Biomedicines

13 pages, 1822 KB

Open AccessReview

Mitochondrial Dysfunction in the Inflammatory Process of Neurodegenerative Diseases

by Salvatore Nesci

Biomedicines 2026, 14(3), 682; https://doi.org/10.3390/biomedicines14030682 (registering DOI) - 16 Mar 2026

Neurodegenerative diseases share a mitochondrial–immune axis in which impaired oxidative phosphorylation reshapes neuronal metabolism and drives chronic inflammation. Complex I play a redox gatekeeper role at the coenzyme Q junction: catalytic defects, misassembly, or reverse electron transport over-reduce the Coenzyme Q pool, increase [...] Read more.

Neurodegenerative diseases share a mitochondrial–immune axis in which impaired oxidative phosphorylation reshapes neuronal metabolism and drives chronic inflammation. Complex I play a redox gatekeeper role at the coenzyme Q junction: catalytic defects, misassembly, or reverse electron transport over-reduce the Coenzyme Q pool, increase electron leak, and elevate ROS. How respiratory supercomplex plasticity (CI-CIII₂, CIII₂-CIV_n, or CI-CIII₂-CIV_n) modulates carrier channelling, flux control, and ROS propensity through dynamic reorganization of the electron transport chain is highlighted. Excess ROS damages lipids and mitochondrial DNA, promoting the release of mitochondrial damage-associated molecular patterns s that activate NLRP3 inflammasome signalling, cGAS-STING-dependent interferon programs, and endosomal TLR9 pathways, establishing feed-forward loops between mitochondrial injury and neuroinflammation. Disease-focused sections integrate evidence from Parkinson’s, Alzheimer’s, amyotrophic lateral sclerosis, and Huntington’s models, and map these mechanisms onto therapeutic opportunities spanning electron transport chain support, supercomplex stabilization, and consider mtDNA-sensing inflammatory nodes. Full article

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

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13 pages, 674 KB

Open AccessArticle

Carboxylesterase 2-Engineered Stem Cell Therapy Shows Superior Efficacy over Cytosine Deaminase in Castration-Resistant Prostate Cancer

by Jae Heon Kim, Miho Song, Sang Hun Lee and Yun Seob Song

Biomedicines 2026, 14(3), 681; https://doi.org/10.3390/biomedicines14030681 - 16 Mar 2026

Abstract

Purpose: Castration-resistant prostate cancer (CRPC) responds poorly to conventional chemotherapy. We evaluated a cell-based enzyme–prodrug therapy using adipose-derived stem cells (ADSCs) engineered to express cytosine deaminase (CD) or carboxylesterase 2 (CE2), paired with their respective prodrugs 5-fluorocytosine (5-FC) or irinotecan (CPT-11), to [...] Read more.

Purpose: Castration-resistant prostate cancer (CRPC) responds poorly to conventional chemotherapy. We evaluated a cell-based enzyme–prodrug therapy using adipose-derived stem cells (ADSCs) engineered to express cytosine deaminase (CD) or carboxylesterase 2 (CE2), paired with their respective prodrugs 5-fluorocytosine (5-FC) or irinotecan (CPT-11), to compare their antitumor efficacy. Materials and Methods: Human telomerase reverse transcriptase (hTERT)-immortalized ADSCs were transduced with CD or CE2, and transgene expression and stem cell phenotype were confirmed. CD expression was verified at the transcript level and by functional 5-FC-to-5-fluorouracil (5-FU) conversion, whereas CE2 expression was verified by transcript analysis and immunoblotting. Tumor tropism toward PC3 prostate cancer cells was tested using migration assays and analysis of chemoattractant ligand/receptor expression. Prodrug-induced self-killing and bystander tumor cell killing were assessed through viability assays and co-culture with PC3 cells. For the CE2/CPT-11 system, SN-38 was not directly quantified; functional activity was inferred from prodrug-dependent cytotoxicity and in vivo efficacy. In vivo efficacy was evaluated in nude mice with PC3 tumors treated systemically with engineered ADSCs plus prodrug. Results: CD- and CE2-expressing ADSCs were successfully established and retained mesenchymal stem cell (MSC) characteristics. Both cell types exhibited significant migration toward PC3 cells. The CE2/CPT-11 system produced stronger prodrug-mediated cytotoxicity than CD/5-FC, with CE2-modified ADSCs showing higher sensitivity to CPT-11 and inducing greater apoptosis in co-cultured PC3 cells. In vivo, both treatments suppressed tumor growth, but CE2/CPT-11 achieved greater inhibition (tumor volume ~26% of control vs. ~32% for CD/5-FC at day 14). No overt clinical toxicity was observed based on body weight and daily clinical monitoring; however, hematology/serum chemistry were not assessed. Conclusions: Engineered ADSCs home to CRPC tumors and enable local prodrug activation, producing significant antitumor effects. Within the constraints of our in vitro assays and subcutaneous xenograft model, CE2/CPT-11 demonstrated stronger efficacy outcomes than CD/5-FC. Mechanistic attribution to intratumoral SN-38 exposure should be confirmed by direct metabolite measurements in future studies. Full article

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

18 pages, 709 KB

Open AccessArticle

Thermal–Inflammatory Index (TI): An Integrated Biomarker of Severity and Prognosis in Chronic Lower-Limb Ulcers

by Bartosz Molasy and Małgorzata Wrzosek

Biomedicines 2026, 14(3), 680; https://doi.org/10.3390/biomedicines14030680 - 16 Mar 2026

Abstract

Background/Objectives: Chronic lower-limb ulcers of mixed etiology are characterized by impaired microcirculation and persistent inflammation, leading to delayed healing, frequent hospitalizations, and a high risk of limb loss. While infrared thermography reflects local perfusion status and systemic inflammatory markers capture whole-body immune activation, [...] Read more.

Background/Objectives: Chronic lower-limb ulcers of mixed etiology are characterized by impaired microcirculation and persistent inflammation, leading to delayed healing, frequent hospitalizations, and a high risk of limb loss. While infrared thermography reflects local perfusion status and systemic inflammatory markers capture whole-body immune activation, these dimensions are usually assessed separately. The objective of this study was to develop and internally evaluate a composite Thermal–Inflammatory Index (TI) integrating wound-bed thermography with systemic inflammatory markers to stratify disease severity and prognosis in patients with chronic lower-limb ulcers. Methods: In this prospective observational study, 82 adults with chronic lower-limb ulcers underwent baseline infrared thermographic assessment of wound-bed temperature using a standardized protocol. Concurrently, neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) were measured. The Thermal–Inflammatory Index was constructed as a standardized composite of inverted wound-bed temperature, NLR, and CRP. A simplified TI score (0–3) was derived using predefined clinical thresholds. The primary endpoint was a composite adverse outcome defined as amputation or failure to achieve complete wound healing within 12 weeks. Secondary outcomes included a prolonged hospital stay (>7 days). Discriminative performance was assessed using receiver operating characteristic analysis, and associations were examined using correlation and logistic regression models. Results: Higher TI values were associated with colder wound beds, elevated systemic inflammatory markers, and increased disease burden. The TI demonstrated moderate discrimination for the composite adverse outcome (AUC 0.75) and prolonged hospitalization (AUC 0.71), performing comparably to the strongest single component (−T_bed, AUC 0.77) while integrating local and systemic information. Each one-standard-deviation increase in TI was independently associated with higher odds of the composite adverse outcome and a prolonged hospital stay. The simplified TI score showed clear stepwise gradients in adverse outcomes and length of hospitalization. Conclusions: The Thermal–Inflammatory Index integrates thermographic and inflammatory signals into a single, clinically interpretable biomarker of severity and prognosis in chronic lower-limb ulcers. TI and the simplified TI score may support early risk stratification using low-cost, bedside-accessible data. Full article

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

14 pages, 918 KB

Open AccessArticle

Clinical and Instrument-Based Evaluation of Plasma IQ Microcurrent Radiofrequency for Periorbital Skin Rejuvenation

by Paweł Kubik, Wojciech Gruszczyński, Aleksandra Pawłowska, Maciej Malinowski, Brygida Baran, Agnieszka Pawłowska-Kubik, Łukasz Kodłubański and Bartłomiej Łukasik

Biomedicines 2026, 14(3), 679; https://doi.org/10.3390/biomedicines14030679 - 16 Mar 2026

Abstract

Background: Non-surgical procedures utilizing microcurrent radiofrequency (RF) represent a non-invasive option for patients experiencing skin laxity and loss of firmness due to aging, hormonal changes, or weight fluctuations. Such treatments benefit individuals seeking both preventive measures to delay visible aging and corrective [...] Read more.

Background: Non-surgical procedures utilizing microcurrent radiofrequency (RF) represent a non-invasive option for patients experiencing skin laxity and loss of firmness due to aging, hormonal changes, or weight fluctuations. Such treatments benefit individuals seeking both preventive measures to delay visible aging and corrective approaches to improve existing skin laxity without invasive surgery. The Plasma IQ medical device generates microcurrent RF energy that produces controlled heating, leading to targeted tissue ablation and subsequent remodelling. This study aimed to evaluate the clinical efficacy of Plasma IQ in the treatment of skin laxity. Materials and Methods: Thirty patients presenting with facial skin laxity and photodamage underwent treatment with the Plasma IQ device. Clinical outcomes were assessed prior to the procedure and at 7, 21 and 90 days post-treatment. Results: RF treatment produced a measurable improvement in skin elasticity (+22.51%). The distance between the upper eyelid margin and the beginning of the eyelid fold increased by 2.01 mm (+46.94%) at day 21 and by 2.11 mm (+49.11%) at day 90. Conclusions: Microcurrent RF delivered by the Plasma IQ device is an effective non-invasive method for periocular skin rejuvenation. The treatment improves skin elasticity, reduces wrinkles around the eyes, and increases the visible distance between the upper eyelid margin and fold, thereby enhancing upper eyelid definition. Full article

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

9 pages, 491 KB

Open AccessEditorial

Peptides and Amino Acids in Drug Development: Where We Stand and Where We Must Go

by Siva S. Panda

Biomedicines 2026, 14(3), 678; https://doi.org/10.3390/biomedicines14030678 - 16 Mar 2026

Abstract

Peptides are now a key part of modern drug development, transforming the industry at an extraordinary rate [...] Full article

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

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18 pages, 1686 KB

Open AccessPerspective

Redefining Idiopathic Normal Pressure Hydrocephalus Using AI-Driven Brain Volumetry

by Juan Sahuquillo, Murad Al-Nusaif, Aasma Sahuquillo-Muxi, Paula Duch, Maria-Antonia Poca and on behalf of the Alzheimer’s Disease Neuroimaging Initiative

Biomedicines 2026, 14(3), 677; https://doi.org/10.3390/biomedicines14030677 - 16 Mar 2026

Abstract

Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible cause of gait disturbance and cognitive impairment in older adults, yet its diagnosis remains challenging and controversial. The core difficulty lies in distinguishing true hydrocephalus from ventricular enlargement secondary to cerebral atrophy or neurodegenerative [...] Read more.

Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible cause of gait disturbance and cognitive impairment in older adults, yet its diagnosis remains challenging and controversial. The core difficulty lies in distinguishing true hydrocephalus from ventricular enlargement secondary to cerebral atrophy or neurodegenerative disease, a distinction now recognized as non-binary. In many patients, ventricular enlargement reflects a continuum ranging from predominantly hydrocephalic iNPH to mixed pathological states combining impaired cerebrospinal fluid (CSF) dynamics and neurodegeneration. Conventional neuroradiological markers, including the Evans Index, the callosal angle, and the disproportionately enlarged subarachnoid-space hydrocephalus (DESH) pattern, provide useful qualitative guidance but are limited by their two-dimensional nature, interobserver variability, and poor sensitivity for differential diagnosis and outcome prediction. Over the past decade, advances in artificial intelligence-based brain volumetry (AI-BrV) have introduced a new paradigm for quantitative structural assessment. By enabling automated, anatomically precise, and reproducible three-dimensional quantification of ventricular and extraventricular CSF, cortical and subcortical gray matter, deep gray matter nuclei, and periventricular white matter, AI-BrV addresses many limitations of traditional imaging approaches. Beyond absolute volume measurements, AI-BrV enables the derivation of composite indices and ratios that may capture disease-specific structural phenotypes and better reflect the underlying pathophysiology of ventricular enlargement. Importantly, AI-BrV pipelines can be applied retrospectively to large legacy neuroimaging datasets and compared with extensive publicly available repositories, facilitating normative modeling, cross-disease analyses, and external validation of volumetric biomarkers. When integrated with clinical data and multivariable statistical or machine-learning frameworks, these approaches hold promise for improving patient selection, refining disease categorization, and supporting more rational decision-making regarding CSF diversion. In this context, AI-BrV offers a unifying framework for reconciling divergent clinical perspectives and advancing iNPH toward a more precise, reproducible, and evidence-based diagnostic and therapeutic paradigm. Full article

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

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1 pages, 154 KB

Open AccessCorrection

Correction: Molnar et al. PET CT Imaging with FDG in the Therapeutical Management of Locally Advanced Cervical Cancer Diagnosed in a 43-Year-Old Patient: Case Report and Review of the Literature. Biomedicines 2025, 13, 83

by Ottó Molnar, Simona Mihuțiu, Oreste Mihai Straciuc, Alexandra Vesa and Liviu Lazar

Biomedicines 2026, 14(3), 676; https://doi.org/10.3390/biomedicines14030676 - 16 Mar 2026

Abstract

References [...] Full article

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

10 pages, 1484 KB

Open AccessBrief Report

A Novel Frameshift Mutation in SLC20A2 in a Korean Patient with Primary Brain Calcification, Parkinsonism and Memory Impairment

by Eva Bagyinszky, Minju Kim, Young Ho Park, Danyeong Kim, Seong Soo A. An and SangYun Kim

Biomedicines 2026, 14(3), 675; https://doi.org/10.3390/biomedicines14030675 (registering DOI) - 16 Mar 2026

Abstract

Objectives: The patient presented various neurological symptoms in her 50s, such as memory issues, insomnia, depression, and motor impairment. Diverse investigations were performed to identify the underlying causes on her neurological symptoms and understand her neuro- deteriorations. Methods: Clinical neurological and brain imaging [...] Read more.

Objectives: The patient presented various neurological symptoms in her 50s, such as memory issues, insomnia, depression, and motor impairment. Diverse investigations were performed to identify the underlying causes on her neurological symptoms and understand her neuro- deteriorations. Methods: Clinical neurological and brain imaging analyses: CT, MRI and PET were performed on the patient. Blood was drawn for the whole-exome sequencing and functional studies with biomarker for amyloid-beta oligomers and SLC20A2 protein in plasma. Results: Brain imaging revealed calcifications in multiple regions, including the subcortical white matter, basal ganglia, thalami, and dentate nuclei. Genetic analysis revealed a c.1152_1153delCA, p.Asn384Lysfs*30 variant in SLC20A2 gene. The decreased SLC20A2 protein levels in plasma in comparison to healthy controls suggested a loss-of-function mechanism from the mutation. The patient had a positive AlzOn result, indicating an increased tendency for amyloid oligomerization and suggesting a potential indirect link between SLC20A2 and amyloid-beta pathways. Conclusions: A novel frameshift mutation, Asn384Lysfs*30, in the SLC20A2 gene was identified in a patient with Primary Brain Calcification (PBC). This mutation was located in a critical large loop region of the protein, where other similar mutations (e.g., Gly366fs89, Ser385Ilefs*70) were previously reported. These findings indicated that mutations in SLC20A2 caused the reduced protein expressions, potentially resulting PBC through haploinsufficiency. Full article

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

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Graphical abstract

7 pages, 179 KB

Open AccessPerspective

Reconsidering Carotid Artery Stenting for Asymptomatic Carotid Stenosis in the Era of Endovascular Evolution

by Chloe DeYoung and Brandon Lucke-Wold

Biomedicines 2026, 14(3), 674; https://doi.org/10.3390/biomedicines14030674 - 16 Mar 2026

Abstract

Management strategies in asymptomatic carotid artery stenosis are largely centered on intensive medical management, with carotid revascularization via endarterectomy or carotid artery stenting being reserved for select patients. This decision may be based on stenosis severity, perioperative risk, and patient preference. Current guidelines [...] Read more.

Management strategies in asymptomatic carotid artery stenosis are largely centered on intensive medical management, with carotid revascularization via endarterectomy or carotid artery stenting being reserved for select patients. This decision may be based on stenosis severity, perioperative risk, and patient preference. Current guidelines emphasize shared decision-making for patients with severe (>70%) stenosis, informed by prior trial data that does not demonstrate superiority of revascularization over independent medical therapy. Other studies more specifically recommend carotid endarterectomy over carotid artery stenting for asymptomatic patients with >60% stenosis. However, these studies are limited by poor statistical power. Recent findings in the CREST-2 trial have challenged this discussion of medical management as an independent primary course of action. The carotid artery stenting arm demonstrated significant long-term reduction in ipsilateral ischemic stroke compared to medical therapy alone. In this perspective, we argue that this new evidence supports a renewed role for carotid artery stenting in carefully selected patients with severe asymptomatic carotid artery stenting. Full article

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

20 pages, 2788 KB

Open AccessReview

Turning Fluids into Data for Precision Oncology: A Multidisciplinary Tumor Board Approach to Malignant Pleural Effusions

by Domenico Damiani, Ilaria Girolami, Esther Hanspeter, Christine Mian, Christine Schwienbacher, Johanna Köhl, Stefania Kinspergher, Giovanni Zambello, Francesco Zaraca, Giovanni Negri, Patrizia Pernter, Mohsen Farsad, Sara Gusella and Georgia Levidou

Biomedicines 2026, 14(3), 673; https://doi.org/10.3390/biomedicines14030673 - 16 Mar 2026

Abstract

Background: Malignant pleural effusion (MPE) represents a frequent and clinically challenging manifestation of advanced malignancy, particularly in metastatic non-small cell lung cancer (NSCLC). Its management requires integration of diagnostic imaging, symptom-directed therapeutic strategies, and, increasingly, molecular profiling technologies. Recent advancements in this [...] Read more.

Background: Malignant pleural effusion (MPE) represents a frequent and clinically challenging manifestation of advanced malignancy, particularly in metastatic non-small cell lung cancer (NSCLC). Its management requires integration of diagnostic imaging, symptom-directed therapeutic strategies, and, increasingly, molecular profiling technologies. Recent advancements in this field based on liquid medium (so-called liquid biopsy) have achieved a significant increase in sensitivity, enhancing our ability to investigate biofluids and suggesting their potential integration into standard diagnostic practices, far beyond the canonical plasma biopsies. Fluid obtained from MPE after cytological sample centrifugation is rich in cell-free DNA and less susceptible to nucleic acid degradation during processing, improving overall diagnostic accuracy. Methods: This narrative review summarizes current evidence on the clinical management of malignant pleural effusions in patients with metastatic NSCLC, integrating imaging, procedural management, and molecular profiling from a multidisciplinary tumor board perspective. The primary objective was to synthesize contemporary knowledge with particular attention to the feasibility, reliability, and reproducibility of pleural fluid-based molecular testing. Results: MPE poses diagnostic and therapeutic challenges for all members of the multidisciplinary tumor board, traditionally associated with an adverse prognosis. However, recent advances in cytopathology, histopathology, and liquid-based techniques demonstrate that MPE could be an important source of prognostic or predictive information. At the same time, optimal patient management requires careful integration of imaging findings and procedural strategies (such as pleurodesis or indwelling pleural catheters) with individualized systemic therapy selection. Cell-free DNA in pleural effusions is a promising field of exploration and study, potentially suitable for future guideline implementation, after validation in adequately powered studies, contributing to improving patient management, particularly useful in fragile subsets. Conclusions: The management of MPE in advanced NSCLC is evolving toward a multidisciplinary, precision-oriented model that integrates clinical evaluation, imaging, procedural interventions, and molecular testing. Liquid biopsy technology has gained enough analytical robustness and clinical feasibility to be a useful tool in routine analysis. Biofluid-based molecular testing may have outstanding potential, contributing to improving patient management, avoiding repetitive procedures, and optimizing the overall efficiency and cost-effectiveness of diagnostic practices. Moreover, collaborative projects among different specialties help in consolidating trust in the tumor board decision-making process. Full article

(This article belongs to the Special Issue Thoracic Malignancies: From Pathophysiology to Novel Therapeutic Approaches)

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13 pages, 1258 KB

Open AccessReview

BRAF Mutations in Myeloid Neoplasms: Prevalence, Co-Mutation Landscape, and Clinical Outcomes—A Comprehensive Review

by Shehab F. Mohamed, Ali Mohamed, Mohamed Fawzi Mudarres, Azza E. A. Abdalla, Abdulrahman F. Al-Mashdali, Mohammed Abdulgayoom, Rowan Mesilhy, Tareq Abuasab, Honar Cherif and Gautam Borthakur

Biomedicines 2026, 14(3), 672; https://doi.org/10.3390/biomedicines14030672 - 15 Mar 2026

Abstract

Background: BRAF is a core component of the RAS–MAPK signaling pathway and an established oncogenic driver in several solid tumors and selected hematologic malignancies. In myeloid neoplasms, BRAF mutations are rare, and their prevalence, molecular context, and clinical significance remain incompletely defined. Available [...] Read more.

Background: BRAF is a core component of the RAS–MAPK signaling pathway and an established oncogenic driver in several solid tumors and selected hematologic malignancies. In myeloid neoplasms, BRAF mutations are rare, and their prevalence, molecular context, and clinical significance remain incompletely defined. Available evidence is scattered across heterogeneous reports involving acute myeloid leukemia, myelodysplastic syndromes, myeloproliferative neoplasms, and overlap myelodysplastic/myeloproliferative neoplasms, with variable descriptions of mutation subtypes, co-mutational profiles, cytogenetic associations, therapeutic approaches, and clinical outcomes. To address these gaps, this review synthesizes data from the published literature up to 2025, summarizing the distribution, genetic landscape, and clinical impact of molecularly confirmed BRAF mutations across the spectrum of myeloid neoplasms. Results: Across published cohorts, BRAF mutations occurred in less than 1% of unselected myeloid neoplasms, with enrichment in chronic myelomonocytic leukemia and therapy-related or secondary acute myeloid leukemia. Both V600E and non-V600E variants were observed, typically within a complex genomic background involving ASXL1, TET2, DNMT3A, SRSF2, and RAS-pathway mutations. Acute myeloid leukemia cases showed poor prognosis, with median overall survival measured in months, whereas myelodysplastic syndromes and chronic myelomonocytic leukemia demonstrated relatively longer survival. Targeted MAPK inhibition produced hematologic responses in selected cases but rarely resulted in durable molecular clearance. Conclusions: BRAF mutations in myeloid neoplasms are rare, heterogeneous, and usually represent secondary events in clonal evolution. Although mutation clearance appears prognostically relevant, current targeted approaches provide limited durability, underscoring the need for prospective studies in this setting. Full article

(This article belongs to the Special Issue Selected Papers from the Tanawwo Workshop on Clinical Research in Precision Medicine, Rare Diseases, and Pharmacogenomics (Doha, Qatar, 2025))

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31 pages, 1646 KB

Open AccessReview

All the Way: A Decade of SIRT1 in Breast Cancer

by Giovanni Pratelli, Mauro Montalbano, Federica Affranchi, Chiara Occhipinti, Marianna Lauricella, Daniela Carlisi and Anna De Blasio

Biomedicines 2026, 14(3), 671; https://doi.org/10.3390/biomedicines14030671 - 15 Mar 2026

Abstract

Breast cancer (BC) is a highly heterogeneous genetic disease, comprising several subtypes with distinct features that significantly influence prognosis and treatment outcomes. Among these subtypes, triple-negative breast cancer (TNBC) is particularly aggressive and makes it resistant to many standard therapies. Epigenetic mechanisms, including [...] Read more.

Breast cancer (BC) is a highly heterogeneous genetic disease, comprising several subtypes with distinct features that significantly influence prognosis and treatment outcomes. Among these subtypes, triple-negative breast cancer (TNBC) is particularly aggressive and makes it resistant to many standard therapies. Epigenetic mechanisms, including acetylation and deacetylation, are crucial in regulating gene expression and maintaining normal cellular functions and are closely associated with BC progression. In this context, the histone deacetylases sirtuins (SIRT1-7) regulate key biological processes like genomic stability, inflammation, cellular senescence, and metabolic functions, increasingly linked to cancer. In particular, SIRT1 shows dual roles, functioning both as a tumor suppressor or an oncogene, contributing to cancer initiation, progression, and metastasis as well as chemotherapy resistance. Despite extensive research in the past decade, the exact role of SIRT1 in BC, especially in TNBC, remains controversial. Recent findings suggest that SIRT1 can be modulated not only through pharmacological approaches but also using natural extracts, offering potential alternative or complementary therapeutic strategies. Additionally, SIRT1 activity is regulated by a complex network of miRNAs, highlighting the need for further investigation. This review aims to summarize recent studies to identify key insights into the role of SIRT1 and explore it as a potential therapeutic target in BC. Full article

(This article belongs to the Special Issue Molecular Research in Breast Cancer)

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23 pages, 4110 KB

Open AccessArticle

Mrgprb4-Lineage Neurons Participate in the Intervention of TENS Effects on Chronic Pain and Anxiety-like Symptoms in an Inflammatory Pain Mouse Model

by Longhua Du, Hongyi Cheng, Jiamian Zhang, Hang Sun, Xia Li, Shuya Wang, Yun Liu, Bing Zhu, Xinyan Gao and Kun Liu

Biomedicines 2026, 14(3), 670; https://doi.org/10.3390/biomedicines14030670 - 15 Mar 2026

Abstract

Background: Mas-related G-protein-coupled receptor b4 (Mrgprb4)-lineage neurons in the peripheral nervous system are a type of C fibers in hairy skin. Our prior work demonstrated that these neurons respond to both noxious and innocuous mechanical and thermal stimuli. Ablating them eliminates the [...] Read more.

Background: Mas-related G-protein-coupled receptor b4 (Mrgprb4)-lineage neurons in the peripheral nervous system are a type of C fibers in hairy skin. Our prior work demonstrated that these neurons respond to both noxious and innocuous mechanical and thermal stimuli. Ablating them eliminates the pleasant sensation elicited by gentle pressure on a mouse’s nape. However, their potential role in mitigating pain and pain-related negative emotions in response to somatic stimuli remains unclear. Methods: A CFA-induced chronic pain and anxiety comorbidity model was established in C57BL/6J mice. In vivo calcium imaging of dorsal root ganglia (DRG) neurons in Mrgprb4-GCaMP6s transgenic mice characterized neuronal responses to transcutaneous electrical nerve stimulation (TENS) at the Zusanli (ST36) acupoint. Optogenetic activation (Mrgprb4-ChR2 mice) and viral ablation of Mrgprb4-lineage neurons were employed to evaluate their role in mediating TENS effects on mechanical pain thresholds and anxiety-like behaviors. Results: In vivo calcium imaging revealed that 0.5 mA TENS preferentially activated Mrgprb4-lineage neurons compared to 2.0 mA TENS. In CFA model mice, 0.5 mA TENS at ST36 significantly increased mechanical pain thresholds and reduced anxiety-like behaviors in the open-field test. Optogenetic activation of Mrgprb4-lineage neurons at ST36 replicated these analgesic and anxiolytic effects, demonstrating the sufficiency of these neurons for therapeutic outcomes. Conversely, viral ablation of L3–L5 Mrgprb4-lineage neurons substantially attenuated the therapeutic effects of 0.5 mA TENS for both pain relief and anxiety reduction, indicating their necessity in mediating TENS efficacy. Conclusions: Mrgprb4-lineage neurons serve as critical peripheral mediators of TENS-induced analgesia and anxiolysis. These findings identify a specific neuronal population underlying the therapeutic effects of somatic stimulation at ST36, providing mechanistic insights that may guide optimization of TENS parameters for treating chronic pain and comorbid anxiety in clinical settings. Full article

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

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19 pages, 61681 KB

Open AccessArticle

EEG Time-Frequency Clustering Reveals Spectral Signatures of Glutamatergic and Cholinergic Activities and Their Interrelations

by Vasily Vorobyov and Alexander Deev

Biomedicines 2026, 14(3), 669; https://doi.org/10.3390/biomedicines14030669 - 15 Mar 2026

Abstract

Background: The discovery of electroencephalogram (EEG) biomarkers of direct transmitter–receptor interactions in studies of neurotransmitter mechanisms underlying brain function remains relevant. Recently, EEG “signatures” of monoaminergic systems have been demonstrated using the “time-frequency clustering” approach. In the current study, the glutamic and cholinergic [...] Read more.

Background: The discovery of electroencephalogram (EEG) biomarkers of direct transmitter–receptor interactions in studies of neurotransmitter mechanisms underlying brain function remains relevant. Recently, EEG “signatures” of monoaminergic systems have been demonstrated using the “time-frequency clustering” approach. In the current study, the glutamic and cholinergic systems were under similar analysis with additional emphasis on their potential interaction. Methods: In non-anesthetized freely moving rats, we studied the EEG effects of agonists for glutamate receptors, injected into the cerebral lateral ventricles, and their modification after pretreatment with corresponding antagonists. The same protocol was used for acetylcholine receptors, activating and blocking substances that penetrate the blood–brain barrier (BBB) after subcutaneous injections. A clustering of significant time-dependent changes in tiny frequency subranges of the EEG spectra was performed. Results: After injections of agonists for glutamate receptors, two clusters with enhanced and suppressed activities around 2/4 and 10 Hz, respectively, were observed in the EEG spectra. These effects were reduced by pretreatment with corresponding receptor blockers. A cholinomimetic, physostigmine, decreased EEG activity around 2 and 10 Hz and increased near 5 and 22 Hz. Scopolamine, blocking muscarinic cholinoreceptors, weakened the effects of physostigmine. Intracerebral pretreatment with NMDA and AMPA receptor blockers differently modified the effects of physostigmine. The results demonstrate the EEG biomarkers of glutamatergic and cholinergic systems, as well as the specificity of interactions between them at the intracerebral level. Conclusions: The developed EEG time-frequency clustering is a potentially useful approach for the clinical evaluation of glutamatergic/cholinergic pathology and its correction by corresponding substances penetrating the BBB. Full article

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

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19 pages, 1487 KB

Open AccessReview

Bridging the Precision Gap in Rheumatoid Arthritis: Spatial Transcriptomics, Spatial Proteomics, and Artificial Intelligence in Precision Health

by Maliha Mashkoor, Shihua Zhang and Allan Stensballe

Biomedicines 2026, 14(3), 668; https://doi.org/10.3390/biomedicines14030668 - 14 Mar 2026

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by complex immune cell associations and continuous joint damage. Personalized clinical assessment and treatment options for RA remain hindered by a precision gap due to an inability to precisely match current global treatment strategies [...] Read more.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by complex immune cell associations and continuous joint damage. Personalized clinical assessment and treatment options for RA remain hindered by a precision gap due to an inability to precisely match current global treatment strategies to individual molecular and spatial disease profiles. Recent advances in spatial transcriptomics and proteomics offer unprecedented opportunities to map molecular heterogeneity and spatial heterogeneity within RA tissues by identifying immune microenvironments activated during the disease, thus enabling precise therapeutic targeting. These techniques address the precision gap in RA by identifying distinct pathogenic subpopulations and cellular niches, providing insights into the biomolecules that possess significant therapeutic responses and are involved in disease progression. This review synthesizes recent findings demonstrating how spatial omics technologies, including spatial transcriptomics and proteomics, together with artificial intelligence, are transforming precision rheumatology. Full article

(This article belongs to the Topic Biomarkers of Disease: Discovery and Clinical Applications)

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22 pages, 7657 KB

Open AccessArticle

Targeting the Glutamine Transporter SLC1A5 Enhances Sensitivity of Acute Myeloid Leukemia to MLN4924

by Yin Wang, Yuancheng Guo, Xiao Tang, Yu Zhu, Haiping Liang, Yali Zhang and Bei Liu

Biomedicines 2026, 14(3), 667; https://doi.org/10.3390/biomedicines14030667 - 14 Mar 2026

Abstract

Background/Objectives: Acute myeloid leukemia (AML) remains a hematologic malignancy with poor prognosis. The neddylation inhibitor MLN4924 has demonstrated potent anti-leukemic activity in preclinical models, yet its clinical translation faces significant challenges. The aim of this study was to explore combination therapy strategies [...] Read more.

Background/Objectives: Acute myeloid leukemia (AML) remains a hematologic malignancy with poor prognosis. The neddylation inhibitor MLN4924 has demonstrated potent anti-leukemic activity in preclinical models, yet its clinical translation faces significant challenges. The aim of this study was to explore combination therapy strategies that could further enhance MLN4924’s anti-leukemia potential. Methods: AML cell lines used in this study were Kasumi-1 and MOLM-13. Cell viability was assessed using CCK-8 assays. mRNA and protein expression levels were determined through RT-qPCR and Western blot, respectively. Flow cytometry was employed to analyze surface markers (SLC1A5, CD11b, CD14, CD16), mitochondrial membrane potential (JC-1), and apoptosis (Annexin V-FITC/PI). In vivo efficacy was validated using an NCG mouse xenograft model. Transcriptomic profiling was performed to explore the potential mechanism by which MLN4924 in combination with V9302 inhibits leukemia. Results: Treatment with MLN4924 significantly upregulated key glutamine metabolic proteins, GLUL and the glutamine transporter SLC1A5, in AML cells. Knockdown of SLC1A5 significantly enhanced AML cell sensitivity to MLN4924. The combination of MLN4924 and the SLC1A5 inhibitor V9302 synergistically inhibited AML cell proliferation, induced monocytic differentiation, and promoted apoptosis. Transcriptomic analysis revealed that this combination therapy prominently suppressed the tricarboxylic acid (TCA) cycle. Conclusions: Neddylation inhibition induces compensatory upregulation of glutamine metabolism in AML. Co-targeting neddylation and glutamine transporter SLC1A5 synergistically exerts anti-leukemic effects, at least in part through disruption of the TCA cycle. This combination represents a novel and effective therapeutic strategy against AML. Full article

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

25 pages, 5765 KB

Open AccessArticle

Innovative Inclusion Complexes Clotrimazole: Hydroxypropyl-β-Cyclodextrin-Modified Polyurethane Networks as Carriers for Slow Drug Delivery

by Suzana M. Cakić, Snežana S. Ilić-Stojanović, Ljubiša B. Nikolić, Vesna D. Nikolić, Ivan S. Ristić, Gordana S. Marković and Nada Č. Nikolić

Biomedicines 2026, 14(3), 666; https://doi.org/10.3390/biomedicines14030666 - 14 Mar 2026

Abstract

Background/Objectives: Inclusion complexes among drugs and cyclodextrin-modified polymers are a topic of recent interest in pharmaceutical research and industry as they might expand the solubility, bioavailability, and stability of the guest molecules. Polyurethanes derived from cyclodextrins show some biomedical applications. In this [...] Read more.

Background/Objectives: Inclusion complexes among drugs and cyclodextrin-modified polymers are a topic of recent interest in pharmaceutical research and industry as they might expand the solubility, bioavailability, and stability of the guest molecules. Polyurethanes derived from cyclodextrins show some biomedical applications. In this study, two cross-linked polyurethane networks based on hydroxypropyl-β-cyclodextrin (HPβCD) and polyethylene glycols (PEG 2000 or PEG 6000) were synthesized with NCO/OH molar ratio 4.3 and 6.3 by the typical two-step polymerization method. Methods: Inclusion complexes of clotrimazole (CLOT) with two HPβCD-modified polyurethane networks and their corresponding physical mixtures were prepared using kneading methods and physical mixing in a 1:6 weight ratio of CLOT:HPβCD. Results: Obtained prepolymers, previously end-capped with isocyanate groups forming urethane links with HPβCD, which were confirmed by FTIR analysis. TGA results indicate a slight increase in thermal stability of the prepared complexes. The characteristic endothermic peak of the CLOT at around 145.90 °C did not appear in the DSC curve of the drug-loaded inclusion complexes. The XRD patterns of physical mixtures showed specific peaks corresponding to pure clotrimazole. SEM micrographs confirmed an elliptical/spherical- and plate-shaped particles without phase segregation, indirectly confirming that CLOT is not separately present due to inclusion into HPβCD and entrapment into polyurethane networks. Novel complexes PUR2/HPβCD-CLOT-IC and PUR3/HPβCD-CLOT-IC were applied as drug carriers, and diffusion-controlled kinetics of CLOT release were best described using Higuchi model. Conclusions: The obtained in vitro results showed surprisingly slow/prolonged clotrimazole release from modified polyurethane networks due to the significant influence of NCO/OH molar ratio and the chosen polyol soft segments chain length with potential in vivo applications. Full article

(This article belongs to the Special Issue Drug Delivery and Nanocarrier)

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16 pages, 6943 KB

Open AccessArticle

Integration of RNA Editing into Multiomics Machine Learning Models for Predicting Drug Responses in Breast Cancer Patients

by Yanara A. Bernal, Alejandro Blanco, Karen Oróstica, Iris Delgado and Ricardo Armisén

Biomedicines 2026, 14(3), 665; https://doi.org/10.3390/biomedicines14030665 - 14 Mar 2026

Abstract

Background: The integration of multi-omics data, such as genomics and transcriptomics, into artificial intelligence models has advanced precision medicine. However, their clinical applicability remains limited due to model complexity. We integrated DNA mutation, RNA expression, and A>I(G) RNA editing data to develop [...] Read more.

Background: The integration of multi-omics data, such as genomics and transcriptomics, into artificial intelligence models has advanced precision medicine. However, their clinical applicability remains limited due to model complexity. We integrated DNA mutation, RNA expression, and A>I(G) RNA editing data to develop a predictive model for drug response in breast cancer. Methods: We analyzed 104 patients from the Breast Cancer Genome-Guided Therapy Study (ClinicalTrials.gov: NCT02022202). Clinical variables, gene expression, tumor and germline DNA variants, and RNA editing features were integrated into machine learning models to predict therapy response. Generalized linear models (GLM), random forest (RF), and support vector machines (SVM) were trained and evaluated across multiple random 70/30 train-test splits. Feature selection was performed exclusively within the training set using LASSO regularization. Model performance was assessed using the F1-score on independent test sets. The additive effect of RNA editing was evaluated using paired comparisons across identical train/test splits. Results: We characterized the cohort using clinical, mutational, transcriptomic, and RNA editing profiles in 69 non-responders and 35 responders. Across repeated splits, adding RNA editing frequently maintained or modestly improved predictive performance, particularly in expression-based models, with paired analyses showing a statistically significant increase in F1-score. Conclusions: RNA editing represents a complementary molecular layer that can enhance multi-omic models for therapy response prediction in breast cancer, supporting further investigation of epitranscriptomic features in precision oncology. Full article

(This article belongs to the Special Issue Bioinformatics Analysis of RNA for Human Health and Disease)

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15 pages, 267 KB

Open AccessArticle

Treatment Priorities in Craniopharyngioma: Perspectives of Survivors and Caregivers

by Nathalie Kayadjanian and Eugenie A. Hsu

Biomedicines 2026, 14(3), 664; https://doi.org/10.3390/biomedicines14030664 - 14 Mar 2026

Abstract

Background/Objectives: While the number and severity of comorbidities affecting survivors of craniopharyngioma (CP) are well documented, little is known about the perspectives of caregivers and survivors regarding treatment priorities. This study aimed to describe the views of caregivers and self-reported survivors on the [...] Read more.

Background/Objectives: While the number and severity of comorbidities affecting survivors of craniopharyngioma (CP) are well documented, little is known about the perspectives of caregivers and survivors regarding treatment priorities. This study aimed to describe the views of caregivers and self-reported survivors on the comorbidities that most significantly impact CP survivors and to identify areas where new treatments are most needed. Methods: Completed surveys of 161 participants recruited in the hypothalamic–pituitary brain tumor patient registry were analyzed. Results: Participants represented 40% caregivers (mostly children) and 60% adult CP survivors, with notable differences in disease duration, age, CP onset, and living conditions. Seventeen health challenges were identified as most important by more than 50% of participants, including symptoms characteristic of hypothalamic dysfunction, neurological issues, and visual impairment. Notably, those differed from the most frequently experienced symptoms. No significant differences emerged between the two groups except for polydipsia, which had a greater impact on self-reported survivors. Most challenges primarily affected the survivors’ daily functioning; however, abnormal social behaviors equally impaired their ability to achieve long-term goals. Temperature dysregulation was the only symptom not deemed very or extremely important in prioritizing new treatment development. Both groups generally aligned on treatment priorities, though survivors placed a modest but significantly greater importance on fatigue and excessive daytime sleepiness, while caregivers placed a modest but significantly greater importance on obesity. Conclusions: Real-world survivor and caregiver perspectives on priority symptoms and treatments can inform care management, strengthen support strategies, and guide patient-focused drug development meaningful to CP survivors. Full article

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

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