Fulvestrant-Mediated Attenuation of the Innate Immune Response Decreases ER+ Breast Cancer Growth In Vivo More Effectively than Tamoxifen

ABSTRACT Clostridioides difficile infection (CDI) is associated with increasing morbidity and mortality posing an urgent threat to public health. Recurrence of CDI after successful treatment with antibiotics is high, thus necessitating discovery of novel therapeutics against this enteric pathogen. Administration of the secondary bile acid ursodeoxycholic acid (UDCA; ursodiol) inhibits the life cycles of various strains of C. difficile in vitro, suggesting that the FDA-approved formulation of UDCA, known as ursodiol, may be able to restore colonization resistance against C. difficile in vivo. However, the mechanism(s) by which ursodiol is able to restore colonization resistance against C. difficile remains unknown. Here, we confirmed that ursodiol inhibits C. difficile R20291 spore germination and outgrowth, growth, and toxin activity in a dose-dependent manner in vitro. In a murine model of CDI, exogenous administration of ursodiol resulted in significant alterations in the bile acid metabolome with little to no changes in gut microbial community structure. Ursodiol pretreatment resulted in attenuation of CDI pathogenesis early in the course of disease, which coincided with alterations in the cecal and colonic inflammatory transcriptome, bile acid-activated receptors nuclear farnesoid X receptor (FXR) and transmembrane G-protein-coupled membrane receptor 5 (TGR5), which are able to modulate the innate immune response through signaling pathways such as NF-κB. Although ursodiol pretreatment did not result in a consistent decrease in the C. difficile life cycle in vivo, it was able to attenuate an overly robust inflammatory response that is detrimental to the host during CDI. Ursodiol remains a viable nonantibiotic treatment and/or prevention strategy against CDI. Likewise, modulation of the host innate immune response via bile acid-activated receptors FXR and TGR5 represents a new potential treatment strategy for patients with CDI.

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Biofunctionalization of 3D-printed silicone implants with immunomodulatory hydrogels for controlling the innate immune response: An in vivo model of tracheal defect repair

Biomaterials ◽

10.1016/j.biomaterials.2020.120549 ◽

2021 ◽

Vol 268 ◽

pp. 120549

Author(s):

J. Barthes ◽

P. Lagarrigue ◽

V. Riabov ◽

G. Lutzweiler ◽

J. Kirsch ◽

...

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Innate Immune ◽

In Vivo Model ◽

Silicone Implants ◽

Tracheal Defect ◽

Defect Repair ◽

3D Printed

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IL-1 drives breast cancer growth and bone metastasis in vivo

Oncotarget ◽

10.18632/oncotarget.12289 ◽

2016 ◽

Vol 7 (46) ◽

pp. 75571-75584 ◽

Cited By ~ 71

Author(s):

Ingunn Holen ◽

Diane V. Lefley ◽

Sheila E. Francis ◽

Sarah Rennicks ◽

Steven Bradbury ◽

...

Keyword(s):

Breast Cancer ◽

Bone Metastasis ◽

Cancer Growth ◽

Breast Cancer Growth

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Estrogen Deprivation and Inhibition of Breast Cancer Growth in Vivo through Activation of the Orphan Nuclear Receptor Liver X Receptor

Molecular Endocrinology ◽

10.1210/me.2007-0187 ◽

2007 ◽

Vol 21 (8) ◽

pp. 1781-1790 ◽

Cited By ~ 81

Author(s):

Haibiao Gong ◽

Ping Guo ◽

Yonggong Zhai ◽

Jie Zhou ◽

Hirdesh Uppal ◽

...

Keyword(s):

Breast Cancer ◽

Liver X Receptor ◽

Cancer Growth ◽

Estrogen Metabolism ◽

Endocrine Disorders ◽

Estrogen Deprivation ◽

Uterine Epithelial Cell ◽

Hepatic Expression ◽

Breast Cancer Growth

Abstract Estrogen plays an important role in normal physiology. It is also a risk factor for breast cancer, and antiestrogen therapies have been shown to be effective in the treatment and prevention of breast cancers. The liver is important for estrogen metabolism, and a compromised liver function has been linked to hyperestrogenism in patients. In this report, we showed that the liver X receptor (LXR) controls estrogen homeostasis by regulating the basal and inducible hepatic expression of estrogen sulfotransferase (Est, or Sult1e1), an enzyme critical for metabolic estrogen deactivation. Genetic or pharmacological activation of LXR resulted in Est induction, which in turn inhibited estrogen-dependent uterine epithelial cell proliferation and gene expression, as well as breast cancer growth in a nude mouse model of tumorigenicity. We further established that Est is a transcriptional target of LXR, and deletion of the Est gene in mice abolished the LXR effect on estrogen deprivation. Interestingly, Est regulation by LXR appeared to be liver specific, further underscoring the role of liver in estrogen metabolism. Activation of LXR failed to induce other major estrogen-metabolizing enzymes, suggesting that the LXR effect on estrogen metabolism is Est specific. In summary, our results have revealed a novel mechanism controlling estrogen homeostasis in vivo and may have implications for drug development in the treatment of breast cancer and other estrogen-related cancerous endocrine disorders.

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Small molecule STAT3 inhibitor, 6Br-6a suppresses breast cancer growth in vitro and in vivo

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2019.109502 ◽

2020 ◽

Vol 121 ◽

pp. 109502 ◽

Cited By ~ 3

Author(s):

Zhe Liu ◽

Xianmin Ge ◽

Yuchen Gu ◽

Yingying Huang ◽

Hao Liu ◽

...

Keyword(s):

Breast Cancer ◽

Small Molecule ◽

Cancer Growth ◽

Breast Cancer Growth

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Effects of Regulatory T Cell Depletion on NK Cell Responses against Listeria monocytogenes in Feline Immunodeficiency Virus Infected Cats

Viruses ◽

10.3390/v11110984 ◽

2019 ◽

Vol 11 (11) ◽

pp. 984

Author(s):

Simões ◽

LaVoy ◽

Dean

Keyword(s):

Immune Response ◽

Listeria Monocytogenes ◽

Dendritic Cell ◽

Innate Immune Response ◽

Feline Immunodeficiency Virus ◽

Innate Immune ◽

Treg Depletion ◽

Cell Responses ◽

Immunodeficiency Virus

Regulatory T cells (Treg) are key players in the maintenance of peripheral tolerance, preventing autoimmune diseases and restraining chronic inflammatory diseases. Evidence suggests Treg cells and NK cells have important roles in feline immunodeficiency virus (FIV) pathogenesis; however, in vivo studies investigating the interplay between these two cell populations are lacking. We previously described innate immune defects in FIV-infected cats characterized by cytokine deficits and impaired natural killer cell (NK) and NK T cell (NKT) functions. In this study, we investigated whether in vivo Treg depletion by treatment with an anti-feline CD25 monoclonal antibody would improve the innate immune response against subcutaneous challenge with Listeria monocytogenes (Lm). Treg depletion resulted in an increased overall number of cells in Lm-draining lymph nodes and increased proliferation of NK and NKT cells in FIV-infected cats. Treg depletion did not normalize expression of perforin or granzyme A by NK and NKT cells, nor did Treg depletion result in improved clearance of Lm. Thus, despite the quantitative improvements in the NK and NKT cell responses to Lm, there was no functional improvement in the early control of Lm. CD1a+ dendritic cell percentages in the lymph nodes of FIV-infected cats were lower than in specific-pathogen-free control cats and failed to upregulate CD80 even when Treg were depleted. Taken together, Treg depletion failed to improve the innate immune response of FIV-infected cats against Lm and this may be due to dendritic cell dysfunction.

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The Exopolysaccharide of Lactobacillus fermentum UCO-979C Is Partially Involved in Its Immunomodulatory Effect and Its Ability to Improve the Resistance against Helicobacter pylori Infection

Microorganisms ◽

10.3390/microorganisms8040479 ◽

2020 ◽

Vol 8 (4) ◽

pp. 479

Author(s):

Valeria Garcia-Castillo ◽

Guillermo Marcial ◽

Leonardo Albarracín ◽

Mikado Tomokiyo ◽

Patricia Clua ◽

...

Keyword(s):

Immune Response ◽

Helicobacter Pylori ◽

Gastric Mucosa ◽

Innate Immune Response ◽

Innate Immune ◽

Helicobacter Pylori Infection ◽

Beneficial Effects ◽

Ifn Γ ◽

H Pylori

Lactobacillus fermentum UCO-979C (Lf979C) beneficially modulates the cytokine response of gastric epithelial cells and macrophages after Helicobacter pylori infection in vitro. Nevertheless, no in vivo studies were performed with this strain to confirm its beneficial immunomodulatory effects. This work evaluated whether Lf979C improves protection against H. pylori infection in mice by modulating the innate immune response. In addition, we evaluated whether its exopolysaccharide (EPS) was involved in its beneficial effects. Lf979C significantly reduced TNF-α, IL-8, and MCP-1 and augmented IFN-γ and IL-10 in the gastric mucosa of H. pylori-infected mice. The differential cytokine profile induced by Lf979C in H. pylori-infected mice correlated with an improved reduction in the pathogen gastric colonization and protection against inflammatory damage. The purified EPS of Lf979C reduced IL-8 and enhanced IL-10 levels in the gastric mucosa of infected mice, while no effect was observed for IFN-γ. This work demonstrates for the first time the in vivo ability of Lf979C to increase resistance against H. pylori infection by modulating the gastric innate immune response. In addition, we advanced knowledge of the mechanisms involved in the beneficial effects of Lf979C by demonstrating that its EPS is partially responsible for its immunomodulatory effect.

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