Koumine Alleviates Lipopolysaccharide-Induced Intestinal Barrier Dysfunction in IPEC-J2 Cells by Regulating Nrf2/NF-κB Pathway

2020 ◽  
Vol 48 (01) ◽  
pp. 127-142 ◽  
Author(s):  
Jing Wu ◽  
Cheng-Lin Yang ◽  
Yuan-Kun Sha ◽  
Yong Wu ◽  
Zhao-Ying Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nuclear Translocation ◽  
Cell Monolayer ◽  
Intestinal Barrier ◽  
Inflammatory Factors ◽  
Growth Promoter ◽  
Protective Effects ◽  
Barrier Dysfunction ◽  
Intestinal Barrier Dysfunction ◽  
Junction Proteins

Gelsemium elegans Benth. (G. elegans), a traditional Chinese medicine, has great potential as an effective growth promoter in animals, however, the mechanism of its actin remains unclear. Here, we evaluated the protective effects of koumine extract from G. elegans against lipopolysaccharide (LPS)-induced intestinal barrier dysfunction in IPEC-J2 cells through alleviation of inflammation and oxidative stress. MTT and LDH assays revealed that koumine significantly reduced LPS cytotoxicity. Transepithelial electrical resistance (TEER) and cell monolayer permeability assays showed that koumine treatment attenuated the LPS-induced intestinal barrier dysfunction with no particularly different effects in tight junction proteins such as ZO-1, claudin-1, and occludin. LPS-triggered inflammatory response was also suppressed by koumine, as evidenced by the downregulated inflammatory factors, including TNF-[Formula: see text], IL-6, IL-1[Formula: see text], NO, iNOS, and COX-2, which was closely connected with the inhibition of NF-[Formula: see text]B pathway for the decrease of phosphorylation of I[Formula: see text]B[Formula: see text] and NF-[Formula: see text]B and nuclear translocation of p-p65. Amount of reactive oxygen species (ROS) and MDA induced by LPS was also reduced by koumine through activation of Nrf2 pathway, and increased in the levels of Nrf2 and HO-1 degradation of keap-1 to promote anti-oxidants, including superoxide dismutase (SOD) and catalase (CAT). To summarize, koumine-reduced the oxidative stress and inflammatory reaction triggered by LPS through regulation of the Nrf2/NF-[Formula: see text]B signaling pathway and preventing intestinal barrier dysfunction.

scholarly journals Cystine reduces tight junction permeability and intestinal inflammation induced by oxidative stress in Caco-2 cells

Amino Acids ◽  
2021 ◽  
Author(s):  
Tatsuya Hasegawa ◽  
Ami Mizugaki ◽  
Yoshiko Inoue ◽  
Hiroyuki Kato ◽  
Hitoshi Murakami
Keyword(s):  
Oxidative Stress ◽  
Tight Junction ◽  
Mrna Expression ◽  
Inflammatory Cytokines ◽  
Inflammatory Responses ◽  
Intestinal Barrier ◽  
Barrier Dysfunction ◽  
Whole Cells ◽  
Intestinal Barrier Dysfunction ◽  
Pro Inflammatory Cytokines

AbstractIntestinal oxidative stress produces pro-inflammatory cytokines, which increase tight junction (TJ) permeability, leading to intestinal and systemic inflammation. Cystine (Cys2) is a substrate of glutathione (GSH) and inhibits inflammation, however, it is unclear whether Cys2 locally improves intestinal barrier dysfunction. Thus, we investigated the local effects of Cys2 on oxidative stress-induced TJ permeability and intestinal inflammatory responses. Caco-2 cells were cultured in a Cys2-supplemented medium for 24 h and then treated with H2O2 for 2 h. We assessed TJ permeability by measuring transepithelial electrical resistance and the paracellular flux of fluorescein isothiocyanate–dextran 4 kDa. We measured the concentration of Cys2 and GSH after Cys2 pretreatment. The mRNA expression of pro-inflammatory cytokines was assessed. In addition, the levels of TJ proteins were assessed by measuring the expression of TJ proteins in the whole cells and the ratio of TJ proteins in the detergent-insoluble fractions to soluble fractions (IS/S ratio). Cys2 treatment reduced H2O2-induced TJ permeability. Cys2 did not change the expression of TJ proteins in the whole cells, however, suppressed the IS/S ratio of claudin-4. Intercellular levels of Cys2 and GSH significantly increased in cells treated with Cys2. Cys2 treatment suppressed the mRNA expression of pro-inflammatory cytokines, and the mRNA levels were significantly correlated with TJ permeability. In conclusion, Cys2 treatment locally reduced oxidative stress-induced intestinal barrier dysfunction possively due to the mitigation of claudin-4 dislocalization. Furthermore, the effect of Cys2 on the improvement of intestinal barrier function is related to the local suppression of oxidative stress-induced pro-inflammatory responses.

scholarly journals The role of zinc deficiency in alcohol-induced intestinal barrier dysfunction

2010 ◽  
Vol 298 (5) ◽  
pp. G625-G633 ◽  
Author(s):  
Wei Zhong ◽  
Craig J. McClain ◽  
Matthew Cave ◽  
Y. James Kang ◽  
Zhanxiang Zhou
Keyword(s):  
Oxidative Stress ◽  
Tight Junction ◽  
Zinc Deficiency ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Alcohol Exposure ◽  
Epithelial Barrier ◽  
Tight Junction Proteins ◽  
Barrier Dysfunction ◽  
Junction Proteins

Disruption of the intestinal barrier is a causal factor in the development of alcoholic endotoxemia and hepatitis. This study was undertaken to determine whether zinc deficiency is related to the deleterious effects of alcohol on the intestinal barrier. Mice were pair fed an alcohol or isocaloric liquid diet for 4 wk, and hepatitis was detected in association with elevated blood endotoxin level. Alcohol exposure significantly increased the permeability of the ileum but did not affect the barrier function of the duodenum or jejunum. Reduction of tight-junction proteins at the ileal epithelium was detected in alcohol-fed mice although alcohol exposure did not cause apparent histopathological changes. Alcohol exposure significantly reduced the ileal zinc concentration in association with accumulation of reactive oxygen species. Caco-2 cell culture demonstrated that alcohol exposure increases the intracellular free zinc because of oxidative stress. Zinc deprivation caused epithelial barrier disruption in association with disassembling of tight junction proteins in the Caco-2 monolayer cells. Furthermore, minor zinc deprivation exaggerated the deleterious effect of alcohol on the epithelial barrier. In conclusion, epithelial barrier dysfunction in the distal small intestine plays an important role in alcohol-induced gut leakiness, and zinc deficiency attributable to oxidative stress may interfere with the intestinal barrier function by a direct action on tight junction proteins or by sensitizing to the effects of alcohol.

scholarly journals Translational Approaches with Antioxidant Phytochemicals against Alcohol-Mediated Oxidative Stress, Gut Dysbiosis, Intestinal Barrier Dysfunction and Fatty Liver Disease

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 384
Author(s):  
Jacob W. Ballway ◽  
Byoung-Joon Song
Keyword(s):  
Oxidative Stress ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Intestinal Barrier ◽  
Leaky Gut ◽  
Barrier Dysfunction ◽  
Intestinal Barrier Dysfunction ◽  
Gut Dysbiosis ◽  
Disease States

Emerging data demonstrate the important roles of altered gut microbiomes (dysbiosis) in many disease states in the peripheral tissues and the central nervous system. Gut dysbiosis with decreased ratios of Bacteroidetes/Firmicutes and other changes are reported to be caused by many disease states and various environmental factors, such as ethanol (e.g., alcohol drinking), Western-style high-fat diets, high fructose, etc. It is also caused by genetic factors, including genetic polymorphisms and epigenetic changes in different individuals. Gut dysbiosis, impaired intestinal barrier function, and elevated serum endotoxin levels can be observed in human patients and/or experimental rodent models exposed to these factors or with certain disease states. However, gut dysbiosis and leaky gut can be normalized through lifestyle alterations such as increased consumption of healthy diets with various fruits and vegetables containing many different kinds of antioxidant phytochemicals. In this review, we describe the mechanisms of gut dysbiosis, leaky gut, endotoxemia, and fatty liver disease with a specific focus on the alcohol-associated pathways. We also mention translational approaches by discussing the benefits of many antioxidant phytochemicals and/or their metabolites against alcohol-mediated oxidative stress, gut dysbiosis, intestinal barrier dysfunction, and fatty liver disease.

scholarly journals Ghrelin Alleviates Intestinal Dysfunction in Sepsis Through the KLF4/MMP2 Regulatory Axis by Activating SIRT1

2021 ◽  
Vol 12 ◽  
Author(s):  
Bin Li ◽  
Zhimin Dou ◽  
Lei Zhang ◽  
Lei Zhu ◽  
Yongqiang Cao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Rat Model ◽  
Interleukin 1 ◽  
Cecal Ligation ◽  
Intestinal Barrier ◽  
Matrix Metalloproteinase 2 ◽  
Inflammatory Factors ◽  
Loss Of Function ◽  
Barrier Dysfunction

Intestinal barrier dysfunction is an important contributor to morbidity caused by sepsis. This study investigates the molecular mechanism by which Ghrelin affects intestinal dysfunction in rat model of sepsis. A rat model of sepsis was established by cecal ligation and puncture (CLP), revealing that Ghrelin was downregulated when sepsis occurs. Increases in the levels of inflammatory factors tumor necrosis factor α (TNF-α), interleukin-1 (IL-1β), IL-6, gastrin, γ-H2AX and 8-OHdG was also detected in this model system, as was an overall increase in oxidative stress. Introduction of exogenous Ghrelin inhibited these increases in inflammatory response and oxidative stress, leading to a reduction of overall sepsis-induced intestinal dysfunction. Ghrelin was then shown to activate SIRT1 expression in vitro, while SIRT1 was found to co-express with KLF4, which in turn was predicted to bind to matrix metalloproteinase 2 (MMP2) promoter. Finally, gain- and loss-of-function experiment demonstrated that SIRT1 upregulated the expression of KLF4 to downregulate MMP2. Collectively, Ghrelin inhibits the oxidative stress and intestinal dysfunction to attenuate sepsis by activating SIRT1 and regulating a KLF4/MMP2 regulatory axis.

scholarly journals Protective Effects of Let-7b on the Expression of Occludin by Targeting P38 MAPK in Preventing Intestinal Barrier Dysfunction

2018 ◽  
Vol 45 (1) ◽  
pp. 343-355 ◽  
Author(s):  
Zhihua Liu ◽  
Yinghai Tian ◽  
Yanqiong Jiang ◽  
Shihua Chen ◽  
Ting Liu ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Conditional Knockout ◽  
Intestinal Barrier Function ◽  
Control Group ◽  
Protective Effects ◽  
Barrier Dysfunction ◽  
Entire Study ◽  
Intestinal Barrier Dysfunction

Background/Aims: Let-7b was dramatically reduced after a dicer knockout of mice with intestinal barrier function injuries. This paper aims to investigate the molecular mechanism of let-7b by targeting p38 MAPK in preventing intestinal barrier dysfunction. Methods: A total of 186 patients were enrolled, with 93 in the control group and 93 in the PRO group. Only 158 patients completed the entire study, whereas the others either did not meet the inclusion criteria or refused to participate. To further verify the role of let-7b, intestinal epithelial conditional knockout (IKO) mice of mmu-let-7b model were established. Serum let-7b, zonulin, IL-6, and TNF-α concentrations were measured by ELISA or quantitative RT-PCR. Permeability assay was done by ussing chamber. The apoptotic cells were identified using an In Situ Cell Death Detection Kit. Protein was detected by western blot. Results: Probiotics can lower infection-related complications, as well as increase the serum and tissue let-7b levels. P38 MAPK was identified as the target of let-7b, as verified by NCM460 cells. P38 MAPK expression was increased, whereas tight-junction (TJ) proteins were significantly decreased in let-7b IKO mice (both P<0.05). Negative regulation of p38 MAPK molecular signaling pathways was involved in the protective effects of let-7b on intestinal barrier function. Conclusion: Let-7b was identified as a novel diagnosis biomarker or a potential treatment target for preventing intestinal barrier dysfunction.

Distribution of tight junction proteins occludin and claudin-1 in cytokine-induced intestinal barrier dysfunction

2000 ◽  
Vol 118 (4) ◽  
pp. A600
Author(s):  
Heinz Schmitz ◽  
Joachim Mankertz ◽  
Natalie Buergel ◽  
Michael Fromm ◽  
Ernst O. Riecken ◽  
...  
Keyword(s):  
Tight Junction ◽  
Intestinal Barrier ◽  
Tight Junction Proteins ◽  
Barrier Dysfunction ◽  
Intestinal Barrier Dysfunction ◽  
Junction Proteins

scholarly journals Enterocyte-specific epidermal growth factor prevents barrier dysfunction and improves mortality in murine peritonitis

2009 ◽  
Vol 297 (3) ◽  
pp. G471-G479 ◽  
Author(s):  
Jessica A. Clark ◽  
Heng Gan ◽  
Alexandr J. Samocha ◽  
Amy C. Fox ◽  
Timothy G. Buchman ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Intestinal Permeability ◽  
Cecal Ligation ◽  
Intestinal Barrier ◽  
Protective Effects ◽  
Barrier Dysfunction ◽  
Intestinal Barrier Dysfunction ◽  
Septic Peritonitis ◽  
Epidermal Growth

Systemic administration of epidermal growth factor (EGF) decreases mortality in a murine model of septic peritonitis. Although EGF can have direct healing effects on the intestinal mucosa, it is unknown whether the benefits of systemic EGF in peritonitis are mediated through the intestine. Here, we demonstrate that enterocyte-specific overexpression of EGF is sufficient to prevent intestinal barrier dysfunction and improve survival in peritonitis. Transgenic FVB/N mice that overexpress EGF exclusively in enterocytes ( IFABP-EGF) and wild-type (WT) mice were subjected to either sham laparotomy or cecal ligation and puncture (CLP). Intestinal permeability, expression of the tight junction proteins claudins-1, -2, -3, -4, -5, -7, and -8, occludin, and zonula occludens-1; villus length; intestinal epithelial proliferation; and epithelial apoptosis were evaluated. A separate cohort of mice was followed for survival. Peritonitis induced a threefold increase in intestinal permeability in WT mice. This was associated with increased claudin-2 expression and a change in subcellular localization. Permeability decreased to basal levels in IFABP-EGF septic mice, and claudin-2 expression and localization were similar to those of sham animals. Claudin-4 expression was decreased following CLP but was not different between WT septic mice and IFABP-EGF septic mice. Peritonitis-induced decreases in villus length and proliferation and increases in apoptosis seen in WT septic mice did not occur in IFABP-EGF septic mice. IFABP-EGF mice had improved 7-day mortality compared with WT septic mice (6% vs. 64%). Since enterocyte-specific overexpression of EGF is sufficient to prevent peritonitis-induced intestinal barrier dysfunction and confers a survival advantage, the protective effects of systemic EGF in septic peritonitis appear to be mediated in an intestine-specific fashion.

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