Propionic Acid Targets the TLR4/NF-κB Signaling Pathway and Inhibits LPS-Induced Intestinal Barrier Dysfunction: In Vitro and In Vivo Studies

Objectives. Substantial studies have demonstrated that an elevated concentration of deoxycholic acid (DCA) in the colonic lumen may play a critical role in the pathogenesis of intestinal barrier dysfunction and inflammatory bowel disease (IBD). The purpose of this study was to investigate the protective effects of GYY4137, as a novel and synthetic H2S donor, on the injury of intestinal barrier induced by sodium deoxycholate (SDC) both in vivo and in vitro. Methods. In this study, Caco-2 monolayers and mouse models with high SDC concentration in the lumen were used to study the effect of GYY4137 on intestinal barrier dysfunction induced by SDC and its underlying mechanisms. Results. In Caco-2 monolayers, a short period of addition of SDC increased the permeability of monolayers obviously, changed distribution of tight junctions (TJs), and improved the phosphorylation level of myosin light chain kinase (MLCK) and myosin light chain (MLC). However, pretreatment with GYY4137 markedly ameliorated the SDC-induced barrier dysfunction. Being injected with GYY4137 could enable mice to resist the SDC-induced injury of the intestinal barrier. Besides, GYY4137 promoted the recovery of the body weight and intestinal barrier histological score of mice with the gavage of SDC. GYY4137 also attenuated the decreased expression level of TJs in mice treated with SDC. Conclusion. Taken together, this research suggests that GYY4137 preserves the intestinal barrier from SDC-induced injury via suppressing the activation of P-MLCK-P-MLC2 signaling pathway and increasing the expression level of tight junctions.

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Dickkopf-1 contributes to hepatocellular carcinoma tumorigenesis by activating the Wnt/β-catenin signaling pathway

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-019-0082-5 ◽

2019 ◽

Vol 4 (1) ◽

Cited By ~ 2

Author(s):

Rui Zhang ◽

Hao-Ming Lin ◽

Ruth Broering ◽

Xiang-de Shi ◽

Xian-huan Yu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Signaling Pathway ◽

Tumor Formation ◽

In Vivo Studies ◽

Qrt Pcr ◽

Subsequent Investigation ◽

Dkk1 Expression ◽

Tumor Number

AbstractDysregulation of dickkopf-related protein 1 (DKK1) expression has been reported in a variety of human cancers. We previously reported that DKK1 was upregulated in hepatocellular carcinoma (HCC). However, the role of DKK1 in HCC remains unclear. This study aimed to investigate the clinical significance and biological functions of DKK1 in HCC. The expression of DKK1 was examined in cirrhotic and HCC tissues by immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). DKK1 was silenced or overexpressed in HCC cell lines, and in vitro and in vivo studies were performed. Immunohistochemistry revealed that DKK1 was weakly expressed in cirrhotic tissues (8/22, 36.4%) but upregulated in HCC tissues (48/53, 90.6%, cohort 1). Significant upregulation of DKK1 was observed in 57.6% (19/33, cohort 2) of HCC tissues by qRT-PCR, and the expression of DKK1 was associated with tumor size (P = 0.024) and tumor number (P = 0.019). Genetic depletion of DKK1 impaired the proliferation, colony-forming ability, invasion, and tumor formation of HCC cells (HepG2 and HUH-7). Conversely, forced expression of DKK1 increased the proliferation, colony-forming ability, and invasion of HepG2 and HUH-7 cells in vitro and enhanced tumor formation in vivo. Subsequent investigation revealed that the DKK1-mediated proliferation and tumorigenicity of HepG2 and HUH-7 cells is dependent on the Wnt/β-catenin signaling pathway. These findings indicate that DKK1 plays an oncogenic role in HCC by activating the Wnt/β-catenin signaling pathway.

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Tu1404 Real-Time TEER Monitoring for the Evaluation of Intestinal Barrier Dysfunction In Vitro

Gastroenterology ◽

10.1016/s0016-5085(16)33028-1 ◽

2016 ◽

Vol 150 (4) ◽

pp. S896

Author(s):

Atsushi Majima ◽

Yuji Naito ◽

Osamu Handa ◽

Yosuke Suyama ◽

Yuriko Onozawa ◽

...

Keyword(s):

Real Time ◽

Intestinal Barrier ◽

Barrier Dysfunction ◽

Intestinal Barrier Dysfunction

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CCAAT/Enhancer-Binding Protein Homologous Protein (CHOP) Deficiency Attenuates Heatstroke-Induced Intestinal Injury

Inflammation ◽

10.1007/s10753-021-01577-x ◽

2021 ◽

Author(s):

Yan Cao ◽

Maiying Fan ◽

Yanfang Pei ◽

Lei Su ◽

Weiwei Xiao ◽

...

Keyword(s):

Protein Expression ◽

Er Stress ◽

Intestinal Barrier ◽

Intestinal Injury ◽

Intestinal Epithelial ◽

Barrier Dysfunction ◽

Homologous Protein

Abstract The intestine is one of the main target organs involved in the pathological process of heatstroke. CCAAT/enhancer-binding protein homologous protein (CHOP) is involved in endoplasmic reticulum (ER) stress-induced apoptosis. This study aimed to explore the role of CHOP in heatstroke-induced intestinal injury and potential therapy. An in vitro heat stress (HS) model using Caco-2 cells was employed. We observed the role of CHOP in apoptosis-mediated intestinal epithelial cell injury secondary to HS by evaluating cell viability, lactate dehydrogenase release, apoptosis levels, and GRP78, PERK, ATF4, CHOP, Bcl-2, and BAX mRNA and protein expression. To further study the role of CHOP in HS-induced intestinal barrier dysfunction, we assessed transepithelial electrical resistance, paracellular tracer flux, ultrastructure of tight junctions, and protein expression of ZO-1 and occludin. Male wild-type mice and CHOP knockout mice were used for in vivo experiments. We evaluated serum d-lactate and diamine oxidase levels, histopathological changes, intestinal ultrastructure, and ZO-1 and occludin protein expression. HS activated the PERK-CHOP pathway and promoted apoptosis by upregulating BAX and downregulating Bcl-2; these effects were prevented by CHOP silencing. Intestinal epithelial barrier function was disrupted by HS in vitro and in vivo. CHOP silencing prevented intestinal barrier dysfunction in Caco-2 cells, whereas CHOP knockout mice exhibited decreased intestinal mucosal injury. The ER stress inhibitor 4-phenylbutyrate (4-PBA) prevented HS-induced intestinal injury in vitro and in vivo. This study indicated that CHOP deficiency attenuates heatstroke-induced intestinal injury and may contribute to the identification of a novel therapy against heatstroke associated with the ER stress pathway.

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Biogenic selenium nanoparticles synthesized by Lactobacillus casei ATCC 393 alleviate diquat-induced intestinal barrier dysfunction in C57BL/6 mice through their antioxidant activity

Food & Function ◽

10.1039/d0fo00132e ◽

2020 ◽

Vol 11 (4) ◽

pp. 3020-3031 ◽

Cited By ~ 3

Author(s):

Lei Qiao ◽

Xina Dou ◽

Shuqi Yan ◽

Baohua Zhang ◽

Chunlan Xu

Keyword(s):

Antioxidant Activity ◽

Oxidative Damage ◽

Signaling Pathway ◽

Lactobacillus Casei ◽

Intestinal Barrier ◽

Selenium Nanoparticles ◽

Barrier Dysfunction ◽

Intestinal Barrier Dysfunction ◽

Nrf2 Signaling Pathway ◽

Biogenic Selenium Nanoparticles

Biogenic SeNPs synthesized by Lactobacillus casei ATCC 393 reversed diquat-induced oxidative damage to the epithelium by activating the Nrf2 signaling pathway.

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siRNA Mediated GSK3β Knockdown Targets Insulin Signaling Pathway and Rescues Alzheimer’s Disease Pathology: Evidence from In Vitro and In Vivo Studies

ACS Applied Materials & Interfaces ◽

10.1021/acsami.1c15305 ◽

2021 ◽

Author(s):

Smriti Gupta ◽

Vishal Singh ◽

Subramaniam Ganesh ◽

Nitin K. Singhal ◽

Rajat Sandhir

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Signaling Pathway ◽

Insulin Signaling ◽

Insulin Signaling Pathway ◽

In Vivo Studies

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Hyperthermia induces injury to the intestinal mucosa in the mouse: evidence for an oxidative stress mechanism

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00595.2011 ◽

2012 ◽

Vol 302 (7) ◽

pp. R845-R853 ◽

Cited By ~ 27

Author(s):

S. R. Oliver ◽

N. A. Phillips ◽

V. L. Novosad ◽

M. P. Bakos ◽

E. E. Talbert ◽

...

Keyword(s):

Oxidative Stress ◽

Protein Oxidation ◽

Intestinal Barrier ◽

Epithelial Lining ◽

Barrier Dysfunction ◽

Histological Evidence ◽

Histological Damage ◽

Underlying Mechanisms

Loss of the intestinal barrier is critical to the clinical course of heat illness, but the underlying mechanisms are still poorly understood. We tested the hypothesis that conditions characteristic of mild heatstroke in mice are associated with injury to the epithelial lining of the intestinal tract and comprise a critical component of barrier dysfunction. Anesthetized mice were gavaged with 4 kDa FITC-dextran (FD-4) and exposed to increasing core temperatures, briefly reaching 42.4°C, followed by 30 min recovery. Arterial samples were collected to measure FD-4 concentration in plasma (in vivo gastrointestinal permeability). The small intestines were then removed to measure histological evidence of injury. Hyperthermia resulted in a ≈2.5-fold elevation in plasma FD-4 and was always associated with significant histological evidence of injury to the epithelial lining compared with matched controls, particularly in the duodenum. When isolated intestinal segments from control animals were exposed to ≥41.5°C, marked increases in permeability were observed within 60 min. These changes were associated with release of lactate dehydrogenase, evidence of protein oxidation via carbonyl formation and histological damage. Coincubation with N-acetylcysteine protected in vitro permeability during hyperthermia and reduced histological damage and protein oxidation. Chelation of intracellular Ca2+ to block tight junction opening during 41.5°C exposure failed to reduce the permeability of in vitro segments. The results demonstrate that hyperthermia exposure in mouse intestine, at temperatures at or below those necessary to induce mild heatstroke, cause rapid and substantial injury to the intestinal lining that may be attributed, in part, to oxidative stress.

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EDR Peptide: Possible Mechanism of Gene Expression and Protein Synthesis Regulation Involved in the Pathogenesis of Alzheimer’s Disease

Molecules ◽

10.3390/molecules26010159 ◽

2020 ◽

Vol 26 (1) ◽

pp. 159

Author(s):

Vladimir Khavinson ◽

Natalia Linkova ◽

Ekaterina Kozhevnikova ◽

Svetlana Trofimova

Keyword(s):

Gene Expression ◽

Signaling Pathway ◽

Animal Studies ◽

Enzyme Synthesis ◽

In Vivo Studies ◽

Neuronal Cultures ◽

Ribonucleic Acids ◽

Synthesis Regulation

The EDR peptide (Glu-Asp-Arg) has been previously established to possess neuroprotective properties. It activates gene expression and synthesis of proteins, involved in maintaining the neuronal functional activity, and reduces the intensity of their apoptosis in in vitro and in vivo studies. The EDR peptide interferes with the elimination of dendritic spines in neuronal cultures obtained from mice with Alzheimer’s (AD) and Huntington’s diseases. The tripeptide promotes the activation of the antioxidant enzyme synthesis in the culture of cerebellum neurons in rats. The EDR peptide normalizes behavioral responses in animal studies and improves memory issues in elderly patients. The purpose of this review is to analyze the molecular and genetics aspects of the EDR peptide effect on gene expression and synthesis of proteins involved in the pathogenesis of AD. The EDR peptide is assumed to enter cells and bind to histone proteins and/or ribonucleic acids. Thus, the EDR peptide can change the activity of the MAPK/ERK signaling pathway, the synthesis of proapoptotic proteins (caspase-3, p53), proteins of the antioxidant system (SOD2, GPX1), transcription factors PPARA, PPARG, serotonin, calmodulin. The abovementioned signaling pathway and proteins are the components of pathogenesis in AD. The EDR peptide can be AD.

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RBP-J Deficiency Promoted The Proliferation and Differentiation of CD133-Positive Ependymal Cells In Vitro and In Vivo Studies

10.21203/rs.3.rs-663313/v1 ◽

2021 ◽

Author(s):

Xin Ye ◽

Mengyi Li ◽

Wei Bian ◽

Junwei Li ◽

Ting Zhang ◽

...

Keyword(s):

Notch Signaling ◽

Signaling Pathway ◽

Notch Signaling Pathway ◽

In Vivo Studies ◽

Ependymal Cells ◽

Ependymal Layer ◽

Proliferation And Differentiation ◽

Mature Neurons

Abstract Although the ependymal cells were reported to have the characteristics of neural stem cells (NSCs), the properties of CD133-ependymal cells have not been uncovered, in particular, it is largely unknown about the effect of Notch signaling pathway on the neurogenesis of CD133-positive ependymal cells. By using the transgenic mouse and primarily cultured ependymal cells, we found that the immunoreactivity for prominin-1/CD133 was exclusively localized in the subventricular zone (SVZ) and ependymal layer of ventricles, moreover, most CD133-positive ependymal cells were co-labeled with Nestin. In addition, RBP-J, a key nuclear effector of Notch signaling pathway, was highly active in CD133-positive ependymal cells. Our results demonstrated that CD133-positive ependymal cells can differentiate into the immature and mature neurons, in particular, the number of CD133-positive ependymal cells differentiating into the immature and mature neurons was significantly increased following the deficiency or interference of RBP-J in vivo or in vitro. By using real-time qPCR and Western blot, we found that RBP-J and Hes1 were down-regulated while Notch1 was up-regulated in the expression levels of mRNAs and proteins following the deficiency or interference of RBP-J in vivo or in vitro. These results demonstrated RBP-J deficiency promoted the proliferation and differentiation of CD133-positive ependymal cells. Therefore, we speculated that RBP-J could maintain CD133-positive ependymal cells in the characteristics of NSCs possibly by regulating Notch1/RBP-J/Hes1 pathway.

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Prophylactic Treatment of Probiotic and Metformin Mitigates Ethanol-Induced Intestinal Barrier Injury: In Vitro, In Vivo, and In Silico Approaches

Mediators of Inflammation ◽

10.1155/2021/5245197 ◽

2021 ◽

Vol 2021 ◽

pp. 1-32

Author(s):

Farhin Patel ◽

Kirti Parwani ◽

Priyashi Rao ◽

Dhara Patel ◽

Rakesh Rawal ◽

...

Keyword(s):

Oxidative Stress ◽

Inflammatory Response ◽

In Silico ◽

Combined Treatment ◽

Intestinal Barrier ◽

Individual Treatment ◽

Barrier Dysfunction ◽

And Oxidative Stress

Ethanol depletes intestinal integrity and promotes gut dysbiosis. Studies have suggested the individual role of probiotics and metformin Met in protecting intestinal barrier function from injuries induced by ethanol. The objective of the current study is to investigate the potential mechanism by which coadministration of probiotic Visbiome® (V) and Met blocks the ethanol-induced intestinal barrier dysfunction/gut leakiness utilizing Caco-2 monolayers, a rat model with chronic ethanol injury, and in silico docking interaction models. In Caco-2 monolayers, exposure to ethanol significantly disrupted tight junction (TJ) localization, elevated monolayer permeability, and oxidative stress compared with controls. However, cotreatment with probiotic V and Met largely ameliorated the ethanol-induced mucosal barrier dysfunction, TJ disruption, and gut oxidative stress compared with ethanol-exposed monolayers and individual treatment of either agent. Rats fed with ethanol-containing Lieber-DeCarli liquid diet showed decreased expression of TJ proteins, and increased intestinal barrier injury resulting in pro-inflammatory response and oxidative stress in the colon. We found that co-administration of probiotic V and Met improved the expression of intestinal TJ proteins (ZO-1 and occludin) and upregulated the anti-inflammatory response, leading to reduced ER stress. Moreover, co-administration of probiotic V and Met inhibited the CYP2E1 and NOX gene expression, and increase the translocation of Nrf-2 as well as anti-oxidative genes (SOD, catalase, Gpx, and HO-1), leading to reduced colonic ROS content and malondialdehyde levels. The combined treatment of probiotic V and Met also improved their binding affinities towards HO-1, Nrf-2, SLC5A8, and GPR109A, which could be attributed to their synergistic effect. Our findings based on in-vitro, in-vivo, and in-silico analyses suggest that the combination of probiotic V and Met potentially acts in synergism, attributable to their property of inhibition of inflammation and oxidative stress against ethanol-induced intestinal barrier injury.

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