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State-of-the-Art Molecular Pharmacology in Spain 2.0

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

Deadline for manuscript submissions: 20 June 2024 | Viewed by 9776

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Special Issue Editors

Prof. Dr. Asia Fernandez Carvajal

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Guest Editor

Institute of Molecular and Cell Biology, Miguel Hernandez University, Elche, Spain
Interests: high-throughput screening; discovery and development of anti-nociceptive drugs; structure–function studies on TRP ion channels; translational research in the field of sensory neurobiology; role of thermoTRP channels in the pathophysiology of migraine
Special Issues, Collections and Topics in MDPI journals

Dr. Gerard Pujadas

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Guest Editor

Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Tarragona, Catalonia, Spain
Interests: drug discovery; drug design
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Pharmacology is a discipline which deals with the interaction of natural, semisynthetic or fully (bio)synthetic therapeutic agents at the cellular and organismal levels. These therapeutic agents can range from small molecules through to macromolecules such as proteins and antibodies. Thus, this field is positioned at the interface of pharmacy/chemistry and physiology/pathophysiology in their broadest sense. It operates at various organizational levels, such as the molecular, subcellular, cellular, organ and systemic platforms. Molecular pharmacology investigates the molecular mode of action of therapeutic agents using cellular, genetic and molecular biology approaches, and is among the most rapidly developing fields of pharmacology.

Authors are invited to submit original research and review articles on molecular pharmacology to this Special Issue. The "Molecular Pharmacology" section aims to publish the latest developments in cellular and molecular pharmacology, with a major emphasis on the mechanism of action of novel drugs, innovative pharmacological technologies, cell signaling, transduction pathway analysis, genomics, proteomics and metabonomics applications in drug action. An additional focus will be the way in which normal biological function is illuminated by knowledge of the action of drugs at the cellular and molecular level.

A large number of research teams in Spain from different institutions and universities are currently working together and devoting considerable efforts to developing and studying molecular pharmacology. This Special Issue is committed to providing an overview of the macromolecular sciences and technologies in Spain.

Prof. Dr. Asia Fernandez Carvajal
Dr. Gerard Pujadas
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

signal transduction
receptor
animal models
preclinical
pharmacodynamics
pharmacokinetics
drug development
drug metabolism
drug delivery
CADD
virtual screening

Published Papers (6 papers)

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Research

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17 pages, 4093 KiB

Open AccessArticle

Podophyllic Aldehyde, a Podophyllotoxin Derivate, Elicits Different Cell Cycle Profiles Depending on the Tumor Cell Line: A Systematic Proteomic Analysis

by Ángela-Patricia Hernández, Lorea Chaparro-González, Olga Garzo-Sánchez, Carlota Arias-Hidalgo, Pablo Juanes-Velasco, Pablo A. García, Mª Ángeles Castro and Manuel Fuentes

Int. J. Mol. Sci. 2024, 25(9), 4631; https://doi.org/10.3390/ijms25094631 - 24 Apr 2024

Viewed by 302

Abstract

When new antitumor therapy drugs are discovered, it is essential to address new target molecules from the point of view of chemical structure and to carry out efficient and systematic evaluation. In the case of natural products and derived compounds, it is of special importance to investigate chemomodulation to further explore antitumoral pharmacological activities. In this work, the compound podophyllic aldehyde, a cyclolignan derived from the chemomodulation of the natural product podophyllotoxin, has been evaluated for its viability, influence on the cell cycle, and effects on intracellular signaling. We used functional proteomics characterization for the evaluation. Compared with the FDA-approved drug etoposide (another podophyllotoxin derivative), we found interesting results regarding the cytotoxicity of podophyllic aldehyde. In addition, we were able to observe the effect of mitotic arrest in the treated cells. The use of podophyllic aldehyde resulted in increased cytotoxicity in solid tumor cell lines, compared to etoposide, and blocked the cycle more successfully than etoposide. High-throughput analysis of the deregulated proteins revealed a selective antimitotic mechanism of action of podophyllic aldehyde in the HT-29 cell line, in contrast with other solid and hematological tumor lines. Also, the apoptotic profile of podophyllic aldehyde was deciphered. The cell death mechanism is activated independently of the cell cycle profile. The results of these targeted analyses have also shown a significant response to the signaling of kinases, key proteins involved in signaling cascades for cell proliferation or metastasis. Thanks to this comprehensive analysis of podophyllic aldehyde, remarkable cytotoxic, antimitotic, and other antitumoral features have been discovered that will repurpose this compound for further chemical transformations and antitumoral analysis. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Pharmacology in Spain 2.0)

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18 pages, 7783 KiB

Open AccessArticle

Osteostatin Mitigates Gouty Arthritis through the Inhibition of Caspase-1 Activation and Upregulation of Nrf2 Expression

by Laura Catalán, María Carmen Carceller, María Carmen Terencio, María José Alcaraz, María Luisa Ferrándiz and María Carmen Montesinos

Int. J. Mol. Sci. 2024, 25(5), 2752; https://doi.org/10.3390/ijms25052752 - 27 Feb 2024

Cited by 1 | Viewed by 676

Abstract

Gouty arthritis results from monosodium urate (MSU) crystal deposition in joints, initiating (pro)-interleukin (IL)-1β maturation, inflammatory mediator release, and neutrophil infiltration, leading to joint swelling and pain. Parathyroid hormone-related protein (107–111) C-terminal peptide (osteostatin) has shown anti-inflammatory properties in osteoblasts and collagen-induced arthritis in mice, but its impact in gouty arthritis models remains unexplored. We investigated the effect of osteostatin on pyroptosis, inflammation, and oxidation in macrophages, as well as its role in the formation of calcium pyrophosphate dihydrate crystals and MSU-induced gouty arthritis in mice models. Osteostatin ameliorated pyroptosis induced by lipopolysaccharide and adenosine 5′-triphosphate (LPS + ATP) in mice peritoneal macrophages by reducing the expression of caspase-1, lactate dehydrogenase release, and IL-1β and IL-18 secretion. Additionally, IL-6 and tumor necrosis factor-α (TNF-α) were also decreased due to the reduced activation of the NF-κB pathway. Furthermore, osteostatin displayed antioxidant properties in LPS + ATP-stimulated macrophages, resulting in reduced production of mitochondrial and extracellular reactive oxygen species and enhanced Nrf2 translocation to the nuclei. In both models of gouty arthritis, osteostatin administration resulted in reduced pro-inflammatory cytokine production, decreased leukocyte migration, and reduced caspase-1 and NF-κB activation. These results highlight the potential of osteostatin as a therapeutic option for gouty arthritis. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Pharmacology in Spain 2.0)

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22 pages, 52995 KiB

Open AccessArticle

β-Lactam TRPM8 Antagonists Derived from Phe-Phenylalaninol Conjugates: Structure–Activity Relationships and Antiallodynic Activity

by Cristina Martín-Escura, M. Ángeles Bonache, Jessy A. Medina, Alicia Medina-Peris, Jorge De Andrés-López, Sara González-Rodríguez, Sara Kerselaers, Gregorio Fernández-Ballester, Thomas Voets, Antonio Ferrer-Montiel, Asia Fernández-Carvajal and Rosario González-Muñiz

Int. J. Mol. Sci. 2023, 24(19), 14894; https://doi.org/10.3390/ijms241914894 - 04 Oct 2023

Viewed by 1019

Abstract

The protein transient receptor potential melastatin type 8 (TRPM8), a non-selective, calcium (Ca²⁺)-permeable ion channel is implicated in several pathological conditions, including neuropathic pain states. In our previous research endeavors, we have identified β-lactam derivatives with high hydrophobic character that exhibit potent and selective TRPM8 antagonist activity. This work describes the synthesis of novel derivatives featuring C-terminal amides and diversely substituted N′-terminal monobenzyl groups in an attempt to increase the total polar surface area (TPSA) in this family of compounds. The primary goal was to assess the influence of these substituents on the inhibition of menthol-induced cellular Ca²⁺ entry, thereby establishing critical structure–activity relationships. While the substitution of the tert-butyl ester by isobutyl amide moieties improved the antagonist activity, none of the N′-monobencyl derivatives, regardless of the substituent on the phenyl ring, achieved the activity of the model dibenzyl compound. The antagonist potency of the most effective compounds was subsequently verified using Patch-Clamp electrophysiology experiments. Furthermore, we evaluated the selectivity of one of these compounds against other members of the transient receptor potential (TRP) ion channel family and some receptors connected to peripheral pain pathways. This compound demonstrated specificity for TRPM8 channels. To better comprehend the potential mode of interaction, we conducted docking experiments to uncover plausible binding sites on the functionally active tetrameric protein. While the four main populated poses are located by the pore zone, a similar location to that described for the N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)-benzamide (AMTB) antagonist cannot be discarded. Finally, in vivo experiments, involving a couple of selected compounds, revealed significant antinociceptive activity within a mice model of cold allodynia induced by oxaliplatin (OXA). Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Pharmacology in Spain 2.0)

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19 pages, 4839 KiB

Open AccessArticle

Riluzole-Loaded Nanostructured Lipid Carriers for Hyperproliferative Skin Diseases

by Xavier Llorente, Gerard Esteruelas, Lorena Bonilla, Mariana Garnica Agudelo, Ingrid Filgaira, Daniel Lopez-Ramajo, Ruoyi C Gong, Concepció Soler, Marta Espina, Maria Luisa García, Joan Manils, Montserrat Pujol and Elena Sánchez-López

Int. J. Mol. Sci. 2023, 24(9), 8053; https://doi.org/10.3390/ijms24098053 - 29 Apr 2023

Cited by 2 | Viewed by 1921

Abstract

Nanocarriers, and especially nanostructured lipid carriers (NLC), represent one of the most effective systems for topical drug administration. NLCs are biodegradable, biocompatible and provide a prolonged drug release. The glutamate release inhibitor Riluzole (RLZ) is a drug currently used for amyotrophic lateral sclerosis (ALS), with anti-proliferative effects potentially beneficial for diseases with excessive cell turnover. However, RLZ possesses low water solubility and high light-sensibility. We present here optimized NLCs loaded with RLZ (RLZ-NLCs) as a potential topical treatment. RLZ-NLCs were prepared by the hot-pressure homogenization method using active essential oils as liquid lipids, and optimized using the design of experiments approach. RLZ-NLCs were developed obtaining optimal properties for dermal application (mean size below 200 nm, negative surface charge and high RLZ entrapment efficacy). In vitro release study demonstrates that RLZ-NLCs allow the successful delivery of RLZ in a sustained manner. Moreover, RLZ-NLCs are not angiogenic and are able to inhibit keratinocyte cell proliferation. Hence, a NLCs delivery system loading RLZ in combination with natural essential oils constitutes a promising strategy against keratinocyte hyperproliferative conditions. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Pharmacology in Spain 2.0)

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Review

Jump to: Research

12 pages, 1095 KiB

Open AccessReview

Current Indications and Future Landscape of Bispecific Antibodies for the Treatment of Lung Cancer

by Hugo Arasanz, Luisa Chocarro, Leticia Fernández-Rubio, Ester Blanco, Ana Bocanegra, Miriam Echaide, Ibone Labiano, Ana Elsa Huerta, Maria Alsina, Ruth Vera, David Escors and Grazyna Kochan

Int. J. Mol. Sci. 2023, 24(12), 9855; https://doi.org/10.3390/ijms24129855 - 07 Jun 2023

Cited by 1 | Viewed by 2383

Abstract

Bispecific antibodies are a promising type of therapy for the treatment of cancer due to their ability to simultaneously inhibit different proteins playing a role in cancer progression. The development in lung cancer has been singularly intense because of the increasingly vast knowledge of the underlying molecular routes, in particular, in oncogene-driven tumors. In this review, we present the current landscape of bispecific antibodies for the treatment of lung cancer and discuss potential scenarios where the role of these therapeutics might expand in the near future. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Pharmacology in Spain 2.0)

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24 pages, 4363 KiB

Open AccessReview

Neurotensin and Alcohol Use Disorders: Towards a Pharmacological Treatment

by Francisco D. Rodríguez, Manuel Lisardo Sánchez and Rafael Coveñas

Int. J. Mol. Sci. 2023, 24(10), 8656; https://doi.org/10.3390/ijms24108656 - 12 May 2023

Cited by 2 | Viewed by 2633

Abstract

Harmful alcohol use is responsible for a group of disorders collectively named alcohol use disorders (AUDs), according to the DSM-5 classification. The damage induced by alcohol depends on the amount, time, and consumption patterns (continuous and heavy episodic drinking). It affects individual global well-being and social and familial environments with variable impact. Alcohol addiction manifests with different degrees of organ and mental health detriment for the individual, exhibiting two main traits: compulsive drinking and negative emotional states occurring at withdrawal, frequently causing relapse episodes. Numerous individual and living conditions, including the concomitant use of other psychoactive substances, lie in the complexity of AUD. Ethanol and its metabolites directly impact the tissues and may cause local damage or alter the homeostasis of brain neurotransmission, immunity scaffolding, or cell repair biochemical pathways. Brain modulator and neurotransmitter-assembled neurocircuitries govern reward, reinforcement, social interaction, and consumption of alcohol behaviors in an intertwined manner. Experimental evidence supports the participation of neurotensin (NT) in preclinical models of alcohol addiction. For example, NT neurons in the central nucleus of the amygdala projecting to the parabrachial nucleus strengthen alcohol consumption and preference. In addition, the levels of NT in the frontal cortex were found to be lower in rats bred to prefer alcohol to water in a free alcohol–water choice compared to wild-type animals. NT receptors 1 and 2 seem to be involved in alcohol consumption and alcohol effects in several models of knockout mice. This review aims to present an updated picture of the role of NT systems in alcohol addiction and the possible use of nonpeptide ligands modulating the activity of the NT system, applied to experimental animal models of harmful drinking behavior mimicking alcohol addiction leading to health ruin in humans. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Pharmacology in Spain 2.0)

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