Biomedicines

14 pages, 2681 KB

Open AccessArticle

Ethylbenzene Exposure and Bronchoalveolar CD4/CD8 T Cells in Hypersensitivity Pneumonitis Development and Clinical Outcome

by Alfredo Minguela, José A. Campillo, María Isabel Aguilar Sanchís, Antonia Baeza Caracena, Francisco Esquembre, Erika M. Novoa-Bolivar, Rosana González-López, Almudena Otalora, Cristina Ortuño-Hernández, Ruth López-Hernández, Lourdes Gimeno, Inmaculada Ruiz-Lorente, Diana Ceballos, Elena Solana-Martínez, Juan Alcántara-Fructuoso, Manuel Muro and José A. Ros

Biomedicines 2025, 13(11), 2611; https://doi.org/10.3390/biomedicines13112611 (registering DOI) - 24 Oct 2025

Abstract

Background: Hypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) characterized by inflammation of the lung parenchyma, alveoli and bronchioles induced by inhalation of organic compounds. Bird-related-HP (BRHP) is the most common type of HP, occurring in susceptible people in regular contact with [...] Read more.

Background: Hypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) characterized by inflammation of the lung parenchyma, alveoli and bronchioles induced by inhalation of organic compounds. Bird-related-HP (BRHP) is the most common type of HP, occurring in susceptible people in regular contact with birds, although a genetic susceptibility is unclear. This study investigates the impact of environmental volatile organic compounds (VOCs) on the development of HP and other pulmonary diseases, and their relationship with pulmonary inflammatory cell composition and patient outcomes. Methods: Geospatial environmental levels of VOCs (benzene, toluene, ethylbenzene, m,p-xylene and o-xylene) in patients’ homes were related to bronchoalveolar lavage (BAL) leukocyte profiles analyzed by flow cytometry of 1515 patients with different lung diseases in the region of Murcia (southeastern Spain). Results: Ethylbenzene levels over the threshold limit of 10 µg/m³ (EB10) were associated with HP (23.9% vs. 15.2%, p < 0.05). A strong association with HP was observed in patients in contact with birds living in areas with EB10 (63.0% vs. 27.4%, p < 0.001). Linear regression analysis showed that age (B = −0.058, p < 0.012), smoking (B = −0.125, p < 0.001), bird contact (B = 0.275, p < 0.001) and EB10 (B = 0.109, p < 0.001) were independent variables associated with HP. In HP patients, BAL CD4/CD8-ratio > 1.5 was associated with shorter overall survival (8.9 years vs. not-reached, p < 0.011), probably due to lower CD8+ T-lymphocyte counts observed in HP fibrotic patients (11.65 ± 2.8% vs. 23.6 ± 2.9%, p = 0.008) and in those who died during follow-up (10.0 ± 1.9% vs. 23.8 ± 2.7%, p = 0.012), suggesting a protective role for CD8+ T cells. Conclusions: High environmental ethylbenzene is strongly associated with BRHP. CD8+ T-lymphocytes could have a protective role in HP, preventing fibrosis and increasing overall survival. Full article

(This article belongs to the Special Issue The Molecular Basis of the Immune Response in Pulmonary Fibrosis)

12 pages, 437 KB

Open AccessReview

The Role of GLP-1 Analogues in the Treatment of Obesity-Related Asthma Phenotype

by Joanna Radzik-Zając

Biomedicines 2025, 13(11), 2610; https://doi.org/10.3390/biomedicines13112610 (registering DOI) - 24 Oct 2025

Abstract

Asthma and obesity are two common chronic diseases of growing clinical and social importance. One of the recognised phenotypes of asthma is obesity-related asthma, which is characterised by a more severe course, resistance to glucocorticosteroids, increased inflammation and poorer symptom control. This article [...] Read more.

Asthma and obesity are two common chronic diseases of growing clinical and social importance. One of the recognised phenotypes of asthma is obesity-related asthma, which is characterised by a more severe course, resistance to glucocorticosteroids, increased inflammation and poorer symptom control. This article discusses the complex pathophysiological mechanism of this phenotype, considering the role of chronic inflammation, immune dysregulation and metabolic disorders resulting from obesity. The potential role of glucagon-like peptide-1(GLP-1) receptor analogues as an innovative therapeutic option in the treatment of asthma in obese individuals, both with and without type 2 diabetes mellitus (T2DM), is also analysed. A literature review indicates that glucagon-like peptide-1 receptor analogue (GLP-1RA) drugs, in addition to their hypoglycaemic and weight-reducing effects, also exhibit anti-inflammatory activity in the respiratory system and may reduce the frequency of asthma exacerbations and improve asthma control. The article reviews current data from experimental and clinical studies, emphasising the need for further research on the use of GLP-1RA as an adjunct to conventional asthma therapy in the context of the obese asthma phenotype. Full article

(This article belongs to the Special Issue Advances in Drug Discovery and Development: From Rational Design to Experimental Validation)

22 pages, 1147 KB

Open AccessReview

Promising Approaches Based on Bioimaging Reporters for Direct Rapid Detection of Mycobacterium tuberculosis

by Oganes A. Ambartsumyan, Olesya A. Skuredina, Platon I. Eliseev, Tatiana E. Tiulkova, Anastasia G. Samoilova and Irina A. Vasilieva

Biomedicines 2025, 13(11), 2609; https://doi.org/10.3390/biomedicines13112609 (registering DOI) - 24 Oct 2025

Abstract

Tuberculosis remains a serious global public health challenge and requires the development of rapid, sensitive, and specific diagnostic tools for effective treatment and disease control. Bioimaging reporters are promising diagnostic tools that exploit the unique biochemical properties of Mycobacterium tuberculosis for real-time detection [...] Read more.

Tuberculosis remains a serious global public health challenge and requires the development of rapid, sensitive, and specific diagnostic tools for effective treatment and disease control. Bioimaging reporters are promising diagnostic tools that exploit the unique biochemical properties of Mycobacterium tuberculosis for real-time detection of viable cells from clinical samples. Moreover, these methods offer significant advantages over the conventional methods currently used in practice, including reduced assay time, increased specificity, and the ability to discriminate viable cells from dead cells. In this review, we highlight reporters of a different nature that the enable direct detection of Mycobacterium tuberculosis, eliminating complex sample preparation. Such reporters could serve as powerful tools in fluorescence microscopy, provide alternative strategies for automated culture-based diagnostic systems, and offer new approaches for developing point-of-care methods and diagnostic devices suitable for clinical practice. Full article

(This article belongs to the Section Microbiology in Human Health and Disease)

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14 pages, 968 KB

Open AccessArticle

Cytokine Dynamics During Ustekinumab Induction as Predictors of Treatment Response in Crohn’s Disease: An Observational Study

by Alejandro Mínguez, Beatriz Mateos, Marisa Iborra, Mariam Aguas, Guillermo Bastida, Alejandro Garrido, Elena Cerrillo, Sonia García, Lluís Tortosa, Inés Moret and Pilar Nos

Biomedicines 2025, 13(11), 2608; https://doi.org/10.3390/biomedicines13112608 (registering DOI) - 24 Oct 2025

Abstract

Background/Objectives: Crohn’s disease (CD) is a chronic immune-mediated disorder with heterogeneous response to biologic therapies. Ustekinumab (UST), an anti-IL-12/23 monoclonal antibody, is effective in CD, but predictive biomarkers of treatment response remain lacking. This study aimed to investigate cytokine dynamics during UST [...] Read more.

Background/Objectives: Crohn’s disease (CD) is a chronic immune-mediated disorder with heterogeneous response to biologic therapies. Ustekinumab (UST), an anti-IL-12/23 monoclonal antibody, is effective in CD, but predictive biomarkers of treatment response remain lacking. This study aimed to investigate cytokine dynamics during UST induction and to evaluate their association with clinical and biochemical outcomes in an observational cohort of CD patients. Methods: We prospectively recruited 31 adult patients with moderate-to-severe active CD initiating UST therapy at a tertiary referral center. Peripheral blood and stool samples were collected at baseline and weeks 4, 8, and 16. UST trough concentrations, C-reactive protein (CRP), fecal calprotectin (FC), hemoglobin, albumin, and 13 serum cytokines (including IL-1β, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17, IL-23, TNF-α, and OSM) were analyzed. Response was defined as a ≥70% reduction in FC at week 16, or, alternatively, CRP < 5 mg/L or a Harvey–Bradshaw Index < 3. Results: Eighteen patients (58%) achieved response at week 16. Responders showed significant reductions in FC, CRP, and disease activity, while non-responders exhibited limited biochemical improvement. Overall, UST induction was associated with a global decrease in proinflammatory cytokines, particularly TNF-α and IL-1β. Responders displayed distinct cytokine patterns, with higher IL-13 levels at week 8 and lower IL-8 concentrations at week 16 compared with non-responders. UST trough levels tended to be higher in responders, and inverse correlations were observed between drug concentrations and several cytokines, including IL-6, IL-8, IL-13, and IL-23. Conclusions: UST induction leads to measurable immunological changes in CD, with differential cytokine dynamics distinguishing responders from non-responders. These findings support the potential of cytokine signatures, in combination with therapeutic drug monitoring, as pharmacodynamic biomarkers to optimize personalized treatment strategies in CD. Full article

(This article belongs to the Special Issue Crohn’s Disease and Ulcerative Colitis: From Pathophysiology to Novel Therapeutic Approaches (3rd Edition))

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27 pages, 7879 KB

Open AccessArticle

Melittin Nanoparticles Mitigate Glyphosate-Induced Nephrotoxicity via Cytokine Modulation and Bax/Nrf2 Pathways

by Amany M. Hamed, Zeyad Elsayed Eldeeb Mohana, Azza M. A. Abouelella, Wafaa A. Abdellah, Dalia A. Elbahy, Noha A. R. Fouda, Dina M. Monir, Safaa S. Soliman, Ahmed Mohamed Mahmoud Abdelfattah Elkassas, Elsayed Eldeeb Mehana Hamouda, Hany M. R. Abdel-Latif, Ahmed R. H. Ahmed and Nadia S. Mahrous

Biomedicines 2025, 13(11), 2607; https://doi.org/10.3390/biomedicines13112607 (registering DOI) - 24 Oct 2025

Abstract

Background/Objectives: Glyphosate-based herbicides (GBHs) are widely used agrochemicals implicated in nephrotoxicity through mechanisms involving oxidative stress, inflammation, and tissue remodeling. Natural peptides such as melittin possess potent anti-inflammatory and antioxidant properties; however, their therapeutic use is limited by instability and toxicity. Nanotechnology-based encapsulation [...] Read more.

Background/Objectives: Glyphosate-based herbicides (GBHs) are widely used agrochemicals implicated in nephrotoxicity through mechanisms involving oxidative stress, inflammation, and tissue remodeling. Natural peptides such as melittin possess potent anti-inflammatory and antioxidant properties; however, their therapeutic use is limited by instability and toxicity. Nanotechnology-based encapsulation presents a promising approach to overcoming these challenges. Objective: This study aimed to evaluate the protective effects of melittin-loaded chitosan–TPP nanoparticles (MEL-NPs) against glyphosate-induced nephrotoxicity in rats, with emphasis on oxidative, inflammatory, and apoptotic pathways. Methods: Female Wistar rats were divided into four groups: control, glyphosate (5 mg/kg/day, 25 days), glyphosate + free melittin, and glyphosate + MEL-NPs (40 µg/kg, orally, 3 times/week). Renal function biomarkers, oxidative stress parameters (MDA, GSH, SOD, CAT, NO), cytokines (TNF-α, IL-6), and serum protein/iron indices were assessed. Western blotting (Nrf2, NGAL), histopathology (H&E), and immunohistochemistry (Bax) were performed. Nanoparticles were characterized by TEM, FTIR, and UV–Vis spectroscopy. Results: Glyphosate exposure caused renal dysfunction, including elevated plasma urea and creatinine levels, and reduced creatinine clearance, indicating impaired glomerular filtration efficiency, oxidative stress (↑increased MDA, NO; ↓decreased GSH, SOD), and upregulation of pro-inflammatory cytokines. Histology revealed tubular degeneration and inflammatory infiltration, while NGAL and Bax were strongly induced. Nrf2 expression was elevated as a compensatory response. Free melittin partially ameliorated these alterations, whereas MEL-NPs provided superior protection, restoring renal function, normalizing oxidative balance, reducing NGAL and Bax expression, and preserving renal histoarchitecture. Conclusions: Melittin nanoparticles confer robust renoprotection against glyphosate-induced nephrotoxicity in rats by modulating oxidative stress, suppressing inflammation, and regulating Nrf2/Bax signaling. These findings highlight nano-melittin as a promising therapeutic platform for managing herbicide-related renal disorders. Full article

(This article belongs to the Section Cell Biology and Pathology)

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15 pages, 704 KB

Open AccessArticle

Fetal Sex Modulates Hofbauer Cells’ Response to Diabetes in Human Placenta

by Zdenek Tauber, Max Mrstik, Adela Burianova, Katerina Koubova and Katerina Cizkova

Biomedicines 2025, 13(11), 2606; https://doi.org/10.3390/biomedicines13112606 (registering DOI) - 24 Oct 2025

Abstract

Background: Hofbauer cells (HBCs) are fetal-origin macrophages in the placental villous stroma that contribute to immune tolerance at the feto–maternal interface. They predominantly display an M2 phenotype, characterized by CD206 expression. Methods: Using immunohistochemistry and morphometric analysis, we quantified HBCs, assessed [...] Read more.

Background: Hofbauer cells (HBCs) are fetal-origin macrophages in the placental villous stroma that contribute to immune tolerance at the feto–maternal interface. They predominantly display an M2 phenotype, characterized by CD206 expression. Methods: Using immunohistochemistry and morphometric analysis, we quantified HBCs, assessed CD206 intensity and morphology, and evaluated apoptotic body accumulation in placental villi. Comparisons were made among pregnancies complicated by type 1 diabetes mellitus (T1DM), gestational diabetes mellitus (GDM), and normoglycemic controls, as well as between male and female fetuses. Results: Significant effects of maternal diabetes and fetal sex on CD206 intensity were observed ([diagnosis: F = 2773.00, p < 0.0001; sex: F = 12.19, p = 0.0005]), with a strong interaction (F = 165.40, p < 0.0001). In controls, CD206 intensity was higher in female than male fetuses (p < 0.0001). Across groups, CD206 intensity decreased progressively from controls to GDM and T1DM, with a more pronounced reduction in females. Reduced CD206 was associated with elongation and irregular HBC morphology and increased IL-1β (r = −0.392, p = 0.003; r = −0.609, p < 0.0001) suggesting less tolerogenic phenotype. For apoptotic bodies, significant main effects of maternal diabetes and fetal sex were detected ([diagnosis: F = 97.16, p < 0.0001; sex: F = 15.88, p = 0.0001]). Accumulation increased progressively from controls to GDM and T1DM, with higher counts in males. Conclusions: Maternal diabetes is associated with reduced CD206 intensity, altered HBC morphology, and accumulation of apoptotic bodies in placental villi. Our results suggest greater HBC plasticity, potentially contributing to a tolerogenic placental environment in females. Full article

(This article belongs to the Special Issue New Advances in Insulin—100 Years Since Its Discovery: 2nd Edition)

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17 pages, 3747 KB

Open AccessArticle

Drug Repurposing for AML: Structure-Based Virtual Screening and Molecular Simulations of FDA-Approved Compounds with Polypharmacological Potential

by Mena Abdelsayed and Yassir Boulaamane

Biomedicines 2025, 13(11), 2605; https://doi.org/10.3390/biomedicines13112605 (registering DOI) - 24 Oct 2025

Abstract

Background: Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by impaired differentiation, apoptosis resistance, and metabolic reprogramming, which collectively contribute to therapeutic resistance and poor clinical outcomes. While targeted agents—such as LSD1 inhibitors, the BCL-2 inhibitor venetoclax, and IDH1 inhibitors—have provided [...] Read more.

Background: Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by impaired differentiation, apoptosis resistance, and metabolic reprogramming, which collectively contribute to therapeutic resistance and poor clinical outcomes. While targeted agents—such as LSD1 inhibitors, the BCL-2 inhibitor venetoclax, and IDH1 inhibitors—have provided clinical benefit, their efficacy is often limited by compensatory signaling and clonal evolution. This study aimed to identify FDA-approved compounds with multitarget potential to simultaneously modulate key epigenetic, apoptotic, and metabolic pathways in AML. Methods: Structure-based virtual screening of 3957 FDA-approved molecules was performed against three AML-relevant targets: lysine-specific demethylase 1 (LSD1), BCL-2, and mutant IDH1 (R132H). Top-ranked hits were evaluated using ADMET prediction and molecular dynamics (MD) simulations to assess pharmacokinetic properties, toxicity, and ligand–protein complex stability over 100 ns trajectories. Results: Three compounds—DB16703, DB08512, and DB16047—exhibited high binding affinities across all three targets with favorable pharmacokinetic and safety profiles. MD simulations confirmed the structural stability of the ligand–protein complexes, revealing persistent hydrogen bonding and minimal conformational deviation. These findings suggest that these repurposed drugs possess a promising multitarget profile capable of addressing AML’s multifactorial pathophysiology. Conclusions: This computational study supports the feasibility of a polypharmacology-based strategy for AML therapy by integrating epigenetic modulation, apoptotic reactivation, and metabolic correction within single molecular scaffolds. However, the identified compounds (Belumosudil, DB08512, and Elraglusib) have not yet demonstrated efficacy in AML models; further preclinical validation is warranted to substantiate these predictions and advance translational development. Full article

(This article belongs to the Special Issue Cardiac and Vascular Diseases: Pathogenesis, Pharmacological Treatments, Advances in Therapies (3rd Edition))

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16 pages, 447 KB

Open AccessReview

Tertiary Hyperparathyroidism in Diabetic Nephropathy: An Underrecognized Complication—A Narrative Review

by Mirona Costea, Dana-Mihaela Tilici, Diana Loreta Paun, Vanda Roxana Nimigean, Sorin Constantin Paun and Rucsandra Elena Danciulescu-Miulescu

Biomedicines 2025, 13(11), 2604; https://doi.org/10.3390/biomedicines13112604 (registering DOI) - 24 Oct 2025

Abstract

Tertiary hyperparathyroidism (THPT) arises in patients with chronic kidney disease (CKD) as a consequence of prolonged secondary hyperparathyroidism and is marked by autonomous parathyroid hormone (PTH) secretion. In some cases, parathyroid hyperplasia persists even after successful renal transplantation, resulting in sustained PTH elevation [...] Read more.

Tertiary hyperparathyroidism (THPT) arises in patients with chronic kidney disease (CKD) as a consequence of prolonged secondary hyperparathyroidism and is marked by autonomous parathyroid hormone (PTH) secretion. In some cases, parathyroid hyperplasia persists even after successful renal transplantation, resulting in sustained PTH elevation and hypercalcaemia. These alterations contribute to bone loss, vascular calcification, and increased cardiovascular risk. Management includes medical therapy with calcimimetics or vitamin D analogues and surgical intervention via parathyroidectomy. However, optimal timing and treatment strategy remain uncertain. This review examines the pathophysiology, clinical manifestations, and current management paradigms of THPT, with an emphasis on areas that require further research and consensus. Full article

(This article belongs to the Special Issue Connections Between Diabetes Mellitus, Other Metabolic and Endocrine Dysfunctions and Cardiovascular Pathologies—Second Edition)

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22 pages, 6008 KB

Open AccessReview

Mitochondrial Dynamics in Aging Heart

by Pankaj Patyal, Gohar Azhar, Ambika Verma, Shakshi Sharma, Jyotsna Shrivastava, Sayed Aliul Hasan Abdi, Xiaomin Zhang and Jeanne Y. Wei

Biomedicines 2025, 13(11), 2603; https://doi.org/10.3390/biomedicines13112603 - 24 Oct 2025

Abstract

Aging is a major risk factor for cardiovascular disease, driving progressive structural and functional decline of the myocardium. Mitochondria, the primary source of ATP through oxidative phosphorylation, are essential for cardiac contractility, calcium homeostasis, and redox balance. In the aging heart, mitochondria show [...] Read more.

Aging is a major risk factor for cardiovascular disease, driving progressive structural and functional decline of the myocardium. Mitochondria, the primary source of ATP through oxidative phosphorylation, are essential for cardiac contractility, calcium homeostasis, and redox balance. In the aging heart, mitochondria show morphological alterations including cristae disorganization, swelling, and fragmentation, along with reduced OXPHOS efficiency. These defects increase proton leak, lower ATP production, and elevate reactive oxygen species (ROS), causing oxidative damage. Concurrent disruptions in mitochondrial fusion and fission further impair turnover and quality control, exacerbating mitochondrial dysfunction and cardiac decline. Serum response factor (SRF) signaling, a crucial regulator of cytoskeletal and metabolic gene expression, plays a key role in modulating mitochondrial function during cardiac aging. Dysregulation of SRF impairs mitochondrial adaptability, contributing to dysfunction. Additionally, reduced levels of nicotinamide adenine dinucleotide (NAD⁺) hinder sirtuin-dependent deacetylation, further compromising mitochondrial efficiency and stress resilience. These cumulative defects activate regulated cell death pathways, leading to cardiomyocyte loss, fibrosis, and impaired diastolic function. Mitochondrial dysfunction therefore serves as both a driver and amplifier of cardiac aging, accelerating the transition toward heart failure. This narrative review aims to provide a comprehensive overview of mitochondrial remodeling in the aging myocardium, examining the mechanistic links between mitochondrial dysfunction and myocardial injury. We also discuss emerging therapeutic strategies targeting mitochondrial bioenergetics and quality control as promising approaches to preserve cardiac function and extend cardiovascular health span in the aging population. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction and Reactive Oxygen Species in Aging and Related Diseases)

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34 pages, 7380 KB

Open AccessArticle

Vitexin as a Potential Antidysmenorrheic Agent: Development of a ZIF-8-Based Immediate-Release System and Evaluation via In Vivo and In Silico Approaches

by José Marcos Teixeira de Alencar Filho, Ana Rita de Sousa França, Luana Beatriz Rocha da Silva, Pedrita Alves Sampaio, Emanuella Chiara Valença Pereira, Ademar Rocha da Silva, Milenna Victória Valentim de Oliveira Alencar, Tarcísio Cícero de Lima Araújo, Pedro Modesto Nascimento Menezes, Salvana Priscylla Manso Costa, Ighor Costa Barreto, Fabrício Souza Silva, Edigênia Cavalcante da Cruz Araújo, Edilson Beserra de Alencar Filho and Larissa Araújo Rolim

Biomedicines 2025, 13(11), 2602; https://doi.org/10.3390/biomedicines13112602 - 24 Oct 2025

Abstract

Background/Objectives: Primary dysmenorrhea is a prevalent condition that causes severe uterine cramps in women worldwide. The objective of this work was to synthesize and characterize a novel immediate-release system using vitexin and ZIF-8, and to evaluate its pharmacological action in a model [...] Read more.

Background/Objectives: Primary dysmenorrhea is a prevalent condition that causes severe uterine cramps in women worldwide. The objective of this work was to synthesize and characterize a novel immediate-release system using vitexin and ZIF-8, and to evaluate its pharmacological action in a model of primary dysmenorrhea. Methods: A 2² full factorial design guided the synthesis of the system. Physicochemical characterization was performed by FT-IR, TG, DSC, SEM, XRD, and in vitro release tests. Pharmacological activity was assessed in an oxytocin-induced dysmenorrhea model in mice. In addition, in silico molecular docking and molecular dynamics simulations were conducted to explore the potential mechanism of action of vitexin. Results: Optimal yield and loading capacity were achieved at the high levels of the factorial design. Characterization analyses confirmed the successful formation of the vitexin@ZIF-8 (VIT@ZIF-8) system. The release study demonstrated a markedly enhanced dissolution rate of vitexin. Both isolated vitexin and VIT@ZIF-8 reduced abdominal writhing when administered orally at 3 and 30 mg/kg, while intraperitoneal activity was observed only at 30 mg/kg. Computational analyses revealed favorable interactions of vitexin with aldose reductase (AKR1C3), suggesting this enzyme as a potential molecular target in dysmenorrhea. Conclusions: The VIT@ZIF-8 system represents a promising strategy to improve the dissolution profile of vitexin, although pharmacological activity in this model was not superior to the isolated compound. The combined in vivo and in silico evidence supports vitexin as a potential antidysmenorrheic agent, possibly through modulation of AKR1C3. These findings open avenues for future studies addressing the molecular pathways of vitexin and for the development of novel therapeutic approaches for primary dysmenorrhea. Full article

(This article belongs to the Section Drug Discovery, Development and Delivery)

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19 pages, 961 KB

Open AccessReview

Context-Dependent Roles of Siglec-F⁺ Neutrophils

by Kisung Sheen, Taesoo Choi and Man S. Kim

Biomedicines 2025, 13(11), 2601; https://doi.org/10.3390/biomedicines13112601 - 24 Oct 2025

Abstract

Recent studies in murine disease models have identified Siglec-F⁺ neutrophils, which express a marker traditionally associated with eosinophils, as a functionally distinct population characterized by extended lifespans and context-dependent roles. While conventional neutrophils typically return to the bone marrow or undergo apoptosis [...] Read more.

Recent studies in murine disease models have identified Siglec-F⁺ neutrophils, which express a marker traditionally associated with eosinophils, as a functionally distinct population characterized by extended lifespans and context-dependent roles. While conventional neutrophils typically return to the bone marrow or undergo apoptosis at the site of inflammation, these cells remain in tissues for extended periods. These cells demonstrate remarkable functional plasticity, promote bacterial clearance and immune activation during infections, foster immunosuppression and tumor progression in cancer, and contribute to tissue remodeling in fibrotic diseases. In this review, we examine the key features governing Siglec-F⁺ neutrophil differentiation and function—including Siglec-F signaling, metabolic programming, and upstream cytokine cues—and explore how targeting these pathways may offer promising avenues for precision immunomodulation. Full article

(This article belongs to the Collection Feature Papers in Immunology and Immunotherapy)

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24 pages, 1290 KB

Open AccessArticle

The Genetic and Embryo–Fetal Developmental Toxicity Profile of the Novel Transgelin Agonist Deg-AZM: Ames, Micronucleus, Chromosomal Aberration, and Rat EFD Studies

by Xiaoting Gu, Ying Xu, Nannan Liu, Keran Li, Xiaoting Wang, Jia Zhang, Xiaoting Zhang, Yanjie Ding, Xiaohe Li, Honggang Zhou, Xiaoyu Ai and Cheng Yang

Biomedicines 2025, 13(11), 2600; https://doi.org/10.3390/biomedicines13112600 - 23 Oct 2025

Abstract

Background: Slow-transit constipation (STC) lacks durable and safe prokinetics. Deglycosylated-azithromycin (Deg-AZM), a novel small-molecule transgelin agonist that restores colonic motility in STC, has been approved for clinical trials in 2024. Objectives: This study aimed to assess the genetic toxicity and embryo–fetal development (EFD) [...] Read more.

Background: Slow-transit constipation (STC) lacks durable and safe prokinetics. Deglycosylated-azithromycin (Deg-AZM), a novel small-molecule transgelin agonist that restores colonic motility in STC, has been approved for clinical trials in 2024. Objectives: This study aimed to assess the genetic toxicity and embryo–fetal development (EFD) toxicity of Deg-AZM through a series of standardized non-clinical safety studies. Methods: We conducted Ames, in vivo micronucleus, and chromosomal aberration tests to evaluate genotoxicity. Acute and 28-day repeated-dose oral toxicity studies were performed in Sprague-Dawley rats. EFD toxicity was assessed in pregnant rats administered Deg-AZM from gestation day (GD) 6 to 15. Toxicokinetic analyses were integrated into repeated-dose and EFD studies. Results: Deg-AZM demonstrated no mutagenic potential in the bacterial reverse-mutation assay at concentrations up to 2500 µg/plate (with metabolic activation) or 150 µg/plate (without metabolic activation). No clastogenic effects were observed in micronucleus or chromosomal aberration assays. The median lethal dose (LD₅₀) exceeded 1600 mg/kg in acute oral toxicity. In the 28-day study, no adverse effects were observed at doses up to 600 mg/kg, though mild hematological and hepatic changes were noted at high doses, all of which were reversible. In the EFD study, Deg-AZM did not induce maternal toxicity, teratogenicity, or adverse fetal outcomes at doses up to 600 mg/kg. Conclusions: Deg-AZM demonstrates a favorable safety profile with no evidence of genetic toxicity or developmental harm at pharmacologically relevant doses, supporting its further development as a therapeutic agent for STC. Full article

(This article belongs to the Section Drug Discovery, Development and Delivery)

20 pages, 1246 KB

Open AccessReview

The Role of Mitochondrial Genome Stability and Metabolic Plasticity in Thyroid Cancer

by Lingyu Ren, Wei Liu, Jiaojiao Zheng, Qiao Wu and Zhilong Ai

Biomedicines 2025, 13(11), 2599; https://doi.org/10.3390/biomedicines13112599 - 23 Oct 2025

Abstract

Mitochondria play a central role in energy metabolism, redox homeostasis, and signal transduction in the thyroid cells. Increasing evidence indicates that mitochondrial DNA (mtDNA) mutations, copy number variations, and haplogroup-specific polymorphisms are closely associated with metabolic reprogramming and malignant progression of thyroid cancer. [...] Read more.

Mitochondria play a central role in energy metabolism, redox homeostasis, and signal transduction in the thyroid cells. Increasing evidence indicates that mitochondrial DNA (mtDNA) mutations, copy number variations, and haplogroup-specific polymorphisms are closely associated with metabolic reprogramming and malignant progression of thyroid cancer. This review summarizes recent advances in the understanding of the impact of mitochondrial genome instability and metabolic plasticity on thyroid tumorigenesis. We discuss how mtDNA alterations disrupt oxidative phosphorylation (OXPHOS), trigger adaptive metabolic rewiring, and interact with key oncogenic pathways, such as HIF-1α, BRAFV600E mutations, and TSHR signaling in thyroid cancer. We also highlight the emerging diagnostic and therapeutic potential of mtDNA in thyroid cancer and outline current challenges and future research directions. Gaining deeper insights into the mitochondria–metabolism axis may provide novel biomarkers and metabolic intervention strategies for precision medicine in thyroid oncology. Full article

(This article belongs to the Special Issue An Update on Mechanisms and Treatments for Thyroid Cancer in Current Oncology, 2nd Edition)

17 pages, 2737 KB

Open AccessArticle

Exosome-Based Proteomic Profiling for Biomarker Discovery in Pediatric Fabry Disease: Insights into Early Diagnosis Monitoring

by Zhihong Lu, Yu Xia, Bingying Wang, Pingping Jiang and Jianhua Mao

Biomedicines 2025, 13(11), 2598; https://doi.org/10.3390/biomedicines13112598 (registering DOI) - 23 Oct 2025

Abstract

Background: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by GLA mutations, leading to deficient α-galactosidase A (α-Gal A) activity and progressive glycosphingolipid accumulation. While α-Gal A activity is the diagnostic gold standard, its sensitivity is reduced in late-onset or [...] Read more.

Background: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by GLA mutations, leading to deficient α-galactosidase A (α-Gal A) activity and progressive glycosphingolipid accumulation. While α-Gal A activity is the diagnostic gold standard, its sensitivity is reduced in late-onset or heterozygous patients. Conventional biomarkers such as lyso-Gb3 provide only limited insight into disease progression and therapeutic response. Exosomes, as stable carriers of disease-specific proteins, may offer complementary biomarkers for early detection and longitudinal monitoring. Methods: Twenty-one pediatric FD patients with confirmed GLA mutations were enrolled. Clinical, enzymatic, renal, and cardiac parameters were assessed. Plasma-derived exosomes were characterized by transmission electron microscopy and proteomic profiling. Differentially expressed proteins were identified using mass spectrometry, analyzed using GO/KEGG enrichment, and validated using RT-PCR, ELISA, and immunofluorescence in patient samples and Gla^−/− mice. Results: Male patients showed markedly reduced α-Gal A activity and elevated lyso-Gb3 compared with females. Although overt renal and cardiac dysfunction was uncommon, several patients exhibited early abnormalities such as proteinuria, an elevated LVMI, or increased cTnI levels. Proteomic analysis identified 2553 proteins, of which 188 were differentially expressed. Fibrosis- and inflammation-related proteins, including THBS1 and CFHR5, were upregulated, while protective factors such as APM1, SERPINA10, and CAB39 were downregulated. IGFBP3 was also elevated and closely linked to tissue remodeling. Enriched pathways were involved in PPAR/AMPK signaling, lipid metabolism, and complement activation. Conclusions: Exosomal proteomic profiling revealed early molecular signatures of cardiorenal involvement in pediatric FD. Key proteins such as THBS1, CFHR5, IGFBP3, APM1, and CAB39 show strong potential as biomarkers for risk stratification, disease monitoring, and therapeutic evaluation. Full article

(This article belongs to the Special Issue Advances in Fabry Disease: From Molecular Insights to Innovative Therapeutics)

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16 pages, 254 KB

Open AccessReview

Advanced Neuroimaging and Emerging Systemic Therapies in Glioblastoma: Current Evidence and Future Directions

by Ilona Bar-Letkiewicz, Anna Pieczyńska, Małgorzata Dudzic, Michał Szkudlarek, Krystyna Adamska and Katarzyna Hojan

Biomedicines 2025, 13(11), 2597; https://doi.org/10.3390/biomedicines13112597 - 23 Oct 2025

Abstract

Despite technological progress, glioblastoma (GBM) continues to confer dismal prognoses. Modern neuroimaging methods are assuming an ever greater role in diagnosing and monitoring brain tumors. This review shows current neuroimaging approaches and systemic therapeutic strategies for glioblastoma, with a focus on emerging and [...] Read more.

Despite technological progress, glioblastoma (GBM) continues to confer dismal prognoses. Modern neuroimaging methods are assuming an ever greater role in diagnosing and monitoring brain tumors. This review shows current neuroimaging approaches and systemic therapeutic strategies for glioblastoma, with a focus on emerging and innovative treatments. Advances in multiparametric magnetic resonance imaging—MRI (diffusion, perfusion, and spectroscopy) and novel positron emission tomography (PET) tracers, complemented by radiomics and artificial intelligence (AI), now refine tumor delineation, differentiate progression from treatment effects, and may help predict treatment responses. Maximal safe resection followed by chemoradiotherapy with temozolomide remains the standard, with the greatest benefit seen in O⁶-methylguanine DNA methyltransferase (MGMT) promoter-methylated tumors. Bevacizumab and other targeted modalities offer mainly progression-free, not overall survival, gains. Immune checkpoint inhibitors (e.g., nivolumab) have not improved survival in unselected GBM, while early multi-antigen CAR-T (chimeric antigen receptor T-cell) strategies show preliminary bioactivity without established durability. While actionable alterations (NTRK fusions and BRAF V600E) justify selective targeted therapy trials, their definitive benefit in classical GBM is unproven. Future priorities include harmonized imaging molecular integration, AI-driven prognostic modeling, novel PET tracers, and strategies to breach or transiently open the blood–brain barrier to enhance drug delivery. Convergence of these domains may convert diagnostic precision into improved patient outcomes. Full article

(This article belongs to the Special Issue Medical Imaging in Brain Tumor: Charting the Future)

29 pages, 6851 KB

Open AccessArticle

Analysis of Immune Cell Infiltration Distribution and Prognostic Value in Obstructive Colorectal Cancer

by Yifan Xue, Zhenxing Jiang, Junnan Gu, Shenghe Deng, Kailin Cai and Ke Wu

Biomedicines 2025, 13(11), 2596; https://doi.org/10.3390/biomedicines13112596 - 23 Oct 2025

Abstract

Objective: This study aims to determine how intestinal obstruction influences the tumor immune microenvironment (TIME) and its impact on prognosis in colorectal cancer (CRC). Methods: Immune cell densities (CD4⁺, CD8⁺, CD20⁺, CD68⁺) within [...] Read more.

Objective: This study aims to determine how intestinal obstruction influences the tumor immune microenvironment (TIME) and its impact on prognosis in colorectal cancer (CRC). Methods: Immune cell densities (CD4⁺, CD8⁺, CD20⁺, CD68⁺) within central tumor (CT) and invasive margin (IM) compartments were quantitatively analyzed using immunohistochemistry (IHC) and QuPath digital pathology in surgical resection samples from 328 patients (164 obstructed colon cancer [OCRC] vs. 164 non-obstructed [NOCRC], cohorts matched by propensity scoring). Findings on tumor-infiltrating immune cell spatial distribution were integrated with peripheral blood immune cell counts and clinicopathological characteristics to characterize the obstructed colon cancer immune microenvironment. Associations with disease-free survival (DFS) and overall survival (OS) were evaluated. Results: OCRC exhibited higher lymphocytic infiltration, particularly in the CT compartment, compared to NOCRC, with significantly elevated CT-CD8⁺ T cell density in T4-stage OCRC (p < 0.005). Obstruction enhanced immune cell correlations across compartments, especially in T4 tumors, and the CD68⁺/CD8⁺ ratio effectively discriminated obstruction status (CT area under the curve (AUC): T4 = 0.879). Peripheral lymphocytopenia was pronounced in obstructive cases (p = 0.003). Critically, T4 OCRC showed a complete loss of all correlations between tumor-infiltrating immune cells and peripheral parameters. Despite increased infiltration, high CD8⁺ density in OCRC correlated with worse prognosis, indicating a paradoxical role influenced by obstruction context. CD68⁺ macrophages in the invasive margin consistently predicted improved survival (Disease-free survival [DFS]: Hazard ratio [HR] = 0.59, p = 0.008). Conclusions: Intestinal obstruction in CRC, particularly in T4-stage tumors, may represent an immunologically active state that alters local immune infiltration and systemic–local immune crosstalk. These findings suggest that obstruction status could refine prognostic stratification and inform therapeutic strategies, although validation in larger cohorts is warranted. Full article

(This article belongs to the Special Issue Decoding Colorectal Cancer: Innovations in Biomarkers, Microbiota, and Therapeutic Resistance)

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26 pages, 3442 KB

Open AccessReview

Complementary Yet Distinct Roles of GLP-1 Receptor Agonists and SGLT2 Inhibitors in Cardiovascular Risk Reduction

by Nóra Homoródi, Éva Varga, Zoltán Szabó, Ferenc Sztanek and Mariann Harangi

Biomedicines 2025, 13(11), 2595; https://doi.org/10.3390/biomedicines13112595 - 23 Oct 2025

Abstract

Novel antidiabetic drugs introduced in the last decade have not only revolutionized the treatment of type 2 diabetes mellitus but have also changed our cardiovascular risk reduction strategy. Glucagon-like peptide-1 (GLP-1) receptor agonists reduce the risk of atherosclerotic diseases primarily through their complex [...] Read more.

Novel antidiabetic drugs introduced in the last decade have not only revolutionized the treatment of type 2 diabetes mellitus but have also changed our cardiovascular risk reduction strategy. Glucagon-like peptide-1 (GLP-1) receptor agonists reduce the risk of atherosclerotic diseases primarily through their complex anti-atherosclerotic effect due to their endothelial function-improving, anti-inflammatory, anti-thrombotic, and plaque-stabilizing effects. Sodium–glucose cotransporter 2 (SGLT2) inhibitors, on the other hand, have a favorable cardiovascular effect, mainly by increasing sodium excretion, reducing plasma volume, enhancing the use of ketone bodies as metabolic substrates in heart and kidney tissues, and reducing oxidative stress and uric acid serum levels. However, when using these two groups of drugs, important questions arise. What criteria should be used to decide on the administration of one or the other class of drugs? Which group of agents can be used more effectively to reduce our patients’ cardiovascular risk? What are the possible adverse effects? What can be gained by combining the two drugs? Our objective was to provide a current literature-based and comparative summary on the mechanisms of action, cardiovascular-risk-reducing efficacy, and safety profiles of these two drug classes, with an emphasis on identifying key factors influencing everyday clinical decision-making. Full article

(This article belongs to the Special Issue Advances in Type 2 Diabetes: Insulin Regulation and Therapeutic Strategies)

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19 pages, 770 KB

Open AccessReview

From Qualitative to Quantitative Functional Assessment in Stroke Rehabilitation with a Focus on Ultrasound Role

by Rosita Rabbito, Eleonora Ficiarà, Lorenzo Priano, Matteo Bigoni, Caterina Guiot and Silvestro Roatta

Biomedicines 2025, 13(11), 2594; https://doi.org/10.3390/biomedicines13112594 - 23 Oct 2025

Abstract

Stroke-surviving patients may present a wide range of neurological deficits affecting both sensory and motor functions as well as the cognitive and the emotional domains, with an impact on independence on daily activities and quality of life in general. Assessment scales are essential [...] Read more.

Stroke-surviving patients may present a wide range of neurological deficits affecting both sensory and motor functions as well as the cognitive and the emotional domains, with an impact on independence on daily activities and quality of life in general. Assessment scales are essential tools for evaluating all these aspects of a patient’s condition and for monitoring their evolution in time, attempting to provide a quantitative index to complex and sometimes indirectly observable parameters. In fact, the use of these scales entails methodological and interpretative challenges that can limit their applicability and effectiveness. This narrative review explores the current state and limitations of assessment scales used in the rehabilitative evaluation of post-stroke patients. Common neurorehabilitation techniques and traditionally used assessment scales for measuring patient progress are reviewed, highlighting their main limitations. As an alternative to the observational approach, direct assessment of the effect of the ongoing rehabilitative process on the functional recovery of the damaged neurological network, based on the recording of their electric signaling or on the modification in regional cerebral blood flow, have been recently proposed. Innovative rehabilitation assessment methods based on quantitative data are reviewed, with a special focus on ultrasound-based techniques, aiming to improve accuracy and sensitivity in clinical assessment. Full article

(This article belongs to the Special Issue Neurodegeneration No More: Cutting-Edge Technologies and Therapies in the Evolution of Neurodegenerative Disease Management—2nd Edition)

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17 pages, 2171 KB

Open AccessReview

The Role of mTOR Signaling in Tumor-Induced Alterations to Neuronal Function in Diffusely Infiltrating Glioma

by Hannah Haile, Sandra Leskinen, Arjun R. Adapa, Alexander R. Goldberg, Ashwin Viswanathan, Charlotte Milligan, Karen Conboy, Catherine Schevon, Peter Canoll and Brian J. A. Gill

Biomedicines 2025, 13(11), 2593; https://doi.org/10.3390/biomedicines13112593 - 23 Oct 2025

Abstract

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that integrates metabolic and environmental signals to regulate cell growth and survival. In the central nervous system, mTOR plays a pivotal role in neuronal development, plasticity, and circuit homeostasis. In diffusely infiltrating gliomas, [...] Read more.

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that integrates metabolic and environmental signals to regulate cell growth and survival. In the central nervous system, mTOR plays a pivotal role in neuronal development, plasticity, and circuit homeostasis. In diffusely infiltrating gliomas, including glioblastomas, mTOR signaling is frequently dysregulated and contributes to malignant progression, therapeutic resistance, and metabolic adaptation. Beyond tumor-intrinsic effects, recent evidence reveals that gliomas actively reprogram peritumoral neurons via mTOR-dependent mechanisms, leading to synaptic remodeling, hyperexcitability, and neurological symptoms such as seizures and cognitive dysfunction. These results position mTOR as a central mediator of both oncogenesis and neurological dysfunction in diffusely infiltrating glioma. While clinical trials of mTOR inhibitors in gliomas have so far shown limited efficacy, emerging data suggest these agents may ameliorate tumor-associated neurological dysfunction. This review synthesizes current knowledge of mTOR signaling across tumor and neuronal compartments in diffusely infiltrating glioma and highlights its potential as a therapeutic target at the intersection of cancer biology and neuroscience. Full article

(This article belongs to the Special Issue mTOR Signaling in Disease and Therapy)

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26 pages, 3693 KB

Open AccessArticle

Mutations in CREBBP and EP300 HAT and Bromo Domains Drive Hypermutation and Predict Survival in GI Cancers Treated with Immunotherapy

by Mariia Gusakova, Fedor Sharko, Aleksandra Mamchur, Eugenia Boulygina, Anastasia Mochalova, Artem Bullikh and Maxim Patrushev

Biomedicines 2025, 13(11), 2592; https://doi.org/10.3390/biomedicines13112592 - 23 Oct 2025

Abstract

Background: The role of CREBBP and EP300 mutations in hypermutation and immunotherapy response in gastroesophageal adenocarcinomas is poorly defined and needs further investigation. Methods: We conducted an in silico analysis of 12 publicly available studies (n = 1871; cBioPortal), stratifying samples by CREBBP/EP300 [...] Read more.

Background: The role of CREBBP and EP300 mutations in hypermutation and immunotherapy response in gastroesophageal adenocarcinomas is poorly defined and needs further investigation. Methods: We conducted an in silico analysis of 12 publicly available studies (n = 1871; cBioPortal), stratifying samples by CREBBP/EP300 status to assess associations with TMB-High, MSI, co-mutation patterns, and mutation localization. Clinical validation was performed in an independent pan-cancer cohort treated with ICIs (n = 1610) and a gastric cancer cohort with WES data (n = 55). Results: Coding mutations in CREBBP and/or EP300 were significantly associated with TMB-high and MSI-high phenotypes (p < 0.001). All studied samples carrying coding mutations in both CREBBP and EP300 exhibited a TMB-high status. PTVs in functional HAT and bromodomain regions were exclusively associated with TMB-high. Incorporating CREBBP and/or EP300 mutation status improved identification of ultra-hypermutated tumors compared with single-gene biomarkers (p < 0.001). Clinically, these mutations predicted improved overall survival in the pan-cancer cohort (median OS 34 vs. 17 months; HR = 0.68, 95% CI 0.52–0.87, p = 0.0026), as well as in bladder (HR = 0.55, p = 0.0337) and gastrointestinal cancer cohorts (HR = 0.31, p = 0.0021) treated with ICIs. In the gastric cancer validation cohort, all tumors with PTVs demonstrated a partial response to anti-PD-1 therapy. Conclusions: We report CREBBP and EP300 coding mutations as novel potential surrogate biomarkers for hypermutation in gastroesophageal adenocarcinomas and demonstrate their association with favorable immunotherapy outcomes, supporting their potential clinical utility for patient stratification. Full article

(This article belongs to the Special Issue Gastrointestinal Diseases: From Pathophysiology to Innovative Therapeutic Approaches)

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13 pages, 1032 KB

Open AccessReview

Thyrotoxicosis and the Heart: An Underrecognized Trigger of Acute Coronary Syndromes

by Larisa Anghel, Anca Diaconu, Laura-Cătălina Benchea, Cristina Prisacariu, Dragoș Viorel Scripcariu, Răzvan-Liviu Zanfirescu, Gavril-Silviu Bîrgoan, Radu Andy Sascău and Cristian Stătescu

Biomedicines 2025, 13(11), 2591; https://doi.org/10.3390/biomedicines13112591 - 23 Oct 2025

Abstract

Background: Thyrotoxicosis is a systemic condition with well-documented cardiovascular effects, but its role as a precipitant of acute coronary syndromes (ACS) is often overlooked. This review summarizes clinical cases and original studies from the last 20 years, describing ACS triggered by thyrotoxicosis. Methods: [...] Read more.

Background: Thyrotoxicosis is a systemic condition with well-documented cardiovascular effects, but its role as a precipitant of acute coronary syndromes (ACS) is often overlooked. This review summarizes clinical cases and original studies from the last 20 years, describing ACS triggered by thyrotoxicosis. Methods: Following PRISMA 2020 guidelines, we searched PubMed, Scopus, and Embase for reports published between 2004–2025. Only case reports and original articles were included. Data extracted included demographics, ECG findings, angiography results, thyroid function, etiology of hyperthyroidism, and outcomes. Results: A total of 35 cases were identified. The mean age was in the fourth decade of life, with a female predominance (57%, 20 out of 35). More than half of the patients presented with ST-segment elevation myocardial infarction (STEMI) or STEMI equivalents (21 out of 35; 60%). Electrocardiographic abnormalities most often involved anterior or inferior leads. Coronary angiography revealed normal vessels or diffuse vasospasm in 18 cases (51%), while thrombotic occlusion was observed in 4 cases (11%), spontaneous dissection in 2 cases (6%), and myocardial bridging in 3 cases (9%). The leading cause of thyrotoxicosis was Graves’ disease (≈65%), followed by painless thyroiditis, iatrogenic causes, and gestational hyperthyroidism. Thyroid storm was reported in approximately 20% of cases and was associated with malignant ventricular arrhythmias or sudden cardiac death. Conclusions: Thyrotoxicosis should be recognized as a rare but important trigger of ACS, especially in young patients without traditional risk factors. Pathophysiological mechanisms include coronary vasospasm, increased myocardial oxygen demand, and hypercoagulability. Early recognition may prevent unnecessary revascularization and optimize outcomes through integrated endocrine and cardiac management. Full article

(This article belongs to the Special Issue Exploring Acute Coronary Syndrome: Insights from Basic and Clinical Research—2nd Edition)

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12 pages, 796 KB

Open AccessReview

Evolving the Diagnosis of Multiple Sclerosis: A New Landscape in Light of the 2024 McDonald Criteria

by Amjad Samara and Daniel Ontaneda

Biomedicines 2025, 13(11), 2590; https://doi.org/10.3390/biomedicines13112590 - 23 Oct 2025

Abstract

Timely and accurate diagnosis of multiple sclerosis (MS) allows for prompt treatment initiation that can alter the disease course and prevent disability accumulation. The 2024 revisions of the McDonald criteria aim to achieve earlier and more precise MS diagnosis by including new neuroimaging [...] Read more.

Timely and accurate diagnosis of multiple sclerosis (MS) allows for prompt treatment initiation that can alter the disease course and prevent disability accumulation. The 2024 revisions of the McDonald criteria aim to achieve earlier and more precise MS diagnosis by including new neuroimaging and biomarker advances. This review highlights key updates, including revised definitions of dissemination in space and time, along with new MRI features, including the central vein sign and paramagnetic rim lesions. We also describe the role of cerebrospinal fluid biomarkers, including oligoclonal bands and kappa-free light chains. The updated criteria formally incorporate incidental imaging and nonspecific symptom presentations to enable diagnosis before either a first clinical attack or progression of neurological disability. Finally, we explore emerging and promising investigational tools for future incorporation into MS diagnosis, including advanced MRI techniques, fluid biomarkers, and applications of artificial intelligence. Full article

(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment—3rd Edition)

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13 pages, 2859 KB

Open AccessArticle

Mitral Annular Disjunction and Arrhythmic Risk: Case Series and State of the Art

by Marisa Varrenti, Eleonora Bonvicini, Leandro Fabrizio Milillo, Ilaria Garofani, Lorenzo Gigli, Matteo Baroni, Alberto Preda, Marco Carbonaro, Roberto Menè, Giulia Colombo, Antonio Frontera, Raffaele Falco, Federica Giordano, Sara Vargiu, Fabrizio Guarracini, Patrizia Pedrotti, Cristina Giannattasio and Patrizio Mazzone

Biomedicines 2025, 13(11), 2589; https://doi.org/10.3390/biomedicines13112589 - 23 Oct 2025

Abstract

Background: Mitral annular disjunction (MAD) is an anatomical abnormality associated with an increased risk of major arrhythmic events, regardless of the presence of mitral valve prolapse. Cardiac magnetic resonance (CMR) plays a key role in diagnosing MAD and identifying myocardial fibrosis, a marker [...] Read more.

Background: Mitral annular disjunction (MAD) is an anatomical abnormality associated with an increased risk of major arrhythmic events, regardless of the presence of mitral valve prolapse. Cardiac magnetic resonance (CMR) plays a key role in diagnosing MAD and identifying myocardial fibrosis, a marker of arrhythmic vulnerability. Aim: This study reports the experience of the De Gasperis Cardiology Centre at Niguarda Hospital (Milan, Italy) in managing high-risk MAD patients who underwent implantable cardioverter–defibrillator (ICD) implantation and describes their main clinical characteristics. Methods: Between January 2020 and April 2025, five patients with MAD who received ICDs were identified and monitored remotely. Although the small sample size limits generalizability, the objective was to characterize factors associated with arrhythmic susceptibility. Results: Four patients exhibited documented ventricular arrhythmias: two with non-sustained and two with sustained ventricular tachycardia. Notably, CMR did not reveal myocardial fibrosis in two symptomatic cases, suggesting that arrhythmic vulnerability may precede detectable structural abnormalities. The observed coexistence of MAD with arrhythmogenic cardiomyopathies and channelopathies underscores the relevance of comprehensive genetic evaluation in these patients. Conclusions: MAD should be considered a potential arrhythmogenic substrate rather than a benign anatomical variant. A multimodal diagnostic approach and individualized risk stratification—potentially integrating genetic findings—are essential for optimal patient management. Full article

(This article belongs to the Special Issue Acute and Chronic Heart Failure: Pathophysiology and New Therapeutic Developments, 2nd Edition)

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16 pages, 4699 KB

Open AccessArticle

Exploring the Early Endometrial–Blastocyst Interactome in Endometriosis: An Integrative Study

by Ana Schafir, Lourdes Materazzi, Lara Castagnola, Agostina Occhiuzzi, Daniel Paparini, Lautaro Tessari, Lautaro Fierro, Marcela Irigoyen, Antonio Cattaneo, Diego Gnocchi, Soledad Gori, Esteban Grasso and Rosanna Ramhorst

Biomedicines 2025, 13(11), 2588; https://doi.org/10.3390/biomedicines13112588 - 23 Oct 2025

Abstract

Background: Background: Endometriosis affects 10% of women of reproductive age. Despite the well-known association between endometriosis and infertility, the mechanisms underlying this association remain to be elucidated. Methods: Implantation and pregnancy success rates were evaluated by a retrospective study of patients that underwent [...] Read more.

Background: Background: Endometriosis affects 10% of women of reproductive age. Despite the well-known association between endometriosis and infertility, the mechanisms underlying this association remain to be elucidated. Methods: Implantation and pregnancy success rates were evaluated by a retrospective study of patients that underwent IVF using euploid embryos comparing healthy vs. endometriosis patients. To study the early embryo–endometrial dialogue, an interactome network was constructed using public RNAseq data from normal secretory-phase endometrial samples and day-5 blastocyst. Public bulk and single-cell RNAseq data from endometrial samples of endometriosis patients were used to detect alterations in the interactome. Results: Endometriosis patients required significantly more IVF attempts compared to those without endometrial pathologies; however, once pregnancy was achieved, the evolution of both groups was similar. The interactome network between normal endometrium and day-5 blastocyst showed a significant enrichment of pathways associated with tissue remodelling, angiogenesis, and immune regulation, which were altered in endometriosis patients. Endometriosis patients also presented an increased frequency and activation of NK, CD4⁺, and CD8⁺ cells, which interfere with embryo–endometrial dialogue. Conclusions: We identified key molecular processes affected by endometriosis specifically involved in the early interaction between the blastocyst, decidual, and resident immune cells, that may underline the reported fertility problems associated with endometriosis. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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17 pages, 5031 KB

Open AccessArticle

Loss of AT8 Nuclear Tau as a Marker of Neuronal Ageing and Alzheimer’s Disease Progression

by Francesca Bruno, Laura Gil, Valentina Sturiale, Carmen Guerrero, Ana Belen Rebolledo, Desiree Brancato, Javier Morales, Salvatore Saccone and Concetta Federico

Biomedicines 2025, 13(11), 2587; https://doi.org/10.3390/biomedicines13112587 - 23 Oct 2025

Abstract

Background/Objectives: Tau protein, a central player in Alzheimer’s disease (AD) pathology, is classically known for its role in microtubule stabilisation. However, accumulating evidence indicates that tau also localises to the neuronal nucleus, particularly the nucleolus, where it may regulate chromatin organisation and transcription. [...] Read more.

Background/Objectives: Tau protein, a central player in Alzheimer’s disease (AD) pathology, is classically known for its role in microtubule stabilisation. However, accumulating evidence indicates that tau also localises to the neuronal nucleus, particularly the nucleolus, where it may regulate chromatin organisation and transcription. In this study, we investigated whether different phosphorylation states of nuclear tau display age- and disease-dependent patterns, with a specific focus on the AT8 epitope (phospho-Ser202/Thr205). Methods: We analysed nuclear tau epitopes (Tau-1, AT8, PHF1, T181, and S262) by indirect immunofluorescence in SK-N-BE neuroblastoma cells under proliferative and retinoic acid-induced differentiated conditions and in post-mortem hippocampal CA1 neurons from foetal, young, aged, and AD brains. Other functional markers (UBTF, Ki67, fibrillarin and acetylated histone H4) were used to assess nuclear organisation and function. Results: Compared with the other epitopes, AT8 was unique in showing dynamic nuclear localisation: absent in proliferating cells but present after differentiation, abundant in young neurons, and significantly reduced in aged and AD samples. Nuclear AT8 co-localised with Ki67, and its decline was associated with neuronal cell cycle re-entry and nucleolar disorganisation. Conclusions: Among multiple nuclear tau epitopes, AT8 was the only one displaying age- and disease-related changes, and its reduction during ageing and AD correlates with nuclear stress, aberrant cell cycle activity, and neuronal vulnerability. Loss of nuclear AT8 may therefore represent an early marker of dysfunction in ageing and AD brains. Full article

(This article belongs to the Section Neurobiology and Clinical Neuroscience)

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27 pages, 1763 KB

Open AccessReview

Molecular Mechanisms of the Ubiquitin-Specific Proteases (USPs) Family in Biliary Tract Cancer and Targeted Intervention Strategies

by Qian Cheng, Delin Ma, Shengmin Zheng, Jialing Hao, Gang Wang, Yanbin Ni and Jiye Zhu

Biomedicines 2025, 13(11), 2586; https://doi.org/10.3390/biomedicines13112586 - 23 Oct 2025

Abstract

Biliary tract carcinoma (BTC) is a group of highly heterogeneous malignancies arising from the biliary epithelium. Anatomically, BTC is categorized into gallbladder cancer (GBC) and cholangiocarcinoma (CCA), with the latter further subdivided into intrahepatic (iCCA), perihilar (pCCA), and distal cholangiocarcinoma (dCCA). Epidemiological studies [...] Read more.

Biliary tract carcinoma (BTC) is a group of highly heterogeneous malignancies arising from the biliary epithelium. Anatomically, BTC is categorized into gallbladder cancer (GBC) and cholangiocarcinoma (CCA), with the latter further subdivided into intrahepatic (iCCA), perihilar (pCCA), and distal cholangiocarcinoma (dCCA). Epidemiological studies reveal a dismal five-year survival rate of less than 20% for BTC patients, with limited responses to current chemotherapy regimens, underscoring the urgent need to unravel its complex molecular pathogenesis. Recent research has increasingly focused on the regulatory networks of post-translational modifications, particularly the ubiquitin-proteasome system (UPS), in tumorigenesis. As the largest subfamily of deubiquitinating enzymes (DUBs), ubiquitin-specific proteases (USPs) regulate the stability of key oncoproteins such as phosphatase and tensin homolog (PTEN) and c-Myc, playing pivotal roles in tumor cell proliferation, apoptosis evasion, invasion, and metastasis. This review systematically summarizes the differential expression profiles of USP family members (e.g., USP1, USP3, USP7, USP8, USP9X, USP21, and USP22) in BTC and their clinical significance, with a focus on elucidating how specific USPs regulate tumor progression through key substrates, including poly(ADP-ribose) polymerase 1 (PARP1), dynamin-1-like protein (DNM1L), and O-GlcNAc transferase (OGT). Furthermore, based on recent advances, we discuss the therapeutic potential of small-molecule USP inhibitors in BTC targeted therapy, providing a theoretical foundation for developing novel precision treatment strategies. Full article

(This article belongs to the Special Issue Ubiquitylation and Deubiquitylation in Health and Diseases)

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12 pages, 653 KB

Open AccessArticle

The Glymphatic System and Obesity: A Diffusion Tensor Imaging ALPS Study

by Kang Min Park, Jin-Hong Wi, Bong Soo Park, Dong Ah Lee and Jinseung Kim

Biomedicines 2025, 13(11), 2585; https://doi.org/10.3390/biomedicines13112585 - 22 Oct 2025

Abstract

Background: Obesity is a known risk factor for neurodegenerative diseases, potentially due to impaired clearance of brain waste through the glymphatic system. While the association between obesity and brain dysfunction has been widely studied in populations with neurological conditions, it remains unclear [...] Read more.

Background: Obesity is a known risk factor for neurodegenerative diseases, potentially due to impaired clearance of brain waste through the glymphatic system. While the association between obesity and brain dysfunction has been widely studied in populations with neurological conditions, it remains unclear whether glymphatic system function is already reduced in neurologically healthy individuals with obesity. This study aimed to investigate whether glymphatic system function, measured via the diffusion tensor image (DTI) analysis along the perivascular space (DTI-ALPS) index, differs according to obesity status in neurologically healthy adults. Methods: We retrospectively analyzed brain DTI data from 62 neurologically healthy participants stratified into underweight (<18.5 kg/m²), normal weight (BMI ≥ 18.5 and <23.0 kg/m²), overweight (BMI ≥ 23.0 and <25.0 kg/m²), and obese (≥25.0 kg/m²) groups based on the World Health Organization Asia-Pacific body mass index (BMI) criteria. Group differences were examined using Mann–Whitney U tests and analysis of covariance, after adjusting for age. Results: Participants with obesity had significantly lower DTI-ALPS index values (1.262 ± 0.150) compared to those in the normal weight (1.405 ± 0.168, p = 0.048) and overweight (1.423 ± 0.195, p = 0.029) categories, even after adjusting for age. The DTI-ALPS index was also significantly reduced in participants with obesity compared to participants in the BMI < 25 kg/m² group (1.410 ± 0.176, p = 0.015). Conclusions: This study provides the first evidence that obesity is linked to reduced glymphatic system function, as reflected by lower DTI-ALPS index in neurologically healthy adults. These findings underscore the importance of maintaining a healthy body weight to preserve brain waste clearance mechanisms and may offer insights into early vulnerability to neurodegenerative changes. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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17 pages, 2917 KB

Open AccessArticle

Terminalia chebula Retz. Fruit Extract Promotes Murine Hair Growth by Suppressing 5α-Reductase and Accelerating the Degradation of Dihydrotestosterone

by Ting Cui, Xiaoqing Wang, Qi Wu, Ye Zhong, Fenglou Wang, Yue Zou, Yushu Wang, Shanshan Jiang and Gang Ma

Biomedicines 2025, 13(11), 2584; https://doi.org/10.3390/biomedicines13112584 - 22 Oct 2025

Abstract

Background/Objectives: Androgenetic alopecia (AGA) is the most common hair loss disorder in dermatological practice. Its primary pathogenesis involves the conversion of testosterone to dihydrotestosterone (DHT) by type II 5α-reductase upon reaching dermal papilla cells (DPCs). DHT impairs DPCs’ activity and inhibits hair growth. [...] Read more.

Background/Objectives: Androgenetic alopecia (AGA) is the most common hair loss disorder in dermatological practice. Its primary pathogenesis involves the conversion of testosterone to dihydrotestosterone (DHT) by type II 5α-reductase upon reaching dermal papilla cells (DPCs). DHT impairs DPCs’ activity and inhibits hair growth. Although the FDA-approved drugs finasteride and minoxidil show certain efficacy, they are also associated with severe side effects. This study aims to explore the effects of Terminalia chebula fruit extract (TCFE) on hair growth and its underlying molecular mechanisms. Methods: We investigated the therapeutic potential of TCFE in hair follicle regeneration, employing a multi-level experimental approach combining in vitro analyses of DPCs, in vivo animal models of AGA, and ex vivo cultures of human hair follicles and scalp tissue. Results: First, RNA-seq analysis and RT-PCR validation revealed that TCFE treatment activated the Wnt and TGF-β3 signaling pathways in DPCs, particularly upregulating the AKR1C gene family, which is involved in DHT metabolism. TCFE also potently inhibited type II 5α-reductase activity and mitigated DHT-induced damage to DPCs. In an AGA mouse model, TCFE reversed the AGA phenotype with efficacy comparable to finasteride. However, unlike finasteride, TCFE specifically enhanced the expression of AKR1C1 and AKR1C3, indicating a distinct mechanism. Finally, in ex vivo organ cultures, TCFE suppressed hair follicle cell apoptosis, promoted proliferation, and thereby stimulated hair growth. Conclusions: These findings suggest that TCFE is a promising natural treatment for AGA, likely acting through multiple mechanisms, including Wnt pathway activation, 5α-reductase inhibition, and enhanced DHT degradation. Full article

(This article belongs to the Special Issue Pathophysiology and Therapeutic Innovations in Skin and Appendage Disorders)

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18 pages, 2314 KB

Open AccessArticle

NMR-Based Metabolomics Reveals Position-Specific Signatures Associated with Physical Demands in Professional Soccer Players

by Suewellyn N. dos Santos, Glydiston E. O. Ananias, Edmilson R. da Rocha, Jr., Alessandre C. Carmo, Edson de S. Bento, Thiago M. de Aquino, Ronaldo V. Thomatieli-Santos, Luiz Rodrigo A. de Lima, Pedro Balikian, Jr., Natália de A. Rodrigues, Gustavo G. de Araujo and Filipe A. B. Sousa

Biomedicines 2025, 13(11), 2583; https://doi.org/10.3390/biomedicines13112583 - 22 Oct 2025

Abstract

Background: Soccer’s varied physical demands require meticulous load monitoring, which is now being advanced by combining GPS for external metrics and NMR-based metabolomics for internal metabolic profiling. This study aimed to investigate how player position influences the metabolomic profile (as a marker of [...] Read more.

Background: Soccer’s varied physical demands require meticulous load monitoring, which is now being advanced by combining GPS for external metrics and NMR-based metabolomics for internal metabolic profiling. This study aimed to investigate how player position influences the metabolomic profile (as a marker of internal load) under known match effort (external load). Methods: This was a longitudinal observational descriptive study involving 12 professional soccer players from the U-20 São Paulo Football Club, enrolled in the 2022 São Paulo State Under-20 Football Championship. Players were monitored across six matches during the season, culminating in a total of 49 individual match observations from those players (4-2-3-1 formation: Central Defenders [CD], n = 9; Full Backs [FB], n = 9; Central Midfielders [CM], n = 14; Wide Midfielders [WM], n = 12; Forwards [F], n = 5). Internal load was assessed via urinary metabolomics, with urine samples collected 24 h post-match. A non-targeted, global metabolomics approach was employed using nuclear magnetic resonance (NMR) spectroscopy. External load was monitored using GPS tracking devices. Multivariate analyses included partial least squares discriminant analysis (PLS-DA), and heat maps. Results: Metabolomic analysis identified 38 metabolites with a Variable Importance in Projection (VIP) score > 1.0, revealing perturbations in carbohydrate metabolism and the tricarboxylic acid (TCA) cycle, amino acid and peptide metabolism, pyrimidine metabolism, and ketone body pathways, and effectively discriminating post-match recovery metabolic profiles. External load metrics varied significantly by player position: CMs covered greater distances below 20 km/h (8702.93 ± 1271.89 m), exhibited higher relative distance (114.29 ± 7.67 m/min), total distance (9193.21 ± 1261.35 m), and player load (945.71 ± 135.82 a.u.); CDs achieved higher peak speeds (31.78 ± 1.20 m/s); and WMs performed greater sprint distances (168.11 ± 91.69 m). Metabolomic profiles indicated that CMs showed stronger associations with markers of muscle damage and inflammation, whereas CDs and WMs were more closely linked to energy metabolism and oxidative stress. Conclusions: These results highlight the importance of a personalized approach to training load monitoring and recovery strategies, considering the distinct physiological and metabolic demands associated with each player position. Full article

(This article belongs to the Section Endocrinology and Metabolism Research)

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Open AccessArticle

Inhibition of PKCθ Abrogates CD8⁺ T Cell-Mediated Neurotoxicity in Murine Cerebral Malaria

by Karin Albrecht-Schgör, Victoria E. Stefan, Martina Steinlechner, Dominik Humer, Kerstin Siegmund, Sebastian Peer, Thomas Gruber, Maja Überegger, Stephanie zur Nedden, Gabriele Baier-Bitterlich, Peter Lackner, Erich Schmutzhard, Nikolaus Thuille, Victoria Klepsch and Gottfried Baier

Biomedicines 2025, 13(11), 2582; https://doi.org/10.3390/biomedicines13112582 - 22 Oct 2025

Abstract

Background: Cerebral malaria (CM) is a severe and often fatal complication of Plasmodium falciparum infection that causes devastating brain injury largely through immune-mediated mechanisms. Pathogenic brain-infiltrating CD8⁺ T cells are key drivers of CM pathology, yet the intracellular signals enabling their [...] Read more.

Background: Cerebral malaria (CM) is a severe and often fatal complication of Plasmodium falciparum infection that causes devastating brain injury largely through immune-mediated mechanisms. Pathogenic brain-infiltrating CD8⁺ T cells are key drivers of CM pathology, yet the intracellular signals enabling their harmful autoimmune-like activity remain poorly defined. Here, we identify protein kinase C θ (PKCθ), a central antigen receptor-signalling mediator, as a critical contributor to experimental cerebral malaria (ECM). Methods/Results: Using a PKCθ null allele mouse strain on a C57BL/6N background, we demonstrate that PKCθ deficiency significantly improves survival in Plasmodium berghei ANKA (PbA)-infected mice without altering parasite burdens in the blood or brain. Mechanistically, loss of PKCθ skews T cell differentiation towards central memory (Tcm) rather than effector memory (Tem) phenotypes, thereby reducing effector differentiation and sequestration of CD8⁺ T cells in the cerebral microvasculature. This prevents extensive neurovascular damage, preserves neural tissue integrity, and alleviates neurological signs and symptoms. Our findings provide genetic evidence that PKCθ drives CD8⁺ T cell-mediated brain injury in ECM. Conclusions: These results underscore the potential for repurposing clinically PKCθ inhibitors as host-targeted interventions to protect against cerebral injury and improve outcomes in patients with CM. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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Biomedicines, Volume 13, Issue 11 (November 2025) – 37 articles

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