Anti-Inflammatory Effects of Novel P2X4 Receptor Antagonists, NC-2600 and NP-1815-PX, in a Murine Model of Colitis

Abstract The pharmacological blockade of P2X4 receptors has shown potential benefits in the management of several immune/inflammatory diseases. However, data regarding the involvement of P2X4 receptors in the pathophysiological mechanisms of action in intestinal inflammation are not well defined. We aimed to evaluate the anti-inflammatory effects of two novel and selective P2X4 receptor antagonists, NC-2600 and NP-1815-PX, and characterize the molecular mechanisms of their action in a murine model of 2,4-dinitrobenzene sulfonic acid (DNBS)-induced colitis. These two drugs and dexamethasone (DEX) were administered orally for 6 days, immediately after the manifestation of DNBS. The body weight decrease, resulting from colitis, was attenuated by NC-2600 and NP-1815-PX, but not DEX. However, all three drugs attenuated the increase in spleen weight and ameliorated macroscopic and microscopic colonic tissue damage. Furthermore, all three compounds decreased tissue IL-1β levels and caspase-1 expression and activity. Colonic tissue increase of tumor necrosis factor was downregulated by DEX, while both NC-2600 and NP-1815-PX were ineffective The reduction of occludin associated with colitis was ameliorated by NC-2600 and NP-1815-PX, but not DEX. In THP-1 cells, lipopolysaccharide and ATP upregulated IL-1β release and NLRP3, caspase-1, caspase-5 and caspase-8 activity, but not of caspase-4. These changes were prevented by NC-2600 and NP-1815-PX treatment. For the first time, the above findings show that the selective inhibition of P2X4 receptors represents a viable approach to manage bowel inflammation via the inhibition of NLRP3 inflammasome signaling pathways.

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Dietary Supplementation with Sea Bass (Lateolabrax maculatus) Ameliorates Ulcerative Colitis and Inflammation in Macrophages through Inhibiting Toll-Like Receptor 4-Linked Pathways

International Journal of Molecular Sciences ◽

10.3390/ijms20122907 ◽

2019 ◽

Vol 20 (12) ◽

pp. 2907 ◽

Cited By ~ 3

Author(s):

Jiali Chen ◽

Muthukumaran Jayachandran ◽

Wenxia Zhang ◽

Lingyuqing Chen ◽

Bin Du ◽

...

Keyword(s):

Molecular Mechanisms ◽

Intestinal Inflammation ◽

In Vitro Study ◽

Sea Bass ◽

Mice Model ◽

Food Material ◽

Lateolabrax Maculatus ◽

Associated Conditions ◽

Anti Inflammatory

Sea bass (Lateolabrax maculatus) is a kind of food material commonly consumed in daily life. In traditional Chinese medicinal books, it has been indicated that sea bass can be applied for managing many inflammation-associated conditions. However, the studies on the pharmacological mechanisms of inflammation of sea bass remain scarce. Hence, this study aims to investigate the molecular mechanisms of the anti-inflammatory activity of sea bass. Anti-inflammatory activities of sea bass were assessed using dextran sulfate sodium (DSS)-induced colitis in a mice model and lipopolysaccharide (LPS)-activated macrophages model. Low body weight and short colon length were observed in DSS-fed mice that were significantly recovered upon sea bass treatments. Moreover, the colon histopathology score showed that sea bass-treated mice had decreased crypt damage, focal inflammation infiltration and the extent of inflammation, suggesting that treatment with sea bass could attenuate intestinal inflammation. In addition, the in-vitro study conjointly indicated that sea bass could suppress the inflammatory mediators in LPS-activated macrophage by inhibiting the TLR4-linked pathway. The present findings demonstrated that sea bass has an inhibitory effect on TLR4 signaling; thus, it could be a promising candidate for treating inflammation-associated conditions. A further justification for the clinical application of sea bass in treating inflammation-associated conditions is necessary.

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Preventative oral methylthioadenosine is anti-inflammatory and reduces DSS-induced colitis in mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00549.2011 ◽

2012 ◽

Vol 303 (1) ◽

pp. G71-G82 ◽

Cited By ~ 10

Author(s):

Nancy M. Benight ◽

Barbara Stoll ◽

Juan C. Marini ◽

Douglas G. Burrin

Keyword(s):

Time Course ◽

Intestinal Inflammation ◽

Tissue Injury ◽

Experimental Colitis ◽

Therapeutic Benefit ◽

The Body ◽

Myeloperoxidase Activity ◽

Matrix Remodeling ◽

Inflammatory Models ◽

Anti Inflammatory

Methylthioadenosine (MTA) is a precursor of the methionine salvage pathway and has been shown to have anti-inflammatory properties in various models of acute and chronic inflammation. However, the anti-inflammatory properties of MTA in models of intestinal inflammation are not defined. We hypothesized that orally administered MTA would be bioavailable and reduce morbidity associated with experimental colitis. We examined clinical, histological, and molecular markers of disease in mice provided oral MTA before (preventative) or after (therapy) the induction of colitis with 3% dextran sulfate sodium (DSS). We found a reduction in disease activity, weight loss, myeloperoxidase activity, and histological damage in mice given preventative MTA compared with DSS alone. We also found that equivalent supplementation with methionine could not reproduce the anti-inflammatory effects of MTA, and that MTA had no detectable adverse effects in control or DSS mice. Expression microarray analysis of colonic tissue showed several dominant pathways related to inflammatory cytokines/chemokines and extracellular matrix remodeling were upregulation by DSS and suppressed in MTA-supplemented mice. MTA is rapidly absorbed in the gastrointestinal tract and disseminated throughout the body, based on a time course analysis of an oral bolus of MTA. This effect is transient, with MTA levels falling to near baseline within 90 min in most organs. Moreover, MTA did not lead to increased blood or tissue methionine levels, suggesting that its effects are specific. However, MTA provided limited therapeutic benefit when administered after the onset of colitis. Our results show that oral MTA supplementation is a safe and effective strategy to prevent inflammation and tissue injury associated with DSS colitis in mice. Additional studies in chronic inflammatory models are necessary to determine if MTA is a safe and beneficial option for the maintenance of remission in human inflammatory bowel disease.

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Differential Physiological Responses Elicited by Ancient and Heritage Wheat Cultivars Compared to Modern Ones

Nutrients ◽

10.3390/nu11122879 ◽

2019 ◽

Vol 11 (12) ◽

pp. 2879 ◽

Cited By ~ 4

Author(s):

Enzo Spisni ◽

Veronica Imbesi ◽

Elisabetta Giovanardi ◽

Giovannamaria Petrocelli ◽

Patrizia Alvisi ◽

...

Keyword(s):

Animal Studies ◽

Molecular Mechanisms ◽

Intestinal Inflammation ◽

Physiological Responses ◽

Point Of View ◽

Wheat Varieties ◽

Gluten Peptide ◽

Pubmed Search ◽

Modern Wheat ◽

Anti Inflammatory

Although ancient, heritage, and modern wheat varieties appear rather similar from a nutritional point of view, having a similar gluten content and a comparable toxicity linked to their undigested gluten peptide, whenever the role of ancient end heritage wheat grains has been investigated in animal studies or in clinical trials, more anti-inflammatory effects have been associated with the older wheat varieties. This review provides a critical overview of existing data on the differential physiological responses that could be elicited in the human body by ancient and heritage grains compared to modern ones. The methodology used was that of analyzing the results of relevant studies conducted from 2010 through PubMed search, by using as keywords “ancient or heritage wheat”, “immune wheat” (protein or peptides), and immune gluten (protein or peptides). Our conclusion is that, even if we do not know exactly which molecular mechanisms are involved, ancient and heritage wheat varieties have different anti-inflammatory and antioxidant proprieties with respect to modern cultivars. It is, therefore, reasonable to assume that the health proprieties attributed to older cultivars could be related to wheat components which have positive roles in the modulation of intestinal inflammation and/or permeability.

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Rosmarinus officinalis L. extract ameliorates intestinal inflammation through MAPKs/NF-κB signaling in a murine model of acute experimental colitis

Food & Function ◽

10.1039/c6fo00244g ◽

2016 ◽

Vol 7 (7) ◽

pp. 3233-3243 ◽

Cited By ~ 11

Author(s):

Kanakaraju Medicherla ◽

Avanee Ketkar ◽

Bidya Dhar Sahu ◽

Godi Sudhakar ◽

Ramakrishna Sistla

Keyword(s):

Murine Model ◽

Intestinal Inflammation ◽

Experimental Colitis ◽

Rosmarinus Officinalis ◽

Anti Inflammatory ◽

Rosmarinus Officinalis L

Anti-inflammatory and anti-colitis effects of Rosmarinus officinalis L. extract (RE).

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Anti-Inflammatory Effects of Berberine Hydrochloride in an LPS-Induced Murine Model of Mastitis

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/5164314 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 3

Author(s):

Xichun Wang ◽

Shibin Feng ◽

Nana Ding ◽

Yanting He ◽

Cheng Li ◽

...

Keyword(s):

Murine Model ◽

Molecular Mechanisms ◽

Neutrophil Infiltration ◽

Mammary Glands ◽

Histopathological Changes ◽

Berberine Hydrochloride ◽

Treatment Groups ◽

Qrt Pcr ◽

Anti Inflammatory ◽

Inflammatory Action

Berberine hydrochloride is an isoquinoline type alkaloid extracted from Berberidaceae, Rutaceae, and other plants. Previous reports have shown that berberine hydrochloride has anti-inflammatory properties. However, the underlying molecular mechanisms remain unclear. In this study, a lipopolysaccharide- (LPS-) induced murine model of mastitis was established to explore the anti-inflammatory action of berberine hydrochloride. Sixty mice that had been lactating for 5–7 days were randomly divided into six groups, including control, LPS, three berberine hydrochloride treatment groups (5, 10, and 20 mg/kg), and a dexamethasone (DEX) (5 mg/kg) group. Berberine hydrochloride was administered intraperitoneally 1 h before and 12 h after LPS-induced mastitis, and all mice were sacrificed 24 h after LPS induction. The pathological and histopathological changes of the mammary glands were observed. The concentrations and mRNA expressions of TNF-α, IL-1β, and IL-6 were measured by ELISA and qRT-PCR. The activation of TLR4 and NF-κB signaling pathways was analyzed by Western blot. Results indicated that berberine hydrochloride significantly attenuated neutrophil infiltration and dose-dependently decreased the secretion and mRNA expressions of TNF-α, IL-1β, and IL-6 within a certain range. Furthermore, berberine hydrochloride suppressed LPS-induced TLR4 and NF-κB p65 activation and the phosphorylation of I-κB. Berberine hydrochloride can provide mice robust protection from LPS-induced mastitis, potentially via the TLR4 and NF-κB pathway.

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Probiotic lactobacilli as a promising strategy to ameliorate disorders associated with intestinal inflammation induced by a non-steroidal anti-inflammatory drug

Scientific Reports ◽

10.1038/s41598-020-80482-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

María José Martínez Monteros ◽

Carolina Maldonado Galdeano ◽

María Florencia Balcells ◽

Ricardo Weill ◽

Juan Andrés De Paula ◽

...

Keyword(s):

Antimicrobial Activity ◽

Small Intestine ◽

Intestinal Inflammation ◽

Body Weight Loss ◽

The Body ◽

Probiotic Supplementation ◽

Severe Condition ◽

Conventional Diet ◽

Anti Inflammatory ◽

Probiotic Lactobacilli

AbstractDamage to the small intestine caused by non-steroidal anti-inflammatory drugs (NSAIDs) occurs more frequently than in the upper gastrointestinal tract, is more difficult to diagnose and no effective treatments exist. Hence, we investigated whether probiotics can control the onset of this severe condition in a murine model of intestinal inflammation induced by the NSAID, indomethacin. Probiotic supplementation to mice reduce the body weight loss, anemia, shortening of the small intestine, cell infiltration into the intestinal tissue and the loss of Paneth and Goblet cells associated with intestinal inflammation. Furthermore, a high antimicrobial activity in the intestinal fluids of mice fed with probiotics compared to animals on a conventional diet was elicited against several pathogens. Interestingly, probiotics dampened the oxidative stress and several local and systemic markers of an inflammatory process, as well as increased the secretion of IL-10 by regulatory T cells. Even more importantly, probiotics induced important changes in the large intestine microbiota characterized by an increase in anaerobes and lactobacilli, and a significant decrease in total enterobacteria. We conclude that oral probiotic supplementation in NSAID-induced inflammation increases intestinal antimicrobial activity and reinforces the intestinal epithelial barrier in order to avoid pathogens and commensal invasion and maintain intestinal homeostasis.

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P006 3D Multicellular intestine-on-a-chip model for disease modelling and drug discovery

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.135 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S132-S133

Author(s):

G Lo Sasso ◽

L Gijzen ◽

D Marescotti ◽

E Naumovska ◽

E Raineri ◽

...

Keyword(s):

Barrier Function ◽

Intestinal Inflammation ◽

The Body ◽

Collagen I ◽

Epithelial Barrier ◽

Human Intestine ◽

In Vivo Models ◽

Anti Inflammatory

Abstract Background One of the major functions of the human intestine is to provide a protective epithelial barrier between the body and digestive environment. Additionally, the interplay of commensal microbes of the gut microbiome with the gut tissue and host immune system significantly contributes to intestinal homeostasis. Crohn’s disease and ulcerative colitis, collectively referred to as inflammatory bowel diseases, are both associated with increased permeability of the epithelial barrier and dysregulated immune response. Great efforts have been made to develop both in vitro and in vivo models of the human intestine in order to understand the development and underlying pathogenesis of IBD. These efforts have provided valuable insights into multiple aspects of the disease. However, none of these models has been able to capture the complexity and multifactorial nature of IBD. Animal models generally fail to accurately predict the efficacy and toxicity of novel compounds in human tissues, while in vitro human intestinal models developed on porous membranes within Transwell inserts fail to accurately recapitulate and mimic key aspects of the in vivo situation. Methods Here, we present the development and characterisation of a 3D multicellular perfused intestine-on-a-chip model in a microfluidic platform, the OrganoPlate®, and its application for investigating intestinal inflammation. The model described here comprises a coculture of Caco-2 and mucus-secreting HT29-MTX cells in the top compartment of the chip and a coculture of immune-competent cells THP-1 and MUTZ-3 in the bottom compartment, lining a collagen-I ECM in the middle. Results We show that the Caco-2 and HT29-MTX coculture form confluent and polarised tubular structures against the collagen-I ECM in the OrganoPlate®, with a stable barrier function over time as well as the capability to secrete mucus. By exposing the cultures to TNFα and/or IL-1β, we were able to induce an inflammatory state, characterised by cytokine release (IL-8) and a decrease in trans-epithelial electrical resistance. Finally, we proved the applicability of the model in screening anti-inflammatory compounds by its reversibility. Using a well-known anti-inflammatory drug, TPCA-1, we were able to prevent cytokine-induced inflammation. This result was evident from the decreased secretion of IL-8 and retention of barrier function in treated cultures, similar to that observed in untreated cultures. Conclusion Overall, this complex 3D multicellular perfused intestine-on-a-chip model provides the versatile modularity of mimicking key features of intestinal inflammation and can, therefore, further support drug screening efforts and provide a platform for personalised medicine.

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In Silico Drug Repurposing for Anti-Inflammatory Therapy: Virtual Search for Dual Inhibitors of Caspase-1 and TNF-Alpha

Biomolecules ◽

10.3390/biom11121832 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1832

Author(s):

Alejandro Speck-Planche ◽

Valeria V. Kleandrova ◽

Marcus T. Scotti

Keyword(s):

Virtual Screening ◽

Wide Spectrum ◽

The Body ◽

Tnf Alpha ◽

Necrosis Factor Alpha ◽

Caspase 1 ◽

Body Tissues ◽

Dual Inhibitors ◽

Anti Inflammatory ◽

Mlp Model

Inflammation involves a complex biological response of the body tissues to damaging stimuli. When dysregulated, inflammation led by biomolecular mediators such as caspase-1 and tumor necrosis factor-alpha (TNF-alpha) can play a detrimental role in the progression of different medical conditions such as cancer, neurological disorders, autoimmune diseases, and cytokine storms caused by viral infections such as COVID-19. Computational approaches can accelerate the search for dual-target drugs able to simultaneously inhibit the aforementioned proteins, enabling the discovery of wide-spectrum anti-inflammatory agents. This work reports the first multicondition model based on quantitative structure–activity relationships and a multilayer perceptron neural network (mtc-QSAR-MLP) for the virtual screening of agency-regulated chemicals as versatile anti-inflammatory therapeutics. The mtc-QSAR-MLP model displayed accuracy higher than 88%, and was interpreted from a physicochemical and structural point of view. When using the mtc-QSAR-MLP model as a virtual screening tool, we could identify several agency-regulated chemicals as dual inhibitors of caspase-1 and TNF-alpha, and the experimental information later retrieved from the scientific literature converged with our computational results. This study supports the capabilities of our mtc-QSAR-MLP model in anti-inflammatory therapy with direct applications to current health issues such as the COVID-19 pandemic.

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Anti-Inflammatory and Antiapoptotic Responses to Infection: A Common Denominator of Human and Bovine Macrophages Infected withMycobacterium aviumSubsp.paratuberculosis

BioMed Research International ◽

10.1155/2013/908348 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 19

Author(s):

Naiara Abendaño ◽

Ramon A. Juste ◽

Marta Alonso-Hearn

Keyword(s):

Molecular Mechanisms ◽

Mononuclear Cells ◽

Intestinal Inflammation ◽

Common Denominator ◽

Bacterial Survival ◽

Peripheral Blood Mononuclear ◽

Susceptible Host ◽

Human Macrophages ◽

Anti Inflammatory ◽

Chronic Intestinal Inflammation

Mycobacterium aviumsubsp.paratuberculosis(Map) is the causative agent of a chronic intestinal inflammation in ruminants named Johne's disease or paratuberculosis and a possible etiopathological agent of human Crohn's disease (CD). Analysis of macrophage transcriptomes in response toMapinfection is expected to provide key missing information in the understanding of the role of this pathogen in establishing an inappropriate and persistent infection in a susceptible host and of the molecular mechanisms that might underlie the early phases of CD. In this paper we summarize transcriptomic studies of human and bovine peripheral blood mononuclear cells (PBMC), monocyte-derived macrophages (MDMs), and macrophages-like cell linesin vitroinfected withMap. Most studies included in this paper consistently reported common gene expression signatures of bovine and human macrophages in response toMapsuch as enhanced expression of the anti-inflammatory cytokines IL-10 and IL-6, which promote bacterial survival. Overexpression of IL-10 could be responsible for theMap-associated reduction in the expression of the proapoptotic TNF-αgene observed in bovine and human macrophages.

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Anti-inflammatory Effects of Cinnamon Extracts on an Animal Model of Intestinal Inflammation (P06-088-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz031.p06-088-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Cited By ~ 1

Author(s):

Jain Nam ◽

Yeeun Park ◽

Min Seo Kim ◽

Ji Yeon Kim

Keyword(s):

Inflammatory Cytokines ◽

Intestinal Inflammation ◽

Activity Index ◽

Development Program ◽

Intestinal Barrier ◽

Value Added ◽

The Body ◽

Mucin 1 ◽

Cinnamon Extract ◽

Anti Inflammatory

Abstract Objectives This study investigated the potential effect of cinnamon extracts on anti-inflammatory action and maintenance of gut barrier integrity in murine colitis, using dextran sulfate sodium (DSS)-induced BALB/c mice. Methods The BALB/c mice were administered either distilled water or three doses of cinnamon extracts for 21 days. To induce intestinal inflammation, 5% DSS was provided as drinking water for the last 7 days. The changes on clinical and histopathological signs, inflammatory cytokines, and tight junction proteins were evaluated in the colon. Swiss roll histology was also performed. Results In contrast to the DSS group, the body weight of the cinnamon extract group was increased, colon shortening was inhibited, and disease activity index (DAI) values and colon injury were lowered. The cinnamon extract group also clearly inhibited the myeloperoxidase (MPO) activity, as well as the inflammatory cytokines and the mRNA concentrations of IL-1β, IL-6, and TNF-α, but not those of the intestinal barrier proteins, zonula occludens (ZO)-1, occludin, E-cadherin, mucin-1, and mucin-2 in colon tissues. Conclusions These results demonstrate the protective effect of cinnamon extracts against intestinal inflammation and suggest that cinnamon could be utilized to prevent and treat inflammatory bowel disease (IBD). Funding Sources This work was supported by Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry and Fisheries(IPET) through High Value-added Food Technology Development Program, funded by Ministry of Agriculture, Food and Rural Affairs(MAFRA)(Project No. 116,012–3).

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