Biomedicines

18 pages, 1010 KB

Open AccessReview

by Paola Verde, Laura Piccardi, Sandro Gentile, Graham A. Roberts, Andrea Mambro, Sofia Pepe and Felice Strollo

Biomedicines 2025, 13(9), 2125; https://doi.org/10.3390/biomedicines13092125 (registering DOI) - 30 Aug 2025

Abstract

Background/Objectives: Following the recent publication of reassuring outcomes from the ARA MED 330 protocol regarding long-term insulin use in pilots, combined with continuous advancements in diabetes technology, European aeromedical examiners are increasingly optimistic about establishing more flexible medical requirements for insulin-treated aviation professionals. [...] Read more.

Background/Objectives: Following the recent publication of reassuring outcomes from the ARA MED 330 protocol regarding long-term insulin use in pilots, combined with continuous advancements in diabetes technology, European aeromedical examiners are increasingly optimistic about establishing more flexible medical requirements for insulin-treated aviation professionals. These professionals have historically been considered unfit for duty due to hypoglycemic risks. According to current research, hypoglycemia, the primary incapacitation risk for flight crew, is considered virtually non-existent among air traffic controllers (ATCOs). Additionally, stress-induced hyperglycemia also represents a low-frequency risk in these professionals, who are experienced in managing highly stressful operational environments. This study presents a narrative review examining stress and its metabolic effects in healthy individuals, ATCOs, and people with diabetes (PwD). Methods: This narrative review was conducted based on a comprehensive PubMed search performed by two independent reviewers (GAR and AM) spanning January 2023 to January 2025. The search strategy focused on English-language, peer-reviewed studies involving human participants and addressed stress, glucose regulation, and occupational factors in ATCOs and people with diabetes. Additional relevant articles were identified through reference screening. A total of 33 studies met the inclusion criteria. Studies focusing solely on oxidative or molecular mechanisms were excluded from the analysis. Results: Stressful events consistently triggered the expected hyperglycemic reaction in both healthy individuals and PwD. However, the literature indicates ATCOs demonstrate remarkable stress resilience and adaptation to the demanding conditions of their work environment, suggesting a unique occupational profile regarding metabolic stress responses. Conclusions: These findings contribute valuable insights to ongoing discussions regarding aeromedical fitness standards. The evidence suggests that ATCOs may not face the same metabolic risks as flight crews, indicating that current medical certification processes for insulin-treated aviation professionals warrant reconsideration in light of this emerging evidence. This research supports the potential for more individualized, occupation-specific aeromedical standards that better reflect the actual risk profiles of different aviation roles. Full article

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

17 pages, 512 KB

Open AccessArticle

Phenotyping Bronchiectasis Frequent Exacerbator: A Single Centre Retrospective Cluster Analysis

by Francesco Rocco Bertuccio, Nicola Baio, Simone Montini, Valentina Ferroni, Vittorio Chino, Lucrezia Pisanu, Marianna Russo, Ilaria Giana, Elisabetta Gallo, Lorenzo Arlando, Klodjana Mucaj, Mitela Tafa, Maria Arminio, Emanuela De Stefano, Alessandro Cascina, Amelia Grosso, Erica Gini, Federica Albicini, Virginia Valeria Ferretti, Eleonora Fresi, Angelo Guido Corsico, Giulia Maria Stella and Valentina Conio Show full author list Hide full author list

Biomedicines 2025, 13(9), 2124; https://doi.org/10.3390/biomedicines13092124 (registering DOI) - 30 Aug 2025

Abstract

Background: Bronchiectasis is a chronic respiratory condition characterized by permanent bronchial dilation, recurrent infections, and progressive lung damage. A subset of patients, known as frequent exacerbators, experience multiple exacerbations annually, leading to accelerated lung function decline, hospitalizations, and reduced quality of life. The [...] Read more.

Background: Bronchiectasis is a chronic respiratory condition characterized by permanent bronchial dilation, recurrent infections, and progressive lung damage. A subset of patients, known as frequent exacerbators, experience multiple exacerbations annually, leading to accelerated lung function decline, hospitalizations, and reduced quality of life. The aim of this study is to identify distinct phenotypes and treatable traits in bronchiectasis frequent exacerbators, since it could be crucial for optimizing patient management. Research question: Could clinically distinct phenotypes and treatable traits be identified among frequent exacerbators with bronchiectasis to guide personalized management strategies? Methods: We analysed a cohort of 56 bronchiectasis frequent exacerbator patients using 21 clinically relevant variables, including pulmonary function tests, radiological patterns, and microbiological data. Hierarchical clustering and k-means algorithms were applied to identify subgroups. Key outcomes included cluster-specific characteristics, treatable traits, and their implications for management. Results: Four distinct clusters were identified: 1. Mild, idiopathic bronchiectasis (Cluster 1): Predominantly mild disease (FACED), idiopathic etiology (93.3%), and cylindrical bronchiectasis with moderate obstruction (60%). 2. Rheumatological and NTM-associated bronchiectasis (Cluster 2): Patients with systemic inflammatory diseases (50%) and NTMever (50%) but minimal infections by Pseudomonas aeruginosa. 3. Mild, post-infective bronchiectasis (Cluster 3): Exclusively mild disease, mixed idiopathic and post-infective etiologies, and preserved lung function. 4. Severe, chronic infection phenotype (Cluster 4): Severe disease with high colonization rates of Pseudomonas aeruginosa (71.4%), advanced structural damage (57.1% varicose, 50% cystic bronchiectasis), and frequent exacerbations. Interpretation: This analysis highlights the heterogeneity of bronchiectasis and its frequent exacerbator phenotype. The treatable traits framework underscores the importance of aggressive infection control and management of airway inflammation in severe cases, while milder clusters may benefit from preventive strategies. These findings support the integration of precision medicine in bronchiectasis care, focusing on phenotype-specific interventions to improve outcomes. Full article

(This article belongs to the Special Issue Advanced Research in Chronic Respiratory Diseases (CRDs))

18 pages, 371 KB

Open AccessReview

Nephroprotective Mechanisms of SGLT2i: Beyond the Glucose-Lowering Effect

by Alessio Mazzieri and Livia Maria Rita Marcon

Biomedicines 2025, 13(9), 2123; https://doi.org/10.3390/biomedicines13092123 (registering DOI) - 30 Aug 2025

Abstract

Chronic kidney disease (CKD) is a fast-growing cause of death worldwide. Systemic hypertension and diabetes mellitus are the major causes of kidney damage leading to a reduction in glomerular filtration rate and to urinary protein loss. Sodium–glucose cotransporter 2 inhibitors (SGLT2is) are drugs [...] Read more.

Chronic kidney disease (CKD) is a fast-growing cause of death worldwide. Systemic hypertension and diabetes mellitus are the major causes of kidney damage leading to a reduction in glomerular filtration rate and to urinary protein loss. Sodium–glucose cotransporter 2 inhibitors (SGLT2is) are drugs able to address both of these deleterious effects, preventing kidney damage from progressing. Initially born as hypoglycemic agents, SGLT2is subsequently proved to have not only positive metabolic but also pleiotropic effects on the kidney and the cardiovascular system. Indeed, they improve the metabolic profile, reducing uric acid, blood sugar levels, and body weight. Moreover, they exert an anti-inflammatory and antifibrotic effect, reducing endothelial dysfunction and reactive oxygen species (ROS) production. Finally, they reduce renal hyperfiltration and control blood pressure, inducing osmotic diuresis and restoring tubulo-glomerular feedback. All these metabolic, anti-inflammatory, and hemodynamic effects contribute to significantly reducing the risk of cardiorenal events, as widely demonstrated in randomized clinical trials. The pleiotropic actions of SGLT2is together with their good tolerability make them a pillar treatment of CKD regardless of the presence of diabetes mellitus. Further studies will be needed in order to expand the indications to populations previously excluded from clinical trials such as transplant recipients or glomerulonephritis patients. This narrative review aims to summarize current knowledge regarding the nephroprotective mechanisms of SGLT2is which, after initial use as a hypoglycemic agent, have assumed a pivotal role in the actual and future management of patients with CKD. Full article

(This article belongs to the Special Issue New Advances in Chronic Kidney Disease: Biology, Diagnosis and Therapy (2nd Edition))

17 pages, 8807 KB

Open AccessArticle

Establishing Human and Canine Xenograft Murine Osteosarcoma Models for Application of Focused Ultrasound Ablation

by Alayna N. Hay, Alex Simon, Lauren N. Ruger, Jessica Gannon, Sheryl Coutermarsh-Ott, Elliana R. Vickers, William Eward, Nathan J. Neufeld, Eli Vlaisavljevich and Joanne Tuohy

Biomedicines 2025, 13(9), 2122; https://doi.org/10.3390/biomedicines13092122 (registering DOI) - 30 Aug 2025

Abstract

Background: Osteosarcoma (OS) is the most commonly occurring type of bone cancer in both humans and canines. The survival outcomes for OS patients have not improved significantly in decades. A novel and innovative treatment option that is currently under investigation for OS in [...] Read more.

Background: Osteosarcoma (OS) is the most commonly occurring type of bone cancer in both humans and canines. The survival outcomes for OS patients have not improved significantly in decades. A novel and innovative treatment option that is currently under investigation for OS in the veterinary field is the focused ultrasound ablation modality, histotripsy. Histotripsy is a non-thermal, non-invasive, non-ionizing ablation modality that destroys tissue through generation of acoustic cavitation. Objective: In the current study, we sought to investigate the utility of an orthotropic OS xenograft murine model for characterization of chronic ablative and clinical outcomes post-histotripsy ablation. Method: Given the high comparative relevance of canine to human OS, histotripsy was delivered to orthotopic OS tumors in both human and canine xenograft murine models. Results: Histotripsy improved limb function in tumor-bearing mice compared to untreated tumor bearing mice. The results of this study demonstrated the utility of the orthotopic OS xenograft murine model for histotripsy-based preclinical studies. Conclusions: The current study is the first published investigation for the use of an orthotopic xenograft murine model for the development of histotripsy ablation for OS. The developmental process of the model, technical limitations, and future directions are discussed. Full article

(This article belongs to the Section Cancer Biology and Oncology)

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29 pages, 1743 KB

Open AccessReview

Roots of Progress: Uncovering Cerebellar Ataxias Using iPSC Models

by Michela Giacich, Valentina Naef, Filippo Maria Santorelli and Devid Damiani

Biomedicines 2025, 13(9), 2121; https://doi.org/10.3390/biomedicines13092121 (registering DOI) - 30 Aug 2025

Abstract

The inaccessibility of human cerebellar tissue and the complexity of its development have historically hindered the study of cerebellar ataxias, a genetically diverse group of neurodegenerative disorders. Induced pluripotent stem cell (iPSC) technology offers a powerful solution, enabling the generation of patient-specific cerebellar [...] Read more.

The inaccessibility of human cerebellar tissue and the complexity of its development have historically hindered the study of cerebellar ataxias, a genetically diverse group of neurodegenerative disorders. Induced pluripotent stem cell (iPSC) technology offers a powerful solution, enabling the generation of patient-specific cerebellar models that retain individual genetic backgrounds. This review examines recent progress in iPSC-derived cerebellar models and their application in relation to major hereditary ataxias, including Friedreich’s ataxia, ataxia–telangiectasia, and spinocerebellar ataxias (SCAs). These models have provided valuable insights into disease mechanisms and supported the development of therapeutic strategies, such as gene therapy and high-throughput drug screening. However, challenges remain, particularly in achieving the full maturation of cerebellar cell types and incorporating microglial interactions. Moreover, emerging evidence suggests that neurodevelopmental alterations may act as early contributors to degeneration. Despite the current limitations, the advancement of patient-derived iPSC cerebellar models holds great promise for uncovering novel disease pathways and for driving precision medicine approaches in cerebellar ataxia research. Full article

(This article belongs to the Special Issue Pluripotent Stem Cells: Current Understanding and Future Directions—2nd Edition)

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37 pages, 1630 KB

Open AccessReview

Pulmonary Emphysema: Current Understanding of Disease Pathogenesis and Therapeutic Approaches

by Abderrazzak Bentaher, Olivier Glehen and Ghania Degobert

Biomedicines 2025, 13(9), 2120; https://doi.org/10.3390/biomedicines13092120 (registering DOI) - 30 Aug 2025

Abstract

Pulmonary emphysema, the main component of chronic obstructive pulmonary disease, is a chronic lung inflammatory disease characterized by the loss of lung elasticity and impaired gas exchange due in large part to the destruction of alveolar walls. Cigarette smoking represents the most frequent [...] Read more.

Pulmonary emphysema, the main component of chronic obstructive pulmonary disease, is a chronic lung inflammatory disease characterized by the loss of lung elasticity and impaired gas exchange due in large part to the destruction of alveolar walls. Cigarette smoking represents the most frequent etiologic factor, but other factors involving environmental pollution and respiratory infections contribute to disease pathogenesis and worsening. In this review, we provide a review about emphysema covering risk factors; underlying mechanisms of disease pathogenesis; experimental models that mimic, as closely as possible, human disease features; and available therapeutics. Lastly, exploratory therapeutic approaches aimed at improving patient health through evidence-based and personalized medicine are presented as well. Full article

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

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14 pages, 2837 KB

Open AccessArticle

Assessment of Diffuse Myocardial Fibrosis and Myocardial Oedema in Sepsis Survivors Using Cardiovascular Magnetic Resonance: Correlation with Left Ventricular Systolic Function

by Ella Jacobs, Samuel Malomo, Thomas Oswald, Anthony Yip, Thomas Alway, Stanislav Hadjivassilev, Steven Coombs, Susan Ellery, Joon Lee, Claire Phillips, Barbara Philips, David Hildick-Smith, Victoria Parish and Alexander Liu

Biomedicines 2025, 13(9), 2119; https://doi.org/10.3390/biomedicines13092119 (registering DOI) - 30 Aug 2025

Abstract

Background/Objectives: Survivors of sepsis can develop left ventricular (LV) systolic function with focal myocardial fibrosis. The relationship between diffuse myocardial fibrosis or oedema and LV systolic function remains unknown in this patient cohort. This study sought to address this knowledge gap using [...] Read more.

Background/Objectives: Survivors of sepsis can develop left ventricular (LV) systolic function with focal myocardial fibrosis. The relationship between diffuse myocardial fibrosis or oedema and LV systolic function remains unknown in this patient cohort. This study sought to address this knowledge gap using cardiovascular magnetic resonance (CMR) parametric mapping methods. Methods: Sepsis survivors who underwent CMR at a UK cardiac centre were included. CMR images analysed include cines, native T1-mapping, native T2-mapping, and post-contrast T1-mapping. Synthetic extracellular volume (ECV) fraction was also estimated. Native myocardial T1 values, native myocardial T2 values, and ECV values were compared against LV ejection fraction (LVEF). Results: Of the 37 sepsis survivors (age 53 ± 16 years old; 57% males), the mean left ventricular ejection fraction (LVEF) was 55% (IQR 43–62), and 43% of the patients had LV systolic dysfunction (LVEF < 50%). Mean native myocardial T1 values were 1055 ± 65 ms (septal) and 1051 ± 60 ms (global). Mean synthetic ECV values were 0.30 ± 0.04. Mean native myocardial T2 values were 52 ± 7 ms (septal) and 53 ± 6 ms (global). Septal and global native myocardial T1 values were not significantly correlated with LVEF (rho = 0.080, p = 0.637; rho = 0.036, p = 0.831, respectively). Synthetic ECV was not significantly correlated to LVEF (rho = −0.082; p = 0.723). Septal and global native myocardial T2 values were weakly correlated with LVEF (rho = 0.261, p = 0.281; rho = 0.216, p = 0.375, respectively). On ROC analysis, the performance of native myocardial T1 values, ECV, and native myocardial T2 values for predicting LV dysfunction was modest (AUC: 0.53 ± 0.10, 0.54 ± 11, and 0.68 ± 0.14; all p > 0.05, respectively). Conclusions: CMR markers of diffuse myocardial fibrosis (native T1-mapping and ECV) and myocardial oedema (native T2-mapping) have weak relationships with left ventricular systolic function in this study cohort of sepsis survivors. Further work is needed to better assess the role of diffuse myocardial fibrosis and oedema in the pathophysiology of post-sepsis cardiomyopathy. Full article

(This article belongs to the Special Issue Pathogenesis, Diagnosis, and Treatment of Cardiomyopathy)

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33 pages, 955 KB

Open AccessReview

Artificial Intelligence-Driven Neuromodulation in Neurodegenerative Disease: Precision in Chaos, Learning in Loss

by Andrea Calderone, Desirèe Latella, Elvira La Fauci, Roberta Puleo, Arturo Sergi, Mariachiara De Francesco, Maria Mauro, Angela Foti, Leda Salemi and Rocco Salvatore Calabrò

Biomedicines 2025, 13(9), 2118; https://doi.org/10.3390/biomedicines13092118 (registering DOI) - 30 Aug 2025

Abstract

Neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS) are marked by progressive network dysfunction that challenges conventional, protocol-based neurorehabilitation. In parallel, neuromodulation, encompassing deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), vagus [...] Read more.

Neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS) are marked by progressive network dysfunction that challenges conventional, protocol-based neurorehabilitation. In parallel, neuromodulation, encompassing deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), vagus nerve stimulation (VNS), and artificial intelligence (AI), has matured rapidly, offering complementary levers to tailor therapy in real time. This narrative review synthesizes current evidence at the intersection of AI and neuromodulation in neurorehabilitation, focusing on how data-driven models can personalize stimulation and improve functional outcomes. We conducted a targeted literature synthesis of peer-reviewed studies identified via PubMed, Embase, Scopus, and reference chaining, prioritizing recent clinical and translational reports on adaptive/closed-loop systems, predictive modeling, and biomarker-guided protocols. Across indications, convergent findings show that AI can optimize device programming, enable state-dependent stimulation, and support clinician decision-making through multimodal biomarkers derived from neural, kinematic, and behavioral signals. Key barriers include data quality and interoperability, model interpretability and safety, and ethical and regulatory oversight. Here we argue that AI-enhanced neuromodulation reframes neurorehabilitation from static dosing to adaptive, patient-specific care. Advancing this paradigm will require rigorous external validation, standardized reporting of control policies and artifacts, clinician-in-the-loop governance, and privacy-preserving analytics. Full article

(This article belongs to the Special Issue Application of Artificial Intelligence in Biomedicines)

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18 pages, 677 KB

Open AccessArticle

The Role of Body Mass Index in Outcomes of Radial Shock Wave Therapy for Adhesive Capsulitis

by Diana-Lidia Tache-Codreanu, Iuliana David, Mihai-Andrei Butum-Cristea, Ana-Maria Tache-Codreanu, Claudia-Camelia Burcea, Elena Rusu, Andrei Tache-Codreanu, Rodica Olteanu, Teodor Dan Poteca and Corina Sporea

Biomedicines 2025, 13(9), 2117; https://doi.org/10.3390/biomedicines13092117 - 29 Aug 2025

Abstract

Background: Radial shock wave therapy (RSWT) has increasingly been integrated into treatment protocols for adhesive capsulitis. While associations with diabetes and other systemic disorders are well documented, the role of obesity remains underexplored, particularly in relation to RSWT outcomes. Methods: Forty patients with [...] Read more.

Background: Radial shock wave therapy (RSWT) has increasingly been integrated into treatment protocols for adhesive capsulitis. While associations with diabetes and other systemic disorders are well documented, the role of obesity remains underexplored, particularly in relation to RSWT outcomes. Methods: Forty patients with adhesive capsulitis completed a 10-day treatment protocol combining RSWT with conventional physiotherapy. Pain (VAS), disability (SPADI), and range of motion (ROM) were assessed at baseline and immediately after treatment. At one-month follow-up, VAS and SPADI were reassessed alongside the Patient Global Impression of Change (PGIC). Correlations between body mass index (BMI) and clinical outcomes were analyzed, and potential confounding effects of comorbidities and affected-side dominance were examined. Clinical relevance was assessed using minimal clinically important differences (MCID) and effect sizes (Cohen’s d). Results: All clinical outcomes improved significantly post-treatment and at follow-up, with most changes exceeding MCID thresholds and showing large effect sizes. Higher BMI was significantly correlated with greater improvements in SPADI, VAS, shoulder extension, and internal rotation. Most comorbidities were negatively associated with outcomes, except neurologic conditions, which supported mobility improvement. Conclusions: RSWT appears effective in alleviating symptoms of adhesive capsulitis. The observed association between higher BMI and greater mobility improvement suggests potential benefits in overweight and obese patients. These findings warrant further investigation. Full article

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

20 pages, 2004 KB

Open AccessArticle

Design, Synthesis, and Computational Insights into PKMYT1 Inhibitors for the Treatment of Breast Cancer

by Jinyu Yu, Haoyu Zhang, Chuanxu Su, Shizhe Yuan, Nian Liu, Yin Sun, Yixiang Sun, Zixuan Gao, Dongmei Zhao and Maosheng Cheng

Biomedicines 2025, 13(9), 2116; https://doi.org/10.3390/biomedicines13092116 - 29 Aug 2025

Abstract

Background: Membrane-associated tyrosine-threonine protein kinase 1 (PKMYT1), which is identified as a synthetic lethal partner of CCNE1, emerged as a promising therapeutic target in oncology. Methods: A series of novel PKMYT1 inhibitors were designed by employing a pharmacophore fusion strategy. [...] Read more.

Background: Membrane-associated tyrosine-threonine protein kinase 1 (PKMYT1), which is identified as a synthetic lethal partner of CCNE1, emerged as a promising therapeutic target in oncology. Methods: A series of novel PKMYT1 inhibitors were designed by employing a pharmacophore fusion strategy. The underlying mechanisms were investigated by means of pharmacological experiments and molecular simulations. Results: Compound MY-14 demonstrated optimal kinase inhibition (IC₅₀ = 0.002 μM) and significant anti-proliferative efficacy against CCNE1-amplified cells (IC_50-HCC1569 = 1.06 μM and IC_50-OVCAR3 = 0.80 μM). Furthermore, MY-14 induced concentration-dependent apoptosis, inhibited colony formation, and effectively arrested cell-cycle progression at the S-phase through synthetic lethality. Molecular dynamics simulations, Hirshfeld surface analysis, dynamic cross-correlation matrix (DCCM), and MM/GBSA calculations elucidated the molecular mechanism underlying MY-14’s interaction with PKMYT1. Conclusions: MY-14 emerged as a promising compound for the development of a novel PKMYT1 inhibitor. Full article

(This article belongs to the Special Issue New Horizons in Enzyme Inhibitor Discovery: Targets, Design and Evaluation)

18 pages, 2557 KB

Open AccessArticle

17βH-Neriifolin Improves Cardiac Remodeling Through Modulation of Calcium Handling Proteins in the Heart Failure Rat Model

by Rajasegar Anamalley, Yusof Kamisah, Nurhanan Murni Yunos and Satirah Zainalabidin

Biomedicines 2025, 13(9), 2115; https://doi.org/10.3390/biomedicines13092115 - 29 Aug 2025

Abstract

Background: Cardiac glycosides such as digoxin have been commonly used for patients with heart failure; however, their toxicity remains a main concern. 17βH-neriifolin (SNA209), a cardiac glycoside compound, has been recently isolated from Ceberra odollum Gaertn and was shown to improve the heart’s [...] Read more.

Background: Cardiac glycosides such as digoxin have been commonly used for patients with heart failure; however, their toxicity remains a main concern. 17βH-neriifolin (SNA209), a cardiac glycoside compound, has been recently isolated from Ceberra odollum Gaertn and was shown to improve the heart’s pumping ability in failing hearts ex vivo. Thus, this study aimed to investigate the potential use of SNA209 as a treatment for isoprenaline (ISO)-induced heart failure in rats. Methods: Forty male Wistar rats were randomly divided into five groups. Heart failure was induced by isoprenaline (ISO, 10 mg/kg/s.c) for 14 days daily, followed by SNA209 treatment (5 mg/kg; p.o) for another 14 days daily. Control rats were given saline as a vehicle for ISO and DMSO as a vehicle for SNA209. Results: Systolic and diastolic blood pressure (SBP and DBP) in all ISO-treated groups were significantly increased compared to the control group (p < 0.05), and SNA209 treatment managed to reduce the SBP and DBP. Additionally, SNA209 treatment significantly increased the heart rate and normalized the ECG parameters in ISO-treated rats. Pro-B-type natriuretic peptide and troponin T level, a cardiac injury markers, was remarkably reduced by SNA209 in the ISO-treated group. Cardiac hypertrophy was evident in increased cardiomyocyte size in ISO groups; however, SNA reduced the cardiomyocyte size. The left ventricular developed pressure (LVDP) in ISO treated with SNA209 was significantly raised, indicating a chronotropic effect. Cardiac Na⁺/K⁺-ATPase expression of the α1 subunit, sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase 2a (SERCA2a), and sodium–calcium exchanger subunit were significantly increased in the SNA treatment groups. Conclusions: The SNA 209 treatment improved cardiac function and structure, likely via modulating intracellular calcium management, so underscoring its potential as an adjuvant therapy for heart failure. Full article

(This article belongs to the Special Issue Advances in Cardiovascular Diseases: Pathophysiological Insights, Therapeutic Strategies and Future Directions)

18 pages, 4651 KB

Open AccessArticle

Identification of Pyroptosis-Related Genes and Immune Landscape in Myocardial Ischemia–Reperfusion Injury

by Yanfang Zhu, Haoyan Zhu, Jia Zhou, Jiahe Wu, Xiaorong Hu, Chenze Li, Huanhuan Cai and Zhibing Lu

Biomedicines 2025, 13(9), 2114; https://doi.org/10.3390/biomedicines13092114 - 29 Aug 2025

Abstract

Background: Cardiomyocyte death is a key factor in myocardial ischemia–reperfusion injury (MI/RI), and the expression patterns and molecular mechanisms of pyroptosis-related genes (PRGs) in ischemia–reperfusion injury are poorly understood. Methods: The mouse MI/RI injury-related datasets GSE61592 and GSE160516 were obtained from the [...] Read more.

Background: Cardiomyocyte death is a key factor in myocardial ischemia–reperfusion injury (MI/RI), and the expression patterns and molecular mechanisms of pyroptosis-related genes (PRGs) in ischemia–reperfusion injury are poorly understood. Methods: The mouse MI/RI injury-related datasets GSE61592 and GSE160516 were obtained from the Gene Expression Omnibus database, and differential expression analysis was performed on each to identify differentially expressed genes (DEGs). The DEGs were intersected with the PRGs obtained from GeneCards to identify differentially expressed PRGs in MI/RI. Enrichment analysis identified key pathways, while PPI network analysis revealed hub genes. The expression patterns and immune cell infiltration of hub genes were also investigated. The molecular docking prediction of key genes was performed using MOE software in conjunction with the ZINC small molecular compounds database. Key gene expression was validated in an external dataset (GSE4105), a mouse MI/RI model, and an HL-1 cell hypoxia/reoxygenation model via RT-qPCR. Results: A total of 29 differentially expressed PRGs were identified, which are primarily associated with pathways such as “immune system process”, “response to stress”, “identical protein binding”, and “extracellular region”. Seven key genes (Fkbp10, Apoe, Col1a2, Ppic, Tlr2, Fstl1, Serpinh1) were screened, all strongly correlated with immune infiltration. Seven FDA-approved small molecule compounds exhibiting the highest docking potential with each key gene were selected based on a comprehensive evaluation of S-scores and hydrogen bond binding energies. Apoe, Tlr2, and Serpinh1 were successfully validated across external datasets, the mouse MI/RI model, and the cardiomyocyte H/R model. Conclusions: Apoe, Tlr2, and Serpinh1 may be key genes involved in MI/RI-related pyroptosis. Targeting these genes may provide new insights into the treatment of MI/RI. Full article

(This article belongs to the Special Issue Pathogenesis, Diagnosis, and Treatment of Cardiomyopathy)

13 pages, 1253 KB

Open AccessArticle

Efficacy of Early Postoperative Subthreshold Micropulse Laser Therapy in Preventing Persistent Macular Oedema in Patients After Epiretinal Membrane Surgery

by Alicja Ziontkowska-Wrzałek, Monika Dzięciołowska, Krzysztof Safranow and Anna Machalińska

Biomedicines 2025, 13(9), 2113; https://doi.org/10.3390/biomedicines13092113 - 29 Aug 2025

Abstract

Background/Objectives: Epiretinal membrane (ERM) is often associated with macular thickening and foveal intraretinal fluid. The aim of this study was to evaluate the efficacy of early postoperative SMLT (577 nm) in preventing persistent macular oedema and to assess its impact on selected functional [...] Read more.

Background/Objectives: Epiretinal membrane (ERM) is often associated with macular thickening and foveal intraretinal fluid. The aim of this study was to evaluate the efficacy of early postoperative SMLT (577 nm) in preventing persistent macular oedema and to assess its impact on selected functional and morphometric retinal parameters after ERM peeling. Methods: A total of 68 pseudophakic patients with ERMs were enrolled and randomly assigned (1:1) to a laser group or a nonlaser control group. SMLT was performed one month after PPV. The functional and morphometric retinal parameters were assessed preoperatively and at one and four months postoperatively via optical coherence tomography (OCT), OCT angiography (OCTA), multifocal electroretinography (mfERG), and microperimetry. Results: The reduction in total retinal volume between the first and fourth postoperative months was significantly greater in the SMLT group than in the control group (p = 0.02). No significant differences in functional parameters were found between the groups. A more substantial reduction in total retinal volume post-SMLT was associated with greater baseline macular thickness, a more advanced ERM stage, worse baseline visual acuity, greater fixation stability, lower initial macular sensitivity and lower preoperative p-wave amplitude in ring R1 on mfERG. Conclusions: SMLT may be considered a therapeutic option in patients with advanced ERM stages and low preoperative visual acuity. Full article

(This article belongs to the Special Issue Advances in Therapeutics for Retinal Degeneration)

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14 pages, 1559 KB

Open AccessArticle

Electroacupuncture Relieves Fibromyalgia Pain in a Female Mouse Model by Augmenting Cannabinoid Receptor 1 Expression and Suppressing Astrocyte and Microglial Activation in Nociceptive Pathways

by I-Han Hsiao, Ming-Chia Lin, Hsin-Cheng Hsu, Younbyoung Chae, I-Ying Lin and Yi-Wen Lin

Biomedicines 2025, 13(9), 2112; https://doi.org/10.3390/biomedicines13092112 - 29 Aug 2025

Abstract

Background/Objectives: Fibromyalgia is a chronic pain syndrome with unclear etiology, meaning that it is difficult to treat effectively. The stimulation of cannabinoid receptor 1 (CB1) suppresses neuronal excitability and synaptic transmission in nociceptive pathways via reducing activity in the calcium channel and [...] Read more.

Background/Objectives: Fibromyalgia is a chronic pain syndrome with unclear etiology, meaning that it is difficult to treat effectively. The stimulation of cannabinoid receptor 1 (CB1) suppresses neuronal excitability and synaptic transmission in nociceptive pathways via reducing activity in the calcium channel and promoting the opening of the potassium channel. Methods: In this study, we examined whether CB1 activity contributes to the antinociceptive efficacy of electroacupuncture (EA) in a mouse fibromyalgia (FM) pain model established using intermittent cold stress (ICS). The model mice demonstrated both mechanical and thermal hyperalgesia measured using the von Frey and Hargreaves tests, respectively. Results: Electroacupuncture effectively reduced both forms of hyperalgesia and enhanced CB1 expression in the dorsal root ganglia, spinal cord, hypothalamus, and periaqueductal gray. In addition, EA attenuated the fibromyalgia-associated reactive transformation of microglia and astrocytes and the activation of the pain-related TLR4–MyD88–TRAF6 signaling pathway. The effects of ICS were also mitigated by the deletion of Trpv1, the gene encoding the transient receptor potential cation channel TRPV1 (capsaicin channel) implicated in nociceptive and inflammatory signaling. Further, the antinociceptive efficacy of EA was partially recapitulated by the acupoint injection of a CB1 agonist and abolished by the injection of a CB1 antagonist, suggesting that activating CB1 is essential for this therapeutic effect. Conclusions: Electroacupuncture can effectively alleviate mechanical and thermal hyperalgesia in a mouse model affected by fibromyalgia pain by activating the CB1 pathway, highlighting the therapeutic potential of CB1 agonism as a therapeutic strategy. Full article

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

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18 pages, 832 KB

Open AccessSystematic Review

Predictive Performance of Machine Learning Models for Heart Failure Readmission: A Systematic Review

by Nader Alnomasy, Petelyne Pangket, Romeo Mostoles, Jr., Habib Alrashedi, Eddieson Pasay-an, Hwayoung Cho, Sharifah Alsayed, Analita Gonzales, Amal A. Mohammad Alharbi, Nuha Ayad H. Alatawi, Sheila Torres, Khulud Abudawood and Fatmah Ahmed Alamoudi

Biomedicines 2025, 13(9), 2111; https://doi.org/10.3390/biomedicines13092111 - 29 Aug 2025

Abstract

Background: Patients with heart failure (HF) are at high risk of readmission, contributing to substantial healthcare costs. This study investigated machine learning (ML) approaches to predict HF readmissions. Methods: A systematic review was conducted using several medical databases, adhering to the PRISMA guidelines, [...] Read more.

Background: Patients with heart failure (HF) are at high risk of readmission, contributing to substantial healthcare costs. This study investigated machine learning (ML) approaches to predict HF readmissions. Methods: A systematic review was conducted using several medical databases, adhering to the PRISMA guidelines, to identify studies employing ML to predict HF readmissions. Three reviewers independently screened the articles and extracted data. Results: Twenty-two studies from six countries were included in this study. Some studies examined 30-day readmissions, whereas others assessed 90-day, 180-day, or 1- to 3-year readmissions. Fourteen studies used supervised learning algorithms, with area under the curve (AUC) values ranging from 0.70 to 0.99, and unsupervised algorithms had AUCs of 0.69 to 0.72. The average age of the patients was 73 years, with approximately equal numbers of males and females. Conclusions: ML can predict HF-related hospitalization across various time frames. Supervised ML approaches and the incorporation of clinical knowledge may enhance model performance. Collaboration between providers and data scientists is needed to improve patient outcomes and reduce costs by using more accurate predictive models. Full article

(This article belongs to the Special Issue Advances in the Pathogenesis and Treatment of Heart Failure and Cardiomyopathy)

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14 pages, 681 KB

Open AccessArticle

Distinct Plasma LPC Signatures Differentiate COVID-19 Sepsis from Other Sepsis Aetiologies

by Vlad Pavel, Patricia Mester, Marcus Höring, Gerhard Liebisch, Stephan Schmid, Martina Müller and Christa Buechler

Biomedicines 2025, 13(9), 2110; https://doi.org/10.3390/biomedicines13092110 - 29 Aug 2025

Abstract

Background/Objectives: Low levels of lysophosphatidylcholine (LPC) in the blood can be used as a diagnostic marker for sepsis. SARS-CoV-2 infection, a more recent cause of sepsis, shares similarities with non-SARS-CoV-2 sepsis but also exhibits distinct features. We have recently shown that plasma cholesteryl [...] Read more.

Background/Objectives: Low levels of lysophosphatidylcholine (LPC) in the blood can be used as a diagnostic marker for sepsis. SARS-CoV-2 infection, a more recent cause of sepsis, shares similarities with non-SARS-CoV-2 sepsis but also exhibits distinct features. We have recently shown that plasma cholesteryl ester levels are higher in patients with SARS-CoV-2 infection than in patients without, and this study analysed whether this may extend to differences in LPC, a bioactive constituent of lipoproteins. Methods: The plasma levels of 13 LPC species were measured by flow injection analysis tandem mass spectrometry (FIA-MS/MS) in 157 patients with systemic inflammatory response syndrome (SIRS), sepsis or septic shock. Of these patients, 24 had SARS-CoV-2 infection. Results: Patients with SIRS exhibited higher plasma levels of the minor LPC species LPC 15:0 and 22:4 compared to those with sepsis or septic shock. Five LPC species were also reduced in the plasma of 31 patients with liver cirrhosis; therefore, patients with cirrhosis or SIRS were excluded from subsequent analyses. Compared to 76 non-COVID-19 patients with sepsis or septic shock, SARS-CoV-2 infection in 21 patients was associated with significantly higher plasma levels of ten individual LPC species and total LPC concentration. In patients with sepsis/septic shock, LPC species showed negative correlations with procalcitonin and interleukin-6, and positive correlations with gamma-glutamyltransferase and cholesteryl ester levels. In contrast, no significant associations were observed between LPC levels and C-reactive protein, aminotransferases, or free cholesterol. Conclusions: Differential LPC levels, despite comparable disease severity, may serve as metabolic biomarkers to distinguish SARS-CoV-2 sepsis from other causes of sepsis and inform targeted therapeutic approaches. Full article

(This article belongs to the Special Issue Molecular Biomarkers and More Efficient Therapies for Sepsis—2nd Edition)

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10 pages, 1709 KB

Open AccessArticle

Comparative Analysis of Small Nerve Fiber Density in Fibromyalgia Syndrome and Small Fiber Neuropathy

by Pietro Falco, Eleonora Galosi, Caterina Maria Leone, Gianfranco De Stefano, Giuseppe Di Pietro, Giulia Di Stefano, Nicoletta Esposito, Enrico Evangelisti, Daniel Litewczuk, Cristina Mollica, Lars Arendt-Nielsen and Andrea Truini

Biomedicines 2025, 13(9), 2109; https://doi.org/10.3390/biomedicines13092109 - 29 Aug 2025

Abstract

Background/Objectives: Fibromyalgia syndrome is commonly associated with reduced intraepidermal nerve fiber density (IENFD), as assessed by skin biopsy, a finding referred to as small fiber pathology (SFP-FMG). The clinical significance of this abnormality, and how it relates to symptoms in fibromyalgia, remains uncertain. [...] Read more.

Background/Objectives: Fibromyalgia syndrome is commonly associated with reduced intraepidermal nerve fiber density (IENFD), as assessed by skin biopsy, a finding referred to as small fiber pathology (SFP-FMG). The clinical significance of this abnormality, and how it relates to symptoms in fibromyalgia, remains uncertain. Reduced IENFD also represents the defining feature of small fiber neuropathy (SFN). While previous observations suggest that IENFD reduction is generally less severe in SFP-FMG than in SFN, no study has directly confirmed this finding in a large cohort. This retrospective study aimed to compare the severity of IENFD reduction in patients with SFP-FMG and those with SFN. Methods: To account for age and sex differences, we used the age-and sex-adjusted axonal loss density (ALD), defined as the percentage reduction from normative IENFD values. We retrospectively analyzed skin biopsy data from 73 patients with SFP-FMG and 134 patients diagnosed with SFN. Results: We found that the reduction in IENFD was significantly milder in patients with SFP-FMG than in those with SFN both at distal and proximal sites. Receiver operating characteristic analysis indicated that an ALD threshold of 37.6% provided good specificity for distinguishing SFN from SFP-FMG. Conclusions: These findings indicate that small fiber damage in fibromyalgia syndrome is quantitatively mild compared to patients with SFN. This may explain the absence of detectable sensory deficits on clinical examination and suggests a limited contribution of peripheral nerve damage to the pathophysiology of fibromyalgia syndrome. Full article

(This article belongs to the Special Issue Advanced Research on Fibromyalgia (3rd Edition))

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14 pages, 1689 KB

Open AccessArticle

Crossing Barriers: PEGylated Gold Nanoparticles as Promising Delivery Vehicles for siRNA Delivery in Alzheimer’s Disease

by Elżbieta Okła, Marcin Hołota, Sylwia Michlewska, Serafin Zawadzki, Katarzyna Miłowska, Javier Sánchez-Nieves, Rafael Gómez, Francisco Javier De la Mata, Maria Bryszewska and Maksim Ionov

Biomedicines 2025, 13(9), 2108; https://doi.org/10.3390/biomedicines13092108 - 29 Aug 2025

Abstract

Background: The proportion of people suffering from neurodegenerative conditions, such as Alzheimer’s disease (AD), is increasing in the population year on year. Despite the constant effort of researchers, these conditions remain incurable and can only be managed by alleviation or delaying of [...] Read more.

Background: The proportion of people suffering from neurodegenerative conditions, such as Alzheimer’s disease (AD), is increasing in the population year on year. Despite the constant effort of researchers, these conditions remain incurable and can only be managed by alleviation or delaying of symptoms. The lack of suitable treatment is caused by constricted access to the brain, limited by the brain-blood barrier. The aim of this work was to investigate two pegylated gold nanoparticles as potential carriers of therapeutic siRNA and their impact on the cellular functions of Human Brain Endothelial Cells. Methods and Results: Nanoparticles AuNP14a and AuNP14b complexed with siRNA were internalized by HBEC-5i cells and located in the cytoplasm. The genotoxicity assay proved that the nucleus was not affected and complexed nanoparticles did not cause DNA damage. The reactive oxygen species formation and mitochondrial membrane potential changes were measured and showed an adaptive response of cells after compound administration. Results obtained in a cytotoxicity assay conducted on astrocytes and pericytes, which are components of the blood–brain barrier, confirmed the biosafety of tested nanoparticles. Conclusions: In summary, it was shown that AuNP14a and AuNP14b are promising candidates as nanocarriers for therapeutic nucleic acids through biological barriers. Full article

(This article belongs to the Special Issue Recent Advances in Targeted Drug Delivery Systems)

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22 pages, 3751 KB

Open AccessArticle

Immunomodulatory Effects of High-Dose Irradiation Regimens in Renal Cell Carcinoma: Insights from an In Vitro Model with Human Peripheral Blood Mononuclear Cell

by Fatima Meniai Merzouki, Guillaume Paul Grolez, Clément Bouchez, Bertrand Leroux, Jérôme Benoit, Olivier Morales and Nadira Delhem

Biomedicines 2025, 13(9), 2107; https://doi.org/10.3390/biomedicines13092107 - 29 Aug 2025

Abstract

Background: Stereotactic ablative radiotherapy (SABR) is increasingly used in the treatment of localized and metastatic renal cell carcinoma (RCC), a malignancy traditionally considered radioresistant. Beyond direct cytotoxicity, SABR may promote immunogenic cell death and modulate the tumor immune microenvironment, though the underlying mechanisms [...] Read more.

Background: Stereotactic ablative radiotherapy (SABR) is increasingly used in the treatment of localized and metastatic renal cell carcinoma (RCC), a malignancy traditionally considered radioresistant. Beyond direct cytotoxicity, SABR may promote immunogenic cell death and modulate the tumor immune microenvironment, though the underlying mechanisms remain incompletely understood. Objectives and Methods: This study examined the immunomodulatory effects of two high-dose irradiation regimens (8 Gy and 3 × 8 Gy) in an in vitro model using two RCC cell lines (ACHN, Caki-2) and peripheral blood mononuclear cells (PBMCs) from healthy donors. Results: The 3 × 8 Gy regimen more effectively reduced tumor cell viability and proliferation, particularly in ACHN cells, suggesting differential radiosensitivity. Both regimens induced secretion of IL-6, IL-8, TGF-β, and VEGF, with levels varying by cell line and dose. Caki-2 cells exhibited a cytokine profile consistent with a pro-inflammatory and potentially immunosuppressive phenotype. Conditioned media from irradiated cells were used to stimulate PBMCs, revealing divergent responses. Media from 3 × 8 Gy-irradiated ACHN cells enhanced PBMC proliferation and increased CD8⁺ T cells and CD11c⁺ monocytes, along with IFN-γ, IL-2, and TNF-α secretion, suggesting immunostimulatory effects. Conversely, media from Caki-2 cells had minimal impact on PBMC proliferation and increased TGF-β levels. Conclusions: These results indicate that high-dose irradiation can differentially modulate immune responses in RCC cell lines, depending on tumor intrinsic properties and irradiation regimen. Further in vivo studies are warranted to validate these findings and support development of SABR immunotherapy combinations guided by predictive immune biomarkers. Full article

(This article belongs to the Special Issue Advances in the Treatment of Kidney and Upper Urinary Tract Cancers: Second Edition)

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