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Cellular Mechanisms and Signaling Pathways in Normal Tissue Repair and...
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Cellular Mechanisms and Signaling Pathways in Normal Tissue Repair and Fibrosis

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

Deadline for manuscript submissions: 30 December 2025 | Viewed by 2396

Special Issue Editors

Prof. Dr. Regina M. Day

E-Mail Website
Guest Editor
Department of Pharmacology, The Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA
Interests: cell biology and signal transduction of normal tissue repair and fibrotic remodeling in the lung; adult stem cells that participate in lung repair; apoptosis; cytoskeletal rearrangement; cellular senescence and inflammation; reactive oxygen species in signal transduction and antioxidant cellular defenses
Special Issues, Collections and Topics in MDPI journals
Dr. Jeffrey R. Koenitzer

E-Mail Website
Guest Editor
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Interests: fibrotic lung disease; pulmonary injury; bioinformatics; animal models; COPD

Special Issue Information

Dear Colleagues,

Fibrotic disorders have been described for all organs, including the heart, liver, kidney, lung, spleen, pancreas, thymus, lymph nodes, bone marrow, brain, skin, gastrointestinal tract, eyes, etc. For many of these organs, the events initiating fibrosis are not well defined, although in some cases, the process appears to involve inflammation and/or tissue injury followed by failed repair, ultimately resulting in fibrotic remodeling. For many of these diseases, fibrosis is progressive, and reversal of fibrosis to form functional tissue has not been described. Recent research describes novel molecular and biochemical pathways involved in fibrotic remodeling and the development of animal models that recapitulate the human diseases.

For this Special Issue, we would like to invite papers that investigate molecular and cellular mechanisms for the initiation and progression of fibrosis and the discovery of antifibrotics. Some potential topics include:

  1. The relationship between inflammation/inflammatory responses and fibrotic remodeling.
  2. The accelerated senescence or loss of adult stem cells in a tissue and the activation of fibrotic remodeling as a response to loss of normal tissue turnover.
  3. The activation of novel signaling pathways that may initiate or perpetuate fibrosis and inhibit normal tissue repair.
  4. Novel animal models for the testing and development of antifibrotic agents.
  5. Agents that delay, suppress, or reverse fibrotic remodeling.

This Special Issue is calling for both original articles and reviews providing to the readers of IJMS comprehensive reviews of fibrosis pathways in any one organ system or a comparison of fibrotic pathways in multiple organs, highlighting similarities and differences.

Prof. Dr. Regina M. Day
Dr. Jeffrey R. Koenitzer
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.

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

  • fibrosis
  • inflammation
  • senescence
  • myofibroblasts
  • Wnt/hedgehog
  • extracellular matrix
  • hedgehog
  • angiotensin II/transforming growth factor-beta
  • ephrins

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Published Papers (3 papers)

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Research

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22 pages, 3221 KB  
Article
Pharmacokinetic Profiling Using 3H-Labeled Eggshell Membrane and Effects of Eggshell Membrane and Lysozyme Oral Supplementation on DSS-Induced Colitis and Human Gut Microbiota
by Miho Shimizu, Wataru Sugai, Eri Ohto-Fujita, Aya Atomi, Norio Nogawa, Koichi Takamiya, Hisao Yoshinaga, Yoshihide Asano, Takashi Yamashita, Shinichi Sato, Atsushi Enomoto, Nozomi Hatakeyama, Shunsuke Yasuda, Kazuya Tanaka, Tomoaki Atomi, Kenji Harada, Yukio Hasebe, Toshiyuki Watanabe and Yoriko Atomi
Int. J. Mol. Sci. 2025, 26(18), 9102; https://doi.org/10.3390/ijms26189102 - 18 Sep 2025
Viewed by 273
Abstract
Eggshell membrane (ESM) is composed of approximately 90% protein. Our previous studies in healthy adults demonstrated that two months of daily ESM intake improved respiratory function, zigzag walking speed, and skin elasticity. The present study aims to address the knowledge gap regarding the [...] Read more.
Eggshell membrane (ESM) is composed of approximately 90% protein. Our previous studies in healthy adults demonstrated that two months of daily ESM intake improved respiratory function, zigzag walking speed, and skin elasticity. The present study aims to address the knowledge gap regarding the in vivo effects of ESM in the context of inflammatory bowel disease (IBD). Proteomic analysis was performed on powdered ESM used as a dietary supplement. To investigate its pharmacokinetics in mice, tritium (3H)-labeled ESM was prepared using the 6Li(n,α)3H nuclear reaction. The therapeutic potential of ESM was further examined in a 2.0% dextran sulfate sodium (DSS)-induced murine model of IBD. In addition, fecal samples from both mice and healthy human subjects were analyzed using a modified terminal restriction fragment length polymorphism (T-RFLP) method. Lysozyme C (LYZ) was the most abundant protein (47%), followed by lysyl oxidase (12%) in ESM used in this study. 3H-ESM was mixed with MediGel, and orally administered to mice. Radioactivity levels were measured in blood, organs (duodenum, small intestine, large intestine, liver, kidney, lung, skin), and rectal feces at 0.5, 2, 5, 24, 48, and 72 h post-administration. Radioactivity in feces indicated excretion of undigested components, while systemic distribution suggested potential whole-body effects of ESM. Oral ESM and LYZ significantly alleviated body weight loss, diarrhea, and hematochezia in a DSS-induced murine model of IBD, leading to a significantly lower disease activity index on day 3 and showing a similar trend on day 5. Gut microbiota analysis showed increased Bacteroidales in the DSS group, while the ESM + DSS group maintained levels similar to the control. In humans, a double-blind, randomized controlled trial was conducted to evaluate the effects of ESM on gut microbiota in healthy adults. Participants received either ESM or placebo for 8 weeks. revealed a significant increase in alpha diversity at weeks 1 and 8 in the ESM group (p < 0.05), with between-group differences evident from week 1 (p < 0.01). ESM intake reduced Bacteroides and significantly increased Bifidobacterium and Lactobacillales at weeks 4 and 8. These findings suggest ESM supplementation promotes beneficial modulation of gut microbiota. These findings suggest that ESM, through its major protein components such as LYZ, may serve as a promising dietary intervention for maintaining intestinal health and mitigating inflammation in the context of IBD. Full article
(This article belongs to the Special Issue Cellular Mechanisms and Signaling Pathways in Normal Tissue Repair and Fibrosis)
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18 pages, 4066 KB  
Article
Furosemide Promotes Inflammatory Activation and Myocardial Fibrosis in Swine with Tachycardia-Induced Heart Failure
by Nisha Plavelil, Robert Goldstein, Michael G. Klein, Luke Michaelson, Mark C. Haigney and Maureen N. Hood
Int. J. Mol. Sci. 2025, 26(13), 6088; https://doi.org/10.3390/ijms26136088 - 25 Jun 2025
Viewed by 413
Abstract
Loop diuretics like furosemide are commonly used in heart failure (HF) treatment, but their effects on disease progression are still unclear. Furosemide treatment accelerates HF deterioration in a swine model, but the mechanism of acceleration is poorly understood. We hypothesized that furosemide activates [...] Read more.
Loop diuretics like furosemide are commonly used in heart failure (HF) treatment, but their effects on disease progression are still unclear. Furosemide treatment accelerates HF deterioration in a swine model, but the mechanism of acceleration is poorly understood. We hypothesized that furosemide activates inflammatory signaling in the failing left ventricular (LV) myocardium, leading to adverse remodeling of the extracellular matrix (ECM). A total of 14 Yorkshire pigs underwent permanent transvenous pacemaker implantation and were paced at 200 beats per minute; 9 non-instrumented pigs provided controls. Seven paced animals received normal saline, and seven received furosemide at a dose of 1 mg/kg intramuscularly. Weekly echocardiograms were performed. Furosemide-treated animals reached the HF endpoint a mean of 3.2 days sooner than saline-treated controls (mean 28.9 ± 3.8 SEM for furosemide and 32.1 ± 2.5 SEM for saline). The inflammatory signaling protein transforming growth factor-beta (TGF-β) and its downstream proteins were significantly (p ≤ 0.05) elevated in the LV after furosemide treatment. The regulatory factors in cell proliferation, mitogen-activated protein kinase signaling pathway proteins, and matrix metalloproteinases were elevated in the furosemide-treated animals (p ≤ 0.05). Our data showed that furosemide treatment increased ECM remodeling and myocardial fibrosis, reflecting increased TGF-β signaling factors, supporting prior results showing worsened HF. Full article
(This article belongs to the Special Issue Cellular Mechanisms and Signaling Pathways in Normal Tissue Repair and Fibrosis)
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Review

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28 pages, 944 KB  
Review
Amphiregulin in Fibrotic Diseases and Cancer
by Tae Rim Kim, Beomseok Son, Chun Geun Lee and Han-Oh Park
Int. J. Mol. Sci. 2025, 26(14), 6945; https://doi.org/10.3390/ijms26146945 - 19 Jul 2025
Cited by 1 | Viewed by 1396
Abstract
Fibrotic disorders pose a significant global health burden due to limited treatment options, creating an urgent need for novel therapeutic strategies. Amphiregulin (AREG), a low-affinity ligand for the epidermal growth factor receptor (EGFR), has emerged as a key mediator of fibrogenesis through dual [...] Read more.
Fibrotic disorders pose a significant global health burden due to limited treatment options, creating an urgent need for novel therapeutic strategies. Amphiregulin (AREG), a low-affinity ligand for the epidermal growth factor receptor (EGFR), has emerged as a key mediator of fibrogenesis through dual signaling pathways. Unlike high-affinity EGFR ligands, AREG induces sustained signaling that activates downstream effectors and promotes the integrin-mediated activation of transforming growth factor (TGF)-β. This enables both canonical and non-canonical EGFR signaling pathways that contribute to fibrosis. Elevated AREG expression correlates with disease severity across multiple organs, including the lungs, kidneys, liver, and heart. The therapeutic targeting of AREG has shown promising antifibrotic and anticancer effects, suggesting a dual-benefit strategy. The increasing recognition of the shared mechanisms between fibrosis and cancer further supports the development of unified treatment approaches. The inhibition of AREG has been shown to sensitize fibrotic tumor microenvironments to chemotherapy, enhancing combination therapy efficacy. Targeted therapies, such as Self-Assembled-Micelle inhibitory RNA (SAMiRNA)-AREG, have demonstrated enhanced specificity and favorable safety profiles in preclinical studies and early clinical trials. Personalized treatment based on AREG expression may improve clinical outcomes, establishing AREG as a promising precision medicine target for both fibrotic and malignant diseases. This review aims to provide a comprehensive understanding of AREG biology and evaluate its therapeutic potential in fibrosis and cancer. Full article
(This article belongs to the Special Issue Cellular Mechanisms and Signaling Pathways in Normal Tissue Repair and Fibrosis)
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