scholarly journals P38 MAPK Pharmacological Inhibitor SB203580 Alleviates Total Parenteral Nutrition-Induced Loss of Intestinal Barrier Function but Promotes Hepatocyte Lipoapoptosis

2017 ◽  
Vol 41 (2) ◽  
pp. 623-634 ◽  
Author(s):  
Yong-Tao Xiao ◽  
Wei-Hui Yan ◽  
Yi Cao ◽  
Jun-Kai Yan ◽  
Wei Cai
Keyword(s):  
Parenteral Nutrition ◽  
Palmitic Acid ◽  
Total Parenteral Nutrition ◽  
P38 Mapk ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Mitogen Activated Protein Kinase ◽  
Intestinal Barrier Function ◽  
P38 Mapk Inhibitor ◽  
Mapk Inhibitor

Background & Aims: Our previous studies have provided evidence that p38 mitogen-activated protein kinase (MAPK) is involved in total parenteral nutrition (TPN)-associated complications, but its exact effects and mechanisms have not been fully understood. This study aimed to evaluate the roles of p38 MAPK inhibitor SB203580 in the TPN-induced loss of intestinal barrier function and liver disease. Methods: A rodent model of TPN was used to analyze the roles of SB203580 in TPN-associated complications.Intestinal barrier function was evaluated by transepithelial electrical resistance (TER) and paracellular permeability in Caco-2 cells. The palmitic acid (PA) was used to induce hepatic lipoapoptosis in vitro. The lipoapoptosis was detected using Caspase-3/7 and lipid staining. Results: In the present study, we showed that SB203580 treatment significantly suppressed TPN-mediated intestinal permeability in rats. SB203580 treatment significantly inhibited IL-1β-induced an increase in tight junction permeability of Caco-2 cells via repressing the p38/ATF-2 signaling. Unexpectedly, SB203580 treatment enhanced hepatic lipoapoptosis in the model of TPN. Palmitic acid (PA)-induced hepatic lipoapoptosis in human liver cells was significantly augmented by the SB203580 treatment. Conclusions: We demonstrate that the p38 MAPK inhibitor SB203508 ameliorates intestinal barrier function but promotes hepatic lipoapoptosis in model of TPN.

Decline in intestinal mucosal IL-10 expression and decreased intestinal barrier function in a mouse model of total parenteral nutrition

2008 ◽  
Vol 294 (1) ◽  
pp. G139-G147 ◽  
Author(s):  
Xiaoyi Sun ◽  
Hua Yang ◽  
Keisuke Nose ◽  
Satoko Nose ◽  
Emir Q. Haxhija ◽  
...  
Keyword(s):  
Parenteral Nutrition ◽  
Tight Junction ◽  
Total Parenteral Nutrition ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Epithelial Barrier ◽  
Intestinal Epithelial ◽  
Intestinal Epithelial Barrier ◽  
Junction Molecules

Loss of intestinal epithelial barrier function (EBF) is a major problem associated with total parenteral nutrition (TPN) administration. We have previously identified intestinal intraepithelial lymphocyte (IEL)-derived interferon-γ (IFN-γ) as a contributing factor to this barrier loss. The objective was to determine whether other IEL-derived cytokines may also contribute to intestinal epithelial barrier breakdown. C57BL6J male mice received TPN or enteral nutrition (control) for 7 days. IEL-derived interleukin-10 (IL-10) was then measured. A significant decline in IEL-derived IL-10 expression was seen with TPN administration, a cytokine that has been shown in vitro to maintain tight junction integrity. We hypothesized that this change in IEL-derived IL-10 expression could contribute to TPN-associated barrier loss. An additional group of mice was given exogenous recombinant IL-10. Ussing chamber experiments showed that EBF markedly declined in the TPN group. TPN resulted in a significant decrease of IEL-derived IL-10 expression. The expression of several tight junction molecules also decreased with TPN administration. Exogenous IL-10 administration in TPN mice significantly attenuated the TPN-associated decline in zonula occludens (ZO)-1, E-cadherin, and occludin expression, as well as a loss of intestinal barrier function. TPN administration led to a marked decline in IEL-derived IL-10 expression. This decline was coincident with a loss of intestinal EBF. As the decline was partially attenuated with the administration of exogenous IL-10, our findings suggest that loss of IL-10 may be a contributing mechanism to TPN-associated epithelial barrier loss.

scholarly journals Enteral versus Parenteral Nutrition: Effect on Intestinal Barrier Function

2009 ◽  
Vol 1165 (1) ◽  
pp. 338-346 ◽  
Author(s):  
Hua Yang ◽  
Yongjia Feng ◽  
Xiaoyi Sun ◽  
Daniel H. Teitelbaum
Keyword(s):  
Parenteral Nutrition ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function

Mitigation of Direct Neurotoxic Effects of Lidocaine and Amitriptyline by Inhibition of p38 Mitogen-activated Protein Kinase In Vitro  and In Vivo 

2006 ◽  
Vol 104 (6) ◽  
pp. 1266-1273 ◽  
Author(s):  
Philipp Lirk ◽  
Ingrid Haller ◽  
Robert R. Myers ◽  
Lars Klimaschewski ◽  
Yi-Chuan Kau ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
P38 Mapk ◽  
Local Anesthetic ◽  
Apoptotic Cell ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitor ◽  
Mapk Inhibitor

Background Local anesthetic-induced direct neurotoxicity (paresthesia, failure to regain normal sensory and motor function) is a potentially devastating complication of regional anesthesia. Local anesthetics activate the p38 mitogen-activated protein kinase (MAPK) system, which is involved in apoptotic cell death. The authors therefore investigated in vitro (cultured primary sensory neurons) and in vivo (sciatic nerve block model) the potential neuroprotective effect of the p38 MAPK inhibitor SB203580 administered together with a clinical (lidocaine) or investigational (amitriptyline) local anesthetic. Methods Cell survival and mitochondrial depolarization as marker of apoptotic cell death was assessed in rat dorsal root ganglia incubated with lidocaine or amitriptyline either with or without the addition of SB203580. Similarly, in a sciatic nerve block model, the authors assessed wallerian degeneration by light microscopy to detect a potential mitigating effect of MAPK inhibition. Results Lidocaine at 40 mm/approximately 1% and amitriptyline at 100 microm reduce neuron count, but coincubation with the p38 MAPK inhibitor SB203580 at 10 mum significantly reduces cytotoxicity and the number of neurons exhibiting mitochondrial depolarization. Also, wallerian degeneration and demyelination induced by lidocaine (600 mm/approximately 15%) and amitriptyline (10 mm/approximately 0.3%) seem to be mitigated by SB203580. Conclusions The cytotoxic effect of lidocaine and amitriptyline in cultured dorsal root ganglia cells and the nerve degeneration in the rat sciatic nerve model seem, at least in part, to be mediated by apoptosis but seem efficiently blocked by an inhibitor of p38 MAPK, making it conceivable that coinjection might be useful in preventing local anesthetic-induced neurotoxicity.

scholarly journals Inhibition of LPS-Induced Activation of Coagulation by p38 MAPK Inhibitor

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Lutz Koch ◽  
Stefan Hofer ◽  
Markus A. Weigand ◽  
David Frommhold ◽  
Johannes Poeschl ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Sandwich Elisa ◽  
Mitogen Activated Protein Kinase ◽  
Toll Like Receptor ◽  
Inhibitory Effects ◽  
Coagulation Activation ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitor ◽  
Mapk Inhibitor

During Gram-negative sepsis, lipopolysaccharide (LPS) activates toll-like receptor (TLR) 4 and induces complex responses of immune system and coagulation. However, the underlying LPS signalling mechanism on coagulation activation remains complex. To determine the role of the intracellular signalling factors p38 mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-κB), and c-Jun N-terminal kinase (JNK) in the procoagulant response to LPS, coagulation process of human whole blood exposed to specific inhibitors was measured by thrombelastography. Samples were stimulated with LPS (100 μg/mL) after preincubation with BAY117082 (specific NF-κB inhibitor), SP600125 (specific JNK inhibitor), SB203580 (specific p38 MAPK inhibitor), or vehicle. SB203580 strongly inhibited LPS-induced coagulation activation, whereas BAY117082 and SP600125 showed no significant effect. Activation of p38 MAPK, NF-κB, and JNK and respective inhibitory effects were confirmed by Multi-Target Sandwich ELISA. In conclusion, activation of p38 MAPK is crucial for early LPS-induced activation of coagulation.

scholarly journals Effect of the p38 MAPK Inhibitor on the Expression of Metalloproteinases and Their Inhibitors during the Formation of Abdominal Adhesions

2021 ◽  
Vol 11 (4) ◽  
pp. 446-450
Author(s):  
Irina Shurygina ◽  
Lyubov Rodionova ◽  
Natalia Ayushinova ◽  
Elena Chepurnykh ◽  
Irina Trukhan ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Abdominal Cavity ◽  
Adhesion Formation ◽  
Intraperitoneal Administration ◽  
Mitogen Activated Protein Kinase ◽  
Control Group ◽  
Genes Encoding ◽  
Male Wistar Rats ◽  
P38 Mapk Inhibitor ◽  
Mapk Inhibitor

Background: The aim of this study was to assess the effect of blockade of the p38 mitogen-activated protein kinase (MAPK) on the expression of genes encoding metalloproteinases (MMPs) during the formation of adhesions in the abdominal cavity. Methods and Results: The experiments were carried out on male Wistar rats (n=75). The studies were carried out in two groups: Group 1 (control, n=35) – modelling the adhesive process; Group 2 (experimental, n=35) – modelling the adhesive process with intraperitoneal administration of Seroguard®—a prolonged form of the p38 MAPK inhibitor. The expression of the MMP1a, MMP2, MMP7, MMP9, and TIMP genes was assessed using real-time PCR. In the control group, overexpression of the MMP1a and MMP7 genes began from 6 hours after modeling the adhesive process, MMP9 – from Day 1, MMP2 – from Day 7 and persisted until the end of observation. With local blockade of p38 MAPK, the level of overexpression of genes encoding MMPs in the early stages was higher than in the control group (MMP1a – by Day 1; MMP7 – by 6 hours and Day 1, MMP9 – by 12 hours). From Day 3 to Day 14, the MMP1a and MMP7 expression in the experimental group was significantly lower than in the control group. Conclusion: The performed study demonstrated the involvement of different types of MMPs—collagenases (MMP1a), gelatinases (MMP2 and 9), matrilysins (MMP7)—in the rearrangement of the extracellular matrix during the process of adhesion formation in the abdominal cavity.

scholarly journals Effects of enteral nutrition on pro-inflammatory factors and intestinal barrier function in patients with acute severe pancreatitis

2019 ◽  
Vol 17 ◽  
pp. 205873921982721 ◽  
Author(s):  
Ying-Jie Chen ◽  
Yao-Dong Zhuang ◽  
Zhe Cai ◽  
You-Ni Zhang ◽  
Sen-Ren Guo
Keyword(s):  
Enteral Nutrition ◽  
Parenteral Nutrition ◽  
Barrier Function ◽  
Tumor Necrosis ◽  
Intestinal Barrier ◽  
Inflammatory Factors ◽  
Intestinal Barrier Function ◽  
Acute Severe Pancreatitis ◽  
Severe Pancreatitis ◽  
Necrosis Factor

The main objective of this study was to explore the effect of enteral nutrition on serum pro-inflammatory cytokines, tumor necrosis factor, and intestinal barrier function in patients with acute severe pancreatitis. A total number of 140 patients were recruited and divided randomly into parenteral nutrition (PN) and enteral nutrition (EN) groups. They received parenteral nutrition and enteral nutrition, respectively. The levels of serum total protein (TP) and albumin (ALB) in peripheral blood were detected in the two groups. Interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNFα) in the two groups were comparatively analyzed. The levels of pro-inflammatory factors (IL-1β, IL-6, and TNFα) for both groups were same, and there was no significant difference ( P < 0.05) between the two groups before treatment. However, after treatment, a significant reduction was found in EN group which were 31.16 ± 1.95, 36.09 ± 9.44, and 29.21 ± 3.85 ng/L, respectively, showing significant lower values as compared to PN group. The levels of TP and ALB in EN group were 64.46 ± 3.77 and 27.19 ± 1.56 g/L, respectively, after treatment, showing significantly ( P < 0.05) elevated values than PN group. The incidence rates of pancreatic necrosis and pancreatic abscess in EN group were 28.57% and 11.43%, respectively, which were found to be lower significantly than PN group. Enteral nutrition is found to be more effective than parenteral nutrition in the treatment of severe acute pancreatitis, which can significantly reduce the level of pro-inflammatory factors as well as the degree of systemic inflammatory response and protect the intestinal barrier function; thus, this study is worthy for awareness and application in clinical practice.

scholarly journals Lactobacillus rhamnosus GG Attenuates Lipopolysaccharide-Induced Inflammation and Barrier Dysfunction by Regulating MAPK/NF-κB Signaling and Modulating Metabolome in the Piglet Intestine

2020 ◽  
Vol 150 (5) ◽  
pp. 1313-1323 ◽  
Author(s):  
Jiangdi Mao ◽  
Siri Qi ◽  
Yanjun Cui ◽  
Xiaoxiao Dou ◽  
Xin M Luo ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Intraperitoneal Injection ◽  
Intestinal Barrier ◽  
Mitogen Activated Protein Kinase ◽  
Intestinal Barrier Function ◽  
Saline Control ◽  
Barrier Dysfunction ◽  
Large White ◽  
Oral Inoculation ◽  
Tnf Α

ABSTRACT Background Probiotic Lactobacillius rhamnosus GG (LGG) shows beneficial immunomodulation on cultured cell lines in vitro and in mouse models. Objective The aim was to investigate the effects of LGG on intestinal injury and the underlying mechanisms by elucidating inflammatory signaling pathways and metabolomic response to LPS stimulation in the piglet intestine. Methods Piglets (Duroc × Landrace × Large White, including males and female; 8.6 ± 1.1 kg) aged 28 d were assigned to 3 groups (n = 6/group): oral inoculation with PBS for 2 wk before intraperitoneal injection of physiological saline [control (CON)] or LPS (25 μg/kg body weight; LPS) or oral inoculation with LGG for 2 wk before intraperitoneal injection of LPS (LGG+LPS). Piglets were killed 4 h after LPS injection. Systemic inflammation, intestinal integrity, inflammation signals, and metabolomic characteristics in the intestine were determined. Results Compared with CON, LPS stimulation significantly decreased ileal zonula occludens 1 (ZO-1; 44%), claudin-3 (44%), and occludin (41%) expression; increased serum diamineoxidase (73%), D-xylose (19%), TNF-α (43%), and IL-6 (55%) concentrations; induced p38 mitogen-activated protein kinase (p38 MAPK; 85%), extracellular signal-regulated kinase (ERK; 96%), and NF-κB p65 phosphorylation (37%) (P &lt; 0.05). Compared with LPS stimulation alone, LGG pretreatment significantly enhanced the intestinal barrier by upregulating expressions of tight junction proteins (ZO-1, 73%; claudin-3, 55%; occludin, 67%), thereby decreasing serum diamineoxidase (26%) and D-xylose (28%) concentrations, and also reduced serum TNF-α expression (16%) and ileal p38 MAPK (79%), ERK (43%) and NF-κB p65 (37%) phosphorylation levels (P &lt; 0.05). Metabolomic analysis showed clear separation between each group. The concentrations of caprylic acid [fold-change (FC) = 2.39], 1-mono-olein (FC = 2.68), erythritol (FC = 4.62), and ethanolamine (FC = 4.47) significantly increased in the intestine of LGG + LPS piglets compared with the LPS group (P &lt; 0.05). Conclusions These data suggest that LGG alleviates gut inflammation, improves intestinal barrier function, and modulates the metabolite profile of piglets challenged with LPS. This trial was registered at the Zhejiang University (http://www.lac.zju.edu.cn) as ZJU20170529.

scholarly journals Oxyresveratrol protective effects against deoxynivalenol-induced intestinal barrier dysfunction and bacterial translocation on porcine intestinal epithelial IPEC-J2 cells

2018 ◽  
Vol 1 ◽  
Author(s):  
Murphy L.Y. Wan ◽  
Ka Ho Ling ◽  
Hani El-Nezami ◽  
Mingfu Wang
Keyword(s):  
Bacterial Translocation ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Mitogen Activated Protein Kinase ◽  
Intestinal Barrier Function ◽  
Epithelial Barrier ◽  
Intestinal Damage ◽  
Protective Effects ◽  
Barrier Dysfunction ◽  
Significant Difference

Deoxynivalenol (DON) is a major mycotoxin contaminant and is known to impair intestinal barrier function. Previous experiments in our laboratory have proven that polyphenols such as resveratrol (RES) may be effective in enhancing epithelial barrier function. Due to the structural similarity of oxyresveratrol (OXY) with RES, it was hypothesized that OXY could also protect against DON-induced intestinal damage. Accordingly, this study aimed to explore potential protective effects of OXY against DON-induced epithelial barrier dysfunction and bacterial translocation on IPEC-J2 cells, in comparison to resveratrol (RES).The results showed that OXY increased transepithelial electrical resistance (TEER) and reduced FD-4 diffusion, whereas DON reduced TEER and increased FD-4 diffusion in IPEC-J2 cells. On the other hand, OXY reduced FD-4 diffusion in DON-damaged cells but showed no significant difference in terms of TEER. Such protective effects coincided with the significantly reduced E. coli translocation in cells co-exposed to DON and OXY. Further mechanistic studies demonstrated that OXY protected against DON-induced barrier dysfunction by enhancing the expression of claudin-4 via mitogen-activated protein kinase(MAPK)-dependent pathways. Apparently, OXY worked through the same way as RES did, with results dovetailed nicely with anticipation. These results imply that OXY may share similar health benefits with RES by enhancing epithelial barrier functions and protecting against DON-induced intestinal damage.

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.

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