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Pharmaceuticals
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New Pharmacologic Approaches to Study and Intervene in Epithelial to...
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New Pharmacologic Approaches to Study and Intervene in Epithelial to Mesenchymal Transition (EMT) and Fibrosis

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 16987

Special Issue Editors

Dr. Raffaele Strippoli

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Guest Editor
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
Interests: peritoneal fibrosis; EMT; biomechanical remodeling; epigenetics
Special Issues, Collections and Topics in MDPI journals
Dr. Marco Cordani

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Guest Editor
Institute for Advanced Studies in Nanoscience (IMDEA Nanociencia), Madrid, Spain
Interests: nanomedicine; cancer therapy; autophagy; ROS; nanoparticles; chemotherapy
Special Issues, Collections and Topics in MDPI journals
Dr. Sergio Valente

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Guest Editor
Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy
Interests: epigenetics; HDACs; SIRTs; DNMTs; drug design
Special Issues, Collections and Topics in MDPI journals
Dr. Marco Tafani

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Guest Editor
Department of Experimental Medicine, Sapienza University, 00161 Rome, ItalyDepartment of Experimental Medicine, Sapienza University, Rome, Italy
Interests: sirtuins; hypoxia inflammation; metabolism; autophagy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Fibrosis is a general mechanism of response to a wide range of insults and is characterized by abnormal production and remodeling of extracellular matrix proteins. This process is regulated by a number of extracellular mediators and deeply impacts cell behavior through changes in mechanosensing, cellular plasticity and cell-to cell communication.

Importantly, due to the incomplete ability of endogenous mechanisms to remove the fibrotic deposits, and since no resolutive therapies are available to date, the persistence of profibrotic conditions may cause scarring and thickening of the affected tissue with persistent organ damage and loss of function. Thus, the establishment of fibrosis is essential in the pathogenesis of a wide array of diseases, ranging from chronical inflammatory and immune-mediated diseases to tumors.

The aim of this Special Issue is to create a platform in which different aspects of pharmacological intervention to study and counteract fibrotic damage may be discussed.

The journal Pharmaceuticals invites both reviews and original articles shedding light on the challenges and opportunities of pharmacological treatment of every aspect of fibrosis. Topics include rational of pharmacological treatment for EMT–MET dynamics, control of fibrosis by autophagy, oxidative response, hypoxia, epigenetic mechanisms, new drugs, and new methods of pharmacological delivery, including nanomedicine. The collection of manuscripts will be published as a Special Issue of the journal.

Dr. Raffaele Strippoli
Dr. Sergio Valente
Dr. Marco Tafani
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. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). 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
  • EMT
  • epigenetics
  • autophagy
  • drug discovery
  • nanomolecular delivery

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Published Papers (4 papers)

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Research

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28 pages, 5408 KiB  
Article
New Insights into the Binding Features of F508del CFTR Potentiators: A Molecular Docking, Pharmacophore Mapping and QSAR Analysis Approach
by Giada Righetti, Monica Casale, Michele Tonelli, Nara Liessi, Paola Fossa, Nicoletta Pedemonte, Enrico Millo and Elena Cichero
Pharmaceuticals 2020, 13(12), 445; https://doi.org/10.3390/ph13120445 - 4 Dec 2020
Cited by 10 | Viewed by 3183
Abstract
Cystic fibrosis (CF) is the autosomal recessive disorder most recurrent in Caucasian populations. To combat this disease, many life-prolonging therapies are required and deeply investigated, including the development of the so-called cystic fibrosis transmembrane conductance regulator (CFTR) modulators, such as correctors and potentiators. [...] Read more.
Cystic fibrosis (CF) is the autosomal recessive disorder most recurrent in Caucasian populations. To combat this disease, many life-prolonging therapies are required and deeply investigated, including the development of the so-called cystic fibrosis transmembrane conductance regulator (CFTR) modulators, such as correctors and potentiators. Combination therapy with the two series of drugs led to the approval of several multi-drug effective treatments, such as Orkambi, and to the recent promising evaluation of the triple-combination Elexacaftor-Tezacaftor-Ivacaftor. This scenario enlightened the effectiveness of the multi-drug approach to pave the way for the discovery of novel therapeutic agents to contrast CF. The recent X-crystallographic data about the human CFTR in complex with the well-known potentiator Ivacaftor (VX-770) opened the possibility to apply a computational study aimed to explore the key features involved in the potentiator binding. Herein, we discussed molecular docking studies performed onto the chemotypes so far discussed in the literature as CFTR potentiator, reporting the most relevant interactions responsible for their mechanism of action, involving Van der Waals interactions and π–π stacking with F236, Y304, F305 and F312, as well as H-bonding F931, Y304, S308 and R933. This kind of positioning will stabilize the effective potentiator at the CFTR channel. These data have been accompanied by pharmacophore analyses, which promoted the design of novel derivatives endowed with a main (hetero)aromatic core connected to proper substituents, featuring H-bonding moieties. A highly predictive quantitative-structure activity relationship (QSAR) model has been developed, giving a cross-validated r2 (r2cv) = 0.74, a non-cross validated r2 (r2ncv) = 0.90, root mean square error (RMSE) = 0.347, and a test set r2 (r2pred) = 0.86. On the whole, the results are expected to gain useful information to guide the further development and optimization of new CFTR potentiators. Full article
(This article belongs to the Special Issue New Pharmacologic Approaches to Study and Intervene in Epithelial to Mesenchymal Transition (EMT) and Fibrosis)
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25 pages, 11524 KiB  
Article
Hepatic Tumor Cell Morphology Plasticity under Physical Constraints in 3D Cultures Driven by YAP–mTOR Axis
by Adam Frtús, Barbora Smolková, Mariia Uzhytchak, Mariia Lunova, Milan Jirsa, Martin Hof, Piotr Jurkiewicz, Vladimir I. Lozinsky, Lucie Wolfová, Yuriy Petrenko, Šárka Kubinová, Alexandr Dejneka and Oleg Lunov
Pharmaceuticals 2020, 13(12), 430; https://doi.org/10.3390/ph13120430 - 28 Nov 2020
Cited by 5 | Viewed by 5614
Abstract
Recent studies undoubtedly show that the mammalian target of rapamycin (mTOR) and the Hippo–Yes-associated protein 1 (YAP) pathways are important mediators of mechanical cues. The crosstalk between these pathways as well as de-regulation of their signaling has been implicated in multiple tumor types, [...] Read more.
Recent studies undoubtedly show that the mammalian target of rapamycin (mTOR) and the Hippo–Yes-associated protein 1 (YAP) pathways are important mediators of mechanical cues. The crosstalk between these pathways as well as de-regulation of their signaling has been implicated in multiple tumor types, including liver tumors. Additionally, physical cues from 3D microenvironments have been identified to alter gene expression and differentiation of different cell lineages. However, it remains incompletely understood how physical constraints originated in 3D cultures affect cell plasticity and what the key mediators are of such process. In this work, we use collagen scaffolds as a model of a soft 3D microenvironment to alter cellular size and study the mechanotransduction that regulates that process. We show that the YAP-mTOR axis is a downstream effector of 3D cellular culture-driven mechanotransduction. Indeed, we found that cell mechanics, dictated by the physical constraints of 3D collagen scaffolds, profoundly affect cellular proliferation in a YAP–mTOR-mediated manner. Functionally, the YAP–mTOR connection is key to mediate cell plasticity in hepatic tumor cell lines. These findings expand the role of YAP–mTOR-driven mechanotransduction to the control hepatic tumor cellular responses under physical constraints in 3D cultures. We suggest a tentative mechanism, which coordinates signaling rewiring with cytoplasmic restructuring during cell growth in 3D microenvironments. Full article
(This article belongs to the Special Issue New Pharmacologic Approaches to Study and Intervene in Epithelial to Mesenchymal Transition (EMT) and Fibrosis)
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Review

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30 pages, 2655 KiB  
Review
Sirtuins and Hypoxia in EMT Control
by Michele Aventaggiato, Federica Barreca, Luigi Sansone, Laura Pellegrini, Matteo A. Russo, Marco Cordani and Marco Tafani
Pharmaceuticals 2022, 15(6), 737; https://doi.org/10.3390/ph15060737 - 10 Jun 2022
Cited by 6 | Viewed by 3578
Abstract
Epithelial–mesenchymal transition (EMT), a physiological process during embryogenesis, can become pathological in the presence of different driving forces. Reduced oxygen tension or hypoxia is one of these forces, triggering a large number of molecular pathways with aberrant EMT induction, resulting in cancer and [...] Read more.
Epithelial–mesenchymal transition (EMT), a physiological process during embryogenesis, can become pathological in the presence of different driving forces. Reduced oxygen tension or hypoxia is one of these forces, triggering a large number of molecular pathways with aberrant EMT induction, resulting in cancer and fibrosis onset. Both hypoxia-induced factors, HIF-1α and HIF-2α, act as master transcription factors implicated in EMT. On the other hand, hypoxia-dependent HIF-independent EMT has also been described. Recently, a new class of seven proteins with deacylase activity, called sirtuins, have been implicated in the control of both hypoxia responses, HIF-1α and HIF-2α activation, as well as EMT induction. Intriguingly, different sirtuins have different effects on hypoxia and EMT, acting as either activators or inhibitors, depending on the tissue and cell type. Interestingly, sirtuins and HIF can be activated or inhibited with natural or synthetic molecules. Moreover, recent studies have shown that these natural or synthetic molecules can be better conveyed using nanoparticles, representing a valid strategy for EMT modulation. The following review, by detailing the aspects listed above, summarizes the interplay between hypoxia, sirtuins, and EMT, as well as the possible strategies to modulate them by using a nanoparticle-based approach. Full article
(This article belongs to the Special Issue New Pharmacologic Approaches to Study and Intervene in Epithelial to Mesenchymal Transition (EMT) and Fibrosis)
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18 pages, 2180 KiB  
Review
Epithelial to Mesenchymal Transition in Patients with Pancreatic Ductal Adenocarcinoma: State-of-the-Art and Therapeutic Opportunities
by Julie Dardare, Andréa Witz, Jean-Louis Merlin, Agathe Bochnakian, Paul Toussaint, Pauline Gilson and Alexandre Harlé
Pharmaceuticals 2021, 14(8), 740; https://doi.org/10.3390/ph14080740 - 29 Jul 2021
Cited by 13 | Viewed by 3588
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the malignancies with the worst prognosis despite a decade of efforts. Up to eighty percent of patients are managed at late stages with metastatic disease, in part due to a lack of diagnosis. The effectiveness of [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is one of the malignancies with the worst prognosis despite a decade of efforts. Up to eighty percent of patients are managed at late stages with metastatic disease, in part due to a lack of diagnosis. The effectiveness of PDAC therapies is challenged by the early and widespread metastasis. Epithelial to mesenchymal transition (EMT) is a major driver of cancer progression and metastasis. This process allows cancer cells to gain invasive properties by switching their phenotype from epithelial to mesenchymal. The importance of EMT has been largely described in PDAC, and its importance is notably highlighted by the two major subtypes found in PDAC: the classical epithelial and the quasi-mesenchymal subtypes. Quasi-mesenchymal subtypes have been associated with a poorer prognosis. EMT has also been associated with resistance to treatments such as chemotherapy and immunotherapy. EMT is associated with several key molecular markers both epithelial and mesenchymal. Those markers might be helpful as a biomarker in PDAC diagnosis. EMT might becoming a key new target of interest for the treatment PDAC. In this review, we describe the role of EMT in PDAC, its contribution in diagnosis, in the orientation and treatment follow-up. We also discuss the putative role of EMT as a new therapeutic target in the management of PDAC. Full article
(This article belongs to the Special Issue New Pharmacologic Approaches to Study and Intervene in Epithelial to Mesenchymal Transition (EMT) and Fibrosis)
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