Modulation of intestinal barrier function by glucocorticoids: Lessons from preclinical models

Tena-Garitaonaindia, Mireia; Arredondo-Amador, María; Mascaraque, Cristina; Asensio, Maitane; Marin, J. J. G.; Medina, Fermín Sánchez de

doi:10.1016/j.phrs.2022.106056

Cited by 27 publications

(22 citation statements)

References 130 publications

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“…This can be explained, on the one hand, by the increased expression of fibronectin (only in Nthy-ori 3-1 cells) and, on the other hand, by an increased formation of TJs, which was particularly observed in metastatic FTC-133 and WRO cells. Glucocorticoid-induced TJ formation and re-organization has been previously described and studied in mouse mammary epithelial cells [ 69 , 70 ] and in preclinical human intestinal models (summarized in [ 71 ]). In our experiments, the RPM also increased the expression of TJ proteins claudin-1 and ZO-1, as well as the formation of TJs, which had an enhancing effect when combined with DEX treatment.…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone Selectively Inhibits Detachment of Metastatic Thyroid Cancer Cells during Random Positioning

Melnik

Cortés-Sánchez

Sandt

et al. 2023

Cancers

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We recently reported that synthetic glucocorticoid dexamethasone (DEX) is able to suppress metastasis-like spheroid formation in a culture of follicular thyroid cancer (FTC)-133 cells cultured under random positioning. We now show that this inhibition was selective for two metastatic thyroid carcinoma cells, FTC-133 and WRO, whereas benign Nthy-ori 3-1 thyrocytes and recurrent ML-1 follicular thyroid cancer cells were not affected by DEX. We then compare Nthy-ori 3-1 and FTC-133 cells concerning their adhesion and mechanosignaling. We demonstrate that DEX disrupts random positioning-triggered p38 stress signaling in FTC-133 cells, thereby antagonizing a variety of biological functions. Thus, DEX treatment of FTC-133 cells is associated with increased adhesiveness, which is mainly caused by the restored, pronounced formation of a normal number of tight junctions. Moreover, we show that Nthy-ori 3-1 and ML-1 cells upregulate the anti-adhesion protein mucin-1 during random positioning, presumably as a protection against mechanical stress. In summary, mechanical stress seems to be an important component in this metastasis model system that is processed differently by metastatic and healthy cells. The balance between adhesion, anti-adhesion and cell–cell connections enables detachment of adherent human cells on the random positioning machine—or not, allowing selective inhibition of thyroid in vitro metastasis by DEX.

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Section: Discussionmentioning

confidence: 99%

Dexamethasone Selectively Inhibits Detachment of Metastatic Thyroid Cancer Cells during Random Positioning

Melnik

Cortés-Sánchez

Sandt

et al. 2023

Cancers

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“…However, the effects of GC on the intestinal epithelial barrier are still unclear. 30 Clinical studies have shown that high-dose of corticosteroids can significantly increase the permeability of the duodenum. 31 Similarly, preclinical studies reached the same conclusions, noting that in colitis-afflicted mice, GCs such as budesonide, had anti-inflammatory effects, but simultaneously compromising the integrity of the intestinal mucosal barrier.…”

Section: Discussionmentioning

confidence: 99%

“…They are commonly utilized in clinical practice as anti-inflammatory and immunosuppressive drugs. However, the effects of GC on the intestinal epithelial barrier are still unclear . Clinical studies have shown that high-dose of corticosteroids can significantly increase the permeability of the duodenum .…”

Section: Discussionmentioning

confidence: 99%

Alpinia katsumadai Hayata Volatile Oil Is Effective in Treating 5-Fluorouracil-Induced Mucositis by Regulating Gut Microbiota and Modulating the GC/GR Pathway and the mPGES-1/PGE2/EP4 Pathways

Liu,

Tang,

Zhang

et al. 2023

J. Agric. Food Chem.

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This study was aimed to investigate the therapeutic effect and mechanism of AKHO on 5-fluorouracil (5-FU)-induced intestinal mucositis in mice. Mouse body weight, diarrhea score, and H&E staining were applied to judge the therapeutic effect of AKHO. 16S rDNA and nontargeted metabolomics have been used to study the mechanism. WB, ELISA, and immunohistochemistry were adopted to validate possible mechanisms. The results demonstrated that AKHO significantly reduced diarrhea scores and intestinal damage induced by 5-FU in mice. AKHO lowered the serum levels of LD and DAO, and upregulated the expressions of ZO-1 and occludin in the ileum. Also, AKHO upregulated the abundance of Lactobacillus in the gut and suppressed KEGG pathways such as cortisol synthesis and secretion and arachidonic acid metabolism. Further validation studies indicated that AKHO downregulated the expressions of prostaglandin E2 (PGE2), microsomal prostaglandin E synthase-1 (mPGES-1), and PGE2 receptor EP4, as well as upregulated the expression of glucocorticoid (GC) receptor (GR), leading to improved intestinal epithelial barrier function. Taken together, AKHO elicited protective effects against 5-FU-induced mucositis by regulating the expressions of tight junction proteins via modulation of GC/GR and mPGES-1/PGE2/EP4 pathway, providing novel insights into the utilization and development of this pharmaceutical/food resource.

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“…In this perspective, the use of glucocorticoids , which exert potent anti-inflammatory actions, has a theoretical basis. Glucocorticoids use in diverse preclinical models of intestinal barrier injury has given contradictory results, and negative effects on gut barrier function have been attributed, at least partly, on their negative impact on mucus production and epithelial healing [ 91 ]. However, preclinical studies on sepsis have demonstrated a positive impact of glucocorticoids based on their anti-inflammatory action, and their TJs preserving effect [ 12 ].…”

Section: Therapeutic Approaches Targeting the Gut Barriermentioning

confidence: 99%

SARS CoV-2-Induced Viral Sepsis: The Role of Gut Barrier Dysfunction

et al. 2022

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A considerable proportion of patients with severe COVID-19 meet Sepsis-3 criteria and share common pathophysiological mechanisms of multiorgan injury with bacterial sepsis, in absence of secondary bacterial infections, a process characterized as “viral sepsis”. The intestinal barrier exerts a central role in the pathophysiological sequence of events that lead from SARS-CoV-2 infection to severe systemic complications. Accumulating evidence suggests that SARS-CoV-2 disrupts the integrity of the biological, mechanical and immunological gut barrier. Specifically, microbiota diversity and beneficial bacteria population are reduced, concurrently with overgrowth of pathogenic bacteria (dysbiosis). Enterocytes’ tight junctions (TJs) are disrupted, and the apoptotic death of intestinal epithelial cells is increased leading to increased gut permeability. In addition, mucosal CD4(+) and CD8(+) T cells, Th17 cells, neutrophils, dendritic cells and macrophages are activated, and T-regulatory cells are decreased, thus promoting an overactivated immune response, which further injures the intestinal epithelium. This dysfunctional gut barrier in SARS-CoV-2 infection permits the escape of luminal bacteria, fungi and endotoxin to normally sterile extraintestinal sites and the systemic circulation. Pre-existing gut barrier dysfunction and endotoxemia in patients with comorbidities including cardiovascular disease, obesity, diabetes and immunosuppression predisposes to aggravated endotoxemia. Bacterial and endotoxin translocation promote the systemic inflammation and immune activation, which characterize the SARS-CoV-2 induced “viral sepsis” syndrome associated with multisystemic complications of severe COVID-19.

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Modulation of intestinal barrier function by glucocorticoids: Lessons from preclinical models

Cited by 27 publications

References 130 publications

Dexamethasone Selectively Inhibits Detachment of Metastatic Thyroid Cancer Cells during Random Positioning

Dexamethasone Selectively Inhibits Detachment of Metastatic Thyroid Cancer Cells during Random Positioning

Alpinia katsumadai Hayata Volatile Oil Is Effective in Treating 5-Fluorouracil-Induced Mucositis by Regulating Gut Microbiota and Modulating the GC/GR Pathway and the mPGES-1/PGE2/EP4 Pathways

SARS CoV-2-Induced Viral Sepsis: The Role of Gut Barrier Dysfunction

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