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New Frontiers in Molecular Research of Digestive 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 Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 15931

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Special Issue Editor

Dr. Robert Y. Tsai

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Guest Editor

Department of Translational Medical Sciences, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA
Interests: stem cells; liver disease; tissue regeneration; aging; cancer biology; DNA damage

Special Issue Information

Dear Colleagues,

Diseases affecting organs in the digestive system, including esophagus, stomach, intestine, liver, gall bladder, and pancreas, pose major health issues worldwide. With the advent of novel scientific concepts and advanced technologies, important breakthroughs are being made in both basic science and translational medicine. The proposed special issue aims to present up-to-date advances in the molecular research of digestive diseases in new frontier areas. These focus areas include, but are not limited to, health disparity, gut microbiome, epigenetics, metabolic disorders, immuno-oncology, biomarker discovery, and personalized medicine. Understanding the molecular basis underlying those key issues may help identify pathogenic mechanisms driving the morbidity, mortality, and drug resistance of diseases previously deemed untreatable, leading to the discovery of new biomarkers for risk prediction and early detection, as well as novel therapeutic interventions. One of the focus areas is health disparity, which has been observed in digestive diseases but is only gaining public awareness in recent years. In addition to differences in socioeconomic status, access to health care, insurance and screening, and micro/macro-environment, there is a rapidly emerging interest in uncovering the biological determinants that may contribute to age, sex/gender, race, and ethnicity related health disparities in digestive diseases. Identifying and filling in the knowledge gaps in the molecular understanding of health disparities as well as other frontier research areas may help facilitate the development of new prevention and treatment strategies to reduce disease morbidity and mortality, and, ultimately, the financial and emotional burdens on the patient, family members, and society as a whole. Both review articles and original research papers are welcomed.

Dr. Robert Y. Tsai
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

gastrointestinal diseases
hepatobiliary diseases
pancreatic diseases
metabolic syndromes
disease prevention
health disparities
gut microbiome
epigenetics
metabolic disorder
immune-oncology
precision medicine

Published Papers (6 papers)

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Research

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16 pages, 2370 KiB

Open AccessArticle

Inhibition of NHE-1 Increases Smoke-Induced Proliferative Activity of Barrett’s Esophageal Cell Line

by Eszter Becskeházi, Marietta Margaréta Korsós, Eleonóra Gál, László Tiszlavicz, Zsófia Hoyk, Mária A. Deli, Zoltán Márton Köhler, Anikó Keller-Pintér, Attila Horváth, Kata Csekő, Zsuzsanna Helyes, Péter Hegyi and Viktória Venglovecz

Int. J. Mol. Sci. 2021, 22(19), 10581; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910581 - 30 Sep 2021

Cited by 2 | Viewed by 1736

Abstract

Several clinical studies indicate that smoking predisposes its consumers to esophageal inflammatory and malignant diseases, but the cellular mechanism is not clear. Ion transporters protect esophageal epithelial cells by maintaining intracellular pH at normal levels. In this study, we hypothesized that smoking affects the function of ion transporters, thus playing a role in the development of smoking-induced esophageal diseases. Esophageal cell lines were treated with cigarettesmoke extract (CSE), and the viability and proliferation of the cells, as well as the activity, mRNA and protein expression of the Na⁺/H⁺ exchanger-1 (NHE-1), were studied. NHE-1 expression was also investigated in human samples. For chronic treatment, guinea pigs were exposed to tobacco smoke, and NHE-1 activity was measured. Silencing of NHE-1 was performed by using specific siRNA. CSE treatment increased the activity and protein expression of NHE-1 in the metaplastic cells and decreased the rate of proliferation in a NHE-1-dependent manner. In contrast, CSE increased the proliferation of dysplastic cells independently of NHE-1. In the normal cells, the expression and activity of NHE-1 decreased due to in vitro and in vivo smoke exposure. Smoking enhances the function of NHE-1 in Barrett’s esophagus, and this is presumably a compensatory mechanism against this toxic agent. Full article

(This article belongs to the Special Issue New Frontiers in Molecular Research of Digestive Diseases)

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15 pages, 8012 KiB

Open AccessArticle

Cocaine and Amphetamine Regulated Transcript (CART) Expression Changes in the Stomach Wall Affected by Experimentally Induced Gastric Ulcerations

by Michal Zalecki, Adrianna Plywacz, Hanna Antushevich and Amelia Franke-Radowiecka

Int. J. Mol. Sci. 2021, 22(14), 7437; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147437 - 12 Jul 2021

Cited by 2 | Viewed by 2130

Abstract

Cocaine- and amphetamine-regulated transcript (CART) is a peptide suggested to play a role in gastrointestinal tract tissue reaction to pathology. Gastric ulceration is a common disorder affecting huge number of people, and additionally, it contributes to the loss of pig livestock production. Importantly, ulceration as a focal disruption affecting deeper layers of the stomach wall differs from other gastrointestinal pathologies and should be studied individually. The pig’s gastrointestinal tract, due to its many similarities to the human counterpart, provides a valuable experimental model for studying digestive system pathologies. To date, the role of CART in gastric ulceration and the expression of the gene encoding CART in porcine gastrointestinal tube are completely unknown. Therefore, we aimed to verify the changes in the CART expression by Q-PCR (gene encoding CART in the tissue) and double immunofluorescence staining combined with confocal microscopy (CART immunofluorescence in enteric nervous system) in the porcine stomach tissues adjacent to gastric ulcerations. Surprisingly, we found that gastric ulcer caused a significant decrease in the expression of CART-encoding gene and huge reduction in the percentage of CART-immunofluorescent myenteric perikarya and neuronal fibers located within the circular muscle layer. Our results indicate a unique CART-dependent gastric response to ulcer disease. Full article

(This article belongs to the Special Issue New Frontiers in Molecular Research of Digestive Diseases)

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15 pages, 1454 KiB

Open AccessArticle

Somatic Mutations in Circulating Cell-Free DNA and Risk for Hepatocellular Carcinoma in Hispanics

by Jingjing Jiao, Jessica I. Sanchez, Erika J. Thompson, Xizeng Mao, Joseph B. McCormick, Susan P. Fisher-Hoch, P. Andrew Futreal, Jianhua Zhang and Laura Beretta

Int. J. Mol. Sci. 2021, 22(14), 7411; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147411 - 10 Jul 2021

Cited by 3 | Viewed by 2575

Abstract

Hispanics are disproportionally affected by liver fibrosis and hepatocellular carcinoma (HCC). Advanced liver fibrosis is a major risk factor for HCC development. We aimed at identifying somatic mutations in plasma cell-free DNA (cfDNA) of Hispanics with HCC and Hispanics with advanced liver fibrosis but no HCC. Targeted sequencing of over 262 cancer-associated genes identified nonsynonymous mutations in 22 of the 27 HCC patients. Mutations were detected in known HCC-associated genes (e.g., CTNNB1, TP53, NFE2L2, and ARID1A). No difference in cfDNA concentrations was observed between patients with mutations and those without detectable mutations. HCC patients with higher cfDNA concentrations or higher number of mutations had a shorter overall survival (p < 0.001 and p = 0.045). Nonsynonymous mutations were also identified in 17 of the 51 subjects with advanced liver fibrosis. KMT2C was the most commonly mutated gene. Nine genes were mutated in both subjects with advanced fibrosis and HCC patients. Again, no significant difference in cfDNA concentrations was observed between subjects with mutations and those without detectable mutations. Furthermore, higher cfDNA concentrations and higher number of mutations correlated with a death outcome in subjects with advanced fibrosis. In conclusion, cfDNA features are promising non-invasive markers for HCC risk prediction and overall survival. Full article

(This article belongs to the Special Issue New Frontiers in Molecular Research of Digestive Diseases)

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18 pages, 2312 KiB

Open AccessArticle

Proinflammatory Interleukin-33 Induces Dichotomic Effects on Cell Proliferation in Normal Gastric Epithelium and Gastric Cancer

by Laura Francesca Pisani, Gian Eugenio Tontini, Carmine Gentile, Beatrice Marinoni, Isabella Teani, Nicoletta Nandi, Pasquale Creo, Emanuele Asti, Luigi Bonavina, Maurizio Vecchi and Luca Pastorelli

Int. J. Mol. Sci. 2021, 22(11), 5792; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115792 - 28 May 2021

Cited by 8 | Viewed by 2528

Abstract

Interleukin (IL)-33 is a member of the interleukin (IL)-1 family of cytokines linked to the development of inflammatory conditions and cancer in the gastrointestinal tract. This study is designed to investigate whether IL-33 has a direct effect on human gastric epithelial cells (GES-1), the human gastric adenocarcinoma cell line (AGS), and the gastric carcinoma cell line (NCI-N87) by assessing its role in the regulation of cell proliferation, migration, cell cycle, and apoptosis. Cell cycle regulation was also determined in ex vivo gastric cancer samples obtained during endoscopy and surgical procedures. Cell lines and tissue samples underwent stimulation with rhIL-33. Proliferation was assessed by XTT and CFSE assays, migration by wound healing assay, and apoptosis by caspase 3/7 activity assay and annexin V assay. Cell cycle was analyzed by means of propidium iodine assay, and gene expression regulation was assessed by RT-PCR profiling. We found that IL-33 has an antiproliferative and proapoptotic effect on cancer cell lines, and it can stimulate proliferation and reduce apoptosis in normal epithelial cell lines. These effects were also confirmed by the analysis of cell cycle gene expression, which showed a reduced expression of pro-proliferative genes in cancer cells, particularly in genes involved in G0/G1 and G2/M checkpoints. These results were confirmed by gene expression analysis on bioptic and surgical specimens. The aforementioned results indicate that IL-33 may be involved in cell proliferation in an environment- and cell-type-dependent manner. Full article

(This article belongs to the Special Issue New Frontiers in Molecular Research of Digestive Diseases)

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Review

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22 pages, 2513 KiB

Open AccessReview

by Wenrui Ye, Stefan Siwko and Robert Y. L. Tsai

Int. J. Mol. Sci. 2021, 22(8), 3820; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083820 - 07 Apr 2021

Cited by 15 | Viewed by 3152

Abstract

Hepatocellular carcinoma (HCC) is the sixth most common cancer and fourth leading cause of cancer-related death worldwide. The number of HCC cases continues to rise despite advances in screening and therapeutic inventions. More importantly, HCC poses two major health disparity issues. First, HCC occurs more commonly in men than women. Second, with the global increase in non-alcoholic fatty liver diseases (NAFLD), it has also become evident that HCC is more prevalent in some races and/or ethnic groups compared to others, depending on its predisposing etiology. Most studies on HCC in the past have been focused on genetic factors as the driving force for HCC development, and the results revealed that genetic mutations associated with HCC are often heterogeneous and involve multiple pathogenic pathways. An emerging new research field is epigenetics, in which gene expression is modified without altering DNA sequences. In this article, we focus on reviewing current knowledge on HCC-related DNA methylation changes that show disparities among different sexes or different racial/ethnic groups, in an effort to establish a point of departure for resolving the broader issue of health disparities in gastrointestinal malignancies using cutting-edge epigenetic approaches. Full article

(This article belongs to the Special Issue New Frontiers in Molecular Research of Digestive Diseases)

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21 pages, 997 KiB

Open AccessReview

Racial Disparity in Drug Disposition in the Digestive Tract

by Song Gao, Edward C. Bell, Yun Zhang and Dong Liang

Int. J. Mol. Sci. 2021, 22(3), 1038; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031038 - 21 Jan 2021

Cited by 9 | Viewed by 2992

Abstract

The major determinants of drug or, al bioavailability are absorption and metabolism in the digestive tract. Genetic variations can cause significant differences in transporter and enzyme protein expression and function. The racial distribution of selected efflux transporter (i.e., Pgp, BCRP, MRP2) and metabolism enzyme (i.e., UGT1A1, UGT1A8) single nucleotide polymorphisms (SNPs) that are highly expressed in the digestive tract are reviewed in this paper with emphasis on the allele frequency and the impact on drug absorption, metabolism, and in vivo drug exposure. Additionally, preclinical and clinical models used to study the impact of transporter/enzyme SNPs on protein expression and function are also reviewed. The results showed that allele frequency of the major drug efflux transporters and the major intestinal metabolic enzymes are highly different in different races, leading to different drug disposition and exposure. The conclusion is that genetic polymorphism is frequently observed in different races and the related protein expression and drug absorption/metabolism function and drug in vivo exposure can be significantly affected, resulting in variations in drug response. Basic research on race-dependent drug absorption/metabolism is expected, and FDA regulations of drug dosing adjustment based on racial disparity are suggested. Full article

(This article belongs to the Special Issue New Frontiers in Molecular Research of Digestive Diseases)

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