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Focus on Gastrointestinal Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 24514

Special Issue Editor

Special Issue Information

Dear Colleagues,

Gastrointestinal diseases are common, multifactorial pathologies associated with specific genetic, infective, environmental, and host factors. The study of the molecular mechanisms underlying the interaction among these factors is essential to understand the pathophysiology of gastrointestinal diseases and to develop new therapies. These are extremely common diseases in the general population, with a high cost for health systems around the world. The emerging roles of the intestinal microbiome and of local and general immune factors are transforming our inderstanding of gastrointestinal diseases. The identification of molecular mechanisms involved in their development has also generated considerable progress in the therapeutic field in the last 20 years: the use of biological drugs that have changed the natural course of inflammatory bowel diseases is a clear example of this. The molecular characterization of the interactions between external pathogens such as Helicobacter pylori and the host can also help to decipher the mechanisms that induce inflammatory processes of the mucosa and mutations that can predispose an individual to the onset of gastrointestinal cancers. For this Special Issue, we invite all interested researchers to contribute with original research articles or literature reviews on all aspects related to the molecular mechanisms involved in pathologies of the gastrointestinal system, with particular interest in, but not limited to, inflammatory intestinal and gastric diseases.

Dr. Marcello Candelli
Guest Editor

Manuscript Submission Information

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Keywords

  • gastrointestinal diseases
  • inflammatory bowel diseases
  • gastric cancer
  • microbiome
  • inflammation
  • animal models
  • in vitro models

Published Papers (7 papers)

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Editorial

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2 pages, 191 KiB  
Editorial
Translational, Precision, and Personalized Medicine in Gastroenterology
Int. J. Mol. Sci. 2022, 23(15), 8201; https://doi.org/10.3390/ijms23158201 - 25 Jul 2022
Viewed by 1168
Abstract
In recent decades, tremendous progress has been made in the medicinal field in understanding the molecular mechanisms underlying human pathologies, due to the significant development of advanced laboratory techniques and technologies [...] Full article
(This article belongs to the Special Issue Focus on Gastrointestinal Diseases)

Research

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13 pages, 1083 KiB  
Article
The Somatic Mutation Paradigm in Congenital Malformations: Hirschsprung Disease as a Model
Int. J. Mol. Sci. 2021, 22(22), 12354; https://doi.org/10.3390/ijms222212354 - 16 Nov 2021
Cited by 3 | Viewed by 2216
Abstract
Patients with Hirschsprung disease (HSCR) do not always receive a genetic diagnosis after routine screening in clinical practice. One of the reasons for this could be that the causal mutation is not present in the cell types that are usually tested—whole blood, dermal [...] Read more.
Patients with Hirschsprung disease (HSCR) do not always receive a genetic diagnosis after routine screening in clinical practice. One of the reasons for this could be that the causal mutation is not present in the cell types that are usually tested—whole blood, dermal fibroblasts or saliva—but is only in the affected tissue. Such mutations are called somatic, and can occur in a given cell at any stage of development after conception. They will then be present in all subsequent daughter cells. Here, we investigated the presence of somatic mutations in HSCR patients. For this, whole-exome sequencing and copy number analysis were performed in DNA isolated from purified enteric neural crest cells (ENCCs) and blood or fibroblasts of the same patient. Variants identified were subsequently validated by Sanger sequencing. Several somatic variants were identified in all patients, but causative mutations for HSCR were not specifically identified in the ENCCs of these patients. Larger copy number variants were also not found to be specific to ENCCs. Therefore, we believe that somatic mutations are unlikely to be identified, if causative for HSCR. Here, we postulate various modes of development following the occurrence of a somatic mutation, to describe the challenges in detecting such mutations, and hypothesize how somatic mutations may contribute to ‘missing heritability’ in developmental defects. Full article
(This article belongs to the Special Issue Focus on Gastrointestinal Diseases)
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26 pages, 6242 KiB  
Article
Proteolytic Cleavage of Bioactive Peptides and Protease-Activated Receptors in Acute and Post-Colitis
Int. J. Mol. Sci. 2021, 22(19), 10711; https://doi.org/10.3390/ijms221910711 - 02 Oct 2021
Cited by 5 | Viewed by 3601
Abstract
The protease activity in inflammatory bowel disease (IBD) and irritable bowel syndrome has been studied extensively using synthetic fluorogenic substrates targeting specific sets of proteases. We explored activities in colonic tissue from a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis rat model by investigating the cleavage [...] Read more.
The protease activity in inflammatory bowel disease (IBD) and irritable bowel syndrome has been studied extensively using synthetic fluorogenic substrates targeting specific sets of proteases. We explored activities in colonic tissue from a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis rat model by investigating the cleavage of bioactive peptides. Pure trypsin- and elastase-like proteases on the one hand and colonic tissue from rats with TNBS-induced colitis in the acute or post-inflammatory phase on the other, were incubated with relevant peptides to identify their cleavage pattern by mass spectrometry. An increased cleavage of several peptides was observed in the colon from acute colitis rats. The tethered ligand (TL) sequences of peptides mimicking the N-terminus of protease-activated receptors (PAR) 1 and 4 were significantly unmasked by acute colitis samples and these cleavages were positively correlated with thrombin activity. Increased cleavage of β-endorphin and disarming of the TL-sequence of the PAR3-based peptide were observed in acute colitis and linked to chymotrypsin-like activity. Increased processing of the enkephalins points to the involvement of proteases with specificities different from trypsin- or chymotrypsin-like enzymes. In conclusion, our results suggest thrombin, chymotrypsin-like proteases and a set of proteases with different specificities as potential therapeutic targets in IBD. Full article
(This article belongs to the Special Issue Focus on Gastrointestinal Diseases)
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Review

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17 pages, 903 KiB  
Review
Humoral Predictors of Malignancy in IPMN: A Review of the Literature
Int. J. Mol. Sci. 2021, 22(23), 12839; https://doi.org/10.3390/ijms222312839 - 27 Nov 2021
Cited by 13 | Viewed by 3686
Abstract
Pancreatic cystic lesions are increasingly detected in cross-sectional imaging. Intraductal papillary mucinous neoplasm (IPMN) is a mucin-producing subtype of the pancreatic cyst lesions arising from the pancreatic duct system. IPMN is a potential precursor of pancreatic cancer. The transformation of IPMN in pancreatic [...] Read more.
Pancreatic cystic lesions are increasingly detected in cross-sectional imaging. Intraductal papillary mucinous neoplasm (IPMN) is a mucin-producing subtype of the pancreatic cyst lesions arising from the pancreatic duct system. IPMN is a potential precursor of pancreatic cancer. The transformation of IPMN in pancreatic cancer is progressive and requires the occurrence of low-grade dysplasia, high-grade dysplasia, and ultimately invasive cancer. Jaundice, enhancing mural nodule >5 mm, main pancreatic duct diameter >10 mm, and positive cytology for high-grade dysplasia are considered high-risk stigmata of malignancy. While increased levels of carbohydrate antigen 19-9 (CA 19-9) (>37 U/mL), main pancreatic duct diameter 5–9.9 mm, cyst diameter >40 mm, enhancing mural nodules <5 mm, IPMN-induced acute pancreatitis, new onset of diabetes, cyst grow-rate >5 mm/year are considered worrisome features of malignancy. However, cross-sectional imaging is often inadequate in the prediction of high-grade dysplasia and invasive cancer. Several studies evaluated the role of humoral and intra-cystic biomarkers in the prediction of malignancy in IPMN. Carcinoembryonic antigen (CEA), CA 19-9, intra-cystic CEA, intra-cystic glucose, and cystic fluid cytology are widely used in clinical practice to distinguish between mucinous and non-mucinous cysts and to predict the presence of invasive cancer. Other biomarkers such as cystic fluid DNA sequencing, microRNA (mi-RNA), circulating microvesicles, and liquid biopsy are the new options for the mini-invasive diagnosis of degenerated IPMN. The aim of this study is to review the literature to assess the role of humoral and intracystic biomarkers in the prediction of advanced IPMN with high-grade dysplasia or invasive carcinoma. Full article
(This article belongs to the Special Issue Focus on Gastrointestinal Diseases)
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16 pages, 273 KiB  
Review
The Era of Janus Kinase Inhibitors for Inflammatory Bowel Disease Treatment
Int. J. Mol. Sci. 2021, 22(21), 11322; https://doi.org/10.3390/ijms222111322 - 20 Oct 2021
Cited by 11 | Viewed by 2860
Abstract
For a significant proportion of patients with inflammatory bowel disease (IBD), primary non-response and secondary loss of response to treatment remain significant issues. Anti-tumor necrosis factor therapies have been licensed for use in IBD. Other disease-related pathways have been targeted as well, including [...] Read more.
For a significant proportion of patients with inflammatory bowel disease (IBD), primary non-response and secondary loss of response to treatment remain significant issues. Anti-tumor necrosis factor therapies have been licensed for use in IBD. Other disease-related pathways have been targeted as well, including the interleukin 12/23 axis and lymphocyte tracking. However, the need for parenteral administration and the associated costs of dispensing and monitoring all biologics remain a burden on healthcare systems and patients. Janus kinase inhibitors are small-molecule drugs that can be administered orally and are relatively inexpensive, thus offering an additional option for treating IBD. They have been shown to be effective in patients with ulcerative colitis (UC), but they are less effective in those with Crohn’s disease (CD). Nonetheless, given the immune-system-based mechanism of these drugs, their safety profile remains a cause for concern. This article provides an overview of Janus kinase (JAK) inhibitors and new trends in the treatment of IBD. Full article
(This article belongs to the Special Issue Focus on Gastrointestinal Diseases)
20 pages, 3059 KiB  
Review
Immunogenetic, Molecular and Microbiotic Determinants of Eosinophilic Esophagitis and Clinical Practice—A New Perspective of an Old Disease
Int. J. Mol. Sci. 2021, 22(19), 10830; https://doi.org/10.3390/ijms221910830 - 07 Oct 2021
Cited by 6 | Viewed by 3365
Abstract
Eosinophilic oesophagitis (EoE) is a chronic, allergic disease associated with a T-lymphocyte response inducing esophageal eosinophilic infiltration in the esophagus. Inflammation and tissue fibrosis are responsible for the main clinical symptoms such as food impaction and dysphagia. The etiopathogenesis is multifactorial in which [...] Read more.
Eosinophilic oesophagitis (EoE) is a chronic, allergic disease associated with a T-lymphocyte response inducing esophageal eosinophilic infiltration in the esophagus. Inflammation and tissue fibrosis are responsible for the main clinical symptoms such as food impaction and dysphagia. The etiopathogenesis is multifactorial in which genetic and environmental factors coexist. The most common trigger is a non-IgE-mediated food allergy to milk, wheat, egg, soybean, nuts, fish, and seafood. The second factor we focus on is the contribution of genetic variation to the risk of EoE, describing the expression profile of selected genes associated with eosinophilic oesophagitis. We raise the topic of treatment, aiming to eliminate inflammation through an elimination diet and/or use of pharmacologic therapy with the use of proton pump inhibitors or steroids and endoscopic procedures to dilate the esophagus. We demonstrate that early diagnosis and effective treatment prevent the development of food impaction and decreased quality of life. The increasing presence of EoE requires bigger awareness among medical specialists concerning clinical features, the course of EoE, diagnostic tools, and management strategies. Full article
(This article belongs to the Special Issue Focus on Gastrointestinal Diseases)
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12 pages, 845 KiB  
Review
Interaction between Lipopolysaccharide and Gut Microbiota in Inflammatory Bowel Diseases
Int. J. Mol. Sci. 2021, 22(12), 6242; https://doi.org/10.3390/ijms22126242 - 10 Jun 2021
Cited by 93 | Viewed by 6371
Abstract
Lipopolysaccharides (LPSs) are bacterial surface glycolipids, produced by Gram-negative bacteria. LPS is known to determine acute inflammatory reactions, particularly in the context of sepsis. However, LPS can also trigger chronic inflammation. In this case, the source of LPS is not an external infection, [...] Read more.
Lipopolysaccharides (LPSs) are bacterial surface glycolipids, produced by Gram-negative bacteria. LPS is known to determine acute inflammatory reactions, particularly in the context of sepsis. However, LPS can also trigger chronic inflammation. In this case, the source of LPS is not an external infection, but rather an increase in endogenous production, which is usually sustained by gut microbiota (GM), and LPS contained in food. The first site in which LPS can exert its inflammatory action is the gut: both GM and gut-associated lymphoid tissue (GALT) are influenced by LPS and shift towards an inflammatory pattern. The changes in GM and GALT induced by LPS are quite similar to the ones seen in IBD: GM loses diversity, while GALT T regulatory (Tregs) lymphocytes are reduced in number, with an increase in Th17 and Th1 lymphocytes. Additionally, the innate immune system is triggered, through the activation of toll-like receptor (TLR)-4, while the epithelium is directly damaged, further triggering inflammation. In this review, we will discuss the importance of the crosstalk between LPS, GM, and GALT, and discuss the possible implications. Full article
(This article belongs to the Special Issue Focus on Gastrointestinal Diseases)
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