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Hepatopancreatic and Intestine Diseases: From Molecular Basis to Therapy

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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 (20 July 2025) | Viewed by 11828

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Dr. Arnau Panisello-Roselló

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Steatohepatitis and Transplantation Research Group. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
Interests: pathophysiology of ischemia reperfusion injury; cell signaling molecular mechanisms; liver transplantation; dynamic preservation strategies (HOPE and NMP); inflammatory mediators; (nitric oxide; DAMPS; inflammasome NLRP3; cytokines)
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Dr. Emma Folch-Puy

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Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC)-IDIBAPS, CIBEREHD, 08036 Barcelona, Catalonia, Spain
Interests: inflammation; pancreatic adenocarcinoma; cell signalling; Reg3beta; immune response; Pancreatitis-Associated Protein (PAP); pancreas isquemia-reperfusion; preservation solutions; liver isquemia-reperfusion injury

Special Issue Information

Dear Colleagues,

"Hepatopancreatic and Intestine Diseases: From Molecular Basis to Therapy" is a Special Issue that delves deeply into the intricate molecular foundations and cutting-edge therapeutic strategies for the treatment of a broad spectrum of diseases affecting the hepatopancreatic system and intestine. The articles in this Special Issue provide profound insights into the complex molecular mechanisms driving these diseases and introduce innovative therapeutic approaches on a molecular level.

Encompassing a diverse range of hepatopancreatic and intestine diseases, such as disorders, viral diseases, inflammatory diseases, and cancers, these articles explore the intricate interplay of genetics, epigenetics, and environmental factors in the pathogenesis of these conditions. They shed light on the molecular pathways orchestrating disease development, unraveling the underlying mechanisms that contribute to their progression.

Moreover, this Special Issue offers a comprehensive overview of state-of-the-art diagnostic tools and treatment options that specifically target the molecular aspects of each disease entity. From pharmacological interventions and surgical techniques to immunotherapies, emerging targeted therapies, and regenerative medicine approaches, the articles in this Special Issue present a wealth of therapeutic possibilities grounded in molecular research.

By emphasizing the importance of interdisciplinary collaboration and personalized medicine, this Special Issue aims to advance the field of hepatopancreatic and intestine diseases at the molecular level, ultimately leading to enhanced patient outcomes. It serves as an invaluable resource for researchers, clinicians, and healthcare professionals dedicated to unraveling the molecular basis of these diseases and revolutionizing their management through molecularly targeted interventions.

Dr. Arnau Panisello-Roselló
Dr. Emma Folch-Puy
Guest Editors

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.

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Keywords

hepatopancreatic diseases
intestine diseases
molecular basis
therapy
pathogenesis
molecular pathways
pharmacological interventions
surgical techniques
immunotherapies
regenerative medicine approaches

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Published Papers (9 papers)

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Research

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19 pages, 6079 KiB

Open AccessArticle

Identification of Salivary Exosome-Derived miRNAs as Potential Biomarkers for Non-Invasive Diagnosis and Proactive Monitoring of Inflammatory Bowel Disease

by Congyi Yang, Jingyi Chen, Yuzheng Zhao, Yalan Xu, Jushan Wu, Jun Xu, Feng Chen and Ning Chen

Int. J. Mol. Sci. 2025, 26(16), 7750; https://doi.org/10.3390/ijms26167750 - 11 Aug 2025

Viewed by 273

Abstract

Inflammatory bowel disease (IBD), a chronic inflammatory disorder with relapsing/remitting characteristics, lacks reliable non-invasive biomarkers for accurate diagnosis and longitudinal monitoring. This study explored salivary exosomal miRNAs as potential biomarkers to address this unmet clinical need. Using discovery (24 IBD patients [11 active, 13 remission] and 6 healthy controls [HCs]) and validation cohorts (102 IBD patients [53 active, 49 remission] and 18 HCs), we analyzed miRNA profiles via reverse transcription quantitative PCR (RT-qPCR). Receiver operating characteristic (ROC) curves evaluated diagnostic performance, with area under the curve (AUC) quantifying discriminatory capacity. Initial screening revealed 23 miRNAs significantly upregulated in IBD salivary exosomes. An 8-miRNA signature distinguished IBD patients from HCs in validation analyses, with five miRNAs (hsa-miR-1246, hsa-miR-142-3p, hsa-miR-16-5p, hsa-miR-301a-3p, and hsa-miR-4516) showing strong correlations with disease activity. The combination of hsa-miR-16-5p and hsa-miR-4516 achieved robust discrimination (AUC = 0.925 for IBD vs. HCs; AUC = 0.82 for active disease vs. remission). A composite model integrating all five miRNAs demonstrated superior performance (AUC = 1.00 for IBD/HC differentiation; AUC = 0.86 for disease activity assessment). These findings reveal dynamic associations between salivary exosomal miRNA signatures and IBD progression, underscoring their utility as non-invasive diagnostic tools. This approach enables serial sampling, enhances patient compliance, and provides actionable insights for personalized disease management, establishing salivary exosomal miRNAs as promising candidates for clinical translation in IBD care. Full article

(This article belongs to the Special Issue Hepatopancreatic and Intestine Diseases: From Molecular Basis to Therapy)

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18 pages, 3229 KiB

Open AccessArticle

AMPK-Targeting Effects of (−)-Epicatechin Gallate from Hibiscus sabdariffa Linne Leaves on Dual Modulation of Hepatic Lipid Accumulation and Glycogen Synthesis in an In Vitro Oleic Acid Model

by Hui-Hsuan Lin, Pei-Tzu Wu, Yu-Hsuan Liang, Ming-Shih Lee and Jing-Hsien Chen

Int. J. Mol. Sci. 2025, 26(15), 7612; https://doi.org/10.3390/ijms26157612 - 6 Aug 2025

Viewed by 204

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) begins with hepatic lipid accumulation and triggers insulin resistance. Hibiscus leaf extract exhibits antioxidant and anti-atherosclerotic activities, and is rich in (−)-epicatechin gallate (ECG). Despite ECG’s well-known pharmacological activities and its total antioxidant capacity being stronger than that of other catechins, its regulatory effects on MASLD have not been fully described previously. Therefore, this study attempted to evaluate the anti-MASLD potential of ECG isolated from Hibiscus leaves on abnormal lipid and glucose metabolism in hepatocytes. First, oleic acid (OA) was used as an experimental model to induce lipid dysmetabolism in human primary hepatocytes. Treatment with ECG can significantly (p < 0.05) reduce the OA-induced cellular lipid accumulation. Nile red staining revealed, compared to the OA group, the inhibition percentages of 29, 61, and 82% at the tested doses of ECG, respectively. The beneficial effects of ECG were associated with the downregulation of SREBPs/HMGCR and upregulation of PPARα/CPT1 through targeting AMPK. Also, ECG at 0.4 µM produced a significant (p < 0.01) decrease in oxidative stress by 83%, and a marked (p < 0.05) increase in glycogen synthesis by 145% on the OA-exposed hepatocytes with insulin signaling blockade. Mechanistic assays indicated lipid and glucose metabolic homeostasis of ECG might be mediated via regulation of lipogenesis, fatty acid β-oxidation, and insulin resistance, as confirmed by an AMPK inhibitor. These results suggest ECG is a dual modulator of lipid and carbohydrate dysmetabolism in hepatocytes. Full article

(This article belongs to the Special Issue Hepatopancreatic and Intestine Diseases: From Molecular Basis to Therapy)

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15 pages, 1882 KiB

Open AccessArticle

Evidence for the Prognostic Value of CDH17 Expression in Colorectal Carcinoma

by Victor Ianole, Simona-Eliza Giușcă and Irina-Draga Căruntu

Int. J. Mol. Sci. 2025, 26(14), 6960; https://doi.org/10.3390/ijms26146960 - 20 Jul 2025

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Abstract

Colorectal cancer (CRC) diagnosed in an advanced stage has an increased predisposition for invasion and metastasis, requiring upgraded prognostic markers. CDH17, a liver-intestine cadherin, is an adhesion molecule implicated in tumor progression. This retrospective study assessed the immunohistochemical expression of CDH17 in 84 CRC cases with lymphovascular invasion (LVI), analyzing its correlation with clinicopathological features and survival outcomes. CDH17 expression was evaluated in the tumor core, invasive front, tumor emboli, and lymph node metastases. Statistical analyses showed significant associations between high CDH17 expression and favorable histological types, as well as low-grade differentiation. However, high CDH17 levels in tumor emboli correlated with advanced T stage and poorer overall survival. Multivariable Cox regression confirmed CDH17 expression in tumor emboli as an independent prognostic factor, indicating an approximately twofold risk of death. These findings suggest that CDH17 may have a dual role—maintaining adhesion in low-grade tumors while facilitating tumor emboli-related dissemination. CDH17 expression, particularly in the tumor emboli, could serve as a valuable prognostic biomarker in CRC with LVI. Full article

(This article belongs to the Special Issue Hepatopancreatic and Intestine Diseases: From Molecular Basis to Therapy)

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15 pages, 2522 KiB

Open AccessArticle

Mitigating Cold Ischemic Injury: HTK, UW and IGL-2 Solution’s Role in Enhancing Antioxidant Defence and Reducing Inflammation in Steatotic Livers

by Raquel G. Bardallo, Gabriela Chullo, Norma Alva, Joan Rosello-Catafau, Yiliam Fundora-Suárez, Teresa Carbonell and Arnau Panisello-Rosello

Int. J. Mol. Sci. 2024, 25(17), 9318; https://doi.org/10.3390/ijms25179318 - 28 Aug 2024

Cited by 2 | Viewed by 1512

Abstract

Liver transplantation remains the only definitive treatment for end-stage liver diseases. However, the increasing prevalence of fatty liver disease among potential donors exacerbates the shortage of suitable organs. This study evaluates the efficacy of the preservation solution Institut Georges Lopez-2 (IGL-2) compared to Histidine–Tryptophan–Ketoglutarate (HTK) and University of Wisconsin (UW) preservation solutions in mitigating ischemia-reperfusion injury (IRI) in steatotic livers. Using Zucker Obese rat livers, we assessed the impact of 24-h static cold storage (SCS) with each solution on transaminase release, glutathione redox balance, antioxidant enzyme activity, lipoperoxidation, and inflammation markers. IGL-2 and UW solutions demonstrated reduced transaminase and lactate levels compared to HTK, indicating better preservation of liver integrity. IGL-2 maintained a higher reduced glutathione/oxidized glutathione (GSH/GSSG) ratio, suggesting more effective management of oxidative stress. Antioxidant enzyme activities catalase, superoxide dismutase, and glutathione peroxidase (CAT, SOD, GPX) were higher in IGL-2 preserved livers, contributing to decreased oxidative damage. Lipid peroxidation markers and inflammatory markers were lower in IGL-2 than in HTK, indicating reduced oxidative stress and inflammation. Additionally, improved mitochondrial function was observed in the IGL-2 group, correlating with reduced reactive oxygen species (ROS) production and lipid peroxidation. These findings suggest that IGL-2 offers superior preservation of liver viability, reduces oxidative stress, and minimizes inflammation compared to HTK and UW solutions. By maintaining a higher ratio of reduced glutathione and antioxidant enzyme activity, IGL-2 effectively mitigates the harmful effects of ischemia-reperfusion injury. The reduced lipid peroxidation and inflammation in the IGL-2 group further underscore its potential in improving liver transplant outcomes. These results highlight the importance of optimizing preservation solutions to enhance the viability and functionality of donor organs, potentially expanding the donor pool and improving the success rates of liver transplantation. Future research should focus on refining preservation techniques and exploring additional protective agents to further improve organ preservation and transplant outcomes. Full article

(This article belongs to the Special Issue Hepatopancreatic and Intestine Diseases: From Molecular Basis to Therapy)

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20 pages, 963 KiB

Open AccessArticle

Circulating Trimethylamine-N-Oxide Is Elevated in Liver Transplant Recipients

by Maria Camila Trillos-Almanza, Mateo Chvatal-Medina, Margery A. Connelly, Han Moshage, TransplantLines Investigators, Stephan J. L. Bakker, Vincent E. de Meijer, Hans Blokzijl and Robin P. F. Dullaart

Int. J. Mol. Sci. 2024, 25(11), 6031; https://doi.org/10.3390/ijms25116031 - 30 May 2024

Cited by 4 | Viewed by 1424

Abstract

Liver transplant recipients (LTRs) have lower long-term survival rates compared with the general population. This underscores the necessity for developing biomarkers to assess post-transplantation mortality. Here we compared plasma trimethylamine-N-oxide (TMAO) levels with those in the general population, investigated its determinants, and interrogated its association with all-cause mortality in stable LTRs. Plasma TMAO was measured in 367 stable LTRs from the TransplantLines cohort (NCT03272841) and in 4837 participants from the population-based PREVEND cohort. TMAO levels were 35% higher in LTRs compared with PREVEND participants (4.3 vs. 3.2 µmol/L, p < 0.001). Specifically, TMAO was elevated in LTRs with metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, and polycystic liver disease as underlying etiology (p < 0.001 for each). Among LTRs, TMAO levels were independently associated with eGFR (std. β = −0.43, p < 0.001) and iron supplementation (std. β = 0.13, p = 0.008), and were associated with mortality (29 deaths during 8.6 years follow-up; log-rank test p = 0.017; hazard ratio of highest vs. lowest tertile 4.14, p = 0.007). In conclusion, plasma TMAO is likely elevated in stable LTRs, with impaired eGFR and iron supplementation as potential contributory factors. Our preliminary findings raise the possibility that plasma TMAO could contribute to increased mortality risk in such patients, but this need to be validated through a series of rigorous and methodical studies. Full article

(This article belongs to the Special Issue Hepatopancreatic and Intestine Diseases: From Molecular Basis to Therapy)

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13 pages, 8634 KiB

Open AccessArticle

The Role of Hypoxia-Inducible Factor 1 Alpha in Acute-on-Chronic Liver Failure

by Marcus M. Mücke, Nihad El Bali, Katharina M. Schwarzkopf, Frank Erhard Uschner, Nico Kraus, Larissa Eberle, Victoria Therese Mücke, Julia Bein, Sandra Beyer, Peter J. Wild, Robert Schierwagen, Sabine Klein, Stefan Zeuzem, Christoph Welsch, Jonel Trebicka and Angela Brieger

Int. J. Mol. Sci. 2024, 25(3), 1542; https://doi.org/10.3390/ijms25031542 - 26 Jan 2024

Viewed by 2435

Abstract

Acute-on-chronic liver failure (ACLF) is associated with increased mortality. Specific therapy options are limited. Hypoxia-inducible factor 1 alpha (HIF-1α) has been linked to the pathogenesis of chronic liver disease (CLD), but the role of HIF-1α in ACLF is poorly understood. In the current study, different etiologies of CLD and precipitating events triggering ACLF were used in four rodent models. HIF-1α expression and the intracellular pathway of HIF-1α induction were investigated using real-time quantitative PCR. The results were verified by Western blotting and immunohistochemistry for extrahepatic HIF-1α expression using transcriptome analysis. Exploratory immunohistochemical staining was performed to assess HIF-1α in human liver tissue. Intrahepatic HIF-1α expression was significantly increased in all animals with ACLF, regardless of the underlying etiology of CLD or the precipitating event. The induction of HIF-1α was accompanied by the increased mRNA expression of NFkB1 and STAT3 and resulted in a marked elevation of mRNA levels of its downstream genes. Extrahepatic HIF-1α expression was not elevated. In human liver tissue samples, HIF-1α expression was elevated in CLD and ACLF. Increased intrahepatic HIF-1α expression seems to play an important role in the pathogenesis of ACLF, and future studies are pending to investigate the role of therapeutic HIF inhibitors in ACLF. Full article

(This article belongs to the Special Issue Hepatopancreatic and Intestine Diseases: From Molecular Basis to Therapy)

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Review

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25 pages, 4622 KiB

Open AccessReview

Immunological Landscape and Molecular Therapeutic Targets of the Tumor Microenvironment in Hepatocellular Carcinoma

by Yusra Zarlashat, Abdul Ghaffar, Flora Guerra and Anna Picca

Int. J. Mol. Sci. 2025, 26(16), 7836; https://doi.org/10.3390/ijms26167836 - 13 Aug 2025

Viewed by 281

Abstract

Hepatocellular carcinoma (HCC) is the most common liver cancer, with poor survival rates in advanced stages due to late diagnosis, tumor heterogeneity, and therapy resistance. The tumor microenvironment (TME) in HCC has a crucial role in tumor progression, characterized by a complex interaction of immune cells, stromal components, and immunosuppressive signaling pathways. Chronic inflammation driven by viral infections, metabolic dysfunction, and alcohol consumption triggers an immunosuppressive TME, promoting immune evasion and tumor growth. Immune cell populations, such as myeloid-derived suppressor cells, regulatory T cells, and tumor-associated macrophages, contribute to immunosuppression, while cytotoxic T lymphocytes and natural killer cells exert anti-tumor effects. Recent advances in immunotherapy, mainly immune checkpoint inhibitors (ICIs) targeting programmed death-ligand 1 and programmed cell death protein 1 and cytotoxic T-lymphocyte-associated protein 4, have revolutionized HCC treatment, though response rates remain limited. Combined therapies using tyrosine kinase inhibitors, anti-angiogenic agents, and ICIs improve patient outcomes. This review discusses the immunological mechanisms contributing to HCC progression, the role of immune cell subsets in tumor evasion, and therapeutic interventions, from conventional treatments to advanced immunotherapies. Ongoing clinical trials, barriers to effective treatment, and future directions to enhance HCC management and patient survival will also be overviewed. Full article

(This article belongs to the Special Issue Hepatopancreatic and Intestine Diseases: From Molecular Basis to Therapy)

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30 pages, 2637 KiB

Open AccessReview

Can Nature Overcome Invasive Gastrointestinal Infections?

by Anna Duda-Madej, Szymon Viscardi, Jakub Stecko, Natalia Szymańska, Ewa Topola, Katarzyna Pacyga and Marta Szandruk-Bender

Int. J. Mol. Sci. 2025, 26(12), 5795; https://doi.org/10.3390/ijms26125795 - 17 Jun 2025

Viewed by 770

Abstract

Invasive bacterial gastrointestinal infections represent a substantial clinical burden worldwide, contributing to significant morbidity and, in severe cases, mortality. The causative bacterial agents of these infections include Shigella spp., enteroinvasive Escherichia coli, Salmonella spp., Campylobacter jejuni, Yersinia enterocolitica, and Listeria monocytogenes. Given the growing challenges of therapy failures and rising antibiotic resistance, there is still an unmet need to identify novel, effective, and safe compounds exhibiting antimicrobial, anti-inflammatory, and immunomodulatory activities. In the present review, we aimed to compile current data regarding three alkaloids—berberine, sanguinarine, and cheleritrin—which hold significant promise in treating bacterial invasive gastrointestinal diseases. Our review extended beyond the direct antimicrobial properties of these compounds against pathogens capable of breaching the intestinal epithelial barrier. We also presented their modulatory effects on intestinal barrier integrity and their influence on the composition and function of the resident gut microbiota, thereby highlighting their potential indirect role in attenuating pathogen invasion and disease progression. Thus, our review presents alkaloids as potential preparations that potentiate the activity of classic anti-infective drugs, as well as substances that, by affecting the microbiome and intestinal mucosa, could be used for inflammatory bowel diseases. Full article

(This article belongs to the Special Issue Hepatopancreatic and Intestine Diseases: From Molecular Basis to Therapy)

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31 pages, 2025 KiB

Open AccessReview

Focusing on Ischemic Reperfusion Injury in the New Era of Dynamic Machine Perfusion in Liver Transplantation

by Gabriela Chullo, Arnau Panisello-Rosello, Noel Marquez, Jordi Colmenero, Merce Brunet, Miguel Pera, Joan Rosello-Catafau, Ramon Bataller, Juan Carlos García-Valdecasas and Yiliam Fundora

Int. J. Mol. Sci. 2024, 25(2), 1117; https://doi.org/10.3390/ijms25021117 - 17 Jan 2024

Cited by 13 | Viewed by 3320

Abstract

Liver transplantation is the most effective treatment for end-stage liver disease. Transplant indications have been progressively increasing, with a huge discrepancy between the supply and demand of optimal organs. In this context, the use of extended criteria donor grafts has gained importance, even though these grafts are more susceptible to ischemic reperfusion injury (IRI). Hepatic IRI is an inherent and inevitable consequence of all liver transplants; it involves ischemia-mediated cellular damage exacerbated upon reperfusion and its severity directly affects graft function and post-transplant complications. Strategies for organ preservation have been constantly improving since they first emerged. The current gold standard for preservation is perfusion solutions and static cold storage. However, novel approaches that allow extended preservation times, organ evaluation, and their treatment, which could increase the number of viable organs for transplantation, are currently under investigation. This review discusses the mechanisms associated with IRI, describes existing strategies for liver preservation, and emphasizes novel developments and challenges for effective organ preservation and optimization. Full article

(This article belongs to the Special Issue Hepatopancreatic and Intestine Diseases: From Molecular Basis to Therapy)

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