scholarly journals JQ1 as a BRD4 Inhibitor Blocks Inflammatory Pyroptosis-Related Acute Colon Injury Induced by LPS

2021 ◽  
Vol 12 ◽  
Author(s):  
Ling Chen ◽  
Xiaolin Zhong ◽  
Wenyu Cao ◽  
Mingli Mao ◽  
Wei Li ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tight Junction ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Tight Junction Proteins ◽  
Colon Injury ◽  
Endotoxin Translocation ◽  
Bet Protein ◽  
Inflammation Cytokines ◽  
Junction Proteins

Endotoxemia is a severe inflammation response induced by infection especially bacterial endotoxin translocation, which severely increases mortality in combination with acute colon injury. Bromodomain-containing protein 4 (BRD4) is an important Bromo and Extra-Terminal (BET) protein to participate in inflammatory responses. However, it is still unknown about the specific connection between BRD4 and inflammation-related pyroptosis in endotoxemia colon. Here, through evaluating the mucous morphology and the expression of tight junction proteins such as occludin and ZO1, we found the upregulation of BRD4 in damaged colon with poor tight junction in an endotoxemia mouse model induced by lipopolysaccharides (LPS). Firstly, the BRD4 inhibitor JQ1 was used to effectively protect colon tight junction in endotoxemia. As detected, high levels of pro-inflammation cytokines IL6, IL1β and IL18 in endotoxemia colon were reversed by JQ1 pretreatment. In addition, JQ1 injection reduced endotoxemia-induced elevation of the phosphorylated NF κB and NLRP3/ASC/caspase 1 inflammasome complex in colon injury. Furthermore, activated pyroptosis markers gasdermins in endotoxemia colon were also blocked by JQ1 pretreatment. Together, our data indicate that BRD4 plays a critical role in regulating pyroptosis-related colon injury induced by LPS, and JQ1 as a BRD4 inhibitors can effectively protect colon from endotoxemia-induced inflammation injury.

scholarly journals MTOR PROMOTES BBB BREAKDOWN IN A MODEL OF ALZHEIMER’S DISEASE

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S256-S256 ◽  
Author(s):  
Stephen F Hernandez ◽  
Candice E Van Skike ◽  
Nick DeRosa ◽  
Veronica Galvan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Tight Junction ◽  
Tg2576 Mouse ◽  
Tight Junction Proteins ◽  
Study Results ◽  
Junction Protein ◽  
Tg2576 Mice ◽  
Junction Proteins

Abstract Cerebral amyloid angiopathy (CAA) is characterized by fibrillar amyloid β (Aβ) association with cerebrovasculature, which leads to impaired brain vascular function, and is present in 87% of people with Alzheimer’s disease (AD). We previously showed that inhibition of mTOR by rapamycin prevented BBB breakdown and reduced vascular fibrillar Aβ in 18-19 month old Tg2576 mice that model AD-associated CAA. This finding suggests that mTOR attenuation restores integrity of the blood brain barrier (BBB) and concomitantly reduces vascular Aβ accumulation in this mouse model. Objective: To determine the mechanisms by which mTOR drives BBB breakdown we measured the abundance of tight junction proteins zonula occludens 1 (ZO-1), occludin, and claudin-5. Methods: We used immunofluorescent confocal microscopy on frozen brain tissue sections of the same Tg2576 mice used in the previous study. Results: We confirm BBB breakdown in Tg2576 mouse brains and showed that some, but not all tight junction proteins measured were decreased in cerebrovasculature of Tg2576 mice. Attenuation of mTOR by rapamycin preserved BBB integrity, decreased vascular Aβ accumulation, and increased levels of tight junction protein abundance in Tg2576 mice, which also showed a reduced numbers of cerebral microhemorrhages. Conclusions: Taken together, these data suggest that mTOR promotes brain vascular Aβ deposition, BBB breakdown and vascular damage in the Tg2576 mouse model. Thus, mTOR inhibitors such as rapamycin – an FDA approved drug - may have promise in the treatment of AD and other dementias with related cerebrovascular dysfunction.

scholarly journals Eugenol attenuates inflammatory response and enhances barrier function during lipopolysaccharide-induced inflammation in the porcine intestinal epithelial cells

2020 ◽  
Vol 98 (8) ◽  
Author(s):  
Qianru Hui ◽  
Emily Ammeter ◽  
Shangxi Liu ◽  
Runqiang Yang ◽  
Peng Lu ◽  
...  
Keyword(s):  
Amino Acid ◽  
Tight Junction ◽  
Barrier Function ◽  
Inflammatory Responses ◽  
Intestinal Epithelial Cells ◽  
Mrna Abundance ◽  
Intestinal Epithelial ◽  
Tight Junction Proteins ◽  
Sodium Dependent ◽  
Junction Proteins

Abstract Eugenol (4-allyl-2-methoxyphenol) is an essential oil component, possessing antimicrobial, anti-inflammatory, and antioxidative properties; however, the effect of eugenol on porcine gut inflammation has not yet been investigated. In this study, an in vitro lipopolysaccharide (LPS)-induced inflammation model in porcine intestinal epithelial cells (IPEC-J2) has been set up. Cells were pretreated with 100 μM (16.42 mg/L) eugenol for 2 h followed by 10 μg/mL LPS stimulation for 6 h. Proinflammatory cytokine secretion; reactive oxygen species; gene expression of proinflammatory cytokines, tight junction proteins, and nutrient transporters; the expression and distribution of zonula occludens-1 (ZO-1); transepithelial electrical resistance (TEER); and cell permeability were measured to investigate the effect of eugenol on inflammatory responses and gut barrier function. The results showed that eugenol pretreatment significantly suppressed the LPS-stimulated interleukin-8 level and the mRNA abundance of tumor necrosis factor-α and restored the LPS-stimulated decrease of the mRNA abundance of tight junction proteins, such as ZO-1 and occludin, and the mRNA abundance of nutrient transporters, such as B0 1 system ASC sodium-dependent neutral amino acid exchanger 2, sodium-dependent glucose transporter 1, excitatory amino acid transporter 1, and peptide transporter 1. In addition, eugenol improved the expression and even redistribution of ZO-1 and tended to increase TEER value and maintained the barrier integrity. In conclusion, a low dose of eugenol attenuated inflammatory responses and enhanced selectively permeable barrier function during LPS-induced inflammation in the IPEC-J2 cell line.

scholarly journals Colquhounia Root Tablet Protects Rat Pulmonary Microvascular Endothelial Cells against TNF-α-Induced Injury by Upregulating the Expression of Tight Junction Proteins Claudin-5 and ZO-1

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Wenjie Zhou ◽  
Guocui Shi ◽  
Jijia Bai ◽  
Shenmao Ma ◽  
Qinfu Liu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tight Junction ◽  
Cell Injury ◽  
Inflammatory Responses ◽  
Microvascular Endothelial Cells ◽  
Protective Effects ◽  
Tight Junction Proteins ◽  
Pulmonary Microvascular Endothelial Cells ◽  
Microvascular Endothelial ◽  
Junction Proteins

Background. There are currently limited effective pharmacotherapy agents for acute lung injury (ALI). Inflammatory response in the lungs is the main pathophysiological process of ALI. Our preliminary data have shown that colquhounia root tablet (CRT), a natural herbal medicine, alleviates the pulmonary inflammatory responses and edema in a rat model with oleic acid-induced ALI. However, the potential molecular action mechanisms underlining its protective effects against ALI are poorly understood. This study aimed to investigate the effects and mechanism of CRT in rat pulmonary microvascular endothelial cells (PMEC) with TNF-α-induced injury. Methods. PMECs were divided into 6 groups: normal control, TNF-α (10 ng/mL TNF-α), Dex (1×10-6 M Dex + 10 ng/mL TNF-α), CRT high (1000 ng/mL CRT + 10 ng/mL TNF-α), CRT medium (500 ng/mL CRT + 10 ng/mL TNF-α), and CRT low group (250 ng/mL CRT + 10 ng/mL TNF-α). Cell proliferation and apoptosis were detected by MTT assay and flow cytometry. Cell micromorphology was observed under transmission electron microscope. The localization and expression of tight junction proteins Claudin-5 and ZO-1 were analyzed by immunofluorescence staining and Western blot, respectively. Results. TNF-a had successfully induced an acute endothelial cell injury model. Dex and CRT treatments had significantly stimulated the growth and reduced the apoptosis of PMECs (all p < 0.05 or 0.01) and alleviated the TNF-α-induced cell injury. The expression of Claudin-5 and ZO-1 in Dex and all 3 CRT groups was markedly increased compared with TNF-a group (all p < 0.05 or 0.01). Conclusion. CRT effectively protects PMECs from TNF-α-induced injury, which might be mediated via stabilizing the structure of tight junction. CRT might be a promising, effective, and safe therapeutic agent for the treatment of ALI.

Tight junction proteins in HCC and metastatic liver tumours

2005 ◽  
Vol 43 (05) ◽  
Author(s):  
Cs Páska ◽  
E Orbán ◽  
A Kiss ◽  
Zs Schaff ◽  
A Szijjártó ◽  
...  
Keyword(s):  
Tight Junction ◽  
Tight Junction Proteins ◽  
Liver Tumours ◽  
Metastatic Liver ◽  
Junction Proteins

Evidence that gene expression of ovarian follicular tight junction proteins is regulated in vivo and in vitro in cattle

2017 ◽  
Vol 95 (3) ◽  
pp. 1313 ◽  
Author(s):  
L. Zhang ◽  
L. F. Schütz ◽  
C. L. Robinson ◽  
M. L. Totty ◽  
L. J. Spicer
Keyword(s):  
Gene Expression ◽  
Tight Junction ◽  
Tight Junction Proteins ◽  
Junction Proteins

New insights in gut-liver axis in wild-type murine imiquimod-induced lupus

Lupus ◽  
2021 ◽  
Vol 30 (6) ◽  
pp. 926-936
Author(s):  
Georges Maalouly ◽  
Joelle Hajal ◽  
Charbel Noujeim ◽  
Michel Choueiry ◽  
Hussein Nassereddine ◽  
...  
Keyword(s):  
Tight Junction ◽  
Fecal Calprotectin ◽  
Liver Inflammation ◽  
Tight Junction Proteins ◽  
Wild Type ◽  
Imiquimod Cream ◽  
E Coli ◽  
Intestinal Pathology ◽  
Nfκb Pathway ◽  
Junction Proteins

Background Intestinal and hepatic manifestations of lupus seem to be underestimated in comparison to other major organ lesions. Although recent data point to gut-liver axis involvement in lupus, gut permeability dysfunction and liver inflammation need to be more investigated. Objective This study aims to assess fecal calprotectin, intestinal tight junction proteins and liver inflammation pathway in wild-type murine imiquimod- induced lupus. Methods C57BL/6 mice were topically treated on their right ears with 1.25 mg of 5% imiquimod cream, three times per week for six weeks. Fecal calprotectin was collected at day 0, 22 and 45. Renal, liver and intestinal pathology, as well as inflammatory markers, intestinal tight junction proteins, and E. coli protein in liver were assessed at sacrifice. Results At six weeks, lupus nephritis was confirmed on histopathology and NGAL and KIM-1 expression. Calprotectin rise started at day 22 and persists at day 45. Protein expression of Claudine, ZO-1 and occludin was significantly decreased. E. coli protein was significantly increased in liver with necro-inflammation and increased TLR4, TLR7, and pNFκB/NFκB liver expression. Conclusion This study is the first to demonstrate early fecal calprotectin increase and liver activation of TLR4- NFκB pathway in wild-type murine imiquimod-induced lupus.

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