Biomedicines

20 pages, 5004 KB

Open AccessEditor’s ChoiceArticle

Maresin1 Alleviates Ischemia Reperfusion Injury After Lung Transplantation by Inhibiting Ferroptosis via the PKA-Hippo-YAP Signaling Pathway

by Peng Deng, You Wu, Li Wan, Xiangfu Sun and Quanchao Sun

Biomedicines 2025, 13(7), 1594; https://doi.org/10.3390/biomedicines13071594 - 30 Jun 2025

Cited by 7 | Viewed by 1937

Abstract

Background: Lung ischemia reperfusion injury (LIRI) is a severe complication after lung transplantation (LT). Ferroptosis contributes to the pathogenesis of LIRI. Maresin1 (MaR1) is an endogenous pro-resolving lipid mediator that exerts protective effects against multiorgan diseases. However, the role and mechanism of [...] Read more.

Background: Lung ischemia reperfusion injury (LIRI) is a severe complication after lung transplantation (LT). Ferroptosis contributes to the pathogenesis of LIRI. Maresin1 (MaR1) is an endogenous pro-resolving lipid mediator that exerts protective effects against multiorgan diseases. However, the role and mechanism of MaR1 in the ferroptosis of LIRI after LT need to be further investigated. Methods: A mouse LT model and a pulmonary vascular endothelial cell line after hypoxia reoxygenation (H/R) culture were established in our study. Histological morphology and inflammatory cytokine levels predicted the severity of LIRI. Cell viability and cell injury were determined by CCK-8 and LDH assays. Ferroptosis biomarkers, including Fe²⁺, MDA, 4-HNE, and GSH, were assessed by relevant assay kits. Transferrin receptor (TFRC) and Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) protein levels were examined by western blotting. In vitro, lipid peroxide levels were detected by DCFH-DA staining and flow cytometry analysis. The ultrastructure of mitochondria was imaged using transmission electron microscopy. Furthermore, the potential mechanism by which MaR1 regulates ferroptosis was explored and verified with signaling pathway inhibitors using Western blotting. Results: MaR1 protected mice from LIRI after LTx, which was reversed by the ferroptosis agonist Sorafenib in vivo. MaR1 administration decreased Fe²⁺, MDA, 4-HNE, TFRC, and ACSL4 contents, increased GSH levels, and ameliorated mitochondrial ultrastructural injury after LTx. In vitro, Sorafenib resulted in lower cell viability and worsened cell injury and enhanced the hallmarks of ferroptosis after H/R culture, which was rescued by MaR1 treatment. Mechanistically, the protein kinase A and YAP inhibitors partly blocked the effects of MaR1 on ferroptosis inhibition and LIRI protection. Conclusions: This study revealed that MaR1 alleviates LIRI and represses ischemia reperfusion-induced ferroptosis via the PKA-Hippo-YAP signaling pathway, which may offer a promising theoretical basis for the clinical application of organ protection after LTx. Full article

(This article belongs to the Special Issue The Role of Iron in Human Diseases)

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11 pages, 704 KB

Open AccessEditor’s ChoiceArticle

Impaired Glucose Tolerance and Altered Body Composition in Obese Young Adults: A Case–Control Study

by Himan Mohamed-Mohamed, Teresa Pardo-Moreno, Margarita Jimenez-Palomares, Bibiana Perez-Ardanaz, Encarnación M. Sánchez-Lara, Maria D. Vazquez-Lara, Mario de La Mata-Fernandez, Victoria García-Morales and Juan José Ramos-Rodríguez

Biomedicines 2025, 13(7), 1569; https://doi.org/10.3390/biomedicines13071569 - 26 Jun 2025

Cited by 5 | Viewed by 2817

Abstract

Background/Objectives: To examine the association between body composition and glucose tolerance in young adults with normal weight, overweight, or obesity. Methods: This observational case–control study included 154 healthy individuals aged 18–25 years. Participants were categorized into three BMI-based groups and underwent [...] Read more.

Background/Objectives: To examine the association between body composition and glucose tolerance in young adults with normal weight, overweight, or obesity. Methods: This observational case–control study included 154 healthy individuals aged 18–25 years. Participants were categorized into three BMI-based groups and underwent anthropometric and body composition assessments using bioelectrical impedance. Glucose tolerance was evaluated via oral glucose tolerance testing, with capillary blood samples collected at baseline and at 30, 60, 90, and 120 min post load. Results: Compared to the normal-weight group, overweight and obese individuals exhibited significantly higher body weight, BMI, visceral and total fat percentages, and reduced muscle mass. Obese participants also showed a significantly greater glucose area under the curve (AUC) and higher fasting and post-load glucose levels. Visceral fat was positively correlated with metabolic impairment. These results indicate a progressive decline in glucose tolerance associated with increasing adiposity and reduced lean mass. Conclusions: Young adults with elevated BMI already demonstrate marked alterations in body composition and impaired glucose tolerance, even in the absence of overt metabolic disease. These findings underscore the importance of the early identification of at-risk individuals using simple, non-invasive tools. Preventive strategies promoting healthy body composition in early adulthood may reduce the future risk of diabetes and its associated complications. Full article

(This article belongs to the Special Issue Biomarkers in Metabolic Disorders, Obesity and Type 2 Diabetes Mellitus)

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27 pages, 719 KB

Open AccessEditor’s ChoiceReview

Urolithin A in Central Nervous System Disorders: Therapeutic Applications and Challenges

by Qiang Zhang, Wan Zhang, Xinya Yuan, Xiaohong Peng and Guangyuan Hu

Biomedicines 2025, 13(7), 1553; https://doi.org/10.3390/biomedicines13071553 - 25 Jun 2025

Cited by 22 | Viewed by 14863

Abstract

With the global trend of population aging becoming increasingly pronounced, the incidence of central nervous system (CNS) disorders continues to rise, posing a significant challenge to public health systems worldwide. Currently, many CNS disorders lack effective treatments, prompting researchers to investigate the therapeutic [...] Read more.

With the global trend of population aging becoming increasingly pronounced, the incidence of central nervous system (CNS) disorders continues to rise, posing a significant challenge to public health systems worldwide. Currently, many CNS disorders lack effective treatments, prompting researchers to investigate the therapeutic potential of natural compounds. Urolithin A (UA), a gut microbiota-derived metabolite of ellagitannins and ellagic acid, can cross the blood–brain barrier and exhibits a favorable safety profile. This review summarizes the biosynthesis, pharmacokinetic profile, and key biological effects of UA, including its promotion of mitophagy and mitochondrial homeostasis, as well as its anti-inflammatory, antioxidant, anti-senescence, and anti-apoptotic properties. We comprehensively summarize the preclinical evidence demonstrating UA’s therapeutic potential in CNS disorders, such as Alzheimer’s disease, Parkinson’s disease, and stroke. Recent clinical trials involving UA are presented, followed by a thorough analysis of the challenges associated with translating UA-based interventions into clinical practice for CNS disorders. This work aims to support the development of UA-based therapies to improve patient outcomes and address the growing global burden of CNS disorders. Full article

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

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20 pages, 751 KB

Open AccessEditor’s ChoiceArticle

Crosstalk Between Metabolic Biomarkers and Pulse Wave Analysis in Hypertensive Patients

by Mirela Baba, Mihaela Ioana Maris, Adina Bucur, Daniela Jianu, Simina Mariana Moroz, Dana Stoian, Constantin Tudor Luca and Ioana Mozos

Biomedicines 2025, 13(7), 1514; https://doi.org/10.3390/biomedicines13071514 - 20 Jun 2025

Cited by 2 | Viewed by 1921

Abstract

Background/Objectives: Hypertension is strongly linked to changes in vascular function and lipid metabolism. This study aimed to examine the relationship between lipid profiles, various metabolic biomarkers, and pulse wave analysis in patients with hypertension. Methods: A group of 66 hypertensive patients, aged 64 [...] Read more.

Background/Objectives: Hypertension is strongly linked to changes in vascular function and lipid metabolism. This study aimed to examine the relationship between lipid profiles, various metabolic biomarkers, and pulse wave analysis in patients with hypertension. Methods: A group of 66 hypertensive patients, aged 64 ± 10 years, participated in pulse wave analysis utilizing an oscillometric device. Multiple lipid serum biomarkers were assessed, such as total cholesterol (TC), triglycerides (TG), and non-HDL cholesterol (non-HDL). Lipid balance index (LBI) was determined by considering TG, LDL, HDL levels, and lipid-lowering medications. Results: Notable correlations were observed for SBP, DBP, and early vascular aging (EVA) with lipid biomarkers. In addition to serum lipids, metabolic syndrome, insulin resistance, and non-alcoholic fatty liver disease (NAFLD) were significantly linked to pulse wave analysis variables. Multiple regression analysis showed that only TC continued to have a significant association with DBP. Conclusions: Total cholesterol, triglycerides, non-HDL cholesterol, and lipid balance index provide information about systolic and diastolic blood pressure, as well as early vascular aging in hypertensive patients. LBI offers valuable vascular insights in hypertensive individuals with cardiovascular risk factors, early vascular aging, insulin resistance, and NAFLD. The connection between metabolic biomarkers and pulse wave measurements in individuals with hypertension offers a comprehensive method for the early identification of vascular injury and could enhance the prediction of major cardiovascular events. Full article

(This article belongs to the Special Issue Lipids and Lipid Metabolism in Cardiovascular Health and Disease)

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12 pages, 1031 KB

Open AccessEditor’s ChoiceArticle

IDH1 Mutation Impacts DNA Repair Through ALKBH2 Rendering Glioblastoma Cells Sensitive to Artesunate

by Olivier Switzeny, Stefan Pusch, Markus Christmann and Bernd Kaina

Biomedicines 2025, 13(6), 1479; https://doi.org/10.3390/biomedicines13061479 - 16 Jun 2025

Cited by 2 | Viewed by 2581

Abstract

Background: Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are enzymes that catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG), which is essential for many metabolic processes, including some steps in DNA repair. In tumors, notably in gliomas, IDH1 and IDH2 [...] Read more.

Background: Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are enzymes that catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG), which is essential for many metabolic processes, including some steps in DNA repair. In tumors, notably in gliomas, IDH1 and IDH2 are frequently mutated. The mutation found in different cancers is functionally active, causing, instead of α-KG, the formation of 2-hydroxyglutarate (2-HG), which inhibits α-KG-dependent enzymes. Gliomas harboring mutated IDH1/2 show a better prognosis than IDH1 wild-type (wt) tumors of the same grade, which might result from the inhibition of DNA repair functions. A DNA repair enzyme dependent on α-KG is alkB homolog 2 (ALKBH2), which removes several lesions from DNA. These findings prompted us to investigate the response of glioma cells to artesunate (ART), a plant ingredient with genotoxic and anticancer activity currently used in several trials. Materials and Methods: We used isogenic glioblastoma cell lines that express IDH1 wild-type or, based on a TET-inducible system, the IDH1 mutant (mt) protein, and treated them with increasing doses of artesunate. We also treated glioblastoma cells with 2-HG, generated ALKBH2 knockout cells, and checked their sensitivity to the cytotoxic effects of artesunate. Results: We show that the cell-killing effect of ART is enhanced if the IDH1 mutant (R132H) is expressed in glioblastoma cells. Further, we show that 2-HG imitates the effect of IDH1mt as 2-HG ameliorates the cytotoxicity of ART. Finally, we demonstrate that the knockout of ALKBH2 causes the sensitization of glioblastoma cells to ART. Conclusions: The data indicate that ALKBH2 protects against the anticancer effect of ART, and the mutation of IDH1/2 commonly occurring in low-grade gliomas sensitizes to ART via an ALKBH2-dependent mechanism. The data support the use of ART in the therapy of IDH1/2-mutated cancers both in combination with chemotherapy and adjuvant treatment. Full article

(This article belongs to the Special Issue Glioma Therapy: Current Status and Future Prospects)

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27 pages, 24451 KB

Open AccessEditor’s ChoiceReview

Point-of-Care Ultrasound Use in Hemodynamic Assessment

by Ahmed Noor, Margaret Liu, Alan Jarman, Travis Yamanaka and Malvika Kaul

Biomedicines 2025, 13(6), 1426; https://doi.org/10.3390/biomedicines13061426 - 10 Jun 2025

Cited by 16 | Viewed by 15528

Abstract

Hemodynamic assessment is critical in emergency and critical care for preventing, diagnosing, and managing shock states that significantly affect patient outcomes. Point-of-care ultrasound (POCUS) has become an invaluable, non-invasive, real-time, and reproducible tool for bedside decision-making. Advancements such as Doppler imaging, advanced critical [...] Read more.

Hemodynamic assessment is critical in emergency and critical care for preventing, diagnosing, and managing shock states that significantly affect patient outcomes. Point-of-care ultrasound (POCUS) has become an invaluable, non-invasive, real-time, and reproducible tool for bedside decision-making. Advancements such as Doppler imaging, advanced critical care ultrasonography, and transesophageal echocardiography (TEE) have expanded its utility, enabling rapid and repeatable evaluations, especially in complex mixed shock presentations. This review explores the role of POCUS in hemodynamic monitoring, emphasizing its ability to assess cardiac output, filling pressures, and vascular congestion, facilitating shock classification and guiding fluid management. We highlight an extensive array of POCUS techniques for evaluating right and left cardiac function and review existing literature on their advantages, limitations, and appropriate clinical applications. Beyond assessing volume status, this review discusses the role of POCUS in predicting fluid responsiveness and supporting more individualized, precise management strategies. Ultimately, while POCUS is a powerful tool for rapid, comprehensive hemodynamic assessment in acute settings, its limitations must be acknowledged and thoughtfully integrated into clinical decision-making. Full article

(This article belongs to the Special Issue Advanced Research in Cardiovascular and Hemodynamic Monitoring)

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22 pages, 3118 KB

Open AccessEditor’s ChoiceReview

Pharmacological and Pathological Implications of Sigma-1 Receptor in Neurodegenerative Diseases

by Noah Drewes, Xiangwei Fang, Nikhil Gupta and Daotai Nie

Biomedicines 2025, 13(6), 1409; https://doi.org/10.3390/biomedicines13061409 - 8 Jun 2025

Cited by 13 | Viewed by 11851

Abstract

Originally identified as a potential receptor for opioids, the sigma-1 receptor is now recognized as an intracellular chaperone protein associated with mitochondria-associated membranes at the endoplasmic reticulum (ER). Over the past two decades, extensive research has revealed that the sigma-1 receptor regulates many [...] Read more.

Originally identified as a potential receptor for opioids, the sigma-1 receptor is now recognized as an intracellular chaperone protein associated with mitochondria-associated membranes at the endoplasmic reticulum (ER). Over the past two decades, extensive research has revealed that the sigma-1 receptor regulates many cellular processes, such as calcium homeostasis, oxidative stress responses, protein folding, and mitochondrial function. The various functions of the sigma-1 receptor highlight its role as a central modulator of neuronal health and may be a promising pharmacological target across multiple neurodegenerative conditions. Herein, we provide an overview of the current pharmacological understanding of the sigma-1 receptor with an emphasis on the signaling mechanisms involved. We examine its pathological implications in common neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and multiple sclerosis. We then highlight how sigma-1 receptor modulation may influence disease progression as well as potential pharmacological mechanisms to alter disease outcomes. The translational potential of sigma-1 receptor therapies is discussed, as well as the most up-to-date results of ongoing clinical trials. This review aims to clarify the therapeutic potential of the sigma-1 receptor in neurodegeneration and guide future research in these diseases. Full article

(This article belongs to the Special Issue Cell Signaling and Molecular Regulation in Neurodegenerative Disease)

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44 pages, 891 KB

Open AccessEditor’s ChoiceReview

Aquaporins in Acute Brain Injury: Insights from Clinical and Experimental Studies

by Stelios Kokkoris, Charikleia S. Vrettou, Nikolaos S. Lotsios, Vasileios Issaris, Chrysi Keskinidou, Kostas A. Papavassiliou, Athanasios G. Papavassiliou, Anastasia Kotanidou, Ioanna Dimopoulou and Alice G. Vassiliou

Biomedicines 2025, 13(6), 1406; https://doi.org/10.3390/biomedicines13061406 - 7 Jun 2025

Cited by 13 | Viewed by 4068

Abstract

Aquaporins (AQPs) are a family of transmembrane water channel proteins facilitating the transport of water and, in some cases, small solutes such as glycerol, lactate, and urea. In the central nervous system (CNS), several aquaporins play crucial roles in maintaining water homeostasis, modulating [...] Read more.

Aquaporins (AQPs) are a family of transmembrane water channel proteins facilitating the transport of water and, in some cases, small solutes such as glycerol, lactate, and urea. In the central nervous system (CNS), several aquaporins play crucial roles in maintaining water homeostasis, modulating cerebrospinal fluid (CSF) circulation, regulating energy metabolism, and facilitating neuroprotection under pathological conditions. Among them, AQP2, AQP4, AQP9, and AQP11 have been implicated in traumatic and non-traumatic brain injuries. The most abundant aquaporin (AQP) in the brain, AQP4, is essential for fluid regulation, facilitating water transport across the blood–brain barrier and glymphatic clearance. AQP2 is primarily known for its function in the kidneys, but it is also expressed in brain regions related to vasopressin signaling and CSF dynamics. AQP9 acts as a channel for glycerol and lactate, thus playing a role in metabolic adaptation during brain injury. AQP11, an intracellular aquaporin, is involved in oxidative stress responses and cellular homeostasis, with emerging evidence suggesting its role in neuroprotection. Aquaporins play a dual role in brain injury; while they help maintain homeostasis, their dysregulation can exacerbate cerebral edema, metabolic dysfunction, and inflammation. In traumatic brain injury (TBI), aquaporins regulate the formation and resolution of cerebral edema. In non-traumatic brain injuries, including ischemic stroke, aneurysmal subarachnoid hemorrhage (aSAH), and intracerebral hemorrhage (ICH), aquaporins influence fluid balance, energy metabolism, and oxidative stress responses. Understanding the specific roles of AQP2, AQP4, AQP9, and AQP11 in these brain injuries may lead to new therapeutic strategies to mitigate secondary damage and improve neurological outcomes. This review explores the function of the above aquaporins in both traumatic and non-traumatic brain injuries, highlighting their potential and limitations as therapeutic targets for neuroprotection and recovery. Full article

(This article belongs to the Special Issue Brain Injury: New Insights into Mechanisms and Future Promising Treatments—Second Edition)

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15 pages, 1420 KB

Open AccessEditor’s ChoiceArticle

Malignancy and Inflammatory Bowel Disease (IBD): Incidence and Prevalence of Malignancy in Correlation to IBD Therapy and Disease Activity—A Retrospective Cohort Analysis over 5 Years

by Agnieszka Jowita Kafel, Anna Muzalyova and Elisabeth Schnoy

Biomedicines 2025, 13(6), 1395; https://doi.org/10.3390/biomedicines13061395 - 6 Jun 2025

Cited by 4 | Viewed by 2219

Abstract

Background/Objectives: Patients with inflammatory bowel disease (IBD) are at an increased risk of various cancers; such as colorectal cancer; skin cancer; bile duct cancer; or lymphoma; with IBD itself not being the sole cause. Inappropriate or ineffective IBD therapy with a continuous [...] Read more.

Background/Objectives: Patients with inflammatory bowel disease (IBD) are at an increased risk of various cancers; such as colorectal cancer; skin cancer; bile duct cancer; or lymphoma; with IBD itself not being the sole cause. Inappropriate or ineffective IBD therapy with a continuous inflammatory burden within the gut leads to an increased risk of malignancy. Our study aimed to investigate the risk of malignancy in our patient cohort; focusing on concomitant therapy; disease duration; and inflammatory burden. Methods: A total of 333 consecutive adult patients with IBD (Crohn’s disease; ulcerative colitis; and IBD unclassified) were included in this study. Data from patients were collected retrospectively using patient charts. The patients were treated in the gastroenterological outpatient clinic of the University Hospital of Augsburg; Germany; between 1 January 2014 and 31 December 2018. Results: The study group included 333 patients; 32 (9.61%) of whom suffered from malignancy (any form). Men (n = 21; 65.62%) tended to develop malignancy more often than women (n = 11; 34.38%, p = 0.051). It was also observed that the probability of developing cancer was 2.40 times higher in male patients than in female patients in our cohort. However, this trend was non-significant (HR = 2.412; p = 0.075). Furthermore; the probability of developing cancer increased with the increasing age at the time of the first diagnosis of IBD (HR = 1.088; p < 0.025). A total of 20 patients (6.00%) received their cancer diagnosis after being diagnosed with IBD. The majority of those patients had skin (n = 6; 30.00%) or colon cancer (n = 5; 25.00%). Other diseases such as CML; NHL; HL; HCC; liver sarcoma; prostate cancer; breast cancer; seminoma; thyroid cancer (a second cancer in one of the patients); or CUP syndrome/lung cancer were diagnosed in single patients. Patients with IBD and colon cancer (n = 5; 25.00%) shared some of the known risk factors for tumour development; such as a long-lasting IBD (n = 5; 100.00%), diagnosis at a young age (under 30; n = 3; 60.00%), and the coexistence of PSC (n = 1; 20.00%). The cancer prevalence rate was relatively low in our cohort despite the use of diverse biologics and immunosuppressive drugs. Faecal calprotectin was confirmed as a relevant tool for inflammation monitoring in this cohort. Conclusions: In our study cohort; we could show a low prevalence rate of malignancy in IBD. There were more malignancies in men and in patients who were diagnosed with IBD at later ages. It can be observed that the prevalence rate of cancer was relatively low despite the use of diverse biologics and immunosuppressive drugs; which is the major conclusion of this study. Additionally; the known correlation between elevated levels of faecal calprotectin and gut inflammation was confirmed through our statistical analysis. The use of calprotectin as a non-invasive screening tool for gut inflammation is advised. Full article

(This article belongs to the Special Issue State-of-the-Art Hepatic and Gastrointestinal Diseases in Germany)

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17 pages, 1580 KB

Open AccessEditor’s ChoiceArticle

Optimal Fractionation Scheduling for Radiotherapy Treatments with Reinforcement Learning, Tumor Growth Modeling and Outcome Modeling

by Mélanie Ghislain, Florian Martin, Manon Dausort, Damien Dasnoy-Sumell, Ana Maria Barragan Montero and Benoît Macq

Biomedicines 2025, 13(6), 1367; https://doi.org/10.3390/biomedicines13061367 - 3 Jun 2025

Cited by 5 | Viewed by 1846

Abstract

Objective: Radiotherapy is a primary method for cancer treatment, wherein radiation doses are divided into multiple sessions or fractions to effectively target tumors and minimize damage to surrounding tissues. Methods: In this study, we leverage reinforcement learning (RL) to enhance treatment planning with [...] Read more.

Objective: Radiotherapy is a primary method for cancer treatment, wherein radiation doses are divided into multiple sessions or fractions to effectively target tumors and minimize damage to surrounding tissues. Methods: In this study, we leverage reinforcement learning (RL) to enhance treatment planning with the aim of improving the adaptability and robustness of RL agents given the inherent inaccuracies in tumor growth models. A 2D simulation model of tumor growth is employed, where tabular RL techniques are used to determine the optimal treatment strategies. We emphasize the significance of tissue damage predictions and incorporate the Lyman NTCP model to assess treatment outcomes, analyzing complications across three simulated body sites: the rectum, head and neck and lung. Results: For all the tumor sites, the RL approach significantly reduces healthy tissue damage by 10.7%, 49.1% and 37.5%, respectively, for rectal, head and neck and lung cancers compared with the baseline treatment. Conclusions: The RL-based approach in radiotherapy not only achieves tumor eradication but also significantly reduces healthy tissue damage compared with traditional treatment methods. This study demonstrates the potential of reinforcement learning to optimize treatment planning in radiotherapy, offering a promising path towards more personalized and effective cancer treatments. Full article

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

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18 pages, 3937 KB

Open AccessEditor’s ChoiceArticle

Preliminary Evaluation of 3D-Printed Alginate/Gelatin Scaffolds for Protein Fast Release as Suitable Devices for Personalized Medicine

by Benedetta Ghezzi, Ruben Foresti, Luisa Pia Scialoia, Maddalena Botti, Arianna Mersanne, Fulvio Ratto, Francesca Rossi, Chiara Martini, Paolo Perini, Elda Favari and Antonio Freyrie

Biomedicines 2025, 13(6), 1365; https://doi.org/10.3390/biomedicines13061365 - 2 Jun 2025

Cited by 4 | Viewed by 2048

Abstract

Background/Objectives: Drug-coated balloons (DCBs) are emerging as a promising treatment for peripheral artery disease; however, current technologies lack flexibility in customizing drug release profiles and composition, limiting their therapeutic potential. This study aims to develop a Gelatin (Gel) and Sodium Alginate (Alg) bioink [...] Read more.

Background/Objectives: Drug-coated balloons (DCBs) are emerging as a promising treatment for peripheral artery disease; however, current technologies lack flexibility in customizing drug release profiles and composition, limiting their therapeutic potential. This study aims to develop a Gelatin (Gel) and Sodium Alginate (Alg) bioink loaded with apolipoprotein A-I (apoA-I) for controlled drug delivery by using additive manufacturing technologies. Methods: We developed and printed via rapid freeze prototyping (RFP) a Gel and Alg bioink loaded with different concentrations of apoA-I. Mechanical properties related to compressional and tensile forces have been studied, as well as the structural stability and active release from the 3D structure of apoA-I (cholesterol efflux assays). The biological behavior of HUVEC cells with and without ApoA-I was assessed by proliferation assay, metabolic activity analysis, and fluorescence imaging. Results: The 3D structures presented breakpoint stress values consistent with the mechanical requirements for integration within a DCB, and the ability to effectively promote cholesterol transport in J774 cells. Moreover, in vitro studies on HUVECs revealed that the scaffolds exhibited no cytotoxic effects, leading to increased ATP levels and enhanced metabolic activity over time, confirming the possibility to obtain RFP-printed Alg/Gel scaffolds able to provide a stable structure capable of controlled apoA-I release. Conclusions: These findings support the potential of Alg/Gel+apoA-I scaffolds as biocompatible drug delivery systems for vascular applications. Their ability to maintain structural integrity while enabling controlled biomolecular release positions them as promising candidates for personalized cardiovascular therapy, facilitating the rapid customization of bioprinted therapeutic platforms. Full article

(This article belongs to the Section Biomedical Engineering and Materials)

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34 pages, 2408 KB

Open AccessEditor’s ChoiceReview

Multidrug-Resistant Infections and Metabolic Syndrome: An Overlooked Bidirectional Relationship

by Carlo Acierno, Riccardo Nevola, Fannia Barletta, Luca Rinaldi, Ferdinando Carlo Sasso, Luigi Elio Adinolfi and Alfredo Caturano

Biomedicines 2025, 13(6), 1343; https://doi.org/10.3390/biomedicines13061343 - 30 May 2025

Cited by 17 | Viewed by 3108

Abstract

Over the past two decades, metabolic syndrome (MetS) and infections caused by multidrug-resistant (MDR) pathogens have emerged as converging global health challenges. Traditionally investigated as separate entities, accumulating evidence increasingly supports a bidirectional relationship between them, mediated by chronic inflammation, immune dysregulation, gut [...] Read more.

Over the past two decades, metabolic syndrome (MetS) and infections caused by multidrug-resistant (MDR) pathogens have emerged as converging global health challenges. Traditionally investigated as separate entities, accumulating evidence increasingly supports a bidirectional relationship between them, mediated by chronic inflammation, immune dysregulation, gut microbiota alterations, and antibiotic-driven expansion of the resistome. This narrative review examines the complex immunometabolic interplay linking MetS and MDR infections, focusing on molecular mechanisms, clinical implications, and prospective research directions. A systematic literature search was conducted using major databases, including PubMed and Scopus, targeting studies from the last 15 years that explore the interface between metabolic dysfunction and antimicrobial resistance. Particular attention is given to key immunometabolic pathways such as the IRS–PI3K–AKT–mTOR axis; the contribution of visceral adiposity and Toll-like receptor (TLR)-mediated inflammation; and the role of gut dysbiosis in augmenting both susceptibility to infections and metabolic derangements. Evidence is presented supporting the hypothesis that MetS increases host vulnerability to MDR pathogens, while chronic MDR infections may reciprocally induce systemic metabolic reprogramming. Viral infections with established metabolic sequelae (e.g., HIV, hepatitis C virus [HCV], and cytomegalovirus [CMV]) are also considered to broaden the conceptual framework. Although current data remain largely associative and fragmented, the emerging MetS–MDR syndemic model poses substantial challenges for translational research, antimicrobial stewardship, and personalized therapeutic strategies. Recognizing this reciprocal relationship is pivotal for refining infection risk stratification, optimizing treatment, and informing public health policies. Further investigations are warranted to elucidate the magnitude and directionality of this association and to identify predictive immunometabolic biomarkers that may guide targeted interventions in high-risk populations. Full article

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

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32 pages, 652 KB

Open AccessEditor’s ChoiceReview

Inflammation in Asthma: Mechanistic Insights and the Role of Biologics in Therapeutic Frontiers

by Mohammad Irshad Reza and Nilesh S. Ambhore

Biomedicines 2025, 13(6), 1342; https://doi.org/10.3390/biomedicines13061342 - 30 May 2025

Cited by 27 | Viewed by 15094

Abstract

Asthma is a chronic and multifaceted respiratory condition that affects over 300 million individuals across the globe. It is characterized by persistent inflammation of the airways, which leads to episodes of wheezing, breathlessness, chest tightness, and coughing. The most prevalent form of asthma [...] Read more.

Asthma is a chronic and multifaceted respiratory condition that affects over 300 million individuals across the globe. It is characterized by persistent inflammation of the airways, which leads to episodes of wheezing, breathlessness, chest tightness, and coughing. The most prevalent form of asthma is classified as Type 2 or T2-high asthma. In this variant, the immune response is heavily driven by eosinophils, mast cells, and T-helper 2 (Th2) cells. These components release a cascade of cytokines, including interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13). This release promotes several processes: the production of immunoglobulin E (IgE), which is integral to allergic responses; the recruitment of eosinophils—white blood cells that contribute to inflammation and tissue damage. Conversely, non-Type 2 or T2-low asthma is typically associated with a different inflammatory profile characterized by neutrophilic inflammation. This type of asthma is driven by T-helper 1 (Th1) and T-helper 17 (Th17) immune responses, which are often present in older adults, smokers, and those suffering from more severe manifestations of the disease. Among asthmatic patients, approximately 80–85% of cases are classified as T2-high asthma, while only 15–20% are T2-low asthma. Treatment of asthma focuses heavily on controlling inflammation. Inhaled corticosteroids remain the cornerstone therapy for managing T2-high asthma. For more severe or treatment-resistant cases, biologic therapies targeting specific inflammatory pathways, such as anti-IgE (omalizumab), anti-IL-5 (mepolizumab, benralizumab), and anti-IL-4/IL-13 (dupilumab), have shown great promise. For T2-low asthma, macrolide antibiotics like azithromycin and other novel therapies are being explored. This article reviews the safety, efficacy, and indications of the currently approved biologics and discusses potential novel biologics for asthma. Full article

(This article belongs to the Special Issue Biological Therapies for Asthma: Targeting Type 1 and Type 2 Inflammation)

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18 pages, 2645 KB

Open AccessEditor’s ChoiceArticle

A Deep Learning Methodology for Screening New Natural Therapeutic Candidates for Pharmacological Cardioversion and Anticoagulation in the Treatment and Management of Atrial Fibrillation

by Tim Dong, Rhys D. Llewellyn, Melanie Hezzell and Gianni D. Angelini

Biomedicines 2025, 13(6), 1323; https://doi.org/10.3390/biomedicines13061323 - 28 May 2025

Cited by 1 | Viewed by 1556

Abstract

Background: The treatment and management of atrial fibrillation poses substantial complexity. A delicate balance in the trade-off between the minimising risk of stroke without increasing the risk of bleeding through anticoagulant optimisations. Natural compounds are often associated with low-toxicity effects, and their effects [...] Read more.

Background: The treatment and management of atrial fibrillation poses substantial complexity. A delicate balance in the trade-off between the minimising risk of stroke without increasing the risk of bleeding through anticoagulant optimisations. Natural compounds are often associated with low-toxicity effects, and their effects on atrial fibrillation have yet to be fully understood. Whilst deep learning (a subtype of machine learning that uses multiple layers of artificial neural networks) methods may be useful for drug compound interaction and discovery analysis, graphical processing units (GPUs) are expensive and often required for deep learning. Furthermore, in limited-resource settings, such as low- and middle-income countries, such technology may not be easily available. Objectives: This study aims to discover the presence of any new therapeutic candidates from a large set of natural compounds that may support the future treatment and management of atrial fibrillation anywhere using a low-cost technique. The objective is to develop a deep learning approach under a low-resource setting where suitable high-performance NVIDIA graphics processing units (GPUs) are not available and to apply to atrial fibrillation as a case study. Methods: The primary training dataset is the MINER-DTI dataset from the BIOSNAP collection. It includes 13,741 DTI pairs from DrugBank, 4510 drug compounds, and 2181 protein targets. Deep cross-modal attention modelling was developed and applied. The Database of Useful Decoys (DUD-E) was used to fine-tune the model using contrastive learning. This application and evaluation of the model were performed on the natural compound NPASS 2018 dataset as well as a dataset curated by a clinical pharmacist and a clinical scientist. Results: the new model showed good performance when compared to existing state-of-the-art approaches under low-resource settings in both the validation set (PR AUC: 0.8118 vs. 0.7154) and test set (PR AUC: 0.8134 vs. 0.7206). Tenascin-C (TNC; NPC306696) and deferoxamine (NPC262615) were identified as strong natural compound interactors of the arrhythmogenic targets ADRB1 and HCN1, respectively. A strong natural compound interactor of the bleeding-related target Factor X was also identified as sequoiaflavone (NPC194593). Conclusions: This study presented a new high-performing model under low-resource settings that identified new natural therapeutic candidates for pharmacological cardioversion and anticoagulation. Full article

(This article belongs to the Special Issue Role of Natural Product in Cardiovascular Disease—2nd Edition)

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15 pages, 1195 KB

Open AccessEditor’s ChoiceArticle

Long-Term Outcomes After High-Dose-Rate Brachytherapy and Hypofractionated External Beam Radiotherapy in Very High-Risk Prostate Cancer: A 24-Year Follow-Up

by Pedro J. Prada Gómez, Ana L. Rivero Pérez, Joaquín Carballido Rodríguez, Javier Anchuelo Latorre, Rosa Fabregat Borrás, Marina Gutiérrez Ruiz, Cristina Rodríguez-Acosta Caballero, Carlos F. Carrascal Gordillo, Maria P. Galdós Barroso and Paola A. Navarrete Solano

Biomedicines 2025, 13(6), 1310; https://doi.org/10.3390/biomedicines13061310 - 27 May 2025

Cited by 5 | Viewed by 3985

Abstract

Purpose: To evaluate the long-term oncological outcomes and toxicity profile based on 24 years of follow-up in patients with localized very high-risk prostate cancer (VHR PCa) treated with a combination of high-dose-rate brachytherapy (HDR-BT) and pelvic external beam radiation therapy (EBRT). Methods [...] Read more.

Purpose: To evaluate the long-term oncological outcomes and toxicity profile based on 24 years of follow-up in patients with localized very high-risk prostate cancer (VHR PCa) treated with a combination of high-dose-rate brachytherapy (HDR-BT) and pelvic external beam radiation therapy (EBRT). Methods: A retrospective analysis was conducted on 87 patients with VHR PCa, classified according to National Comprehensive Cancer Network (NCCN) criteria, who received HDR-BT and EBRT. Androgen deprivation therapy (ADT) was administered to 72 patients (82.8%). The primary endpoints were biochemical control and cancer-specific survival (CSS), while the secondary endpoints included local control rates, tumor-free survival (TFS), overall survival (OS), and treatment-related toxicity. Results: The 24-year biochemical control rate was 68% (standard deviation [SD]: ±4%), while CSS and TFS at 24 years were 82% (SD ±4%) and 78% (SD ±4%), respectively. Local control rates remained at 98% at 24 years. Furthermore, the OS rate at 24 years was 30%. Multivariate Cox regression analysis identified the T category in the TNM classification as the only factor significantly associated with biochemical control, with 24-year rates of 69%, 71%, and 50% for patients with T-classifications of ≤T2c, T3a, and T3b-T4, respectively (p = 0.024). Notably, no grade ≥3 late toxicities were observed during the follow-up period. Conclusions: The 24-year outcomes support the viability and therapeutic efficacy of EBRT combined with a conformal HDR-BT boost for patients with VHR PCa. Full article

(This article belongs to the Special Issue Prostate Cancer Targeted Therapy: Highlighting Advances in Precision Medicine and Rational Combination Approaches)

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11 pages, 1096 KB

Open AccessEditor’s ChoiceCommunication

Exosomal Protein Biomarkers in Arthritis: Deciphering the Inflammatory Profiles of RA and OA

by Claudia M. Brenis Gómez, Chamaida Plasencia-Rodríguez, Marta Novella-Navarro, Ana Martínez-Feito, Alejandro Balsa, Enrique Calvo-Aranda and Borja Hernández-Breijo

Biomedicines 2025, 13(6), 1283; https://doi.org/10.3390/biomedicines13061283 - 23 May 2025

Cited by 4 | Viewed by 1811

Abstract

Background/Objectives: Rheumatoid arthritis (RA) and osteoarthritis (OA) are highly prevalent diseases and their pathophysiology, diagnosis and treatment continue to be challenging. The aim of this study was to characterize and differentiate the profiles of the serum extracellular vesicles (EVs) isolated from RA [...] Read more.

Background/Objectives: Rheumatoid arthritis (RA) and osteoarthritis (OA) are highly prevalent diseases and their pathophysiology, diagnosis and treatment continue to be challenging. The aim of this study was to characterize and differentiate the profiles of the serum extracellular vesicles (EVs) isolated from RA and OA patients. Methods: This study included nine patients diagnosed with RA, eight patients with OA during a flare and five healthy controls (HCs). Blood samples were collected and EVs from the serum were isolated for further performance of flow cytometry and proteomic analysis. Results: The extracellular vesicles from HC samples exhibited smaller sizes and were more concentrated than exosomes from RA and OA samples. Surface protein expression was analyzed by flow cytometry. The results showed an enrichment of exosomes derived from antigen-presenting cells in RA samples; this was evidenced by their expression of CD14 and HLA-DR. Proteomic analysis identified 45 differentially expressed proteins between RA and OA patients. Furthermore, Ingenuity Pathway Analysis (IPA) identified inflammatory pathways such as the IL-1β and IL-6 signaling pathways as being enhanced in RA-derived exosomes, while the MYC and ROCK2 signaling pathways were enhanced in OA-derived exosomes. Conclusions: Our results show serum-derived exosomes from RA and OA patients harbor different surface proteins and cargo profiles, mirroring the different pathophysiologic mechanisms underlying these diseases. These results also highlight the promising use of exosomes as disease biomarkers. Full article

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

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20 pages, 4500 KB

Open AccessEditor’s ChoiceReview

Spatial Heterogeneity of Intratumoral Microbiota: A New Frontier in Cancer Immunotherapy Resistance

by Qiwen Tan, Xiongjing Cao, Falong Zou, Hanwenchen Wang, Lijuan Xiong and Shenghe Deng

Biomedicines 2025, 13(5), 1261; https://doi.org/10.3390/biomedicines13051261 - 21 May 2025

Cited by 19 | Viewed by 4340

Abstract

The intratumoral microbiota, as an important component of the tumor microenvironment, is increasingly recognized as a key factor in regulating responses to cancer immunotherapy. Recent studies have revealed that the intratumoral microbiota is not uniformly distributed but instead exhibits significant spatial heterogeneity, with [...] Read more.

The intratumoral microbiota, as an important component of the tumor microenvironment, is increasingly recognized as a key factor in regulating responses to cancer immunotherapy. Recent studies have revealed that the intratumoral microbiota is not uniformly distributed but instead exhibits significant spatial heterogeneity, with its distribution patterns influenced by factors such as tumor anatomy, local immune status, and therapeutic interventions. This spatial heterogeneity not only alters the interactions between microbes and the host immune system but may also reshape the immunogenic and immunosuppressive landscapes of tumors. The enrichment or depletion of microbiota in different tumor regions can influence immune cell infiltration patterns, metabolic pathway activities, and immune checkpoint molecule expression, thereby driving the development of resistance to immunotherapy. Moreover, certain bacterial metabolites form concentration gradients between the tumor core and margins, thereby regulating immune cell function. Therefore, understanding and manipulating the spatial distribution of intratumoral microbiota, particularly in resistant patients, holds promise for developing new strategies to overcome immunotherapy resistance. In the future, precise modulation strategies targeting microbial spatial heterogeneity, such as engineered bacterial vectors, probiotic combinations, and phage therapy, may open new avenues for immunotherapy. Full article

(This article belongs to the Special Issue Novel Progress in Cancer Immunotherapy)

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19 pages, 16275 KB

Open AccessEditor’s ChoiceArticle

Targeting the ZMYM2-ANXA9 Axis with FLT3 Inhibitor G749 Overcomes Oxaliplatin Resistance in Colorectal Cancer

by Dezheng Lin, Yucheng Xu, Huanmiao Zhan, Yufan Liang, Riyun Liu, Jun Liu, Dandong Luo, Xiaochuan Chen, Jiawei Cai and Yifeng Zou

Biomedicines 2025, 13(5), 1247; https://doi.org/10.3390/biomedicines13051247 - 20 May 2025

Cited by 4 | Viewed by 1919

Abstract

Background: Chemoresistance and tumor recurrence remain major obstacles in colorectal cancer (CRC) therapy. Elucidating the molecular mechanisms underlying treatment resistance is critical for improving therapeutic outcomes. Methods: We analyzed transcriptomic profiles from public datasets (TCGA and GSE39582) to identify differentially expressed genes [...] Read more.

Background: Chemoresistance and tumor recurrence remain major obstacles in colorectal cancer (CRC) therapy. Elucidating the molecular mechanisms underlying treatment resistance is critical for improving therapeutic outcomes. Methods: We analyzed transcriptomic profiles from public datasets (TCGA and GSE39582) to identify differentially expressed genes associated with a poor response to neoadjuvant chemotherapy in CRC patients. Among 298 candidate genes, ANXA9 emerged as significantly overexpressed in chemoresistant tumors and associated with a poor prognosis. These findings were further validated in an independent cohort of 146 Stage III CRC patients using immunohistochemistry and survival analysis. The expression of ANXA9 was evaluated in oxaliplatin acquired-resistant CRC cell lines via qPCR and Western blot. Functional studies, including RNA interference, colony formation, apoptosis assays, and drug sensitivity testing, were performed in vitro and in vivo to assess the role of ANXA9. A high-throughput drug screen identified G749, a FLT3 inhibitor, as a potential therapeutic agent. Results: ANXA9 expression was significantly elevated in non-responders to chemotherapy and oxaliplatin-resistant CRC cell lines. The knockdown of ANXA9 reduced proliferation and enhanced oxaliplatin sensitivity. G749 was found to suppress ANXA9 expression in a dose-dependent manner and inhibit CRC cell growth in vitro and in patient-derived organoids. In a CRC xenograft mouse model, G749 reduced the tumor burden without observable toxicity. Mechanistically, we identified ZMYM2 as a transcriptional regulator of ANXA9. ChIP-qPCR confirmed ZMYM2 binding to the ANXA9 promoter, especially in resistant cells. Silencing ZMYM2 suppressed tumor cell growth and restored chemosensitivity. Conclusions: The ZMYM2-ANXA9 signaling axis drives chemoresistance and tumor progression in CRC. FLT3 inhibition by G749 effectively downregulates ANXA9 and sensitizes tumors to chemotherapy, highlighting a novel therapeutic approach for chemoresistant CRC. Full article

(This article belongs to the Special Issue Progress in Immunopharmacy)

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28 pages, 1299 KB

Open AccessEditor’s ChoiceReview

Cardiac Amyloidosis: A Narrative Review of Diagnostic Advances and Emerging Therapies

by Dana Emilia Movila, Alexandru Catalin Motofelea, Dragos Cozma, Oana Albai, Alexandra Christa Sima, Minodora Andor, Tudor Ciocarlie and Simona Ruxanda Dragan

Biomedicines 2025, 13(5), 1230; https://doi.org/10.3390/biomedicines13051230 - 19 May 2025

Cited by 9 | Viewed by 5282

Abstract

Background/Objectives: Cardiac amyloidosis (CA) is an underdiagnosed and potentially life-threatening infiltrative cardiomyopathy characterized by the extracellular deposition of misfolded amyloid fibrils in cardiac tissue. It is most commonly associated with light-chain (AL) amyloidosis and transthyretin (ATTR) amyloidosis, either hereditary or wild-type. The [...] Read more.

Background/Objectives: Cardiac amyloidosis (CA) is an underdiagnosed and potentially life-threatening infiltrative cardiomyopathy characterized by the extracellular deposition of misfolded amyloid fibrils in cardiac tissue. It is most commonly associated with light-chain (AL) amyloidosis and transthyretin (ATTR) amyloidosis, either hereditary or wild-type. The disease often presents with non-specific symptoms, leading to delayed diagnosis and treatment. This study aims to provide a comprehensive overview of the pathophysiology, diagnostic strategies, and current therapeutic approaches for cardiac amyloidosis, with a focus on improving early detection and clinical outcomes. Methods: A narrative review was conducted using databases such as PubMed and Scopus, covering the period from September 2016 to March 2025. Keywords such as “cardiac amyloidosis”, “cardiac amyloidosis from transthyretin”, “cardiomyopathy”, “transthyretin”, “immunoglobulin light-chain amyloidosis”, and “familial amyloidosis” were used. Relevant clinical trials and guideline-based management recommendations were also included. Results: This review highlights that non-invasive imaging modalities and serum biomarker analyses are key to reducing diagnostic delays. New therapeutic developments, including gene-editing technologies and RNA-based therapies, show promise in early trials. Multidisciplinary management and increased awareness are crucial for timely diagnosis and treatment optimization. Conclusions: The early recognition of cardiac amyloidosis remains a major clinical challenge. Advances in non-invasive diagnostics and emerging disease-modifying therapies are transforming the prognosis of affected patients. Continued research and heightened clinical suspicion are essential to improve outcomes in this complex and heterogeneous disease. Full article

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

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25 pages, 840 KB

Open AccessEditor’s ChoiceReview

Stem Cell Therapy for Myocardial Infarction Recovery: Advances, Challenges, and Future Directions

by Nicholas T. Le, Matthew W. Dunleavy, William Zhou, Sumrithbir S. Bhatia, Rebecca D. Kumar, Suyin T. Woo, Gonzalo Ramirez-Pulido, Kaushik S. Ramakrishnan and Ahmed H. El-Hashash

Biomedicines 2025, 13(5), 1209; https://doi.org/10.3390/biomedicines13051209 - 16 May 2025

Cited by 12 | Viewed by 9037

Abstract

Myocardial infarction (MI) is a leading cause of morbidity worldwide, resulting from ischemic damage and necrosis to cardiomyocytes. While the standard treatment regimen for MI can be successful in restoring coronary perfusion, it typically does not resolve myocardial damage, which can leave patients [...] Read more.

Myocardial infarction (MI) is a leading cause of morbidity worldwide, resulting from ischemic damage and necrosis to cardiomyocytes. While the standard treatment regimen for MI can be successful in restoring coronary perfusion, it typically does not resolve myocardial damage, which can leave patients particularly vulnerable to complications such as heart failure or electrical conduction abnormalities. Stem cell therapies offer a promising novel approach aimed at restoring cardiac function and decreasing the incidence of functional complications after an MI. This review used a literature search to evaluate the current landscape of stem cell therapy for post-MI recovery and focuses on the stem cell candidates for MI recovery therapy, delivery methods of such treatment, and their effectiveness. Both preclinical and clinical trials have demonstrated the safety of stem cells, but have struggled with limited cell retention, inconsistent efficacy, and survival. Mechanisms are employed by stem cells to promote regeneration, such as paracrine signaling, angiogenesis, and structural remodeling, in addition to the various stem cell delivery methods, including intracoronary infusion, direct myocardial injection, and intravenous administration. Furthermore, some strategies to combat past challenges in this field are discussed; for instance, extracellular vesicles, bioengineered patches, hydrogels, gene editing, and bioprinting. This article will provide a framework for future research in stem cell therapies and highlight the current progress in the field. Full article

(This article belongs to the Section Gene and Cell Therapy)

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20 pages, 1406 KB

Open AccessEditor’s ChoiceReview

Cytokines Meet Phages: A Revolutionary Pathway to Modulating Immunity and Microbial Balance

by Rossella Cianci, Mario Caldarelli, Paola Brani, Annalisa Bosi, Alessandra Ponti, Cristina Giaroni and Andreina Baj

Biomedicines 2025, 13(5), 1202; https://doi.org/10.3390/biomedicines13051202 - 15 May 2025

Cited by 23 | Viewed by 4883

Abstract

Bacteriophages are a unique and fascinating group of viruses, known for their highly specific ability to infect and replicate within bacterial cells. While their potential as antibacterial agents has been recognized for decades, recent research has revealed complex interactions between phages and the [...] Read more.

Bacteriophages are a unique and fascinating group of viruses, known for their highly specific ability to infect and replicate within bacterial cells. While their potential as antibacterial agents has been recognized for decades, recent research has revealed complex interactions between phages and the human immune system, offering new insights into their role in immune modulation. New evidence reveals a dynamic and intricate relationship between phages and cytokines, suggesting their ability to regulate inflammation, immune tolerance, and host–pathogen interaction. Herein, we review how phages affect the production of cytokines and the behavior of immune cells indirectly by lysis of bacterium or directly on mammalian cells. Phages have been shown to induce both pro- and anti-inflammatory responses and recently, they have been explored in personalized immunotherapy, cancer immunotherapy, and microbiome modulation, which are the focus of this review. Several challenges remain despite significant progress, including practical obstructions related to endotoxins along with host microbiome variability and regulatory issues. Nevertheless, the potential of bacteriophages to modulate immune responses makes them attractive candidates for the future of precision medicine. Full article

(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development: 2nd Edition)

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10 pages, 654 KB

Open AccessEditor’s ChoiceArticle

Characterization of Coronary Artery Disease in Sepsis Survivors

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

Biomedicines 2025, 13(5), 1181; https://doi.org/10.3390/biomedicines13051181 - 13 May 2025

Cited by 8 | Viewed by 1855

Abstract

Background: Sepsis survivors are at risk of developing myocardial infarction and heart failure. It remains unclear whether coronary artery disease (CAD) is a major contributor to the development of these complications. This study sought to characterize the burden and distribution of significant CAD [...] Read more.

Background: Sepsis survivors are at risk of developing myocardial infarction and heart failure. It remains unclear whether coronary artery disease (CAD) is a major contributor to the development of these complications. This study sought to characterize the burden and distribution of significant CAD in sepsis survivors. Methods: Sepsis survivors who underwent computed tomography coronary angiography (CTCA) or invasive coronary angiography (ICA) in a UK tertiary cardiac center for suspected ischemic heart disease were retrospectively studied. Results: Of the 30 sepsis survivors (age 57 ± 12 years; 50% males), 21 patients underwent CTCA and 9 patients underwent ICA a median 39 days [IQR 12–152] from the sepsis episode. Eight patients (~27%) had angiographically significant CAD (n = 6 severe [>70%] stenosis; n = 2 moderate [50–70%] stenosis). The CT coronary calcium score was higher in patients with significant CAD compared to patients without significant CAD (638 [368–1015] vs. 4 [1–72]; p < 0.001). Of the 8 patients with significant CAD, 3 patients had LV systolic dysfunction (38%) on echocardiography and 8/21 (38%) patients without significant CAD had LV systolic dysfunction (p = 1.00). Long-term adverse complications (all-cause mortality and/or heart failure hospitalization) occurred 3/8 (38%) patients with significant CAD and 4/22 (18%) patients without significant CAD (p = 0.345). Conclusions: A minority of sepsis survivors have significant CAD. The presence of significant CAD cannot fully explain the occurrence of post-sepsis LV systolic dysfunction and adverse outcomes. The ischemic and non-ischemic mechanisms underlying post-sepsis cardiovascular disease require further investigation. Full article

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

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24 pages, 6945 KB

Open AccessEditor’s ChoiceArticle

Circular Nucleic Acids Act as an Oncogenic MicroRNA Sponge to Inhibit Hepatocellular Carcinoma Progression

by Qianyi Zhang, Pengcheng Sun, Guang Hu, Xuanyao Yu, Wen Zhang, Xuan Feng, Lan Yu and Pengfei Zhang

Biomedicines 2025, 13(5), 1171; https://doi.org/10.3390/biomedicines13051171 - 11 May 2025

Cited by 7 | Viewed by 2668

Abstract

Background: Aberrant expression of microRNAs in neoplastic lesions may serve as potential personalized therapeutic targets. To inhibit oncogenic microRNAs (oncomiRs) expression and restore tumor suppressor proteins, linear miRNA sponges have been developed, leading to several drugs in clinical trials. Despite their efficacy, chemically [...] Read more.

Background: Aberrant expression of microRNAs in neoplastic lesions may serve as potential personalized therapeutic targets. To inhibit oncogenic microRNAs (oncomiRs) expression and restore tumor suppressor proteins, linear miRNA sponges have been developed, leading to several drugs in clinical trials. Despite their efficacy, chemically synthesized miRNA inhibitors face challenges with sustained inhibition and high production costs, hindering widespread clinical adoption. Additionally, single-stranded circular RNAs (circRNAs) act as miRNA sponges, enhancing protein expression and demonstrating stability and therapeutic potential in cancer treatment. Our approach involves the use of synthetic single-stranded circular nucleic acids, including circDNA and circRNA, to selectively target and inhibit a variety of aberrantly overexpressed oncomiRs in tumors. The objective of this strategy is to restore the expression levels of multiple tumor suppressor factors and to suppress the malignant progression of tumors. Methods: Our methodology comprises a two-step process. First, we identified tumor suppressor genes (TSGs) with abnormally low expression in hepatocellular carcinoma (HCC) tumor cells by transcriptomic analysis and targeted the upstream cancer miRNA clusters of these TSGs. Second, we designed and validated a fully complementary circDNA or circRNA construct, ligated by T4 DNA ligase or T4 RNA ligase, respectively, that specifically targets the sponge oncomiRs both in vitro and in vivo to inhibit the malignant progression of HCC. Results: CircNAs demonstrated superior, long-lasting therapeutic efficacy against HCC compared to inhibitors. Furthermore, we compared the immune effects in vivo of three different nucleic acid adsorption carriers, including commercial miRNA inhibitor, circDNA, and circRNA. We found that the miRNA inhibitor activates a more robust inflammatory response compared to circDNA and circRNA. Conclusions: These findings underscore the substantial therapeutic potential of circDNA in tumorigenesis and provide novel insights for the formulation of personalized treatment plans for malignant tumors, such as HCC. Full article

(This article belongs to the Special Issue MicroRNA and Its Role in Human Health, 2nd Edition)

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18 pages, 1376 KB

Open AccessEditor’s ChoiceReview

Emerging Epigenetic Therapies for the Treatment of Cardiac Fibrosis

by Nerea Garitano, Laura Pilar Aguado-Alvaro and Beatriz Pelacho

Biomedicines 2025, 13(5), 1170; https://doi.org/10.3390/biomedicines13051170 - 11 May 2025

Cited by 10 | Viewed by 4046

Abstract

Fibrosis is a pathological process characterized by excessive extracellular matrix (ECM) deposition, leading to tissue stiffening and organ dysfunction. It is a major contributor to chronic diseases affecting various organs, with limited therapeutic options available. Among the different forms of fibrosis, cardiac fibrosis [...] Read more.

Fibrosis is a pathological process characterized by excessive extracellular matrix (ECM) deposition, leading to tissue stiffening and organ dysfunction. It is a major contributor to chronic diseases affecting various organs, with limited therapeutic options available. Among the different forms of fibrosis, cardiac fibrosis is particularly relevant due to its impact on cardiovascular diseases (CVDs), which remain the leading cause of morbidity and mortality worldwide. This process is driven by activated cardiac fibroblasts (CFs), which promote ECM accumulation in response to chronic stressors. Epigenetic mechanisms, including DNA methylation, histone modifications, and chromatin remodeling, are key regulators of fibroblast activation and fibrotic gene expression. Enzymes such as DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), histone acetyltransferases (HATs), and histone deacetylases (HDACs) have emerged as potential therapeutic targets, and epigenetic inhibitors have shown promise in modulating these enzymes to attenuate fibrosis by controlling fibroblast function and ECM deposition. These small-molecule compounds offer advantages such as reversibility and precise temporal control, making them attractive candidates for therapeutic intervention. This review aims to provide a comprehensive overview of the mechanisms by which epigenetic regulators influence cardiac fibrosis and examines the latest advances in preclinical epigenetic therapies. By integrating recent data from functional studies, single-cell profiling, and drug development, it highlights key molecular targets, emerging therapeutic strategies, and current limitations, offering a critical framework to guide future research and clinical translation. Full article

(This article belongs to the Section Molecular Genetics and Genetic Diseases)

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28 pages, 1422 KB

Open AccessEditor’s ChoiceSystematic Review

Experimental Models of Type 2 Diabetes Mellitus Induced by Combining Hyperlipidemic Diet (HFD) and Streptozotocin Administration in Rats: An Integrative Review

by Ana Karolinne da Silva Brito, Ana Victória da Silva Mendes, Boris Timah Acha, Amanda Suellenn da Silva Santos Oliveira, Joyce Lopes Macedo, Akemi Suzuki Cruzio, Maria das Graças Prianti, Raquel Rodrigues de Abreu, Massimo Lucarini, Alessandra Durazzo, Maria do Carmo de Carvalho e Martins and Daniel Dias Rufino Arcanjo

Biomedicines 2025, 13(5), 1158; https://doi.org/10.3390/biomedicines13051158 - 9 May 2025

Cited by 35 | Viewed by 14321

Abstract

Type 2 diabetes mellitus (DM2) is a metabolic disorder characterized by chronic hyperglycemia associated with low insulin production and/or insulin resistance. A high-fat diet (HFD) combined with a low dose of streptozotocin (STZ) in an animal model produces a disease that mimics type [...] Read more.

Type 2 diabetes mellitus (DM2) is a metabolic disorder characterized by chronic hyperglycemia associated with low insulin production and/or insulin resistance. A high-fat diet (HFD) combined with a low dose of streptozotocin (STZ) in an animal model produces a disease that mimics type 2 diabetes mellitus in humans. However, there is wide variation in the methods of inducing diabetes in terms of the dose of STZ, the duration of the induction period, and the composition of the diet used, all of which could result in biological responses that are not typical of the disease. This review aims to investigate the characteristics of an experimental model of type 2 diabetes mellitus by combining a high-fat diet with low doses of streptozotocin in Wistar rats. This is an integrative review conducted by searching in the Medline, Lilacs, and Embase databases using the keywords “type 2 diabetes mellitus”, “high-fat diet”, “streptozotocin” and “Wistar rats”. Articles published in English between 2018 and 2025 were included. The induction of DM2 in young male rats with a high-fat HFD for a period of at least 3 weeks followed by a low dose of STZ resulted in metabolic, histological, inflammatory, and oxidative changes, and alterations in the signaling pathways of glycemic and lipid metabolism in different tissues, replicating the characteristics observed in humans. HFD-fed + STZ-induced Wistar rats constitute an effective animal model for studying DM2. Full article

(This article belongs to the Special Issue Animal Models for the Study of Cardiovascular Physiology)

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14 pages, 1908 KB

Open AccessEditor’s ChoiceArticle

Safety and Efficacy of Regorafenib and 5-Fluorouracil Combination Therapy in Refractory Metastatic Colorectal Cancer After Third-Line Treatment: An Institutional Experience

by Maen Abdelrahim, Abdullah Esmail, Ebtesam Al-Najjar, Bayan Khasawneh, Godsfavour Umoru, Waseem Abdelrahim, Karen Abboud and Veronica B. Ajewole

Biomedicines 2025, 13(5), 1151; https://doi.org/10.3390/biomedicines13051151 - 9 May 2025

Cited by 2 | Viewed by 1679

Abstract

Background: Colorectal carcinoma (CRC) is one of the most common cancer types along with breast, prostate, and lung cancer. Many patients with CRC present with metastatic disease despite receiving standard first- and second-line therapies; thus emerges the demand for implementing new therapies [...] Read more.

Background: Colorectal carcinoma (CRC) is one of the most common cancer types along with breast, prostate, and lung cancer. Many patients with CRC present with metastatic disease despite receiving standard first- and second-line therapies; thus emerges the demand for implementing new therapies that could improve outcomes among CRC patients. This case series was conducted to assess the efficacy and safety of regorafenib plus 5-fluorouracil (5-FU) in patients with refractory metastatic CRC (mCRC). Methods: We conducted a retrospective analysis of data from adult patients aged 18 and above who were diagnosed with refractory mCRC and received regorafenib plus 5-FU combination therapy at Houston Methodist Hospital between November 2017 and October 2023. Our study focuses on assessing key outcomes, including Overall Survival [OS], Progression-Free Survival [PFS], and safety. Results: Among the 12 patients we included in this study who underwent regorafenib plus 5-FU combination therapy for refractory mCRC after receiving at least three prior lines of treatment, the best response for six patients (50%) was successfully achieved, with disease control within 7–12 weeks from therapy initiation. Patients had an overall good tolerance for this treatment regimen and reported only the most common adverse events, including Hand-Foot Syndrome (HFS), mucositis, and hypertension (HTN), which were mostly resolved with dose adjustment of medications. Conclusions: This study highlights that using a combination of regorafenib plus 5-FU can be a potential treatment option for patients with refractory mCRC. Additional research, including prospective clinical trials, is required to assess the effectiveness and safety of regorafenib and 5-FU combination therapy in comparison to other currently limited treatment options. Full article

(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancers: From Microbiota Modulation to New Therapeutic Approaches)

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20 pages, 1818 KB

Open AccessEditor’s ChoiceReview

Oligodendroglioma: Advances in Molecular Mechanisms and Immunotherapeutic Strategies

by Yongxin Zhao, Yan Yu, Weizhi Chen, Xiaojun Zhang, Jing Lv and Heping Zhao

Biomedicines 2025, 13(5), 1133; https://doi.org/10.3390/biomedicines13051133 - 7 May 2025

Cited by 3 | Viewed by 6431

Abstract

Oligodendroglioma is a central nervous system tumor defined by IDH1/2 mutations and 1p/19q co-deletion. Current management involves maximal resection followed by radiotherapy/chemotherapy, yielding a 20-year survival rate of 37% for grade 3 tumors according to the WHO 2021 classification. As these tumors primarily [...] Read more.

Oligodendroglioma is a central nervous system tumor defined by IDH1/2 mutations and 1p/19q co-deletion. Current management involves maximal resection followed by radiotherapy/chemotherapy, yielding a 20-year survival rate of 37% for grade 3 tumors according to the WHO 2021 classification. As these tumors primarily affect young to middle-aged patients, novel therapies are urgently needed to improve outcomes. Immunotherapy has revolutionized tumor treatment by modulating immune responses. However, its application in oligodendrogliomas faces two major hurdles, including the immunosuppressive tumor microenvironment (TME) and the blood–brain barrier’s restrictive properties. This review first examines oligodendroglioma’s molecular alterations to refine diagnosis and guide targeted therapies. Next, we focus on the oligodendroglioma TME to evaluate emerging immunotherapies, including oncolytic viruses, immune checkpoint blockade, chimeric antigen receptor (CAR) T-cell therapy, and cancer vaccines. Finally, we discuss current challenges and future directions to overcome therapeutic limitations and advance treatment strategies. Full article

(This article belongs to the Special Issue Feature Reviews in Tumor Immunology)

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34 pages, 2833 KB

Open AccessEditor’s ChoiceReview

Current Status and Future Perspectives of Nuclear Medicine in Prostate Cancer from Imaging to Therapy: A Comprehensive Review

by Joohee Lee and Taejin Kim

Biomedicines 2025, 13(5), 1132; https://doi.org/10.3390/biomedicines13051132 - 7 May 2025

Cited by 12 | Viewed by 8338

Abstract

Nuclear medicine has emerged as a critical modality in the diagnostic and therapeutic management of urological malignancies, particularly prostate cancer. Advances in single-photon emission computed tomography/computed tomography (CT) and positron emission tomography/CT (PET/CT) have enhanced tumor assessment across staging, treatment response, and recurrence [...] Read more.

Nuclear medicine has emerged as a critical modality in the diagnostic and therapeutic management of urological malignancies, particularly prostate cancer. Advances in single-photon emission computed tomography/computed tomography (CT) and positron emission tomography/CT (PET/CT) have enhanced tumor assessment across staging, treatment response, and recurrence settings. Molecular imaging, which offers insights beyond traditional anatomical imaging, is increasingly integral in specific clinical scenarios. Theranostic nuclear medicine, which combines diagnostic imaging with targeted therapy, has become a well-established treatment option, particularly for patients with metastatic castration-resistant prostate cancer (mCRPC). The development of the prostate-specific membrane antigen (PSMA) radioligands has revolutionized clinical management by enabling precise disease staging and delivering effective radioligand therapy (RLT). Ongoing research aims to refine the role of PSMA PET imaging in staging and treatment monitoring, while optimizing PSMA-targeted RLT for broader clinical use. Given that prostate cancer remains highly prevalent, the anticipated increase in the demand for RLT presents both challenges and opportunities for nuclear medicine services globally. Theranostic approaches exemplify personalized medicine by enabling the tailoring of treatments to individual tumor biology, thereby improving survival outcomes and maintaining patients’ quality of life with minimal toxicity. Although the current focus is on advanced disease, future research holds promise for expanding these strategies to earlier stages, potentially enhancing curative prospects. This evolving field not only signifies a paradigm shift in the care of prostate cancer patients but also underscores the growing importance of nuclear medicine in delivering precision oncology. Full article

(This article belongs to the Special Issue Urogenital Cancers: New Molecular and Translational Aspects on Carcinogenesis and Treatments)

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18 pages, 2646 KB

Open AccessEditor’s ChoiceArticle

The IL-6/JAK/STAT3 Axis in Cholangiocarcinoma and Primary Sclerosing Cholangitis: Unlocking Therapeutic Strategies Through Patient-Derived Organoids

by Corinna Boden, Laura K. Esser, Leona Dold, Bettina Langhans, Taotao Zhou, Dominik J. Kaczmarek, Maria A. Gonzalez-Carmona, Tobias J. Weismüller, Glen Kristiansen, Jörg C. Kalff, Michael Hölzel, Hanno Matthaei, Marieta I. Toma and Vittorio Branchi

Biomedicines 2025, 13(5), 1083; https://doi.org/10.3390/biomedicines13051083 - 29 Apr 2025

Cited by 6 | Viewed by 3433

Abstract

Background/Objectives: Primary sclerosing cholangitis (PSC) is a rare, incurable liver disease characterized by chronic biliary inflammation and fibrosis. PSC is a significant risk factor for biliary tract cancer (BTC). This study aims to evaluate STAT3 expression in BTC and its prognostic significance as [...] Read more.

Background/Objectives: Primary sclerosing cholangitis (PSC) is a rare, incurable liver disease characterized by chronic biliary inflammation and fibrosis. PSC is a significant risk factor for biliary tract cancer (BTC). This study aims to evaluate STAT3 expression in BTC and its prognostic significance as well as explore the potential of organoids derived from PSC and liver tumor patients as an in vitro model for testing novel therapeutic strategies in both PSC and BTC. Methods: Fresh tissue samples obtained from 10 PSC patients through targeted endoscopic retrograde cholangiography (ERC) and biopsy samples from liver tumor patients were used to establish organoid cultures. Organoids were treated with different agents and the therapeutic effect was measured by CellTiterGlo. Treatment with the JAK inhibitor baricitinib was followed by the measurement of cytokine concentrations in the supernatant. Archived formalin-fixed paraffin-embedded (FFPE) samples from 55 surgically resected BTC tumors were analyzed for STAT3 expression using immunohistochemistry. Results: We successfully established organoid cultures from all ERC samples. STAT3 protein expression was detected in 56% of tumor samples and 69% of the immune microenvironment. STAT3 positivity in the immune cell compartment was associated with longer disease-free survival, although the multivariate analysis could not confirm its value as an independent prognostic factor. Chemotherapy testing on liver tumor organoids showed various degrees of decreases in viability after treatment with gemcitabine, cisplatin, and cabozantinib. Baricitinib treatment significantly reduced IL-6 and MCP-1 secretion in cholangiocarcinoma Conclusions: The patient-derived organoid model of PSC and liver tumors is a valuable tool for testing novel and established therapeutic strategies, including JAK inhibitors and chemotherapy regimens. STAT3 expression in the immune microenvironment of BTC may serve as a prognostic marker. Further studies are needed to explore the integration of co-cultured organoid systems with stromal and immune components to improve physiological relevance. Full article

(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancers: From Microbiota Modulation to New Therapeutic Approaches)

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12 pages, 1069 KB

Open AccessEditor’s ChoiceArticle

Perimesencephalic Subarachnoid Hemorrhage Is Not Always a Benign Condition: Hemorrhage Volume as a Predictor for Complications and Clinical Outcome

by Emily Hoffmann, Công Duy Bùi, Alexandra Valls Chavarria, Michael Müther, Markus Holling, Manfred Musigmann, Max Masthoff, Mostafa Ergawy, Tobias D. Faizy, Christian Paul Stracke, Hermann Krähling and Burak Han Akkurt

Biomedicines 2025, 13(5), 1061; https://doi.org/10.3390/biomedicines13051061 - 27 Apr 2025

Cited by 1 | Viewed by 3064

Abstract

Objective: The benign nature of perimesencephalic subarachnoid hemorrhage (pmSAH) can be challenged by the occurrence of complications. Given the limited prognostic value of established clinical parameters for the development of complications in patients with pmSAH, this study evaluates the potential of volumetric hemorrhage [...] Read more.

Objective: The benign nature of perimesencephalic subarachnoid hemorrhage (pmSAH) can be challenged by the occurrence of complications. Given the limited prognostic value of established clinical parameters for the development of complications in patients with pmSAH, this study evaluates the potential of volumetric hemorrhage quantification for risk assessment and the evaluation of the clinical outcome. Material and Methods: In this retrospective single-center study, we analyzed all consecutive patients diagnosed with pmSAH between 2010 and 2023 at a tertiary care academic medical center in Germany. The volumetric quantification of the hemorrhage in cm³ was performed using non-contrast CT imaging. The occurrence of clinical complications, including hydrocephalus, vasospasm, and delayed cerebral ischemia (DCI), were assessed. Clinical outcomes were determined by the Glasgow Outcome Scale (GOS) at discharge. Multivariable logistic regression models were used to assess the correlation between quantified hemorrhage volumes and the occurrence of complications and clinical outcomes (GOS) controlled for other variables such as age, sex, cardiovascular risk factors, clinical symptoms, and the modified Fisher scale. Results: A total of 82 patients (58.5% male, 54.8 ± 12.1 years) were enrolled. The median World Federation of Neurosurgical Societies (WFNS) score for all patients at admission was 1.0 (IQR 1.0–1.0). During the clinical course, hydrocephalus occurred in 29%, vasospasm in 14.6%, and DCI in 8.5% of all patients. Hemorrhage volume quantification was found to be the strongest independent predictor for hydrocephalus (OR 1.28; 95% CI 1.02–1.61; p = 0.032) and vasospasm (OR 1.25; 95% CI 1.07–1.46; p = 0.007) and showed a high predictive accuracy in ROC analyses (AUC = 0.77 and 0.76, respectively). Conversely, neither clinical parameters nor the modified Fisher scale were associated with these complications. A higher hemorrhage volume was also significantly correlated with a worse functional outcome (GOS; β = –0.07, CI: −0.12–−0.02, p = 0.021). Conclusions: In patients with pmSAH, the volumetric quantification of hemorrhage may be an adequate prognostic parameter regarding the occurrence of hydrocephalus and vasospasm. In addition, the quantitative assessment of hemorrhage volumes was strongly associated with clinical outcomes in these patients. Despite the generally benign nature of pmSAH, this imaging biomarker could improve individualized clinical management strategies and inform about the risk for the occurrence of complications. Full article

(This article belongs to the Special Issue Emerging Biomarkers and Therapeutic Approaches in Neurovascular Diseases)

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25 pages, 3082 KB

Open AccessEditor’s ChoiceReview

Advancing Head and Neck Cancer Therapies: From Conventional Treatments to Emerging Strategies

by Aleksandra Mordzińska-Rak, Ilona Telejko, Grzegorz Adamczuk, Tomasz Trombik, Andrzej Stepulak and Ewa Błaszczak

Biomedicines 2025, 13(5), 1046; https://doi.org/10.3390/biomedicines13051046 - 25 Apr 2025

Cited by 21 | Viewed by 6735

Abstract

Head and neck cancers (HNCs), particularly head and neck squamous cell carcinoma (HNSCC), are among the most aggressive and prevalent malignancies of the upper aerodigestive tract. As the incidence of HNCs continues to rise, this cancer type presents a significant public health challenge. [...] Read more.

Head and neck cancers (HNCs), particularly head and neck squamous cell carcinoma (HNSCC), are among the most aggressive and prevalent malignancies of the upper aerodigestive tract. As the incidence of HNCs continues to rise, this cancer type presents a significant public health challenge. Despite conventional treatment options, such as surgery, chemotherapy, and radiotherapy, the five-year survival rates remain relatively low due to resistance to these therapies, local recurrence, local lymph node metastasis, and in some advanced cases also distant metastasis. Consequently, patients with HNCs face a high mortality risk and have reduced quality of life due to the side effects of chemo- and radiotherapy. Furthermore, targeted therapies and immunotherapies have also shown limited effectiveness in many cases, with issues related to resistance and the accessibility of these treatments. Therefore, new strategies, such as those based on combination therapies and nanotechnology, are being explored to improve the treatment of HNC patients. The proteolysis-targeting chimeras (PROTACs) also emerged as a promising therapeutic approach, though research is still ongoing to bring this technology into clinical practice. Here, we aim to highlight the current knowledge of HNC therapies, with a focus on recent advancements, including nanomedicine and PROTAC-based strategies. The development and advancement of novel emerging therapies hold promise for the improvement of patients’ survival and quality of life. Full article

(This article belongs to the Special Issue Novel Approaches towards Targeted Head and Neck Cancer Therapies)

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23 pages, 9420 KB

Open AccessEditor’s ChoiceArticle

Druggability Studies of Benzene Sulfonamide Substituted Diarylamide (E3) as a Novel Diuretic

by Hang Zhang, Shuyuan Wang, Nannan Li, Yue Xu, Zhizhen Huang, Yukun Zhang, Jing Li, Yinglin Zuo, Min Li, Runtao Li and Baoxue Yang

Biomedicines 2025, 13(4), 992; https://doi.org/10.3390/biomedicines13040992 - 18 Apr 2025

Cited by 3 | Viewed by 1884

Abstract

Background/Objectives: Urea transporters (UTs) play an important role in the urine-concentrating mechanism and have been regarded as a novel drug target for developing salt-sparing diuretics. Our previous studies found that diarylamides 1H and 25a are specific UT inhibitors and have oral diuretic [...] Read more.

Background/Objectives: Urea transporters (UTs) play an important role in the urine-concentrating mechanism and have been regarded as a novel drug target for developing salt-sparing diuretics. Our previous studies found that diarylamides 1H and 25a are specific UT inhibitors and have oral diuretic activity. However, these compounds necessitate further optimization and comprehensive druggability studies. Methods: The optimal compound was identified through structural optimization. Experiments were conducted to investigate its UT inhibitory activity and evaluate its diuretic effect. Furthermore, disease models were utilized to assess the compound’s efficacy in treating hyponatremia. Pharmacokinetic studies were performed to examine its metabolic stability, and toxicity tests were conducted to evaluate its safety. Results: Based on the chemical structure of compound 25a, we synthesized a novel diarylamide compound, E3, by introducing a benzenesulfonamide group into its side chain. E3 exhibited dose-dependent inhibition of UT at the nanomolar level and demonstrated oral diuretic activity without causing electrolyte excretion disorders in both mice and rats. Experiments on UT-B^−/− and UT-A1^−/− mice indicated that E3 enhances the diuretic effect primarily by inhibiting UT-A1 more effectively than UT-B. Furthermore, E3 displayed good metabolic stability and favorable pharmacokinetic characteristics. E3 significantly ameliorated hyponatremia through diuresis in a rat model. Importantly, E3 did not induce acute oral toxicity, subacute oral toxicity, genotoxicity, or cardiotoxicity. Conclusions: Our study confirms that E3 exerts a diuretic effect by specifically inhibiting UTs and has good druggability, which offers potential for E3 to be developed into a new diuretic for the treatment of hyponatremia. Full article

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

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21 pages, 645 KB

Open AccessEditor’s ChoiceSystematic Review

A Systematic Review of Pneumonitis Following Treatment with Immune Checkpoint Inhibitors and Radiotherapy

by Melina Yerolatsite, Nanteznta Torounidou, Anna-Lea Amylidi, Iro-Chrisavgi Rapti, George Zarkavelis, Eleftherios Kampletsas and Paraskevi V. Voulgari

Biomedicines 2025, 13(4), 946; https://doi.org/10.3390/biomedicines13040946 - 12 Apr 2025

Cited by 7 | Viewed by 6300

Abstract

Background: Immune checkpoint inhibitors (ICIs) are increasingly included in management guidelines for various types of cancer. However, immune-related adverse events (irAEs) are an inevitable consequence of these therapies. Some of these side effects, such as pneumonitis, can be particularly serious. Additionally, the combination [...] Read more.

Background: Immune checkpoint inhibitors (ICIs) are increasingly included in management guidelines for various types of cancer. However, immune-related adverse events (irAEs) are an inevitable consequence of these therapies. Some of these side effects, such as pneumonitis, can be particularly serious. Additionally, the combination of ICIs with radiotherapy (RT) may further increase the risk of pneumonitis. Objective: The aim of this systematic review is to examine all available studies on pneumonitis following the use of ICIs and RT to assess its appearance and severity. Methods: We systematically searched four different databases (PubMed, Scopus, Cochrane, and DOAJ) to identify all relevant studies within our scope. Additionally, we reviewed the references of the studies we found, as well as those of other systematic reviews and meta-analyses. We assessed the risk of bias using the Cochrane Risk of Bias Tool version 2 for randomized controlled trials and the RTI Risk of Bias Item Bank for non-randomized trials. Finally, we extracted relevant data into an Excel file and presented them in tables throughout this study. Results: A total of 58 articles met our inclusion criteria, comprising 4889 patients across multiple studies and nine case reports. Due to significant heterogeneity in study methodologies and data reporting, a cumulative statistical analysis was not performed. The included studies were published between 2017 and 2025. The incidence of pneumonitis varied, with retrospective studies showing higher rates compared to randomized and non-randomized controlled trials. Case reports described a range of pneumonitis presentations, treatments, and outcomes, with corticosteroids being the primary treatment. Conclusions: The incidence of pneumonitis varied, with retrospective studies showing the highest rates compared to other study designs. Early detection and management of pneumonitis in patients receiving RT and/or ICIs are crucial for improving outcomes. Identifying high-risk patients through predictive models, radiomics, and biomarkers may help tailor treatment strategies and minimize toxicity. Further research is needed to establish the most appropriate diagnostic criteria, optimize management approaches, and refine advanced imaging and biomarker-based risk stratification to improve patient care. Interdisciplinary collaboration is essential for reducing the risk of pneumonitis and improving patient outcomes. Full article

(This article belongs to the Special Issue Advances in Immunotherapy and Radiation Therapy for Cancer)

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14 pages, 265 KB

Open AccessEditor’s ChoiceReview

Kidney Transplantation in Congenital Abnormalities of Kidney and Urinary Tract (CAKUT)

by Silvio Maringhini and Lars Pape

Biomedicines 2025, 13(4), 932; https://doi.org/10.3390/biomedicines13040932 - 10 Apr 2025

Cited by 2 | Viewed by 2920

Abstract

Congenital anomalies of the kidney and urinary tract (CAKUT) are a common cause of chronic kidney disease in children. Most patients will reach end-stage renal function and dialysis or transplantation in childhood or early adulthood. Patients with CAKUT deserve a careful evaluation before [...] Read more.

Congenital anomalies of the kidney and urinary tract (CAKUT) are a common cause of chronic kidney disease in children. Most patients will reach end-stage renal function and dialysis or transplantation in childhood or early adulthood. Patients with CAKUT deserve a careful evaluation before a kidney transplant; detailed imaging and functional studies are necessary, particularly in the presence of lower urinary tract abnormalities, and surgical procedures are advisable in selected cases. A higher incidence of complications has been reported after a kidney transplant in CAKUT, mainly urinary tract infections. However, in the long term, the prognosis seems to be comparable to other kidney diseases. A large number of reports are available in the literature on medical and surgical management of patients with CAKUT before, during, and after a kidney transplant; almost all recommendations of surgical procedures before a kidney transplantation are based on retrospective not controlled studies or personal opinions; prospective controlled studies are needed. In this narrative, nonsystematic review, we report the results of recently published selected studies and underline questions that should be addressed in future guidelines. Full article

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

19 pages, 7484 KB

Open AccessEditor’s ChoiceArticle

Comprehensive Integrated Analysis Reveals the Spatiotemporal Microevolution of Cancer Cells in Patients with Bone-Metastatic Prostate Cancer

by Yinghua Feng, Xiuli Zhang, Guangpeng Wang, Feiya Yang, Ruifang Li, Lu Yin, Dong Chen, Wenkuan Wang, Mingshuai Wang, Zhiyuan Hu, Yuan Sh and Nianzeng Xing

Biomedicines 2025, 13(4), 909; https://doi.org/10.3390/biomedicines13040909 - 9 Apr 2025

Cited by 5 | Viewed by 3973

Abstract

Background/Objectives: Bone metastasis is a frequent and life-threatening event in advanced cancers, affecting up to 70–85% of prostate cancer patients. Understanding the cellular and molecular mechanisms underlying bone metastasis is essential for developing targeted therapies. This study aimed to systematically characterize the heterogeneity [...] Read more.

Background/Objectives: Bone metastasis is a frequent and life-threatening event in advanced cancers, affecting up to 70–85% of prostate cancer patients. Understanding the cellular and molecular mechanisms underlying bone metastasis is essential for developing targeted therapies. This study aimed to systematically characterize the heterogeneity and microenvironmental adaptation of prostate cancer bone metastases using single-cell transcriptomics. Methods: We integrated the largest single-cell transcriptome dataset to date, encompassing 124 samples from primary prostate tumors, various bone metastatic sites, and non-malignant tissues (e.g., benign prostatic hyperplasia, normal bone marrow). After quality control, 602,497 high-quality single-cell transcriptomes were analyzed. We employed unsupervised clustering, gene expression profiling, mutation analysis, and metabolic pathway reconstruction to characterize cancer cell subtypes and tumor microenvironmental remodeling. Results: Cancer epithelial cells dominated the tumor microenvironment but exhibited pronounced heterogeneity, posing challenges for conventional clustering methods. By integrating genetic and metabolic features, we revealed key evolutionary trajectories of epithelial cancer cells during metastasis. Notably, we identified a novel epithelial subpopulation, NEndoCs, characterized by unique differentiation patterns and distinct spatial distribution across metastatic niches. We also observed significant metabolic reprogramming and recurrent mutations linked to prostate-to-bone microenvironmental transitions. Conclusions: This study comprehensively elucidates the mutation patterns, metabolic reprogramming, and microenvironment adaptation mechanisms of bone metastasis in prostate cancer, providing key molecular targets and clinical strategies for the precise treatment of bone metastatic prostate cancer. Full article

(This article belongs to the Special Issue Urogenital Cancers: New Molecular and Translational Aspects on Carcinogenesis and Treatments)

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20 pages, 1979 KB

Open AccessEditor’s ChoiceArticle

TGF-β1 Improves Nerve Regeneration and Functional Recovery After Sciatic Nerve Injury by Alleviating Inflammation

by Maorong Jiang, Zihan Ding, Yuxiao Huang, Taoran Jiang, Yiming Xia, Dandan Gu, Xi Gu, Huiyuan Bai and Dengbing Yao

Biomedicines 2025, 13(4), 872; https://doi.org/10.3390/biomedicines13040872 - 3 Apr 2025

Cited by 10 | Viewed by 2353

Abstract

Background: Peripheral nerves have a certain regenerative ability, but their repair and regeneration after injury is a complex process, usually involving a large number of genes and proteins. In a previous study, we analyzed the gene expression profile in rats after sciatic nerve [...] Read more.

Background: Peripheral nerves have a certain regenerative ability, but their repair and regeneration after injury is a complex process, usually involving a large number of genes and proteins. In a previous study, we analyzed the gene expression profile in rats after sciatic nerve injury and found significant changes in transforming growth factor-beta 1 (TGF-β1) expression, suggesting that TGF-β1 may be involved in the process of nerve regeneration after injury. Methods: In this study, we first detected the time-course expression and localization of TGF-β1 in dorsal root ganglion (DRG) tissues in a rat sciatic nerve transection model via RT-qPCR. Secondly, we investigated the bioactive roles of TGF-β1 in primary cultured DRG neuron cells through a CCK8 assay, TUNEL assay, and immunofluorescence staining. Thirdly, we explored the neuroprotective roles of TGF-β1 in an in vivo model of sciatic nerve regeneration through morphological observation, behavioral, and electrophysiological tests, and a molecular biological measure. Results: We found that TGF-β1 expression was increased after injury and mainly located in the cytoplasm and nuclei of neuron cells in the DRG. TGF-β1 may regulate the viability, apoptosis, and neurite outgrowth of primary DRG neuron cells. In our in vivo model of sciatic nerve regeneration, TGF-β1 improved nerve regeneration and neuronal function recovery after sciatic nerve injury, alleviated the inflammatory response, and relieved neuropathic pain via the TGF-β1/smad2 pathway. Conclusions: This study provides an experimental and theoretical basis for using TGF-β1 as a neuroprotective agent after peripheral nerve injury in clinical practice in the future. Full article

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

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36 pages, 2379 KB

Open AccessEditor’s ChoiceReview

The Role of NK Cells in Cancer Immunotherapy: Mechanisms, Evasion Strategies, and Therapeutic Advances

by Paula Morcillo-Martín-Romo, Javier Valverde-Pozo, María Ortiz-Bueno, Maurizio Arnone, Laura Espinar-Barranco, Celia Espinar-Barranco and María Eugenia García-Rubiño

Biomedicines 2025, 13(4), 857; https://doi.org/10.3390/biomedicines13040857 - 2 Apr 2025

Cited by 38 | Viewed by 14712

Abstract

Background/Objectives: Natural killer (NK) cells play a crucial role in tumor surveillance by exerting cytotoxic activity and modulating immune responses. However, tumors employ diverse evasion strategies that limit NK cell effectiveness. This review aims to explore the molecular mechanisms of NK cell activation [...] Read more.

Background/Objectives: Natural killer (NK) cells play a crucial role in tumor surveillance by exerting cytotoxic activity and modulating immune responses. However, tumors employ diverse evasion strategies that limit NK cell effectiveness. This review aims to explore the molecular mechanisms of NK cell activation and inhibition in cancer, the influence of the tumor microenvironment, and the latest advancements in NK cell-based immunotherapies, including adoptive NK cell transfer and Chimeric Antigen Receptor-Natural Killer (CAR-NK) cell therapies. Methods: A comprehensive literature review was conducted, prioritizing peer-reviewed studies from the last decade on NK cell biology, tumor immune evasion, and immunotherapeutic applications. The analysis includes data from preclinical models and clinical trials evaluating NK cell expansion strategies, cytokine-based stimulation, and CAR-NK cell therapy developments. Results: NK cells eliminate tumors through cytotoxic granule release, death receptor pathways, and cytokine secretion. However, tumor cells evade NK-mediated immunity by downregulating activating ligands, secreting immunosuppressive molecules, and altering the tumor microenvironment. Novel NK cell-based therapies, such as CAR-NK cells and combination approaches with immune checkpoint inhibitors, enhance NK cell persistence and therapeutic efficacy against both hematologic and solid malignancies. Clinical trials suggest improved safety profiles compared to CAR-T therapies, with reduced cytokine release syndrome and graft-versus-host disease. Conclusions: While NK cell-based immunotherapies hold great promise, challenges remain, including limited persistence and tumor-induced immunosuppression. Addressing these hurdles will be critical for optimizing NK cell therapies and advancing next-generation, off-the-shelf immunotherapeutics for broader clinical applications. Full article

(This article belongs to the Special Issue The Role of NK Cells in Cancer Immunotherapy: Mechanisms, Evasion Strategies, and Therapeutic Advances)

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33 pages, 13491 KB

Open AccessEditor’s ChoiceArticle

Investigating the Prognostic Role of Telomerase-Related Cellular Senescence Gene Signatures in Breast Cancer Using Machine Learning

by Qiong Li and Hongde Liu

Biomedicines 2025, 13(4), 826; https://doi.org/10.3390/biomedicines13040826 - 30 Mar 2025

Cited by 3 | Viewed by 2414

Abstract

Background: Telomeres and cellular senescence are critical biological processes implicated in cancer development and progression, including breast cancer, through their influence on genomic stability and modulation of the tumor microenvironment. Methods: This study integrated bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq) [...] Read more.

Background: Telomeres and cellular senescence are critical biological processes implicated in cancer development and progression, including breast cancer, through their influence on genomic stability and modulation of the tumor microenvironment. Methods: This study integrated bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq) data to establish a gene signature associated with telomere maintenance and cellular senescence for prognostic prediction in breast cancer. Telomere-related genes (TEGs) and senescence-associated genes were curated from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. A comprehensive machine learning framework incorporating 101 algorithmic combinations across 10 survival modeling approaches, including random survival forests and ridge regression, was employed to develop a robust prognostic model. Results: A set of 19 key telomere- and senescence-related genes was identified as the optimal prognostic signature. The model demonstrated strong predictive accuracy and was successfully validated in multiple independent cohorts. Functional enrichment analyses indicated significant associations with immune responses and aging-related pathways. Single-cell transcriptomic analysis revealed marked cellular heterogeneity, identifying distinct subpopulations (fibroblasts and immune cells) with divergent risk scores and biological pathway activity. Additionally, pseudo-time trajectory analysis and intercellular communication mapping provided insights into the dynamic evolution of the tumor microenvironment. Immunohistochemical (IHC) validation using data from the Human Protein Atlas confirmed differential protein expression between normal and tumor tissues for several of the selected genes, reinforcing their biological relevance and clinical utility. Conclusions: This study presents a novel 19-gene telomere- and senescence-associated signature with strong prognostic value in breast cancer. These findings enhance our understanding of tumor heterogeneity and may inform precision oncology approaches and future therapeutic strategies. Full article

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

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23 pages, 1947 KB

Open AccessEditor’s ChoiceReview

Microbiome and Postbiotics in Skin Health

by Santosh Kumar Prajapati, Lalitha Lekkala, Dhananjay Yadav, Shalini Jain and Hariom Yadav

Biomedicines 2025, 13(4), 791; https://doi.org/10.3390/biomedicines13040791 - 25 Mar 2025

Cited by 59 | Viewed by 28841

Abstract

The skin microbiome, a diverse and dynamic ecosystem of microorganisms, plays a pivotal role in maintaining skin health by interacting with skin cells, immune components, and structural barriers. It is essential for skin homeostasis, immune defense, and protection against pathogenic colonization. Dysbiosis in [...] Read more.

The skin microbiome, a diverse and dynamic ecosystem of microorganisms, plays a pivotal role in maintaining skin health by interacting with skin cells, immune components, and structural barriers. It is essential for skin homeostasis, immune defense, and protection against pathogenic colonization. Dysbiosis in the microbiome has been implicated in numerous dermatological conditions, including acne, eczema, psoriasis, and rosacea. Acne, the most prevalent skin condition, affects up to 85% of individuals at some point in their lives, while eczema and psoriasis impose significant public health and economic burdens. The composition of the skin microbiome varies across skin types and anatomical sites, with sebaceous, moist, and dry areas fostering distinct microbial communities. Emerging therapeutic strategies such as microbiome-targeted treatments offer novel avenues for addressing skin diseases. Among these approaches, postbiotics have gained significant attention for their safety and efficacy. Unlike probiotics, postbiotics are non-viable microbial cells or their metabolites, which reduce safety concerns while providing functional benefits such as UV protection and wound healing. This review consolidates current insights into the role of the skin microbiome in health and disease, emphasizing postbiotics as a promising therapeutic strategy by exploring the clinical and commercial potential of microbiome-based treatments, particularly postbiotics, and their ability to redefine dermatological care and improve patient outcomes. Full article

(This article belongs to the Special Issue Wound Healing: From Basic to Clinical Research)

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14 pages, 1848 KB

Open AccessEditor’s ChoiceArticle

The Influence of Pituitary Morphology on the Occurrence of Hormonal Disorders in Patients with Empty Sella or Partial Empty Sella

by Bernadetta Kałuża, Mariusz Furmanek, Jan Domański, Aleksandra Żuk-Łapan, Emilia Babula, Iga Poprawa, Małgorzata Landowska, Karolina Jarząbek, Justyna Popczyńska, Paulina Filipowicz, Małgorzata Wielgolewska, Jerzy Walecki and Edward Franek

Biomedicines 2025, 13(4), 762; https://doi.org/10.3390/biomedicines13040762 - 21 Mar 2025

Cited by 3 | Viewed by 3005

Abstract

Background/Objectives: The aim of the study was to prospectively assess the impact of certain parameters of pituitary morphology assessed with the use of magnetic resonance imaging on the occurrence of hormonal disorders in patients with primary partial empty sella (PES) or primary empty [...] Read more.

Background/Objectives: The aim of the study was to prospectively assess the impact of certain parameters of pituitary morphology assessed with the use of magnetic resonance imaging on the occurrence of hormonal disorders in patients with primary partial empty sella (PES) or primary empty sella (ES). Methods: Forty-three patients were divided into two groups: group 1—patients with PES (n = 20); group 2—patients with ES (n = 23). Results: Patients with ES were characterized by larger both the transverse (14.8 ± 2.9 mm vs. 17.2 ± 2.9 mm, p = 0.016) and anteroposterior (AP) diameters of the pituitary (11.4 ± 1.4 mm vs. 13.2 ± 1.9 mm, p = 0.003), a smaller craniocaudal (CC) diameter (3.9 ± 0.62 mm vs. 2.2 ± 0.6 mm, p = 0.001), and a lower pituitary volume (332.8 ± 107.6 mm³ vs. 243.5 ± 70.9 mm³, p = 0.001). Moreover, an AP infundibular displacement was more common in patients with ES (7 [35%] vs. 16 [69.6%]., p = 0.023). Despite the fact that secondary adrenocortical insufficiency was shown to be significantly more common and ACTH levels to be significantly lower (27.5 ± 13.2 pg/mL vs. 21.8 ± 17.6 pg/mL, p = 0.039) in patients with ES (0 [0%] vs. 3 [13.4%], p = 0.046), univariate logistic regression did not reveal any significant associations of pituitary diameters, pituitary volume, or pituitary stalk displacement with endocrine disorders, such as secondary adrenocortical insufficiency or hyperprolactinemia, which was confirmed with multivariate logistic regression adjusted for age, sex, BMI, and arterial hypertension. Conclusions: Radiologically assessed CC, AP, and transverse pituitary diameters, pituitary volume, or pituitary stalk displacement in patients with PES or ES have no bearing on the rates of hormonal disorders. Nonetheless, certain hormonal disorders may be more common in patients with ES, which suggests a need for hormone-level assessments in this population. Full article

(This article belongs to the Special Issue State-of-the-Art Endocrinology and Metabolism Research in Poland (Volume II))

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17 pages, 2449 KB

Open AccessEditor’s ChoiceArticle

Endocrine-Disrupting Activities of Flavones on Steroid Receptors: Structural Requirements and Synthesis of Novel Flavone with Improved Estrogenic Activity

by Steven K. Nordeen, Vijay Kumar, Betty J. Bona, Joshua D. Batson, Donald S. Backos and Michael F. Wempe

Biomedicines 2025, 13(3), 748; https://doi.org/10.3390/biomedicines13030748 - 19 Mar 2025

Cited by 8 | Viewed by 2223

Abstract

Background/Objectives: Flavonoids are common ubiquitous components of plants and are consumed by humans and livestock in their diets. Many different activities have been proposed for a variety of flavonoids that play a role in the benefits of a plant-rich diet. On the downside, [...] Read more.

Background/Objectives: Flavonoids are common ubiquitous components of plants and are consumed by humans and livestock in their diets. Many different activities have been proposed for a variety of flavonoids that play a role in the benefits of a plant-rich diet. On the downside, excessive exposure to some flavonoids comes with a risk of endocrine disruption. Our objective was to define the structural elements of flavones and selected other flavonoids required for endocrine-disrupting activities on each of four steroid receptors, estrogen, androgen, progesterone, and glucocorticoid receptors. Methods: This work presents a systematic screen for the hormone agonist or antagonist activity of a selected panel of flavonoids on estrogen, androgen, progesterone, and glucocorticoid receptors. The screen is focused on the positional requirements of hydroxyl substituents on the flavone backbone. Results: Each receptor exhibited a distinct pattern for structural requirements of the flavones to impact receptor signaling. The most active flavones exhibited antagonist activity on androgen and progesterone receptors with an IC₅₀ of 0.5 and 2 µM, respectively. Flavones only exhibited weak antagonism on glucocorticoid receptors. When active, flavones acted as estrogen receptor agonists. The findings were utilized to design and synthesize a novel flavone, 3-fluoro, 6,4′-dihydroxyflavone 14, that displays increased potency as an estrogen agonist (EC₅₀~30 nM). Modeling of the binding of this novel flavone predicts increased preference for ERα versus ERβ relative to the estrogenic phytoestrogen, genistein. Conclusions: The structural requirements for flavones to act as estrogen agonists and antagonists of other steroid receptors are defined. The synthesis of a novel flavone offers potential for topical applications where systemic estrogen activity is undesired. However, the results highlight the potential for endocrine disruption when certain flavones are consumed in quantity as supplements. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Steroid Hormone Action—2nd Edition)

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19 pages, 1600 KB

Open AccessEditor’s ChoiceReview

Application of the Human Proteome in Disease, Diagnosis, and Translation into Precision Medicine: Current Status and Future Prospects

by Yawen Xie, Xiaoying Chen, Maokai Xu and Xiaochun Zheng

Biomedicines 2025, 13(3), 681; https://doi.org/10.3390/biomedicines13030681 - 10 Mar 2025

Cited by 15 | Viewed by 6215

Abstract

This review summarizes the existing studies of human proteomics technology in the medical field with a focus on the development mechanism of a disease and its potential in discovering biomarkers. Through a systematic review of the relevant literature, we found the significant advantages [...] Read more.

This review summarizes the existing studies of human proteomics technology in the medical field with a focus on the development mechanism of a disease and its potential in discovering biomarkers. Through a systematic review of the relevant literature, we found the significant advantages and application scenarios of proteomics technology in disease diagnosis, drug development, and personalized treatment. However, the review also identifies the challenges facing proteomics technologies, including sample preparation of low-abundance proteins, massive amounts of data analysis, and how research results can be better used in clinical practice. Finally, this work discusses future research directions, including the development of more effective proteomics technologies, strengthening the integration of multi-source omics technologies, and promoting the application of AI in the human proteome. Full article

(This article belongs to the Special Issue The Human Proteome in Disease, Diagnostics and Translation into Precision Medicine: Current Status and Future Prospects)

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17 pages, 268 KB

Open AccessEditor’s ChoiceReview

Severe Asthma and Active SARS-CoV-2 Infection: Insights into Biologics

by Sara Manti, Michela Leotta, Federica D’Amico, Simone Foti Randazzese, Giuseppe Fabio Parisi and Salvatore Leonardi

Biomedicines 2025, 13(3), 674; https://doi.org/10.3390/biomedicines13030674 - 10 Mar 2025

Cited by 4 | Viewed by 2312

Abstract

Since the onset of the COVID-19 pandemic, managing asthma has become significantly more challenging. Both national and international guidelines emphasize the importance of continuing prescribed medications to maintain asthma control and prevent exacerbations. However, the emergence of SARS-CoV-2 infection has raised concerns about [...] Read more.

Since the onset of the COVID-19 pandemic, managing asthma has become significantly more challenging. Both national and international guidelines emphasize the importance of continuing prescribed medications to maintain asthma control and prevent exacerbations. However, the emergence of SARS-CoV-2 infection has raised concerns about the safety of biologic therapies during acute COVID-19 episodes, necessitating a careful and individualized approach to their use. Biologic therapies, including omalizumab, dupilumab, mepolizumab, reslizumab, benralizumab, and tezepelumab, which target specific pathways in severe asthma, have revolutionized asthma management by improving symptom control and reducing exacerbation rates. Despite their proven benefits, the intersection of biologic therapy and active SARS-CoV-2 infection has prompted questions regarding potential immunomodulatory effects and risks. This review aimed to synthesize the current literature on the antiviral effects and safety of biologic drugs in severe asthmatic patients with active SARS-CoV-2 infection, encompassing both pediatric and adult populations. Full article

(This article belongs to the Special Issue Molecular Targets for Biological Therapies of Severe Asthma: Second Edition)

17 pages, 805 KB

Open AccessEditor’s ChoiceReview

Personalized Nutrition in Chronic Kidney Disease

by Nishigandha Pradhan, Jennifer Kerner, Luciana A. Campos and Mirela Dobre

Biomedicines 2025, 13(3), 647; https://doi.org/10.3390/biomedicines13030647 - 6 Mar 2025

Cited by 18 | Viewed by 14521

Abstract

A personalized approach to nutrition in patients with chronic kidney disease (CKD) represents a promising paradigm shift in disease management, moving beyond traditional one-size-fits-all dietary recommendations. Patients with CKD often have other comorbidities and face unique nutritional challenges, including protein-energy wasting (PEW), sarcopenia, [...] Read more.

A personalized approach to nutrition in patients with chronic kidney disease (CKD) represents a promising paradigm shift in disease management, moving beyond traditional one-size-fits-all dietary recommendations. Patients with CKD often have other comorbidities and face unique nutritional challenges, including protein-energy wasting (PEW), sarcopenia, and impaired renal excretion of nutrients, which complicate dietary planning. Current guidelines focus primarily on nutrient restrictions—such as limiting protein, sodium, potassium, and phosphorus. However, these generalized recommendations often result in suboptimal adherence and outcomes. Personalized nutrition, which adapts dietary recommendations to individual characteristics, such as genotype, phenotype, and socio-cultural preferences, has gained traction across various chronic diseases. However, its application in nephrology remains underexplored, and despite promising results from studies such as Food4Me, questions remain about the real-world impact of such strategies. The aims of this review are (1) to summarize the evidence on the current state of nutritional recommendations in CKD, (2) to discuss the emerging role of multi-omics approaches in informing personalized nutrition advice in CKD, and (3) to provide an opinion on nutritional challenges faced by patients with CKD and the importance of collaboration with the renal dietician. We conclude that despite barriers, such as the cost and data integration, personalized nutrition holds the potential to improve CKD outcomes, enhance quality of life, and empower patients through tailored dietary strategies for better disease management. Full article

(This article belongs to the Special Issue Pathological Biomarkers in Precision Medicine)

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14 pages, 1078 KB

Open AccessEditor’s ChoiceArticle

Early Changes in the Plasma Lipidome of People at Very High Cardiovascular Risk: A New Approach to Assessing the Risk of Cardiovascular Changes

by Joanna Waś, Piotr Dobrowolski, Aleksander Prejbisz, Magdalena Niedolistek, Ilona Kowalik, Anna Drohomirecka, Dorota Sokołowska and Jolanta Krzysztoń-Russjan

Biomedicines 2025, 13(3), 643; https://doi.org/10.3390/biomedicines13030643 - 6 Mar 2025

Cited by 1 | Viewed by 1738

Abstract

Background/Objectives: Cardiovascular disease (CVD) remains the leading cause of death worldwide and requires a deeper understanding of its pathogenesis for effective prevention and treatment. Familial hypercholesterolemia (FH), characterized by high levels of LDL cholesterol, is a significant risk factor for CVD. FH background [...] Read more.

Background/Objectives: Cardiovascular disease (CVD) remains the leading cause of death worldwide and requires a deeper understanding of its pathogenesis for effective prevention and treatment. Familial hypercholesterolemia (FH), characterized by high levels of LDL cholesterol, is a significant risk factor for CVD. FH background remains unexplained despite advances in genetic testing. The aim was identification early changes in the plasma lipidome of individuals at high cardiovascular risk (HCVR) using liquid chromatography coupled with mass spectrometry. Methods: The lipidomic analysis examined over 400 compounds. Twenty individuals with suspected FH, very high cardiovascular risk (VHCVR), and undetectable mutations in the LDLR, APOB, or PCSK9 genes were compared to control group in a qualitative-quantitative analysis. Results: Multivariate analyses revealed statistically significant alterations in glycerophospholipids (GC), with a notable increase in phosphatidylcholines ((O-36:0/16:0), OR (95% CI): 1.246 (1.042–1.490), p = 0.0157), phosphatidylethanolamines ((O-40:7/22:6), OR (95% CI): 1.119 (1.039–1.205), p = 0.0028), and phosphatidylglycerol ((40:8/20:4), OR (95% CI): 1.053 (1.008–1.101), p = 0.0219) only in patients with HCVR. These changes, particularly in major classes of GC, underscored their potential as biomarkers for early assessment of cardiovascular risk. Lipidomic profiling revealed associations between specific lipid species and the comorbidities of arterial hypertension, atherosclerosis, and insulin resistance, implicating their role in atherosclerotic cardiovascular disease (ASCVD). Conclusions: This study points early changes in the plasma lipidome in individuals at HCVR, underline potential biomarkers, therapeutic targets for ASCVD, and offer opportunities to improve ASCVD diagnosis, therapy, and risk management strategies through detailed personalized medical approach. Full article

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

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27 pages, 5680 KB

Open AccessEditor’s ChoiceArticle

Synergistic Effects of Green Nanoparticles on Antitumor Drug Efficacy in Hepatocellular Cancer

by Mirela Claudia Rîmbu, Liliana Popescu, Mirela Mihăilă, Roxana Colette Sandulovici, Daniel Cord, Carmen-Marinela Mihăilescu, Mona Luciana Gălățanu, Mariana Panțuroiu, Carmen-Elisabeta Manea, Adina Boldeiu, Oana Brîncoveanu, Mihaela Savin, Alexandru Grigoroiu, Florin Dan Ungureanu, Emilia Amzoiu, Mariana Popescu and Elena Truță

Biomedicines 2025, 13(3), 641; https://doi.org/10.3390/biomedicines13030641 - 5 Mar 2025

Cited by 9 | Viewed by 4824

Abstract

Background/Objectives: Cancer remains one of the leading causes of mortality worldwide. Despite significant advancements in treatment strategies and drug development, survival rates remain low and the adverse effects of conventional therapies severely impact patients’ quality of life. This study evaluates the therapeutic [...] Read more.

Background/Objectives: Cancer remains one of the leading causes of mortality worldwide. Despite significant advancements in treatment strategies and drug development, survival rates remain low and the adverse effects of conventional therapies severely impact patients’ quality of life. This study evaluates the therapeutic potential of plant-derived extracts in hepatocellular carcinoma treatment, with a focus on minimizing side effects while enhancing efficacy. Methods: This research investigates the in vitro synergistic effect of silver bio-nanoparticles synthesized from Clematis vitalba, Melissa officinalis, and Taraxacum officinale extracts (Clematis vitalbae extractum—CVE, Melissae extractum—ME, Taraxaci extractum—TE) in combination with liver cancer drugs, sunitinib (SNTB) and imatinib (IMTB), on HepG2 (human hepatocellular carcinoma) and HUVEC (human umbilical vein endothelial) cell lines. The silver nanoparticles (AgNPs) were characterized using UV-Vis spectroscopy, dynamic light scattering (DLS), zeta potential analysis, and scanning electron microscopy (SEM). The antitumor effects were evaluated through cell viability assays after 24 and 48 h of exposure, with additional cytotoxicity tests on HUVEC cells. Results: Results indicated that Melissa officinalis-derived silver nanoparticles (ME AgNPs) and Clematis vitalba extract with silver nanoparticles (CVE AgNPs) significantly reduced HepG2 cell viability. Their efficacy improved when combined with conventional therapies (SNTB + ME AgNPs 1:1 vs. SNTB: 20.01% vs. 25.73%, p = 0.002; IMTB + ME AgNPs 1:1 vs. IMTB: 17.80% vs. 18.08%, p = 0.036; SNTB + CVE AgNPs 1:1 vs. SNTB: 18.73% vs. 25.73%, p = 0.000; SNTB + CVE AgNPs 1:2 vs. SNTB: 26.62% vs. 41.00%, p = 0.018; IMTB + CVE AgNPs 1:1 vs. IMTB: 12.99% vs. 18.08%, p = 0.001). Taraxacum extract exhibited similar cytotoxicity to its nanoparticle formulation but did not exceed the efficacy of the extract alone at 24 h. Selectivity index assessments confirmed that AgNPs-based formulations significantly improve cytotoxicity and selectivity to HepG2 cells. Among the tested extracts, CVE demonstrated the strongest antitumor effect, enhancing the efficacy of synthetic drugs (CI < 1). SNTB + TE AgNPs (5% EtOH) also demonstrated consistent synergy at high doses, while SNTB + CVE AgNPs provided broad-range synergy, making it suitable for dose-escalation strategies. Conclusions: These findings underscore the potential of nanoparticle-based formulations in combination therapies with targeted kinase inhibitors such as sunitinib and imatinib. Future research should focus on in vivo validation and clinical trials to confirm these findings. Full article

(This article belongs to the Special Issue Nanoparticle-Based Drug Delivery in Cancer Therapy: Current Progress and Challenges)

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16 pages, 953 KB

Open AccessEditor’s ChoiceArticle

Enhancing Cardiovascular Risk Prediction with a Simplified Carotid IMT Protocol: Evidence from the IMPROVE Study

by Fabrizio Veglia, Anna Maria Malagoni, Mauro Amato, Rona J. Strawbridge, Kai Savonen, Philippe Giral, Antonio Gallo, Matteo Pirro, Bruna Gigante, Per Eriksson, Douwe J. Mulder, Beatrice Frigerio, Daniela Sansaro, Alessio Ravani, Daniela Coggi, Roberta Baetta, Nicolò Capra, Elena Tremoli and Damiano Baldassarre

Biomedicines 2025, 13(3), 584; https://doi.org/10.3390/biomedicines13030584 - 26 Feb 2025

Cited by 3 | Viewed by 3294

Abstract

Background/Objectives: Carotid intima-media thickness (CIMT) has long been used as an index of subclinical atherosclerosis, but its role as a risk modifier in cardiovascular (CV) risk optimization has recently been questioned due to methodological problems, such as lack of protocol standardization and [...] Read more.

Background/Objectives: Carotid intima-media thickness (CIMT) has long been used as an index of subclinical atherosclerosis, but its role as a risk modifier in cardiovascular (CV) risk optimization has recently been questioned due to methodological problems, such as lack of protocol standardization and scanning difficulties. In this multicentre, longitudinal, and observational study, we tested the predictive ability of two new CIMT variables detectable with a simplified, quick, and easy-to-standardize protocol. Methods: CIMT was measured in 3165 subjects from six centers, in five European countries, belonging to the IMPROVE study. The two variables tested were the average of two maximal CIMT measures taken, from a single angle, in the right and left common carotids (1CC-IMT_{mean-of-2-max}) or bifurcations (BIF-IMT_{mean-of-2-max}). The ability to predict CV events, on top of the SCORE2/SCORE2-OP risk algorithm, was quantified by the time-dependent increase in the receiver operating characteristic (ROC) area under the curve (AUC). Results: During a median follow-up of 7.1 years, 367 cardio-, cerebro-, and peripheral-vascular events were registered. Both CIMT variables tested were associated with CV risk, but 1CC-IMT_{mean-of-2-max} was also able to significantly increase the ROC AUC over the risk score (+0.017, p = 0.014). The result was stable after running several sensitivity analyses. Conclusions: 1CC-IMT_{mean-of-2-max} is able to significantly improve the predictive capacity of SCORE2/SCORE2-OP. Being based on a simple and easily standardized measurement protocol, this new variable is a promising candidate for application in mass screening and risk assessment in primary prevention. Full article

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

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16 pages, 2030 KB

Open AccessEditor’s ChoiceArticle

Sonidegib Inhibits the Adhesion of Acute Myeloid Leukemia to the Bone Marrow in Hypoxia: An Optical Tweezer Study

by Katarzyna Gdesz-Birula, Sławomir Drobczyński, Krystian Sarat and Kamila Duś-Szachniewicz

Biomedicines 2025, 13(3), 578; https://doi.org/10.3390/biomedicines13030578 - 25 Feb 2025

Cited by 4 | Viewed by 1737

Abstract

Background: Acute myeloid leukemia (AML) is a heterogeneous disease highly resistant to chemotherapeutic agents. Leukemia stem cells (LSCs) can enter a dormant state and avoid apoptosis in the protective niche of the bone marrow (BM) microenvironment. Moreover, bone marrow stromal cells protect leukemia [...] Read more.

Background: Acute myeloid leukemia (AML) is a heterogeneous disease highly resistant to chemotherapeutic agents. Leukemia stem cells (LSCs) can enter a dormant state and avoid apoptosis in the protective niche of the bone marrow (BM) microenvironment. Moreover, bone marrow stromal cells protect leukemia cells by promoting pro-survival signaling pathways and drug resistance. Therefore, attenuating interactions between leukemia cells and BM cells may have a positive therapeutic effect. Objectives: In this work, we hypothesized that sondages may inhibit the adhesion of leukemia cells to the bone marrow by inhibiting the Hedgehog (Hh) signaling pathway. The Hedgehog pathway is a key therapeutic target in AML due to its role in leukemic cell growth and survival. Methods: We investigated the effects of sonidegib on the adhesion of individual OCI-AML3 cells to a bone marrow stromal spheroid derived from the HS-5 cell line. For this purpose, we precisely determined the minimum cell-to-cell adhesion time using optical tweezers under normoxic (21% of O₂) and hypoxic (1% of O₂) conditions. Results: Our results demonstrated that sonidegib significantly increased the minimum cell-to-cell adhesion time necessary for leukemic cells to establish adhesive bonds with bone marrow stromal cells, thereby indicating a reduction in their adhesive properties. Additionally, we showed that sonidegib is particularly effective at hypoxic oxygen concentrations. Conclusions: The results obtained in this study suggest that sonidegib, through its modulation of the Hedgehog signaling pathway, holds promise as a potential therapeutic approach to target leukemic cell adhesion within the bone marrow microenvironment. Full article

(This article belongs to the Special Issue 3D Cell Culture Systems for Biomedical Research)

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20 pages, 512 KB

Open AccessEditor’s ChoiceArticle

Applying Wearable Sensors and Machine Learning to the Diagnostic Challenge of Distinguishing Parkinson’s Disease from Other Forms of Parkinsonism

by Rana M. Khalil, Lisa M. Shulman, Ann L. Gruber-Baldini, Stephen G. Reich, Joseph M. Savitt, Jeffrey M. Hausdorff, Rainer von Coelln and Michael P. Cummings

Biomedicines 2025, 13(3), 572; https://doi.org/10.3390/biomedicines13030572 - 25 Feb 2025

Cited by 9 | Viewed by 3020

Abstract

Background/Objectives: Parkinson’s Disease (PD) and other forms of parkinsonism share motor symptoms, including tremor, bradykinesia, and rigidity. The overlap in their clinical presentation creates a diagnostic challenge, as conventional methods rely heavily on clinical expertise, which can be subjective and inconsistent. This highlights [...] Read more.

Background/Objectives: Parkinson’s Disease (PD) and other forms of parkinsonism share motor symptoms, including tremor, bradykinesia, and rigidity. The overlap in their clinical presentation creates a diagnostic challenge, as conventional methods rely heavily on clinical expertise, which can be subjective and inconsistent. This highlights the need for objective, data-driven approaches such as machine learning (ML) in this area. However, applying ML to clinical datasets faces challenges such as imbalanced class distributions, small sample sizes for non-PD parkinsonism, and heterogeneity within the non-PD group. Methods: This study analyzed wearable sensor data from 260 PD participants and 18 individuals with etiologically diverse forms of non-PD parkinsonism, which were collected during clinical mobility tasks using a single sensor placed on the lower back. We evaluated the performance of ML models in distinguishing these two groups and identified the most informative mobility tasks for classification. Additionally, we examined the clinical characteristics of misclassified participants and presented case studies of common challenges in clinical practice, including diagnostic uncertainty at the patient’s initial visit and changes in diagnosis over time. We also suggested potential steps to address the dataset challenges which limited the models’ performance. Results: Feature importance analysis revealed the Timed Up and Go (TUG) task as the most informative for classification. When using the TUG test alone, the models’ performance exceeded that of combining all tasks, achieving a balanced accuracy of 78.2%, which is within 0.2% of the balanced diagnostic accuracy of movement disorder experts. We also identified differences in some clinical scores between the participants correctly and falsely classified by our models. Conclusions: These findings demonstrate the feasibility of using ML and wearable sensors for differentiating PD from other parkinsonian disorders, addressing key challenges in its diagnosis and streamlining diagnostic workflows. Full article

(This article belongs to the Special Issue Challenges in the Diagnosis and Treatment of Parkinson’s Disease)

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19 pages, 9168 KB

Open AccessEditor’s ChoiceReview

The Journey of Copper-Impregnated Dressings in Wound Healing: From a Medical Hypothesis to Clinical Practice

by Gadi Borkow and Eyal Melamed

Biomedicines 2025, 13(3), 562; https://doi.org/10.3390/biomedicines13030562 - 24 Feb 2025

Cited by 21 | Viewed by 8998

Abstract

Background/Objectives. Chronic wounds pose a substantial global healthcare burden exacerbated by aging populations and the increasing prevalence of conditions such as diabetes, peripheral vascular disease, and venous insufficiency. Impaired physiological repair mechanisms, including angiogenesis, collagen synthesis, and re-epithelialization, hinder the healing process in [...] Read more.

Background/Objectives. Chronic wounds pose a substantial global healthcare burden exacerbated by aging populations and the increasing prevalence of conditions such as diabetes, peripheral vascular disease, and venous insufficiency. Impaired physiological repair mechanisms, including angiogenesis, collagen synthesis, and re-epithelialization, hinder the healing process in chronic wounds. Many of these physiological processes are dependent on their interaction with copper. We hypothesized that the targeted delivery of copper ions to the wound bed would enhance healing. Methods. Wound dressings impregnated with copper oxide microparticles were designed to ensure the controlled release of copper ions. The efficacy of these dressings was evaluated using non-infected wound models, including diabetic mouse models compared against control and silver dressings. Outcome measures included wound closure rates, epidermal skin quality assessed by histopathological examination, and gene expression profiling. Clinical applications were assessed through diverse case studies and controlled trials involving chronic wound management. Results. Copper dressings significantly accelerated wound closure and enhanced angiogenesis compared to control and silver dressings. Histopathological analyses revealed faster granulation tissue formation, epidermal regeneration, and neovascularization. Gene expression studies showed upregulation of critical angiogenic factors such as VEGF and HIF-1α. Investigations and clinical observations corroborated improved healing across various chronic wound types, including non-infected wounds. Conclusions. Copper is essential for wound healing, and copper-impregnated dressings provide a promising solution for chronic wound management. By enhancing angiogenesis and tissue regeneration, these dressings go beyond antimicrobial action, offering a cost-effective and innovative alternative to conventional therapies. Copper dressings represent a transformative advancement in addressing the challenges of chronic wound care. Full article

(This article belongs to the Special Issue Wound Healing: From Basic to Clinical Research)

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