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Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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24 pages, 1973 KB  
Review
Integrin and Its Associated Proteins as a Mediator for Mechano-Signal Transduction
by Kazuo Katoh
Biomolecules 2025, 15(2), 166; https://doi.org/10.3390/biom15020166 - 23 Jan 2025
Cited by 16 | Viewed by 6428
Abstract
Mechano-signal transduction is a process in which cells perceive extracellular mechanical signals, convert them into intracellular biochemical signals, and produce a response. Integrins are cell surface receptors that sense the extracellular mechanical cues and bind to the extracellular matrix (ECM). This binding induces [...] Read more.
Mechano-signal transduction is a process in which cells perceive extracellular mechanical signals, convert them into intracellular biochemical signals, and produce a response. Integrins are cell surface receptors that sense the extracellular mechanical cues and bind to the extracellular matrix (ECM). This binding induces integrin clustering and activation. Cytoplasmic tails of activated integrins interact and induce cytoskeleton tensions via several adaptor proteins. Integrins monitor extracellular stiffness via cytoskeleton tensions and modulate ECM stiffness via downstream signaling pathways regulating the expression of genes of ECM components. Integrin-mediated mechano-transduction is very crucial for the cell as it regulates the cell physiology both in normal and diseased conditions according to extracellular mechanical cues. It regulates cell proliferation, survival, and migration. Abnormal mechanical cues such as extreme and prolonged mechanical stress result in pathological conditions including fibrosis, cancers, skin, and autoimmune disorders. This paper aims to explore the role of integrins and their associated proteins in mechano-signal transduction. It highlights the integrins and their associated proteins as targets for therapy development. Furthermore, it also presents the challenges to the targeted drug development, which can be drug resistance and cytotoxicity. It is concluded in this paper that research on integrin-mediated mechano-signal transduction and its relationship with cell physiology and pathologies will be an important step towards the development of effective therapies. Full article
(This article belongs to the Special Issue New Insights into Integrins)
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22 pages, 2458 KB  
Review
Metabolic Dysfunction-Associated Steatotic Liver Disease: Pathogenetic Links to Cardiovascular Risk
by Vlad Alexandru Ionescu, Gina Gheorghe, Nicolae Bacalbasa and Camelia Cristina Diaconu
Biomolecules 2025, 15(2), 163; https://doi.org/10.3390/biom15020163 - 22 Jan 2025
Cited by 8 | Viewed by 2516
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is correlated with an increased cardiovascular risk, independent of other traditional risk factors. The mechanisms underlying this pathogenic link are complex yet remain incompletely elucidated. Among these, the most significant are visceral adiposity, low-grade inflammation and oxidative [...] Read more.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is correlated with an increased cardiovascular risk, independent of other traditional risk factors. The mechanisms underlying this pathogenic link are complex yet remain incompletely elucidated. Among these, the most significant are visceral adiposity, low-grade inflammation and oxidative stress, endothelial dysfunction, prothrombotic status, insulin resistance, dyslipidemia and postprandial hyperlipemia, gut dysbiosis, and genetic mutations. Cardiovascular diseases are the leading cause of death in patients with MASLD. These patients have an increased incidence of coronary artery disease, carotid artery disease, structural and functional cardiac abnormalities, and valvulopathies, as well as arrhythmias and cardiac conduction disorders. In this review, we present the latest data on the association between MASLD and cardiovascular risk, focusing on the pathogenic mechanisms that explain the correlation between these two pathologies. Given the high rates of cardiovascular morbidity and mortality among patients with MASLD, we consider it imperative to raise awareness of the risks associated with this condition within the general population. Further research is essential to clarify the mechanisms underlying the increased cardiovascular risk linked to MASLD. This understanding may facilitate the identification of new diagnostic and prognostic biomarkers for these patients, as well as novel therapeutic targets. Full article
(This article belongs to the Special Issue New Insights into Cardiometabolic Diseases)
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16 pages, 5637 KB  
Article
Deletion of Murine APP Aggravates Tau and Amyloid Pathologies in the 5xFADXTg30 Alzheimer’s Disease Model
by Kunie Ando, Andreea-Claudia Kosa, Yasmina Mehadji, Hinde Lasri, Lidia Lopez-Gutierrez, Carolina Quintanilla-Sánchez, Emmanuel Aydin, Emilie Doeraene, Alain Wathelet-Depauw, Siranjeevi Nagaraj, Jean-Pierre Brion and Karelle Leroy
Biomolecules 2025, 15(2), 159; https://doi.org/10.3390/biom15020159 - 21 Jan 2025
Cited by 2 | Viewed by 2594
Abstract
Alzheimer’s disease is characterized by two key neuropathological lesions: amyloid plaques composed of amyloid β and neurofibrillary tangles formed by hyperphosphorylated tau. Amyloid β is produced through successive cleavages of amyloid precursor protein (APP) via the amyloidogenic pathway. While increasing evidence suggests that [...] Read more.
Alzheimer’s disease is characterized by two key neuropathological lesions: amyloid plaques composed of amyloid β and neurofibrillary tangles formed by hyperphosphorylated tau. Amyloid β is produced through successive cleavages of amyloid precursor protein (APP) via the amyloidogenic pathway. While increasing evidence suggests that APP plays critical roles in neuronal function and that its proteolytic derivative, sAPPα, has neurotrophic effects, the impact of APP deletion on both amyloid and tau pathologies remains poorly understood. Here, we introduce a novel transgenic mouse model, 5xFAD×Tg30XAPP-/-, in which murine APP is deleted in the presence of both amyloid and tau pathologies. Using this innovative model, we demonstrate for the first time that deletion of APP exacerbates tau aggregation, amyloid deposition, and gliosis compared to control 5xFAD×Tg30 mice. This study provides the first in vivo evidence that APP deletion has profound and detrimental effects on both amyloid and tau pathologies in a transgenic model of Alzheimer’s disease, highlighting the previously unappreciated role of APP in the regulation of these neurodegenerative processes. Full article
(This article belongs to the Special Issue Amyloid-Beta and Alzheimer’s Disease)
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19 pages, 2476 KB  
Review
From Polydeoxyribonucleotides (PDRNs) to Polynucleotides (PNs): Bridging the Gap Between Scientific Definitions, Molecular Insights, and Clinical Applications of Multifunctional Biomolecules
by Cíntia Marques, Alexandre Porcello, Marco Cerrano, Farid Hadjab, Michèle Chemali, Kelly Lourenço, Basste Hadjab, Wassim Raffoul, Lee Ann Applegate and Alexis E. Laurent
Biomolecules 2025, 15(1), 148; https://doi.org/10.3390/biom15010148 - 19 Jan 2025
Cited by 15 | Viewed by 22502
Abstract
Polydeoxyribonucleotides (PDRNs) and polynucleotides (PNs) are similar DNA-derived biopolymers that have garnered significant scientific attention since the 1990s for their potential applications in wound healing and skin rejuvenation. These biopolymers exhibit a broad molecular weight (MW) range, typically spanning from 50 to 1500 [...] Read more.
Polydeoxyribonucleotides (PDRNs) and polynucleotides (PNs) are similar DNA-derived biopolymers that have garnered significant scientific attention since the 1990s for their potential applications in wound healing and skin rejuvenation. These biopolymers exhibit a broad molecular weight (MW) range, typically spanning from 50 to 1500 kDa. However, recent studies have expanded this range to encompass fragments as small as 1 kDa and as large as 10,000 kDa. Clinically, PDRN/PN formulations, commercially available in various galenic forms (gels, creams, serums, masks, and injectables), have demonstrated promising effects in significantly promoting skin regeneration, reducing inflammation, improving skin texture, preventing scar formation, and mitigating wrinkles. Importantly, despite their widespread use in cosmetology and aesthetic dermatology, the interchangeable use of the terms “PDRN” and “PN” in the scientific literature (to describe polymers of varying lengths) has led to considerable confusion within the medical and scientific communities. To specifically address this PDRN/PN ambiguity, this narrative review proposes a standardized structure-based nomenclature for these DNA-derived polymers, the “Marques Polynucleotide Cutoff”, set at 1500 kDa. Thus, we propose that the term “PDRN” should be exclusively reserved for small- and medium-chain polymers (MW < 1500 kDa), while the term “PN” should specifically be used to denote longer-chain polymers (MW ≥ 1500 kDa). In a broader perspective, this classification is based on the distinct physicochemical properties and therapeutic effects of these DNA fragments of various MWs, which are comprehensively discussed in the present review. Full article
(This article belongs to the Special Issue Molecular Advances in Wound Healing and Skin Regeneration)
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20 pages, 4065 KB  
Article
Development of a Combined 2D-MGD TLC/HPTLC Method for the Separation of Terpinen-4-ol and α-Terpineol from Tea Tree, Melaleuca alternifolia, Essential Oil
by Aimé Vázquez and Nurhayat Tabanca
Biomolecules 2025, 15(1), 147; https://doi.org/10.3390/biom15010147 - 18 Jan 2025
Cited by 3 | Viewed by 2820
Abstract
Tea tree oil (TTO), acquired from Melaleuca alternifolia (Maiden & Betche) Cheel, Myrtaceae, is a widely utilized essential oil (EO) due to its bioactive properties. The identification and quantification of TTO ingredients is generally performed by GC-MS, which provides the most accurate results. [...] Read more.
Tea tree oil (TTO), acquired from Melaleuca alternifolia (Maiden & Betche) Cheel, Myrtaceae, is a widely utilized essential oil (EO) due to its bioactive properties. The identification and quantification of TTO ingredients is generally performed by GC-MS, which provides the most accurate results. However, in some instances, the cost and time of analysis may pose a challenge. Thin-layer chromatography (TLC) and high-performance thin-layer chromatography (HPTLC) offer a simpler, faster, cost-effective alternative capable of simultaneously analyzing and quantifying multiple samples. In addition, for more complex oils, two-dimensional (2D) or multigradient development (MGD) TLC provide better separation. Nevertheless, further development is sometimes necessary for the isolation of comigrating components. This study showcases a combined 2D-MGD TLC/HPTLC method for the successful separation of TTO components of interest. While human error, limited separation, and the partial evaporation of volatile components may still present a challenge during the process, considerable recovery of mono- and sesquiterpenes was achieved. This protocol also resulted in the successful isolation of target oxygenated monoterpenes (OMs) producing highly pure terpinen-4-ol (100%) and α-terpineol (≥94%), confirmed by GC-MS. The accurate enantiomeric distribution of these major OMs was verified by GC-FID through the use of a chiral cyclodextrin-based stationary phase. The observed positive enantiomer range (area percent) as well as (+)/(−) ratio for each terpinen-4-ol and α-terpineol were within acceptable ISO criteria. Full article
(This article belongs to the Special Issue Feature Papers in the Natural and Bio-Derived Molecules Section)
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23 pages, 845 KB  
Review
Structure-Based Approaches for Protein–Protein Interaction Prediction Using Machine Learning and Deep Learning
by Despoina P. Kiouri, Georgios C. Batsis and Christos T. Chasapis
Biomolecules 2025, 15(1), 141; https://doi.org/10.3390/biom15010141 - 17 Jan 2025
Cited by 7 | Viewed by 6463
Abstract
Protein–Protein Interaction (PPI) prediction plays a pivotal role in understanding cellular processes and uncovering molecular mechanisms underlying health and disease. Structure-based PPI prediction has emerged as a robust alternative to sequence-based methods, offering greater biological accuracy by integrating three-dimensional spatial and biochemical features. [...] Read more.
Protein–Protein Interaction (PPI) prediction plays a pivotal role in understanding cellular processes and uncovering molecular mechanisms underlying health and disease. Structure-based PPI prediction has emerged as a robust alternative to sequence-based methods, offering greater biological accuracy by integrating three-dimensional spatial and biochemical features. This work summarizes the recent advances in computational approaches leveraging protein structure information for PPI prediction, focusing on machine learning (ML) and deep learning (DL) techniques. These methods not only improve predictive accuracy but also provide insights into functional sites, such as binding and catalytic residues. However, challenges such as limited high-resolution structural data and the need for effective negative sampling persist. Through the integration of experimental and computational tools, structure-based prediction paves the way for comprehensive proteomic network analysis, holding promise for advancements in drug discovery, biomarker identification, and personalized medicine. Future directions include enhancing scalability and dataset reliability to expand these approaches across diverse proteomes. Full article
(This article belongs to the Special Issue Structural Proteomics–Structural Biology Led by Advancements in Mass Spectrometry Techniques)
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31 pages, 1768 KB  
Review
Proteomic Profiling Towards a Better Understanding of Genetic Based Muscular Diseases: The Current Picture and a Look to the Future
by Marc Pauper, Andreas Hentschel, Malte Tiburcy, Sergi Beltran, Tobias Ruck, Ulrike Schara-Schmidt and Andreas Roos
Biomolecules 2025, 15(1), 130; https://doi.org/10.3390/biom15010130 - 15 Jan 2025
Cited by 5 | Viewed by 2566
Abstract
Proteomics accelerates diagnosis and research of muscular diseases by enabling the robust analysis of proteins relevant for the manifestation of neuromuscular diseases in the following aspects: (i) evaluation of the effect of genetic variants on the corresponding protein, (ii) prediction of the underlying [...] Read more.
Proteomics accelerates diagnosis and research of muscular diseases by enabling the robust analysis of proteins relevant for the manifestation of neuromuscular diseases in the following aspects: (i) evaluation of the effect of genetic variants on the corresponding protein, (ii) prediction of the underlying genetic defect based on the proteomic signature of muscle biopsies, (iii) analysis of pathophysiologies underlying different entities of muscular diseases, key for the definition of new intervention concepts, and (iv) patient stratification according to biochemical fingerprints as well as (v) monitoring the success of therapeutic interventions. This review presents—also through exemplary case studies—the various advantages of mass proteomics in the investigation of genetic muscle diseases, discusses technical limitations, and provides an outlook on possible future application concepts. Hence, proteomics is an excellent large-scale analytical tool for the diagnostic workup of (hereditary) muscle diseases and warrants systematic profiling of underlying pathophysiological processes. The steady development may allow to overcome existing limitations including a quenched dynamic range and quantification of different protein isoforms. Future directions may include targeted proteomics in diagnostic settings using not only muscle biopsies but also liquid biopsies to address the need for minimally invasive procedures. Full article
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40 pages, 1258 KB  
Review
Current Treatment Regimens and Promising Molecular Therapies for Chronic Hepatobiliary Diseases
by Marilena Durazzo, Arianna Ferro, Victor Manuel Navarro-Tableros, Andrea Gaido, Paolo Fornengo, Fiorella Altruda, Renato Romagnoli, Søren K. Moestrup, Pier Luigi Calvo and Sharmila Fagoonee
Biomolecules 2025, 15(1), 121; https://doi.org/10.3390/biom15010121 - 14 Jan 2025
Cited by 4 | Viewed by 4350
Abstract
Chronic hepatobiliary damage progressively leads to fibrosis, which may evolve into cirrhosis and/or hepatocellular carcinoma. The fight against the increasing incidence of liver-related morbidity and mortality is challenged by a lack of clinically validated early-stage biomarkers and the limited availability of effective anti-fibrotic [...] Read more.
Chronic hepatobiliary damage progressively leads to fibrosis, which may evolve into cirrhosis and/or hepatocellular carcinoma. The fight against the increasing incidence of liver-related morbidity and mortality is challenged by a lack of clinically validated early-stage biomarkers and the limited availability of effective anti-fibrotic therapies. Current research is focused on uncovering the pathogenetic mechanisms that drive liver fibrosis. Drugs targeting molecular pathways involved in chronic hepatobiliary diseases, such as inflammation, hepatic stellate cell activation and proliferation, and extracellular matrix production, are being developed. Etiology-specific treatments, such as those for hepatitis B and C viruses, are already in clinical use, and efforts to develop new, targeted therapies for other chronic hepatobiliary diseases are ongoing. In this review, we highlight the major molecular changes occurring in patients affected by metabolic dysfunction-associated steatotic liver disease, viral hepatitis (Delta virus), and autoimmune chronic liver diseases (autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis). Further, we describe how this knowledge is linked to current molecular therapies as well as ongoing preclinical and clinical research on novel targeting strategies, including nucleic acid-, mesenchymal stromal/stem cell-, and extracellular vesicle-based options. Much clinical development is obviously still missing, but the plethora of promising potential treatment strategies in chronic hepatobiliary diseases holds promise for a future reversal of the current increase in morbidity and mortality in this group of patients. Full article
(This article belongs to the Section Molecular Medicine)
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22 pages, 3557 KB  
Review
Acral Melanoma: A Review of Its Pathogenesis, Progression, and Management
by Soo Hyun Kim and Hensin Tsao
Biomolecules 2025, 15(1), 120; https://doi.org/10.3390/biom15010120 - 14 Jan 2025
Cited by 6 | Viewed by 6409
Abstract
Acral melanoma is a distinct subtype of cutaneous malignant melanoma that uniquely occurs on ultraviolet (UV)-shielded, glabrous skin of the palms, soles, and nail beds. While acral melanoma only accounts for 2–3% of all melanomas, it represents the most common subtype among darker-skinned, [...] Read more.
Acral melanoma is a distinct subtype of cutaneous malignant melanoma that uniquely occurs on ultraviolet (UV)-shielded, glabrous skin of the palms, soles, and nail beds. While acral melanoma only accounts for 2–3% of all melanomas, it represents the most common subtype among darker-skinned, non-Caucasian individuals. Unlike other cutaneous melanomas, acral melanoma does not arise from UV radiation exposure and is accordingly associated with a relatively low tumor mutational burden. Recent advances in genomic, transcriptomic, and epigenomic sequencing have revealed genetic alterations unique to acral melanoma, including novel driver genes, high copy number variations, and complex chromosomal rearrangements. This review synthesizes the current knowledge on the clinical features, epidemiology, and treatment approaches for acral melanoma, with a focus on the genetic pathogenesis that gives rise to its unique tumor landscape. These findings highlight a need to deepen our genetic and molecular understanding to better target this challenging subtype of melanoma. Full article
(This article belongs to the Section Molecular Medicine)
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20 pages, 1827 KB  
Article
Evaluating the Diagnostic Value of Lymphocyte Subsets in Bronchoalveolar Lavage Fluid and Peripheral Blood Across Various Diffuse Interstitial Lung Disease Subtypes
by Sonoko Harada, Motoyasu Kato, Kazuyuki Nakagome, Hitoshi Sasano, Yuki Tanabe, Tomohito Takeshige, Yuuki Sandhu, Kei Matsuno, Shoko Ueda, Sumiko Abe, Takayasu Nishimaki, Shun Shinomiya, Jun Ito, Sachiko Miyake, Ko Okumura, Makoto Nagata, Kazuhisa Takahashi and Norihiro Harada
Biomolecules 2025, 15(1), 122; https://doi.org/10.3390/biom15010122 - 14 Jan 2025
Cited by 2 | Viewed by 1833
Abstract
Diffuse interstitial lung diseases (ILD) include conditions with identifiable causes such as chronic eosinophilic pneumonia (CEP), sarcoidosis (SAR), chronic hypersensitivity pneumonitis (CHP), and connective tissue disease-associated interstitial pneumonia (CTD), as well as idiopathic interstitial pneumonia (IIP) of unknown origin. In non-IIP diffuse lung [...] Read more.
Diffuse interstitial lung diseases (ILD) include conditions with identifiable causes such as chronic eosinophilic pneumonia (CEP), sarcoidosis (SAR), chronic hypersensitivity pneumonitis (CHP), and connective tissue disease-associated interstitial pneumonia (CTD), as well as idiopathic interstitial pneumonia (IIP) of unknown origin. In non-IIP diffuse lung diseases, bronchoalveolar lavage (BAL) fluid appearance is diagnostic. This study examines lymphocyte subsets in BAL fluid and peripheral blood of 56 patients with diffuse ILD, excluding idiopathic pulmonary fibrosis (IPF), who underwent BAL for diagnostic purposes. Patients were classified into CEP, SAR, CHP, CTD, and IIP groups, and clinical data, BAL cell analysis, and peripheral blood mononuclear cell analysis were compared. Eosinophils and type 3 innate lymphocytes (ILC3s) were significantly increased in the BAL fluid of the CEP group. Receiver operating characteristic curve analysis identified eosinophils ≥ 8% in BAL cells and ILC3s ≥ 0.0176% in the BAL lymphocyte fraction as thresholds distinguishing CEP. SAR patients exhibited significantly elevated CD4/CD8 ratios in the BAL fluid, with a ratio of 3.95 or higher and type 1 innate lymphoid cell frequency ≥ 0.254% as differentiation markers. High Th1 cell frequency (≥17.4%) in BAL lymphocytes in IIP, elevated serum KL-6 (≥2081 U/mL) and SP-D (≥261 ng/mL) in CHP, and increased BAL neutrophils (≥2.0%) or a low CD4/CD8 ratio (≤1.2) in CTD serve as distinguishing markers for each ILD. Excluding CEP and SAR, CD4+ T cell frequencies, including Th1, Th17, and Treg cells in peripheral blood, may differentiate IIP, CHP, and CTD. Full article
(This article belongs to the Special Issue Eosinophils in Allergy and Related Diseases—Selected Papers from “The Workshop on Eosinophils in Allergy and Related Diseases 2022 and 2023”)
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23 pages, 1132 KB  
Review
Endometrial Receptivity–Lessons from “Omics”
by Louie Ye and Evdokia Dimitriadis
Biomolecules 2025, 15(1), 106; https://doi.org/10.3390/biom15010106 - 11 Jan 2025
Cited by 10 | Viewed by 5818
Abstract
The window of implantation (WOI) is a critical phase of the menstrual cycle during which the endometrial lining becomes receptive and facilitates embryo implantation. Drawing on findings from various branches of “omics”, including genomics, epigenomics, transcriptomics, proteomics, lipidomics, metabolomics, and microbiomics, this narrative [...] Read more.
The window of implantation (WOI) is a critical phase of the menstrual cycle during which the endometrial lining becomes receptive and facilitates embryo implantation. Drawing on findings from various branches of “omics”, including genomics, epigenomics, transcriptomics, proteomics, lipidomics, metabolomics, and microbiomics, this narrative review aims to (1) discuss mechanistic insights on endometrial receptivity and its implication in infertility; (2) highlight advances in investigations for endometrial receptivity; and (3) discuss novel diagnostic and therapeutic strategies that may improve reproductive outcomes. Full article
(This article belongs to the Special Issue Embryo Implantation: New Molecular Insights in Endometrial Receptivity, Trophoblast Invasion and Signaling)
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21 pages, 3712 KB  
Article
Comprehensive Metabolomics in Mouse Mast Cell Model of Allergic Rhinitis for Profiling, Modulation, Semiquantitative Analysis, and Pathway Analysis
by Akshay Suresh Patil and Yan Xu
Biomolecules 2025, 15(1), 109; https://doi.org/10.3390/biom15010109 - 11 Jan 2025
Cited by 3 | Viewed by 1979
Abstract
Allergic rhinitis affects millions globally, causing significant discomfort and reducing the quality of life. This study investigates the metabolic alterations in murine mast cells (MC/9) under allergic rhinitis conditions induced by lipopolysaccharide (LPS) stimulation, employing UHPLC-QTOF-MS-based untargeted and targeted metabolomics. The analysis identified [...] Read more.
Allergic rhinitis affects millions globally, causing significant discomfort and reducing the quality of life. This study investigates the metabolic alterations in murine mast cells (MC/9) under allergic rhinitis conditions induced by lipopolysaccharide (LPS) stimulation, employing UHPLC-QTOF-MS-based untargeted and targeted metabolomics. The analysis identified 44 significantly regulated metabolites, including histamine, leukotrienes, prostaglandins, thromboxanes, and ceramides. Key metabolic pathways such as arachidonic acid, histidine, and sphingolipid metabolisms were notably modulated. The study further examined the therapeutic effects of triprolidine and zileuton, demonstrating their capacity to reverse LPS-induced metabolic shifts. Triprolidine primarily modulated histidine and sphingolipid metabolism, while zileuton targeted arachidonic acid and sphingolipid metabolism. These findings underscore the utility of metabolomics analysis in elucidating the complex biochemical pathways involved in allergic rhinitis and highlight the potential of metabolomics for evaluating therapeutic interventions. This study enhances our understanding of mast cell metabolism in allergic responses and provides a robust model for assessing the efficacy of anti-allergic agents, paving the way for more effective treatments. Full article
(This article belongs to the Section Cellular Biochemistry)
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24 pages, 6736 KB  
Article
Genome Mining and Characterization of Two Novel Lacticaseibacillus rhamnosus Probiotic Candidates with Bile Salt Hydrolase Activity
by Gianluigi Agolino, Marianna Cristofolini, Amanda Vaccalluzzo, Davide Tagliazucchi, Alice Cattivelli, Alessandra Pino, Cinzia Caggia, Lisa Solieri and Cinzia Lucia Randazzo
Biomolecules 2025, 15(1), 86; https://doi.org/10.3390/biom15010086 - 8 Jan 2025
Cited by 9 | Viewed by 3350
Abstract
Bile salt hydrolase (BSH; EC 3.5.1.24) is the microbial enzyme that catalyzes the conversion of primary bile acids (BAs) into secondary ones, promoting microbial adaptation and modulating several host’s biological functions. Probiotics with BSH activity are supposed to survive harsh intestinal conditions and [...] Read more.
Bile salt hydrolase (BSH; EC 3.5.1.24) is the microbial enzyme that catalyzes the conversion of primary bile acids (BAs) into secondary ones, promoting microbial adaptation and modulating several host’s biological functions. Probiotics with BSH activity are supposed to survive harsh intestinal conditions and exert a cholesterol-lowering effect. Here, Lacticaseibacillus rhamnosus strains (VB4 and VB1), isolated from the vaginal ecosystem, were submitted to a genomic survey, in vitro BSH activity, and BAs tolerance assay to unravel their probiotic potential as BAs modulators. The draft genomes of Lcb. rhamnosus VB4 and VB1 strains comprised 2769 and 2704 CDSs, respectively. Gene annotation revealed numerous strain-specific genes involved in metabolism and transport, as well as in DNA recombination. Each strain harbors a single bsh gene, encoding a C-N amide hydrolase, which conserved the essential residues required in the BSH core site. According to the results, compared to VB1, the VB4 strain tolerated better BAs stress and was more active in deconjugating BAs. However, BAs stress increased the bsh gene transcription in the VB1 strain but not in the VB4 strain, suggesting a partially nonlinear relationship between BSH activity and gene expression. In conclusion, despite the complexity of the BSH transcriptional system, the results support the VB4 strain as a promising BAs-deconjugating probiotic candidate. Full article
(This article belongs to the Special Issue Prebiotics and Probiotics in Health and Disease: Looking at the Future)
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21 pages, 4172 KB  
Article
Early-Stage Luminal B-like Breast Cancer Exhibits a More Immunosuppressive Tumor Microenvironment than Luminal A-like Breast Cancer
by Tânia Moura, Olga Caramelo, Isabel Silva, Sandra Silva, Manuela Gonçalo, Maria Antónia Portilha, João N. Moreira, Ana M. Gil, Paula Laranjeira and Artur Paiva
Biomolecules 2025, 15(1), 78; https://doi.org/10.3390/biom15010078 - 7 Jan 2025
Cited by 7 | Viewed by 4561
Abstract
Background: Breast cancer is a heterogeneous malignant disease with a varying prognosis and is classified into four molecular subtypes. It remains one of the most prevalent cancers globally, with the tumor microenvironment playing a critical role in disease progression and patient outcomes. Methods: [...] Read more.
Background: Breast cancer is a heterogeneous malignant disease with a varying prognosis and is classified into four molecular subtypes. It remains one of the most prevalent cancers globally, with the tumor microenvironment playing a critical role in disease progression and patient outcomes. Methods: This study evaluated tumor samples from 40 female patients with luminal A and B breast cancer, utilizing flow cytometry to phenotypically characterize the immune cells and tumor cells present within the tumor tissue. Results: The luminal B-like tumor samples exhibited increased infiltration of CD4+ cells, regulatory T cells (Tregs), and Th17 cells and decreased levels of NK cells, γδ T cells, Th1 cells, and follicular T cells, which is indicative of a more immunosuppressive tumor microenvironment. Conclusions: These findings suggest that luminal B-like tumors have a microenvironment that is less supportive of effective anti-tumor immune responses compared to luminal A tumors. This study enhances the understanding of the immunological differences between luminal subtypes of breast cancer and identifies potential new therapeutic targets and biomarkers that could drive advancements in precision medicine for breast cancer management. Full article
(This article belongs to the Special Issue Advances in Cellular and Molecular Mechanisms in Immuno-Oncology and Onco-Hematology)
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15 pages, 4795 KB  
Article
Epithelial–Mesenchymal Transition Suppression by ML210 Enhances Gemcitabine Anti-Tumor Effects on PDAC Cells
by Keisuke Takemura, Kyohei Ikeda, Hayato Miyake, Yoshio Sogame, Hiroaki Yasuda, Nobuhiro Okada, Kazumi Iwata, Junichi Sakagami, Kanji Yamaguchi, Yoshito Itoh and Atsushi Umemura
Biomolecules 2025, 15(1), 70; https://doi.org/10.3390/biom15010070 - 6 Jan 2025
Cited by 2 | Viewed by 1587
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the world. Neoadjuvant chemotherapy (NAC) has become a standard treatment for patients scheduled for surgical resection, but the high rate of postoperative recurrence is a critical problem. Optimization of NAC is desirable [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the world. Neoadjuvant chemotherapy (NAC) has become a standard treatment for patients scheduled for surgical resection, but the high rate of postoperative recurrence is a critical problem. Optimization of NAC is desirable to reduce postoperative recurrence and achieve long-term survival. However, if a patient’s general condition deteriorates due to NAC toxicity, surgical outcomes may be compromised. Therefore, we aimed to identify drug(s) that can be used in combination with gemcitabine (GEM), a drug widely used for the treatment of PDAC, to inhibit distant metastatic recurrence, particularly after surgery. After several screening steps, ML210, a low molecular weight chemical, was found to suppress the epithelial–mesenchymal transition (EMT) in PDAC cells in combination with GEM. Specifically, low dose ML210 in combination with GEM was sufficient for cell migration without apparent toxicity or cell death. Mechanistically, ML210, which was developed as a glutathione peroxidase 4 (GPX4) inhibitor to induce lipid peroxidation, increased the oxidized lipid concentrations in PDAC cells. The oxidization of the cell membrane lipids may suppress EMT, including cell migration. Since EMT is a major malignant phenotype of PDAC, our findings may lead to the advancement of PDAC therapy, especially in the prevention of postoperative recurrence. Full article
(This article belongs to the Section Cellular Biochemistry)
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19 pages, 1567 KB  
Article
No Relation Between Cognitive Impairment, Physical Disability and Serum Biomarkers in a Cohort of Progressive Multiple Sclerosis Patients
by Bartosz Gajewski, Iwona Karlińska, Małgorzata Domowicz, Igor Bednarski, Mariola Świderek-Matysiak and Mariusz Stasiołek
Biomolecules 2025, 15(1), 68; https://doi.org/10.3390/biom15010068 - 6 Jan 2025
Cited by 2 | Viewed by 1455
Abstract
Despite significant efforts, there is still an existing need to identify diagnostic tools that would enable fast and reliable detection of the progressive stage of multiple sclerosis (MS) and help in monitoring the disease course and/or treatment effects. The aim of this prospective [...] Read more.
Despite significant efforts, there is still an existing need to identify diagnostic tools that would enable fast and reliable detection of the progressive stage of multiple sclerosis (MS) and help in monitoring the disease course and/or treatment effects. The aim of this prospective study in a group of people with progressive MS was to determine whether changes in the levels of selected serum biomarkers and in cognitive function may predict disease progression, and therefore refine the decision-making process in the evaluation of MS patients. Forty two (42) patients with progressive MS completed all the study procedures; the mean duration of follow-up was 12.97 months. During the observation period, serum concentration of chitinase-3 like-protein-1 (CHI3L1/YKL-40) decreased significantly in the whole study group (from 4034.95 ± 262.62 to 2866.43 ± 173.37; p = 0.0005), as well as in subgroups of people with secondary progressive and primary progressive MS (SPMS: from 3693.81 ± 388.68 to 2542.76 ± 256.59; p = 0.0207; and PPMS: from 4376.09 ± 353.27 to 3190.09 ± 233.22; p = 0.0089, respectively). A significant worsening of Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) scores was detected in the whole study group (from 1.18 ± 0.14 to 1.34 ± 0.15; p = 0.0331) as well as in the PPMS subgroup (from 1.04 ± 0.18 to 1.26 ± 0.20; p = 0.0216). No correlations between the analyzed molecular parameters or the results of neuropsychological tests and physical disability were observed. In conclusion, an emphasis should be placed on furthering the search for multimodal biomarkers of disease progression, especially in the PMS population, based on simultaneous analysis of several factors, such as blood biomarkers and cognitive profiles. Full article
(This article belongs to the Section Molecular Biomarkers)
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14 pages, 2356 KB  
Review
HBV cccDNA: The Molecular Reservoir of Hepatitis B Persistence and Challenges to Achieve Viral Eradication
by André Boonstra and Gulce Sari
Biomolecules 2025, 15(1), 62; https://doi.org/10.3390/biom15010062 - 4 Jan 2025
Cited by 10 | Viewed by 8940
Abstract
Hepatitis B virus (HBV) is a major global health issue, with an estimated 254 million people living with chronic HBV infection worldwide as of 2022. Chronic HBV infection is the leading cause of cirrhosis and liver cancer. Current treatment with nucleos(t)ide analogs is [...] Read more.
Hepatitis B virus (HBV) is a major global health issue, with an estimated 254 million people living with chronic HBV infection worldwide as of 2022. Chronic HBV infection is the leading cause of cirrhosis and liver cancer. Current treatment with nucleos(t)ide analogs is effective in the suppression of viral activity but generally requires lifelong treatment. They fail to eradicate the HBV viral reservoir, called covalently closed circular DNA (cccDNA), which replicates in the nucleus of liver cells. The cccDNA serves as the sole template for viral replication, as it generates the pregenomic RNA (pgRNA) necessary for producing new viral genomes. This stable form of viral DNA can reactivate the virus when treatment is stopped. HBV cccDNA is therefore one of the main challenges in curing chronic HBV infections. By targeting steps such as cccDNA formation, capsid assembly, or particle secretion, researchers continue to seek ways to interfere with HBV replication and to reduce its persistence, ultimately to eradicate HBV as a global health problem. This review provides an overview of what is currently known about cccDNA formation and biogenesis and the ongoing efforts to target and eradicate it to cure chronic HBV infections. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying Liver Diseases)
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22 pages, 7344 KB  
Article
Characterization of the Sodium Multi-Vitamin Transporter in the Mosquito Anopheles stephensi and Its Capacity to Mobilize Pantothenate and Biotin
by Jun Isoe, Brendan F. Riske, Megan E. Dobson, Hannah L. Kaylor, Jessica C. Brady, Yared Debebe, Laura M. Saavedra, Shirley Luckhart and Michael A. Riehle
Biomolecules 2025, 15(1), 59; https://doi.org/10.3390/biom15010059 - 3 Jan 2025
Cited by 2 | Viewed by 1736
Abstract
Pantothenate (Pan), or vitamin B5, is essential for the synthesis of co-enzyme A (CoA), acetyl-CoA, and numerous downstream physiological processes. We previously demonstrated that Pan is not only essential for mosquito survival, but also for the development of malaria parasites within the mosquito, [...] Read more.
Pantothenate (Pan), or vitamin B5, is essential for the synthesis of co-enzyme A (CoA), acetyl-CoA, and numerous downstream physiological processes. We previously demonstrated that Pan is not only essential for mosquito survival, but also for the development of malaria parasites within the mosquito, suggesting that targeting Pan and CoA biosynthesis may be a novel approach for malaria control. However, little is known about how Pan is acquired and mobilized within the mosquito. In this work, we examined Pan levels in the important human malaria vector Anopheles stephensi, including the abundance of Pan during immature development and adulthood. We also assessed the distribution of Pan in various adult tissues and examined the impact of provisioning Pan to the mosquito via a sugar or blood meal on mosquito survival and reproduction. Furthermore, we examined how Pan was mobilized in the mosquito via a putative Pan transporter, the A. stephensi sodium multi-vitamin transporter. We demonstrated that this transporter is capable of mobilizing both Pan and biotin (vitamin B7) in a dose dependent manner. We also assessed the distribution of A. stephensi sodium multi-vitamin transporter in the mosquito and its capacity to transport vitamins. This work establishes the basic physiology of Pan uptake and mobilization in the mosquito, providing essential information for Pan based malaria control strategies. Full article
(This article belongs to the Special Issue New Insights into Molecular Mechanisms and Therapeutics for Malaria)
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17 pages, 2791 KB  
Article
Enhancement of Doxorubicin Efficacy by Bacopaside II in Triple-Negative Breast Cancer Cells
by Sima Kianpour Rad, Kenny K. L. Yeo, Runhao Li, Fangmeinuo Wu, Saifei Liu, Saeed Nourmohammadi, William M. Murphy, Yoko Tomita, Timothy J. Price, Wendy V. Ingman, Amanda R. Townsend and Eric Smith
Biomolecules 2025, 15(1), 55; https://doi.org/10.3390/biom15010055 - 3 Jan 2025
Cited by 6 | Viewed by 2118
Abstract
Background: Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options and high resistance to chemotherapy. Doxorubicin is commonly used, but its efficacy is limited by variable sensitivity and resistance. Bacopaside II, a saponin compound, has shown anti-cancer potential. This study [...] Read more.
Background: Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options and high resistance to chemotherapy. Doxorubicin is commonly used, but its efficacy is limited by variable sensitivity and resistance. Bacopaside II, a saponin compound, has shown anti-cancer potential. This study evaluates the effects of doxorubicin and bacopaside II, both individually and in combination, across TNBC subtypes to explore mechanisms of resistance and enhanced drug efficacy. Methods: The growth-inhibitory effects of doxorubicin and bacopaside II were assessed in four TNBC cell lines. IC50 values were determined using dose–response assays, and doxorubicin accumulation was measured via spectral flow cytometry. ATP-binding cassette (ABC) transporter expression (ABCB1, ABCC1, ABCC3, and ABCG2) was analyzed for correlations with drug sensitivity. In silico docking assessed the binding affinity of bacopaside II to ABC transporters. A 3D culture model simulated drug-resistant TNBC, and combination effects were evaluated with live-cell imaging. Results: Doxorubicin sensitivity varied across TNBC molecular subtypes, correlating to intracellular accumulation. Bacopaside II inhibited growth across subtypes, inducing apoptosis in sensitive cells and necrosis in resistant cells. Bacopaside II increased doxorubicin accumulation, independent of P-glycoprotein (ABCB1), possibly through interactions with other ABC transporters. In drug-resistant 3D cultures, bacopaside II maintained efficacy and enhanced doxorubicin accumulation, counteracting ABC transporter-mediated resistance. The doxorubicin and bacopaside II combination showed synergistic growth inhibition. Conclusions: Bacopaside II enhances doxorubicin efficacy in TNBC by increasing drug accumulation and overcoming ABC transporter-mediated resistance, suggesting its potential as an adjuvant in TNBC treatment. These findings support further investigation of bacopaside II, particularly for resistant TNBC subtypes. Full article
(This article belongs to the Section Natural and Bio-derived Molecules)
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14 pages, 2405 KB  
Article
The Inhibitory Effects of Alpha 1 Antitrypsin on Endosomal TLR Signaling Pathways
by Ahmed S. Elshikha, Georges Abboud, Rigena Avdiaj, Laurence Morel and Sihong Song
Biomolecules 2025, 15(1), 43; https://doi.org/10.3390/biom15010043 - 1 Jan 2025
Cited by 2 | Viewed by 1755
Abstract
Endosomal toll-like receptors (TLRs) TLR7, TLR8, and TLR9 play an important role in systemic lupus erythematosus (SLE) pathogenesis. The proteolytic processing of these receptors in the endolysosome is required for signaling in response to DNA and single-stranded RNA, respectively. Targeting this proteolytic processing [...] Read more.
Endosomal toll-like receptors (TLRs) TLR7, TLR8, and TLR9 play an important role in systemic lupus erythematosus (SLE) pathogenesis. The proteolytic processing of these receptors in the endolysosome is required for signaling in response to DNA and single-stranded RNA, respectively. Targeting this proteolytic processing may represent a novel strategy to inhibit TLR-mediated pathogenesis. Human alpha 1 antitrypsin (hAAT) is a protease inhibitor with anti-inflammatory and immunoregulatory properties. However, the effect of hAAT on endosomal TLRs remains elusive. In this study, we first tested the effect of hAAT on TLR9 signaling in dendritic cells (DCs). We showed that hAAT inhibited TLR9-mediated DC activation and cytokine production. Human AAT also lowered the expressions of interferon signature genes. Western blot analysis showed that hAAT reduced the expression of the active form (cleaved) of TLR9 in DCs, indicating a novel mechanism of hAAT function in the immune system. We next tested the effect of hAAT on TLR7/8 signaling. Similar to the effect on TLR9 signaling, hAAT also inhibited R848 (TLR7 and 8 agonist)-induced DC activation and functions and lowered the expressions of interferon signature genes. Our in vivo studies using hAAT transgenic mice also showed that hAAT attenuated R848-induced pathogenesis. Specifically, hAAT completely blocked the R848 induction of germinal center T cells (GC T), B cells (GC B), and plasma cells (GC PCs), as well as T follicular T helper cells (TFH), which are all critical in lupus development. These data demonstrated that hAAT inhibited TLR7/8 and TLR9 signaling pathways, which are critical for lupus development. These findings not only advanced the current knowledge of hAAT biology, but also implied an insight into the clinical application of hAAT. Full article
(This article belongs to the Special Issue Roles of Alpha-1 Antitrypsin in Human Health and Disease Models)
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37 pages, 12904 KB  
Review
Targeting Invasion: The Role of MMP-2 and MMP-9 Inhibition in Colorectal Cancer Therapy
by Alireza Shoari, Arghavan Ashja Ardalan, Alexandra M. Dimesa and Mathew A. Coban
Biomolecules 2025, 15(1), 35; https://doi.org/10.3390/biom15010035 - 30 Dec 2024
Cited by 23 | Viewed by 6953
Abstract
Colorectal cancer (CRC) remains one of the most prevalent and lethal cancers worldwide, prompting ongoing research into innovative therapeutic strategies. This review aims to systematically evaluate the role of gelatinases, specifically MMP-2 and MMP-9, as therapeutic targets in CRC, providing a critical analysis [...] Read more.
Colorectal cancer (CRC) remains one of the most prevalent and lethal cancers worldwide, prompting ongoing research into innovative therapeutic strategies. This review aims to systematically evaluate the role of gelatinases, specifically MMP-2 and MMP-9, as therapeutic targets in CRC, providing a critical analysis of their potential to improve patient outcomes. Gelatinases, specifically MMP-2 and MMP-9, play critical roles in the processes of tumor growth, invasion, and metastasis. Their expression and activity are significantly elevated in CRC, correlating with poor prognosis and lower survival rates. This review provides a comprehensive overview of the pathophysiological roles of gelatinases in CRC, highlighting their contribution to tumor microenvironment modulation, angiogenesis, and the metastatic cascade. We also critically evaluate recent advancements in the development of gelatinase inhibitors, including small molecule inhibitors, natural compounds, and novel therapeutic approaches like gene silencing techniques. Challenges such as nonspecificity, adverse side effects, and resistance mechanisms are discussed. We explore the potential of gelatinase inhibition in combination therapies, particularly with conventional chemotherapy and emerging targeted treatments, to enhance therapeutic efficacy and overcome resistance. The novelty of this review lies in its integration of recent findings on diverse inhibition strategies with insights into their clinical relevance, offering a roadmap for future research. By addressing the limitations of current approaches and proposing novel strategies, this review underscores the potential of gelatinase inhibitors in CRC prevention and therapy, inspiring further exploration in this promising area of oncological treatment. Full article
(This article belongs to the Special Issue Matrix Metalloproteinases: Mechanisms, Functions and Therapeutic Potential)
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21 pages, 3475 KB  
Review
VDAC1: A Key Player in the Mitochondrial Landscape of Neurodegeneration
by Shirel Argueti-Ostrovsky, Shir Barel, Joy Kahn and Adrian Israelson
Biomolecules 2025, 15(1), 33; https://doi.org/10.3390/biom15010033 - 30 Dec 2024
Cited by 6 | Viewed by 4385
Abstract
Voltage-Dependent Anion Channel 1 (VDAC1) is a mitochondrial outer membrane protein that plays a crucial role in regulating cellular energy metabolism and apoptosis by mediating the exchange of ions and metabolites between mitochondria and the cytosol. Mitochondrial dysfunction and oxidative stress are central [...] Read more.
Voltage-Dependent Anion Channel 1 (VDAC1) is a mitochondrial outer membrane protein that plays a crucial role in regulating cellular energy metabolism and apoptosis by mediating the exchange of ions and metabolites between mitochondria and the cytosol. Mitochondrial dysfunction and oxidative stress are central features of neurodegenerative diseases. The pivotal functions of VDAC1 in controlling mitochondrial membrane permeability, regulating calcium balance, and facilitating programmed cell death pathways, position it as a key determinant in the delicate balance between neuronal viability and degeneration. Accordingly, increasing evidence suggests that VDAC1 is implicated in the pathophysiology of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and others. This review summarizes the current findings on the contribution of VDAC1 to neurodegeneration, focusing on its interactions with disease-specific proteins, such as amyloid-β, α-synuclein, and mutant SOD1. By unraveling the complex involvement of VDAC1 in neurodegenerative processes, this review highlights potential avenues for future research and drug development aimed at alleviating mitochondrial-related neurodegeneration. Full article
(This article belongs to the Special Issue The Central Role of Mitochondrial Protein VDAC1 in Human Diseases – Honorary Special Issue Commemorating the Work of Prof. Varda Shoshan-Barmatz)
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15 pages, 2431 KB  
Article
Visceral Adipose Tissue Inflammation and Vascular Complications in a Rat Model with Severe Dyslipidemia: Sex Differences and PAI-1 Tissue Involvement
by Irena Markova, Martina Hüttl, Natalie Gayova, Denisa Miklankova, Kristyna Cerna, Martina Kavanova, Petra Skaroupkova, Sona Cacanyiova and Hana Malinska
Biomolecules 2025, 15(1), 19; https://doi.org/10.3390/biom15010019 - 27 Dec 2024
Cited by 4 | Viewed by 1601
Abstract
We investigated the sex-dependent effects of inflammatory responses in visceral adipose tissue (VAT) and perivascular adipose tissue (PVAT), as well as hematological status, in relation to cardiovascular disorders associated with prediabetes. Using male and female hereditary hypertriglyceridemic (HHTg) rats—a nonobese prediabetic model featuring [...] Read more.
We investigated the sex-dependent effects of inflammatory responses in visceral adipose tissue (VAT) and perivascular adipose tissue (PVAT), as well as hematological status, in relation to cardiovascular disorders associated with prediabetes. Using male and female hereditary hypertriglyceridemic (HHTg) rats—a nonobese prediabetic model featuring dyslipidemia, hepatic steatosis, and insulin resistance—we found that HHTg females exhibited more pronounced hypertriglyceridemia than males, while HHTg males had higher non-fasting glucose levels. Additionally, HHTg females had higher platelet counts, larger platelet volumes, and lower antithrombin inhibitory activity. Regarding low-grade chronic inflammation, HHTg males exhibited increased serum leptin and leukocyte levels, while females had increased serum interleukin-6 (IL-6). Both sexes had increased circulating plasminogen activator inhibitor-1 (PAI-1), higher PAI-1 gene expression in VAT and PVAT, and elevated intercellular adhesion molecule-1 (ICAM-1) gene expression in the aorta, contributing to endothelial dysfunction in the HHTg strain. However, HHTg females had lower tumor necrosis factor alpha (TNFα) gene expression in the aorta. Severe dyslipidemia in this prediabetic model was associated with hypercoagulation and low-grade chronic inflammation. The increase in PAI-1 expression in both VAT and PVAT seems to indicate a link between inflammation and vascular dysfunction. Despite the more pronounced dyslipidemia and procoagulation status in females, their milder inflammatory response may reflect an association between reduced cardiovascular damage and prediabetes. Full article
(This article belongs to the Section Biological Factors)
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23 pages, 4348 KB  
Article
Extracellular Vesicles and Tunnelling Nanotubes as Mediators of Prostate Cancer Intercellular Communication
by Jessica K. Heatlie, Joanna Lazniewska, Courtney R. Moore, Ian R. D. Johnson, Bukuru D. Nturubika, Ruth Williams, Mark P. Ward, John J. O’Leary, Lisa M. Butler and Doug A. Brooks
Biomolecules 2025, 15(1), 23; https://doi.org/10.3390/biom15010023 - 27 Dec 2024
Cited by 5 | Viewed by 2993
Abstract
Prostate cancer (PCa) pathogenesis relies on intercellular communication, which can involve tunnelling nanotubes (TNTs) and extracellular vesicles (EVs). TNTs and EVs have been reported to transfer critical cargo involved in cellular functions and signalling, prompting us to investigate the extent of organelle and [...] Read more.
Prostate cancer (PCa) pathogenesis relies on intercellular communication, which can involve tunnelling nanotubes (TNTs) and extracellular vesicles (EVs). TNTs and EVs have been reported to transfer critical cargo involved in cellular functions and signalling, prompting us to investigate the extent of organelle and protein transfer in PCa cells and the potential involvement of the androgen receptor. Using live cell imaging microscopy, we observed extensive formation of TNTs and EVs operating between PCa, non-malignant, and immune cells. PCa cells were capable of transferring lysosomes, mitochondria, lipids, and endoplasmic reticulum, as well as syndecan-1, sortilin, Glut1, and Glut4. In mechanistic studies, androgen-sensitive PCa cells exhibited changes in cell morphology when stimulated by R1881 treatment. Overexpression assays of a newly designed androgen receptor (AR) plasmid revealed its novel localization in PCa cellular vesicles, which were also transferred to neighbouring cells. Selected molecular machinery, thought to be involved in intercellular communication, was investigated by knockdown studies and Western blotting/immunofluorescence/scanning electron microscopy (SEM). PCa TNTs and EVs transported proteins and organelles, which may contain specialist signalling, programming, and energy requirements that support cancer growth and progression. This makes these important intercellular communication systems ideal potential targets for therapeutic intervention. Full article
(This article belongs to the Special Issue Advances in the Pathology of Prostate Cancer)
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16 pages, 1075 KB  
Review
The Intersection of Epigenetics and Senolytics in Mechanisms of Aging and Therapeutic Approaches
by Daiana Burdusel, Thorsten R. Doeppner, Roxana Surugiu, Dirk M. Hermann, Denissa Greta Olaru and Aurel Popa-Wagner
Biomolecules 2025, 15(1), 18; https://doi.org/10.3390/biom15010018 - 26 Dec 2024
Cited by 6 | Viewed by 5164
Abstract
The biological process of aging is influenced by a complex interplay of genetic, environmental, and epigenetic factors. Recent advancements in the fields of epigenetics and senolytics offer promising avenues for understanding and addressing age-related diseases. Epigenetics refers to heritable changes in gene expression [...] Read more.
The biological process of aging is influenced by a complex interplay of genetic, environmental, and epigenetic factors. Recent advancements in the fields of epigenetics and senolytics offer promising avenues for understanding and addressing age-related diseases. Epigenetics refers to heritable changes in gene expression without altering the DNA sequence, with mechanisms like DNA methylation, histone modification, and non-coding RNA regulation playing critical roles in aging. Senolytics, a class of drugs targeting and eliminating senescent cells, address the accumulation of dysfunctional cells that contribute to tissue degradation and chronic inflammation through the senescence-associated secretory phenotype. This scoping review examines the intersection of epigenetic mechanisms and senolytic therapies in aging, focusing on their combined potential for therapeutic interventions. Senescent cells display distinct epigenetic signatures, such as DNA hypermethylation and histone modifications, which can be targeted to enhance senolytic efficacy. Epigenetic reprogramming strategies, such as induced pluripotent stem cells, may further complement senolytics by rejuvenating aged cells. Integrating epigenetic modulation with senolytic therapy offers a dual approach to improving healthspan and mitigating age-related pathologies. This narrative review underscores the need for continued research into the molecular mechanisms underlying these interactions and suggests future directions for therapeutic development, including clinical trials, biomarker discovery, and combination therapies that synergistically target aging processes. Full article
(This article belongs to the Section Molecular Medicine)
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35 pages, 1450 KB  
Review
Epigenetic Properties of Compounds Contained in Functional Foods Against Cancer
by Giulia Casari, Brenda Romaldi, Andrea Scirè, Cristina Minnelli, Daniela Marzioni, Gianna Ferretti and Tatiana Armeni
Biomolecules 2025, 15(1), 15; https://doi.org/10.3390/biom15010015 - 26 Dec 2024
Cited by 15 | Viewed by 4575
Abstract
Epigenetics encompasses reversible and heritable genomic changes in histones, DNA expression, and non-coding RNAs that occur without modifying the nucleotide DNA sequence. These changes play a critical role in modulating cell function in both healthy and pathological conditions. Dysregulated epigenetic mechanisms are implicated [...] Read more.
Epigenetics encompasses reversible and heritable genomic changes in histones, DNA expression, and non-coding RNAs that occur without modifying the nucleotide DNA sequence. These changes play a critical role in modulating cell function in both healthy and pathological conditions. Dysregulated epigenetic mechanisms are implicated in various diseases, including cardiovascular disorders, neurodegenerative diseases, obesity, and mainly cancer. Therefore, to develop innovative therapeutic strategies, research for compounds able to modulate the complex epigenetic landscape of cancer is rapidly surging. Dietary phytochemicals, mostly flavonoids but also tetraterpenoids, organosulfur compounds, and isothiocyanates, represent biologically active molecules found in vegetables, fruits, medicinal plants, and beverages. These natural organic compounds exhibit epigenetic modulatory properties by influencing the activity of epigenetics key enzymes, such as DNA methyltransferases, histone acetyltransferases and deacetylases, and histone methyltransferases and demethylases. Due to the reversibility of the modifications that they induce, their minimal adverse effects, and their potent epigenetic regulatory activity, dietary phytochemicals hold significant promise as antitumor agents and warrant further investigation. This review aims to consolidate current data on the diverse epigenetic effects of the six major flavonoid subclasses, as well as other natural compounds, in the context of cancer. The goal is to identify new therapeutic epigenetic targets for drug development, whether as stand-alone treatments or in combination with conventional antitumor approaches. Full article
(This article belongs to the Special Issue Bioactive Molecules: Structures, Functions and Potential Uses for Cancer Prevention and Targeted Therapies (2nd Edition))
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25 pages, 1456 KB  
Review
The Role of Neuroglia in the Development and Progression of Schizophrenia
by Neha S. Rawani, Allen W. Chan, Kathryn G. Todd, Glen B. Baker and Serdar M. Dursun
Biomolecules 2025, 15(1), 10; https://doi.org/10.3390/biom15010010 - 25 Dec 2024
Cited by 8 | Viewed by 4282
Abstract
Schizophrenia is a complex heterogenous disorder thought to be caused by interactions between genetic and environmental factors. The theories developed to explain the etiology of schizophrenia have focused largely on the dysfunction of neurotransmitters such as dopamine, serotonin and glutamate with their receptors, [...] Read more.
Schizophrenia is a complex heterogenous disorder thought to be caused by interactions between genetic and environmental factors. The theories developed to explain the etiology of schizophrenia have focused largely on the dysfunction of neurotransmitters such as dopamine, serotonin and glutamate with their receptors, although research in the past several decades has indicated strongly that other factors are also involved and that the role of neuroglial cells in psychotic disorders including schizophrenia should be given more attention. Although glia were originally thought to be present in the brain only to support neurons in a physical, metabolic and nutritional capacity, it has become apparent that these cells have a variety of important physiological roles and that abnormalities in their function may make significant contributions to the symptoms of schizophrenia. In the present paper, we review the interactions of brain microglia, astrocytes and oligodendroglia with aspects such as transmitter dysregulation, neuro-inflammation, oxidative stress, synaptic function, the gut microbiome, myelination and the blood–brain barrier that appear to affect the cause, development and treatment of schizophrenia. We also review crosstalk between microglia, astrocytes and oligodendrocytes and the effects of antipsychotics on neuroglia. Problems associated with studies on specific biomarkers for glia in schizophrenia are discussed. Full article
(This article belongs to the Section Cellular Biochemistry)
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21 pages, 3504 KB  
Article
G Protein-Coupled Receptor 17 Inhibits Glucagon-like Peptide-1 Secretion via a Gi/o-Dependent Mechanism in Enteroendocrine Cells
by Jason M. Conley, Alexander Jochim, Carmella Evans-Molina, Val J. Watts and Hongxia Ren
Biomolecules 2025, 15(1), 9; https://doi.org/10.3390/biom15010009 - 25 Dec 2024
Cited by 5 | Viewed by 5898
Abstract
Gut peptides, including glucagon-like peptide-1 (GLP-1), regulate metabolic homeostasis and have emerged as the basis for multiple state-of-the-art diabetes and obesity therapies. We previously showed that G protein-coupled receptor 17 (GPR17) is expressed in intestinal enteroendocrine cells (EECs) and modulates nutrient-induced GLP-1 secretion. [...] Read more.
Gut peptides, including glucagon-like peptide-1 (GLP-1), regulate metabolic homeostasis and have emerged as the basis for multiple state-of-the-art diabetes and obesity therapies. We previously showed that G protein-coupled receptor 17 (GPR17) is expressed in intestinal enteroendocrine cells (EECs) and modulates nutrient-induced GLP-1 secretion. However, the GPR17-mediated molecular signaling pathways in EECs have yet to be fully deciphered. Here, we expressed the human GPR17 long isoform (hGPR17L) in GLUTag cells, a murine EEC line, and we used the GPR17 synthetic agonist MDL29,951 together with pharmacological probes and genetic approaches to quantitatively assess the contribution of GPR17 signaling to GLP-1 secretion. Constitutive hGPR17L activity inhibited GLP-1 secretion, and MDL29,951 treatment further inhibited this secretion, which was attenuated by treatment with the GPR17 antagonist HAMI3379. MDL29,951 promoted both Gi/o and Gq protein coupling to mediate cyclic AMP (cAMP) and calcium signaling. hGPR17L regulation of GLP-1 secretion appeared to be Gq-independent and dependent upon Gi/o signaling, but was not correlated with MDL29,951-induced whole-cell cAMP signaling. Our studies revealed key signaling mechanisms underlying the role of GPR17 in regulating GLP-1 secretion and suggest future opportunities for pharmacologically targeting GPR17 with inverse agonists to maximize GLP-1 secretion. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Metabolic Regulation Used by G Protein-Coupled Receptors)
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11 pages, 4359 KB  
Article
High Glucose Sensitizes Male and Female Rat Cardiomyocytes to Wnt/β-Catenin Signaling
by Ruonan Gu, Jerry Wang, Julianne Morin, Aizhu Lu and Wenbin Liang
Biomolecules 2024, 14(12), 1639; https://doi.org/10.3390/biom14121639 - 20 Dec 2024
Cited by 2 | Viewed by 1198
Abstract
Wnt/β-catenin signaling has been shown to regulate gene expressions in cardiomyocytes. However, it is not known if this effect is dependent on the sex of cells or the glucose level in the culture medium. In the present study, ventricular myocytes were prepared from [...] Read more.
Wnt/β-catenin signaling has been shown to regulate gene expressions in cardiomyocytes. However, it is not known if this effect is dependent on the sex of cells or the glucose level in the culture medium. In the present study, ventricular myocytes were prepared from male and female neonatal rats and maintained in either a glucose-rich (25 mM) medium or a low-glucose (3 mM), lipid-rich medium. Real-time quantitative PCR was used to measure changes in target genes (Axin2, Scn5a, and Tbx3) after treatment with 1, 3, or 10 µM of CHIR-99021, an activator of Wnt/β-catenin signaling. CHIR induced similar changes in Axin2, Tbx3, and Scn5a transcripts in male and female NRVMs in both media, suggesting the absence of sex difference. However, cells in a high-glucose medium showed greater increases in Axin2 and Tbx3 transcripts than cells in a low-glucose medium. In addition, a low concentration of CHIR (1 µM) reduced the Scn5a transcript in cells in a high-glucose medium but not in a low-glucose medium, suggesting an increased sensitivity to Wnt signaling by high glucose. A non-linear relationship was identified between Axin2 transcript upregulation and Scn5a transcript downregulation in CIHR-treated NRVMs. These data suggest that high glucose sensitizes both male and female cardiomyocytes to Wnt/β-catenin signaling. Full article
(This article belongs to the Section Molecular Medicine)
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14 pages, 5656 KB  
Article
Celecoxib Combined with Tocilizumab Has Anti-Inflammatory Effects and Promotes the Recovery of Damaged Cartilage via the Nrf2/HO-1 Pathway In Vitro
by Miyako Shimasaki, Shusuke Ueda, Masaru Sakurai, Norio Kawahara, Yoshimichi Ueda and Toru Ichiseki
Biomolecules 2024, 14(12), 1636; https://doi.org/10.3390/biom14121636 - 20 Dec 2024
Cited by 2 | Viewed by 1610
Abstract
Inflammation and oxidative stress are crucial for osteoarthritis (OA) pathogenesis. Despite the potential of pharmacological pretreatment of chondrocytes in preventing OA, its efficacy in preventing the progression of cartilage damage and promoting its recovery has not been examined. In this study, an H [...] Read more.
Inflammation and oxidative stress are crucial for osteoarthritis (OA) pathogenesis. Despite the potential of pharmacological pretreatment of chondrocytes in preventing OA, its efficacy in preventing the progression of cartilage damage and promoting its recovery has not been examined. In this study, an H2O2-induced human OA-like chondrocyte cell model was created using H1467 primary human chondrocytes to evaluate the efficacy of interleukin (IL)-6 and cyclooxygenase (COX)-2 inhibitors (tocilizumab and celecoxib, respectively) in the prevention and treatment of cartilage damage. H2O2 significantly elevated the IL-6, COX-2, and matrix metalloproteinase (MMP)-13 levels. Although monotherapy decreased the levels, nuclear shrinkage and altered cell morphology, similar to those in the H2O2 group, were observed. The expression of these factors was significantly lower in the combination therapy group, and the cell morphology was maintained. Moreover, the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway was activated, and levels of the antioxidant protein heme oxygenase-1 (HO-1) were increased, especially in the combination group, indicating an anti-inflammatory effect. The treatment groups, particularly the combination group, demonstrated increased cell viability. Overall, the drug combination exhibited superior efficacy in preventing the progression of cartilage damage and promoted its recovery compared with the monotherapy. Given that the drugs herein are already in clinical use, they are suitable candidates for OA treatment. Full article
(This article belongs to the Section Cellular Biochemistry)
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17 pages, 6802 KB  
Article
The Effect of Tyre and Road Wear Particles on the Terrestrial Isopod Armadillidium pallasii
by Giorgia Torreggiani, Chiara Manfrin, Anita Giglio, Andrea Dissegna, Cinzia Chiandetti, Paola Giotta, Monia Renzi, Serena Anselmi, Tecla Bentivoglio, Agnieszka Babczyńska, Silvia Battistella, Paolo Edomi and Piero G. Giulianini
Biomolecules 2024, 14(12), 1640; https://doi.org/10.3390/biom14121640 - 20 Dec 2024
Cited by 6 | Viewed by 1759
Abstract
(1) Car tyre microplastic particles (TMPs) significantly contribute to global microplastic pollution, with an estimated annual production of 6 million tonnes. However, the impact of TMPs, particularly tyre and road wear particles (TRWPs), resulting from tyre abrasion on the road on terrestrial organisms, [...] Read more.
(1) Car tyre microplastic particles (TMPs) significantly contribute to global microplastic pollution, with an estimated annual production of 6 million tonnes. However, the impact of TMPs, particularly tyre and road wear particles (TRWPs), resulting from tyre abrasion on the road on terrestrial organisms, is poorly understood. This study investigated the effects of TMPs and TRWPs on the growth, immune response, behaviour, and cognition of the woodlouse Armadillidium pallasii over 30 days; (2) TMPs and TRWPs were mixed together in the first experiment and provided at different concentrations of 1.25%, 2.5%, 5%, and 10% (w/w), and with soil at 5% and 10% (w/w) concentrations in the second experiment. (3) No differences in survival or immune responses were observed in both experiments. However, isopods exposed to TRWPs showed significant weight gain at lower concentrations but no gain at higher levels. Behavioural tests revealed increased vigilance in TRWP-exposed animals. Micro-FTIR analysis showed that the number of TMPs and TRWPs in the isopods correlated with soil concentrations, and particle size decreased during the experiment. (4) The study highlights the physiological and behavioural effects of TRWPs and the role of detritivorous species in the biofragmentation of TMPs and TRWPs, contributing to the biogeochemical plastic cycle. Full article
(This article belongs to the Special Issue Host Molecules and Molecular Mechanisms in Insects and Crustaceans)
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15 pages, 3263 KB  
Article
COVID-19 Exacerbates Neurovascular Uncoupling and Contributes to Endothelial Dysfunction in Patients with Mild Cognitive Impairment
by Cameron D. Owens, Camila B. Pinto, Zsofia Szarvas, Mihaly Muranyi, Ana Clara da C. Pinaffi-Langley, Anna Peterfi, Peter Mukli, Sam Detwiler, Lauren Olay, Zalan Kaposzta, Kenneth Smith, Angelia C. Kirkpatrick, Faddi Saleh Velez, Stefano Tarantini, Anna Csiszar, Zoltan I. Ungvari, Calin I. Prodan and Andriy Yabluchanskiy
Biomolecules 2024, 14(12), 1621; https://doi.org/10.3390/biom14121621 - 18 Dec 2024
Cited by 4 | Viewed by 2032
Abstract
Mild cognitive impairment (MCI) affects nearly 20% of older adults worldwide, with no targetable interventions for prevention. COVID-19 adversely affects cognition, with >70% of older adults with Long COVID presenting with cognitive complaints. Neurovascular coupling (NVC), an essential mechanism of cognitive function, declines [...] Read more.
Mild cognitive impairment (MCI) affects nearly 20% of older adults worldwide, with no targetable interventions for prevention. COVID-19 adversely affects cognition, with >70% of older adults with Long COVID presenting with cognitive complaints. Neurovascular coupling (NVC), an essential mechanism of cognitive function, declines with aging and is further attenuated in neurocognitive disorders. The effect of COVID-19 on NVC responses has yet to be addressed in older adults who are vulnerable to dementia progression. Participants with MCI and a history of COVID-19 (COV+, N = 31) and MCI participants with no history of infection (COV− N = 11) participated in this cross-sectional study to determine if COVID-19 affects cerebrocortical NVC responses and vascular function. Functional near-infrared spectroscopy was used to measure cerebrocortical NVC responses, and endothelial function was assessed via insonation of the brachial artery during a flow-mediated dilation protocol. NVC responses were elicited by the working memory n-back paradigm. NVC in the left dorsolateral prefrontal cortex and endothelial function was decreased in the COV+ group compared to the COV− group. These data provide mechanistic insight into how COVID-19 may exacerbate long-term cognitive sequela seen in older adults, highlighting the urgent need for further research and clinical trials to explore novel therapeutic interventions aimed at preserving/restoring NVC. Full article
(This article belongs to the Special Issue The Role of Vascular Dysfunction in Neuronal Degeneration and Cognitive Impairment (2nd Edition))
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37 pages, 2261 KB  
Review
Decoding FGF/FGFR Signaling: Insights into Biological Functions and Disease Relevance
by Oshadi Edirisinghe, Gaëtane Ternier, Zeina Alraawi and Thallapuranam Krishnaswamy Suresh Kumar
Biomolecules 2024, 14(12), 1622; https://doi.org/10.3390/biom14121622 - 18 Dec 2024
Cited by 15 | Viewed by 10123
Abstract
Fibroblast Growth Factors (FGFs) and their cognate receptors, FGFRs, play pivotal roles in a plethora of biological processes, including cell proliferation, differentiation, tissue repair, and metabolic homeostasis. This review provides a comprehensive overview of FGF-FGFR signaling pathways while highlighting their complex regulatory mechanisms [...] Read more.
Fibroblast Growth Factors (FGFs) and their cognate receptors, FGFRs, play pivotal roles in a plethora of biological processes, including cell proliferation, differentiation, tissue repair, and metabolic homeostasis. This review provides a comprehensive overview of FGF-FGFR signaling pathways while highlighting their complex regulatory mechanisms and interconnections with other signaling networks. Further, we briefly discuss the FGFs involvement in developmental, metabolic, and housekeeping functions. By complementing current knowledge and emerging research, this review aims to enhance the understanding of FGF-FGFR-mediated signaling and its implications for health and disease, which will be crucial for therapeutic development against FGF-related pathological conditions. Full article
(This article belongs to the Section Cellular Biochemistry)
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13 pages, 1473 KB  
Article
Beneficial Effects of a Nutraceutical Combination on Lipid Profiles in Children with Moderate and Severe Hypercholesterolemia
by Anastasia Garoufi, Maria Papadaki, Michalis Kalogiannis, Urania Zerva, Marietta Charakida, Antonios Marmarinos and Achilleas Attilakos
Biomolecules 2024, 14(12), 1608; https://doi.org/10.3390/biom14121608 - 16 Dec 2024
Cited by 2 | Viewed by 1677
Abstract
The aim of the present study was to evaluate the efficacy and safety of the long-term use of a dietary supplement containing red yeast rice (RYR), combined with other natural compounds, in children and adolescents with primary hypercholesterolemia. A nutraceutical, containing RYR, policosanols, [...] Read more.
The aim of the present study was to evaluate the efficacy and safety of the long-term use of a dietary supplement containing red yeast rice (RYR), combined with other natural compounds, in children and adolescents with primary hypercholesterolemia. A nutraceutical, containing RYR, policosanols, coenzyme Q10, astaxanthin and folic acid (commercial name: Armolipid), was administered once daily in 84 children/adolescents with moderate or severe primary hypercholesterolemia. Moreover, 19 of the participants consumed 1.5–2.5 g of phytosterols daily until the initiation of dietary supplementation with Armolipid. Clinical and laboratory evaluation took place before and 6 and 16 months after treatment. Nutraceutical consumption resulted in a significant decrease in total cholesterol, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol and apolipoprotein B levels, which was maintained with long-term administration (p < 0.001). No changes were observed in high-density lipoprotein cholesterol, triglycerides, apolipoprotein A1 and lipoprotein (a) levels. In children previously on phytosterol supplementation, Armolipid use exerted a further significant reduction in atherogenic lipoproteins. Armolipid may be an effective and safe complementary treatment for children with moderate and severe hypercholesterolemia. More prospective studies on larger cohorts are needed to establish the role of nutraceuticals containing RYR, policosanols and other natural compounds in the treatment of children with hypercholesterolemia. Full article
(This article belongs to the Special Issue Therapeutic Potential of Natural Products in Metabolic Diseases)
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20 pages, 6959 KB  
Article
Dissecting Cytophagalysin: Structural and Biochemical Studies of a Bacterial Pappalysin-Family Metallopeptidase
by Eva Estevan-Morió, Juan Sebastián Ramírez-Larrota, Enkela Bushi and Ulrich Eckhard
Biomolecules 2024, 14(12), 1604; https://doi.org/10.3390/biom14121604 - 16 Dec 2024
Cited by 1 | Viewed by 1435
Abstract
Cytophaga is a genus of Gram-negative bacteria occurring in soil and the gut microbiome. It is closely related to pathogenic Flavobacterium spp. that cause severe diseases in fish. Cytophaga strain L43-1 secretes cytophagalysin (CPL1), a 137 kDa peptidase with reported collagenolytic and gelatinolytic [...] Read more.
Cytophaga is a genus of Gram-negative bacteria occurring in soil and the gut microbiome. It is closely related to pathogenic Flavobacterium spp. that cause severe diseases in fish. Cytophaga strain L43-1 secretes cytophagalysin (CPL1), a 137 kDa peptidase with reported collagenolytic and gelatinolytic activity. We performed highly-confident structure prediction calculations for CPL1, which identified 11 segments and domains, including a signal peptide for secretion, a prosegment (PS) for latency, a metallopeptidase (MP)-like catalytic domain (CD), and eight immunoglobulin (Ig)-like domains (D3–D10). In addition, two short linkers were found at the D8–D9 and D9–D10 junctions, and the structure would be crosslinked by four disulfide bonds. The CPL1 CD was found closest to ulilysin from Methanosarcina acetivorans, which assigns CPL1 to the lower-pappalysin family within the metzincin clan of MPs. Based on the structure predictions, we aimed to produce constructs spanning the full-length enzyme, as well as PS+CD, PS+CD+D3, and PS+CD+D3+D4. However, we were successful only with the latter three constructs. We could activate recombinant CPL1 by PS removal employing trypsin, and found that both zymogen and mature CPL1 were active in gelatin zymography and against a fluorogenic gelatin variant. This activity was ablated in a mutant, in which the catalytic glutamate described for lower pappalyins and other metzincins was replaced by alanine, and by a broad-spectrum metal chelator. Overall, these results proved that our recombinant CPL1 is a functional active MP, thus supporting the conclusions derived from the structure predictions. Full article
(This article belongs to the Collection Feature Papers in 'Biomacromolecules: Proteins')
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18 pages, 4510 KB  
Article
Determination of Free Fatty Acids in Breast Milk Reveals the Presence of Hydroxypalmitic and Stearic Acids
by Maroula G. Kokotou
Biomolecules 2024, 14(12), 1602; https://doi.org/10.3390/biom14121602 - 14 Dec 2024
Cited by 1 | Viewed by 2844
Abstract
Breast milk is a rich source of fatty acids (FAs) while being irreplaceable for the health and development of an infant. Herein, we present a fast and simple method for the direct detection and quantification of 37 free FAs (FFAs) in breast milk [...] Read more.
Breast milk is a rich source of fatty acids (FAs) while being irreplaceable for the health and development of an infant. Herein, we present a fast and simple method for the direct detection and quantification of 37 free FAs (FFAs) in breast milk samples, avoiding any derivatization step, and a study on the % variation of FA contents in samples collected from the same mother within five consecutive days. The average breakdown of FAs was 60.5% saturated and 39.5% unsaturated, in which polyunsaturated FAs were 13.3% and monounsaturated FAs 26.2%. The most abundant FFA in the breast milk samples was C12:0 (18.3%), followed by C10:0 (15.0%), suggesting that further attention must be paid to the presence and role of medium-chain FAs. Among unsaturated FAs, oleic acid (C18:1 n-9) (13.3%) and linoleic acid (C18:2 n-6) (10.1%) were the most abundant. Remarkable variations of FFA contents within the five consecutive days were observed for C8:0, C10:0, C12:0, C18:1 n-9, and C18:2 n-6. The two isomers α-linolenic acid (C18:3 n-3) and γ-linolenic acid (C18:3 n-6) were quantified in all breast milk samples. The ratio of γ-linolenic acid, which most recently is important for cardiac metabolic maturation, to α-linolenic acid was found to be 1:2. Most importantly, in the present study, we explored the presence of bioactive saturated monohydroxy fatty acids (SHFAs), demonstrating for the first time the existence of distinct hydroxypalmitic and hydroxystearic acids (HPAs and HSAs, respectively) in breast milk. Full article
(This article belongs to the Special Issue Cutting-Edge Research on the Analysis of Small Biomolecules in Foods, Plants, and Biological Samples, 2nd Edition)
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29 pages, 2853 KB  
Review
Notch Signaling and PD-1/PD-L1 Interaction in Hepatocellular Carcinoma: Potentialities of Combined Therapies
by Annapaola Montagner, Andrea Arleo, Fabrizia Suzzi, Antonino B. D’Assoro, Fabio Piscaglia, Laura Gramantieri and Catia Giovannini
Biomolecules 2024, 14(12), 1581; https://doi.org/10.3390/biom14121581 - 11 Dec 2024
Cited by 5 | Viewed by 3088
Abstract
Immunotherapy has shown significant improvement in the survival of patients with hepatocellular carcinoma (HCC) compared to TKIs as first-line treatment. Unfortunately, approximately 30% of HCC exhibits intrinsic resistance to ICIs, making new therapeutic combinations urgently needed. The dysregulation of the Notch signaling pathway [...] Read more.
Immunotherapy has shown significant improvement in the survival of patients with hepatocellular carcinoma (HCC) compared to TKIs as first-line treatment. Unfortunately, approximately 30% of HCC exhibits intrinsic resistance to ICIs, making new therapeutic combinations urgently needed. The dysregulation of the Notch signaling pathway observed in HCC can affect immune cell response, reducing the efficacy of cancer immunotherapy. Here, we provide an overview of how Notch signaling regulates immune responses and present the therapeutic rationale for combining Notch signaling inhibition with ICIs to improve HCC treatment. Moreover, we propose using exosomes as non-invasive tools to assess Notch signaling activation in hepatic cancer cells, enabling accurate stratification of patients who can benefit from combined strategies. Full article
(This article belongs to the Special Issue Cancer Immunotherapy and the PD-1/PD-L1 Checkpoint Pathway)
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19 pages, 6004 KB  
Article
Inhibitory Effects of Cenobamate on Multiple Human Cardiac Ion Channels and Possible Arrhythmogenic Consequences
by Andreea Larisa Mateias, Florian Armasescu, Bogdan Amuzescu, Alexandru Dan Corlan and Beatrice Mihaela Radu
Biomolecules 2024, 14(12), 1582; https://doi.org/10.3390/biom14121582 - 11 Dec 2024
Cited by 2 | Viewed by 2108
Abstract
Cenobamate is a novel third-generation antiepileptic drug used for the treatment of focal onset seizures and particularly for multi-drug-resistant epilepsy; it acts on multiple targets: GABAA receptors (EC50 42–194 µM) and persistent neuronal Na+ currents (IC50 59 µM). Side [...] Read more.
Cenobamate is a novel third-generation antiepileptic drug used for the treatment of focal onset seizures and particularly for multi-drug-resistant epilepsy; it acts on multiple targets: GABAA receptors (EC50 42–194 µM) and persistent neuronal Na+ currents (IC50 59 µM). Side effects include QTc interval shortening with >20 ms, but not <300 ms. Our in vitro cardiac safety pharmacology study was performed via whole-cell patch-clamp on HEK293T cells with persistent/inducible expression of human cardiac ion channel isoforms hNav1.5 (INa), hCav1.2 (α1c + β2 + α2δ1) (ICaL), hKv7.1 + minK (IKs), and hKv11.1 (hERG) (IKr). We found IC50 of 87.6 µM (peak INa), 46.5 µM (late INa), and 509.75 µM (ICaL). In experiments on Ncyte® ventricular cardiomyocytes, APD90 was reduced with 28.6 ± 13.5% (mean ± SD) by cenobamate 200 µM. Cenobamate’s marked inhibition of INa raises the theoretical possibility of cardiac arrhythmia induction at therapeutic concentrations in the context of preexisting myocardial pathology, in the presence of action potential conduction and repolarization heterogeneity. This hypothetical mechanism is consistent with the known effects of class Ib antiarrhythmics. In simulations with a linear strand of 50 cardiomyocytes with variable inter-myocyte conductance based on a modified O’Hara–Rudy model, we found a negligible cenobamate-induced conduction delay in normal tissue, but a marked delay and also a block when gap junction conduction was already depressed. Full article
(This article belongs to the Special Issue New Discoveries in the Field of Neuropharmacology)
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19 pages, 6915 KB  
Article
RIPK4 Downregulation Reduces ABCG2 Expression, Increasing BRAF-Mutated Melanoma Cell Susceptibility to Cisplatin- and Doxorubicin-Induced Apoptosis
by Bartlomiej Olajossy, Norbert Wronski, Ewelina Madej, Joanna Komperda, Małgorzata Szczygieł and Agnieszka Wolnicka-Glubisz
Biomolecules 2024, 14(12), 1573; https://doi.org/10.3390/biom14121573 - 10 Dec 2024
Cited by 2 | Viewed by 1820
Abstract
Melanoma cells remain resistant to chemotherapy with cisplatin (CisPt) and doxorubicin (DOX). The abnormal expression of Receptor-Interacting Protein Kinase 4 (RIPK4) in certain melanomas contributes to tumour growth through the NFκB and Wnt/β-catenin signalling pathways, which are known to regulate chemoresistance and recurrence. [...] Read more.
Melanoma cells remain resistant to chemotherapy with cisplatin (CisPt) and doxorubicin (DOX). The abnormal expression of Receptor-Interacting Protein Kinase 4 (RIPK4) in certain melanomas contributes to tumour growth through the NFκB and Wnt/β-catenin signalling pathways, which are known to regulate chemoresistance and recurrence. Despite this, the role of RIPK4 in response to chemotherapeutics in melanoma has not been reported. In this study, we examined how the downregulation and overexpression of RIPK4 affect the sensitivity of BRAF-mutated melanoma cells (A375 and WM266.4) to CisPt and DOX along with determining the underlying mechanism. Using two RIPK4 silencing methods (siRNA and CRISPR/Cas9) and overexpression (dCas9-VPR), we assessed CisPt and DOX-induced apoptosis using caspase 3/7 activity, annexin V/7AAD staining, and FASC analysis. In addition, qRT-PCR and Western blotting were used to detect apoptosis-related genes and proteins such as cleaved PARP, p53, and cyclin D1. We demonstrated that the overexpression of RIPK4 inhibits, while its downregulation enhances, CisPt- or DOX-induced apoptosis in melanoma cells. The effects of downregulation are similar to those observed with pre-incubation with cyclosporin A, an ABCG2 inhibitor. Additionally, our findings provide preliminary evidence of crosstalk between RIPK4, BIRC3, and ABCG2. The results of these studies suggest the involvement of RIPK4 in the observed resistance to CisPt or DOX. Full article
(This article belongs to the Special Issue Molecular Advances in Drug Resistance and Novel Therapies for Cancer)
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16 pages, 7244 KB  
Article
Disruption of Sex-Linked Sox3 Causes ZW Female-to-Male Sex Reversal in the Japanese Frog Glandirana rugosa
by Ikuo Miura, Yoshinori Hasegawa, Michihiko Ito, Tariq Ezaz and Mitsuaki Ogata
Biomolecules 2024, 14(12), 1566; https://doi.org/10.3390/biom14121566 - 9 Dec 2024
Cited by 1 | Viewed by 7429
Abstract
Sox3 is an ancestral homologous gene of the male-determining Sry in eutherian mammals and determines maleness in medaka fish. In the Japanese frog, Glandirana rugosa, Sox3 is located on the Z and W chromosomes. To assess the sex-determining function of Sox3 in [...] Read more.
Sox3 is an ancestral homologous gene of the male-determining Sry in eutherian mammals and determines maleness in medaka fish. In the Japanese frog, Glandirana rugosa, Sox3 is located on the Z and W chromosomes. To assess the sex-determining function of Sox3 in this frog, we investigated its expression in gonads during early tadpole development and conducted genome-editing experiments. We found that the Sox3 mRNA levels in the gonads/mesonephroi were much higher in ZW females than that in ZZ males, and that the W-borne allele was dominantly expressed. A higher expression in ZW females preceded the onset of the sexually dimorphic expression of other autosomal sex differentiation genes. The Sox3 protein was detected by immunostaining in the somatic cells of early tadpole gonads around the boundary between the medulla and cortex in ZW females, whereas it was outside the gonads in ZZ males. Disrupting Sox3 using TALEN, which targets two distinct sites, generated sex-reversed ZW males and hermaphrodites, whereas no sex reversal was observed in ZZ males. These results suggest that the sex-linked Sox3 is involved in female determination in the ZZ-ZW sex-determining system of the frog, an exact opposite function to the male determination of medaka Sox3y and eutherian Sry. Full article
(This article belongs to the Special Issue Molecular Insights into Sex and Evolution)
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14 pages, 5665 KB  
Article
Sustainable Lipase Immobilization: Chokeberry and Apple Waste as Carriers
by Karina Jasińska, Maksym Nowosad, Aleksander Perzyna, Andrzej Bielacki, Stanisław Dziwiński, Bartłomiej Zieniuk and Agata Fabiszewska
Biomolecules 2024, 14(12), 1564; https://doi.org/10.3390/biom14121564 - 8 Dec 2024
Cited by 4 | Viewed by 1301
Abstract
In the modern world, the principles of the bioeconomy are becoming increasingly important. Recycling and reusability play a crucial role in sustainable development. Green chemistry is based on enzymes, but immobilized biocatalysts are still often designed with synthetic polymers. Insoluble carriers for immobilized [...] Read more.
In the modern world, the principles of the bioeconomy are becoming increasingly important. Recycling and reusability play a crucial role in sustainable development. Green chemistry is based on enzymes, but immobilized biocatalysts are still often designed with synthetic polymers. Insoluble carriers for immobilized biocatalysts, particularly those derived from agro-industrial waste such as mesoporous lignocellulosic materials, offer a promising alternative. By using waste materials as support for enzymes, we can reduce the environmental impact of waste disposal and contribute to the development of efficient bioprocessing technologies. The current study aimed to assess the possibility of using apple and chokeberry pomace as carriers for the immobilization of Palatase 20000L (lipase from Rhizomucor miehei). The analysis of lignocellulosic materials revealed that chokeberry pomace has a higher neutral detergent fiber (NDF) and lignin contents than apple pomace. Moreover, Scanning Electron Microscopy (SEM) observations indicated similar compact structures in both pomaces. The lipase activity assays demonstrated that immobilization of lipase from R. miehei onto apple and chokeberry pomace improves their properties, especially the synthetic activity. The findings highlight the potential of utilizing fruit pomaces not only as a source of bioactive compounds but also in enhancing enzyme stability for industrial applications. Full article
(This article belongs to the Special Issue Recent Advances in the Enzymatic Synthesis of Bioactive Compounds)
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23 pages, 4076 KB  
Article
Lipid Nanoparticles Enable Efficient In Vivo DNA Knock-In via HITI-Mediated Genome Editing
by Jun Hirose, Emi Aizawa, Shogo Yamamoto, Mingyao Xu, Shigenori Iwai and Keiichiro Suzuki
Biomolecules 2024, 14(12), 1558; https://doi.org/10.3390/biom14121558 - 6 Dec 2024
Cited by 1 | Viewed by 3829
Abstract
In vivo genome editing holds great therapeutic potential for treating monogenic diseases by enabling precise gene correction or addition. However, improving the efficiency of delivery systems remains a key challenge. In this study, we investigated the use of lipid nanoparticles (LNPs) for in [...] Read more.
In vivo genome editing holds great therapeutic potential for treating monogenic diseases by enabling precise gene correction or addition. However, improving the efficiency of delivery systems remains a key challenge. In this study, we investigated the use of lipid nanoparticles (LNPs) for in vivo knock-in of ectopic DNA. Our in vitro experiments demonstrated that the homology-independent targeted integration (HITI)-mediated genome-editing method achieved significantly higher knock-in efficiency at the Alb locus in hepatic cells compared to the traditional homology-directed repair (HDR)-mediated approach. By optimizing LNP composition and administration routes, we successfully achieved HITI-mediated GFP knock-in (2.1–2.7%) in the livers of mice through intravenous delivery of LNP-loaded genome editing components. Notably, repeated intravenous dosing led to a twofold increase in liver GFP knock-in efficiency (4.3–7.0%) compared to a single dose, highlighting the potential for cumulative genome editing effects. These findings provide a solid foundation for the use of LNPs in in vivo knock-in strategies, paving the way for future genome-editing therapies. Full article
(This article belongs to the Special Issue Advances in CRISPR/Cas Systems for Genome Editing Applications in Biomedical Research)
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13 pages, 2789 KB  
Article
miRNA Expression: I/R Cardiomyocyte and Sevoflurane
by José Luis Guerrero-Orriach, Maria Dolores Carmona-Luque, Guillermo Quesada Muñoz and Maria Jose Rodriguez Capitán
Biomolecules 2024, 14(12), 1554; https://doi.org/10.3390/biom14121554 - 5 Dec 2024
Cited by 3 | Viewed by 1227
Abstract
Background: The effects of anesthetic drugs on myocardial cells have been a subject of research for the last 50 years. The clinical benefits of halogenated agents, particularly sevoflurane, have been demonstrated in cardiac surgery patients. These benefits are due to the action of [...] Read more.
Background: The effects of anesthetic drugs on myocardial cells have been a subject of research for the last 50 years. The clinical benefits of halogenated agents, particularly sevoflurane, have been demonstrated in cardiac surgery patients. These benefits are due to the action of different enzymes and a variety of molecular pathways mediated by the action of small noncoding RNAs (sRNA) such as microRNAs (miRNAs). However, the modulation potential induced by anesthetic drugs on the miRNA expression and their cardioprotective effects is unknown. Objective: To analyze the variation in the expression of a panel of miRNAs induced by halogenated agents to identify their cardioprotective effects. Aims: Variations in the expression of specific miRNAs induce the potential cardioprotective effects of halogenated agents. Methods: An ischemia/reperfusion (I/R) in vitro model of primary human cardiac myocytes (HCMs) was performed. Four study groups were performed: control group (standard culture conditions), I/R group (without hypnotic drugs exposition), I/R-propofol group (I/R-P), and I/R-sevoflurane group (I/R-S). The secretion of p53 and Akt1 cytokines was quantified in the different cell study groups using an Enzyme-Linked ImmunoSorbent Assay, and the differentially expressed miRNAs were identified carrying out a complete genomic sequencing using the Next Generation Sequencing (NGS). Results: HCMs subjected to the I/R procedure and exposed to sevoflurane showed lower secretion levels of p53 factor and higher levels of Akt-1 cytokine compared to HCMs exposed to propofol (p53: I/R-S: 10.43 ± 0.91 ng/mL; I/R-P: 137.92 ± 7.53 ng/mL; p > 0.05); (Akt1: I/R-S: 0.62 ± 0.12 ng/mL; I/R-P: 0.23 ± 0.05 ng/mL; p > 0.05). The miRNA gene expression analysis (NGS) showed significantly increased expression of the hsa-miR-140-5p and hsa-miR-455-5p, both miRNAs associated with cardiac function; the hsa-miR-98-5p and hsa-miR-193a-5p, both related to apoptosis inhibition; and the hsa-let-7d-5p associated with myocardial protection. This increase was observed in the HCMs group exposed to sevoflurane in comparison to the propofol group. Conclusions: Sevoflurane-induced miRNAs overexpression confers cardioprotection through various mechanisms at the DNA level and the different signaling pathways levels, such as Akt/ERK. Full article
(This article belongs to the Section Molecular Medicine)
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31 pages, 2293 KB  
Review
Role of the Receptor for Advanced Glycation End Products (RAGE) and Its Ligands in Inflammatory Responses
by Kaylen Cross, Stefan W. Vetter, Yousuf Alam, Md. Zahidul Hasan, Anupom Deb Nath and Estelle Leclerc
Biomolecules 2024, 14(12), 1550; https://doi.org/10.3390/biom14121550 - 4 Dec 2024
Cited by 11 | Viewed by 5300
Abstract
Since its discovery in 1992, the receptor for advanced glycation end products (RAGE) has emerged as a key receptor in many pathological conditions, especially in inflammatory conditions. RAGE is expressed by most, if not all, immune cells and can be activated by many [...] Read more.
Since its discovery in 1992, the receptor for advanced glycation end products (RAGE) has emerged as a key receptor in many pathological conditions, especially in inflammatory conditions. RAGE is expressed by most, if not all, immune cells and can be activated by many ligands. One characteristic of RAGE is that its ligands are structurally very diverse and belong to different classes of molecules, making RAGE a promiscuous receptor. Many of RAGE ligands are damaged associated molecular patterns (DAMPs) that are released by cells under inflammatory conditions. Although RAGE has been at the center of a lot of research in the past three decades, a clear understanding of the mechanisms of RAGE activation by its ligands is still missing. In this review, we summarize the current knowledge of the role of RAGE and its ligands in inflammation. Full article
(This article belongs to the Section Biomacromolecules: Proteins, Nucleic Acids and Carbohydrates)
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11 pages, 262 KB  
Review
CXCL13 as a Biomarker: Background and Utility in Multiple Sclerosis
by Andrew R. Pachner, Steven Pike, Andrew D. Smith and Francesca Gilli
Biomolecules 2024, 14(12), 1541; https://doi.org/10.3390/biom14121541 - 30 Nov 2024
Cited by 5 | Viewed by 2889
Abstract
CXCL13 is a chemokine which is upregulated within the CNS in multiple sclerosis, Lyme neuroborreliosis, and other inflammatory diseases and is increasingly clinically useful as a biomarker. This review provides background for understanding its function in the immune system and its relationship to [...] Read more.
CXCL13 is a chemokine which is upregulated within the CNS in multiple sclerosis, Lyme neuroborreliosis, and other inflammatory diseases and is increasingly clinically useful as a biomarker. This review provides background for understanding its function in the immune system and its relationship to ectopic lymphoid follicles. Also reviewed are its utility in multiple sclerosis and Lyme neuroborreliosis and potential problems in its measurement. CXCL13 has the potential to be an exceptionally useful biomarker in a range of inflammatory diseases. Full article
(This article belongs to the Section Molecular Biomarkers)
20 pages, 3445 KB  
Review
Structure and Dynamics of the Bacterial Flagellar Motor Complex
by Shuichi Nakamura and Tohru Minamino
Biomolecules 2024, 14(12), 1488; https://doi.org/10.3390/biom14121488 - 22 Nov 2024
Cited by 9 | Viewed by 5721
Abstract
Many bacteria swim in liquids and move over solid surfaces by rotating flagella. The bacterial flagellum is a supramolecular protein complex that is composed of about 30 different flagellar proteins ranging from a few to tens of thousands. Despite structural and functional diversities [...] Read more.
Many bacteria swim in liquids and move over solid surfaces by rotating flagella. The bacterial flagellum is a supramolecular protein complex that is composed of about 30 different flagellar proteins ranging from a few to tens of thousands. Despite structural and functional diversities of the flagella among motile bacteria, the flagellum commonly consists of a membrane-embedded rotary motor fueled by an ion motive force across the cytoplasmic membrane, a universal joint, and a helical propeller that extends several micrometers beyond the cell surface. The flagellar motor consists of a rotor and several stator units, each of which acts as a transmembrane ion channel complex that converts the ion flux through the channel into the mechanical work required for force generation. The rotor ring complex is equipped with a reversible gear that is regulated by chemotactic signal transduction pathways. As a result, bacteria can move to more desirable locations in response to environmental changes. Recent high-resolution structural analyses of flagella using cryo-electron microscopy have provided deep insights into the assembly, rotation, and directional switching mechanisms of the flagellar motor complex. In this review article, we describe the current understanding of the structure and dynamics of the bacterial flagellum. Full article
(This article belongs to the Section Molecular Biophysics: Structure, Dynamics, and Function)
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50 pages, 3272 KB  
Review
Anti-Diabetic Therapies and Cancer: From Bench to Bedside
by Dimitris Kounatidis, Natalia G. Vallianou, Irene Karampela, Eleni Rebelos, Marina Kouveletsou, Vasileios Dalopoulos, Petros Koufopoulos, Evanthia Diakoumopoulou, Nikolaos Tentolouris and Maria Dalamaga
Biomolecules 2024, 14(11), 1479; https://doi.org/10.3390/biom14111479 - 20 Nov 2024
Cited by 18 | Viewed by 5286
Abstract
Diabetes mellitus (DM) is a significant risk factor for various cancers, with the impact of anti-diabetic therapies on cancer progression differing across malignancies. Among these therapies, metformin has gained attention for its potential anti-cancer effects, primarily through modulation of the AMP-activated protein kinase/mammalian [...] Read more.
Diabetes mellitus (DM) is a significant risk factor for various cancers, with the impact of anti-diabetic therapies on cancer progression differing across malignancies. Among these therapies, metformin has gained attention for its potential anti-cancer effects, primarily through modulation of the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) pathway and the induction of autophagy. Beyond metformin, other conventional anti-diabetic treatments, such as insulin, sulfonylureas (SUs), pioglitazone, and dipeptidyl peptidase-4 (DPP-4) inhibitors, have also been examined for their roles in cancer biology, though findings are often inconclusive. More recently, novel medications, like glucagon-like peptide-1 (GLP-1) receptor agonists, dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists, and sodium-glucose co-transporter-2 (SGLT-2) inhibitors, have revolutionized DM management by not only improving glycemic control but also delivering substantial cardiovascular and renal benefits. Given their diverse metabolic effects, including anti-obesogenic properties, these novel agents are now under meticulous investigation for their potential influence on tumorigenesis and cancer advancement. This review aims to offer a comprehensive exploration of the evolving landscape of glucose-lowering treatments and their implications in cancer biology. It critically evaluates experimental evidence surrounding the molecular mechanisms by which these medications may modulate oncogenic signaling pathways and reshape the tumor microenvironment (TME). Furthermore, it assesses translational research and clinical trials to gauge the practical relevance of these findings in real-world settings. Finally, it explores the potential of anti-diabetic medications as adjuncts in cancer treatment, particularly in enhancing the efficacy of chemotherapy, minimizing toxicity, and addressing resistance within the framework of immunotherapy. Full article
(This article belongs to the Special Issue Nutrition, Metabolism, and Obesity: Novel Strategies and Molecular Mechanisms—Future Perspectives)
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17 pages, 3880 KB  
Article
The Antifungal Potential of Ozonated Extra-Virgin Olive Oil Against Candida albicans: Mechanisms and Efficacy
by Simone Augello, Valentina Cameli, Arianna Montanari, Stefano Tacconi, Daniela Uccelletti, Luciana Dini and Emily Schifano
Biomolecules 2024, 14(11), 1472; https://doi.org/10.3390/biom14111472 - 19 Nov 2024
Cited by 5 | Viewed by 3977
Abstract
The growing emergence of resistance mechanisms and side effects associated with antifungal agents highlight the need for alternative therapies. This study aims to investigate the antifungal potential of ozonated extra-virgin olive oil (EOO) against Candida albicans, with the goal of developing eco-friendly [...] Read more.
The growing emergence of resistance mechanisms and side effects associated with antifungal agents highlight the need for alternative therapies. This study aims to investigate the antifungal potential of ozonated extra-virgin olive oil (EOO) against Candida albicans, with the goal of developing eco-friendly and highly effective treatments based on natural products. Antifungal activity was evaluated via cell viability and biofilm formation assays using Crystal Violet and Sytox green staining. The results showed that EOO reduced C. albicans viability in a dose-dependent manner, achieving over 90% cell death at a 3% (v/v) concentration. Transmission Electron Microscopy (TEM) revealed cell wall structural damage, and ROS levels increased by approximately 60% compared to untreated controls within 10 min of treatment. Additionally, the expression of autophagy-related genes atg-7 and atg-13was upregulated by 2- and 3.5-fold, respectively, after 15 min, suggesting a stress-induced cell death response. EOO also significantly inhibited hyphal formation and biofilm development, thus reducing C. albicans pathogenicity while preserving cell biocompatibility. EOO antifungal activity was also observed in the case of Candida glabrata. In conclusion, ozonated olive oil demonstrates potent antifungal activity against C. albicans by reducing cell viability, inhibiting hyphal and biofilm formation, and triggering oxidative stress and autophagy pathways. These findings position EOO as a promising alternative therapy for fungal infections. Full article
(This article belongs to the Special Issue Molecular Profiling and Identification of Molecular Signatures Associated with Natural Products)
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15 pages, 4388 KB  
Article
Exosomes from Human Periodontal Ligament Stem Cells Promote Differentiation of Osteoblast-like Cells and Bone Healing in Rat Calvarial Bone
by Mhd Safwan Albougha, Hideki Sugii, Orie Adachi, Bara Mardini, Serina Soeno, Sayuri Hamano, Daigaku Hasegawa, Shinichiro Yoshida, Tomohiro Itoyama, Junko Obata and Hidefumi Maeda
Biomolecules 2024, 14(11), 1455; https://doi.org/10.3390/biom14111455 - 17 Nov 2024
Cited by 4 | Viewed by 2934
Abstract
Deep caries and severe periodontitis cause bone resorption in periodontal tissue, and severe bone resorption leads to tooth loss. Periodontal ligament stem cells (PDLSCs) are important for the healing of defective periodontal tissue. It is increasingly understood that healing of periodontal tissue is [...] Read more.
Deep caries and severe periodontitis cause bone resorption in periodontal tissue, and severe bone resorption leads to tooth loss. Periodontal ligament stem cells (PDLSCs) are important for the healing of defective periodontal tissue. It is increasingly understood that healing of periodontal tissue is mediated through the secretion of trophic factors, particularly exosomes. This study investigated the effects of exosomes from human PDLSCs (HPDLSCs-Exo) on human osteoblast-like cells in vitro and on the healing of rat calvarial bone defects in vivo. HPDLSCs-Exo were isolated and characterized by their particle shape, size (133 ± 6.4 nm), and expression of surface markers (CD9, CD63, and CD81). In vitro results showed that HPDLSCs-Exo promoted the migration, mineralization, and expression of bone-related genes such as alkaline phosphatase (ALP), bone morphogenetic protein 2 (BMP2), osteocalcin (OCN), and osteopontin (OPN) in human osteoblast-like cells. Furthermore, in vivo results showed that more newly formed bone was observed in the HPDLSCs-Exo-treated group than in the non-treated group at the defect sites in rats. These results indicated that HPDLSCs-Exo could promote osteogenesis in vitro and in vivo, and this suggests that HPDLSCs-Exo may be an attractive treatment tool for bone healing in defective periodontal tissue. Full article
(This article belongs to the Special Issue Therapeutic Strategies via Skeletal and Mesenchymal Stem Cells in the Cranial and Dental Fields)
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26 pages, 1684 KB  
Review
Ferroptosis in Cancer: Epigenetic Control and Therapeutic Opportunities
by Roberta Veglia Tranchese, Sabrina Battista, Laura Cerchia and Monica Fedele
Biomolecules 2024, 14(11), 1443; https://doi.org/10.3390/biom14111443 - 13 Nov 2024
Cited by 11 | Viewed by 5114
Abstract
Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a critical pathway in cancer biology. This review delves into the epigenetic mechanisms that modulate ferroptosis in cancer cells, focusing on how DNA methylation, histone modifications, and non-coding [...] Read more.
Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a critical pathway in cancer biology. This review delves into the epigenetic mechanisms that modulate ferroptosis in cancer cells, focusing on how DNA methylation, histone modifications, and non-coding RNAs influence the expression and function of essential genes involved in this process. By unraveling the complex interplay between these epigenetic mechanisms and ferroptosis, the article sheds light on novel gene targets and functional insights that could pave the way for innovative cancer treatments to enhance therapeutic efficacy and overcome resistance in cancer therapy. Full article
(This article belongs to the Special Issue New Insights into Essential Genes and Functions)
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