Butyrate enhances the production of nitric oxide in mouse vascular endothelial cells in response to gamma interferon

Morikawa, Akiko; Sugiyama, Tsuyoshi; Koide, Naoki; Mori, Isamu; Mu, Mya Mya; Yoshida, Tomoaki; Hassan, Ferdaus; Islam, Shamima; Yokochi, Takashi

doi:10.1177/09680519040100010401

Cited by 10 publications

(3 citation statements)

References 21 publications

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“…In a previous study, butyrate significantly reduced NO production in LPS-stimulated RAW cells, and the inhibition was reversed by the removal of butyrate ( 46 ). Another study reported from the same group showed that butyrate increased NO production in the murine vascular endothelial cell line (END-D) in response to LPS or IFN-γ ( 47 ). Recently, NaB was reported to markedly suppress macrophage-driven inflammation in a non-alcoholic steatohepatitis model.…”

Section: Resultsmentioning

confidence: 99%

The postbiotic sodium butyrate synergizes the antiproliferative effects of dexamethasone against the AGS gastric adenocarcinoma cells

Eladwy,

Alsherbiny,

Chang

et al. 2024

Front. Nutr.

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A growing body of literature underlines the fundamental role of gut microbiota in the occurrence, treatment, and prognosis of cancer. In particular, the activity of gut microbial metabolites (also known as postbiotics) against different cancer types has been recently reported in several studies. However, their in-depth molecular mechanisms of action and potential interactions with standard chemotherapeutic drugs remain to be fully understood. This research investigates the antiproliferative activities of postbiotics- short-chain fatty acid (SCFA) salts, specifically magnesium acetate (MgA), sodium propionate (NaP), and sodium butyrate (NaB), against the AGS gastric adenocarcinoma cells. Furthermore, the potential synergistic interactions between the most active SCFA salt-NaB and the standard drug dexamethasone (Dex) were explored using the combination index model. The molecular mechanisms of the synergy were investigated using reactive oxygen species (ROS), flow cytometry and biochemometric and liquid chromatography-mass spectrometry (LC–MS)-driven proteomics analyses. NaB exhibited the most significant inhibitory effect (p < 0.05) among the tested SCFA salts against the AGS gastric cancer cells. Additionally, Dex and NaB exhibited strong synergy at a 2:8 ratio (40 μg/mL Dex + 2,400 μg/mL NaB) with significantly greater inhibitory activity (p < 0.05) compared to the mono treatments against the AGS gastric cancer cells. MgA and NaP reduced ROS production, while NaB exhibited pro-oxidative properties. Dex displayed antioxidative effects, and the combination of Dex and NaB (2,8) demonstrated a unique pattern, potentially counteracting the pro-oxidative effects of NaB, highlighting an interaction. Dex and NaB individually and in combination (Dex:NaB 40:2400 μg/mL) induced significant changes in cell populations, suggesting a shift toward apoptosis (p < 0.0001). Analysis of dysregulated proteins in the AGS cells treated with the synergistic combination revealed notable downregulation of the oncogene TNS4, suggesting a potential mechanism for the observed antiproliferative effects. These findings propose the potential implementation of NaB as an adjuvant therapy with Dex. Further investigations into additional combination therapies, in-depth studies of the molecular mechanisms, and in vivo research will provide deeper insights into the use of these postbiotics in cancer, particularly in gastric malignancies.

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Section: Resultsmentioning

confidence: 99%

The postbiotic sodium butyrate synergizes the antiproliferative effects of dexamethasone against the AGS gastric adenocarcinoma cells

Eladwy,

Alsherbiny,

Chang

et al. 2024

Front. Nutr.

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“…Nitrite in the culture supernatant was measured for NO productivity in a microplate reader by the Griess method as described elsewhere (11, 12). Potassium nitrite diluted in culture medium was used as a standard.…”

Section: Methodsmentioning

confidence: 99%

Nystatin‐induced nitric oxide production in mouse macrophage‐like cell line RAW264.7

Koide

Naiki

Morikawa

et al. 2009

Microbiology and Immunology

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Nystatin is known to deplete lipid rafts from mammalian cell membranes. Lipid rafts have been reported to be necessary for lipopolysaccharide signaling. In this study, it was unexpectedly found that lipopolysaccharide-induced nitric oxide production was not inhibited, but rather increased in the presence of a non-cytotoxic concentration of nystatin. Surprisingly, treatment with nystatin induced only NO production and iNOS expression in RAW264.7 cells. At the concentration used, no changes in the expression of GM1 ganglioside, a lipid raft marker on RAW264.7 cells, was seen. From studies using several kinds of inhibitors for signaling molecules, nystatin-induced NO production seems to occur via the iκB/NF-κB and the PI3 K/Akt pathway. Furthermore, because nystatin is known to activate the Na-K pump, we examined whether the Na-K pump inhibitor amiloride suppresses nystatin-induced NO production. It was found that amiloride significantly inhibited nystatin-induced NO production. The results suggest that a moderate concentration of nystatin induces NO production by Na-pump activation through the PI3 kinase/Akt/NF-κB pathway without affecting the condition of lipid rafts.Key words lipopolysaccharide, nitric oxide, nystatin, RAW264.7 cells.NO acts as a releasing factor that mediates vasodilation, a neuronal messenger molecule, and a major regulatory molecule and principal cytotoxic mediator of the immune system (1-5). A large amount of NO is synthesized by an inducible isoform of NO synthase (iNOS) that, once expressed, produces NO for long periods of time (3, 6). iNOS-mediated NO production is enhanced by and LPS in vitro (6, 7). NO has emerged as an important cytotoxic and cytostatic effector in host defense against a number of pathogens, including viruses, bacteria, fungi, and parasites.Nystatin is clinically used as anti-fungal drug. On the other hand, nystatin is also known as a lipid depleter and List of Abbreviations:Akt, protein kinase B; COX-2, cyclooxygenase-2; CTB, cholera toxin B; ERK1/2, extracellular signal-regulated kinase 1/2; GPI, glycosylphosphatidylinositol; IFN, interferon; IκB, inhibitor of nuclear factor κB; iNOS, inducible NO synthase; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MyD88, myeloid differentiation response gene 88; NF-κB, nuclear factor κB; NO, nitric oxid; PKB, protein kinase B; PI3K/Akt, phosphatidylionsitol 3-kinase/Akt; TLR, Toll-like receptor; TNF, tumor necrosis factor. often utilized in lipid rafts studies (8,9). Lipid rafts are glycolipid-enriched membrane domains that are rich in cholesterol and sphingolipids. Certain proteins associated with cellular signaling processes have been shown to associate with lipid rafts (10). Proteins that have shown association to the lipid rafts include GPI-anchored proteins, doubly-acylated tyrosine kinases of the Src family, and transmembrane proteins. Lipid rafts have been implicated in a number of physiological and pathological processes. Unexpectedly, we found that non-cytotoxic doses of nystatin caused NO p...

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“…In fibroblasts, butyrate inhibits proliferation and decreases proline-reach protein synthesis, hyaluronate, and collagen [ 35 , 36 ]. The effects of butyrate in endothelial cells are linked to NO production [ 37 ], the downregulation of endothelin-1 expression [ 38 ], and inhibition of angiogenesis via the attenuation of HIF-1α, VEGF-, and COX-mediated signaling [ 27 , 39 , 40 ]. The anti-inflammatory effects of butyrate are mediated via decreased inflammatory cytokine production and down-regulation of VCAM-1 and ICAM-1 in endothelial cells [ 29 , 41 , 42 ].…”

Section: Introductionmentioning

confidence: 99%

The Short-Chain Fatty Acid Butyrate Attenuates Pulmonary Vascular Remodeling and Inflammation in Hypoxia-Induced Pulmonary Hypertension

Karoor

Strassheim

Sullivan

et al. 2021

IJMS

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Pulmonary hypertension (PH) is a progressive cardiovascular disorder in which local vascular inflammation leads to increased pulmonary vascular remodeling and ultimately to right heart failure. The HDAC inhibitor butyrate, a product of microbial fermentation, is protective in inflammatory intestinal diseases, but little is known regarding its effect on extraintestinal diseases, such as PH. In this study, we tested the hypothesis that butyrate is protective in a Sprague–Dawley (SD) rat model of hypoxic PH. Treatment with butyrate (220 mg/kg intake) prevented hypoxia-induced right ventricular hypertrophy (RVH), hypoxia-induced increases in right ventricular systolic pressure (RVSP), pulmonary vascular remodeling, and permeability. A reversal effect of butyrate (2200 mg/kg intake) was observed on elevated RVH. Butyrate treatment also increased the acetylation of histone H3, 25–34 kDa, and 34–50 kDa proteins in the total lung lysates of butyrate-treated animals. In addition, butyrate decreased hypoxia-induced accumulation of alveolar (mostly CD68+) and interstitial (CD68+ and CD163+) lung macrophages. Analysis of cytokine profiles in lung tissue lysates showed a hypoxia-induced upregulation of TIMP-1, CINC-1, and Fractalkine and downregulation of soluble ICAM (sICAM). The expression of Fractalkine and VEGFα, but not CINC-1, TIMP-1, and sICAM was downregulated by butyrate. In rat microvascular endothelial cells (RMVEC), butyrate (1 mM, 2 and 24 h) exhibited a protective effect against TNFα- and LPS-induced barrier disruption. Butyrate (1 mM, 24 h) also upregulated tight junctional proteins (occludin, cingulin, claudin-1) and increased the acetylation of histone H3 but not α-tubulin. These findings provide evidence of the protective effect of butyrate on hypoxic PH and suggest its potential use as a complementary treatment for PH and other cardiovascular diseases.

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Butyrate enhances the production of nitric oxide in mouse vascular endothelial cells in response to gamma interferon

Cited by 10 publications

References 21 publications

The postbiotic sodium butyrate synergizes the antiproliferative effects of dexamethasone against the AGS gastric adenocarcinoma cells

The postbiotic sodium butyrate synergizes the antiproliferative effects of dexamethasone against the AGS gastric adenocarcinoma cells

Nystatin‐induced nitric oxide production in mouse macrophage‐like cell line RAW264.7

The Short-Chain Fatty Acid Butyrate Attenuates Pulmonary Vascular Remodeling and Inflammation in Hypoxia-Induced Pulmonary Hypertension

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