Biomedicines

14 pages, 1848 KB

Open AccessArticle

bZIP-Domain Variant Allele Frequency Helps to Refine Risk Stratification in CEBPA-Mutated AML

by Kainan Zhang, Xiaohang Ma, Xiaoxuan Lu, Guorui Ruan, Fangfang Wei, Hao Jiang, Yingjun Chang, Xiaojun Huang and Xiaosu Zhao

Biomedicines 2026, 14(1), 256; https://doi.org/10.3390/biomedicines14010256 - 22 Jan 2026

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Abstract

Objectives: To investigate the prognostic value of CEBPA (CCAAT/enhancer-binding protein α) molecular features, such as variant allele frequency (VAF), in patients with de novo acute myeloid leukemia (AML). Methods: Next-generation sequencing (NGS) was used to detect CEBPA mutations in 162 patients [...] Read more.

Objectives: To investigate the prognostic value of CEBPA (CCAAT/enhancer-binding protein α) molecular features, such as variant allele frequency (VAF), in patients with de novo acute myeloid leukemia (AML). Methods: Next-generation sequencing (NGS) was used to detect CEBPA mutations in 162 patients with newly diagnosed AML (except acute promyelocytic leukemia). Results: We established 44.2% as the optimal threshold for both maximum VAF and bZIP-domain VAF. The high-VAF group showed higher leukemia burden and inferior event-free survival (EFS). bZIP-domain VAF demonstrated superior prognostic value over maximum VAF (HR: 3.174 vs. 2.460) and was validated across subgroups, namely cytogenetically normal acute myeloid leukemia (CN-AML), chemotherapy-only, and low/intermediate-risk subgroups. Multivariate analysis confirmed high bZIP-domain VAF and DNMT3A mutation as independent risk factors. Conclusions: Our results confirm that the bZIP-domain VAF of CEBPA mutations is a more effective predictor of relapse than the maximum VAF, offering a valuable tool for the early identification of patients at high risk of relapse. Full article

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

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13 pages, 1120 KB

Open AccessArticle

The Role of NLR, PLR, SII and CRP Pre- and Post-Treatment with Infliximab in Rheumatoid Arthritis

by Diellor Rizaj, Avni Kryeziu, Artidon Kelmendi, Behar Raci, Shend Kryeziu and Visar Baftijari

Biomedicines 2026, 14(1), 255; https://doi.org/10.3390/biomedicines14010255 - 22 Jan 2026

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Abstract

Background: Inflammatory activity in rheumatoid arthritis can be determined by normal blood count ratios such as Neutrophil Lymphocyte Ratio (NLR), Platelet Lymphocyte Ratio (PLR), Systemic Immune Inflammation Index (SII), and C-reactive Protein (CRP). Objective: The aim of this research is to [...] Read more.

Background: Inflammatory activity in rheumatoid arthritis can be determined by normal blood count ratios such as Neutrophil Lymphocyte Ratio (NLR), Platelet Lymphocyte Ratio (PLR), Systemic Immune Inflammation Index (SII), and C-reactive Protein (CRP). Objective: The aim of this research is to determine how these markers change after therapy and whether their pre- and post-treatment differences follow patterns that allow for simple parametric analyses. Methods: A prospective cohort of 52 RA patients (30 females and 22 males) was examined. The patients’ blood samples were tested at baseline and at the end of their 6-month Infliximab treatment. Hematologic markers such as NLR, PLR, and SII were calculated from the complete blood count (CBC), and CRP levels were measured. The statistical methods of Shapiro–Wilk (SW), Kolmogorov–Smirnov (KS), and Anderson–Darling (AD) were used, and later, paired t-tests were used to generate statistics where necessary. Results: Post-treatment measurements were consistently lower for all four biomarkers. QQ-plots and formal tests revealed that the differences between findings were essentially normal, allowing for paired t-tests. The mean decreases were as follows: NLR −1.10 (95% CI −1.48 to −0.71), PLR −43.0 (−55.4 to −30.7), SII −299 (−388 to −211), and CRP −11.36 (−13.18 to −9.54), all p < 0.001. CRP showed the greatest drop, with significant decreases in PLR and SII and a moderate decline in NLR, indicating therapy-related attenuation of systemic inflammation. Conclusions: The study shows that six months of infliximab therapy results in a consistent post-treatment decrease in all four biomarkers: NLR, PLR, SII, and CRP. Because the pre-post differences were roughly normal, CRP revealed the greatest decrease, with significant decreases in PLR and SII and a moderate decrease in NLR, consistent with systemic inflammation reduction. When combined, the CBC-derived indices track with CRP and can serve as practical, low-cost markers for monitoring therapy response in RA, despite the single-arm design. Full article

(This article belongs to the Special Issue Pathogenesis and Novel Therapeutics in Musculoskeletal Conditions, 3rd Edition)

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15 pages, 1900 KB

Open AccessArticle

Exploratory Analysis of Coagulation and Fibrinolysis Trajectories After IL-6 Antagonist Therapy in COVID-19: A Case Series

by Emőke Henrietta Kovács, Máté Rottler, Zoltán Ruszkai, Csanád Geréd, Tamás Kiss, Margit Csata, Barbara Réger, Rita Jakabfi-Csepregi, István Papp, Caner Turan, Péter Hegyi, János Fazakas, Zsolt Molnár and Krisztián Tánczos

Biomedicines 2026, 14(1), 254; https://doi.org/10.3390/biomedicines14010254 - 22 Jan 2026

Cited by 1 | Viewed by 347

Abstract

Background/Objectives: Severe COVID-19 is marked by IL-6-driven inflammation, endothelial injury, and dysregulated coagulation. Although IL-6 antagonists improve clinical outcomes, their effects on the temporal evolution of coagulation and fibrinolysis remain insufficiently defined. This study characterizes inflammatory, endothelial, coagulation, and fibrinolytic trajectories following [...] Read more.

Background/Objectives: Severe COVID-19 is marked by IL-6-driven inflammation, endothelial injury, and dysregulated coagulation. Although IL-6 antagonists improve clinical outcomes, their effects on the temporal evolution of coagulation and fibrinolysis remain insufficiently defined. This study characterizes inflammatory, endothelial, coagulation, and fibrinolytic trajectories following IL-6 receptor blockade in critically ill COVID-19 patients. Methods: In this prospective, exploratory multicenter case series (ClinicalTrials.gov NCT05218369), 15 ICU patients with PCR- or antigen-confirmed COVID-19 received tocilizumab per protocol. Serial sampling at five timepoints (T0–T4) included routine laboratories, comprehensive viscoelastic hemostatic assays (ClotPro^®), and ELISA-based endothelial and fibrinolytic biomarkers. Analyses were primarily descriptive, emphasizing temporal patterns through boxplots; paired Wilcoxon tests with FDR correction contextualized within-patient changes. Results: Patients exhibited marked inflammation, hyperfibrinogenemia, endothelial activation, and delayed fibrinolysis at baseline. IL-6 blockade induced rapid suppression of CRP and PCT, progressive declines in fibrinogen, and modest platelet increases. In contrast, vWF antigen and activity further increased, indicating persistent endothelial dysfunction. Viscoelastic testing showed preserved thrombin generation and sustained high clot firmness, while biochemical markers (rising PAI-1, modest PAP increase, and progressively increasing D-dimer) and VHA indices suggested ongoing antifibrinolytic activity despite resolution of systemic inflammation. Conclusions: IL-6 antagonism was associated with rapid attenuation of systemic inflammation but was not accompanied by normalization of endothelial activation or fibrinolytic resistance. The observed hemostatic profile was consistent with attenuation of inflammation-associated coagulation features, while endothelial and prothrombotic alterations appeared to persist during follow-up, warranting further investigation in larger controlled studies. Full article

(This article belongs to the Special Issue The End of the COVID-19 Pandemic—What Is Currently Known and What Could Have Been Useful Four Years Ago? (2nd Edition))

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21 pages, 1102 KB

Open AccessReview

The Lactate Nexus: A Molecular Bridge Linking Physical Activity, Sleep, and Cognitive Enhancement

by Alimjan Ablitip, Kefeng Zheng, Hao Ding, Yicong Cui, Xindong Ma and Yanwei You

Biomedicines 2026, 14(1), 253; https://doi.org/10.3390/biomedicines14010253 - 22 Jan 2026

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Abstract

Physical activity (PA) and quality sleep are essential for cognitive health, providing synergistic protection against age-related cognitive decline. However, the shared molecular pathways that explain their combined and interactive benefits remain poorly understood. This review suggests that lactate, long dismissed as a metabolic [...] Read more.

Physical activity (PA) and quality sleep are essential for cognitive health, providing synergistic protection against age-related cognitive decline. However, the shared molecular pathways that explain their combined and interactive benefits remain poorly understood. This review suggests that lactate, long dismissed as a metabolic waste product, is a unifying mechanism. We introduce the “Lactate Nexus”, a conceptual framework that proposes lactate functions as a key signalling molecule, mechanistically linking the pro-cognitive effects of both daytime exercise and nighttime sleep. We begin by outlining lactate’s evolving role—from an energy substrate shuttled from astrocytes to neurons (the Astrocyte–Neuron Lactate Shuttle) to a pleiotropic signal. As a signal, lactate influences neuroplasticity via NMDA receptors, neuroinflammation via the HCAR1 receptor, and gene expression through the epigenetic modification of histone lactylation. We then compile evidence demonstrating how PA provides a substantial lactate signal that activates these pathways and primes the brain’s metabolic infrastructure. Crucially, we integrate this with proof that lactate levels naturally increase during slow-wave sleep to support memory consolidation and glymphatic clearance. The “Lactate Nexus” framework offers a comprehensive molecular explanation for the synergy between PA and sleep, positioning lactate as a key signalling mediator and a promising biomarker and therapeutic target for fostering lifelong cognitive resilience. Full article

(This article belongs to the Special Issue Advances in Molecular Research on Physical Activity, Sleep and Cognitive Function)

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16 pages, 1542 KB

Open AccessArticle

Microbiota-Derived Proteins Shape T Cell Responses in Healthy and Colorectal Cancer Subjects

by Elena Niccolai, Giulia Nannini, Serena Martinelli, Valentina Puca, Viviana De Luca, Laura Fortuna, Fabio Cianchi, Simone Carradori, Clemente Capasso, Rossella Grande and Amedeo Amedei

Biomedicines 2026, 14(1), 252; https://doi.org/10.3390/biomedicines14010252 - 22 Jan 2026

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Abstract

Background/Objectives: Fusobacterium nucleatum and Akkermansia muciniphila are key components of the human microbiota, influencing health and disease. F. nucleatum is associated with colorectal cancer (CRC) and poor prognosis through its pro-inflammatory and pro-tumorigenic activity, whereas A. muciniphila is linked to metabolic benefits and [...] Read more.

Background/Objectives: Fusobacterium nucleatum and Akkermansia muciniphila are key components of the human microbiota, influencing health and disease. F. nucleatum is associated with colorectal cancer (CRC) and poor prognosis through its pro-inflammatory and pro-tumorigenic activity, whereas A. muciniphila is linked to metabolic benefits and anti-inflammatory effects. This study aimed to evaluate the immunomodulatory impact of protein extracts from these bacteria on peripheral T cell responses in healthy individuals and CRC patients. Methods: Peripheral blood mononuclear cells (PBMCs) were exposed to bacterial extracts, individually or in combination, and T cell subsets were analyzed by polychromatic flow cytometry. Results: In healthy donors, F. nucleatum increased Th0, Th2, and Tc9 cell frequencies while reducing Th1, Th1/Th17, and Treg cells. Conversely, A. muciniphila promoted a pro-inflammatory-associated T cell phenotype characterized by higher Th0, Th2, Th17, and Tc17 cells. Combined exposure enhanced Th0, Th17, and Tc17 cells while decreasing Th9 cells. In CRC patients, bacterial extracts induced no significant changes in T cell subsets. Conclusions: These findings indicate that F. nucleatum skews immune responses toward humoral and mucosal defense, whereas A. muciniphila enhances T cell polarization toward subsets usually associated with pro-inflammatory immune responses in healthy subjects. Further studies are needed to clarify their systemic immunological roles and interactions within the tumor microenvironment of CRC. Full article

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

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19 pages, 5453 KB

Open AccessArticle

Alzheimer’s Disease-Associated Molecular Abnormalities in White Matter Glia and Related Pathologies Detected in Unfractionated and O4-Selected Serum Exosomes Using a Liquid Biopsy Approach

by Suzanne M. de la Monte and Ming Tong

Biomedicines 2026, 14(1), 251; https://doi.org/10.3390/biomedicines14010251 - 22 Jan 2026

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Abstract

Background/Objectives: White matter degeneration is a significant and early mediator of cognitive impairment in Alzheimer’s disease (AD), yet the critical pathologic features remain poorly understood, under-detected, and therapeutically untargeted. Herein, we characterize molecular features of white matter glial cells in AD brains [...] Read more.

Background/Objectives: White matter degeneration is a significant and early mediator of cognitive impairment in Alzheimer’s disease (AD), yet the critical pathologic features remain poorly understood, under-detected, and therapeutically untargeted. Herein, we characterize molecular features of white matter glial cells in AD brains and assess the utility of non-invasive approaches for detecting related abnormalities in extracellular vesicles (EVs) isolated from serum (SEV). In addition, results from unfractionated (SEV-T) and O4 sulfatide-selected SEVs were compared to determine whether white matter abnormalities were detected with greater sensitivity in oligodendrocyte-specific SEVs (SEV-O4). Methods: Oligodendrocyte glycoprotein and astrocyte mRNA levels were measured in postmortem human AD and control frontal lobe white matter by RT-PCR. Immunoreactivity to oligodendrocyte glycoproteins, astrocyte structural proteins, neurofilament light chain (NfL), and aspartyl-asparaginyl-β-hydroxylase (ASPH) was measured by ELISA in SEV-T and SEV-O4 from patients with moderate AD or normal aging. Results: AD brain pathology was associated with significantly reduced mRNA expression of multiple oligodendrocyte glycoproteins and increased mRNA expression of astrocytic structural genes. SEV analyses demonstrated significantly increased immunoreactivity to 2′,3′-cyclic nucleotide 3′ phosphodiesterase (CNPase), myelin-associated glycoprotein 1 (MAG1), astrocyte proteins, and ASPH, a potent activator of Notch and myelin-regulated homeostatic functions. There were no significant benefits of measuring SEV-O4 compared with SEV-T immunoreactivity. Conclusions: AD is associated with significant molecular abnormalities in oligodendrocyte and astrocyte function in brain tissue. The abnormalities detected in SEVs likely reflect oligodendrocyte injury and degeneration, as well as astrocytic activation. The findings suggest that low-invasive SEV approaches, including the novel analysis of ASPH upregulation, can be used to detect and monitor AD white matter degeneration. Full article

(This article belongs to the Special Issue Advances in Liquid Biopsy from Technological Innovation to Therapeutic Intervention)

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6 pages, 195 KB

Open AccessEditorial

Connections Between Diabetes Mellitus, Other Metabolic and Endocrine Dysfunctions and Cardiovascular Pathologies—Second Edition

by Cristina Tudoran and Dragos Cozma

Biomedicines 2026, 14(1), 250; https://doi.org/10.3390/biomedicines14010250 - 22 Jan 2026

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Abstract

The association between cardiovascular (CV) pathologies and metabolic/endocrine dysfunctions was first observed a long time ago, and great emphasis has been given to this relationship [...] Full article

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

15 pages, 4765 KB

Open AccessArticle

Retinal Thickness Profiles in Parkinsonian Syndromes: Discerning Parkinson’s Disease, Multiple System Atrophy, and Progressive Supranuclear Palsy via Optical Coherence Tomography

by Marko Svetel, Gorica Marić, Marija Božić, Tatjana Pekmezović, Igor Petrović, Jana Jakšić, Ana Dimitrijević, Una Lazić, Smiljana Kostić, Milica Knežević, Tiana Petrović, Sanja Petrović Pajić, Vesna Šobot, Jelena Vasilijević and Marina Svetel

Biomedicines 2026, 14(1), 249; https://doi.org/10.3390/biomedicines14010249 - 22 Jan 2026

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Abstract

Background/Objectives: Clinical differentiation between Parkinson’s disease (PD) and atypical parkinsonism (AP) remains complex. Current diagnostic procedures helpful in their distinction lack specificity, making non-invasive tools like optical coherence tomography (OCT) crucial in evaluating possible retinal changes as potential biomarkers. Our study examined [...] Read more.

Background/Objectives: Clinical differentiation between Parkinson’s disease (PD) and atypical parkinsonism (AP) remains complex. Current diagnostic procedures helpful in their distinction lack specificity, making non-invasive tools like optical coherence tomography (OCT) crucial in evaluating possible retinal changes as potential biomarkers. Our study examined the thickness of the ganglion cell inner plexiform layer complex (GCIPL), peripapillary retinal nerve fiber layer (RNFL) and macular segments in individuals with PD, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and healthy controls (HC). The objective of our study was to determine if OCT analyses can effectively discriminate PD patients from HC and whether retinal thickness can distinguish typical PD patients from those with AP. Methods: Research was an observational, cross-sectional study. Multiple retinal layers measured with OCT of PD and AP patients were compared with age- and sex-matched HC. An intergroup assessment was conducted. Results: Patients with PD and PSP exhibit a thinner GCIPL compared to HC, with no difference observed in the MSA group. GCIPL thickness between investigational groups does not differentiate between PD and AP. The RNFL and central macula thickness were statistically significantly reduced in all patient groups compared to HC. The RNFL was thinner in PSP compared to PD. Nearly all inner and outer macular segments were thinner in the investigational groups compared to HC. The preservation of outer nasal segments distinguished HC from both typical and AP. Patients with PSP and PD differed in the thickness of all macular segments, being thinner in PSP patients. Conclusions: Thickness of multiple retinal layers and macular regions might serve as a distinguishing feature between PD, AP and HC. Full article

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

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12 pages, 949 KB

Open AccessPerspective

An Integrative Roadmap for Advancing Colorectal Cancer Organoid

by Youqing Zhu, Ke He and Zhi Shi

Biomedicines 2026, 14(1), 248; https://doi.org/10.3390/biomedicines14010248 - 22 Jan 2026

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Abstract

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. Compared with traditional two-dimensional (2D) models, patient-derived CRC organoids more faithfully preserve the genomic, transcriptomic, and architectural features of primary tumors, making them a powerful intermediate platform bridging basic discovery [...] Read more.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. Compared with traditional two-dimensional (2D) models, patient-derived CRC organoids more faithfully preserve the genomic, transcriptomic, and architectural features of primary tumors, making them a powerful intermediate platform bridging basic discovery and clinical translation. Over the past several years, organoid systems have rapidly expanded beyond conventional epithelial-only cultures toward increasingly complex architectures, including immune-organoid co-culture models and mini-colon systems that enable long-term, spatially resolved tracking of tumor evolution. These advanced platforms, combined with high-throughput technologies and clustered regularly interspaced short palindromic repeats (CRISPR)-based functional genomics, have substantially enhanced our ability to dissect CRC mechanisms, identify therapeutic vulnerabilities, and evaluate drug responses in a physiologically relevant context. However, current models still face critical limitations, such as the lack of systemic physiology (e.g., gut–liver or gut–brain axes), limited standardization across platforms, and the need for large-scale, prospective clinical validation. These gaps highlight an urgent need for next-generation platforms and computational frameworks. The development of high-throughput multi-omics, CRISPR-based perturbation, drug screening technologies, and artificial intelligence-driven predictive approaches will offer a promising avenue to address these challenges, accelerating mechanistic studies of CRC, enabling personalized therapy, and facilitating clinical translation. In this perspective, we propose a roadmap for CRC organoid research centered on two major technical pillars: advanced organoid platforms, including immune co-culture and mini-colon systems, and mechanistic investigations leveraging multi-omics and CRISPR-based functional genomics. We then discuss translational applications, such as high-throughput drug screening, and highlight emerging computational and translational strategies that may support future clinical validation and precision medicine. Full article

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

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15 pages, 3536 KB

Open AccessReview

Extracellular Matrix in Human Disease and Therapy: From Pathogenic Remodeling to Biomaterial Platforms and Precision Diagnostics

by Jun-Hyeog Jang

Biomedicines 2026, 14(1), 247; https://doi.org/10.3390/biomedicines14010247 - 21 Jan 2026

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Abstract

The extracellular matrix (ECM) is a dynamic, tissue-specific network that integrates biochemical and mechanical cues to regulate cell behavior and organ homeostasis. Increasing evidence indicates that dysregulated ECM remodeling is an upstream driver of chronic human diseases rather than a passive consequence of [...] Read more.

The extracellular matrix (ECM) is a dynamic, tissue-specific network that integrates biochemical and mechanical cues to regulate cell behavior and organ homeostasis. Increasing evidence indicates that dysregulated ECM remodeling is an upstream driver of chronic human diseases rather than a passive consequence of injury. This review summarizes principles of ECM organization, mechanotransduction, and pathological remodeling and highlights translational opportunities for ECM-targeted therapies, biomaterial platforms, and precision diagnostics. We conducted a narrative synthesis of foundational and recent literature covering ECM composition and turnover, stiffness-dependent signaling, and disease-associated remodeling across fibrosis/cardiovascular disease, cancer, and metabolic disorders, together with advances in ECM-based biomaterials, drug delivery, and ECMderived biomarkers and imaging. Across organs, a self-reinforcing cycle of altered matrix composition, excessive crosslinking, and stiffness-dependent mechanotransduction (including integrin–FAK and YAP/TAZ pathways) sustains fibroinflammation, myofibroblast persistence, and progressive tissue dysfunction. In tumors, aligned and crosslinked ECM promotes invasion, immune evasion, and therapy resistance while also shaping perfusion and drug penetration. Translational strategies increasingly focus on modulating ECM synthesis and crosslinking, normalizing rather than ablating matrix architecture, and targeting ECM–cell signaling axes in combination with anti-fibrotic, cytotoxic, or immunotherapeutic regimens. ECM biology provides a unifying framework linking pathogenesis, therapy, and precision diagnostics across chronic diseases. Clinical translation will benefit from standardized quantitative measures of matrix remodeling, mechanism-based biomarkers of ECM turnover, and integrative imaging–omics approaches for patient stratification and treatment monitoring. Full article

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

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23 pages, 3422 KB

Open AccessArticle

Therapeutic Exosomes Carrying VEGFA siRNA Inhibit Pathological Corneal Angiogenesis via PI3K–Akt–Caspase-3 Signaling

by Woojune Hur, Basanta Bhujel, Seorin Lee, Seheon Oh, Ho Seok Chung, Hun Lee and Jae Yong Kim

Biomedicines 2026, 14(1), 246; https://doi.org/10.3390/biomedicines14010246 - 21 Jan 2026

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Abstract

Background/Objectives: Neovascularization, defined as the sprouting of new blood vessels from pre-existing vasculature, is a critical pathological feature in ocular diseases such as pathological myopia and represents a leading cause of corneal vision loss. Vascular endothelial growth factor A (VEGFA) plays a pivotal [...] Read more.

Background/Objectives: Neovascularization, defined as the sprouting of new blood vessels from pre-existing vasculature, is a critical pathological feature in ocular diseases such as pathological myopia and represents a leading cause of corneal vision loss. Vascular endothelial growth factor A (VEGFA) plays a pivotal role in endothelial cell proliferation, migration, survival by anti-apoptotic signaling, and vascular permeability. Dysregulation of VEGFA is closely linked to pathological neovascularization. Exosomes, nanosized phospholipid bilayer vesicles ranging from 30 to 150 nm, have emerged as promising gene delivery vehicles due to their intrinsic low immunogenicity, superior cellular uptake, and enhanced in vivo stability. This study aimed to investigate whether highly purified mesenchymal stem cell (MSC)-derived exosomes loaded with VEGFA siRNA labeled with FAM can effectively suppress pathological corneal neovascularization (CNV) via targeeted cellular transduction and VEGFA inhibition. Furthermore, we examined whether the therapeutic effect involves the modulation of the PI3K–Akt–Caspase-3 signaling axis. Methods: Exosomes purified by chromatography were characterized by electronmicroscopy, standard marker immunoblotting, and nanoparticle tracking analysis. In vitro, we assessed exosome uptake and cytoplasmic release, suppression of VEGFA mRNA/protein, cell viability, and apoptosis. In a mouse CNV model, we evaluated tissue reach and stromal retention after repeated intrastromal injections; anterior segment angiogenic indices; CD31/VEGFA immunofluorescence/immunoblotting; phosphorylated PI3K and Akt; cleaved caspase-3; histology (H&E); and systemic safety (liver, kidney, and spleen). Results: Exosomes were of high quality and showed peak efficacy at 48 h, with decreased VEGFA mRNA/protein, reduced viability, and increased apoptosis in vitro. In vivo, efficient delivery and stromal retention were observed, with accelerated inhibition of neovascularization after Day 14 and maximal effect on Days 17–19. Treatment reduced CD31 and VEGFA, decreased p-PI3K and p-Akt, and increased cleaved caspase-3. Histologically, concurrent reductions in neovascularization, inflammatory cell infiltration, and inflammatory epithelial thickening were observed, alongside a favorable systemic safety profile. Conclusions:VEGFA siRNA-loaded exosomes effectively reduce pathological CNV via a causal sequence of intracellular uptake, cytoplasmic release, targeted inhibition, and phenotypic suppression. Supported by consistent PI3K–Akt inhibition and caspase-3–mediated apoptosis induction, these exosomes represent a promising local gene therapy that can complement existing antibody-based treatments. Full article

(This article belongs to the Special Issue Stem Cell Therapy: Traps and Tricks)

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12 pages, 1222 KB

Open AccessArticle

Impact of Deep-Learning-Based Respiratory Motion Correction on [¹⁸F] FDG PET/CT Test–Retest Reliability and Consistency of Tumor Quantification in Patients with Lung Cancer

by Shijia Weng, Limei Jiang, Runze Wu, Yuanyan Cao, Yuan Li and Qian Wang

Biomedicines 2026, 14(1), 245; https://doi.org/10.3390/biomedicines14010245 - 21 Jan 2026

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Abstract

Objectives: Respiratory motion degrades the quantitative accuracy and test–retest (TRT) reliability of fluorine-18 fluorodeoxyglucose ([¹⁸F] FDG) positron emission tomography (PET)/computed tomography (CT) in lung cancer. This study investigated whether a deep-learning-based respiratory motion correction (RMC) method improves the TRT reliability and [...] Read more.

Objectives: Respiratory motion degrades the quantitative accuracy and test–retest (TRT) reliability of fluorine-18 fluorodeoxyglucose ([¹⁸F] FDG) positron emission tomography (PET)/computed tomography (CT) in lung cancer. This study investigated whether a deep-learning-based respiratory motion correction (RMC) method improves the TRT reliability and image quality of [¹⁸F] FDG PET tumor quantification compared with non-motion-corrected (NMC) reconstructions. Methods: Thirty-one patients with primary lung cancer underwent three PET acquisitions: whole body free breathing (Scan1), thoracic free breathing (Scan2), and thoracic controlled breathing (ScanCB). Each dataset was reconstructed with and without RMC. Visual assessments of liver motion artifacts, lesion clarity, and PET-CT co-registration were scored. Lung tumors were segmented to derive standardized uptake value max (SUVmax), SUVmean, metabolic tumor volume (MTV), PET-derived lesion length (PLL), and total lesion glycolysis (TLG). Visual image scores and TRT reliability of tumor quantification were compared using Kruskal–Wallis one-way analysis of variance and intraclass correlation coefficients (ICCs). Results: RMC reconstructions achieved higher visual scores of lesion clarity and PET-CT co-registration across all lung lobes and significantly reduced liver motion artifacts compared with NMC reconstructions. Differences in SUVmax, SUVmean, PLL, MTV, and TLG between Scan2 and ScanCB were significantly smaller with RMC than with NMC. ICCs for SUVmax, SUVmean, MTV, and TLG were higher between scans with RMC than NMC reconstructions, indicating improved TRT reliability. Conclusions: The deep-learning-based RMC method improved the image quality and TRT reproducibility of [¹⁸F] FDG PET/CT quantification in lung cancer, supporting its potential for routine adoption in therapy-response assessments. Full article

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

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23 pages, 13240 KB

Open AccessArticle

Modulation of Bromo- and Extra-Terminal Domain (BET) Proteins Exerts Neuroprotective Effects in Cell Culture Models of Parkinson’s Disease

by Noemi Martella, Daniele Pensabene, Mayra Colardo, Maurizio Muzzi, Emanuele Bisesto, Michela Varone, Giuseppina Caretti, Angela Di Porzio, Valentina Barrella, Arianna Mazzoli, Sabrina Di Bartolomeo, Sandra Moreno and Marco Segatto

Biomedicines 2026, 14(1), 244; https://doi.org/10.3390/biomedicines14010244 - 21 Jan 2026

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Abstract

Background/Objectives: Parkinson’s disease (PD) is one of the most prevalent neurodegenerative disorders. Despite its multifactorial etiology, PD pathophysiology shared specific features such as cytoplasmic α-synuclein inclusions, oxidative stress, mitochondrial dysfunction, and impaired autophagy. Bromodomain and Extra-Terminal domain (BET) proteins, functioning as epigenetic [...] Read more.

Background/Objectives: Parkinson’s disease (PD) is one of the most prevalent neurodegenerative disorders. Despite its multifactorial etiology, PD pathophysiology shared specific features such as cytoplasmic α-synuclein inclusions, oxidative stress, mitochondrial dysfunction, and impaired autophagy. Bromodomain and Extra-Terminal domain (BET) proteins, functioning as epigenetic readers, have recently emerged as promising therapeutic targets due to their regulatory role in redox homeostasis, neuroinflammation, and autophagy. However, their potential involvement in PD pathophysiology remains largely unexplored. Therefore, we aimed at evaluating whether BET modulation could ameliorate the parkinsonian phenotype in two cellular models. Methods: Differentiated SH-SY5Y and N1E-115 neuronal cells were exposed to rotenone toxin to mimic PD phenotype and co-treated with the small BET inhibitor JQ1. Results: BET inhibition significantly counteracted rotenone-induced cell death, neuromorphological alterations, and α-synuclein accumulation. These protective effects were accompanied by restoration of redox balance, as indicated by enhanced activation of the antioxidant system and suppression of the pro-oxidant NADPH oxidase complex. Moreover, JQ1 treatment alleviated mitochondrial dysfunction and corrected autophagy impairments triggered by rotenone. Conclusions: These data highlight a novel role for BET proteins in neurodegeneration, suggesting that their modulation may represent a promising approach to counteract PD neuropathology. Full article

(This article belongs to the Special Issue Cell Metabolism in Brain Physiology and Pathology: From Molecular Mechanisms to Therapeutic Targets)

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20 pages, 983 KB

Open AccessReview

In Vivo Models of Diabetes: Unravelling Molecular Pathways in Metabolic and Skeletal Complications

by Haryati Ahmad Hairi, Nor Hidayah Mustafa, Ahmad Nazrun Shuid and Muhammad Zulfiqah Sadikan

Biomedicines 2026, 14(1), 243; https://doi.org/10.3390/biomedicines14010243 - 21 Jan 2026

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Abstract

Background/Objectives: Diabetic osteoporosis (DOP) is a metabolic bone disorder marked by reduced bone mass, impaired microarchitecture and elevated fracture risk arising from type 1 and type 2 diabetes. Understanding its pathophysiology is essential for developing effective interventions. Method: A broad literature [...] Read more.

Background/Objectives: Diabetic osteoporosis (DOP) is a metabolic bone disorder marked by reduced bone mass, impaired microarchitecture and elevated fracture risk arising from type 1 and type 2 diabetes. Understanding its pathophysiology is essential for developing effective interventions. Method: A broad literature search of Scopus and PubMed (2015–2025) using diabetic osteoporosis-related keywords identified relevant English in vivo studies, which were screened, extracted, and narratively summarised for this review. Results: In vivo models, including high-fat-diet (HFD), streptozotocin (STZ) and combined HFD + STZ protocols, are widely used to investigate DOP mechanisms. HFD models mimic obesity-induced insulin resistance, chronic hyperglycaemia and low-grade inflammation, leading to suppressed osteoblast activity, enhanced osteoclastogenesis and accumulation of advanced glycation end products (AGEs). Ultimately, they compromise bone microarchitecture and mechanical strength. STZ models replicate type 1 diabetes by inducing β-cell destruction, insulin deficiency, oxidative stress, osteoblast apoptosis and inflammatory pathways promoting bone resorption. The combined HFD + STZ model integrates insulin resistance and partial β-cell dysfunction, closely reflecting type 2 diabetes pathology, including trabecular bone loss, collagen glycation and disrupted osteoblast–osteoclast signalling. Mechanistically, DOP involves impaired insulin/IGF-I signalling, AGE–RAGE interactions, oxidative stress and inflammation, resulting in diminished bone formation and quality. These models provide robust platforms for exploring molecular mechanisms and evaluating potential therapies, including Wnt pathway modulators, antioxidants and ferroptosis inhibitors. Conclusions: Collectively, preclinical in vivo models are indispensable for understanding DOP pathophysiology and developing strategies to mitigate diabetic bone fragility. Full article

(This article belongs to the Special Issue Musculoskeletal Diseases: From Molecular Basis to Therapy—3rd Edition)

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13 pages, 721 KB

Open AccessArticle

Direct Relationship Between Heparin Binding to Midkine and Pleiotrophin and the Development of Acute Deep Vein Thrombosis

by Suna Aydin, İsmail Polat, Kevser Tural, Nurullah Duger, Kader Ugur, İbrahim Sahin, Suleyman Aydin and Do-Youn Lee

Biomedicines 2026, 14(1), 242; https://doi.org/10.3390/biomedicines14010242 - 21 Jan 2026

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Abstract

Background/Objectives: The underlying molecular mechanisms of deep vein thrombosis (DVT), which continues to be a major global public health concern, remain unclear. A key component of anticoagulant therapy, heparin (HP) interacts with heparin-binding growth factors including pleiotrophin (PTN) and midkine (MK), both [...] Read more.

Background/Objectives: The underlying molecular mechanisms of deep vein thrombosis (DVT), which continues to be a major global public health concern, remain unclear. A key component of anticoagulant therapy, heparin (HP) interacts with heparin-binding growth factors including pleiotrophin (PTN) and midkine (MK), both of which have basic amino acid-rich domains that have a strong affinity for HP. The purpose of this study was to determine if changes in the levels of circulating HP, MK, and PTN are linked to the onset of acute DVT. Methods: Thirty patients diagnosed with acute DVT by venous Doppler ultrasonography (VDU) and 28 healthy controls with normal VDU findings were enrolled. Serum HP, MK, and PTN concentrations were measured using ELISA. In DVT patients, blood samples were obtained before and after routine subcutaneous low-molecular-weight heparin treatment; controls provided a single blood sample. ROC curve analysis was used to assess diagnostic performance. Results: Prior to treatment, patients with acute DVT exhibited significantly lower serum HP levels (p < 0.05) and significantly higher MK and PTN levels compared with healthy controls (both p < 0.05). Following heparin administration, serum HP levels increased significantly (p < 0.05), while MK and PTN levels showed a decreasing trend that did not reach statistical significance (p > 0.05). ROC curve analysis demonstrated limited diagnostic performance for HP (sensitivity 10.3%, specificity 68.8%), PTN (62.1%, 54.2%), and MK (82.8%, 35.4%). Conclusions: Decreased circulating HP and increased MK and PTN levels are characteristics of acute DVT that may indicate endogenous HP sequestration through binding to these growth factors. This imbalance could lead to less free HP being available, which would encourage the formation of thrombus. Therapeutic approaches that target MK- and PTN-mediated HP interactions may constitute a unique approach for the therapy of acute DVT, as evidenced by the partial normalization seen after exogenous heparin delivery. Full article

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

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24 pages, 1329 KB

Open AccessReview

The Great Potential of DNA Methylation in Triple-Negative Breast Cancer: From Biological Basics to Clinical Application

by Wanying Xie, Ying Wen, Siqi Gong, Qian Long and Qiongyan Zou

Biomedicines 2026, 14(1), 241; https://doi.org/10.3390/biomedicines14010241 - 21 Jan 2026

Viewed by 477

Abstract

Triple-negative breast cancer (TNBC), which is characterized by a lack of the estrogen receptor, the progesterone receptor, and HER2 expression, is the most aggressive breast cancer subtype and has a poor prognosis and high recurrence rates because of frequent chemotherapy resistance. As a [...] Read more.

Triple-negative breast cancer (TNBC), which is characterized by a lack of the estrogen receptor, the progesterone receptor, and HER2 expression, is the most aggressive breast cancer subtype and has a poor prognosis and high recurrence rates because of frequent chemotherapy resistance. As a crucial epigenetic regulator, DNA methylation modulates gene expression through aberrant methylation patterns, contributing to tumor progression and therapeutic resistance. Early diagnosis and treatment of TNBC are vital for its prognosis. The development of DNA methylation testing technology and the application of liquid biopsy provide technological support for early diagnosis and treatment. Additionally, preclinical and early-phase clinical studies suggest that epigenetic therapies targeting DNA methylation may hold promise for TNBC treatment, pending larger clinical trials. Furthermore, research on DNA methylation-based prognostic models enables personalized precision treatment for patients, helping to reduce unnecessary therapies and improve overall survival. The emerging role of DNA methylation patterns in predicting the therapeutic response and overcoming drug resistance is highlighted. In this narrative review, we integrate current research findings and clinical perspectives. We propose that DNA methylation presents promising research prospects for the diagnosis, treatment and prognosis prediction of TNBC. Future efforts should focus on translating methylation-driven insights into clinically actionable strategies, ultimately advancing precision oncology for this challenging disease. Full article

(This article belongs to the Special Issue Epigenetics in Human Cancer: Emerging Biomarkers and Therapeutic Targets)

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28 pages, 837 KB

Open AccessSystematic Review

Effects of Dietary Interventions on Nutritional Status in Patients with Gastrointestinal Cancers: A Systematic Review

by Camelia Maria Caragescu (Lup), Laura Grațiela Vicaș, Angela Mirela Antonescu, Nicole Alina Marian, Octavia Gligor, Mariana Eugenia Mureșan, Patricia-Andrada Grigore and Eleonora Marian

Biomedicines 2026, 14(1), 240; https://doi.org/10.3390/biomedicines14010240 - 21 Jan 2026

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Abstract

Introduction/Object: Gastrointestinal cancers are among the most common types of neoplasms and are often associated with malnutrition, which affects physical performance, treatment tolerance and prognosis. This paper aims to synthesize, through a systematic search, the evidence on the impact of nutritional interventions [...] Read more.

Introduction/Object: Gastrointestinal cancers are among the most common types of neoplasms and are often associated with malnutrition, which affects physical performance, treatment tolerance and prognosis. This paper aims to synthesize, through a systematic search, the evidence on the impact of nutritional interventions on nutritional status in patients with digestive cancers prone to malnutrition. Methods: A systematic search was performed in PubMed, MDPI, Web of Science and ScienceDirect, for articles published between 2009 and 2025. Overall, 14,503 records were identified, and after screening of titles, abstracts and full-text evaluation, 80 studies (cross-sectional and cohort) were included. Data extraction was performed by a single researcher, using pre-established criteria and a standardized table, and the assessment of study quality was performed qualitatively, taking into account study design, sample size, nutritional assessment methods and clarity of reporting of results. Results: Evidence suggests that individualized and early applied nutritional interventions contribute to maintaining weight and protein status, improve tolerance to oncological treatments and may positively influence patient survival. Conclusions: Nutritional therapy plays a crucial role in preventing complications and supporting the body during oncological treatment, optimizing patients’ quality of life. This review provides a clear synthesis of the current evidence and recognizes methodological limitations related to the qualitative assessment of the included studies. Full article

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

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18 pages, 2912 KB

Open AccessArticle

Correlation Between Endocrine and Other Clinical Factors with Peripapillary Retinal Nerve Fiber Layer Thickness After Surgical Treatment of Pediatric Craniopharyngioma

by Agnieszka Bogusz-Wójcik, Klaudia Rakusiewicz-Krasnodębska, Wojciech Hautz, Maciej Jaworski, Paweł Kowalczyk and Elżbieta Moszczyńska

Biomedicines 2026, 14(1), 239; https://doi.org/10.3390/biomedicines14010239 - 21 Jan 2026

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Abstract

Background: Visual dysfunction resulting from damage to the optic nerve and retinal neurons represents a significant concern in the postoperative management of childhood-onset craniopharyngioma (CP) survivors. The study aims to evaluate the influence of clinical parameters assessed in patients before and after [...] Read more.

Background: Visual dysfunction resulting from damage to the optic nerve and retinal neurons represents a significant concern in the postoperative management of childhood-onset craniopharyngioma (CP) survivors. The study aims to evaluate the influence of clinical parameters assessed in patients before and after neurosurgery of CP on peripapillary retinal nerve fiber layer (RNFL) thickness results, using optical coherence tomography (OCT) as early markers of compressive neuropathy. Methods: This study retrospectively examined 73 eyes from 38 individuals diagnosed with CP and 64 eyes from 32 healthy controls matched for age and sex. All patients in the study group underwent a complete endocrine examination before and after surgery. Moreover, all participants in both groups underwent a thorough ophthalmological examination and OCT imaging. The average RNFL thickness was analyzed, along with the RNFL in the superior and inferior sectors and in eight peripapillary sectors around the optic nerve. Clinical variables were analyzed to assess how they relate to alterations in RNFL thickness within specific sectors. Results: After surgery, the peripapillary RNFL thickness was much lower in the CP group than in the healthy control group. Preoperative factors significantly affecting RNFL reduction are as follows: age below 5 years at the time of diagnosis, birth in the country, optic disc oedema, delayed puberty, arginine vasopressin deficiency (AVD), growth hormone deficiency (GHD), hyperprolactinemia, and the degree of preoperative hypothalamic involvement. Moreover, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), as well as the end of AVD, memory disorder and hyperfagia after surgery, correlated with damage to RNFL. Conclusions: CP causes significant thinning of the RNFL, which demonstrates the tumor’s impact on the visual pathway. Monitoring optic nerve damage and assessing outcomes after surgery can be performed effectively using OCT. Additionally, the relationship between RNFL thickness in specific areas and clinical indicators can provide vital information for diagnosing and monitoring. This highlights their usefulness in forecasting visual results. As a result, ongoing RNFL assessments should be part of the long-term management of CP patients to improve visual outlook and identify ongoing or remaining damage. Full article

(This article belongs to the Special Issue Pediatric Tumors: Diagnosis, Pathogenesis, Treatment, and Outcome)

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9 pages, 480 KB

Open AccessArticle

Effect of First-Line Combination Systemic Therapy on Favorable-Risk Clear Cell Renal Cell Carcinoma: A Retrospective Study

by Soon Il Lee, Minsuk Kwon, Sung Hee Lim and Se Hoon Park

Biomedicines 2026, 14(1), 238; https://doi.org/10.3390/biomedicines14010238 - 21 Jan 2026

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Abstract

Background/Objectives: For patients with advanced or metastatic clear cell renal cell carcinoma (RCC), combinations of immune checkpoint inhibitors (ICIs) and VEGFR-targeted tyrosine kinase inhibitors (TKIs) are standard first-line therapies. However, the clinical benefit of these regimens in patients with favorable IMDC risk [...] Read more.

Background/Objectives: For patients with advanced or metastatic clear cell renal cell carcinoma (RCC), combinations of immune checkpoint inhibitors (ICIs) and VEGFR-targeted tyrosine kinase inhibitors (TKIs) are standard first-line therapies. However, the clinical benefit of these regimens in patients with favorable IMDC risk remains unclear. Methods: We retrospectively analyzed 147 patients with favorable-risk metastatic RCC treated with first-line systemic therapy at the Samsung Medical Center between 2019 and 2023. Treatment regimens included TKI monotherapy (n = 110) or ICI–TKI combinations (n = 37). Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were evaluated using Kaplan–Meier and Cox regression analyses. Results: At a median follow-up of 46.3 months, the overall median PFS was 20.1 months (95% CI, 14.5–25.7). Median PFS was 26.2 months with ICI–TKI combinations versus 17.0 months with TKI monotherapy (HR 1.32; 95% CI, 0.82–2.12; p = 0.25). In multivariate analysis, TKI monotherapy (HR 14.01; p = 0.002) and liver metastasis (HR 9.17; p < 0.001) were independent predictors of shorter PFS. ORR was significantly higher with combination therapy (68% vs. 46%; p = 0.01). Median OS was not reached in either group, with 3-year OS rates of 89% and 84%, respectively. Conclusions: The findings suggest that even within the favorable-risk population, clinical heterogeneity influences treatment outcomes, emphasizing the need for individualized therapy selection and refined prognostic models. Full article

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

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19 pages, 4422 KB

Open AccessArticle

In Vitro and In Vivo Efficacy of Epithelial Barrier-Promoting Barriolides as Potential Therapy for Ulcerative Colitis

by Jon P. Joelsson, Michael J. Parnham, Laurène Froment, Aude Rapet, Andreas Hugi, Janick Stucki, Nina Hobi and Jennifer A. Kricker

Biomedicines 2026, 14(1), 237; https://doi.org/10.3390/biomedicines14010237 - 21 Jan 2026

Viewed by 311

Abstract

Background/Objectives: Ulcerative colitis (UC) is an inflammatory bowel disease and a major cause of ulcers and chronic inflammation in the colon and rectum. Recurring symptoms include abdominal pain, rectal bleeding, and diarrhoea, and patients with UC are at a higher risk of [...] Read more.

Background/Objectives: Ulcerative colitis (UC) is an inflammatory bowel disease and a major cause of ulcers and chronic inflammation in the colon and rectum. Recurring symptoms include abdominal pain, rectal bleeding, and diarrhoea, and patients with UC are at a higher risk of developing comorbidities such as colorectal cancer and poor mental health. In UC, the decreased diversity and changed metabolic profile of gut microbiota, along with a diminished mucus layer, leads to disruption of the underlying epithelial barrier, with an ensuing excessive and detrimental inflammatory response. Treatment options currently rely on drugs that reduce the inflammation, but less emphasis has been placed on improving the resilience of the epithelial barrier. Macrolide antibiotics exhibit epithelial barrier-enhancing capacities unrelated to their antibacterial properties. Methods: We investigated two novel barriolides, macrolides with reduced antibacterial effects in common bacterial strains. Gut epithelial cell barrier resistance in the Caco-2 cell line, with and without co-culture with mucus-producing HT-29 cells, was increased when treated with barriolides. Using ^AXGut-on-Chip technology with inflammatory cytokine-stimulated Caco-2/HT-29 co-cultures, the effectiveness of the barriolides was confirmed. Lastly, we reveal the barrier-enhancing and inflammation-reducing effects of the barriolides in a dextran-sulphate sodium (DSS)-induced colitis mouse model. Results: We show the predictive power of the novel ^AXGut-on-Chip system and the effectiveness of the novel barriolides. Indications include reduced inflammatory response, increased epithelial barrier and decreased overall clinical score. Conclusions: The results of this study indicate the notion that barriolides could be used as a treatment option for UC. Full article

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

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16 pages, 703 KB

Open AccessArticle

Associations of Transforming Growth Factor-β (TGF-β) with Chronic Kidney Disease Progression in Patients Attending a Tertiary Hospital in Johannesburg, South Africa

by Alfred Meremo, Raquel Duarte, Caroline Dickens, Therese Dix-Peek, Deogratius Bintabara, Graham Paget and Saraladevi Naicker

Biomedicines 2026, 14(1), 236; https://doi.org/10.3390/biomedicines14010236 - 21 Jan 2026

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Abstract

Introduction: The global prevalence of chronic kidney disease (CKD) is increasing and it is associated with higher mortality rates. Transforming growth factor-beta (TGF-β) can serve as a novel biomarker for early prediction of chronic kidney disease (CKD) progression. Methods: This was a prospective [...] Read more.

Introduction: The global prevalence of chronic kidney disease (CKD) is increasing and it is associated with higher mortality rates. Transforming growth factor-beta (TGF-β) can serve as a novel biomarker for early prediction of chronic kidney disease (CKD) progression. Methods: This was a prospective longitudinal study among black patients with CKD who attended the Charlotte Maxeke Johannesburg Academic Hospital between September 2019 and March 2022. Patients provided urine and blood samples for laboratory investigations at study entry (0) and at 24 months follow up. Baseline serum and urine TGF-β1, TGF-β2 and TGF-β3 levels were measured using ELISAs. Multivariable logistic regression analysis was utilized to determine if TGF-β isoforms could predict CKD progression. Results: A total of 312 patients were enrolled at baseline, of whom 275 (88.1%) had early-stage CKD (Stage 1–3). A majority, 95.2% (297/312), of the patients completed the study after 2 years follow up. The prevalence of CKD progression was 47.8% when measured by a sustained decline in eGFR of >4 mL/min/1.73 m²/year or more and 51.9% when measured by a change in uPCR > 30%. The patients with CKD progression had significantly lower eGFR and increased urine protein–creatinine ratios compared to non-progressors. Furthermore, comparing progressors with non-progressors, the median serum TGF-β1 was 21210 (15915–25745) ng/L vs. 24200 (17570–29560) ng/L and the median urine TGF-β3 was 17.5 (5.4–76.2) ng/L vs. 2.8 (1.8–15.3) ng/L, respectively. Baseline serum and urine TGF-β isoforms were unable to discriminate between CKD progressors and non-progressors after multivariable logistic regression analysis. Conclusions: Despite the multiple roles of TGF-β isoforms in kidney disease, baseline levels were not predictive of chronic kidney disease progression. Full article

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

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33 pages, 1245 KB

Open AccessArticle

Domain-Adaptive MRI Learning Model for Precision Diagnosis of CNS Tumors

by Wiem Abdelbaki, Hend Alshaya, Inzamam Mashood Nasir, Sara Tehsin, Salwa Said and Wided Bouchelligua

Biomedicines 2026, 14(1), 235; https://doi.org/10.3390/biomedicines14010235 - 21 Jan 2026

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Abstract

Background: Diagnosing CNS tumors through MRI is limited by significant variability in scanner hardware, acquisition protocols, and intensity characteristics at clinical centers, resulting in substantial domain shifts that lead to diminished reliability for automated models. Methods: We present a Domain-Adaptive MRI Learning Model [...] Read more.

Background: Diagnosing CNS tumors through MRI is limited by significant variability in scanner hardware, acquisition protocols, and intensity characteristics at clinical centers, resulting in substantial domain shifts that lead to diminished reliability for automated models. Methods: We present a Domain-Adaptive MRI Learning Model (DA-MLM) consisting of an adversarially aligned hybrid 3D CNN–transformer encoder with contrastive regularization and covariance-based feature harmonization. Varying sequence MRI inputs (

T 1

,

T 1 c e

,

T 2

, and

F L A I R

) were inputted to multi-scale convolutional layers followed by global self-attention to effectively capture localized tumor structure and long-range spatial context, with domain adaptation that harmonizes feature distribution across datasets. Results: On the BraTS 2020 dataset, we found DA-MLM achieved 94.8% accuracy, 93.6% macro-F1, and 96.2% AUC, improving upon previously established benchmarks by 2–4%. DA-MLM also attained Dice score segmentation of 93.1% (WT), 91.4% (TC), and 89.5% (ET), improving upon 2–3.5% for CNN and transformer methods. On the REMBRANDT dataset, DA-MLM achieved 92.3% accuracy with segmentation improvements of 3–7% over existing U-Net and expert annotations. Robustness testing indicated 40–60% less degradation under noise, contrast shift, and motion artifacts, and synthetic shifts in scanner location showed negligible performance impairment (<0.06). Cross-domain evaluation also demonstrated 5–11% less degradation than existing methods. Conclusions: In summary, DA-MLM demonstrates improved accuracy, segmentation fidelity, and robustness to perturbations, as well as strong cross-domain generalization indicating the suitability for deployment in multicenter MRI applications where variation in imaging performance is unavoidable. Full article

(This article belongs to the Special Issue Diagnosis, Pathogenesis and Treatment of CNS Tumors (2nd Edition))

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17 pages, 440 KB

Open AccessArticle

The Differences Between Dopamine Agonist-Resistant and -Non-Resistant Prolactinomas: Are There Any Predictors of a Good Response?

by Maria Komisarz-Calik, Anna Bogusławska, Aleksandra Gamrat-Żmuda, Mari Minasyan, Beata Piwońska-Solska, Jacek Kunicki, Grzegorz Zieliński, Agata Faron-Górecka, Alicja Hubalewska-Dydejczyk and Aleksandra Gilis-Januszewska

Biomedicines 2026, 14(1), 234; https://doi.org/10.3390/biomedicines14010234 - 21 Jan 2026

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Abstract

Background/Objectives: Dopamine agonists (DAs) are the first-line therapy for prolactinomas; however, a subset of patients exhibits resistance or incomplete response. Methods: This retrospective study included 85 of 125 eligible consecutive patients with prolactinoma who were treated with DA, followed for a [...] Read more.

Background/Objectives: Dopamine agonists (DAs) are the first-line therapy for prolactinomas; however, a subset of patients exhibits resistance or incomplete response. Methods: This retrospective study included 85 of 125 eligible consecutive patients with prolactinoma who were treated with DA, followed for a median of 52.0 (31.5–86.8) months. Clinical, biochemical, and radiological parameters were analyzed at baseline and at 6 and 12 months. Resistance was defined as failure to normalize serum prolactin concentration (PRL) or achieve ≥ 30% reduction in tumor maximal diameter after standard DA therapy. Logistic regression analyses were performed to identify predictors of DA resistance and treatment response. Results: The cohort comprised 54 males (63.5%) and 31 females (36.1%), with a mean age of 41.5 ± 17.2 years. In total, 22.4% had giant prolactinomas. After 6 months of treatment, 24.7% achieved PRL normalization, and 29.4% demonstrated ≥ 50% reduction in tumor volume. At 12 months, PRL normalized in 40% of patients, and a ≥50% volume reduction was observed in 41.2%. DA-resistant patients, compared to DA-non-resistant, were predominantly men (80.0% vs. 56.7%, p = 0.042), with a higher proportion of giant adenomas (44.0% vs. 13.3%, p = 0.002) and significantly higher baseline PRL (2000.000 ng/mL vs. 478.985 ng/mL, p = 0.012). Early reduction in maximal tumor diameter at 6 months predicted a favorable therapeutic response at 12 months (aOR = 1.156; 95% CI = 1.001–1.335, p = 0.049). Conclusions: Male sex, higher baseline PRL, and larger tumor size can be predictors of DA resistance. On the other hand, early radiological tumor shrinkage may predict favorable treatment outcomes. However, new markers of DA resistance, particularly molecular ones, should be identified. Full article

(This article belongs to the Special Issue State-of-the-Art Endocrine Cancer Biology and Oncology)

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23 pages, 3301 KB

Open AccessArticle

Local Diagnostic Reference Levels for Intracranial Aneurysm Coil-Only Embolization Using a Low-Dose Technique

by Mariusz Sowa, Joanna Sowa, Kamil Węglarz and Maciej Budzanowski

Biomedicines 2026, 14(1), 233; https://doi.org/10.3390/biomedicines14010233 - 21 Jan 2026

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Abstract

Background/Objectives: Optimizing routine neurointerventional workflow and minimizing exposure to ionizing radiation during coil-only endovascular treatment of intracranial aneurysms depend on operator experience, reduced frame rates during both fluoroscopy and digital subtraction angiography (DSA), and the use of advanced angiographic systems. The low-dose protocol [...] Read more.

Background/Objectives: Optimizing routine neurointerventional workflow and minimizing exposure to ionizing radiation during coil-only endovascular treatment of intracranial aneurysms depend on operator experience, reduced frame rates during both fluoroscopy and digital subtraction angiography (DSA), and the use of advanced angiographic systems. The low-dose protocol implemented in this study used the lowest available fluoroscopy frame rate (3.125 frames per second [fps]) and a nominal acquisition rate of 2 fps (actual = 2.45 fps) for DSA, three-dimensional (3D) rotational angiography, two-dimensional (2D)/3D mapping, and roadmapping. Methods: This retrospective analysis encompassed 245 coil-only procedures performed at a single tertiary center from 2018 to 2024. Data collected for each procedure included dose-area product (DAP), reference air kerma (K_a,r), fluoroscopy time (FT), and the total number of DSA frames. Local diagnostic reference levels (DRLs; 75th percentile [P75]) and typical values (50th percentile [P50]) were determined and descriptively compared with values reported in the literature. Results: The P75 values, representing DRLs, were 22.4 Gy·cm² for DAP (literature range, 123–272.8 Gy·cm²), 268 mGy for K_a,r (1171–4240 mGy), 18 min 56 s for FT, and 285 DSA frames. The P50 values were 13.8 Gy·cm² for DAP (78.7–179.0 Gy·cm²), 196 mGy for K_a,r (801–2804 mGy), 13 min 25 s for FT, and 208 DSA frames. Conclusions: In this single-center cohort, dose metrics for coil-only intracranial aneurysm treatment were within the lower range of published values. Cross-study comparisons are descriptive and require cautious interpretation. The proposed local DRLs may support quality assurance, dose optimization, and patient safety in comparable clinical settings. Further multi-center and multi-operator studies are warranted to evaluate transferability and applicability beyond coil-only procedures. Full article

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

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12 pages, 616 KB

Open AccessArticle

The Central Role of Liver Function at Treatment Initiation and Its Preservation at Progression for Post-Progression Survival After Atezolizumab Plus Bevacizumab in Advanced Hepatocellular Carcinoma

by Mizuki Ariga, Teiji Kuzuya, Hisanori Muto, Yoshihiko Tachi, Mariko Kobayashi, Hijiri Sugiyama, Sayaka Morisaki, Gakushi Komura, Takuji Nakano, Hiroyuki Tanaka, Kazunori Nakaoka, Eizaburo Ohno, Kohei Funasaka, Mitsuo Nagasaka, Ryoji Miyahara and Yoshiki Hirooka

Biomedicines 2026, 14(1), 232; https://doi.org/10.3390/biomedicines14010232 - 21 Jan 2026

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Abstract

Background/Objectives: Atezolizumab plus bevacizumab (Atz+Bev) is widely used for advanced hepatocellular carcinoma (HCC), yet predictors of post-progression survival (PPS), a clinically meaningful endpoint reflecting the feasibility of treatment sequencing, remain unclear. We aimed to identify determinants of PPS and factors associated with [...] Read more.

Background/Objectives: Atezolizumab plus bevacizumab (Atz+Bev) is widely used for advanced hepatocellular carcinoma (HCC), yet predictors of post-progression survival (PPS), a clinically meaningful endpoint reflecting the feasibility of treatment sequencing, remain unclear. We aimed to identify determinants of PPS and factors associated with successful transition to subsequent therapy after progressive disease (PD) on Atz+Bev. Methods: We retrospectively analyzed 132 patients with HCC who initiated Atz+Bev with Child–Pugh A and Eastern Cooperative Oncology Group performance status (ECOG PS) 0/1. PPS was defined as survival from radiological PD to death; tumor response was assessed by RECIST v1.1. Results: Among 132 patients treated with Atz+Bev, median progression-free and overall survival were 9.2 and 21.2 months. PD occurred in 97 patients, with a median PPS of 9.2 months. At PD, 76 patients (78.4%) maintained both Child–Pugh A and ECOG PS 0/1; 93.4% of these patients transitioned to subsequent therapy, compared with 38.0% of patients who did not maintain Child–Pugh A and ECOG PS 0/1. The median PPS values were 14.7 and 2.0 months, respectively (p < 0.0001). In this PD cohort, disease control achieved with subsequent therapy after radiological PD was associated with longer PPS (16.1 vs. 5.0 mosnths; p = 0.0002). ECOG PS 0, Child–Pugh A, absence of portal vein invasion, and AFP < 400 ng/mL at PD independently predicted prolonged PPS. A baseline Child–Pugh score of 5 independently predicted preservation of Child–Pugh A and ECOG PS 0/1 at PD. Conclusions: Initiating Atz+Bev under optimal liver function (Child–Pugh 5) and preserving hepatic reserve and performance status through progression are critical for enabling subsequent therapy and achieving longer PPS. Full article

(This article belongs to the Special Issue Advanced Research in Anticancer Inhibitors and Targeted Therapy)

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14 pages, 1920 KB

Open AccessArticle

Effects of Physical Activity Level on Microsaccade Dynamics During Optic Flow Stimulation in Adults with Type 2 Diabetes

by Milena Raffi, Alessandra Laffi, Andrea Meoni, Michela Persiani, Lucia Brodosi, Alba Nicastri, Maria Letizia Petroni and Alessandro Piras

Biomedicines 2026, 14(1), 231; https://doi.org/10.3390/biomedicines14010231 - 21 Jan 2026

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Abstract

Background: Microsaccades are small fixational eye movements tightly linked to attention and oculomotor control. Although diabetes mellitus is associated with retinal and neural alterations that may impair visuomotor function, the influence of physical activity on microsaccade behaviour in individuals with type 2 [...] Read more.

Background: Microsaccades are small fixational eye movements tightly linked to attention and oculomotor control. Although diabetes mellitus is associated with retinal and neural alterations that may impair visuomotor function, the influence of physical activity on microsaccade behaviour in individuals with type 2 diabetes mellitus (T2DM) remains unknown. This study investigated whether habitual physical activity modulates microsaccade characteristics during fixation under different optic flow stimuli. Given that optic flow engages motion processing and gaze stabilisation pathways that may be affected by diabetes-related microvascular/neural changes, it can reveal subtle visuomotor alterations during fixation. Methods: Twenty-eight adults with T2DM and no diagnosed retinopathy performed a fixation task while viewing optic flow stimuli made of moving dots. Eye movements were recorded using an EyeLink system. Physical activity behaviour was assessed at baseline and at a 6-month follow-up after a low-threshold aerobic circuit training programme. Classification as physically active (≥600 MET-min/week) or inactive (<600 MET-min/week) was based on the 6-month assessment. Microsaccade characteristics were analysed by repeated-measures ANOVA. Results: Microsaccade rate was modulated by optic flow (p = 0.044, η²p = 0.106) and showed a significant stimulus × group × sex interaction (p = 0.005, η²p = 0.163), indicating sex-dependent differences in how optic flow modulated microsaccade rate across physically active and inactive participants. A time × stimulus interaction effect was found in peak velocity (p = 0.03, η²p = 0.114) and amplitude (p = 0.02, η²p = 0.127), consistent with modest context-dependent changes over time. Conclusions: These findings suggest that physical activity modulates microsaccade generation and supports the potential of microsaccade metrics as sensitive indicators of oculomotor function in diabetes. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Approaches in Diabetic Microvascular Complications, 2nd Edition)

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16 pages, 1084 KB

Open AccessReview

State-of-the-Art Research and New Pharmacological Perspectives on Renal Involvement in Duchenne Muscular Dystrophy: A Narrative Review

by Michela De Bellis, Paola Imbrici, Roberta Lenti, Antonella Liantonio and Annamaria De Luca

Biomedicines 2026, 14(1), 230; https://doi.org/10.3390/biomedicines14010230 - 21 Jan 2026

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Abstract

Background: Although Duchenne muscular dystrophy (DMD) is primarily characterized as a skeletal muscle-wasting disorder, the resulting pathophysiological changes extend to multiple non-muscle tissues and organ systems. Among these, renal and urinary tract dysfunctions have been reported, albeit in relatively few studies, as [...] Read more.

Background: Although Duchenne muscular dystrophy (DMD) is primarily characterized as a skeletal muscle-wasting disorder, the resulting pathophysiological changes extend to multiple non-muscle tissues and organ systems. Among these, renal and urinary tract dysfunctions have been reported, albeit in relatively few studies, as potential complications in DMD patients, sometimes occurring from an early age. Importantly, as life expectancy improves, the incidence of renal impairment is also expected to increase. This narrative review summarizes the available evidence on kidney involvement in DMD and discusses the associated biomarkers of renal dysfunction within the context of multisystem disease progression. Methods: The review draws on data from both human and animal studies and analyzes published evidence to explore kidney involvement in DMD, with a focus on clinical manifestations, biomarkers of renal dysfunction, and potential pathogenic mechanisms. Results: Available data indicate a close association between cardiac and renal dysfunction, particularly in patients with advanced-stage DMD. The review explores potential underlying mechanisms of renal impairment, including intrinsic dystrophin deficiency in the kidney, secondary effects of cardiovascular complications, and the nephrotoxic impact of drug therapies, highlighting renal function as an active determinant of clinical risk. Conclusions: While cardiac function monitoring is already a cornerstone of multidisciplinary care for this multisystem disease, systematic assessment of renal function should also be implemented, with implications for clinical management and drug safety. Moreover, the risk of drug-induced nephrotoxicity warrants attention in both clinical management and the development of novel therapeutic strategies for DMD. Full article

(This article belongs to the Special Issue Kidney Disease: From Pathophysiology to Treatment)

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11 pages, 594 KB

Open AccessReview

Chronic Urticaria and Malignancy: A Review Uncovering the Common Links

by Eralda Lekli, Mehmet Hoxha, Maria Bova, Juarda Gjonbrataj, Kleida Mati, Gentian Vyshka and Etleva Qirko

Biomedicines 2026, 14(1), 229; https://doi.org/10.3390/biomedicines14010229 - 21 Jan 2026

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Abstract

Background: Chronic urticaria (CU) is a complex skin condition, frequently challenging both patients and clinicians and requiring wise individualized management. While allergy, autoimmunity, and depression are recognized comorbidities, evidence linking CU and malignancy remains underexplored. Screening for malignancy is not a routine [...] Read more.

Background: Chronic urticaria (CU) is a complex skin condition, frequently challenging both patients and clinicians and requiring wise individualized management. While allergy, autoimmunity, and depression are recognized comorbidities, evidence linking CU and malignancy remains underexplored. Screening for malignancy is not a routine standard of care for CU patients. Methods: A literature review was conducted to explore the potential risk or associations, including immune mechanisms, between CU and malignancy, based on searches in the PubMed and Google Scholar databases. Results: Scientific evidence on the malignancy risk in CU and its causal relationship is limited to a few population-based studies and case reports. A higher incidence of hematologic malignancy in CU patients has been reported in several publications, but the overall risk of malignancy in the CU population remains controversial. Antihistamine resistance, ultra-low IgE, and older age at the time of CU diagnosis may be related to a higher risk of malignancy, especially shortly after CU diagnosis. Immunological pathways linking CU and cancer are not clear. Immune system dysregulation, including alterations in immune checkpoints, is a feature of both cancer and CU. Such dysregulation may promote immunotolerance, abnormal immune responses, and mast cell activation through novel autoantigens and autoantibodies involved in the tumor microenvironment. Conclusions: There is growing, although limited, evidence suggesting a possible link between CU and malignancy, especially hematologic cancers. Large multicenter cohort studies are warranted to determine whether CU may act as a clinical harbinger of malignancy and to identify patient subsets that may benefit from targeted cancer screening. Full article

(This article belongs to the Special Issue Urticaria: New Insights into Pathogenesis, Diagnosis and Therapy)

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22 pages, 1234 KB

Open AccessReview

The Mechanism and Regulation of Disulfidptosis and Its Role in Disease

by Yiming Wan, Mengjia Jing, Lumiao Zhang, Qianben Song, Xilin Ye, Zhenzhen Zhou, Wei Yan and Yu Fu

Biomedicines 2026, 14(1), 228; https://doi.org/10.3390/biomedicines14010228 - 21 Jan 2026

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Abstract

Disulfidptosis is a recently identified form of regulatory cell death (RCD), Which has emerged as a research hotspot due to its distinctive feature of accumulating protein disulfide bonds, setting it apart from other RCD mechanisms. This discovery may offer new therapeutic strategies for [...] Read more.

Disulfidptosis is a recently identified form of regulatory cell death (RCD), Which has emerged as a research hotspot due to its distinctive feature of accumulating protein disulfide bonds, setting it apart from other RCD mechanisms. This discovery may offer new therapeutic strategies for cancer and various chronic diseases. This review aims to summarize the molecular mechanisms, inhibitors, regulatory networks, distinctions and connections between disulfidptosis and other regulatory death pathways, and the application of disulfidptosis in tumors and other chronic diseases. It also identifies unresolved issues and provides an outlook on future prospects. Full article

(This article belongs to the Special Issue Feature Reviews in Cell Death)

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19 pages, 2612 KB

Open AccessArticle

Enhanced Bone Formation in Segmental Defect Healing Using 3D Printed Scaffolds Containing Bone Marrow Stromal Cells and Small Molecules Targeting Chondrogenesis and Osteogenesis

by Charles H. Rundle, Sheila Pourteymoor, Enoch Lai, Chandrasekhar Kesavan and Subburaman Mohan

Biomedicines 2026, 14(1), 227; https://doi.org/10.3390/biomedicines14010227 - 20 Jan 2026

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Abstract

Background/Objectives: Nonunion bone healing results from a critical size defect that fails to bridge a bone injury to produce bony union. Novel approaches are critical for refining therapy in clinically challenging bone injuries, but the complex and coordinated nature of fracture callus tissue [...] Read more.

Background/Objectives: Nonunion bone healing results from a critical size defect that fails to bridge a bone injury to produce bony union. Novel approaches are critical for refining therapy in clinically challenging bone injuries, but the complex and coordinated nature of fracture callus tissue development requires study outside of the simple closed murine fracture model. Methods: We have utilized a three-dimensional printing approach to develop a scaffold construct with layers designed to sequentially release small molecule therapy within the tissues of a murine endochondral segmental defect to augment different mechanisms of fracture repair during critical stages of nonunion bone healing. Initially, a sonic hedgehog (SHH) agonist is released from a fibrin layer to promote chondrogenesis. A prolyl-hydroxylase domain (PHD)2 inhibitor is subsequently released from a β-tricalcium phosphate (β-TCP) layer to promote hypoxia-inducible factor (HIF)-1α regulation of angiogenesis. This sequential approach to therapy delivery is assisted by the inclusion of bone marrow stromal cells (BMSCs) to increase the cell substrate available for the small molecule therapy. Results: Immunohistochemistry of fracture callus tissue revealed increased expression of PTCH1 and HIF1α, targets of hedgehog and hypoxia signaling pathways, respectively, in the SAG21k/IOX2-treated mice compared to vehicle control. MicroCT and histology analyses showed increased bone in the fracture callus of mice that received therapy compared to control vehicle scaffolds. Conclusions: While our findings establish feasibility for the use of BMSCs and small molecules in the fibrin gel/β-TCP scaffolds to promote new bone formation for segmental defect healing, further optimization of these approaches is required to develop a fracture callus capable of completing bony union in a large defect. Full article

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

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Biomedicines, Volume 14, Issue 1 (January 2026) – 256 articles

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