Biomolecules

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15 pages, 2182 KiB

Open AccessArticle

A Lipidomic Approach to Studying the Downregulation of Free Fatty Acids by Cytosolic Phospholipase A₂ Inhibitors

by Asimina Bourboula, Christiana Mantzourani, Ioanna Chalatsa, Christina Machalia, Evangelia Emmanouilidou, Maroula G. Kokotou and George Kokotos

Biomolecules 2025, 15(5), 626; https://doi.org/10.3390/biom15050626 (registering DOI) - 27 Apr 2025

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Abstract

Inhibitors of cytosolic phospholipase A₂ (GIVA cPLA₂) have received great attention, since this enzyme is involved in a number of inflammatory diseases, including cancer and auto-immune and neurodegenerative diseases. Traditionally, the effects of GIVA cPLA₂ inhibitors in cells have [...] Read more.

Inhibitors of cytosolic phospholipase A₂ (GIVA cPLA₂) have received great attention, since this enzyme is involved in a number of inflammatory diseases, including cancer and auto-immune and neurodegenerative diseases. Traditionally, the effects of GIVA cPLA₂ inhibitors in cells have been studied by determining the inhibition of arachidonic acid release. However, although to a lesser extent, GIVA cPLA₂ may also hydrolyze glycerophospholipids, releasing other free fatty acids (FFAs), such as linoleic acid or oleic acid. In the present work, we applied a liquid chromatography–high-resolution mass spectrometry method to study the levels of intracellular FFAs, after treating cells with selected GIVA cPLA₂ inhibitors. Six inhibitors belonging to different chemical classes were studied, using SH-SY5Y neuroblastoma cells as a model. This lipidomic approach revealed that treatment with each inhibitor created a distinct intracellular FFA profile, suggesting not only inhibitory potency against GIVA cPLA₂, but also other parameters affecting the outcome. Potent inhibitors were found to reduce not only arachidonic acid, but also other long-chain FAs, such as adrenic or linoleic acid, even medium-chain FAs, such as caproic or caprylic acid, suggesting that GIVA cPLA₂ inhibitors may affect FA metabolic pathways in general. The downregulation of intracellular FFAs may have implications in reprogramming FA metabolism in neurodegenerative diseases and cancer. Full article

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21 pages, 1247 KiB

Open AccessArticle

Association of Lower COMT Activity Alleles with Aggressive Traits in Male Youth with Conduct Disorder Living in a Correctional Facility

by Lucija Tudor, Josip Podobnik, Gordana Nedic Erjavec, Matea Nikolac Perkovic, Jaanus Harro, Margus Kanarik, Darko Marcinko, Dubravka Svob Strac, Melita Cusek, Vlatka Kovac and Nela Pivac

Biomolecules 2025, 15(4), 554; https://doi.org/10.3390/biom15040554 - 9 Apr 2025

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Abstract

Aggression constitutes a significant behavioral issue associated with delinquent behavior, commonly observed in youth diagnosed with conduct disorder (CD) and living in correctional facilities. Catechol-o-methyl-transferase (COMT) gene variants modify the environmental sensitivity associated with the risk of aggression. This study evaluated the association [...] Read more.

Aggression constitutes a significant behavioral issue associated with delinquent behavior, commonly observed in youth diagnosed with conduct disorder (CD) and living in correctional facilities. Catechol-o-methyl-transferase (COMT) gene variants modify the environmental sensitivity associated with the risk of aggression. This study evaluated the association of COMT rs4680 and rs4818 polymorphisms with aggressive behavior in 341 male adolescents living inside and outside a correctional facility, with or without a diagnosis of CD. Aggression was assessed using the Hare Psychopathy Checklist: Youth Version (PCL-YV), Modified Overt Aggression Scale (MOAS) and Swanson, Nolan and Pelham Questionnaire. COMT rs4680 and rs4818 polymorphisms were genotyped using TaqMan SNP Genotyping Assays. A similar prevalence of the COMT genotypes or haplotypes was found between adolescents with or without CD, suicidal behavior, or detention in correctional facility. In youth with CD, the COMT rs4680 A allele was associated with higher MOAS verbal aggression, aggression toward objects, irritability (subjective and open), and PCL-YV interpersonal domain scores compared with carriers of the COMT rs4680 G allele. COMT rs4818 GC carriers with CD had higher scores on the MOAS subjective irritability than GG heterozygotes. These novel findings revealed the association of lower COMT rs4680 and rs4818 activity alleles with aggression in detained male adolescents with CD. Full article

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26 pages, 14775 KiB

Open AccessArticle

Conformational Propensities of a DNA Hairpin with a Stem Sequence from the c-MYC Promoter

by Arees Garabet, Iztok Prislan, Nataša Poklar Ulrih, James W. Wells and Tigran V. Chalikian

Biomolecules 2025, 15(4), 483; https://doi.org/10.3390/biom15040483 - 26 Mar 2025

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Abstract

G-quadruplexes and i-motifs are four-stranded non-canonical structures of DNA. They exist in the cell, where they are implicated in the conformational regulation of cellular events, such as transcription, translation, DNA replication, telomere homeostasis, and genomic instability. Formation of the G-quadruplex and i [...] Read more.

G-quadruplexes and i-motifs are four-stranded non-canonical structures of DNA. They exist in the cell, where they are implicated in the conformational regulation of cellular events, such as transcription, translation, DNA replication, telomere homeostasis, and genomic instability. Formation of the G-quadruplex and i-motif conformations in the genome is controlled by their competition with the pre-existing duplex. The fate of that competition depends upon the relative stabilities of the competing conformations, leading ultimately to a distribution of double helical, tetrahelical, and coiled conformations that coexist in dynamic equilibrium with each other. We previously developed a CD spectroscopy-based procedure to characterize the distribution of conformations adopted by equimolar mixtures of complementary G- and C-rich DNA strands from the promoter regions of the c-MYC, VEGF, and Bcl-2 oncogenes. In those bimolecular systems, duplex-to-tetraplex and duplex-to-coil transitions are accompanied by strand separation and an associated entropic cost. This situation is distinct from the pseudo-monomolecular nature of conformational transformations within the genome, where strand separation does not occur. To mimic better the situation in the genome, we here extend our studies to a monomolecular DNA construct—a hairpin—in which complementary G- and C-rich strands featuring sequences from the promoter region of the c-MYC oncogene are linked by a dT₁₁ loop. We used our CD-based procedure to quantify the distribution of conformational states sampled by the hairpin at pH 5.0 and 7.0 as a function of temperature and the concentration of KCl. The data were analyzed according to a thermodynamic model based on equilibria between the different conformational states to evaluate the thermodynamic properties of the duplex-to-coil, G-quadruplex-to-coil, and i-motif-to-coil transitions of the hairpin. The results have implications for the modulation of such transitions as a means of therapeutic intervention. Full article

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15 pages, 852 KiB

Open AccessArticle

Liver Injury Following Intravenous Methylprednisolone Pulse Therapy in Multiple Sclerosis: The Experience from a Single Academic Liver Center

by Dimitris Kounatidis, Natalia G. Vallianou, Georgios Kontos, Hariklia Kranidioti, Nikolaos Papadopoulos, Alexandros Panagiotopoulos, Krystalia Dimitriou, Vasileios Papadimitropoulos, Melanie Deutsch, Spilios Manolakopoulos, Dimitrios Vassilopoulos and John Koskinas

Biomolecules 2025, 15(3), 437; https://doi.org/10.3390/biom15030437 - 19 Mar 2025

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Abstract

Intravenous methylprednisolone (IVMP) pulses, widely used for managing multiple sclerosis (MS) exacerbations, can lead to acute liver injury, presenting a diagnostic challenge in distinguishing between drug-induced autoimmune-like hepatitis (DI-ALH) and idiopathic autoimmune hepatitis (AIH). This study aimed to delineate the clinical and biochemical [...] Read more.

Intravenous methylprednisolone (IVMP) pulses, widely used for managing multiple sclerosis (MS) exacerbations, can lead to acute liver injury, presenting a diagnostic challenge in distinguishing between drug-induced autoimmune-like hepatitis (DI-ALH) and idiopathic autoimmune hepatitis (AIH). This study aimed to delineate the clinical and biochemical features of IVMP-induced liver injury, discern its etiology, and evaluate the efficacy of glucocorticoid (GC) therapy in treatment. A retrospective analysis of 13 relapsing MS patients with IVMP-induced liver injury was conducted. Liver injury was classified as hepatocellular, cholestatic, or mixed, with severity assessment guiding liver biopsy in selected cases. Causality was assessed using the Roussel Uclaf Causality Assessment Method (RUCAM) and the Simplified Diagnostic Criteria for AIH. All patients were initially monitored for a minimum of six months, with a mean follow-up period of 4.30 years. The median onset of liver injury was 37.46 days post-IVMP, with a mean peak alanine transaminase (ALT) level of 618.46 U/L. antinuclear antibody (ANA) positivity was observed in 61.53% of cases, with elevated serum immunoglobulin G (IgG) at 15.38%. Hepatocellular injury was universal among patients, and causality assessment predominantly supported DI-ALH. GC therapy was administered in six cases, achieving favorable outcomes in all but one, which necessitated rituximab. Biochemical normalization occurred within a mean of 55.41 days, with GC-treated patients recovering faster (48 days). These findings support the hypothesis that IVMP can induce hepatocellular injury, likely DI-ALH, during MS exacerbations. A tapering GC regimen proved effective in promoting recovery, particularly in severe cases. Additionally, this study introduced a diagnostic and therapeutic algorithm for managing IVMP-induced liver injury, offering a practical framework for clinical application. Full article

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Review

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31 pages, 2634 KiB

Open AccessReview

Molecular Mechanisms in the Carcinogenesis of Oral Squamous Cell Carcinoma: A Literature Review

by Laertty Garcia de Sousa Cabral, Isabela Mancini Martins, Ellen Paim de Abreu Paulo, Karina Torres Pomini, Jean-Luc Poyet and Durvanei Augusto Maria

Biomolecules 2025, 15(5), 621; https://doi.org/10.3390/biom15050621 (registering DOI) - 25 Apr 2025

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Abstract

The tumor microenvironment (TME) plays a crucial role in the development, progression, and metastasis of oral squamous cell carcinoma (OSCC). The TME comprises various cellular and acellular components, including immune cells, stromal cells, cytokines, extracellular matrix, and the oral microbiome, all of which [...] Read more.

The tumor microenvironment (TME) plays a crucial role in the development, progression, and metastasis of oral squamous cell carcinoma (OSCC). The TME comprises various cellular and acellular components, including immune cells, stromal cells, cytokines, extracellular matrix, and the oral microbiome, all of which dynamically interact with tumor cells to influence their behavior. Immunosuppression is a key feature of the OSCC TME, with regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs) contributing to an environment that allows tumor cells to evade immune surveillance and supports angiogenesis. The oral microbiome also plays a pivotal role in OSCC pathogenesis, as dysbiosis, or imbalances in the microbiota, can lead to chronic inflammation, which promotes carcinogenesis through the production of pro-inflammatory cytokines and reactive oxygen species (ROS). Pathogens like Porphyromonas gingivalis and Fusobacterium nucleatum have, hence, been implicated in OSCC-driven tumor progression, as they induce inflammation, activate oncogenic pathways, and modulate immune responses. In this review, we discuss how the interplay between immunosuppression and microbiome-driven inflammation creates a tumor-promoting environment in OSCC, leading to treatment resistance and poor patient outcomes, and explore the potential therapeutic implication of a better understanding of OSCC etiology and molecular changes. Full article

(This article belongs to the Special Issue Insights from the Editorial Board Members)

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38 pages, 2476 KiB

Open AccessReview

Understanding the Role of Adipokines in Cardiometabolic Dysfunction: A Review of Current Knowledge

by Sayantap Datta, Saisudha Koka and Krishna M. Boini

Biomolecules 2025, 15(5), 612; https://doi.org/10.3390/biom15050612 - 23 Apr 2025

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Abstract

Cardiometabolic risk and associated dysfunctions contribute largely to the recent rise in mortality globally. Advancements in multi-omics in recent years promise a better understanding of potential biomarkers that enable an early diagnosis of cardiometabolic dysfunction. However, the molecular mechanisms driving the onset and [...] Read more.

Cardiometabolic risk and associated dysfunctions contribute largely to the recent rise in mortality globally. Advancements in multi-omics in recent years promise a better understanding of potential biomarkers that enable an early diagnosis of cardiometabolic dysfunction. However, the molecular mechanisms driving the onset and progression of cardiometabolic disorders remain poorly understood. Adipokines are adipocyte-specific cytokines that are central to deleterious cardiometabolic alterations. They exhibit both pro-inflammatory and anti-inflammatory effects, complicating their association with cardiometabolic disturbances. Thus, understanding the cardiometabolic association of adipokines from a molecular and signaling perspective assumes great importance. This review presents a comprehensive outline of the most prominent adipokines exhibiting pro-inflammatory and/or anti-inflammatory functions in cardiometabolic dysfunction. The review also presents an insight into the pathophysiological implications of such adipokines in different cardiometabolic dysfunction conditions, the status of adipokine druggability, and future studies that can be undertaken to address the existing scientific gap. A clear understanding of the functional and mechanistic role of adipokines can potentially improve our understanding of cardiovascular disease pathophysiology and enhance our current therapeutic regimen in the years to come. Full article

(This article belongs to the Special Issue Insights from the Editorial Board Members)

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Other

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13 pages, 804 KiB

Open AccessOpinion

Is Senolytic Therapy in Cardiovascular Diseases Ready for Translation to Clinics?

by Zhihong Yang, Duilio M. Potenza and Xiu-Fen Ming

Biomolecules 2025, 15(4), 545; https://doi.org/10.3390/biom15040545 - 8 Apr 2025

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Abstract

Aging is a predominant risk factor for cardiovascular diseases. There is evidence demonstrating that senescent cells not only play a significant role in organism aging but also contribute to the pathogenesis of cardiovascular diseases in younger ages. Encouraged by recent findings that the [...] Read more.

Aging is a predominant risk factor for cardiovascular diseases. There is evidence demonstrating that senescent cells not only play a significant role in organism aging but also contribute to the pathogenesis of cardiovascular diseases in younger ages. Encouraged by recent findings that the elimination of senescent cells by pharmacogenetic tools could slow down and even reverse organism aging in animal models, senolytic drugs have been developed, and the translation of results from basic research to clinical settings has been initiated. Because numerous studies in the literature show beneficial therapeutic effects of targeting senescent cells in cardiomyopathies associated with aging and ischemia/reperfusion and in atherosclerotic vascular disease, senolytic drugs are considered the next generation of therapies for cardiovascular disorders. However, recent studies have reported controversial results or detrimental effects caused by senolytic therapeutic approaches, including worsening of cardiac dysfunction, instability of atherosclerotic plaques, and even an increase in mortality in animal models, which challenges the translation of senolytic therapy into the clinical practice. This brief review article will focus on (1) analyzing and discussing the beneficial and detrimental effects of senolytic therapeutic approaches in cardiovascular diseases and cardiovascular aging and (2) future research directions and questions that are essential to understand the controversies and to translate preclinical results of senolytic therapies into clinical practice. Full article

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14 pages, 1918 KiB

Open AccessPerspective

Rediscovery of PHI-1/PPP1R14B: Emerging Roles of Cellular PP1 Signaling Mediated by the PPP1R14B Gene Product in Multiple Cancers and Beyond

by Masumi Eto

Biomolecules 2025, 15(3), 344; https://doi.org/10.3390/biom15030344 - 27 Feb 2025

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Abstract

PHI-1, encoded by PPP1R14B, regulates cellular protein phosphatase-1 (PP1) signaling and has emerged as both a biomarker and therapeutic target. Initially identified as a phospholipase-neighboring gene (PNG), PHI-1 is now known for its phosphorylation-dependent inhibition of PP1 holoenzymes, with bi-directional roles depending [...] Read more.

PHI-1, encoded by PPP1R14B, regulates cellular protein phosphatase-1 (PP1) signaling and has emerged as both a biomarker and therapeutic target. Initially identified as a phospholipase-neighboring gene (PNG), PHI-1 is now known for its phosphorylation-dependent inhibition of PP1 holoenzymes, with bi-directional roles depending on its expression levels. Under physiological conditions, PHI-1 selectively regulates PP1 activity to maintain cellular homeostasis, whereas its pathological upregulation promotes oncogenic pathways, stabilizes tumor-promoting proteins, and modulates immune responses. This article explores PHI-1’s emerging role as a pan-cancer biomarker in parallel with emphasizing its physiological functions in signaling networks, smooth muscle contraction, cytoskeletal dynamics, and selective proteostasis. The mechanistic insights highlight PHI-1’s potential in precision oncology, offering opportunities for developing diagnostics and therapies that target its conditional functions. Full article

(This article belongs to the Special Issue Insights from the Editorial Board Members)

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