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Inflammatory Signaling Pathways Involved in Gastrointestinal Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (20 November 2023) | Viewed by 14330

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Dr. Diana Di Liberto

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Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Section of Biochemistry, University of Palermo, 90127 Palermo, Italy
Interests: inflammatory diseases; cancer; oxidative stress; biochemical mechanisms of cell death and survival (apoptosis, necrosis, autophagy); nutraceuticals; food intolerance
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Prof. Dr. Marianna Lauricella

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Section of Biochemistry, Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), University of Palermo, 90127 Palermo, Italy
Interests: mechanisms of oxidative stress induction and main antioxidant systems; biochemical pathways of cell death and survival (apoptosis, necrosis, autophagy) in tumor cells; effects of phytocompounds in obesity reduction
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Inflammation is a defensive response of the innate and adaptive immune systems against injury and/or harmful microorganisms to restore homeostasis. The importance of inflammatory signaling pathways in diseases has been recognized, and signaling molecules implicated in these pathways are thought to be promising targets for new therapeutic strategies. Many studies have demonstrated that inflammation-related signaling pathways influence the homeostasis and health of the human gastrointestinal system.

The main goal of this Issue is to shed light, through both original research and review articles, on the role of immune inflammatory signaling pathways in gastrointestinal inflammation and tumors, and on the latest progress in the corresponding regulatory mechanisms. We also welcome the submission of research papers evaluating strategies to reduce inflammation in inflammatory gastrointestinal diseases. Meanwhile, this Issue explores the effects and mechanisms of different signaling pathways in tumors such as gastric cancer and colorectal cancer, as well as inflammatory diseases such as inflammatory bowel disease (IBD), intestinal-related sepsis, colonitis and celiac disease. Full knowledge of the inflammatory signaling pathways could be helpful not only for the prevention but also for the novel treatment of these diseases.

Generally, pure clinical research or model studies, survey studies, and correlation research are outside of the scope of IJMS. However, clinical or model submissions with biomolecular experiments are welcomed.

Dr. Diana Di Liberto
Dr. Marianna Lauricella
Guest Editors

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Keywords

inflammatory signaling pathways
gastrointestinal diseases
gastrointestinal cancer
inflammatory bowel disease
colonitis
colorectal cancer
cytokine

Related Special Issue

Inflammatory Signaling Pathways Involved in Gastrointestinal Diseases: Second Edition in International Journal of Molecular Sciences

Published Papers (10 papers)

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Editorial

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6 pages, 191 KiB

Open AccessEditorial

Special Issue: “Inflammatory Signaling Pathways Involved in Gastrointestinal Diseases”

by Marianna Lauricella and Diana Di Liberto

Int. J. Mol. Sci. 2024, 25(2), 1287; https://doi.org/10.3390/ijms25021287 - 20 Jan 2024

Viewed by 598

Abstract

Inflammation is a defensive response of the innate and adaptive immune systems against injury and/or harmful microorganisms to restore homeostasis [...] Full article

(This article belongs to the Special Issue Inflammatory Signaling Pathways Involved in Gastrointestinal Diseases)

Research

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22 pages, 7498 KiB

Open AccessArticle

Broccoli Cultivated with Deep Sea Water Mineral Fertilizer Enhances Anti-Cancer and Anti-Inflammatory Effects of AOM/DSS-Induced Colorectal Cancer in C57BL/6N Mice

by Yeon-Jun Lee, Yanni Pan, Daewoo Lim, Seung-Hwan Park, Sin-Il Sin, KyuBum Kwack and Kun-Young Park

Int. J. Mol. Sci. 2024, 25(3), 1650; https://doi.org/10.3390/ijms25031650 - 29 Jan 2024

Viewed by 949

Abstract

This study aimed to determine the alleviating effect of broccoli grown with deep sea water mineral (DSWM) fertilizer extracted from deep sea water on the development of colorectal cancer in C57BL/6N mice treated with AOM/DSS. Naturaldream Fertilizer Broccoli (NFB) cultured with deep sea water minerals (DSWM) showed a higher antioxidant effect and mineral content. In addition, orally administered NFB, showed a level of recovery in the colon and spleen tissues of mice compared with those in normal mice through hematoxylin and eosin (H&E) staining. Orally administered NFB showed the inhibition of the expression of inflammatory cytokine factors IL-1β, IL-6, TNF, IFN-γ, and IL-12 while increasing the expression of IL-10. Furthermore, the expression of inflammatory cytokines and NF-κB in the liver tissue was inhibited, and that of inflammatory enzymes, such as COX-2 and iNOS, was reduced. In the colon tissue, the expression of p53 and p21 associated with cell cycle arrest increased, and that of Bcl-2 associated with apoptosis decreased. Additionally, the expression of Bax, Bad, Bim, Bak, caspase 9, and caspase 3 increased, indicating enhanced activation of apoptosis-related factors. These results demonstrate that oral administration of broccoli cultivated using DSWM significantly restores spleen and colon tissues and simultaneously inhibits the NF-κB pathway while significantly decreasing cytokine expression. Moreover, by inducing cell cycle arrest and activating cell apoptosis, they also suggest alleviating AOM/DSS-induced colon cancer symptoms in C57BL/6N mice. Full article

(This article belongs to the Special Issue Inflammatory Signaling Pathways Involved in Gastrointestinal Diseases)

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11 pages, 1965 KiB

Open AccessArticle

Mucosal Genes Encoding Clock, Inflammation and Their Mutual Regulators Are Disrupted in Pediatric Patients with Active Ulcerative Colitis

by Sapir Labes, Oren Froy, Yuval Tabach, Raanan Shamir, Dror S. Shouval and Yael Weintraub

Int. J. Mol. Sci. 2024, 25(3), 1488; https://doi.org/10.3390/ijms25031488 - 25 Jan 2024

Viewed by 779

Abstract

Patients with active ulcerative colitis (UC) display a misalignment of the circadian clock, which plays a vital role in various immune functions. Our aim was to characterize the expression of clock and inflammation genes, and their mutual regulatory genes in treatment-naïve pediatric patients with UC. Using the Inflammatory Bowel Disease Transcriptome and Metatranscriptome Meta-Analysis (IBD TaMMA) platform and R algorithms, we analyzed rectal biopsy transcriptomic data from two cohorts (206 patients with UC vs. 20 healthy controls from the GSE-109142 study, and 43 patients with UC vs. 55 healthy controls from the GSE-117993 study). We compared gene expression levels and correlation of clock genes (BMAL1, CLOCK, PER1, PER2, CRY1, CRY2), inflammatory genes (IκB, IL10, NFκB1, NFκB2, IL6, TNFα) and their mutual regulatory genes (RORα, RORγ, REV-ERBα, PGC1α, PPARα, PPARγ, AMPK, SIRT1) in patients with active UC and healthy controls. The clock genes BMAL1, CLOCK, PER1 and CRY1 and the inflammatory genes IκB, IL10, NFκB1, NFκB2, IL6 and TNFα were significantly upregulated in patients with active UC. The genes encoding the mutual regulators RORα, RORγ, PGC1α, PPARα and PPARγ were significantly downregulated in patients with UC. A uniform pattern of gene expression was found in healthy controls compared to the highly variable expression pattern in patients with UC. Among the healthy controls, inflammatory genes were positively correlated with clock genes and they all showed reduced expression. The difference in gene expression levels was associated with disease severity and endoscopic score but not with histological score. In patients with active UC, clock gene disruption is associated with abnormal mucosal immune response. Disrupted expression of genes encoding clock, inflammation and their mutual regulators together may play a role in active UC. Full article

(This article belongs to the Special Issue Inflammatory Signaling Pathways Involved in Gastrointestinal Diseases)

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21 pages, 6844 KiB

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Pro-Inflammatory Cytokines Enhanced In Vitro Cytotoxic Activity of Clostridioides difficile Toxin B in Enteric Glial Cells: The Achilles Heel of Clostridioides difficile Infection?

by Katia Fettucciari, Andrea Spaterna, Pierfrancesco Marconi and Gabrio Bassotti

Int. J. Mol. Sci. 2024, 25(2), 958; https://doi.org/10.3390/ijms25020958 - 12 Jan 2024

Viewed by 682

Abstract

Bacterial infections are characterized by an inflammatory response, which is essential for infection containment but is also responsible for negative effects on the host. The pathogen itself may have evolved molecular mechanisms to antagonize the antimicrobial effects of an inflammatory response and to enhance its pathogenicity using inflammatory response mediators, such as cytokines. Clostridioides difficile (C. difficile) infection (CDI) causes gastrointestinal diseases with markedly increasing global incidence and mortality rates. The main C. difficile virulence factors, toxin A and B (TcdA/TcdB), cause cytopathic/cytotoxic effects and inflammation. We previously demonstrated that TcdB induces enteric glial cell (EGC) apoptosis, which is enhanced by the pro-inflammatory cytokine tumor necrosis factor alpha plus interferon gamma (CKs). However, it is unknown whether CKs-enhanced TcdB cytotoxicity (apoptosis/necrosis) is affected by the timing of the appearance of the CKs. Thus, we simulated in vitro, in our experimental model with TcdB and EGCs, three main situations of possible interactions between TcdB and the timing of CK stimulation: before TcdB infection, concomitantly with infection, or at different times after infection and persisting over time. In these experimental conditions, which all represent situations of possible interactions between C. difficile and the timing of CK stimulation, we evaluated apoptosis, necrosis, and cell cycle phases. The CKs, in all of these conditions, enhanced TcdB cytotoxicity, which from apoptosis became necrosis when CK stimulation persisted over time, and was most relevant after 48 h of TcdB:EGCs interaction. Particularly, the enhancement of apoptosis by CKs was dependent on the TcdB dose and in a less relevant manner on the CK stimulation time, while the enhancement of necrosis occurred always independently of the TcdB dose and CK stimulation time. However, since in all conditions stimulation with CKs strongly enhanced the TcdB cytotoxicity, it always had a negative impact on C. difficile pathogenicity. This study might have important implications for the treatment of CDI. Full article

(This article belongs to the Special Issue Inflammatory Signaling Pathways Involved in Gastrointestinal Diseases)

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15 pages, 2121 KiB

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Effects of Cirsium palustre Extracts and Their Main Flavonoids on Colon Motility—An Ex Vivo Study

by Dominika Szadkowska, Magdalena Chłopecka, Jakub W. Strawa, Katarzyna Jakimiuk, Daniel Augustynowicz, Michał Tomczyk and Marta Mendel

Int. J. Mol. Sci. 2023, 24(24), 17283; https://doi.org/10.3390/ijms242417283 - 09 Dec 2023

Cited by 1 | Viewed by 810

Abstract

For centuries, various species from the genus Cirsium have been utilized in traditional medicine worldwide. A number of ethnopharmacological reports have pointed out that Cirsium plants can be applied to diminish digestive problems. Among them, Cirsium palustre (L.) Scop. (Asteraceae) stands out as a promising herbal drug candidate because its constituents exhibit antimicrobial and antioxidant potential, as evidenced by ethnopharmacological reports. As a result, the species is particularly intriguing as an adjunctive therapy for functional gastrointestinal and motility disorders. Our research goal was to verify how the extracts, fractions, and main flavonoids of C. palustre affect colon contractility under ex vivo conditions. An alternative model with porcine-isolated colon specimens was used to identify the effects of C. palustre preparations and their primary flavonoids. LC-ESI-MS was utilized to evaluate the impacts of methanol (CP1), methanolic 50% (CP2), and aqueous (CP3) extracts as well as diethyl ether (CP4), ethyl acetate (CP5), and n-butanol (CP6) fractions. Additionally, the impacts of four flavonoids, apigenin (API), luteolin (LUT), apigenin 7-O-glucuronide (A7GLC), and chrysoeriol (CHRY), on spontaneous and acetylcholine-induced motility were assessed under isometric conditions. The results showed that C. palustre extracts, fractions, and their flavonoids exhibit potent motility-regulating effects on colonic smooth muscle. The motility-regulating effect was observed on spontaneous and acetylcholine-induced contractility. All extracts and fractions exhibited an enhancement of the spontaneous contractility of colonic smooth muscle. For acetylcholine-induced activity, CP1, CP2, and CP4 caused a spasmolytic effect, and CP5 and CP6 had a spasmodic effect. LUT and CHRY showed a spasmolytic effect in the case of spontaneous and acetylcholine-induced activity. In contrast, API and A7GLC showed a contractile effect in the case of spontaneous and pharmacologically induced activity. Considering the results obtained from the study, C. palustre could potentially provide benefits in the treatment of functional gastrointestinal disorders characterized by hypomotility and hypermotility. Full article

(This article belongs to the Special Issue Inflammatory Signaling Pathways Involved in Gastrointestinal Diseases)

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13 pages, 2337 KiB

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A Novel Mechanism of Immunoproteasome Regulation via miR-369-3p in Intestinal Inflammatory Response

by Viviana Scalavino, Emanuele Piccinno, Anna Maria Valentini, Mauro Mastronardi, Raffaele Armentano, Gianluigi Giannelli and Grazia Serino

Int. J. Mol. Sci. 2022, 23(22), 13771; https://doi.org/10.3390/ijms232213771 - 09 Nov 2022

Cited by 4 | Viewed by 1258

Abstract

The immunoproteasome is a multi-catalytic protein complex expressed in hematopoietic cells. Increased expression of immuno-subunits followed by increased proteasome activities is associated with the pathogenesis of IBD. Therefore, the identification of molecules that could inhibit the activities of this complex has been widely studied. microRNAs are small molecules of non-coding RNA that regulate the expression of target genes. Our purpose was to demonstrate that miR-369-3p is able to reduce the expression of the PSMB9 subunit and consequently modulate the catalytic activities of immunoproteasome. After bioinformatics prediction of the gene target of miR-369-3p, we validated its modulation on PSMB9 expression in the RAW264.7 cell line in vitro. We also found that miR-369-3p indirectly reduced the expression of other immunoproteasome subunits and that this regulation reduced the catalytic functions of the immunoproteasome. Increased levels of PSMB9 were observed in colon samples of acute IBD patients compared to the remission IBD group and control group. Our data suggest that miR-369-3p may be a future alternative therapeutic approach to several compounds currently used for the treatment of inflammatory disorders including IBD. Full article

(This article belongs to the Special Issue Inflammatory Signaling Pathways Involved in Gastrointestinal Diseases)

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Review

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27 pages, 977 KiB

Open AccessReview

Foodomics-Based Approaches Shed Light on the Potential Protective Effects of Polyphenols in Inflammatory Bowel Disease

by Giovanni Pratelli, Bartolo Tamburini, Daniela Carlisi, Anna De Blasio, Antonella D’Anneo, Sonia Emanuele, Antonietta Notaro, Federica Affranchi, Michela Giuliano, Aurelio Seidita, Marianna Lauricella and Diana Di Liberto

Int. J. Mol. Sci. 2023, 24(19), 14619; https://doi.org/10.3390/ijms241914619 - 27 Sep 2023

Cited by 3 | Viewed by 1483

Abstract

Inflammatory bowel disease (IBD) is a chronic and progressive inflammatory disorder affecting the gastrointestinal tract (GT) caused by a wide range of genetic, microbial, and environmental factors. IBD is characterized by chronic inflammation and decreased gut microbial diversity, dysbiosis, with a lower number of beneficial bacteria and a concomitant increase in pathogenic species. It is well known that dysbiosis is closely related to the induction of inflammation and oxidative stress, the latter caused by an imbalance between reactive oxygen species (ROS) production and cellular antioxidant capacity, leading to cellular ROS accumulation. ROS are responsible for intestinal epithelium oxidative damage and the increased intestinal permeability found in IBD patients, and their reduction could represent a potential therapeutic strategy to limit IBD progression and alleviate its symptoms. Recent evidence has highlighted that dietary polyphenols, the natural antioxidants, can maintain redox equilibrium in the GT, preventing gut dysbiosis, intestinal epithelium damage, and radical inflammatory responses. Here, we suggest that the relatively new foodomics approaches, together with new technologies for promoting the antioxidative properties of dietary polyphenols, including novel delivery systems, chemical modifications, and combination strategies, may provide critical insights to determine the clinical value of polyphenols for IBD therapy and a comprehensive perspective for implementing natural antioxidants as potential IBD candidate treatment. Full article

(This article belongs to the Special Issue Inflammatory Signaling Pathways Involved in Gastrointestinal Diseases)

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13 pages, 1024 KiB

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Inflammatory Bowel Diseases: An Updated Overview on the Heat Shock Protein Involvement

by Federica Scalia, Francesco Carini, Sabrina David, Marco Giammanco, Margherita Mazzola, Francesca Rappa, Noemi Irma Bressan, Giorgio Maida and Giovanni Tomasello

Int. J. Mol. Sci. 2023, 24(15), 12129; https://doi.org/10.3390/ijms241512129 - 28 Jul 2023

Cited by 1 | Viewed by 1424

Abstract

Inflammatory bowel diseases (IBDs) represent chronic idiopathic disorders, including Crohn’s disease (CD) and ulcerative colitis (UC), in which one of the trigger factors is represented by aberrant immune interactions between the intestinal epithelium and the intestinal microbiota. The involvement of heat shock proteins (HSPs) as etiological and pathogenetic factors is becoming of increasing interest. HSPs were found to be differentially expressed in the intestinal tissues and sera of patients with CD and UC. It has been shown that HSPs can play a dual role in the disease, depending on the stage of progression. They can support the inflammatory and fibrosis process, but they can also act as protective factors during disease progression or before the onset of one of the worst complications of IBD, colorectal cancer. Furthermore, HSPs are able to mediate the interaction between the intestinal microbiota and intestinal epithelial cells. In this work, we discuss the involvement of HSPs in IBD considering their genetic, epigenetic, immune and molecular roles, referring to the most recent works present in the literature. With our review, we want to shed light on the importance of further exploring the role of HSPs, or even better, the role of the molecular chaperone system (CS), in IBD: various molecules of the CS including HSPs may have diagnostic, prognostic and therapeutic potential, promoting the creation of new drugs that could overcome the side-effects of the therapies currently used. Full article

(This article belongs to the Special Issue Inflammatory Signaling Pathways Involved in Gastrointestinal Diseases)

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19 pages, 1105 KiB

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Inflammatory Bowel Disease: Crosstalk between Histamine, Immunity, and Disease

by Kristina A. Dvornikova, Olga N. Platonova and Elena Y. Bystrova

Int. J. Mol. Sci. 2023, 24(12), 9937; https://doi.org/10.3390/ijms24129937 - 09 Jun 2023

Cited by 8 | Viewed by 3194

Abstract

Inflammatory bowel disease (IBD) is increasingly recognized as a serious, worldwide public health concern. It is generally acknowledged that a variety of factors play a role in the pathogenesis of this group of chronic inflammatory diseases. The diversity of molecular actors involved in IBD does not allow us to fully assess the causal relationships existing in such interactions. Given the high immunomodulatory activity of histamine and the complex immune-mediated nature of inflammatory bowel disease, the role of histamine and its receptors in the gut may be significant. This paper has been prepared to provide a schematic of the most important and possible molecular signaling pathways related to histamine and its receptors and to assess their relevance for the development of therapeutic approaches. Full article

(This article belongs to the Special Issue Inflammatory Signaling Pathways Involved in Gastrointestinal Diseases)

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16 pages, 2576 KiB

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Signaling Pathways in the Pathogenesis of Barrett’s Esophagus and Esophageal Adenocarcinoma

by Ksenia Maslenkina, Liudmila Mikhaleva, Maxim Naumenko, Rositsa Vandysheva, Michail Gushchin, Dmitri Atiakshin, Igor Buchwalow and Markus Tiemann

Int. J. Mol. Sci. 2023, 24(11), 9304; https://doi.org/10.3390/ijms24119304 - 26 May 2023

Cited by 3 | Viewed by 1948

Abstract

Barrett’s esophagus (BE) is a premalignant lesion that can develop into esophageal adenocarcinoma (EAC). The development of Barrett’s esophagus is caused by biliary reflux, which causes extensive mutagenesis in the stem cells of the epithelium in the distal esophagus and gastro-esophageal junction. Other possible cellular origins of BE include the stem cells of the mucosal esophageal glands and their ducts, the stem cells of the stomach, residual embryonic cells and circulating bone marrow stem cells. The classical concept of healing a caustic lesion has been replaced by the concept of a cytokine storm, which forms an inflammatory microenvironment eliciting a phenotypic shift toward intestinal metaplasia of the distal esophagus. This review describes the roles of the NOTCH, hedgehog, NF-κB and IL6/STAT3 molecular pathways in the pathogenesis of BE and EAC. Full article

(This article belongs to the Special Issue Inflammatory Signaling Pathways Involved in Gastrointestinal Diseases)

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