修回日期: 2015-10-29
接受日期: 2015-11-03
在线出版日期: 2015-12-08
内质网应激(endoplasmic reticulum stress, ERS)是研究溃疡性结肠炎(ulcerative colitis, UC)发病机制的主要热点, 通过启动未折叠蛋白反应(unfolded protein response, UPR)来保护和修复肠道黏膜上皮细胞的损伤. 内质网应激主要通过三种信号通路来介导炎性因子的分泌, 其中蛋白激酶R样内质网激酶(protein kinase R-like ER kinase, PERK)通路与UC发病关系最为密切. 肠道黏膜上皮细胞(intestinal mucosa epithelial cells, IEC)具有发达的内质网结构, 是代谢最为旺盛的细胞群之一. 持续严重的ERS促使细胞损伤、死亡, 导致肠黏膜上皮细胞激活核因子-κB(nuclear factor-κB, NF-κB), 引起多种炎性因子的分泌, 促进炎症病变的发生. 中药治疗UC疗效显著, 有其独特优势, 可通过信号通路抑制NF-κB炎性因子分泌, 保护肠道屏障功能.
核心提示: 内质网应激(endoplasmic reticulum stress, ERS)是溃疡性结肠炎(ulcerative colitis, UC)发病的主要原因, 深入研究ERS和肠道黏膜上皮细胞炎性因子之间的作用机制已经成为关注的热点, 对于探讨UC发病有着重要意义.
引文著录: 郑烈, 戴彦成, 张亚利, 陈璇, 方晨晔, 唐志鹏. 内质网应激信号分子PERK在溃疡性结肠炎肠黏膜损伤中的研究进展. 世界华人消化杂志 2015; 23(34): 5493-5498
Revised: October 29, 2015
Accepted: November 3, 2015
Published online: December 8, 2015
Endoplasmic reticulum stress (ERS) is the main focus in the study of the pathogenesis of ulcerative colitis, and it protects and repairs the intestinal epithelial cell (IEC) injury through unfolded protein response (UPR). Protein kinase R-like ER kinase (PERK) is an endoplasmic reticulum-localized type I transmembrane protein, with serine/threonine protein kinase activity. IECs are one of cell populations with the most vigorous metabolism and have abundant endoplasmic reticulum. Early ERS can activate PERK-eIF2 alpha channel and inhibit the synthesis of proteins to protect cells. However, sustained severe ERS promotes cell damage and death, activates nuclear factor-kappa B in IECs, causes the secretion of a variety of inflammatory cytokines, and promotes the occurrence of inflammatory lesions.
- Citation: Zheng L, Dai YC, Zhang YL, Chen X, Fang CY, Tang ZP. Role of endoplasmic reticulum stress signaling molecule PERK in bowel mucosal injury in ulcerative colitis. Shijie Huaren Xiaohua Zazhi 2015; 23(34): 5493-5498
- URL: https://www.wjgnet.com/1009-3079/full/v23/i34/5493.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v23.i34.5493
溃疡性结肠炎(ulcerative colitis, UC)是一种慢性黏膜炎症、组织破坏的非特异性肠道炎性疾病, 发病的根本原因和复发因素尚未完全明确, 主要是由环境因素、免疫因素、微生物因素和遗传因素等多种因素相互作用所致[1]. 近年来, UC在我国的患病率约为11.62/100万[2,3], 有明显增高趋势. 作为细胞内最大的膜网络结构-内质网(endoplasmic reticulum, ER), 具有完成蛋白质的合成及新生肽链的折叠、组装和运输的重任. 当肠黏膜上皮细胞内质网稳态受到体内、外因素破坏时, 内质网功能受到影响, 蛋白加工受阻, 出现大量未折叠蛋白或错误折叠蛋白, 发生内质网应激(endoplasmic reticulum stress, ERS). 最近有研究[4]表明, ERS被认为是UC中导致肠道炎症病变的主要原因, 过度ERS可能导致肠黏膜屏障功能受损,继而参与UC发病, 这一机制已经为学者所关注[5,6]. 因此, 深入研究ERS和肠道黏膜上皮细胞炎性因子之间的作用机制已经成为关注的热点, 对于探讨UC发病有着重要意义, 也进一步为临床指导用药奠定重要基础. 本文就关于ERS及其信号分子蛋白激酶相关的内质网激酶(protein kinase-related ER kinase, PERK)导致的核因子-κB(nuclear factor-κB, NF-κB)在肠道黏膜上皮细胞中的促炎作用作一综述.
多项研究[7-9]表明, ERS是由于在蛋白质合成中, 受到病原微生物、营养底物缺乏、脂肪超载、炎性因子、缺血缺氧等应激原严重持续性刺激后出现过多未折叠或错误折叠蛋白, 从而引起多条信号通路反应, 称为未折叠蛋白反应(unfolded protein response, UPR), 其主要通过降解细胞内过多未折叠蛋白或错误折叠蛋白, 恢复细胞内稳态环境. UPR主要通过蛋白激酶R样内质网激酶-活化转录因子4(protein kinase related endoplasmic reticulum kinase- activating transcription factor 4, PERK-ATF4), 活化转录因子6(activating transcription factor 6, ATF6)和肌醇需求酶1α-X盒式链接蛋白-1(inositol requiring kinase 1α- X box binding protein 1, IRE1-XBP1)三种信号通路与其相关的转录因子进行复杂的反应[10-14], 这些网络信号表达了多种基因以恢复细胞稳态. 未发生UPR时, 内质网三种跨膜感受器IRE1、PERK和ATF6都与热休克蛋白A5(heat shock protein A5, HSPA5)链接保持无活性状态. 当发生ERS时, HSPA5从内质网感受器上解离, 与未折叠或错误折叠蛋白结合, 导致内质网激活, 从而诱发以上3种信号通路和UPR目标基因的激活, 其中与UC发病最为关键的是PERK信号通路. 严重持续性ERS可引起应激细胞和局部炎症细胞的细胞凋亡[15].
关于ERS和UPR引起炎症性肠病(inflammatory bowel disease, IBD)发病的结果显示, 克罗恩病和UC活动期患者回肠和结肠上皮细胞均有ERS信号标志[16-19]. ERS是由于错误折叠蛋白或未折叠蛋白过多聚集而被激活的, UPR就是通过增加帮助蛋白折叠, 阻止mRNA翻译, 恢复内质网正常功能. 最关键就是刺激PERK-真核翻译起始因子2a(translational initiation factor 2 in eukaryotes, eIF2a)-ATF4信号通路发生[20,21], 通过激活PERK-eIF2a-ATF4信号通路[22-27], 催化底物eIF2a发生磷酸化, eIF2a磷酸化后一方面抑制蛋白质的翻译和合成, 降低内质网中错误折叠蛋白的积累, 减轻内质网压力; 另一方面选择性的促进ATF-4的翻译, 增加伴侣分子的合成, 上调与氨基酸代谢、蛋白分泌相关的基因表达而促进细胞生存[15].
ATF4是cAMP反应元件结合转录因子家族成员之一, 他的mRNA包含位于5'-非翻译序列的上游开放阅读框架和内部核糖体进入位点. ATF-4还可激活CHOP及GADD34蛋白的表达, GADD34可促进elF2a脱磷酸化, 恢复内质网蛋白合成[28]. 然后P-eIF2a通过一个含有丝氨酸/苏氨酸磷酸酶(PP1)复合物发生去磷酸化, 研究[29]表明PP1复合物能被小分子物质salubrinal抑制, 该物质能选择性阻断P-eIF2a的去磷酸化. Salubrinal已经证明在多种细胞中研究ERS和PERK-eIF2a-ATF4通路关系是有意义的[30,31]. PERK信号通路可通过磷酸化的BAD, 减少未折叠蛋白或错误蛋白的合成, 减轻内质网负担, 维持平衡稳态[32].
近年的研究[33]发现UPR通路既可促进细胞生存又可诱导细胞凋亡, UPR的多条通路与蛋白翻译、过氧化物质产生、Bcl-2蛋白表达、钙离子浓度、microRNA表达及JNK通路等的精确调节有关.
肠道屏障功能障碍被认为是炎症性肠病(inflammatory bowel disease, IBD)的主要病因之一, 肠黏膜损伤具有增加细胞间渗透性的特征[34,35]. 正常情况下, 肠黏膜通过claudin-1和ZO-1蛋白紧密链接来维持肠道屏障功能和完整性. 而肠道黏膜上皮细胞(intestinal mucosa epithelial cells, IEC)代谢最旺盛, 内质网结构和功能最为发达. IEC中分泌黏液蛋白功能最强的是Paneth细胞和杯状(Goblet)细胞, 当UPR功能正常时, 对于维持ER稳态极其重要. 然而过度ERS时, 肠黏膜claudin-1和ZO-1蛋白异常表达, 肠黏黏膜损害, 上皮细胞发生ERS, 肠屏障功能紊乱. Kaser等[36]表明, 肠上皮UPR途径缺陷可引起黏膜屏障损害和IBD. 新的一项研究[16]也支持ERS与肠黏膜屏障破坏的密切关系. 各种原因导致IEC内未折叠蛋白过度产生和蓄积, 易于出现ERS过度而引起炎症, 损伤肠黏膜屏障, 使细胞更新修复能力下降, 肠黏膜结构发生改变, 从而导致UC的发生.
ERS和炎症反应在多种疾病病理过程表现复杂, 如神经退行性病变、呼吸系统、心血管系统、肿瘤、糖尿病和其他代谢性疾病[37,38]. UPR通过PERK、IRE1和ATF6三种途径引起炎症反应, 进而诱导激活NF-κB[20]. 正常情况下, NF-κB通常位于细胞浆中, 与NF-κB抑制蛋白(inhibitor of NF-κB, IκB)蛋白呈无活性形式结合, 从而防止其激活和核移位. 急性或慢性应激通过降解IκB的蛋白酶体导致NF-κB的激活. IRE1a降解IκB引起NF-κB的激活和核移位, 而PERK激活NF-κB通过平移IκB的抑制.
NF-κB是细胞内一种重要的核转录因子, 当肠道黏膜上皮细胞损伤后增加了有毒物质和多种微生物对肠壁的渗透性[39-42], 肠道黏膜上皮细胞受到外界持续刺激后发生ERS, PERK被激活后通过多种下游细胞内信号传导导致NF-κB的激活,然后刺激促炎因子的分泌, 包括白介素-1(interleukin, IL-1)、IL-6、IL-8、环氧化物酶-2(cyclooxygenase-2, COX-2)、诱导的一氧化氮合成酶(induced nitric oxide synthase, iNOS), 促进炎性细胞的聚集[42,43]. Altavilla等[44]研究发现NF-κB是一个快速反应的转录因子, 在炎症反应中通过表达炎症介质、黏附分子和酶等起作用.
ERS时内质网蛋白折叠负荷增加, 通过PERK-eIF2a介导的翻译减缓, 直接促进NF-κB激活. 研究[45]发现钙耦合剂和抗氧化剂有助于ERS时激活NF-κB激活, 由此推测NF-κB激活可能与氧化应激和钙渗漏有关. 在UC患者结肠炎症区域NF-κB活性增加, 多种炎症细胞因子和黏附分子表达上调.
中医药在治疗UC有独特优势, 研究[46]表明, 芍黄安肠汤对UC有较好的疗效, 其作用机制可能是抑制TLR4的表达, 影响MyD88信号通路下游的基因表达, 从而抑制NF-κB的活化, 最终减轻机体炎症反应. 汉黄芩素[47]在体外通过TLR4-MyD88-TAK1介导的NF-κB信号通路来降低IL-1、IL-6、IL-8、COX-2、iNOS等炎性介质来抑制炎症反应和保护肠道屏障功能. 黄芩汤[48]对UC的治疗作用可能是通过抑制NF-κB p65通路活化, 进而下调促炎细胞因子NO、IL-6、TNF-α和PGE2表达实现的. 痛泻要方[49]对TNBS/乙醇法UC大鼠模型结肠黏膜NF-κB p65基因和蛋白的表达量有下调作用, 提示痛泻要方治疗UC的作用机制之一可能是与NF-κB信号通路被激活有关. 芍药汤[50]能明显降低胃肠湿热型UC大鼠模型结肠黏膜NF-κB相对活性, 可能是其治疗UC作用的机制之一.
目前, ERS研究较多的是在2型糖尿病、脂肪肝、神经性病变、各种肿瘤等慢性疾病, 但在IBD方面报道极少, 而且随着分子通路研究的深入, ERS在UC发病机制中成为人们研究的重点. 由于ERS通过多条通路对UC患者表达不同的炎性因子, 而不同的炎性因子可以反作用于ERS的多种信号通路, 也可激活体内获得性免疫促进细胞因子的表达. 因此, ERS已成为探索治疗UC肠道黏膜损伤作用的新机制.
溃疡性结肠炎(ulcerative colitis, UC)是一种慢性黏膜炎症、组织破坏的非特异性炎性疾病, 发病机制较为复杂. 内质网作为细胞内最大的膜网络结构, 当肠黏膜上皮细胞内质网受到体内、外因素破坏时, 内质网功能受到影响, 出现大量未折叠蛋白或错误折叠蛋白, 发生内质网应激(endoplasmic reticulum stress, ERS), 由于ERS通过多条通路对UC患者表达不同的炎性因子, 而不同的炎性因子可以反作用于ERS的多种信号通路, 也可激活体内获得性免疫促进细胞因子的表达. 因此ERS已成为探索治疗UC肠道黏膜损伤作用的新机制.
江学良, 教授, 主任医师, 中国人民解放军济南军区总医院消化科; 王学美, 研究员, 北京大学第一医院中西医结合研究室
正常情况下, 肠黏膜claudin-1和ZO-1蛋白通过紧密链接来维持肠道屏障功能的完整性. 而肠道黏膜上皮细胞(intestinal mucosa epithelial cells, IEC)代谢最旺盛, 内质网结构和功能最为发达. 过度ERS时, claudin-1和ZO-1蛋白异常表达, 肠黏膜损害, 肠屏障功能紊乱. ERS中的PERK通路对UC肠黏膜损害有着决定性作用, 目前尚无文献报道, 已经成为大家所关注的重要问题.
Kaser等表明, 肠上皮UPR途径缺陷可引起黏膜屏障损害和炎症性肠病(inflammatory bowel disease, IBD). 新的一项研究也支持ERS与肠黏膜屏障破坏的密切关系.
目前ERS对UC的发病机制尚无文献报道. 那么, ERS中PERK通路是如何介导核因子-κB(nuclear factor-κB, NF-κB)致炎因子作用于肠道黏膜上皮细胞导致UC发病是 大家研究的主要热点. 同时多项研究表明, 中药具有通过信号通路抑制NF-κB炎性因子的优势, 对大家今后采用中药方治疗UC提供重要依据.
UC的发病机制一直以来都是研究的热点和难点, 如果能从ERS找到突破口, 将为阐明UC的发病机制提供重要依据.
未折叠蛋白反应: 指各种原因引起错误折叠及未折叠蛋白质在内质网中积蓄, 致使ERS蛋白转录增加、其他蛋白翻译减少、蛋白质降解增多的一种反应, 能恢复细胞内稳态环境.
本文就关于ERS及其信号分子PERK导致的NF-κB炎性因子在肠道黏膜上皮细胞中的可能促炎作用作了综述, 并进一步提出中药通过信号通路抑制NF-κB炎性因子的优势, ERS有可能成为探索治疗UC肠道黏膜损伤作用的新机制.
编辑: 郭鹏 电编: 闫晋利
| 1. | Zhang YZ, Li YY. Inflammatory bowel disease: pathogenesis. World J Gastroenterol. 2014;20:91-99. [PubMed] [DOI] |
| 2. | Zhao J, Ng SC, Lei Y, Yi F, Li J, Yu L, Zou K, Dan Z, Dai M, Ding Y. First prospective, population-based inflammatory bowel disease incidence study in mainland of China: the emergence of "western" disease. Inflamm Bowel Dis. 2013;19:1839-1845. [PubMed] [DOI] |
| 3. | Ye L, Cao Q, Cheng J. Review of inflammatory bowel disease in China. ScientificWorldJournal. 2013;2013:296470. [PubMed] [DOI] |
| 4. | Hosomi S, Kaser A, Blumberg RS. Role of endoplasmic reticulum stress and autophagy as interlinking pathways in the pathogenesis of inflammatory bowel disease. Curr Opin Gastroenterol. 2015;31:81-88. [PubMed] [DOI] |
| 5. | Koh SJ, Kim JW, Kim BG, Lee KL, Chun J, Kim JS. Fexofenadine regulates nuclear factor-κB signaling and endoplasmic reticulum stress in intestinal epithelial cells and ameliorates acute and chronic colitis in mice. J Pharmacol Exp Ther. 2015;352:455-461. [PubMed] [DOI] |
| 6. | Negroni A, Prete E, Vitali R, Cesi V, Aloi M, Civitelli F, Cucchiara S, Stronati L. Endoplasmic reticulum stress and unfolded protein response are involved in paediatric inflammatory bowel disease. Dig Liver Dis. 2014;46:788-794. [PubMed] [DOI] |
| 7. | Shkoda A, Ruiz PA, Daniel H, Kim SC, Rogler G, Sartor RB, Haller D. Interleukin-10 blocked endoplasmic reticulum stress in intestinal epithelial cells: impact on chronic inflammation. Gastroenterology. 2007;132:190-207. [PubMed] |
| 8. | Hu S, Ciancio MJ, Lahav M, Fujiya M, Lichtenstein L, Anant S, Musch MW, Chang EB. Translational inhibition of colonic epithelial heat shock proteins by IFN-gamma and TNF-alpha in intestinal inflammation. Gastroenterology. 2007;133:1893-1904. [PubMed] |
| 9. | Heazlewood CK, Cook MC, Eri R, Price GR, Tauro SB, Taupin D, Thornton DJ, Png CW, Crockford TL, Cornall RJ. Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLoS Med. 2008;5:e54. [PubMed] [DOI] |
| 10. | Ribeiro CM, O'Neal WK. Endoplasmic reticulum stress in chronic obstructive lung diseases. Curr Mol Med. 2012;12:872-882. [PubMed] |
| 11. | Morito D, Nagata K. ER Stress Proteins in Autoimmune and Inflammatory Diseases. Front Immunol. 2012;3:48. [PubMed] [DOI] |
| 12. | Hosoi T, Ozawa K. Endoplasmic reticulum stress in disease: mechanisms and therapeutic opportunities. Clin Sci (Lond). 2010;118:19-29. [PubMed] [DOI] |
| 13. | Doyle KM, Kennedy D, Gorman AM, Gupta S, Healy SJ, Samali A. Unfolded proteins and endoplasmic reticulum stress in neurodegenerative disorders. J Cell Mol Med. 2011;15:2025-2039. [PubMed] [DOI] |
| 14. | Wang S, Kaufman RJ. The impact of the unfolded protein response on human disease. J Cell Biol. 2012;197:857-867. [PubMed] [DOI] |
| 15. | Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 2012;13:89-102. [PubMed] [DOI] |
| 16. | Kaser A, Adolph TE, Blumberg RS. The unfolded protein response and gastrointestinal disease. Semin Immunopathol. 2013;35:307-319. [PubMed] |
| 17. | Bogaert S, De Vos M, Olievier K, Peeters H, Elewaut D, Lambrecht B, Pouliot P, Laukens D. Involvement of endoplasmic reticulum stress in inflammatory bowel disease: a different implication for colonic and ileal disease? PLoS One. 2011;6:e25589. [PubMed] [DOI] |
| 18. | McGuckin MA, Eri RD, Das I, Lourie R, Florin TH. ER stress and the unfolded protein response in intestinal inflammation. Am J Physiol Gastrointest Liver Physiol. 2010;298:G820-G832. [PubMed] [DOI] |
| 19. | Adolph TE, Tomczak MF, Niederreiter L, Ko HJ, Böck J, Martinez-Naves E, Glickman JN, Tschurtschenthaler M, Hartwig J, Hosomi S. Paneth cells as a site of origin for intestinal inflammation. Nature. 2013;503:272-276. [PubMed] [DOI] |
| 20. | Zhang K, Kaufman RJ. From endoplasmic-reticulum stress to the inflammatory response. Nature. 2008;454:455-462. [PubMed] [DOI] |
| 21. | Ron D. Translational control in the endoplasmic reticulum stress response. J Clin Invest. 2002;110:1383-1388. [PubMed] |
| 22. | Saito A, Ochiai K, Kondo S, Tsumagari K, Murakami T, Cavener DR, Imaizumi K. Endoplasmic reticulum stress response mediated by the PERK-eIF2(alpha)-ATF4 pathway is involved in osteoblast differentiation induced by BMP2. J Biol Chem. 2011;286:4809-4818. [PubMed] [DOI] |
| 23. | Ye J, Koumenis C. ATF4, an ER stress and hypoxia-inducible transcription factor and its potential role in hypoxia tolerance and tumorigenesis. Curr Mol Med. 2009;9:411-416. [PubMed] |
| 24. | Koromilas AE, Mounir Z. Control of oncogenesis by eIF2α phosphorylation: implications in PTEN and PI3K-Akt signaling and tumor treatment. Future Oncol. 2013;9:1005-1015. [PubMed] |
| 25. | Mounir Z, Krishnamoorthy JL, Wang S, Papadopoulou B, Campbell S, Muller WJ, Hatzoglou M, Koromilas AE. Akt determines cell fate through inhibition of the PERK-eIF2α phosphorylation pathway. Sci Signal. 2011;4:ra62. [PubMed] |
| 26. | Kusio-Kobialka M, Podszywalow-Bartnicka P, Peidis P, Glodkowska-Mrowka E, Wolanin K, Leszak G, Seferynska I, Stoklosa T, Koromilas AE, Piwocka K. The PERK-eIF2α phosphorylation arm is a pro-survival pathway of BCR-ABL signaling and confers resistance to imatinib treatment in chronic myeloid leukemia cells. Cell Cycle. 2012;11:4069-4078. [PubMed] |
| 27. | Atkins C, Liu Q, Minthorn E, Zhang SY, Figueroa DJ, Moss K, Stanley TB, Sanders B, Goetz A, Gaul N. Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res. 2013;73:1993-2002. [PubMed] |
| 28. | Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell. 2000;6:1099-1108. [PubMed] |
| 29. | Boyce M, Bryant KF, Jousse C, Long K, Harding HP, Scheuner D, Kaufman RJ, Ma D, Coen DM, Ron D. A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science. 2005;307:935-939. [PubMed] |
| 30. | Zhang P, Hamamura K, Jiang C, Zhao L, Yokota H. Salubrinal promotes healing of surgical wounds in rat femurs. J Bone Miner Metab. 2012;30:568-579. [PubMed] [DOI] |
| 31. | He L, Lee J, Jang JH, Sakchaisri K, Hwang J, Cha-Molstad HJ, Kim KA, Ryoo IJ, Lee HG, Kim SO. Osteoporosis regulation by salubrinal through eIF2α mediated differentiation of osteoclast and osteoblast. Cell Signal. 2013;25:552-560. [PubMed] [DOI] |
| 34. | Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007;448:427-434. [PubMed] [DOI] |
| 35. | Su L, Shen L, Clayburgh DR, Nalle SC, Sullivan EA, Meddings JB, Abraham C, Turner JR. Targeted epithelial tight junction dysfunction causes immune activation and contributes to development of experimental colitis. Gastroenterology. 2009;136:551-563. [PubMed] [DOI] |
| 36. | Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H, Nieuwenhuis EE, Higgins DE, Schreiber S, Glimcher LH. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell. 2008;134:743-756. [PubMed] [DOI] |
| 37. | Garg AD, Kaczmarek A, Krysko O, Vandenabeele P, Krysko DV, Agostinis P. ER stress-induced inflammation: does it aid or impede disease progression? Trends Mol Med. 2012;18:589-598. [PubMed] [DOI] |
| 38. | Chaudhari N, Talwar P, Parimisetty A, Lefebvre d'Hellencourt C, Ravanan P. A molecular web: endoplasmic reticulum stress, inflammation, and oxidative stress. Front Cell Neurosci. 2014;8:213. [PubMed] [DOI] |
| 39. | Bhattacharyya S, Gill R, Chen ML, Zhang F, Linhardt RJ, Dudeja PK, Tobacman JK. Toll-like receptor 4 mediates induction of the Bcl10-NFkappaB-interleukin-8 inflammatory pathway by carrageenan in human intestinal epithelial cells. J Biol Chem. 2008;283:10550-10558. [PubMed] [DOI] |
| 40. | Chiu YH, Lu YC, Ou CC, Lin SL, Tsai CC, Huang CT, Lin MY. Lactobacillus plantarum MYL26 induces endotoxin tolerance phenotype in Caco-2 cells. BMC Microbiol. 2013;13:190. [PubMed] [DOI] |
| 41. | McElroy SJ, Hobbs S, Kallen M, Tejera N, Rosen MJ, Grishin A, Matta P, Schneider C, Upperman J, Ford H. Transactivation of EGFR by LPS induces COX-2 expression in enterocytes. PLoS One. 2012;7:e38373. [PubMed] [DOI] |
| 42. | Dou W, Zhang J, Li H, Kortagere S, Sun K, Ding L, Ren G, Wang Z, Mani S. Plant flavonol isorhamnetin attenuates chemically induced inflammatory bowel disease via a PXR-dependent pathway. J Nutr Biochem. 2014;25:923-933. [PubMed] [DOI] |
| 44. | Altavilla D, Saitta A, Squadrito G, Galeano M, Venuti SF, Guarini S, Bazzani C, Bertolini A, Caputi AP, Squadrito F. Evidence for a role of nuclear factor-kappaB in acute hypovolemic hemorrhagic shock. Surgery. 2002;131:50-58. [PubMed] |
| 45. | Deniaud A, Sharaf el dein O, Maillier E, Poncet D, Kroemer G, Lemaire C, Brenner C. Endoplasmic reticulum stress induces calcium-dependent permeability transition, mitochondrial outer membrane permeabilization and apoptosis. Oncogene. 2008;27:285-299. [PubMed] |
| 49. | Wang W, Xia T, Yu X. Wogonin suppresses inflammatory response and maintains intestinal barrier function via TLR4-MyD88-TAK1-mediated NF-κB pathway in vitro. Inflamm Res. 2015;64:423-431. [PubMed] [DOI] |