scholarly journals Effects of Wine and Its Microbial-Derived Metabolites on Intestinal Permeability Using Simulated Gastrointestinal Digestion/Colonic Fermentation and Caco-2 Intestinal Cell Models

2021 ◽  
Vol 9 (7) ◽  
pp. 1378
Author(s):  
Irene Zorraquín-Peña ◽  
Diego Taladrid ◽  
Alba Tamargo ◽  
Mariana Silva ◽  
Natalia Molinero ◽  
...  
Keyword(s):  
Gallic Acid ◽  
Intestinal Permeability ◽  
Statistical Significance ◽  
Intestinal Barrier ◽  
Paracellular Permeability ◽  
Intestinal Cell ◽  
Mrna Levels ◽  
Protective Effects ◽  
Colonic Fermentation ◽  
Wine Polyphenols

This paper explores the effects of wine polyphenols on intestinal permeability in in vitro conditions. A red wine (2500 mg/L of gallic acid equivalents) was sequentially subjected to gastrointestinal and colonic digestion in the Dynamic Gastrointestinal Simulator (simgi®) to obtain two simulated fluids: intestinal-digested wine (IDW) and colonic-digested wine (CDW). The two fluids were incubated with Caco-2 cell monolayers grown in Transwell® inserts, and paracellular permeability was measured as transport of FITC-dextran. Non-significant decreases (p > 0.05) in paracellular permeability were found, which was attributed to the relatively low phenolic concentration in the solutions tested (15.6 and 7.8 mg of gallic acid equivalents/L for IDW and CDW, respectively) as quercetin (200 µM) and one of its microbial-derived phenolic metabolites, 3,4-dihydroxyphenylacetic acid (200 µM), led to significant decreases (p < 0.05). The expression of tight junction (TJ) proteins (i.e., ZO-1 and occludin) in Caco-2 cells after incubation with IDW and CDW was also determined. A slight increase in mRNA levels for occludin for both IDW and CDW fluids, albeit without statistical significance (p > 0.05), was observed. Analysis of the microbiome and microbial activity during wine colonic fermentation revealed relevant changes in the relative abundance of some families/genera (i.e., reduction in Bacteroides and an increase in Veillonella, Escherichia/Shigella and Akkermansia) as well as in the microbial production of SCFA (i.e., a significant increase in propionic acid in the presence of IDW), all of which might affect paracellular permeability. Both direct and indirect (microbiota-mediated) mechanisms might be involved in the protective effects of (wine) polyphenols on intestinal barrier integrity. Overall, this paper reinforces (wine) polyphenols as a promising dietary strategy to improve gut functionality, although further studies are needed to evaluate the effect on the intestinal barrier under different conditions.

scholarly journals Gastrointestinal Digestion of a Grape Pomace Extract: Impact on Intestinal Barrier Permeability and Interaction with Gut Microbiome

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2467
Author(s):  
Diego Taladrid ◽  
Dolores González de Llano ◽  
Irene Zorraquín-Peña ◽  
Alba Tamargo ◽  
Mariana Silva ◽  
...  
Keyword(s):  
Statistical Significance ◽  
Intestinal Barrier ◽  
Short Chain Fatty Acids ◽  
Paracellular Permeability ◽  
Grape Pomace ◽  
Mrna Levels ◽  
Cell Monolayers ◽  
Two Fluids ◽  
Potential Benefits ◽  
The Impact

Grape pomace (GP) is a winemaking by-product rich in polyphenols and fibre. Supplementation with GP extracts has shown potential benefits against oxidative stress- and inflammation-related pathologies. As a new nutritional target, this paper explores the impact of the ingestion of a grape pomace extract on intestinal barrier functionality. A GP extract was sequentially subjected to gastrointestinal and colonic digestion using the dynamic gastrointestinal simulator (simgi®). This generated two simulated fluids: intestinal-digested extract (IDE) and colonic-digested extract (CDE). The effects of these two fluids on paracellular permeability and the expression of tight junction (TJ) proteins (i.e., zonula occludens-1 (ZO-1) and occludin) were assessed in Caco-2-cell monolayers grown in Transwell® inserts. The IDE fluid significantly (p < 0.001) reduced the paracellular transport of FITC-dextran with respect to the control, whereas no significant differences (p > 0.05) were found for CDE, which could be due, at least partially, to the pro-leaky effect of the colonic digestion medium. Accordant slight increases in the mRNA levels of both ZO-1 and occludin were observed for IDE, but without statistical significance. Additionally, the colonic fermentation of the GP extract promoted the production of short-chain fatty acids (SCFA) and phenolic metabolites and led to changes in the relative abundance of some bacteria that might affect paracellular permeability. Overall, this paper reports first trends about the effects of grape pomace extracts on intestinal permeability that would require further confirmation in future experiments.

scholarly journals Lactobacillus rhamnosus GG culture supernatant ameliorates acute alcohol-induced intestinal permeability and liver injury

2012 ◽  
Vol 303 (1) ◽  
pp. G32-G41 ◽  
Author(s):  
Yuhua Wang ◽  
Yanlong Liu ◽  
Anju Sidhu ◽  
Zhenhua Ma ◽  
Craig McClain ◽  
...  
Keyword(s):  
Liver Injury ◽  
Intestinal Permeability ◽  
Culture Supernatant ◽  
Ex Vivo ◽  
Liver Steatosis ◽  
Lactobacillus Rhamnosus ◽  
Intestinal Barrier ◽  
Chow Diet ◽  
Mrna Levels ◽  
Lactobacillus Rhamnosus Gg

Endotoxemia is a contributing cofactor to alcoholic liver disease (ALD), and alcohol-induced increased intestinal permeability is one of the mechanisms of endotoxin absorption. Probiotic bacteria have been shown to promote intestinal epithelial integrity and protect barrier function in inflammatory bowel disease (IBD) and in ALD. Although it is highly possible that some common molecules secreted by probiotics contribute to this action in IBD, the effect of probiotic culture supernatant has not yet been studied in ALD. We examined the effects of Lactobacillus rhamnosus GG culture supernatant (LGG-s) on the acute alcohol-induced intestinal integrity and liver injury in a mouse model. Mice on standard chow diet were supplemented with supernatant from LGG culture (109 colony-forming unit/mouse) for 5 days, and one dose of alcohol at 6 g/kg body wt was administered via gavage. Intestinal permeability was measured by FITC-FD-4 ex vivo. Alcohol-induced liver injury was examined by measuring the activity of alanine aminotransferase (ALT) in plasma, and liver steatosis was evaluated by triglyceride content and Oil Red O staining of the liver sections. LGG-s pretreatment restored alcohol-induced reduction in ileum mRNA levels of claudin-1, intestine trefoil factor (ITF), P-glycoprotein (P-gp), and cathelin-related antimicrobial peptide (CRAMP), which play important roles on intestinal barrier integrity. As a result, LGG-s pretreatment significantly inhibited the alcohol-induced intestinal permeability, endotoxemia and subsequently liver injury. Interestingly, LGG-s pretreatment increased ileum mRNA expression of hypoxia-inducible factor (HIF)-2α, an important transcription factor of ITF, P-gp, and CRAMP. These results suggest that LGG-s ameliorates the acute alcohol-induced liver injury by promoting HIF signaling, leading to the suppression of alcohol-induced increased intestinal permeability and endotoxemia. The use of bacteria-free LGG culture supernatant provides a novel strategy for prevention of acute alcohol-induced liver injury.

scholarly journals Enterocyte-specific epidermal growth factor prevents barrier dysfunction and improves mortality in murine peritonitis

2009 ◽  
Vol 297 (3) ◽  
pp. G471-G479 ◽  
Author(s):  
Jessica A. Clark ◽  
Heng Gan ◽  
Alexandr J. Samocha ◽  
Amy C. Fox ◽  
Timothy G. Buchman ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Intestinal Permeability ◽  
Cecal Ligation ◽  
Intestinal Barrier ◽  
Protective Effects ◽  
Barrier Dysfunction ◽  
Intestinal Barrier Dysfunction ◽  
Septic Peritonitis ◽  
Epidermal Growth

Systemic administration of epidermal growth factor (EGF) decreases mortality in a murine model of septic peritonitis. Although EGF can have direct healing effects on the intestinal mucosa, it is unknown whether the benefits of systemic EGF in peritonitis are mediated through the intestine. Here, we demonstrate that enterocyte-specific overexpression of EGF is sufficient to prevent intestinal barrier dysfunction and improve survival in peritonitis. Transgenic FVB/N mice that overexpress EGF exclusively in enterocytes ( IFABP-EGF) and wild-type (WT) mice were subjected to either sham laparotomy or cecal ligation and puncture (CLP). Intestinal permeability, expression of the tight junction proteins claudins-1, -2, -3, -4, -5, -7, and -8, occludin, and zonula occludens-1; villus length; intestinal epithelial proliferation; and epithelial apoptosis were evaluated. A separate cohort of mice was followed for survival. Peritonitis induced a threefold increase in intestinal permeability in WT mice. This was associated with increased claudin-2 expression and a change in subcellular localization. Permeability decreased to basal levels in IFABP-EGF septic mice, and claudin-2 expression and localization were similar to those of sham animals. Claudin-4 expression was decreased following CLP but was not different between WT septic mice and IFABP-EGF septic mice. Peritonitis-induced decreases in villus length and proliferation and increases in apoptosis seen in WT septic mice did not occur in IFABP-EGF septic mice. IFABP-EGF mice had improved 7-day mortality compared with WT septic mice (6% vs. 64%). Since enterocyte-specific overexpression of EGF is sufficient to prevent peritonitis-induced intestinal barrier dysfunction and confers a survival advantage, the protective effects of systemic EGF in septic peritonitis appear to be mediated in an intestine-specific fashion.

scholarly journals The Protective Effects of Lactoferrin on Aflatoxin M1-Induced Compromised Intestinal Integrity

2021 ◽  
Vol 23 (1) ◽  
pp. 289
Author(s):  
Ya-Nan Gao ◽  
Song-Li Li ◽  
Xue Yang ◽  
Jia-Qi Wang ◽  
Nan Zheng
Keyword(s):  
Adherens Junction ◽  
Intestinal Barrier ◽  
Mapk Signaling ◽  
Regulatory Subunit ◽  
Intestinal Cell ◽  
Aflatoxin M1 ◽  
Protective Effects ◽  
Barrier Dysfunction ◽  
Intestinal Integrity ◽  
Study Results

Aflatoxin M1 (AFM1), the only toxin with maximum residue levels in milk, has adverse effects on the intestinal barrier, resulting in intestinal inflammatory disease. Lactoferrin (LF), one of the important bioactive proteins in milk, performs multiple biological functions, but knowledge of the protective effects of LF on the compromised intestinal barrier induced by AFM1 has not been investigated. In the present study, results using Balb/C mice and differentiated Caco-2 cells showed that LF intervention decreased AFM1-induced increased intestinal permeability, improved the protein expression of claudin-3, occludin and ZO-1, and repaired the injured intestinal barrier. The transcriptome and proteome were used to clarify the underlying mechanisms. It was found that LF reduced the intestinal barrier dysfunction caused by AFM1 and was associated with intestinal cell survival related pathways, such as cell cycle, apoptosis and MAPK signaling pathway and intestinal integrity related pathways including endocytosis, tight junction, adherens junction and gap junction. The cross-omics analysis suggested that insulin receptor (INSR), cytoplasmic FMR1 interacting protein 2 (CYFIP2), dedicator of cytokinesis 1 (DOCK1) and ribonucleotide reductase regulatory subunit M2 (RRM2) were the potential key regulators as LF repaired the compromised intestinal barrier. These findings indicated that LF may be an alternative treatment for the compromised intestinal barrier induced by AFM1.

scholarly journals Short-Chain Fatty Acids Manifest Stimulative and Protective Effects on Intestinal Barrier Function Through the Inhibition of NLRP3 Inflammasome and Autophagy

2018 ◽  
Vol 49 (1) ◽  
pp. 190-205 ◽  
Author(s):  
Yanhai Feng ◽  
Yu Wang ◽  
Pei Wang ◽  
Yalan Huang ◽  
Fengjun Wang
Keyword(s):  
Nlrp3 Inflammasome ◽  
Barrier Function ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Intestinal Barrier ◽  
Short Chain Fatty Acids ◽  
Paracellular Permeability ◽  
Intestinal Barrier Function ◽  
Protective Effects ◽  
Permeability Increase

Background/Aims: Short-chain fatty acids (SCFAs) are the major energy resources of intestinal epithelial cells. It has been reported that SCFAs can repair the dysfunction of intestinal barrier, however, the underlying mechanisms are still not fully understood. Here, we investigated the stimulative and protective effects of SCFAs on intestinal barrier function and the possible mechanisms. Methods: To investigate the effects of SCFAs on intestinal barrier function, the Caco-2 monolayers were exposed to acetate, propionate, butyrate respectively or simultaneously without or with lipopolysaccharide (LPS). Next, Caco-2 cells were treated with trichostatin A and etomoxir to identify whether SCFAs act as HDAC inhibitors or energy substances. To activate NLRP3 inflammasome and autophagy, Caco-2 cells were treated with LPS+ATP and rapamycin respectively without or with SCFAs. The transepithelial electrical resistance (TER) and paracellular permeability were respectively detected with a Millicell-ERS voltohmmeter and fluorescein isothiocyanate-labeled dextran. Immunoblotting and immunofluorescence were applied to analyze the expression and distribution of tight junction proteins, and the activation of NLRP3 inflammasome and autophagy. Results: Acetate (0.5mM), propionate(0.01mM) and butyrate (0.01mM) alone or in combination significantly increased TER, and stimulated the formation of tight junction. SCFAs also dramatically attenuated the LPS-induced TER reduction and paracellular permeability increase, accompanying significantly alleviated morphological disruption of ZO-1 and occludin. Meanwhile, the activation of NLRP3 inflammasome and autophagy induced by LPS were significantly inhibited by SCFAs. Trichostatin A imitated the inhibiting action of SCFAs on NLRP3 inflammasome, whereas etomoxir blocked the action of SCFAs on protecting intestinal barrier and inhibiting autophagy. In addition, the activation of autophagy and NLRP3 inflammasome by rapamycin and LPS+ATP resulted in TER reduction, paracellular permeability increase and morphological disruption of both ZO-1 and occludin, which was alleviated by SCFAs. Conclusion: It is suggested that SCFAs stimulate the formation of intestinal barrier, and protect the intestinal barrier from the disruption of LPS through inhibiting NLRP3 inflammasome and autophagy. In addition, SCFAs act as energy substances to protect intestinal barrier and inhibit autophagy, but act as HDAC inhibitors to suppress NLRP3 inflammasome. Furthermore, the mutual promoting action between NLRP3 inflammasome and autophagy would destroy intestinal barrier function, which could be alleviated by SCFAs.

Effects of High Intensity Statin Therapy in the Treatment of Diabetic Dyslipidemia in Patients with Coronary Artery Disease

2018 ◽  
Vol 24 (4) ◽  
pp. 427-441 ◽  
Author(s):  
Marija Vavlukis ◽  
Sasko Kedev
Keyword(s):  
Statin Therapy ◽  
High Intensity ◽  
Statistical Significance ◽  
Incident Diabetes ◽  
Moderate Intensity ◽  
Protective Effects ◽  
Pcsk9 Inhibitors ◽  
Diabetic Dyslipidemia ◽  
Patients With Diabetes

Background: Diabetic dyslipidemia has specifics that differ from dyslipidemia in patients without diabetes, which contributes to accelerated atherosclerosis equally as dysglycemia. The aim of this study was to deduce the interdependence of diabetic dyslipidemia and cardiovascular diseases (CVD), therapeutic strategies and the risk of diabetes development with statin therapy. Method: We conducted a literature review of English articles through PubMed, PubMed Central and Cochrane, on the role of diabetic dyslipidemia in atherosclerosis, the antilipemic treatment with statins, and the role of statin therapy in newly developed diabetes, by using key words: atherosclerosis, diabetes mellitus, diabetic dyslipidemia, CVD, statins, nicotinic acid, fibrates, PCSK9 inhibitors. Results: hyperglycemia and dyslipidemia cannot be treated separately in patients with diabetes. It seems that dyslipidemia plays one of the key roles in the development of atherosclerosis. High levels of TG, decreased levels of HDL-C and increased levels of small dense LDL- C particles in the systemic circulation are the most specific attributes of diabetic dyslipidemia, all of which originate from an inflated flux of free fatty acids occurring due to the preceding resistance to insulin, and exacerbated by elevated levels of inflammatory adipokines. Statins are a fundamental treatment for diabetic dyslipidemia, both for dyslipidemia and for CVD prevention. The use of statin treatment with high intensity is endorsed for all diabetes-and-CVD patients, while a moderate - intensity treatment can be applied to patients with diabetes, having additional risk factors for CVD. Statins alone are thought to possess a small, although of statistical significance, risk of incident diabetes, outweighed by their benefits. Conclusion: As important as hyperglycemia and glycoregulation are in CVD development in patients with diabetes, diabetic dyslipidemia plays an even more important role. Statins remain the cornerstone of antilipemic treatment in diabetic dyslipidemia, and their protective effects in CVD progression overcome the risk of statin- associated incident diabetes.

Hepato-renal protective effects of gallic acid and p-coumaric acid in nicotinamide/streptozotocin-induced diabetic rats

2016 ◽  
Vol 5 (06) ◽  
pp. 4641 ◽  
Author(s):  
Adel Abdel Moneim* ◽  
Sanaa M. Abd El-Twab ◽  
Mohamed B. Ashour ◽  
Ahmed I. Yousef
Keyword(s):  
Body Weight ◽  
Gallic Acid ◽  
Protein Profile ◽  
Serum Glucose ◽  
Diabetic Rats ◽  
Hypoglycemic Agents ◽  
Protective Effects ◽  
Coumaric Acid ◽  
Experimental Type

The goal of diabetes treatment is primarily to save life and alleviate symptoms and secondary to prevent long-term diabetic complications resulting from hyperglycemia. Thus, our present investigation was designed to evaluate the hepato-renal protective effects of gallic acid and p-coumaric acid in nicotinamide/streptozotocin (NA/STZ)-induced diabetic rats. Experimental type 2 diabetes was induced by a single intraperitoneal (i.p.) injection of STZ (65 mg/kg b.wt.), after 15 min of i.p. injection of NA (120 mg/kg b.wt.). Gallic acid and p-coumaric acid were orally administered to diabetic rats at a dose of 20, 40 mg/kg b.wt./day, respectively, for 6 weeks. Body weight, serum glucose, protein profile, liver function enzymes and kidney function indicators was assayed. Treatment with either gallic acid or p-coumaric acid significantly ameliorated the elevated levels of glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea and uric acid. Both compounds were also found to restore total protein, albumin, and globulin as well as body weight of diabetic rats to near normal values. It can conclude that both gallic acid and p-coumaric acid have potent hypoglycemic and hepato-renal protective effects in diabetic rats. Therefore, our results suggest promising hypoglycemic agents that can attenuate the progression of diabetic hepatopathy and nephropathy.

scholarly journals Protective Effect of Psoralea corylifolia L. Seed Extract against Palmitate-Induced Neuronal Apoptosis in PC12 Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Yunkyoung Lee ◽  
Hee-Sook Jun ◽  
Yoon Sin Oh
Keyword(s):  
Pc12 Cells ◽  
Molecular Mechanisms ◽  
Neuronal Cell ◽  
Marker Genes ◽  
Heme Oxygenase 1 ◽  
Mrna Levels ◽  
Protective Effects ◽  
Psoralea Corylifolia ◽  
Antioxidant Genes ◽  
Bax Protein

The extract of Psoralea corylifolia seeds (PCE) has been widely used as a herbal medicine because of its beneficial effect on human health. In this study, we investigated the protective effects and molecular mechanisms of PCE on palmitate- (PA-) induced toxicity in PC12 cells, a neuron-like cell line. PCE significantly increased cell viability in PA-treated PC12 cells and showed antiapoptotic effects, as evidenced by decreased expression of cleaved caspase-3, cleaved poly(ADP-ribose) polymerase, and bax protein as well as increased expression of bcl-2 protein. In addition, PCE treatment reduced PA-induced reactive oxygen species production and upregulated mRNA levels of antioxidant genes such as nuclear factor (erythroid-derived 2)-like 2 and heme oxygenase 1. Moreover, PCE treatment recovered the expression of autophagy marker genes such as beclin-1 and p62, which was decreased by PA treatment. Treatment with isopsoralen, one of the major components of PCE extract, also recovered the expression of autophagy marker genes and reduced PA-induced apoptosis. In conclusion, PCE exerts protective effects against lipotoxicity via its antioxidant function, and this effect is mediated by activation of autophagy. PCE might be a potential pharmacological agent to protect against neuronal cell injury caused by oxidative stress or lipotoxicity.

scholarly journals AB0073 INTESTINAL PERMEABILITY IN SPONDYLOARTHRITIS: A SYSTEMATIC REVIEW OF THE LITERATURE

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1067.1-1067
Author(s):  
S. Hecquet ◽  
P. Totoson ◽  
H. Martin ◽  
C. Prati ◽  
D. Wendling ◽  
...  
Keyword(s):  
Systematic Review ◽  
Disease Activity ◽  
Intestinal Permeability ◽  
Intestinal Inflammation ◽  
Intestinal Barrier ◽  
Basic Research ◽  
Final Analysis ◽  
Potential Marker ◽  
Inflammatory Drugs ◽  
Permeability Evaluation

Background:Growing evidence argue for a role of the gut in the pathophysiology of various chronic rheumatic diseases such as spondyloarthritis (SpA). This so-called “gut-joint axis” involves dysbiosis, bacterial translocation, intestinal inflammation and increase in intestinal permeability. Recent data from clinical and basic research suggested that the integrity of the intestinal barrier might be a key determinant in translating autoimmunity to inflammation, making intestinal permeability a potential marker or a target for future therapies.Objectives:To analyse the available data on intestinal permeability in SpA patients and the effects of drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) on intestinal permeability.Methods:A systematic review was conducted. Without date restriction, the following databases were searched through September 1, 2020: Medline, Embase and Cochrane. Studies with patients with SpA assessing the intestinal permeability were selected. Some of the included studies have assessed the effect of NSAIDs on intestinal permeability.Results:A total of 12 studies were included in the final analysis. The 12 studies involved a total of 268 SpA patients, including 240 ankylosing spondylitis (AS). Among the studies included, four studies used the lactulose/mannitol test, four studies used the 51Cr-ethylenediaminetetraacetic test and two studies used the polyethylene glycols test. Nine of the 12 studies reported increased intestinal permeability regardless on the method used for intestinal permeability evaluation. Four studies evaluated the link between disease activity, assessed by CRP and ESR levels, and intestinal permeability and showed no correlation between increased intestinal permeability and markers of disease activity in AS patients. As regards the effects of NSAIDs on intestinal permeability, data are controversial. Two studies, including one evaluating indomethacin, did not show any influence of NSAIDs in AS patients, one study showed an increase in intestinal permeability under NSAIDs in only 60% of the patients, another study reported increased intestinal permeability. When comparing the effect of NSAIDs in patients with AS to healthy subjects, one study reported a comparable NSAIDs-induced increase in intestinal permeability in both groups.Conclusion:The results of our review suggest that increased intestinal permeability is present in SpA patients even in the absence of NSAIDs use and regardless of the method used to assess intestinal permeability. The effects of NSAIDs on intestinal permeability in SpA patients is more controversial and further studies are needed to clarify them.Disclosure of Interests:None declared

scholarly journals Comparing the protective effects of resveratrol, curcumin and sulforaphane against LPS/IFN-γ-mediated inflammation in doxorubicin-treated macrophages

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Haidy A. Saleh ◽  
Eman Ramdan ◽  
Mohey M. Elmazar ◽  
Hassan M. E. Azzazy ◽  
Anwar Abdelnaser
Keyword(s):  
Nitric Oxide ◽  
Inflammatory Response ◽  
Raw 264.7 Cells ◽  
Inos Mrna ◽  
No Production ◽  
Raw 264.7 ◽  
Mrna Levels ◽  
Protective Effects ◽  
Tnf Α ◽  
Ifn Γ

AbstractDoxorubicin (DOX) chemotherapy is associated with the release of inflammatory cytokines from macrophages. This has been suggested to be, in part, due to DOX-mediated leakage of endotoxins from gut microflora, which activate Toll-like receptor 4 (TLR4) signaling in macrophages, causing severe inflammation. However, the direct function of DOX on macrophages is still unknown. In the present study, we tested the hypothesis that DOX alone is incapable of stimulating inflammatory response in macrophages. Then, we compared the anti-inflammatory effects of curcumin (CUR), resveratrol (RES) and sulforaphane (SFN) against lipopolysaccharide/interferon-gamma (LPS/IFN-γ)-mediated inflammation in the absence or presence of DOX. For this purpose, RAW 264.7 cells were stimulated with LPS/IFN-γ (10 ng/mL/10 U/mL) in the absence or presence of DOX (0.1 µM). Our results showed that DOX alone is incapable of stimulating an inflammatory response in RAW 264.7 macrophages. Furthermore, after 24 h of incubation with LPS/IFN-γ, a significant increase in tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and inducible nitric oxide synthase (iNOS) mRNA levels was observed. Similarly, nitric oxide (NO) production and TNF-α and IL-6 protein levels were significantly upregulated. Moreover, in LPS/IFN-γ-treated macrophages, the microRNAs (miRNAs) miR-146a, miR-155, and miR-21 were significantly overexpressed. Interestingly, upon testing CUR, RES, and SFN against LPS/IFN-γ-mediated inflammation, only SFN was able to significantly reverse the LPS/IFN-γ-mediated induction of iNOS, TNF-α and IL-6 and attenuate miR-146a and miR-155 levels. In conclusion, SFN, at the transcriptional and posttranscriptional levels, exhibits potent immunomodulatory action against LPS/IFN-γ-stimulated macrophages, which may indicate SFN as a potential treatment for DOX-associated inflammation.

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