Shaoshan Nanlu, Changsha, Hunan, China
| | - Yan Long
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, No.161 Shaoshan Nanlu, Changsha, Hunan, China
| | - Tian Hu
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, No.161 Shaoshan Nanlu, Changsha, Hunan, China
| | - Mengling Li
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, No.161 Shaoshan Nanlu, Changsha, Hunan, China
| | - Jinyue Hu
- Medical Research Center, Changsha Central Hospital Affiliated to University of South China, No.161 Shaoshan Nanlu, Changsha, Hunan, China
| | - Yueming Shen
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, No.161 Shaoshan Nanlu, Changsha, Hunan, China.
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Moura FA, Siqueira AIDAN. Gut-liver axis in sepsis-associated liver injury: Epidemiology, challenges and clinical practice. World J Gastroenterol 2025; 31:99987. [PMID: 39777244 PMCID: PMC11684188 DOI: 10.3748/wjg.v31.i1.99987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 10/15/2024] [Accepted: 11/13/2024] [Indexed: 12/09/2024] Open
Abstract
Although the liver has a remarkable regenerative capacity, sepsis-associated liver injury (SLI) is a complication often seen in intensive care units. Due to its role in immune and inflammatory regulation, the liver is particularly vulnerable during severe infections. Understanding the global prevalence, causes, and management of SLI is essential to improve outcomes and reduce healthcare costs. This paper aims to explore these factors, with an emphasis on identifying effective strategies for clinical management. Zhang et al's bibliometric analysis of 787 publications (745 original articles and 42 reviews, mostly in animal models) from 2000 to 2023 highlights the growing interest in SLI, focusing on oxidative stress, gut microbiota, and inflammatory processes. Key components such as nuclear factor-kappa B and the NOD-like receptor thermal protein domain associated protein 3 inflammasome pathway, along with their links to gut microbiota imbalance and oxidative stress, are crucial for understanding SLI pathogenesis. The gut-liver axis, particularly the role of intestinal permeability and bacterial translocation in liver inflammation, is emphasized. In this context, bacterial translocation is especially relevant for critically ill patients, as it can exacerbate liver inflammation. The findings underscore the need for integrated care in intensive care units, prioritizing gut health and careful antibiotic use to prevent dysbiosis. Despite extensive research, there remains a lack of clinical trials to validate therapeutic approaches. The abundance of experimental studies highlights potential therapeutic targets, stressing the need for high-quality randomized clinical trials to translate these findings into clinical practice.
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Affiliation(s)
- Fabiana Andréa Moura
- College of Nutrition, Federal University of Alagoas, Maceio 57072-970, Alagoas, Brazil
- College of Medicine, Federal University of Alagoas, Maceio 57072-970, Alagoas, Brazil
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Li M, Zhao Y, Zhang J, Jiang W, Peng S, Hu J, Shen Y. Deubiquitinase USP14 is upregulated in Crohn's disease and inhibits the NOD2 pathway mediated inflammatory response in vitro. Eur J Histochem 2024; 68:4101. [PMID: 39252535 PMCID: PMC11445697 DOI: 10.4081/ejh.2024.4101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 08/16/2024] [Indexed: 09/11/2024] Open
Abstract
The nucleotide binding oligomerization domain containing 2 (NOD2) protein and its ligand N-acetyl muramyl dipeptide (MDP) are crucially involved in Crohn's disease (CD). However, the mechanism by which NOD2 signaling is regulated in CD patients remains unclear. Ubiquitin specific protease (USP14) is a deubiquitylase that plays an important role in immunity. This study aimed to investigate the mechanism by which UPS14 regulates NOD2 induced inflammatory response in CD and inflammatory bowel diseases (IBD). Our results showed that USP14 protein and mRNA levels in intestinal tissues of CD patients were significantly higher than those in healthy controls. In addition, USP14 was upregulated in IBD mouse model. While treatment with MDP, TNF-α or the Toll-like receptor 1/2 agonist Pam3CSK4 all led to significantly higher mRNA levels of TNF-α, IL-8 and IL-1β in THP-1 cells, pretreatment with USP14 inhibitor IU1 could stimulate further upregulation of TNF-α, IL-8 and IL-1β. In particular, MDP promoted the activation of JNK, ERK1/2 and p38 as well as NF-kB in THP-1 cells, and IU1 significantly enhanced the MDP-induced activation of these proteins without effects on USP14 protein level. Furthermore, the JNK inhibitor sp600125, ERK1/2 inhibitor U0126 or P38 MAPK inhibitor PD169316 significantly decreased the mRNA levels of TNF-α, IL-8 and IL-1β in THP-1 cells stimulated by both IU1 and MDP. In conclusion, our findings suggest that USP14 could inhibit MDP-induced activation of MAPK signaling and the inflammation response involved in IBD, and that USP14 is a potential therapeutic target for IBD.
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Affiliation(s)
- Mengling Li
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, Changsha, Hunan.
| | - Yan Zhao
- Department of Pathology, Changsha Central Hospital Affiliated to University of South China, Changsha, Hunan.
| | - Jiayi Zhang
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, Changsha, Hunan.
| | - Wang Jiang
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, Changsha, Hunan.
| | - Siyuan Peng
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, Changsha, Hunan.
| | - Jinyue Hu
- Medical Research Center, Changsha Central Hospital Affiliated to University of South China, Changsha, Hunan.
| | - Yueming Shen
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, Changsha, Hunan.
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Martins ASDP, de Araújo ORP, Gomes ADS, Araujo FLC, Oliveira Junior J, de Vasconcelos JKG, Rodrigues Junior JI, Cerqueira IT, Lins Neto MÁDF, Bueno NB, Goulart MOF, Moura FA. Effect of Curcumin Plus Piperine on Redox Imbalance, Fecal Calprotectin and Cytokine Levels in Inflammatory Bowel Disease Patients: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Pharmaceuticals (Basel) 2024; 17:849. [PMID: 39065700 PMCID: PMC11279814 DOI: 10.3390/ph17070849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 06/11/2024] [Accepted: 06/24/2024] [Indexed: 07/28/2024] Open
Abstract
The development and course of inflammatory bowel disease (IBD) are significantly influenced by inflammation and oxidative stress. Antioxidant therapy is a promising therapeutic option to enhance the clinical results of these individuals in this particular scenario. The purpose of this study is to assess the impact of curcumin, with or without piperine, on cytokines, fecal calprotectin (CalF), and oxidative stress enzymatic and non-enzymatic indicators in patients with IBD. METHODS Patients with Crohn's disease (CD) or ulcerative colitis (UC) who were at least 18 years old and had intact liver and kidney function participated in this randomized, double-blind trial (trial registration: ensaiosclinicos.gov.br as RBR-89q4ydz). For 12 weeks, participants were randomly assigned to one of three groups: placebo, curcumin (1000 mg/day), or curcumin plus piperine (1000 mg + 10 mg/day). In order to examine oxidative stress indicators, CalF, and pro-inflammatory cytokines, blood and fecal samples were obtained, both prior to and following the intervention time. RESULTS After adjusting for age, sex, and type of IBD, the curcumin plus piperine group had substantially higher serum levels of superoxide dismutase (SOD) than the placebo group (4346.9 ± 879.0 vs. 3614.5 ± 731.5; p = 0.041). There were no discernible variations between the groups in CalF, inflammatory markers, or other indicators of oxidative stress. CONCLUSIONS In patients with inflammatory bowel disease (IBD), our study indicates that a 12-week curcumin plus piperine treatment effectively increases enzymatic antioxidant defense, especially SOD. These results demonstrate the potential therapeutic benefits of managing redox imbalance in individuals with IBD.
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Affiliation(s)
- Amylly Sanuelly da Paz Martins
- Pós-Graduação da Rede Nordeste de Biotecnologia (RENORBIO), Universidade Federal de Alagoas (UFAL), Maceió 57072-970, AL, Brazil;
| | - Orlando Roberto Pimentel de Araújo
- Instituto de Química e Biotecnologia (IQB/UFAL), Universidade Federal de Alagoas (UFAL), Maceió 57072-970, AL, Brazil; (O.R.P.d.A.); (I.T.C.)
| | - Amanda da Silva Gomes
- Pós-Graduação em Nutrição (PPGNUT), Universidade Federal de Alagoas (UFAL), Maceió 57072-970, AL, Brazil; (A.d.S.G.); (J.I.R.J.); (N.B.B.)
| | - Fernanda Lívia Cavalcante Araujo
- Faculdade de Nutrição (FANUT), Universidade Federal de Alagoas (UFAL), Maceió 57072-970, AL, Brazil; (F.L.C.A.); (J.O.J.); (J.K.G.d.V.)
| | - José Oliveira Junior
- Faculdade de Nutrição (FANUT), Universidade Federal de Alagoas (UFAL), Maceió 57072-970, AL, Brazil; (F.L.C.A.); (J.O.J.); (J.K.G.d.V.)
| | - Joice Kelly Gomes de Vasconcelos
- Faculdade de Nutrição (FANUT), Universidade Federal de Alagoas (UFAL), Maceió 57072-970, AL, Brazil; (F.L.C.A.); (J.O.J.); (J.K.G.d.V.)
| | - José Israel Rodrigues Junior
- Pós-Graduação em Nutrição (PPGNUT), Universidade Federal de Alagoas (UFAL), Maceió 57072-970, AL, Brazil; (A.d.S.G.); (J.I.R.J.); (N.B.B.)
| | - Islany Thaissa Cerqueira
- Instituto de Química e Biotecnologia (IQB/UFAL), Universidade Federal de Alagoas (UFAL), Maceió 57072-970, AL, Brazil; (O.R.P.d.A.); (I.T.C.)
| | | | - Nassib Bezerra Bueno
- Pós-Graduação em Nutrição (PPGNUT), Universidade Federal de Alagoas (UFAL), Maceió 57072-970, AL, Brazil; (A.d.S.G.); (J.I.R.J.); (N.B.B.)
| | - Marília Oliveira Fonseca Goulart
- Pós-Graduação da Rede Nordeste de Biotecnologia (RENORBIO), Universidade Federal de Alagoas (UFAL), Maceió 57072-970, AL, Brazil;
- Instituto de Química e Biotecnologia (IQB/UFAL), Universidade Federal de Alagoas (UFAL), Maceió 57072-970, AL, Brazil; (O.R.P.d.A.); (I.T.C.)
- Programa de Pós-Graduação em Química e Biotecnologia (PPGQB), Universidade Federal de Alagoas (UFAL), Maceió 57072-970, AL, Brazil
- Pós-Graduação em Ciências da Saúde (PPGCS), Universidade Federal de Alagoas (UFAL), Maceió 57072-970, AL, Brazil
| | - Fabiana Andréa Moura
- Pós-Graduação em Nutrição (PPGNUT), Universidade Federal de Alagoas (UFAL), Maceió 57072-970, AL, Brazil; (A.d.S.G.); (J.I.R.J.); (N.B.B.)
- Faculdade de Nutrição (FANUT), Universidade Federal de Alagoas (UFAL), Maceió 57072-970, AL, Brazil; (F.L.C.A.); (J.O.J.); (J.K.G.d.V.)
- Pós-Graduação em Ciências Médicas (PPGCM), Universidade Federal de Alagoas (UFAL), Maceió 57072-970, AL, Brazil;
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da Paz Martins AS, de Andrade KQ, de Araújo ORP, da Conceição GCM, da Silva Gomes A, Goulart MOF, Moura FA. Extraintestinal Manifestations in Induced Colitis: Controversial Effects of N-Acetylcysteine on Colon, Liver, and Kidney. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2023; 2023:8811463. [PMID: 37577725 PMCID: PMC10423092 DOI: 10.1155/2023/8811463] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 06/18/2023] [Accepted: 07/10/2023] [Indexed: 08/15/2023]
Abstract
Ulcerative colitis (UC) is a chronic and recurrent inflammatory bowel disease (IBD) characterized by continuous inflammation in the colonic mucosa. Extraintestinal manifestations (EIM) occur due to the disruption of the intestinal barrier and increased permeability caused by redox imbalance, dysbiosis, and inflammation originating from the intestine and contribute to morbidity and mortality. The aim of this study is to investigate the effects of oral N-acetylcysteine (NAC) on colonic, hepatic, and renal tissues in mice with colitis induced by dextran sulfate sodium (DSS). Male Swiss mice received NAC (150 mg/kg/day) in the drinking water for 30 days before and during (DSS 5% v/v; for 7 days) colitis induction. On the 38th day, colon, liver, and kidney were collected and adequately prepared for the analysis of oxidative stress (superoxide dismutase (SOD), catalase (CAT), glutathione reduced (GSH), glutathione oxidized (GSSG), malondialdehyde (MDA), and hydrogen peroxide (H2O2)) and inflammatory biomarkers (myeloperoxidase (MPO) -, tumor necrosis factor alpha - (TNF-α, and interleukin-10 (IL-10)). In colon, NAC protected the histological architecture. However, NAC did not level up SOD, in contrast, it increased MDA and pro-inflammatory effect (increased of TNF-α and decreased of IL-10). In liver, colitis caused both oxidative (MDA, SOD, and GSH) and inflammatory damage (IL-10). NAC was able only to increase GSH and GSH/GSSG ratio. Kidney was not affected by colitis; however, NAC despite increasing CAT, GSH, and GSH/GSSG ratio promoted lipid peroxidation (increased MDA) and pro-inflammatory action (decreased IL-10). Despite some beneficial antioxidant effects of NAC, the negative outcomes concerning irreversible oxidative and inflammatory damage in the colon, liver, and kidney confirm the nonsafety of the prophylactic use of this antioxidant in models of induced colitis, suggesting that additional studies are needed, and its use in humans not yet recommended for the therapeutic routine of this disease.
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Affiliation(s)
- Amylly Sanuelly da Paz Martins
- Doctoral Program of the Northeast Biotechnology Network, Federal University of Alagoas, Maceió 57072-970, Alagoas, Brazil
| | | | | | | | - Amanda da Silva Gomes
- College of Nutrition, Federal University of Alagoas, Maceió 57072-970, Alagoas, Brazil
| | - Marília Oliveira Fonseca Goulart
- Doctoral Program of the Northeast Biotechnology Network, Federal University of Alagoas, Maceió 57072-970, Alagoas, Brazil
- Institute of Chemistry and Biotechnology, Federal University of Alagoas, Maceió 57072-970, Alagoas, Brazil
- Institute of Biological and Health Sciences, Federal University of Alagoas, Maceió 57072-970, Alagoas, Brazil
| | - Fabiana Andréa Moura
- College of Nutrition, Federal University of Alagoas, Maceió 57072-970, Alagoas, Brazil
- College of Medicine, Federal University of Alagoas, Maceió 57072-970, Alagoas, Brazil
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Li L, Wang Y, Zhao L, Ye G, Shi F, Li Y, Zou Y, Song X, Zhao X, Yin Z, Wu X, Li W, Tang H. Sanhuang xiexin decoction ameliorates secondary liver injury in DSS-induced colitis involve regulating inflammation and bile acid metabolism. JOURNAL OF ETHNOPHARMACOLOGY 2022; 299:115682. [PMID: 36058478 DOI: 10.1016/j.jep.2022.115682] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/23/2022] [Accepted: 08/26/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE SanHuang XieXin decoction (SXD) is a widely applicated traditional Chinese medicine (TCM) with a significant gut-liver axis regulation effect. AIM OF THE STUDY To evaluate the therapeutic effect and elucidate the possible underlying molecular mechanisms of SXD on liver damage secondary to ulcerative colitis (UC) in mice. MATERIALS AND METHODS A model of liver damage secondary to UC was induced by drinking 5% dextran sodium sulfate (DSS) in mice. These mice were treated with one of three doses of SXD or sulfasalazine (SASP), then liver samples were collected and tested. RESULTS The results reveal that SXD treatment reduced liver cells swelling, and inhibited the accumulation of the hepatic-pro-inflammatory cytokines IL-1β and tumor necrosis factor-α (TNF-α) in mice with colitis. In addition, SXD reduced the production of nitric oxide (NO) and malondialdehyde (MDA), and increased the activities of superoxide dismutase (SOD). In inflammation regulating, SXD significantly down regulated the protein expression of MyD88 and p-Iκα, but upregulated Iκα. In bile acid metabolism regulating, SXD significantly down regulated the protein expression of FXR, MRP2, BESP and SHP. Therefore, SXD treatment can regulate the TLR4-NF-κB and bile acid metabolism pathways to alleviate liver inflammation and cholestasis. CONCLUSIONS These results demonstrate that SXD is a potential alternative therapeutic medicine for the treatment of liver damage secondary to colitis.
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Affiliation(s)
- Lixia Li
- Department of Pharmacy, Sichuan Agricultural University, Chengdu, 611130, China
| | - Yingjie Wang
- Department of Pharmacy, Sichuan Agricultural University, Chengdu, 611130, China
| | - Ling Zhao
- Department of Pharmacy, Sichuan Agricultural University, Chengdu, 611130, China
| | - Gang Ye
- Department of Pharmacy, Sichuan Agricultural University, Chengdu, 611130, China
| | - Fei Shi
- Department of Pharmacy, Sichuan Agricultural University, Chengdu, 611130, China
| | - Yinglun Li
- Department of Pharmacy, Sichuan Agricultural University, Chengdu, 611130, China
| | - Yuanfeng Zou
- Department of Pharmacy, Sichuan Agricultural University, Chengdu, 611130, China
| | - Xu Song
- Department of Pharmacy, Sichuan Agricultural University, Chengdu, 611130, China
| | - Xinghong Zhao
- Department of Pharmacy, Sichuan Agricultural University, Chengdu, 611130, China
| | - Zhongqiong Yin
- Department of Pharmacy, Sichuan Agricultural University, Chengdu, 611130, China
| | - Xueyuan Wu
- Chengdu Agricultural College, Chengdu, 611130, China
| | - Wen Li
- Pharmacy College, Chengdu University of Traditional Chinese Medicine, State Key Laboratory of Characteristic Chinese Drug Resources in Southwest China, Chengdu, 611137, China
| | - Huaqiao Tang
- Department of Pharmacy, Sichuan Agricultural University, Chengdu, 611130, China.
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Long Y, Zhao Y, Ma X, Zeng Y, Hu T, Wu W, Deng C, Hu J, Shen Y. Endoplasmic reticulum stress contributed to inflammatory bowel disease by activating p38 MAPK pathway. Eur J Histochem 2022; 66. [PMID: 35603939 PMCID: PMC9178311 DOI: 10.4081/ejh.2022.3415] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 05/16/2022] [Indexed: 11/26/2022] Open
Abstract
Recent evidence suggests that endoplasmic reticulum (ER) stress plays a vital role in inflammatory bowel disease (IBD). Therefore, the aim of this study was to investigate the mechanism by which ER stress promotes inflammatory response in IBD. The expression of Gro-α, IL-8 and ER stress indicator Grp78 in colon tissues from patients with Crohn’s disease (CD) and colonic carcinoma was analyzed by immunohistochemistry staining. Colitis mouse model was established by the induction of trinitrobenzene sulphonic acid (TNBS), and the mice were treated with ER stress inhibitor tauroursodeoxycholic acid (TUDCA). Then the body weight, colon length and colon inflammation were evaluated, and Grp78 and Gro-α in colon tissues were detected by immunohistochemistry. Epithelial cells of colon cancer HCT116 cells were treated with tunicamycin to induce ER stress. Grp78 was detected by Western blot, and chemokines were measured by PCR and ELISA. The expression levels of Grp78, Gro-α and IL-8 were significantly upregulated in intestinal tissues of CD patients. Mice with TNBS induced colitis had increased expression of Grp78 and Gro-α in colonic epithelia. TUDCA reduced the severity of TNBS-induced colitis. In HCT116 cells, tunicamycin increased the expression of Grp78, Gro-α and IL-8 in a concentration-dependent manner. Furthermore, p38 MAPK inhibitor significantly inhibited the upregulation of Gro-α and IL-8 induced by tunicamycin. In conclusion, ER stress promotes inflammatory response in IBD, and the effects may be mediated by the activation of p38 MAPK signaling pathway.
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Affiliation(s)
- Yan Long
- Department of Digestive Diseases, Changsha Central Hospital, Changsha.
| | - Yan Zhao
- Department of Pathology, Changsha Central Hospital, Changsha.
| | - Xiaoqing Ma
- Zhongshan City People Hospital, Zhongshan, Guangdong.
| | - Ya Zeng
- Department of Digestive Diseases, Changsha Central Hospital, Changsha.
| | - Tian Hu
- Department of Digestive Diseases, Changsha Central Hospital, Changsha.
| | - Weijie Wu
- Department of Digestive Diseases, Changsha Central Hospital, Changsha.
| | - Chongtian Deng
- Department of Digestive Diseases, Changsha Central Hospital, Changsha.
| | - Jinyue Hu
- Central Laboratory, Changsha Central Hospital, Changsha.
| | - Yueming Shen
- Department of Digestive Diseases, Changsha Central Hospital, Changsha.
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TLR4 promoted endoplasmic reticulum stress induced inflammatory bowel disease via the activation of p38 MAPK pathway. Biosci Rep 2022; 42:231095. [PMID: 35352794 PMCID: PMC9069439 DOI: 10.1042/bsr20220307] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 03/27/2022] [Accepted: 03/29/2022] [Indexed: 11/17/2022] Open
Abstract
Endoplasmic reticulum (ER) stress contribute to inflammatory bowel disease (IBD). However, the mechanistic link between toll-like receptor 4 (TLR4) and ER stress in IBD remains elusive. This study aimed to investigate the mechanism by which ER stress and TLR4 promote inflammation in IBD. IBD mouse model was established by the induction of TNBS, and Grp78 and TLR4 in intestine tissues were detected by immunohistochemistry. THP-1 cells were treated with lipopolysaccharides (LPS), ER stress inducer or inhibitor tauroursodeoxycholic acid (TUDCA), or p38 MAPK inhibitor. The activation of MAPK signaling was detected by Western blot, and the production and secretion of inflammatory factors were detected by PCR and ELISA. We found that the expression levels of TLR4 and GRP78 were significantly higher in the intestine of IBD model mice compared with control mice but were significantly lower in the intestine of IBD model mice treated with ER stress inhibitor TUDCA. ER stress inducer significantly increased while ER stress inhibitor TUDCA significantly decreased the expression and secretion of TNF-α, IL-1β and IL-8 in THP-1 cells treated by LPS. Only p38 MAPK signaling was activated in THP-1 cells treated by ER stress inducer. Furthermore, p38 inhibitor SB203580 inhibited the production and secretion of TNF-α, IL-1β and IL-8 in THP-1 cells treated with LPS. In conclusion, TLR4 promotes ER stress induced inflammation in IBD, and the effects may be mediated by p38 MAPK signaling. TLR4 and p38 MAPK signaling are novel therapeutic targets for IBD.
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