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Biomolecules
Volume 15
Issue 4
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Biomolecules, Volume 15, Issue 4 (April 2025) – 150 articles

Cover Story (view full-size image): The archaellum is a rotary molecular propeller that enables archaea to swim, follow nutrients, evade perils and conquer new habitats. While functionally analogous to bacterial flagella, it is distinct in structure and mechanism. Unlike the bacterial flagellum, which is powered by a proton motive force, the archaellum is driven by ATP hydrolysis. It is composed of protein subunits called archaellins and assembled by a specialised molecular machinery homologous to bacterial type IV pilus systems. Studying its structure and dynamics offers fresh insight into the evolutionary divergence of motility systems and inspires innovation in nanotechnology and molecular engineering. View this paper
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7 pages, 647 KiB  
Perspective
RNA-Mediated Non-Mendelian Inheritance in Mice: The Power of Memory
by Minoo Rassoulzadegan
Biomolecules 2025, 15(4), 605; https://doi.org/10.3390/biom15040605 - 21 Apr 2025
Viewed by 137
Abstract
The mouse genome is transcribed at different rates in both directions from the newly formed genome after fertilization. During embryonic genomic activation (EGA/ZGA), the first RNA metabolism creates heterogeneity between blastomeres. Indeed, ZGA-dependent maternal RNA degradation is crucial to regulate gene expression and [...] Read more.
The mouse genome is transcribed at different rates in both directions from the newly formed genome after fertilization. During embryonic genomic activation (EGA/ZGA), the first RNA metabolism creates heterogeneity between blastomeres. Indeed, ZGA-dependent maternal RNA degradation is crucial to regulate gene expression and enable the initiation and acquisition of full developmental competence. Subsequently, from the new genome, in addition to mRNAs, a wide range of regulatory ncRNAs are also transcribed. Regulatory ncRNAs (non-coding RNAs) have profoundly influenced fields ranging from developmental biology to RNA-mediated non-Mendelian inheritance, exhibiting sequence-specific functions. To date, the database cataloging ncRNA is not exhaustive, but their high sequence diversity, length and low expression level can vary within the same genome depending on environmental conditions, making understanding their functions often ambiguous. Indeed, during transcription control, cellular RNA content varies continuously. This phenomenon is observed in genetically identical organisms studied—bacteria, flies, plants and mammals—due to changes in transcription rates, and therefore, it impacts cellular memory. Importantly, experimental data regarding the simple modification of RNAs levels by microinjection into fertilized mouse eggs suggest that they certainly play a driving role in establishing and transmitting newly formed expression information. The idea here is that, even in a stable genome, transcripts can vary rapidly and significantly in response to environmental changes, initiated by transcriptional variations in the genome, thus altering cellular memory. Full article
(This article belongs to the Section Molecular Genetics)
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16 pages, 12866 KiB  
Article
Regeneration of Two-Walled Infrabony Periodontal Defects in Swine After Buccal Fat Pad-Derived Dedifferentiated Fat Cell Autologous Transplantation
by Daisuke Akita, Naoki Tsukimura, Tomohiko Kazama, Rie Takahashi, Yoshiki Taniguchi, Jin Inoue, Ayana Suzuki, Nodoka Tanabe, Keisuke Seki, Yoshinori Arai, Masatake Asano, Shuichi Sato, Yoshiyuki Hagiwara, Koichiro Kano, Masaki Honda and Taro Matsumoto
Biomolecules 2025, 15(4), 604; https://doi.org/10.3390/biom15040604 - 20 Apr 2025
Viewed by 164
Abstract
Mature adipocyte-derived dedifferentiated fat (DFAT) cells show proliferative capabilities and multipotency. Given that the buccal fat pad (BFP) serves as a readily available resource for DFAT cell isolation, BFP-derived DFAT (BFP-DFAT) cells are a promising candidate in orofacial tissue engineering. In this research, [...] Read more.
Mature adipocyte-derived dedifferentiated fat (DFAT) cells show proliferative capabilities and multipotency. Given that the buccal fat pad (BFP) serves as a readily available resource for DFAT cell isolation, BFP-derived DFAT (BFP-DFAT) cells are a promising candidate in orofacial tissue engineering. In this research, we assessed the regenerative capacity of the periodontium through autologous BFP-DFAT cell transplantation in adult swine (micro-minipigs; MMPs). The BFP-DFAT cells were transplanted into inflammation-inducing two-walled infrabony periodontal defects located on the mesial of the second mandibular premolar (n = 6). Twelve weeks post-transplantation, a remarkable attachment gain was noted in the DFAT group, based on probing depths and clinical attachment levels. Histological and immunohistochemical analyses indicated new continuous cellular cementum and alveolar bone formation within the created infrabony defect. Well-organized periodontal ligament-like fibers were embedded between newly formed cementum and the alveolar bone. Histometric analysis demonstrated that the DFAT group had a 2.2-fold increase in new alveolar bone length and a 2.2-fold enhancement in vascularization than those in the control group. Except for minor inflammation in the lungs, no teratomas were detected in the recipient MMPs. BFP-DFAT cells significantly enhanced periodontal tissue regeneration, thus representing an optimal source for tissue engineering applications in dentistry. Full article
(This article belongs to the Special Issue Biologics and Biomaterials for Periodontal Treatment: Current and Future Challenges)
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15 pages, 3023 KiB  
Article
Link N Directly Targets IL-1β to Suppress Inflammation and Regulate Sensory Pain in Intervertebral Disc Degeneration
by Michael P. Grant, Muskan Alad, Fajer Yousef, Laura M. Epure, John Antoniou and Fackson Mwale
Biomolecules 2025, 15(4), 603; https://doi.org/10.3390/biom15040603 - 19 Apr 2025
Viewed by 243
Abstract
Intervertebral disc (IVD) disease is typically characterized by the degradation of IVD tissue, secretion of inflammatory and painful factors, and hyperinnervation of the disc. The pro-inflammatory cytokine interleukin-1β (IL-1β) has been regarded as a principal factor in orchestrating disc degeneration. Link N (LN) [...] Read more.
Intervertebral disc (IVD) disease is typically characterized by the degradation of IVD tissue, secretion of inflammatory and painful factors, and hyperinnervation of the disc. The pro-inflammatory cytokine interleukin-1β (IL-1β) has been regarded as a principal factor in orchestrating disc degeneration. Link N (LN) is a peptide derived from the link protein that has been shown to promote extracellular disc regeneration even in an inflammatory milieu; however, no mechanism(s) has been described for their behaviour to date. Building on prior studies on LN, we hypothesize that LN directly inhibits IL-1β. IVD degeneration was experimentally induced in New Zealand white rabbits, followed by the injection of either sLN or saline as the vehicle control. To determine the expression of markers of pain, histology was performed. Cultured human Nucleus Pulposus disc cells (hNP) were used to determine the effects of LN on IL-1β-induced changes in gene expression, including the effects on IL-1β, TNFα, and IL6 signalling. Isolated murine dorsal root ganglia (DRG) neurons were used to assess the effect of LN on IL-1β-induced neuronal hyperactivity. LN significantly reduced IL-1β-induced NF-κB activation in a dose-dependent manner in disc cells and was further able to modulate IL-1β-induced gene expression, inflammatory mediators, and neurotrophic factors. Peptide docking simulations revealed that LN could interact with IL-1β. A direct interaction of LN and IL-1β was revealed through co-immunoprecipitation experiments. Although IL-1β was able to hypersensitize DRG neurons following a seven-day exposure, as demonstrated by Ca2+ imaging, this effect was significantly blunted when co-treated with LN. LN demonstrates a novel mechanism of action by directly inhibiting IL-1β, in addition to mitigating IL-1β-induced hypersensitivity in DRG neurons. These data suggest a potential role for LN in reducing discogenic pain. Full article
(This article belongs to the Section Molecular Medicine)
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17 pages, 3557 KiB  
Article
The Role of Antigen Carbohydrate 125 in Modulating Soluble ST2: Prognostic-Related Effects in Acute Heart Failure
by Arancha Martí-Martínez, Julio Núñez, Herminio López-Escribano, Elena Revuelta-López, Anna Mollar, Marta Peiró, Juan Sanchis, Antoni Bayés-Genís, Arturo Carratala, Òscar Miró, Pere Llorens and Pablo Herrero-Puente
Biomolecules 2025, 15(4), 602; https://doi.org/10.3390/biom15040602 - 18 Apr 2025
Viewed by 190
Abstract
Background: Acute heart failure (AHF) is a complex syndrome associated with high mortality and hospital readmissions, characterized by volume overload and inflammation. Soluble ST2 (sST2) and antigen carbohydrate 125 (CA125) are emerging biomarkers that reflect these processes and may interact to influence long-term [...] Read more.
Background: Acute heart failure (AHF) is a complex syndrome associated with high mortality and hospital readmissions, characterized by volume overload and inflammation. Soluble ST2 (sST2) and antigen carbohydrate 125 (CA125) are emerging biomarkers that reflect these processes and may interact to influence long-term outcomes in AHF patients. This study aims to examine the prognostic relationship between sST2 and CA125 in predicting mortality and heart failure (HF)-related hospitalizations in patients with decompensated heart failure. Methods: In a cohort of 635 patients with AHF, we investigated whether the prognostic value of sST2 varies according to CA125 levels (≤35 vs. >35 U/mL). The endpoints were: (a) time to all-cause death, and (b) the combination of time to death or new HF admission. Results: This study of EAHFE registry data shows that the association between sST2 and long-term adverse outcomes (mortality and HF hospitalizations) in patients with AHF was differentially influenced by CA125 concentrations (p-value for interactions = 0.031 and 0.029, respectively). Higher sST2 was associated with the risk of death and the combined risk of death/HF readmission when CA125 was >35 U/mL [HR = 1.02 (CI 95%: 1.01–1.04), p = 0.006 and 1.02 (CI 95%: 1.01–1.03); p = 0.013 per increase in 10 ng/mL, respectively], but not when CA125 was ≤35 U/mL. Conclusions: This study highlights the prognostic interaction between sST2 and CA125 in AHF. Elevated sST2 predicts poor outcomes mainly in patients with high CA125 levels (>35 U/mL), suggesting CA125’s role in modulating inflammatory activity in HF. Further research is needed. Full article
(This article belongs to the Special Issue Chronic Heart Failure: From Molecular Mechanisms to Therapies Strategies)
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22 pages, 7835 KiB  
Article
Identification of TSSK1 and TSSK2 as Novel Targets for Male Contraception
by Saman Nayyab, Marıá Gracia Gervasi, Darya A. Tourzani, Yeva Shamailova, Hiroki Akizawa, Mahboubeh Taghavi, Wei Cui, Rafael Fissore, Ana Maria Salicioni, Gunda I. Georg, Elizabeth Snyder and Pablo E. Visconti
Biomolecules 2025, 15(4), 601; https://doi.org/10.3390/biom15040601 - 18 Apr 2025
Viewed by 233
Abstract
The testis-specific serine kinases (TSSKs) are post-meiotically expressed in testicular germ cells. Their testis-specific expression, together with their putative role in phosphorylation pathways, suggests that TSSKs have relevant roles in spermiogenesis, sperm function, or both. Independent Tssk3 and Tssk6 knockout mice, as well [...] Read more.
The testis-specific serine kinases (TSSKs) are post-meiotically expressed in testicular germ cells. Their testis-specific expression, together with their putative role in phosphorylation pathways, suggests that TSSKs have relevant roles in spermiogenesis, sperm function, or both. Independent Tssk3 and Tssk6 knockout mice, as well as the double Tssk1/Tssk2 KO males, are sterile. However, the double KO results are silent regarding the individual roles of TSSK1 and TSSK2. The aim of this study was to develop independent mutant mouse models of Tssk1 and Tssk2, using CRISPR/Cas9, to evaluate their independent roles in reproduction. Male heterozygous pups were used to establish one Tssk1 and two independent Tssk2 mutant lines. Natural mating mutant Tssk1 and Tssk2 homozygous males but not females were found to be sterile. Additionally, homozygous males have lower sperm numbers and decreased motility, and were infertile in vitro. Anti-TSSK2 antibodies were validated against Tssk2 mutants and used in Western blot and immunofluorescence experiments. TSSK2 is localized to the sperm head; importantly, it is present in the testes and sperm from Tssk1 mutant mice, confirming individual mutation. Our results indicate that both TSSK1 and TSSK2 are individually essential for male reproduction and support both kinases as suitable nonhormonal male contraceptive targets. Full article
(This article belongs to the Collection Feature Papers in Section 'Molecular Medicine')
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19 pages, 2854 KiB  
Article
Sex-Specific Inflammatory Profiles Affect Neuropsychiatric Issues in COVID-19 Survivors
by Mariagrazia Palladini, Mario Gennaro Mazza, Beatrice Bravi, Margherita Bessi, Maria Cristina Lorenzi, Sara Spadini, Rebecca De Lorenzo, Patrizia Rovere-Querini, Roberto Furlan and Francesco Benedetti
Biomolecules 2025, 15(4), 600; https://doi.org/10.3390/biom15040600 - 18 Apr 2025
Viewed by 429
Abstract
Post-COVID syndrome has unveiled intricate connections between inflammation, depressive psychopathology, and cognitive impairment. This study investigates these relationships in 101 COVID-19 survivors, focusing on sex-specific variations. Utilizing path modelling techniques, we analyzed the interplay of a one-month 48-biomarker inflammatory panel, with three-months of [...] Read more.
Post-COVID syndrome has unveiled intricate connections between inflammation, depressive psychopathology, and cognitive impairment. This study investigates these relationships in 101 COVID-19 survivors, focusing on sex-specific variations. Utilizing path modelling techniques, we analyzed the interplay of a one-month 48-biomarker inflammatory panel, with three-months of depressive symptoms and cognitive performance. The findings indicate that cognitive impairment is influenced by both inflammation and depression in the overall cohort. However, prominent sex-specific differences emerged. In females, a lingering imbalance between pro- and anti-inflammatory responses—likely reflecting the long-lasting immune alterations triggered by COVID-19—significantly affects cognitive functioning and shows a marginal, though not statistically significant, association with depressive symptoms. This suggests that a mixed inflammatory profile may contribute to these outcomes. Conversely, in males, inflammation was inversely associated with depression severity, with protective effects from regulatory mediators (IL-2, IL-4, IL-6, IL-15, LIF, TNF-α, β-NGF) against depression. In males, cognitive impairment appeared to be driven mainly by depressive symptoms, with minimal influence from inflammatory markers. These results highlight distinct sex-specific pathways in immune and inflammatory responses post-COVID-19, potentially shaped by endocrine mechanisms. The findings suggest that persistent inflammation may foster long-term neuropsychiatric sequelae, possibly through its effects on the brain, and underscore the need for sex-tailored therapeutic strategies to address the lasting impact of COVID-19. Full article
(This article belongs to the Section Biological Factors)
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23 pages, 2666 KiB  
Article
Progression and Augmentation Therapy in PiSZ and PiZZ Alpha-1 Antitrypsin Deficiency: A Longitudinal Functional and Densitometric Study
by Soha Esmaili, Juan Luis Rodríguez Hermosa, Gianna Vargas Centanaro, José Luis Álvarez-Sala, Iman Esmaili and Myriam Calle Rubio
Biomolecules 2025, 15(4), 599; https://doi.org/10.3390/biom15040599 - 17 Apr 2025
Viewed by 263
Abstract
Background: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder associated with an increased risk of developing chronic obstructive pulmonary disease (COPD) with variable phenotypic expression among different genotypes. While the PiZZ genotype is well characterized, the clinical and structural progression of PiSZ individuals [...] Read more.
Background: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder associated with an increased risk of developing chronic obstructive pulmonary disease (COPD) with variable phenotypic expression among different genotypes. While the PiZZ genotype is well characterized, the clinical and structural progression of PiSZ individuals remains less defined. This study evaluates genotype-specific disease trajectories and the impact of augmentation therapy over a two-year follow-up. Methods: A prospective observational cohort study was conducted, including 74 AATD patients (41 PiSZ, 33 PiZZ), stratified by augmentation therapy status. Disease progression was assessed through lung function decline (forced expiratory volume in one second [FEV1], diffusing capacity for carbon monoxide [DLCO], carbon monoxide transfer coefficient [KCO]) and densitometric changes (15th percentile lung density [PD-15], percentage of lung voxels below −950 Hounsfield units [HU-950]). Mixed-effects models and multivariable regression analyses were performed to evaluate genotype-specific progression patterns and treatment effects. Results: Results: PiZZ individuals exhibited significantly greater annual decline in lung function and densitometric parameters compared to PiSZ individuals, with more pronounced loss in basal lung regions and with greater decline in advanced stages, in contrast to the PiSZ genotype, which showed greater progression in earlier stages. Augmentation therapy was associated with a significant reduction in PD-15 decline in both genotypes, with the greatest benefit observed in PiZZ patients and in those diagnosed within five years of disease onset. Smoking and frequent exacerbations were identified as independent risk factors for accelerated disease progression. Conclusions: PiZZ individuals experience a more aggressive disease trajectory than PiSZ individuals in the absence of treatment. Augmentation therapy effectively mitigates disease progression in both genotypes, with greater efficacy when initiated early. Smoking and frequent exacerbations were identified as independent risk factors for accelerated disease progression. These findings underscore the importance of genotype-specific monitoring and personalized therapeutic strategies in AATD to optimize clinical outcomes. Full article
(This article belongs to the Section Biomacromolecules: Proteins, Nucleic Acids and Carbohydrates)
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23 pages, 1177 KiB  
Review
Matrix Metalloproteinases: Pathophysiologic Implications and Potential Therapeutic Targets in Cardiovascular Disease
by Daniela Maria Tanase, Emilia Valasciuc, Ioana-Bianca Anton, Evelina Maria Gosav, Nicoleta Dima, Andrei Ionut Cucu, Claudia Florida Costea, Diana Elena Floria, Loredana Liliana Hurjui, Claudia Cristina Tarniceriu, Manuela Ciocoiu and Mariana Floria
Biomolecules 2025, 15(4), 598; https://doi.org/10.3390/biom15040598 - 17 Apr 2025
Viewed by 315
Abstract
Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that play a crucial role in extracellular matrix (ECM) remodeling and are implicated in the pathogenesis of various cardiovascular diseases (CVDs). Their dysregulation has been linked to atherosclerosis, myocardial infarction (MI), heart failure (HF), [...] Read more.
Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that play a crucial role in extracellular matrix (ECM) remodeling and are implicated in the pathogenesis of various cardiovascular diseases (CVDs). Their dysregulation has been linked to atherosclerosis, myocardial infarction (MI), heart failure (HF), and aortic stenosis, contributing to vascular inflammation, plaque destabilization, and adverse cardiac remodeling. Recent research highlights MMPs’ involvement beyond ECM degradation, influencing lipoprotein metabolism, inflammatory signaling, and intracellular processes critical for cardiovascular homeostasis. Despite their pathological role, MMPs remain promising therapeutic targets, with pharmacological inhibitors, gene therapy, and tissue inhibitors of metalloproteinases (TIMPs) emerging as potential interventions. However, the clinical translation of MMP-targeting therapies remains challenging due to off-target effects and complex regulatory mechanisms. This review provides an updated synthesis of the molecular mechanisms, disease-specific roles, and therapeutic implications of MMPs in cardiovascular pathology, aiming to bridge the gap between fundamental research and clinical applications. Full article
(This article belongs to the Special Issue Role of Matrix Metalloproteinase in Health and Disease)
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14 pages, 1928 KiB  
Article
Diagnostic Utility of Bronchoalveolar Lavage Flow Cytometric Leukocyte Profiling in Interstitial Lung Disease and Infection
by Erika M. Novoa-Bolivar, José A. Ros, Sonia Pérez-Fernández, José A. Campillo, Ruth López-Hernández, Rosana González-López, Inmaculada Ruiz-Lorente, Almudena Otálora-Alcaraz, Cristina Ortuño-Hernández, Lourdes Gimeno, Diana Ceballos-Francisco, Manuel Muro, Elena Solana-Martínez, Pablo Martínez-Camblor and Alfredo Minguela
Biomolecules 2025, 15(4), 597; https://doi.org/10.3390/biom15040597 - 17 Apr 2025
Viewed by 200
Abstract
Interstitial lung diseases (ILD) represent a diverse group of disorders that primarily affect the pulmonary interstitium and, less commonly, involve the alveolar and vascular epithelium. Overlapping clinical, radiological and histopathological features make proper classification difficult, requiring multiple complementary methodologies, including flow cytometry of [...] Read more.
Interstitial lung diseases (ILD) represent a diverse group of disorders that primarily affect the pulmonary interstitium and, less commonly, involve the alveolar and vascular epithelium. Overlapping clinical, radiological and histopathological features make proper classification difficult, requiring multiple complementary methodologies, including flow cytometry of bronchoalveolar lavages (BAL). This retrospective study analyzed BAL flow cytometry data from 1074 real-life patients, quantifying alveolar macrophages, CD4/CD8 lymphocytes, neutrophils, eosinophils, and CD1a+ Langerhans cells, with the aim of evaluating its diagnostic utility in ILD and pulmonary infection. Clustering and logistic regression analyses identified seven distinct leukocyte profiles: lymphocytic (associated with hypersensitivity pneumonitis, cryptogenic organizing pneumonia, and lymphocytic interstitial pneumonia), sarcoidosis, macrophagic (including nonspecific interstitial pneumonia, desquamative interstitial pneumonitis, pneumoconiosis, and unclassifiable ILD), neutrophilic (including usual interstitial pneumonia, respiratory bronchiolitis ILD, and acute interstitial pneumonia), infectious diseases, eosinophilic ILD, and Langerhans cell histiocytosis. The estimated leukocyte profiles were associated with different overall survival (OS) outcomes. Neutrophilic profiles, both infectious and non-infectious, correlated with poorer OS, particularly in patients without pulmonary fibrosis. Furthermore, corticosteroids and other immunosuppressive therapies did not show significant OS differences across leukocyte profiles. Although the gold standard in BAL cytology continues to be cytopathology, these results support BAL flow cytometry as a rapid and reliable complementary tool to aid in the classification of interstitial lung diseases based on immune cell profiles, providing valuable predictive information and contributing to personalized therapeutic approaches. Full article
(This article belongs to the Special Issue Immune-Related Biomarkers: 2nd Edition)
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26 pages, 2942 KiB  
Review
HPMA Copolymers: A Versatile Platform for Targeted Peptide Drug Delivery
by Ya Li, Liangda Xing, Mingliang Zhu, Xian Li, Fangfang Wei, Wenyan Sun and Yinnong Jia
Biomolecules 2025, 15(4), 596; https://doi.org/10.3390/biom15040596 - 17 Apr 2025
Viewed by 315
Abstract
Peptide drugs have been broadly applied in cancer treatment and diagnosis due to their ability to accurately identify biomarkers with good biocompatibility. However, their clinical application is limited by protease degradation, which induces short circulation half-life, low bioavailability, and high renal clearance. In [...] Read more.
Peptide drugs have been broadly applied in cancer treatment and diagnosis due to their ability to accurately identify biomarkers with good biocompatibility. However, their clinical application is limited by protease degradation, which induces short circulation half-life, low bioavailability, and high renal clearance. In recent years, delivery systems based on nanomaterial technology have become an important strategy to break through the bottleneck of peptide drug delivery. Among them, N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers have attracted much attention due to their good biocompatibility, hydrophilicity, and low immunogenicity. The high molecular weight of HPMA copolymer–peptide can circumvent renal clearance, significantly prolong the circulation time in the body, and achieve drug accumulation and microenvironment-triggered release synergistically with EPR effects and active targeting. This review introduces the basic properties of HPMA copolymers, including solubility, biocompatibility, and tunable chemical structure. The important applications of HPMA copolymer–peptide in tumor diagnosis and treatment are discussed. This review deepens our understanding of the future development of HPMA copolymers and will provide more references for improving peptides by simple copolymers. Full article
(This article belongs to the Special Issue Experimental and Theoretical Approaches to Protein-Targeting Drug Discovery: 2nd Edition)
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18 pages, 4306 KiB  
Article
Development of an Optimized Two-Step Solid-Phase Extraction Method for Urinary Nucleic Acid Adductomics
by Alexandra Keidel, Jazmine Virzi, Laura Deloso, Carolina Möller, Dale Chaput, Theresa Evans-Nguyen, Yuan-Jhe Chang, Mu-Rong Chao, Chiung-Wen Hu and Marcus S. Cooke
Biomolecules 2025, 15(4), 594; https://doi.org/10.3390/biom15040594 - 17 Apr 2025
Viewed by 255
Abstract
The exposome represents the totality of endogenous and exogenous exposures across the lifespan. These exposures may result in DNA and RNA damage, in the form of adducts, which is a key factor in the etiology of a variety of human diseases, including cancer. [...] Read more.
The exposome represents the totality of endogenous and exogenous exposures across the lifespan. These exposures may result in DNA and RNA damage, in the form of adducts, which is a key factor in the etiology of a variety of human diseases, including cancer. It is understood that, following their repair, nucleic acid adducts are excreted into the urine, making urine an ideal, non-invasive matrix in which to study the whole-body nucleic acid adductome (the totality of nucleic acid adducts). However, the measurement of these adducts in urine presents challenges due to matrix interference and the variety of the chemical nature across the spectrum of nucleic adducts making their “one-size-fits-all” extraction by solid-phase extraction (SPE) challenging. Here, different types of SPE sorbents, and their combination, were evaluated for maximal recovery of nucleic acid adducts from urine. The SPE column combination of ENV+ coupled with PHE provided the best retention of a cocktail of 20 nucleic acid adduct standards. An untargeted high resolution mass spectrometry approach incorporating FeatureHunter 1.3 software was used to demonstrate the ability of this SPE method to successfully recover endogenous urinary nucleic acid adducts in addition to those represented by the cocktail of isotopically labeled standards. Using our approach, FeatureHunter 1.3 recognized approximately 500 adducts in both mouse and human urine samples. Isotopically labeled standards were used to identify a selection of the endogenous adducts and begin the characterization of the urinary nucleic acid adductome of mice and humans. Full article
(This article belongs to the Special Issue Recent Advances in Adduct Science)
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18 pages, 846 KiB  
Review
Recent Stem-Cell-Based and Stem-Cell-Free Possibilities for the Therapeutic Management of the Osteonecrosis of the Jaw
by Merita Mazreku, L’uboš Danišovič, Martin Klein and Mária Kleinová
Biomolecules 2025, 15(4), 595; https://doi.org/10.3390/biom15040595 - 16 Apr 2025
Viewed by 213
Abstract
Osteonecrosis of the jaw (ONJ), including the maxilla and mandible, is considered a challenging therapeutic problem, mainly due to the lack of understanding of its pathogenesis. It is well known that ONJ is a severe side effect caused by certain medications used to [...] Read more.
Osteonecrosis of the jaw (ONJ), including the maxilla and mandible, is considered a challenging therapeutic problem, mainly due to the lack of understanding of its pathogenesis. It is well known that ONJ is a severe side effect caused by certain medications used to treat bone metastasis and osteoporosis, such as bisphosphonates, which inhibit bone resorption. Other therapeutics with similar side effects are, for instance, receptor activators of nuclear factor kappa-B ligand (RANK-L) inhibitor (denosumab), tyrosine kinase inhibitors (sunitinib), and antiangiogenics (bevacizumab). The conservative or surgical treatment of these medication-related osteonecroses of the jaw (MRONJs) is generally effortful and still not entirely effective. Therefore, the research seeks alternative treatment options like tissue engineering and stem cell therapy, which predominantly represent mesenchymal stem cells (MSCs) and their derivatives, such as extracellular vesicles. Moreover, it was published that novel stem cell therapy could even prevent the onset of MRONJ. On the other hand, the administration of stem cells may also be accompanied by some other health risks, such as an increased chance of cancer metastasis occurrence in cancer patients. The current review paper summarizes the most recent progress in stem-cell-based and stem-cell-free treatment options for the ONJ. Similarly, we discuss this novel approach’s future perspectives and possible obstacles. Full article
(This article belongs to the Special Issue Stem Cells in Musculoskeletal Tissue Engineering)
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17 pages, 3351 KiB  
Article
Fungal Warriors: Effects of Beauveria bassiana and Purpureocillium lilacinum on CCYV-Carrying Whiteflies
by Dan Zhai, Hang Lu, Suyao Liu, Jialei Liu, Wanyu Zhang, Jingjing Wu, Jingjing Li, Rune Bai, Fengming Yan and Chenchen Zhao
Biomolecules 2025, 15(4), 593; https://doi.org/10.3390/biom15040593 - 16 Apr 2025
Viewed by 245
Abstract
Bemisia tabaci is a major agricultural pest that affects both greenhouse and field crops by feeding on plant sap, which impairs plant growth, and by secreting honeydew, promotes sooty mold growth that further reduces photosynthesis. Additionally, these insects are vectors for viruses such [...] Read more.
Bemisia tabaci is a major agricultural pest that affects both greenhouse and field crops by feeding on plant sap, which impairs plant growth, and by secreting honeydew, promotes sooty mold growth that further reduces photosynthesis. Additionally, these insects are vectors for viruses such as the cucurbit chlorotic yellows virus (CCYV), which causes significant damage to cucurbit crops. Traditional chemical pesticide treatments have limitations, including the development of resistance, harm to non-target organisms, and environmental contamination. Traditional chemical pesticides have limitations when it comes to controlling plants infested by CCYV and whitefly. However, the underlying reasons for these limitations remain unclear, as does the impact of entomopathogenic fungi on whitefly responses. This study explores the potential of using biological control agents, specifically Beauveria bassiana and Purpureocillium lilacinum, to manage whitefly populations and control CCYV transmission. Laboratory experiments were conducted to evaluate the pathogenicity of these fungi on non/viruliferous whitefly. The results indicated that both fungi effectively reduced whitefly populations, with B. bassiana showing particularly strong adverse effects. Whiteflies infected with CCYV exhibited a higher LC50 to B. bassiana and P. lilacinum. Furthermore, bio-pesticides significantly altered the bacterial microbiome dynamics of the whitefly. Interestingly, CCYV increased the susceptibility of whiteflies to entomopathogenic fungus. The findings suggest that these biocontrol agents offer a sustainable alternative to chemical pesticides. Our study unraveled a new horizon for the multiple interaction theories among bio-pesticides–insects–symbionts–viruses. Full article
(This article belongs to the Special Issue Microbial Biocontrol and Plant-Microbe Interactions)
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16 pages, 3419 KiB  
Article
[18F]Mefway: Imaging Serotonin 5HT1A Receptors in Human Postmortem Alzheimer’s and Parkinson’s Disease Anterior Cingulate. Potential Applications to Human Positron Emission Tomography Studies
by Noresa L. Gonzaga, Fariha Karim, Christopher Liang and Jogeshwar Mukherjee
Biomolecules 2025, 15(4), 592; https://doi.org/10.3390/biom15040592 - 16 Apr 2025
Viewed by 214
Abstract
Serotonin 5HT1A receptors may be affected in neurodegeneration, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Using the selective 5HT1A receptor positron emission tomography (PET) imaging agent, [18F]mefway, autoradiographic studies from postmortem human brains of AD, PD, and [...] Read more.
Serotonin 5HT1A receptors may be affected in neurodegeneration, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Using the selective 5HT1A receptor positron emission tomography (PET) imaging agent, [18F]mefway, autoradiographic studies from postmortem human brains of AD, PD, and cognitively normal (CN) subjects were carried out. Levels of [18F]mefway binding were compared with monoamine oxidase A (MAO-A) measured using [18F]FAZIN3 binding and dopamine D2/D3 receptors measured using [18F]fallypride binding in the same subjects. Autoradiograms of brain sections of the anterior cingulate and corpus callosum from CN, PD, and AD subjects (n = 6 in each group) were analyzed. Significant increased binding of [18F]mefway was found in the AD (+30%) and PD (+11%) brains compared to CN brains. This increase positively correlated to increased [18F]FAZIN3 binding, suggesting greater 5HT1A receptor availability when MAO-A levels are higher. Differences in [18F]fallypride binding in the three groups were not significant. Our results support the finding that the availability of 5HT1A receptors in AD and PD is elevated in the anterior cingulate cortex and is negatively correlated with MAO-A. This upregulation may potentially be a response to lower serotonin levels due to the increased levels of MAO-A activity in this brain region or other neuroinflammatory changes. Thus, 5HT1A receptors may be a potential target for diagnostic and therapeutic approaches for AD and PD. Full article
(This article belongs to the Special Issue Biomolecular Approaches and Drugs for Neurodegeneration—2nd Edition)
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19 pages, 15873 KiB  
Article
Molecular Basis of Dipeptide Recognition in Drosophila melanogaster Angiotensin I-Converting Enzyme Homologue, AnCE
by Joanna Żukowska, Kyle S. Gregory, Adam Robinson, R. Elwyn Isaac and K. Ravi Acharya
Biomolecules 2025, 15(4), 591; https://doi.org/10.3390/biom15040591 - 16 Apr 2025
Viewed by 246
Abstract
Human angiotensin-I-converting enzyme (ACE) is involved in vasoregulation, inflammation, and neurodegenerative disorders. The enzyme is formed of two domains; the C-domain (cACE) is primarily involved in blood pressure regulation, whereas the N-domain (nACE) is strongly linked to fibrosis; hence, designing domain-specific inhibitors could [...] Read more.
Human angiotensin-I-converting enzyme (ACE) is involved in vasoregulation, inflammation, and neurodegenerative disorders. The enzyme is formed of two domains; the C-domain (cACE) is primarily involved in blood pressure regulation, whereas the N-domain (nACE) is strongly linked to fibrosis; hence, designing domain-specific inhibitors could make a difference between treating one condition without having a negative effect on another. AnCE (a close homologue of ACE) is derived from Drosophila melanogaster and has a high similarity specifically to cACE. Due to high similarity and ease of crystallisation, AnCE has been chosen as a model protein for ACE studies and for the design of ACE inhibitors. In this study, enzyme kinetic assays and X-ray crystallography techniques revealed the significance of using dipeptides as selective inhibitors for AnCE and how this knowledge could be applied to cACE and nACE. All the dipeptides tested in this study were shown to bind AnCE in two distinct locations, i.e., the non-prime and prime subsites. It was found that a hydrophobic residue at the S1 and S1′ subsites, with a tryptophan at the S2 and S2′ subsites, showed highest affinity towards AnCE. It was also observed that a key pocket within the S2′ subsite had a major influence on the binding orientation within the prime subsites and could potentially explain ACE’s dipeptidyl carboxypeptidase activity. Importantly these dipeptides are found in functional foods, making them potentially available from diets. Knowledge of the dipeptide binding presented here could aid in the development of ACE domain-specific inhibitors. Full article
(This article belongs to the Section Molecular Biophysics: Structure, Dynamics, and Function)
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33 pages, 15037 KiB  
Article
Persea americana Peel: A Promising Source of Nutraceutical for the Mitigation of Cardiovascular Risk in Arthritic Rats Through the Gut–Joint Axis
by Doha A. Mohamed, Asmaa A. Ramadan, Hoda B. Mabrok, Gamil E. Ibrahim and Shaimaa E. Mohammed
Biomolecules 2025, 15(4), 590; https://doi.org/10.3390/biom15040590 - 16 Apr 2025
Viewed by 275
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by the inflammation of synovial fluid. The incidence of cardiovascular diseases (CVDs) is increasing in RA patients. This research is the first report to investigate the anti-arthritic effect of avocado peel nutraceutical (APN) [...] Read more.
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by the inflammation of synovial fluid. The incidence of cardiovascular diseases (CVDs) is increasing in RA patients. This research is the first report to investigate the anti-arthritic effect of avocado peel nutraceutical (APN) and its potential in mitigating the cardiovascular risk associated with RA. The antioxidant activity and phytochemical composition of APN were assessed. The potential interaction of APN’s active compounds with protein tyrosine phosphatase non-receptor type 22 (PTPN22) was studied using molecular docking. The impact of APN on the plasma lipid profile, oxidative and inflammatory markers, and the indices of coronary risk and atherogenicity as CVD markers were evaluated. The gene expression of COX-2, IL-6, IL-1β, IL-10, and TNF-α in liver and spleen tissues were measured. The rat gut microbiota profile was investigated using 16S rRNA amplicon sequencing. APN exhibited high antioxidant activity, low atherogenicity and thrombogenicity indices, and a high ratio of hypocholesterolemic to hypercholesterolemic fatty acids indicating its cardioprotective potential. The administration of APN led to a reduction in oxidative stress markers, inflammatory markers, dyslipidemia, and CVD markers. APN administration downregulated the expression of COX-2, IL-6, IL-1β, and TNF-α genes, while the IL-10 gene was significantly upregulated in the liver and spleen. Treatment with APN was favorable in restoring eubiosis in the gut by modulating RA-associated bacterial taxa linked to impaired immune function and cardiometabolic diseases. In molecular docking, β-amyrin and ellagic acid showed the highest binding affinity for PTPN22. APN may represent a promising approach to ameliorating the cardiovascular risk of RA. The present results will be offering a foundation for future in-depth research in nutraceuticals from agriculture by-products. Additionally, they will be supporting the public health policies aimed at preventing and controlling rheumatoid arthritis. Full article
(This article belongs to the Section Molecular Medicine)
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12 pages, 1002 KiB  
Review
Optimizing Immunotherapy: The Synergy of Immune Checkpoint Inhibitors with Artificial Intelligence in Melanoma Treatment
by Mohammad Saleem, Abigail E. Watson, Aisha Anwaar, Ahmad Omar Jasser and Nabiha Yusuf
Biomolecules 2025, 15(4), 589; https://doi.org/10.3390/biom15040589 - 16 Apr 2025
Viewed by 332
Abstract
Immune checkpoint inhibitors (ICIs) have transformed melanoma treatment; however, predicting patient responses remains a significant challenge. This study reviews the potential of artificial intelligence (AI) to optimize ICI therapy in melanoma by integrating various diagnostic tools. Through a comprehensive literature review, we analyzed [...] Read more.
Immune checkpoint inhibitors (ICIs) have transformed melanoma treatment; however, predicting patient responses remains a significant challenge. This study reviews the potential of artificial intelligence (AI) to optimize ICI therapy in melanoma by integrating various diagnostic tools. Through a comprehensive literature review, we analyzed studies on AI applications in melanoma immunotherapy, focusing on predictive modeling, biomarker identification, and treatment response prediction. Key findings highlight the efficacy of AI in improving ICI outcomes. Machine learning models successfully identified prognostic cytokine signatures linked to nivolumab clearance. The combination of AI with RNAseq analysis had the potential for the development of personalized treatment with ICIs. A machine learning-based approach was able to assess the risk-benefit ratio for the prediction of immune-related adverse events (irAEs) using the electronic health record (EHR) data. Deep learning algorithms demonstrated high accuracy in tumor microenvironment analysis, including tumor region identification and lymphocyte detection. AI-assisted quantification of tumor-infiltrating lymphocytes (TILs) proved prognostically valuable in primary melanoma and predictive of anti-PD-1 therapy response in metastatic cases. Integrating multiple diagnostic modalities, such as CT imaging and laboratory data, modestly enhanced predictive performance for 1-year survival in advanced cancers treated with immunotherapy. These findings underscore the potential of AI-driven approaches to refine biomarker identification, treatment prediction, and patient stratification in melanoma immunotherapy. While promising, clinical validation and implementation challenges remain. Full article
(This article belongs to the Special Issue Cancer Immunotherapy and the PD-1/PD-L1 Checkpoint Pathway)
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24 pages, 2704 KiB  
Article
Valproate Damaging Effect on Erythrocyte Metabolism as a Decisive Factor in the Development of Encephalopathy
by Lyudmila Tikhonova, Eugene Maevsky, Carmina Montoliu and Elena Kosenko
Biomolecules 2025, 15(4), 588; https://doi.org/10.3390/biom15040588 - 15 Apr 2025
Viewed by 322
Abstract
Background: Valproic acid (VPA) is a mainstay of treatment for epilepsy. Although VPA is generally considered well tolerated, it has serious adverse effects related to the pathological impact on cerebral perfusion and oxidative metabolism, leading to progressive encephalopathy. Erythrocytes directly deliver oxygen to [...] Read more.
Background: Valproic acid (VPA) is a mainstay of treatment for epilepsy. Although VPA is generally considered well tolerated, it has serious adverse effects related to the pathological impact on cerebral perfusion and oxidative metabolism, leading to progressive encephalopathy. Erythrocytes directly deliver oxygen to the tissues. To understand how the brain pathology may be related to limited oxygenation, it is important to determine whether VPA-related changes occur in the intracellular erythrocyte metabolism responsible for the oxygen transport function. Methods: To determine whether different therapeutic VPA doses affect major metabolic pathways in rat erythrocytes, the activity of rate-limiting enzymes and levels of metabolites of glycolysis, the Rapoport–Luebering shunt, the pentose phosphate pathway and the antioxidant systems were measured. Results: Our data showed that VPA-induced G6PD inhibition leads to profound oxidative stress, increased MetHb formation and decreased 2,3-DPG and ATP levels in erythrocytes that underlie the loss of their oxygen transport function, thus being a cause of a brain energy crisis that precedes encephalopathy. Conclusions: The measurement of parameters in metabolic pathways modulating the redox-signaling and oxygen-carrying capacity of erythrocytes is needed for further elucidation of complex mechanisms underlying VPA-induced brain hypoperfusion and encephalopathy. Full article
(This article belongs to the Section Cellular Biochemistry)
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54 pages, 4709 KiB  
Review
Exosomal Biomarkers: A Comprehensive Overview of Diagnostic and Prognostic Applications in Malignant and Non-Malignant Disorders
by Mahda Delshad, Mohammad-Javad Sanaei, Mohammad Hossein Mohammadi, Amir Sadeghi and Davood Bashash
Biomolecules 2025, 15(4), 587; https://doi.org/10.3390/biom15040587 - 15 Apr 2025
Viewed by 557
Abstract
Exosomes are small extracellular vesicles, ranging from 30 to 150 nm, that are essential in cell biology, mediating intercellular communication and serving as biomarkers due to their origin from cells. Exosomes as biomarkers for diagnosing various illnesses have gained significant investigation due to [...] Read more.
Exosomes are small extracellular vesicles, ranging from 30 to 150 nm, that are essential in cell biology, mediating intercellular communication and serving as biomarkers due to their origin from cells. Exosomes as biomarkers for diagnosing various illnesses have gained significant investigation due to the high cost and invasive nature of current diagnostic procedures. Exosomes have a clear advantage in the diagnosis of diseases because they include certain signals that are indicative of the genetic and proteomic profile of the ailment. This feature gives them the potential to be useful liquid biopsies for real-time, noninvasive monitoring, enabling early cancer identification for the creation of individualized treatment plans. According to our analysis, the trend toward utilizing exosomes as diagnostic and prognostic tools has raised since 2012. In this regard, the proportion of malignant indications is higher compared with non-malignant ones. To be precise, exosomes have been used the most in gastrointestinal, thoracic, and urogenital cancers, along with cardiovascular, diabetic, breathing, infectious, and brain disorders. To the best of our knowledge, this is the first research to examine all registered clinical trials that look at exosomes as a diagnostic and prognostic biomarker. Full article
(This article belongs to the Section Molecular Biomarkers)
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20 pages, 2562 KiB  
Review
Vitamin D and Acute Kidney Injury: A Reciprocal Relationship
by Chandrashekar Annamalai and Pragasam Viswanathan
Biomolecules 2025, 15(4), 586; https://doi.org/10.3390/biom15040586 - 15 Apr 2025
Viewed by 398
Abstract
Vitamin D is a sterol prohormone with no intrinsic biological activity. Calcitriol, the active form of vitamin D, is synthesized in the kidneys. It has well-known pleiotropic and cytoprotective properties. In addition to regulating parathyroid hormone secretion and enhancing gut calcium absorption, it [...] Read more.
Vitamin D is a sterol prohormone with no intrinsic biological activity. Calcitriol, the active form of vitamin D, is synthesized in the kidneys. It has well-known pleiotropic and cytoprotective properties. In addition to regulating parathyroid hormone secretion and enhancing gut calcium absorption, it exhibits antioxidant, anti-inflammatory, antiproliferative, and antineoplastic effects. However, the role of vitamin D in AKI is unclear, unlike in CKD. Thus, this review aimed to understand how dysregulated vitamin D homeostasis occurs in AKI, as well as to explore how vitamin D deficiency and excess influence AKI. A comprehensive literature search was conducted between January 2000 and June 2024 to uncover relevant works detailing vitamin D homeostasis in health as well as investigating the impact of vitamin D deficiency and excess in humans, animals, and in vitro cell models of AKI. According to the findings of this review, vitamin D appears to have a reciprocal relationship with AKI. Acute renal injury, among other factors, can cause hypo- or hypervitaminosis D. Conversely, AKI can also be caused by vitamin D deficiency and toxicity. Even though hypovitaminosis D is associated with AKI, it is uncertain how it impacts AKI outcomes in distinct clinical scenarios. Newer therapeutic options might emerge as a result of understanding these challenges. Vitamin D supplementation may ameliorate renal injury but needs further validation. Furthermore, hypervitaminosis D has also been implicated in AKI by causing hypercalcemia and hyperphosphatemia. It is crucial to avoid prolonged, uncontrolled, and unsupervised supraphysiological vitamin D administration, especially intramuscular injection. Full article
(This article belongs to the Special Issue Recent Trends in Kidney and Cardiovascular Diseases)
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22 pages, 4981 KiB  
Article
A Novel Phosphorylated Tau Conformer Implicated in the Tauopathy Pathogenesis of Human Neurons
by Nahid Tofigh, Sadaf Agahi, Gholamhossein Riazi, Mahboobeh Ghalamkar Moazzam and Koorosh Shahpasand
Biomolecules 2025, 15(4), 585; https://doi.org/10.3390/biom15040585 - 15 Apr 2025
Viewed by 279
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder with no effective treatments. Hyperphosphorylation of tau protein contributes to neurodegeneration in AD. Previous studies have identified pT231-tau in the cis conformation as an early driver of neurodegeneration in tauopathy models. Here, we identify a novel [...] Read more.
Alzheimer’s disease (AD) is a neurodegenerative disorder with no effective treatments. Hyperphosphorylation of tau protein contributes to neurodegeneration in AD. Previous studies have identified pT231-tau in the cis conformation as an early driver of neurodegeneration in tauopathy models. Here, we identify a novel neurotoxic pT231-tau conformer in human AD neurons, distinct from both cis and trans conformations, which we propose as the gauche pT231-tau conformer. Notably, levels of this conformer were elevated in neurons subjected to aging-associated stress. In order to confirm the stress, we examined p21 accumulation in both human iPSC-derived and mouse cortical neurons under aging stress. Targeted elimination of the gauche pT231-tau conformer mitigated neurodegeneration in human AD cultures. These findings suggest the gauche pT231-tau conformer plays a key role in tau-mediated neurodegeneration and may be a potential therapeutic target for AD. Full article
(This article belongs to the Special Issue Pathogenesis and Neuropathology of Alzheimer's Disease)
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15 pages, 2264 KiB  
Article
Germline PDCDL1 Gene Variants Are Associated with Increased Primary Melanoma Thickness
by Elizabeth Córdoba-Lanús, Omar García-Pérez, Leticia Melgar-Vilaplana, Angélica Domínguez-de-Barros and Ricardo Fernández-de-Misa
Biomolecules 2025, 15(4), 584; https://doi.org/10.3390/biom15040584 - 15 Apr 2025
Viewed by 203
Abstract
Background: The incidence of malignant melanoma (MM) continues to increase annually, and tumour invasiveness is a main prognostic factor. Single-nucleotide polymorphisms (SNPs) have become key tools in the study of cancer genetics, influencing susceptibility and prognosis. Methods: In the present study, [...] Read more.
Background: The incidence of malignant melanoma (MM) continues to increase annually, and tumour invasiveness is a main prognostic factor. Single-nucleotide polymorphisms (SNPs) have become key tools in the study of cancer genetics, influencing susceptibility and prognosis. Methods: In the present study, we analysed the relationship between five SNPs on the PDCDL1 gene (rs822336, rs822337, rs822338, rs229736, rs4143815) with prognosis as well as primary tumour invasiveness characteristics in 377 whole blood samples from MM individuals. Results: Patients who presented the rs822336 CG or GG genotypes (OR = 3.01, 95% CI = 1.53–5.92; p = 0.0017), TA or TT in rs822337 (OR = 2.45, 95% CI = 1.22–4.93; p = 0.0098), and CT or CC of rs822338 (OR = 2.23, 95% CI = 1.05–4.73; p = 0.028) were at an increased risk of developing invasive melanomas. Cases with the AG or GG genotype in rs2297136 presented a lower risk (OR = 0.29, 95% CI = 0.11–0.75; p = 0.0038) of invasive MM. The genetic analysis at the haplotype level resulted in similar findings (OR: 2.95, 95% CI: 1.08–8.10), p = 0.036). Furthermore, patients carrying the homozygous AA genotype in rs2297136 had thicker tumours than those harbouring the AG or GG (1.4 mm vs. 1.0 and 0.8 mm; p = 0.030). No significant association was found between the studied SNPs and melanoma-specific survival (MSS) nor progression-free survival (PFS). Conclusions: Current results suggest that SNPs rs822336, rs822337, rs822338, and rs2297136 genotypes in the PDCDL1 gene are associated with the risk of tumour invasiveness and tumour thickness in MM. Further studies on SNPs considering genetic and epigenetic factors are needed for a better understanding of malignant melanoma susceptibility and its prognosis. Full article
(This article belongs to the Special Issue Cancer Immunotherapy and the PD-1/PD-L1 Checkpoint Pathway)
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23 pages, 8974 KiB  
Article
Plasma Exosomal Proteomics Identifies Differentially Expressed Proteins as Biomarkers for Acute Myocardial Infarction
by Jie Zhou, Hai-Tao Hou, Huan-Xin Chen, Yu Song, Xiao-Lin Zhou, Li-Li Zhang, Hong-Mei Xue, Qin Yang and Guo-Wei He
Biomolecules 2025, 15(4), 583; https://doi.org/10.3390/biom15040583 - 15 Apr 2025
Viewed by 242
Abstract
Myocardial infarction (MI), including ST-elevation MI (STEMI) and non-ST-elevation MI (NSTEMI), has been the leading cause of hospitalization and death. Exosomes participate in many physiological and pathological processes and have important effects on cell communication and function. This study analyzed the proteomic characteristics [...] Read more.
Myocardial infarction (MI), including ST-elevation MI (STEMI) and non-ST-elevation MI (NSTEMI), has been the leading cause of hospitalization and death. Exosomes participate in many physiological and pathological processes and have important effects on cell communication and function. This study analyzed the proteomic characteristics of plasma exosomes with the discovery of exosomal differentially expressed proteins (DEPs) in MI patients. Proteomics technology was used to identify the plasma exosomal DEPs in 41 patients in STEMI, NSTEMI, unstable angina, and CONTROL groups, and 406 exosomal DEPs were discovered. Further, 36 selected exosomal DEPs were validated with parallel reaction monitoring (PRM) in a new cohort of STEMI, NSTEMI, and CONTROL groups, and 7 were successfully verified. There were three (F13A1, TSPAN33, and YWHAZ) in the STEMI group and six (F13A1, TSPAN33, ITGA2B, GP9, GP5, and PPIA) in the NSTEMI group, and all were down-regulated compared to the CONTROL group with high sensitivity and specificity in MI that may be developed as biomarkers for MI and may become possible therapeutic targets for MI. Bioinformatics analysis revealed that these seven exosomal DEPs are of great significance in the molecular mechanism of MI. Therefore, the present study has provided insights to further explore the pathological mechanism and possible therapeutic targets in MI. Full article
(This article belongs to the Section Biomacromolecules: Proteins, Nucleic Acids and Carbohydrates)
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16 pages, 1222 KiB  
Article
A Pangenomic Approach to Improve Population Genetics Analysis and Reference Bias in Underrepresented Middle Eastern and Horn of Africa Populations
by Adrien Oliva, Rachel Foare, Peter Campbell, Natalie A. Twine, Denis C. Bauer and Angad Singh Johar
Biomolecules 2025, 15(4), 582; https://doi.org/10.3390/biom15040582 - 15 Apr 2025
Viewed by 692
Abstract
Genomics plays a crucial role in addressing health disparities, yet most studies rely on the hg38 linear reference genome, limiting the potential of pangenomic approaches, particularly for underrepresented populations. In this study, we focus on characterising East African populations, particularly Somalis, by constructing [...] Read more.
Genomics plays a crucial role in addressing health disparities, yet most studies rely on the hg38 linear reference genome, limiting the potential of pangenomic approaches, particularly for underrepresented populations. In this study, we focus on characterising East African populations, particularly Somalis, by constructing a variation graph using Mozabites from the Human Genome Diversity Project (HGDP) given their ancestral affinity with Somalis. We evaluated the effectiveness of this graph-based reference in estimating effective population sizes (Ne) in Bedouins compared to the hg38 reference and examined its impact on allele frequencies and genome-wide association studies (GWAS). Applying a coalescent model to the graph-based reference produced a Ne estimate of approximately 17 for the Bedouin population, which was significantly lower than the estimate from the hg38 reference (approximately 79,000). Only the graph-based estimate fell within the 95% confidence interval in simulations, indicating improved accuracy. Moreover, graph variants exhibited significantly lower allele frequencies (p-value < 2.2 × 10−16), suggesting potential effects on the interpretation and power of GWAS. Notably, GWAS variants specific to Bedouins derived from the graph showed lower frequencies (p = 0.023) than those obtained from the linear reference. These findings suggest that a pangenomic approach, informed by populations with ancestral affinities such as the Mozabites, provides more accurate estimates of Ne and allele frequencies. This highlights the importance of pangenomic strategies to better capture genetic diversity in underrepresented populations, a critical step towards improving population genetics studies, personalised medicine, and equitable healthcare. Full article
(This article belongs to the Special Issue The Genomics Era: From Reference Genomes to Pan-Genomic Approach, 2nd Edition)
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15 pages, 6772 KiB  
Article
Melatonin MT1 Receptor Expression in Luminal Invasive Ductal Breast Carcinoma in Postmenopausal Women
by Leda Pistiolis, Sahar Alawieh, Thorhildur Halldorsdottir, Anikó Kovács and Roger Olofsson Bagge
Biomolecules 2025, 15(4), 581; https://doi.org/10.3390/biom15040581 - 15 Apr 2025
Viewed by 264
Abstract
Laboratory and animal studies indicate that melatonin exerts a negative impact on breast cancer progression and metastasis. These actions are both receptor-dependent and -independent. Of the two transmembrane melatonin receptors identified in humans, breast cancer expresses only MT1. The aim of this study [...] Read more.
Laboratory and animal studies indicate that melatonin exerts a negative impact on breast cancer progression and metastasis. These actions are both receptor-dependent and -independent. Of the two transmembrane melatonin receptors identified in humans, breast cancer expresses only MT1. The aim of this study was to investigate the expression of MT1 in hormone-receptor-positive, HER2-negative invasive ductal breast carcinoma in postmenopausal women and its possible correlations with clinicopathological parameters and survival. A total of 118 patients with luminal A/B primary breast cancer with or without axillary metastases were identified. The MT1 receptor expression was immunohistochemically assessed as a percentage of stained cells and a weighted index (WI) (percentage multiplied by staining intensity). Most tumor samples (84.7%) and metastasized lymph nodes (96%) stained positive for MT1, with varying intensity. No statistically significant correlations were found between the MT1 expression or the WI in the primary tumor and the patient and tumor characteristics, or the MT1 and WI in the metastasized lymph nodes. The survival analysis did not reveal a significant effect of MT1 expression or the WI on the risk of recurrence or survival. Full article
(This article belongs to the Special Issue Melatonin in Normal Physiology and Disease, 2nd Edition)
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34 pages, 3038 KiB  
Review
Not Just an Alternative Energy Source: Diverse Biological Functions of Ketone Bodies and Relevance of HMGCS2 to Health and Disease
by Varshini V. Suresh, Sathish Sivaprakasam, Yangzom D. Bhutia, Puttur D. Prasad, Muthusamy Thangaraju and Vadivel Ganapathy
Biomolecules 2025, 15(4), 580; https://doi.org/10.3390/biom15040580 - 14 Apr 2025
Viewed by 440
Abstract
Ketogenesis, a mitochondrial metabolic pathway, occurs primarily in liver, but kidney, colon and retina are also capable of this pathway. It is activated during fasting and exercise, by “keto” diets, and in diabetes as well as during therapy with SGLT2 inhibitors. The principal [...] Read more.
Ketogenesis, a mitochondrial metabolic pathway, occurs primarily in liver, but kidney, colon and retina are also capable of this pathway. It is activated during fasting and exercise, by “keto” diets, and in diabetes as well as during therapy with SGLT2 inhibitors. The principal ketone body is β-hydroxybutyrate, a widely recognized alternative energy source for extrahepatic tissues (brain, heart, muscle, and kidney) when blood glucose is sparse or when glucose transport/metabolism is impaired. Recent studies have identified new functions for β-hydroxybutyrate: it serves as an agonist for the G-protein-coupled receptor GPR109A and also works as an epigenetic modifier. Ketone bodies protect against inflammation, cancer, and neurodegeneration. HMGCS2, as the rate-limiting enzyme, controls ketogenesis. Its expression and activity are regulated by transcriptional and post-translational mechanisms with glucagon, insulin, and glucocorticoids as the principal participants. Loss-of-function mutations occur in HMGCS2 in humans, resulting in a severe metabolic disease. These patients typically present within a year after birth with metabolic acidosis, hypoketotic hypoglycemia, hepatomegaly, steatotic liver damage, hyperammonemia, and neurological complications. Nothing is known about the long-term consequences of this disease. This review provides an up-to-date summary of the biological functions of ketone bodies with a special focus on HMGCS2 in health and disease. Full article
(This article belongs to the Special Issue Research on Fatty Acid Oxidation and Fatty Acid Oxidation Disorders)
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30 pages, 2591 KiB  
Review
Exploring the Roles of Liver X Receptors in Lipid Metabolism and Immunity in Atherosclerosis
by Kaori Endo-Umeda and Makoto Makishima
Biomolecules 2025, 15(4), 579; https://doi.org/10.3390/biom15040579 - 14 Apr 2025
Viewed by 348
Abstract
Hypercholesterolemia causes atherosclerosis by inducing immune cell migration and chronic inflammation in arterial walls. Recent single-cell analyses reveal the presence of lipid-enriched foamy macrophages, as well as other macrophage subtypes, neutrophils, T cells, and B cells, in atherosclerotic plaques in both animal models [...] Read more.
Hypercholesterolemia causes atherosclerosis by inducing immune cell migration and chronic inflammation in arterial walls. Recent single-cell analyses reveal the presence of lipid-enriched foamy macrophages, as well as other macrophage subtypes, neutrophils, T cells, and B cells, in atherosclerotic plaques in both animal models and humans. These cells interact with each other and other cells, including non-immune cells such as endothelial cells and smooth muscle cells. They thereby regulate metabolic, inflammatory, phagocytic, and cell death processes, thus affecting the progression and stability of atherosclerotic plaques. The nuclear receptors liver X receptor (LXR)α and LXRβ are transcription factors that are activated by oxysterols and regulate lipid metabolism and immune responses. LXRs regulate cholesterol homeostasis by controlling cholesterol’s transport, absorption, synthesis, and breakdown in the liver and intestine. LXRs are also highly expressed in tissue-resident and monocyte-derived macrophages and other immune cells, including both myeloid cells and lymphocytes, and they regulate both innate and adaptive immune responses. Interestingly, LXRs have immunosuppressive and immunoregulatory functions that are cell-type-dependent. In animal models of atherosclerosis, LXRs have been shown to be involved in both progression and regression phases. The pharmacological activation of LXR enhances cholesterol efflux from macrophages and promotes atherosclerosis progression. Deleting LXR in immune cells, especially myeloid cells, accelerates atherosclerosis by increasing monocyte migration, macrophage proliferation and activation, and neutrophil extracellular traps (NETs); furthermore, the deletion of hematopoietic LXRs impairs the regression of atherosclerotic plaques. Therefore, LXRs in immune cells may be a potent therapeutic target for atherosclerosis. Full article
(This article belongs to the Special Issue Advances in Liver X Receptors)
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12 pages, 989 KiB  
Communication
Synthesis and Antiproliferative Effects of Grossheimin-Derived Aminoanalogues
by Meruyert Ashimbayeva, Zsolt Szakonyi, Sergazy M. Adekenov, Nikoletta Szemerédi, Gabriella Spengler and Tam Minh Le
Biomolecules 2025, 15(4), 578; https://doi.org/10.3390/biom15040578 - 14 Apr 2025
Viewed by 294
Abstract
Grossheimin, a guaiane-type sesquiterpene lactone, displayed a diverse range of biological activities, including anticancer, anti-inflammatory and antimicrobial effects. Various amino analogues of grossheimin were prepared through a Michael addition at its highly active α-methylene-γ-lactone motif. On the other hand, grossheimin was reduced to [...] Read more.
Grossheimin, a guaiane-type sesquiterpene lactone, displayed a diverse range of biological activities, including anticancer, anti-inflammatory and antimicrobial effects. Various amino analogues of grossheimin were prepared through a Michael addition at its highly active α-methylene-γ-lactone motif. On the other hand, grossheimin was reduced to diol, which was then subjected to nucleophilic addition or acetylation to introduce heteroatoms associated with oxygen, sulfur or nitrogen functionalities. All of the synthesised Michael and acetylated adducts were evaluated for their in vitro cytotoxic action on human colon adenocarcinoma lines, including Colo205 and Colo320. The bioassay results indicated that the acetylated adducts displayed a potent cytotoxic effect compared to grossheimin, the parent molecule. A docking study was also performed to exploit the observed results. Full article
(This article belongs to the Special Issue Recent Advances in the Isolation, Chemical and Biological Characterization and Synthesis of Bioactive Metabolites from Plants)
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17 pages, 6352 KiB  
Article
The B22 Dilemma: Structural Basis for Conformational Differences in Proinsulin B-Chain Arg22 Mutants
by Srivastav Ranganathan and Anoop Arunagiri
Biomolecules 2025, 15(4), 577; https://doi.org/10.3390/biom15040577 - 12 Apr 2025
Viewed by 299
Abstract
Proinsulin has three distinct regions: the well-folded A- and B-chains and the dynamic disordered C-peptide. The highly conserved B-chain is a hotspot for diabetes-associated mutations, including the severe loss-of-function R(B22)Q mutation linked to childhood-onset diabetes. Here, we explore R(B22)’s role in proinsulin stability [...] Read more.
Proinsulin has three distinct regions: the well-folded A- and B-chains and the dynamic disordered C-peptide. The highly conserved B-chain is a hotspot for diabetes-associated mutations, including the severe loss-of-function R(B22)Q mutation linked to childhood-onset diabetes. Here, we explore R(B22)’s role in proinsulin stability using AlphaFold-predicted structures and metadynamics simulations to achieve enhanced sampling of the free energy landscape. Our results show that R(B22) stabilizes proinsulin by interacting with N86. Substituting R(B22) with E or Q disrupts this interaction, increasing conformational flexibility. The R(B22)Q variant exhibits a flattened free energy landscape, favoring unfolded states. Additional substitutions, including Gly, Ala, Lys, Tyr, Asp, and Phe, destabilize proinsulin to varying extents by weakening hydrogen bonding. Disrupting the R(B22)–N86 interaction broadly reduces inter-chain contacts, raising the risk of aggregation-prone states. Given the link between R(B22) mutations and diabetes, our study provides crucial molecular insights into proinsulin instability. These findings highlight the role of key inter-domain (A-Chain–B-chain, B-Chain–C-peptide, and A-Chain–C-peptide) interactions in maintaining protein structures and the implications this has for understanding disease-associated proinsulin variants. Full article
(This article belongs to the Special Issue Protein Self-Assembly in Diseases and Function)
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Systematic Review
Etiologies of Multidrug-Resistant Epilepsy in Latin America: A Comprehensive Review of Structural, Genetic, Metabolic, Inflammatory, and Infectious Origins: A Systematic Review
by Mario S. Hinojosa-Figueroa, Mishell Cruz-Caraguay, Alejandro Torres Pasquel, Vanesa Puga Rosero, Camila Belen Eguiguren Chavez, Jose A. Rodas and Jose E. Leon-Rojas
Biomolecules 2025, 15(4), 576; https://doi.org/10.3390/biom15040576 - 12 Apr 2025
Viewed by 361
Abstract
Epilepsy is a prevalent neurological disorder that affects millions worldwide, with a significant portion of individuals experiencing drug-resistant forms of the condition. In Latin America, the challenge of identifying the underlying causes of multidrug-resistant epilepsy (MDRE) is particularly pressing. (1) Background: This systematic [...] Read more.
Epilepsy is a prevalent neurological disorder that affects millions worldwide, with a significant portion of individuals experiencing drug-resistant forms of the condition. In Latin America, the challenge of identifying the underlying causes of multidrug-resistant epilepsy (MDRE) is particularly pressing. (1) Background: This systematic review aims to highlight the critical importance of understanding the etiology of MDRE in Latin America. (2) Methods: A systematic review of Medline (PubMed), Scopus, and Web of Science was conducted following the PRISMA methodology; articles were selected if they included information on the etiology of MDRE in Latin-American participants, and the NHLBI tool was used to assess bias. (3) Results: A total of 37 published articles were finally included in the review. The most frequently documented cause of drug-resistant epilepsy was structural, affecting 725 patients, with hippocampal atrophy and sclerosis predominantly involving both the right and left lobes. The second most common cause was genetic, identified in 362 individuals who exhibited polymorphisms in genes such as ABCB1, CYP2C9, SCN1A, SLC6A4, and MDR-1, among others. The third most frequent cause was metabolic, and the fourth was inflammatory, affecting 258 individuals, which was associated with various inflammatory markers, including IL-1β, IL-6, CD8+, CD-25, and HLA-DR. Finally, infectious causes were also reported. (4) Conclusions: Structural causes are the leading etiology of MDRE in Latin America, followed by genetic, metabolic, inflammatory, and infectious origins. The regional pattern contrasts with findings from Europe and Asia, highlighting the influence of socioeconomic, environmental, and population-specific genetic factors. Our findings underscore the urgent need for regionally tailored research and interventions, particularly in understudied areas such as infectious causes and neuroinflammation. Full article
(This article belongs to the Special Issue Molecular Biomarkers of Epileptogenesis)
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