Biomedicines

24 pages, 7614 KB

Open AccessArticle

Identification and Functional Validation of PTH2R as a Therapeutic Target in Lung Adenocarcinoma

by Changmin Liu, Yongfu Wang, Wei Liu, Yizhen Yuan, Yajing Xue, Pengzhuo Tao, Dan Sun, Te Kian Keong, Shilin Chen and Chi Song

Biomedicines 2026, 14(2), 489; https://doi.org/10.3390/biomedicines14020489 - 23 Feb 2026

Viewed by 701

Abstract

Background: One of the main causes of cancer-related mortality globally is lung adenocarcinoma (LUAD), necessitating the development of novel therapeutic targets. The parathyroid hormone type 2 receptor (PTH2R) exhibits differential expression across multiple cancers, yet its role in LUAD remains unclear. Methods [...] Read more.

Background: One of the main causes of cancer-related mortality globally is lung adenocarcinoma (LUAD), necessitating the development of novel therapeutic targets. The parathyroid hormone type 2 receptor (PTH2R) exhibits differential expression across multiple cancers, yet its role in LUAD remains unclear. Methods: Through an integrated analysis of multiple public databases (including SangerBox 3.0, UALCAN, Kaplan–Meier Plotter, and TIMER), we identified PTH2R—a member of the family B1 GPCRs—as a candidate therapeutic target with significant prognostic value in LUAD. Subsequently, the antitumor effects of PTH2R knockdown and melatonin were evaluated through cell proliferation, colony formation, migration, and apoptosis assays. Transcriptome analysis revealed key biological processes and signaling pathways regulated by PTH2R, identified key genes modulated by PTH2R, and validated core gene expression via RT-qPCR. Results: PTH2R is a potential therapeutic target for lung adenocarcinoma. Both PTH2R knockdown and melatonin treatment significantly inhibited LUAD cell proliferation, colony formation, and migration capabilities while promoting apoptosis. Notably, the combination of PTH2R knockdown and melatonin treatment demonstrated synergistically enhanced antitumor effects. Transcriptome analysis revealed two key genes within the PTH2R signaling pathway, and RT-qPCR validated the expression of these two key genes. Conclusions: Our work provides the first evidence confirming the substantial value of PTH2R as a novel therapeutic target for LUAD. It preliminarily demonstrates the mechanism by which melatonin inhibits LUAD by targeting PTH2R, offering crucial experimental evidence and theoretical support for developing precision therapeutic strategies against this cancer. Full article

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

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10 pages, 1646 KB

Open AccessArticle

Aortic Valve Annular Properties in Cardiac Amyloidosis—Insights from the Three-Dimensional Speckle Tracking Echocardiographic MAGYAR-Path Study

by Attila Nemes, Nóra Ambrus and Zita Borbényi

Biomedicines 2026, 14(2), 488; https://doi.org/10.3390/biomedicines14020488 - 23 Feb 2026

Viewed by 415

Abstract

Introduction. The etiology of cardiac amyloidosis (CA) involves the systemic or localized deposition of misfolded amyloid proteins within the myocardial interstitium and valvular structures. The primary objective of this study was to employ three-dimensional speckle-tracking echocardiography (3DSTE) to perform a detailed analysis of [...] Read more.

Introduction. The etiology of cardiac amyloidosis (CA) involves the systemic or localized deposition of misfolded amyloid proteins within the myocardial interstitium and valvular structures. The primary objective of this study was to employ three-dimensional speckle-tracking echocardiography (3DSTE) to perform a detailed analysis of the aortic valve annulus (AVA) and left ventricular (LV) strains in CA patients and to compare these parameters with those of matched healthy controls. Methods. The initial cohort for this study comprised 35 individuals diagnosed with CA. However, 12 patients were subsequently excluded from the final analysis due to suboptimal image quality precluding accurate measurement of AVA dimensions and/or LV strains. The final analytical group, therefore, consisted of 23 CA patients (14 males), with a mean age of 64.6 ± 7.1 years. The results obtained from the CA patient group were compared with those of a healthy control cohort comprising 23 individuals (14 males; mean age: 53.2 ± 5.3 years). Results. In CA patients, AVA area was greater in end-diastole in 11 out of 23 cases (48%), and in end-systole in 8 out of 23 cases (35%), while it proved to be equal in 4 out of 23 cases (17%). The ratio of healthy controls with greater end-diastolic AVA area (12 out of 23, 52%) and greater end-systolic AVA area (11 out of 23, 48%) did not differ from that of CA patients. End-diastolic and end-systolic maximum and minimum AVA diameters, areas and perimeters did not differ between CA patients and matched controls. AVA plane systolic excursion (AAPSE) was found to be significantly impaired in all CA patients irrespective of AVA area size. Basal LV radial (RS), circumferential (CS) and longitudinal (LS) strains were reduced in CA patients compared with those of controls. End-systolic AVA dimensions tended to be reduced in CA patients with greater end-diastolic AVA area compared with those with greater end-systolic AVA area. While basal LV-RS and LV-CS proved to be similar between CA subgroups, basal LV-LS tended to be higher in CA patients with greater end-systolic AVA area. Controls with greater end-diastolic AVA area showed lower basal LV-RS and LV-LS compared with those with greater end-systolic AVA area. CA patients with equal end-diastolic and end-systolic AVA area (n = 4) showed similarly reduced AAPSE, basal LV-RS, basal LV-CS and LV-LS. Conclusions. In the presence of CA, the AVA is not dilated; however, its spatial displacement is reduced, suggesting its functional impairment, as represented by AAPSE, possibly due to the reduction in all concomitant LV strain parameters. Full article

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

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5 pages, 179 KB

Open AccessEditorial

New Advances in Cardiovascular Drugs: In Memory of Professor Akira Endo

by Alfredo Caturano

Biomedicines 2026, 14(2), 487; https://doi.org/10.3390/biomedicines14020487 - 23 Feb 2026

Viewed by 461

Abstract

In this Special Issue, we honor the memory of a giant within cardiovascular pharmacology, Professor Akira Endo, whose scientific vision profoundly transformed the prevention and treatment of cardiovascular disease [...] Full article

(This article belongs to the Special Issue New Advances in Cardiovascular Drugs: In Memory of Professor Akira Endo)

24 pages, 1601 KB

Open AccessReview

Heart Failure in the Molecular Era: Redefining Our Understanding of Disease Mechanisms and Perspectives

by Manuel Mallol-Simmonds, Alfredo Parra-Lucares, Ivan Canete, Cristian Avila, Josseline Pena-Silva and Sergio Bustamante

Biomedicines 2026, 14(2), 486; https://doi.org/10.3390/biomedicines14020486 - 23 Feb 2026

Viewed by 1170

Abstract

Heart failure (HF) is a global health challenge characterized by the heart’s inability to satisfy metabolic demands, driven by renin–angiotensin–aldosterone system (RAAS) overactivation, a neurohormonal imbalance, and emerging mechanisms like the gut–heart axis and mitochondrial dysfunction. Affecting over 6 million adults in the [...] Read more.

Heart failure (HF) is a global health challenge characterized by the heart’s inability to satisfy metabolic demands, driven by renin–angiotensin–aldosterone system (RAAS) overactivation, a neurohormonal imbalance, and emerging mechanisms like the gut–heart axis and mitochondrial dysfunction. Affecting over 6 million adults in the US alone, HF incurs a 5-year mortality rate of 50% and escalating costs projected to double by 2030. This review examines HF’s molecular paradigms, integrating established pathways with advances in omics, stem cell therapy, genetic modification, and personalized medicine. The RAAS blockade remains central, yet its efficacy is limited in HF with preserved ejection fraction (HFpEF). Stem cell therapies (mesenchymal and induced pluripotent stem cells) show regenerative potential but face poor retention (<10% survival at 30 days). CRISPR/Cas9 offers precision, though off-target effects persist. The gut microbiome, via trimethylamine N-oxide, exacerbates inflammation, while omics technologies promise biomarkers for tailored treatments. Challenges include translating these innovations into practice, particularly for HFpEF. Future directions involve novel HFpEF therapies, enhanced stem cell delivery, precise genetic tools, and microbiome interventions, supported with artificial intelligence. By 2030, these advances could shift HF management toward regeneration, contingent on overcoming translational barriers through global collaboration. Full article

(This article belongs to the Special Issue Heart Failure: New Diagnostic and Therapeutic Approaches)

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43 pages, 1997 KB

Open AccessReview

The Synthetic Extracellular Matrix as a Maestro of the In Vitro Stem Cell Niche: Orchestrating Fate and Function

by Subhajit Giri and Pratyush Rajesh

Biomedicines 2026, 14(2), 485; https://doi.org/10.3390/biomedicines14020485 - 23 Feb 2026

Viewed by 1577

Abstract

Human-induced pluripotent stem cells (hiPSCs) have an innate ability to differentiate into the three germ layers: the ectoderm, endoderm, and mesoderm. By using targeted differentiation methods and carefully controlling growth factors, morphogens, and signaling modulators, hiPSCs can be guided to develop into specific [...] Read more.

Human-induced pluripotent stem cells (hiPSCs) have an innate ability to differentiate into the three germ layers: the ectoderm, endoderm, and mesoderm. By using targeted differentiation methods and carefully controlling growth factors, morphogens, and signaling modulators, hiPSCs can be guided to develop into specific lineage cell types. For clinical applications of hiPSCs and their derivatives, it is crucial to use xenogen-free, chemically defined culture media, reagents, recombinant growth factors, morphogens, and extracellular matrix (ECM) scaffolds. One major obstacle is the widespread use of Matrigel as an hiPSC culture matrix. Matrigel, derived from Engelbreth–Holm–Swarm (EHS) mouse sarcoma, is an extract of basement membrane material with a complex, poorly defined, and variable composition. It also exhibits batch-to-batch variability in mechanical and biochemical properties and is difficult to modify, which limits its rational use in the production of therapeutic cells and organoids. Synthetic ECM matrices and scaffolds offer a promising alternative because they can have a fully defined composition, highly tunable physical properties, surface modifications, and functionalization with recombinant signaling peptides and growth factors. This provides a suitable microenvironment for hiPSC culture and the directed differentiation towards lineage-specific cells and organoid development, and can be used in clinical-grade tissue transplantation and regenerative medicine. Full article

(This article belongs to the Special Issue Human Stem Cells in Disease Modelling and Treatment (2nd Edition))

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17 pages, 6236 KB

Open AccessArticle

Identification and Validation of Signature Genes in Invasiveness-Associated Modules of Nonfunctioning Pituitary Adenomas

by Xin Ma, Hongyu Wu, Yu Zhang, Zhijun Yang and Pinan Liu

Biomedicines 2026, 14(2), 484; https://doi.org/10.3390/biomedicines14020484 - 23 Feb 2026

Viewed by 502

Abstract

Background: Invasive non-functional pituitary adenomas (NFPAs) are associated with high recurrence and unfavorable clinical outcomes, yet their underlying molecular mechanisms remain incompletely understood. This study aimed to identify robust biomarkers of invasiveness by integrating transcriptional networks, machine learning, and epigenetic regulation. Methods: RNA [...] Read more.

Background: Invasive non-functional pituitary adenomas (NFPAs) are associated with high recurrence and unfavorable clinical outcomes, yet their underlying molecular mechanisms remain incompletely understood. This study aimed to identify robust biomarkers of invasiveness by integrating transcriptional networks, machine learning, and epigenetic regulation. Methods: RNA sequencing was performed on 32 NFPA samples (15 invasive, 17 non-invasive). Weighted gene co-expression network analysis (WGCNA) was used to identify invasiveness-associated modules, which were validated in public datasets (GSE169498, GSE51618). Candidate genes were prioritized using machine learning, and their epigenetic regulation was studied using DNA methylation datasets (GSE207937, GSE115783). Results: We identified a five-gene signature associated with invasiveness (KIFC3, PNMA3, ARHGAP18, LRRC10B, and KCNC4). All five genes were consistently downregulated in invasive NFPAs (all p < 0.01) and were enriched in oxidative phosphorylation and neuroactive ligand–receptor interaction pathways. A machine learning validation approach (Random Forest followed by forward stepwise logistic regression) showed strong discriminative performance for this signature (mean AUC = 0.919). DNA methylation analyses indicated no robust differences at the genome-wide level or across promoter regions of the core genes; nevertheless, several locus-specific CpG sites (e.g., near KIFC3) showed suggestive methylation changes. Conclusions: Using an integrative multi-omics framework, we identified a novel five-gene signature associated with NFPA invasiveness. The coordinated downregulation of these genes may reflect alterations in cellular energy metabolism and microenvironmental signaling. Although the signature demonstrated promising diagnostic potential, its transcriptional repression is unlikely to be primarily explained by DNA methylation. These findings provide candidate markers and mechanistic hypotheses for understanding invasive NFPA and developing risk-stratification tools. Full article

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

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21 pages, 1696 KB

Open AccessArticle

Aortic Elastic Properties and Albumin-Based Inflammatory Indices in Dyspneic Third-Trimester Pregnant Women: A Prospective Observational Study

by Birsen Ertekin, Hatice Eyiol, Azmi Eyiol, Fatih İkiz and Rukiye Ozcelik Tepe

Biomedicines 2026, 14(2), 483; https://doi.org/10.3390/biomedicines14020483 - 22 Feb 2026

Viewed by 464

Abstract

Background: Dyspnea is a frequent complaint during pregnancy and is often considered a benign physiological finding; however, it may also reflect underlying subclinical cardiovascular alterations. Pregnancy-related vascular remodeling and low-grade systemic inflammation may contribute to changes in aortic elastic properties and inflammatory biomarkers, [...] Read more.

Background: Dyspnea is a frequent complaint during pregnancy and is often considered a benign physiological finding; however, it may also reflect underlying subclinical cardiovascular alterations. Pregnancy-related vascular remodeling and low-grade systemic inflammation may contribute to changes in aortic elastic properties and inflammatory biomarkers, particularly in symptomatic women. Objective: This study aimed to compare aortic elastic properties and albumin-based inflammatory indices between dyspneic and asymptomatic third-trimester pregnant women. A secondary aim was to establish reference values for echocardiographic and biomarker parameters in dyspneic pregnancy. Methods: In this prospective observational study, third-trimester pregnant women (≥27 gestational weeks) presenting to the emergency department (ED) with dyspnea were consecutively enrolled and compared with age-matched asymptomatic pregnant controls. Demographic, laboratory, and echocardiographic data were recorded. Aortic strain, aortic distensibility, and aortic stiffness were calculated using transthoracic echocardiography. Albumin-based inflammatory indices, including the hemoglobin–albumin–lymphocyte–platelet (HALP) score, prognostic nutritional index (PNI), C-reactive protein-to-albumin ratio (CAR), and RDW-to-albumin ratio (RAR), were analyzed. Receiver operating characteristic (ROC) and correlation analyses were performed. Results: A total of 241 pregnant women were included (121 dyspneic, 120 controls). Demographic characteristics were comparable between groups. Dyspneic pregnant women exhibited significantly lower aortic strain and aortic distensibility and higher aortic stiffness compared with controls (for all p < 0.05). Among laboratory parameters, CAR levels were significantly elevated in the dyspneic group (p < 0.001), whereas HALP, PNI, and RAR did not differ significantly. After adjustment for potential confounders, differences in aortic elastic properties remained significant. CAR demonstrated moderate discriminative ability for dyspnea (AUC = 0.692), while aortic elastic parameters showed modest predictive performance. In combined prediction models incorporating CAR with echocardiographic parameters, discriminatory performance improved, with area under the curve values exceeding 0.70. Weak positive correlations were observed between PNI and aortic strain and distensibility. Conclusions: Dyspneic third-trimester pregnant women exhibit impaired aortic elastic properties and increased CAR levels, suggesting the presence of subclinical vascular and inflammatory alterations. Assessment of aortic elasticity and CAR may provide a simple and practical approach for early cardiovascular risk stratification in symptomatic pregnancy, particularly in ED settings. Further multicenter studies with longitudinal follow-up are warranted to clarify their prognostic significance. Full article

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

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29 pages, 847 KB

Open AccessReview

Focusing on Prostate-Specific Membrane Antigen in Precision Diagnosis and Treatment of Prostate Cancer

by Xinyi Ren, Lingling Zhang, Ran An, Hongchen Song, Mingjun Shi and Zhenchang Wang

Biomedicines 2026, 14(2), 482; https://doi.org/10.3390/biomedicines14020482 - 22 Feb 2026

Viewed by 949

Abstract

Prostate cancer (PCa) is the most common malignant tumor of the male genitourinary system, and its incidence and mortality have shown a marked global increase in recent years. Prostate-specific membrane antigen (PSMA), a type II transmembrane glycoprotein highly expressed in PCa cells, has [...] Read more.

Prostate cancer (PCa) is the most common malignant tumor of the male genitourinary system, and its incidence and mortality have shown a marked global increase in recent years. Prostate-specific membrane antigen (PSMA), a type II transmembrane glycoprotein highly expressed in PCa cells, has emerged as a vital molecular target in the field of PCa precision diagnosis and therapy. In recent years, significant advances have been achieved in PSMA-based molecular imaging, radioligand therapy, and the development of novel targeted drugs. This review aims to summarize and critically discuss recent advances in PSMA-targeted molecular imaging, radioligand therapy, and emerging therapeutic strategies, highlighting their roles in precision diagnosis and personalized treatment of PCa. PSMA positron emission tomography/computed tomography (PET/CT) imaging using radionuclides such as ⁶⁸Ga and ¹⁸F has markedly improved the accuracy of primary tumor staging, localization of recurrent lesions, and therapeutic response assessment. Radioligand therapies, such as ¹⁷⁷Lu-PSMA-617 and ²²⁵Ac-PSMA-617, have prolonged survival and demonstrated symptomatic benefits in multiple clinical trials, and are now applied in early disease stages, including chemotherapy-naïve and hormone-sensitive settings. Meanwhile, PSMA-targeted antibodies and antibody–drug conjugates (PSMA-ADCs), as well as bispecific T-cell engagers (BiTEs) and chimeric antigen receptor T-cell (CAR-T) therapies, are constantly being optimized and show promising clinical potential. Furthermore, PSMA-targeted nanoplatforms enable precise delivery of chemotherapeutic agents, photosensitizers, or imaging probes, achieving integrated diagnosis and therapy with multimodal imaging guidance, and offering new strategies for individualized treatment. Taken together, the evidence summarized in this review highlights PSMA as a pivotal molecular target supporting precision diagnosis and personalized treatment across the continuum of prostate cancer management. Full article

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

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14 pages, 6808 KB

Open AccessArticle

Effect of Vitamin D3 on Transected and Crushed Injuries in Rat Sciatic Nerve Healing

by Inanc Dogan Cicek, Handan Derebasinlioglu, Ayse Demirkazik and Hatice Reyhan Egilmez

Biomedicines 2026, 14(2), 481; https://doi.org/10.3390/biomedicines14020481 - 22 Feb 2026

Viewed by 509

Abstract

Background: Peripheral nerve injury can happen for a variety of causes. Despite major breakthroughs in microsurgery, nerve repair results are not always sufficient. Methods: Thirty-two Wistar albino rats were split into four groups: primary nerve repair (PNR), PNR with vitamin D3 treatment, nerve [...] Read more.

Background: Peripheral nerve injury can happen for a variety of causes. Despite major breakthroughs in microsurgery, nerve repair results are not always sufficient. Methods: Thirty-two Wistar albino rats were split into four groups: primary nerve repair (PNR), PNR with vitamin D3 treatment, nerve crush injury (NCI), and NCI with vitamin D3 treatment. In the PNR + D3 and NCI + D3 groups, 1 mcg/kg of vitamin D3 was given intraperitoneally on days 1, 3, 5, and 7 of the 12-week healing period. Electrophysiological measurements were taken prior to the injury. At 12 weeks after damage, a hot plate test was performed to assess acute pain, and the electrophysiological measurements were repeated. Before the rats were sacrificed, biopsy samples from the right sciatic nerve were collected for histopathological evaluation. Results: Post-healing action potential values were not statistically different between the PNR and PNR + D3 groups; however, they were considerably lower in the NCI + D3 group than in the NCI group. The reaction time in the hot plate test was considerably slower in the D3-treated groups compared to the control groups. Histopathology score was substantially higher in the PNR + D3 group as compared to the PNR group, and lower in the NCI + D3 group as compared to the NCI group. Conclusions: Other than improved myelination, vitamin D3 treatment following primary repair of transected nerves produced no statistically significant improvement. Vitamin D3 treatment caused a negative impact on the crush injury, as assessed by the findings of histopathology and electrophysiological measurements. Overall, the results indicate that the efficacy of vitamin D3 treatment may vary depending on the type of injury. Full article

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

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24 pages, 1286 KB

Open AccessReview

Periodontitis-Induced Immune Reprogramming: Implications for Cancer Immunotherapy Response

by Claudia Florina Bogdan-Andreescu, Ștefan-Dimitrie Albu, Dan Alexandru Slăvescu, Lucia Bubulac, Viorica Tudor, Oana Botoacă, Andreea-Mariana Bănățeanu, Emin Cadar and Cristina-Crenguţa Albu

Biomedicines 2026, 14(2), 480; https://doi.org/10.3390/biomedicines14020480 - 22 Feb 2026

Viewed by 827

Abstract

Background: Chronic periodontitis is a prevalent inflammatory disease. It goes beyond the oral cavity, exerting systemic immunomodulatory effects through continuous low-grade inflammation, microbial dysbiosis, and cytokine spillover. Accumulating evidence suggests that the immunological consequences of periodontitis may influence systemic immune homeostasis and alter [...] Read more.

Background: Chronic periodontitis is a prevalent inflammatory disease. It goes beyond the oral cavity, exerting systemic immunomodulatory effects through continuous low-grade inflammation, microbial dysbiosis, and cytokine spillover. Accumulating evidence suggests that the immunological consequences of periodontitis may influence systemic immune homeostasis and alter responses to cancer immunotherapies, specifically checkpoint blockade. Objectives: This narrative review describes how periodontal inflammation induces systemic immune reprogramming. It also investigates possible effects on the efficacy of immunotherapy. Methods: The paper synthesizes current findings on molecular and cellular mechanisms linking periodontitis to immune dysfunction. It underscores the mutual signaling pathways NF-κB, STAT3, and PD-1/PD-L1 that connect oral and systemic immunity. Results: Chronic periodontal inflammation reprograms innate and adaptive immune responses. It elevates proinflammatory mediators, such as IL-1β, IL-6, and TNF-α. It alters T-cell polarization and promotes myeloid cell “training”. This process may lead to immune exhaustion, impaired antigen presentation, and treatment resistance. Preclinical and new clinical data suggest that controlling periodontal inflammation may partially reduce systemic inflammatory burden, although clinical evidence in immunotherapy-treated cancer cohorts remains limited. Conclusions: Periodontal health should be considered in the management of immunotherapy. This can facilitate new studies that integrate oral and systemic immunology. Understanding the two-way link between periodontal inflammation and systemic immune reprogramming may offer fresh opportunities for personalized immunomodulation and combined interventions. Full article

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

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16 pages, 1854 KB

Open AccessArticle

Sepsis Diagnosis in the Intensive Care Unit: A Comparative Study of Rapid Molecular Diagnostics and Conventional Blood Cultures

by Dragana Unic-Stojanovic, Nikolina Kangrga, Ivana Cirkovic, Irina Malesevic, Ivana Djokovic Mrdakovic, Jovan Petrovic and Milovan Bojic

Biomedicines 2026, 14(2), 479; https://doi.org/10.3390/biomedicines14020479 - 22 Feb 2026

Viewed by 635

Abstract

Background: Sepsis remains a leading cause of morbidity and mortality worldwide, where timely and accurate pathogen detection is critical for improved outcomes. Conventional blood cultures are the gold standard but are limited by prolonged turnaround times and suboptimal sensitivity, often delaying targeted therapy. [...] Read more.

Background: Sepsis remains a leading cause of morbidity and mortality worldwide, where timely and accurate pathogen detection is critical for improved outcomes. Conventional blood cultures are the gold standard but are limited by prolonged turnaround times and suboptimal sensitivity, often delaying targeted therapy. Methods: This single-center retrospective study evaluated the diagnostic performance and clinical utility of the T2Bacteria and T2Resistance Panels compared with conventional blood cultures in 30 adult patients admitted to the cardiovascular intensive care unit with a suspected bloodstream infection. Results: The T2Bacteria Panel demonstrated high diagnostic accuracy for on-panel organisms (100%), detecting all cases of Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa, while blood cultures detected 9 of 12 on-panel infections. In contrast, two off-panel organisms were isolated from five patients exclusively by blood cultures, highlighting the complementary roles of both methods. Importantly, antimicrobial therapy was modified in 6 of 10 T2-positive patients (60%) based on T2 results, preceding blood culture reporting by a median of more than 100 h. Conclusions: These findings underscore the value of T2 assays in enabling earlier, evidence-based therapeutic decisions and supporting antimicrobial stewardship. While limited by the sample size and single-center design, these findings—consistent with pathogen distributions reported in European ICU settings—suggest that integrating T2-based diagnostics into cardiovascular ICU workflows may enhance early therapeutic decision-making and antimicrobial stewardship. Full article

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

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17 pages, 319 KB

Open AccessArticle

Genetic, Sociodemographic and Clinical Determinants of COVID-19 Severity in the Republic of Srpska: Exploring Potential Links with Neanderthal-Derived Variants

by Milena Dubravac Tanasković, Biljana Mijović, Jovan Kulić, Bojan Joksimović, Kristina Drašković-Mališ, Srđan Mašić, Jelena Vladičić-Mašić, Ljiljana Krsmanović, Danijela Radulović and Nikolina Elez-Burnjaković

Biomedicines 2026, 14(2), 478; https://doi.org/10.3390/biomedicines14020478 - 22 Feb 2026

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Abstract

Background/Objectives: COVID-19 severity is influenced by a complex interplay between host, viral, and environmental factors. Emerging evidence suggests that Neanderthal-derived genetic variants may influence the progression and severity of SARS-CoV-2 infection. This study aimed to evaluate the association between selected Neanderthal-derived variants and [...] Read more.

Background/Objectives: COVID-19 severity is influenced by a complex interplay between host, viral, and environmental factors. Emerging evidence suggests that Neanderthal-derived genetic variants may influence the progression and severity of SARS-CoV-2 infection. This study aimed to evaluate the association between selected Neanderthal-derived variants and COVID-19 severity in the population of the Republic of Srpska, considering relevant clinical, sociodemographic, and lifestyle factors. Methods: This multicentric cross-sectional study included 402 participants, classified as healthy or SARS-CoV-2-positive individuals. A total of 378 COVID-19-positive participants were further stratified according to disease severity and hospitalization status. All individuals were genotyped for the Neanderthal-derived OAS3 rs1156361 (C/T) and LZTFL1 rs35044562 (A/G) variants. Detailed sociodemographic, clinical, and lifestyle data were also collected. Results: A higher frequency of the LZTFL1 rs35044562 AG genotype was observed among hospitalized patients compared with non-hospitalized individuals (36.8% vs. 20.9%; p = 0.005), while the AA genotype was more prevalent among non-hospitalized patients (77.3% vs. 63.2%, p = 0.015). Multivariable logistic analysis showed that carriers of the LZTFL1 AG genotype had a higher chance of hospitalization compared to AA carriers (adjusted OR = 1.372, 95% CI = 0.763–6.383, and p = 0.021). Hospitalized patients more frequently carried the combined CT (OAS3) and AG (LZTFL1) genotypes, supporting a potential synergistic effect. Several sociodemographic factors, including age, sex, education, employment, and urban residence, were also associated with COVID-19 severity, while no significant associations were observed in allele-based analyses. Conclusions: LZTFL1 gene polymorphisms may influence COVID-19 severity, with heterozygote-specific and combined risk effects observed. These preliminary findings are exploratory and require validation in larger cohorts, but may guide future studies and targeted interventions in high-risk groups. Full article

(This article belongs to the Special Issue Oxidative Stress, Inflammation and Endothelial Dysfunction in COVID-19 Era and Long COVID-19 Complications)

15 pages, 2995 KB

Open AccessArticle

Increased Cerebral Vein Diameters Are Associated with Age and White Matter Hyperintensity

by Gokhan Duygulu and Fulya Kahraman

Biomedicines 2026, 14(2), 477; https://doi.org/10.3390/biomedicines14020477 - 21 Feb 2026

Viewed by 513

Abstract

Objective: White matter hyperintensity (WMH) is one of the most common and prominent changes seen in elderly individuals, especially on MRI. WMH is associated with serious conditions such as hemorrhagic and ischemic stroke, depression and dementia. Recently, the relationship between cerebral venous diameter [...] Read more.

Objective: White matter hyperintensity (WMH) is one of the most common and prominent changes seen in elderly individuals, especially on MRI. WMH is associated with serious conditions such as hemorrhagic and ischemic stroke, depression and dementia. Recently, the relationship between cerebral venous diameter and WMH was described. This study aimed to investigate the relationship between the Fazekas scale, which evaluates the severity of WMH, and cerebral vein diameters, age and clinical outcomes analysis. Materials and Methods: MRI images of 660 patients were examined retrospectively. FLAIR and SWI (MiniP) images were used to evaluate WMH and cerebral vein diameters. Internal cerebral veins (ICV), thalamostriate veins (TSV), anterior septal veins (ASV) and superior sagittal sinus (SSS) diameters were measured. Cerebral vein diameters were compared with age, WMH, hypertension, hyperlipidemia, diabetes mellitus, lacunar infarct and microhemorrhage presence. Results: In the presence of hypertension, hyperlipidemia, diabetes, lacunar infarction and microhemorrhage, Fazekas score, mean ICV-right, ICV-left, ASV-right, ASV-left, TSV-right and TSV-left values were significantly higher. The mean ICV-right, ICV-left, ASV-right, ASV-left, TSV-right and TSV-left values of the middle-aged and elderly groups were significantly higher than the young group. A strong positive correlation was observed between age and mean ICV-right, ICV-left, ASV-right and ASV-left values, while a moderate positive correlation was shown with TSV-right and TSV-left values. A weak negative correlation was determined with SSS values. Conclusions: Cerebral vein diameter increases with age and is associated with the severity of WMH. Clinicians can monitor cerebral vein diameter to predict the severity of WMH. Full article

(This article belongs to the Special Issue Modern Applications of Advanced Imaging to Neurological Disease)

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31 pages, 1766 KB

Open AccessReview

Opioid Receptors in Psychedelia: Indirect Serotonergic Modulation of Direct KOR Activation by Salvinorin A

by Maximiliano Ganado, Carmen Rubio, Javier Pérez-Villavicencio, Norma Serrano, Héctor Romo-Parra, Ángel Lee and Moisés Rubio-Osornio

Biomedicines 2026, 14(2), 476; https://doi.org/10.3390/biomedicines14020476 - 21 Feb 2026

Viewed by 2675

Abstract

The neuropharmacology of psychedelics has traditionally focused on serotonergic mechanisms, particularly 5-HT2A receptor activation. However, this paradigm incompletely explains the diversity of neurobiological and therapeutic effects observed across psychedelic compounds. Non-classical psychedelics such as salvinorin A, the primary active constituent of Salvia divinorum [...] Read more.

The neuropharmacology of psychedelics has traditionally focused on serotonergic mechanisms, particularly 5-HT2A receptor activation. However, this paradigm incompletely explains the diversity of neurobiological and therapeutic effects observed across psychedelic compounds. Non-classical psychedelics such as salvinorin A, the primary active constituent of Salvia divinorum, challenge this framework through direct kappa opioid receptor (KOR) agonism, representing a serotonin-independent pathway to altered consciousness. This review systematically examines the role of the endogenous opioid system in mediating psychedelic effects, with emphasis on salvinorin A’s unique KOR-dependent mechanisms. We synthesized preclinical and clinical evidence from in vitro studies, genetically modified animal models, optogenetic circuit dissection, and human neuroimaging trials. Salvinorin A’s selective KOR activation is characterized by pronounced β-arrestin-biased signaling, distinguishing it from endogenous dynorphins and classical KOR agonists. This produces rapid receptor desensitization, transient functional plasticity, and profound dissociative effects mediated through thalamocortical disruption, mesolimbic dopaminergic suppression, and fragmentation of large-scale brain networks. Classical serotonergic psychedelics indirectly engage opioid systems through downstream 5-HT2A signaling, contributing to analgesic and mood-regulatory effects via secondary MOR/DOR modulation. Despite being a potent opioid agonist, salvinorin A exhibits low abuse potential due to aversive phenomenology, dopaminergic suppression, and absence of positive reinforcement in animal models. Incorporating opioid receptor pharmacology into psychedelic neuroscience expands mechanistic understanding beyond serotonin-centric models, revealing multiple neurochemical pathways capable of inducing therapeutically relevant altered states. This framework enables rational development of biased KOR ligands and establishes salvinorin A as a paradigmatic model for non-serotonergic psychedelia with applications in treatment-resistant depression, addiction, and chronic pain. Full article

(This article belongs to the Special Issue Dopamine Signaling Pathway in Health and Disease—2nd Edition)

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25 pages, 1103 KB

Open AccessSystematic Review

Mesenchymal Stem Cell-Based Therapies Applied in Neurological Diseases: A Systematic Review

by Ana Trabulo, Patrícia Sousa, Rui Alvites and Ana Colette Maurício

Biomedicines 2026, 14(2), 475; https://doi.org/10.3390/biomedicines14020475 - 21 Feb 2026

Cited by 1 | Viewed by 1232

Abstract

Background/Objectives: Neurodegenerative diseases (NDs) have a severe impact on patients’ quality of life, and effective treatments remain limited. As the focus is on treating the symptoms, the root cause of the problem is commonly not addressed. Mesenchymal stem cells show an emerging [...] Read more.

Background/Objectives: Neurodegenerative diseases (NDs) have a severe impact on patients’ quality of life, and effective treatments remain limited. As the focus is on treating the symptoms, the root cause of the problem is commonly not addressed. Mesenchymal stem cells show an emerging potential due to the ability for self-renewal combined with their capability for differentiation into various cell lines, which makes them a strong candidate for regenerative therapies in general, and for application in neurological issues in particular. This article provides an overview of the safety, efficacy, and challenges associated with the use of mesenchymal stem cells (MSCs) and their derived secretome in clinical and preclinical models of Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS). Methods: A systematic search was conducted on PubMed to identify published studies providing clinical and preclinical evidence on the use of MSCs in neurodegenerative disorders. Results: Overall, the literature consistently indicates that MSCs and their derivatives exert disease-modifying effects across multiple NDs. Across AD, PD, HD and ALS, preclinical studies uniformly report improvements in behavioural outcomes, attenuation of neuroinflammation, and neuroprotective effects, largely mediated by MSCs’ paracrine signalling rather than direct cell replacement. Clinical studies to date consistently support the safety and feasibility of MSC-based therapies, while efficacy signals remain modest, heterogeneous and predominantly short-term, highlighting the need for larger, well-controlled trials. Conclusions: Integration of genetic engineering, preconditioning, and EV technology may represent an emerging therapeutic approach that may complement existing neuroregeneration treatments, offering a scalable and minimally invasive frontier to improve long-term clinical outcomes in patients with AD, PD, HD, and ALS. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Neurodegenerative Diseases (3rd Edition))

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16 pages, 4455 KB

Open AccessArticle

Nano-Structural Characterization of Human Aponeurotic Tissue by Atomic Force Microscopy

by Adelina Tanevski, Andreea Ludușanu, Bogdan Mihnea Ciuntu, Balan Gheorghe, Ștefan Octavian Georgescu, Valentin Bernic, Raoul-Vasile Lupușoru, Delia Gabriela Ciobanu Apostol, Ștefan Lucian Toma and Cristian Dumitru Lupașcu

Biomedicines 2026, 14(2), 474; https://doi.org/10.3390/biomedicines14020474 - 21 Feb 2026

Viewed by 513

Abstract

Background: The structural integrity of the abdominal wall is critically dependent on the organization of aponeurotic tissue, a dense collagen-rich connective structure responsible for directional force transmission. While the clinical relevance of the aponeurosis is well recognized in abdominal wall reconstruction, its nano-scale [...] Read more.

Background: The structural integrity of the abdominal wall is critically dependent on the organization of aponeurotic tissue, a dense collagen-rich connective structure responsible for directional force transmission. While the clinical relevance of the aponeurosis is well recognized in abdominal wall reconstruction, its nano-scale structural organization remains insufficiently characterized. Atomic force microscopy (AFM) provides a suitable approach for investigating surface morphology and nano-architectural features of biological tissues. Methods: Human aponeurotic tissue samples were analyzed using atomic force microscopy operated in contact-mode deflection and topography imaging. Two-dimensional and three-dimensional surface topographies were acquired at the micrometer scale to assess nano-architectural organization. Areal surface roughness parameters (Sa, Sq, Sp, Sv, Sy) were calculated to quantify morphological heterogeneity. AFM deflection imaging was used to evaluate relative spatial variations in deflection imaging contrast under the applied scanning conditions across collagen-dense and interfibrillar regions. Results: AFM analysis revealed a well-organized fibrillar architecture with preferential orientation, consistent with the anisotropic organization of aponeurotic connective tissue. Deflection images demonstrated spatial heterogeneity in deflection contrast at the scanned scale, reflecting variations in the tip–sample interaction signal between collagen-dense and interfibrillar regions. Surface topography showed a continuous morphology with moderate height variations and smooth transitions between structural elements. Roughness parameters reflected a compact extracellular matrix organization within the scanned areas, without features suggestive of surface disruption. Conclusions: Atomic force microscopy enables detailed nano-scale structural characterization of human aponeurotic tissue and reveals spatial heterogeneity in deflection imaging contrast under specific contact-mode scanning conditions. These findings provide a baseline nano-scale descriptive reference dataset for macroscopically normal aponeurotic tissue, supporting future comparative investigations without implying validated mechanical differences or direct tissue–implant interaction analysis within the present study. Full article

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

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17 pages, 411 KB

Open AccessArticle

Exercise-Associated Changes in Body Composition and Metabolic Biomarkers Following an Eight-Week Submaximal Exercise Program in Women Across Different BMI Categories and with Type 2 Diabetes

by Kıvanç Buru, Vedat Çınar, Taner Akbulut, Mehdi Aslan, Meva Ceren Orgun, Fidan Çınar, Orhan Uluçay and Do-Youn Lee

Biomedicines 2026, 14(2), 473; https://doi.org/10.3390/biomedicines14020473 - 21 Feb 2026

Viewed by 614

Abstract

Background/Objectives: This study evaluated exercise-induced changes in body composition and metabolic biomarkers in women across distinct BMI categories and individuals with Type 2 diabetes. Methods: In this quasi-experimental study, 40 sedentary women were stratified into five groups (n = 8): [...] Read more.

Background/Objectives: This study evaluated exercise-induced changes in body composition and metabolic biomarkers in women across distinct BMI categories and individuals with Type 2 diabetes. Methods: In this quasi-experimental study, 40 sedentary women were stratified into five groups (n = 8): underweight, normal weight, overweight, obese, and T2DM. The rigorous eight-week supervised program utilized submaximal exercise at 70–85% heart rate reserve, calculated via the Karvonen method and monitored by telemetry. Assessments included anthropometric parameters (BMI, fat mass, visceral fat) and serum biomarkers (irisin, myonectin, HIF-1α, insulin, glucose). Fasting venous samples were collected at baseline and 72 h post-intervention to minimize acute effects, then analyzed using validated ELISA protocols. Statistical data were evaluated using parametric or non-parametric tests with significance set at p < 0.05. Results: Post-intervention, significant reductions in weight, fat mass, and visceral fat occurred in overweight, obese, and T2DM groups (p < 0.05). Muscle mass increased across all cohorts. Fasting insulin and glucose decreased significantly in all except the underweight group, with the most pronounced improvements in T2DM and obese participants. Serum irisin increased significantly across all groups (p < 0.05), indicating a universal exercise-induced myokine response. Conversely, myonectin levels decreased significantly only in the normal-weight group, while HIF-1α increased specifically in the T2DM cohort. These findings suggest that baseline BMI and metabolic status are critical determinants of exercise responsiveness, leading to heterogeneous biomarker patterns despite consistent improvements in body composition and basic glycemic regulation. Conclusions: An eight-week submaximal program effectively improves body composition and glycemic regulation, though specific biomarker responses are highly dependent on baseline BMI and metabolic status. Full article

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

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17 pages, 1759 KB

Open AccessArticle

Potential Involvement of Ferroptosis in Duchenne Muscular Dystrophy-Associated Cardiomyopathy

by Nadezhda Fefelova, Sri Harika Pamarthi, Satvik Mareedu, Andreas Ivessa, Diego Fraidenraich, Gopal J. Babu, Judith K. Gwathmey and Lai-Hua Xie

Biomedicines 2026, 14(2), 472; https://doi.org/10.3390/biomedicines14020472 - 21 Feb 2026

Viewed by 840

Abstract

Background/Objectives: Cardiomyopathy (CM) is a leading cause of morbidity and mortality in Duchenne muscular dystrophy (DMD) patients. Ferroptosis, an iron-dependent form of cell death characterized by lipid peroxidation, is implicated in various cardiovascular diseases. However, the role of ferroptosis in DMD-CM remains unexplored. [...] Read more.

Background/Objectives: Cardiomyopathy (CM) is a leading cause of morbidity and mortality in Duchenne muscular dystrophy (DMD) patients. Ferroptosis, an iron-dependent form of cell death characterized by lipid peroxidation, is implicated in various cardiovascular diseases. However, the role of ferroptosis in DMD-CM remains unexplored. Methods: Here, we used dystrophin and utrophin double-knockout (mdx:utr^−/−) mice as a model that exhibits cardiac pathological phenotypes similar to those seen in DMD patients to investigate the potential role of ferroptosis. Results: We observed an increased level of iron deposition and lipid peroxidation in the hearts of mdx:utr^−/− mice. Live/Dead viability assays revealed that mdx:utr^−/− cardiomyocytes exhibited greater susceptibility to ferroptosis than WT cardiomyocytes both at baseline and upon exposure to ferroptosis inducers. We also used mdx:utr^−/− mice with a heterozygous sarcolipin (SLN) knockout background (sln^+/−) to investigate the effect of SLN reduction on ferroptosis susceptibility in DMD-CM. Notably, ferroptosis was significantly suppressed in cardiomyocytes from mdx:utr^−/−:sln^+/− mice (p < 0.01). Western blot analysis confirmed the upregulation of transferrin receptor 1 (TfR1) and 15-lipoxygenase-1 (15LOX1), along with the downregulation of heme oxygenase-1 (HMOX-1) and ferroptosis suppressor protein 1 (FSP1) in mdx:utr^−/− hearts, while glutathione peroxidase 4 (GPX4) levels remained unchanged. A similar pattern of alterations in ferroptosis-related biomarkers was observed in human heart samples from DMD patients compared to healthy controls. Conclusions: Our results provide direct evidence that ferroptosis contributes to the pathology of DMD-CM and suggest that reducing SLN expression and inhibiting ferroptosis may represent potential therapeutic strategies for this condition. Full article

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

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21 pages, 12003 KB

Open AccessArticle

CRISP3, a Potential Tumor Suppressor, Inhibits the Progression of High-Grade Serous Ovarian Carcinoma by Modulating the PI3K/AKT Pathway

by Mingjun Ma, Xiu Tian, Weiwei Cao, Chao Wang, Yue Zhang, Jiani Yang, Shanshan Cheng, Sijia Gu, Jianxiao Li, Yaqian Zhao, Yaodi Shao, Chao Huang, Shuo Shi, Renhao Xue, Chen Chu, Jindan Sheng and Yu Wang

Biomedicines 2026, 14(2), 471; https://doi.org/10.3390/biomedicines14020471 - 20 Feb 2026

Viewed by 744

Abstract

Background: Ovarian cancer (OC) remains the most common cause of gynecological cancer-related death, and about 70% of these deaths are from advanced high-grade serous ovarian cancer (HGSOC). Cysteine-rich secretory protein 3 (CRISP3) is related to various human diseases; however, the roles and [...] Read more.

Background: Ovarian cancer (OC) remains the most common cause of gynecological cancer-related death, and about 70% of these deaths are from advanced high-grade serous ovarian cancer (HGSOC). Cysteine-rich secretory protein 3 (CRISP3) is related to various human diseases; however, the roles and mechanisms of CRISP3 in HGSOC remain unclear. Methods: The clinical significance of CRISP3 in patients with OC was analyzed using the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases. CRISP3 expression in OC tissues was validated by RNA-sequencing (RNA-seq), quantitative PCR, and immunohistochemistry. Furthermore, we explored the effect of CRISP3 expression modulation on the biological behavior of HGSOC through CCK-8, EdU, and Transwell assays in vitro, and the differences in CRISP3 during the progression of HGSOC in vivo. We utilized RNA-seq, GSEA and Western blotting to detect CRISP3’s regulatory mechanisms. Finally, we employed data from the IMvigor210 cohort and TCGA to assess the correlation of CRISP3 with clinical response to immunotherapy, and the landscape of immune cell infiltration. Results: CRISP3 expression was markedly reduced in HGSOC. In vitro studies demonstrated that CRISP3 knockdown significantly enhanced proliferation, migration, and invasion of HGSOC cells, whereas its overexpression suppressed these malignant phenotypes. Moreover, CRISP3 expression was found to be downregulated during OC progression in vivo. Mechanistically, CRISP3 acted as a tumor suppressor through the PI3K/AKT signaling pathway to inhibit the progression and metastasis of HGSOC. Additionally, we observed an association between CRISP3 expression and CD8⁺ T cell, macrophage, neutrophil and Th1 cell infiltration. Conclusions: We demonstrate that CRISP3 suppresses tumorigenesis in HGSOC by regulating the PI3K/AKT pathway, and that alterations in its expression correlate with disease progression, supporting its utility as a biomarker. Full article

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

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12 pages, 872 KB

Open AccessArticle

Possible Effects of Topical Rho-Kinase Inhibitor on Schlemm’s Canal Morphology Parameters

by Aysha Siddika Mukta, Aika Tsutsui, Teruhiko Hamanaka, Sachiko Kaidzu, Kanae Kobayashi, Nobuo Ishida and Masaki Tanito

Biomedicines 2026, 14(2), 470; https://doi.org/10.3390/biomedicines14020470 - 20 Feb 2026

Viewed by 685

Abstract

Background: To evaluate the effects of preoperative topical ripasudil, a Rho-associated protein kinase (ROCK) inhibitor, on Schlemm’s canal (SC) morphology in patients with primary open-angle glaucoma (POAG). Methods: This study included 95 SC specimens obtained during trabeculectomy from 95 patients with [...] Read more.

Background: To evaluate the effects of preoperative topical ripasudil, a Rho-associated protein kinase (ROCK) inhibitor, on Schlemm’s canal (SC) morphology in patients with primary open-angle glaucoma (POAG). Methods: This study included 95 SC specimens obtained during trabeculectomy from 95 patients with POAG. Based on preoperative treatment, patients were divided into two groups: ripasudil (−) group (n = 68) receiving four topical medications [FP receptor agonist, β-blocker, carbonic anhydrase inhibitor (CAI), and α₂ agonist], and ripasudil (+) group (n = 27) receiving the same four medications plus ripasudil. SC morphology parameters were assessed in thrombomodulin (TBM)-stained sections, including length parameters [TBM-positive/negative and opened/closed SC lengths] and area parameters [TBM-positive/negative and opened SC areas]. Between-group comparisons were performed using unpaired t-tests, and multiple regression analysis was conducted to adjust for age, gender, preoperative intraocular pressure (IOP), and oral CAI use. Results: The ripasudil (+) group had significantly longer total SC length (TSC: 302.5 µm) than the ripasudil (−) group (273.0 µm, p = 0.023). Among area parameters, the ripasudil (+) group showed significantly larger opened SC area (OSC-A: 2689 µm² vs. 1881 µm², p = 0.008) and TBM-negative opened SC area (NOSC-A: 716 µm² vs. 305 µm², p = 0.001), whereas TBM-positive opened SC area (POSC-A) was not significantly different between groups (2001 µm² vs. 1575 µm², p = 0.096). After multivariate adjustment, ripasudil use remained significantly associated with longer TSC (p = 0.011) and larger OSC-A (p = 0.014) and NOSC-A (p = 0.001). Conclusions: Preoperative use of topical ripasudil was associated with preservation of SC lumen morphology, particularly in regions lacking SC endothelium. These findings provide a theoretical basis for therapeutic strategies employing ROCK inhibitors to maintain SC morphology and function. Full article

(This article belongs to the Special Issue Glaucoma: New Diagnostic and Therapeutic Approaches, 3rd Edition)

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22 pages, 5295 KB

Open AccessArticle

In Vitro Investigations on the Antioxidant Effects of Vitamin D in a Panel of Cancer Cell Lines

by Lina Elsalem, Farah A. Shobaki, Nosayba Al-Azzam, Abrar A. Aleikish and Haneen A. Basheer

Biomedicines 2026, 14(2), 469; https://doi.org/10.3390/biomedicines14020469 - 20 Feb 2026

Viewed by 596

Abstract

Background: Oxidative stress plays a critical role in cancer initiation and progression. Although vitamin D exhibits multiple anti-tumorigenic properties, its antioxidant effects across different cancer types remain incompletely characterized. This study aimed to evaluate the antioxidant role of vitamin D in cancer. Methods: [...] Read more.

Background: Oxidative stress plays a critical role in cancer initiation and progression. Although vitamin D exhibits multiple anti-tumorigenic properties, its antioxidant effects across different cancer types remain incompletely characterized. This study aimed to evaluate the antioxidant role of vitamin D in cancer. Methods: This in vitro study was conducted using breast (MCF-7, MDA-MB-231), colorectal (HCT-116, HT-29), and head and neck (Detroit-562, FaDu) cancer cell lines. Cells were treated with 1,25-dihydroxyvitamin D₃ (1 nM, 10 nM, and 100 nM) for 48 h. Reactive oxygen species (ROS) were quantified using the ROS-Glo™ H₂O₂ assay. Oxidative stress biomarkers were assessed by measuring 8-hydroxy-2′-deoxyguanosine (8-OHdG) using enzyme-linked immunosorbent assay (ELISA), while thiobarbituric acid reactive substances (TBARS) and protein carbonyls (PC) were measured using colorimetric assays. Xanthine oxidase (XOD) protein levels were determined by ELISA, whereas superoxide dismutase (SOD) and catalase (CAT) activity and/or expression were evaluated using colorimetric assays. Results: Vitamin D significantly reduced ROS levels in all investigated cell lines in a dose-dependent manner compared with control cells (p < 0.05). Levels of 8-OHdG and TBARS were significantly decreased across all cell lines, whereas reductions in PC and XOD were cell-type-dependent. Vitamin D significantly increased SOD activity and protein expression in all cell lines, while CAT activity was elevated in most cell lines. Conclusions: This study provides proof-of-concept evidence that vitamin D exerts dose-dependent and cell-specific antioxidant effects in cancer. These findings suggest potential antioxidant roles for vitamin D in the prevention or treatment of breast, colorectal, and head and neck cancers. Full article

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

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22 pages, 1024 KB

Open AccessReview

Epigenetic Regulation of Sebaceous and Meibomian Glands: From Development to Disease

by Xuming Zhu and Sixia Huang

Biomedicines 2026, 14(2), 468; https://doi.org/10.3390/biomedicines14020468 - 20 Feb 2026

Cited by 1 | Viewed by 1038

Abstract

Sebaceous glands (SGs) and their specialized subtype, Meibomian glands (MGs), play essential roles in skin and ocular surface homeostasis by producing lipids that maintain barrier integrity and stabilize the tear film. Dysregulation of SG and MG biology contributes to a spectrum of disorders, [...] Read more.

Sebaceous glands (SGs) and their specialized subtype, Meibomian glands (MGs), play essential roles in skin and ocular surface homeostasis by producing lipids that maintain barrier integrity and stabilize the tear film. Dysregulation of SG and MG biology contributes to a spectrum of disorders, ranging from benign hyperplasia to sebaceous carcinoma and age-related MG dysfunction. Accumulating evidence highlights the importance of epigenetic regulation, including histone modifications, DNA methylation, and non-coding RNAs (ncRNAs), in controlling SG and MG development, homeostasis, and disease susceptibility. Notably, histone modifiers and ncRNAs modulate acinar differentiation, lipid synthesis, and progenitor cell function. Despite these advances, many epigenetic mechanisms, such as histone lactylation, sumoylation, and phosphorylation, remain underexplored, and several common SG/MG disorders, including chalazion and seborrhea, lack mechanistic studies at the epigenetic level. This review synthesizes current knowledge on SG and MG biology, emphasizing epigenetic regulation, and highlights critical gaps to guide future research aimed at improving the understanding and treatment of SG- and MG-related disorders. Full article

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

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14 pages, 797 KB

Open AccessArticle

Cardiorenal and Metabolic Convergence in Acute Heart Failure: Severe Cardiorenometabolic Syndrome as a High-Risk Phenotype

by Raquel López-Vilella, Borja Guerrero Cervera, Julia Martínez Solé, Sara Huélamo Montoro, Víctor Donoso Trenado, Mireia Company Langa, Valero Soriano Alfonso, Luis Martínez Dolz and Luis Almenar-Bonet

Biomedicines 2026, 14(2), 467; https://doi.org/10.3390/biomedicines14020467 - 20 Feb 2026

Viewed by 622

Abstract

Background: Cardiorenometabolic syndrome (CRMS) reflects the interaction between heart failure (HF), chronic kidney disease, and metabolic disorders. Its prognostic impact during the acute phase of HF remains poorly defined. The primary objective of this study was to assess whether severe CRMS (sCRMS: estimated [...] Read more.

Background: Cardiorenometabolic syndrome (CRMS) reflects the interaction between heart failure (HF), chronic kidney disease, and metabolic disorders. Its prognostic impact during the acute phase of HF remains poorly defined. The primary objective of this study was to assess whether severe CRMS (sCRMS: estimated glomerular filtration rate <45 mL/min/1.73 m² associated with type 2 diabetes mellitus and/or obesity) predicts worse clinical outcomes. Methods: This was a retrospective observational study of a prospective cohort including 2228 patients admitted for acute HF between 2015 and 2025. Clinical characteristics and outcomes (mortality, HF readmission, and the composite endpoint) were compared between patients with and without sCRMS. Results: sCRMS was present in 486 patients (21.8%) who were older, had worse functional class, and a higher burden of cardiovascular comorbidities. They presented more frequently with systemic congestion and less often with de novo HF. During follow-up, sCRMS was associated with higher mortality (29.4% vs. 18.4%), HF readmissions (56.2% vs. 33.5%), and the composite endpoint (85.6% vs. 51.9%) (all p < 0.001). In multivariable analysis, sCRMS remained an independent predictor of mortality (HR 1.25), readmissions (HR 1.24), and overall morbidity and mortality (HR 1.20). Conclusions: In patients hospitalized for acute HF, sCRMS consistently identified a clinically vulnerable phenotype with an unfavorable prognosis. These findings support the value of sCRMS as a simple and reproducible prognostic marker and highlight the need for integrated cardiorenometabolic strategies during post-discharge follow-up. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—4th Edition)

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15 pages, 841 KB

Open AccessArticle

An Implantable Loop Recorder in the Diagnosis of Cardiac Arrhythmias: The Importance of Drug Treatment in Predicting Pacemaker Requirement

by Jelena Vučković-Filipović, Vladimir Ignjatović, Isidora Stanković, Neda Ćićarić, Vesna Ignjatović, Goran Davidović, Vladimir Miloradović, Violeta Irić-Ćupić, Ivan Simić and Natasa Djordjevic

Biomedicines 2026, 14(2), 466; https://doi.org/10.3390/biomedicines14020466 - 19 Feb 2026

Viewed by 681

Abstract

Background: An implantable loop recorder (ILR) represents the gold standard in the diagnosis of cardiac arrhythmias in patients with neurological or cardiac symptoms. Our study aimed to determine the real-world diagnostic effectiveness of ILRs in detecting arrhythmias requiring permanent pacemaker implantation. Methods [...] Read more.

Background: An implantable loop recorder (ILR) represents the gold standard in the diagnosis of cardiac arrhythmias in patients with neurological or cardiac symptoms. Our study aimed to determine the real-world diagnostic effectiveness of ILRs in detecting arrhythmias requiring permanent pacemaker implantation. Methods: The study enrolled and followed up for two years 62 ILR recipients from the Cardiology Clinic of the Clinical Center Kragujevac, Serbia. Results: The most common indication for pacemaker implantation was pauses in cardiac activity (83%). The use of oral anticoagulants (OR: 11.80; 95% CI: 1.76, 79.4), ACE inhibitors or AT receptor blockers (OR: 3.87; 95% CI: 1.21, 12.35), and diuretics (OR: 5.29; 95% CI: 1.55, 18.04) had a statistically significant impact on the detection of pacemaker-requiring arrhythmias by an ILR. After adjustment for other factors of influence, oral anticoagulants (OR: 7.82; 95% CI: 1.08, 56.9) and diuretics (OR: 3.68; 95% CI: 1.04, 13.00) remained significant in predicting pacemaker requirement in ILR recipients. Conclusions: An ILR represents an effective diagnostic approach in detecting cardiac arrhythmias requiring permanent pacemaker implantation, especially in patients treated with oral anticoagulants or diuretics. Full article

(This article belongs to the Special Issue Cardiac Arrhythmias: Technological Frontiers, Therapeutic Approaches and Future Directions)

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9 pages, 222 KB

Open AccessArticle

Tongue Pressure as a Predictor of Tongue Base Collapse in Patients with Obstructive Sleep Apnea Syndrome

by Ying-Chieh Hsu, Meng-Xun Goh, Tung-Tsun Huang and Hsueh-Yu Li

Biomedicines 2026, 14(2), 465; https://doi.org/10.3390/biomedicines14020465 - 19 Feb 2026

Viewed by 867

Abstract

Background: This study investigated the association between tongue strength, measured using the Iowa Oral Performance Instrument (IOPI), and upper airway collapse patterns observed during drug-induced sleep endoscopy (DISE) in patients with obstructive sleep apnea syndrome (OSAS). Methods: Thirty patients who underwent [...] Read more.

Background: This study investigated the association between tongue strength, measured using the Iowa Oral Performance Instrument (IOPI), and upper airway collapse patterns observed during drug-induced sleep endoscopy (DISE) in patients with obstructive sleep apnea syndrome (OSAS). Methods: Thirty patients who underwent polysomnography, DISE, and tongue pressure measurement were retrospectively analyzed. Upper airway collapse was assessed using the VOTE classification. The tongue strength task performed using the IOPI requires participants to compress an air-filled bulb placed on the hard palate with anterior tongue to generate maximum isometric tongue pressure. Group comparisons and ordinal logistic regression with Firth’s penalized likelihood were performed to evaluate associations between tongue pressure and collapse patterns. Results: The participants had a mean age of 41.5 ± 12.5 years, including 27 males and 3 females. The mean tongue strength was 50.4 ± 15.3 kPa, with no significant sex-related differences. Patients with tongue strength <40 kPa showed significantly higher odds of tongue base collapse (adjusted OR 12.79, 95% CI 1.30–126.91) and epiglottic collapse (adjusted OR 54.05, 95% CI 1.66–1760.25). No significant differences were observed for velum or oropharyngeal collapse. Conclusions: Lower tongue strength was associated with increased likelihood of tongue base collapse during DISE. Tongue strength measurement may serve as a practical, non-invasive tool for identifying patients with reduced tongue muscle function and potential tongue-related airway obstruction. Full article

(This article belongs to the Special Issue Obstructive Sleep Apnea: Mechanisms, Comorbidities, and Optimization of Emerging and Established Therapies)

20 pages, 1004 KB

Open AccessSystematic Review

Mapping the Evidence on Virtual Reality for Post-Intensive Care Syndrome: A Systematic Review and a Five-Axis VR-PICS Taxonomy

by Inês Oliveira, André Torneiro, João Ferreira-Coimbra, Adriana Sampaio, Nicolas A. Morgenstern, Eva Oliveira, António Coelho and Nuno F. Rodrigues

Biomedicines 2026, 14(2), 464; https://doi.org/10.3390/biomedicines14020464 - 19 Feb 2026

Viewed by 722

Abstract

Background: Post-Intensive Care Syndrome (PICS), comprising physical, cognitive, and psychological impairments, affects 50–75% of Intensive Care Unit (ICU) survivors and leads to long-term deficits. Virtual Reality (VR) has emerged as a tool to reduce ICU-related stress and support recovery, yet evidence remains fragmented [...] Read more.

Background: Post-Intensive Care Syndrome (PICS), comprising physical, cognitive, and psychological impairments, affects 50–75% of Intensive Care Unit (ICU) survivors and leads to long-term deficits. Virtual Reality (VR) has emerged as a tool to reduce ICU-related stress and support recovery, yet evidence remains fragmented and heterogeneous. Objective: To systematically review the safety, feasibility, and effects of immersive VR interventions targeting PICS-related outcomes in ICU and post-ICU populations, and to introduce a standardized taxonomy to classify and compare VR interventions in critical care contexts. Methods: This systematic review followed PRISMA 2020 guidelines and was registered in PROSPERO (CRD420251174623). Seven databases (Cochrane Library, PubMed, ScienceDirect, IEEE Xplore, ACM Digital Library, SpringerLink, and Scopus) were searched from inception to 2 August 2025. Eligible studies included ICU patients receiving immersive VR via head-mounted displays and targeting at least one PICS domain. Two reviewers independently screened studies and extracted data. Methodological quality was assessed using the Mixed Methods Appraisal Tool (MMAT, 2018). Due to substantial heterogeneity, findings were synthesized narratively. Results: Eleven studies were included. The most consistent effects concerned acute psychological outcomes, with 63.6% of studies reporting reduced anxiety or distress. Evidence for physical, cognitive, or long-term outcomes was limited and inconsistent, largely due to small samples, non-randomized designs, and brief intervention dosing. Conclusion: Current evidence supports VR as a feasible adjunct for acute psychological support in ICU settings. However, meaningful rehabilitation effects remain underexplored. The Five-Axis VR-PICS taxonomy clarifies intervention heterogeneity and provides a structured framework to guide rehabilitation-oriented VR research in critical care. Full article

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

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9 pages, 830 KB

Open AccessReview

RBP4 in Ageing

by María Paz Nieto-Bona, María García-De Frutos and Adriana Izquierdo-Lahuerta

Biomedicines 2026, 14(2), 463; https://doi.org/10.3390/biomedicines14020463 - 19 Feb 2026

Viewed by 1091

Abstract

Background: The protein that binds to retinol 4 (RBP4), is a lipocalin-family protein, secreted primarily by the adipose tissue and the liver, and has also been reported to be produced by other tissues, including the kidney. This protein mediates the transport of vitamin [...] Read more.

Background: The protein that binds to retinol 4 (RBP4), is a lipocalin-family protein, secreted primarily by the adipose tissue and the liver, and has also been reported to be produced by other tissues, including the kidney. This protein mediates the transport of vitamin A (retinol) in the circulation, bound to a transporter protein, transthyretin. In recent years, RBP4 has been shown to contribute to the development of insulin resistance and a range of metabolic disorders such as type 2 diabetes mellitus, gestational diabetes, obesity, metabolic syndrome, hyperuricaemia, metabolic dysfunction-associated steatotic liver disease (MASLD), and cardiorenal diseases. Objectives: The objective was to analyse the role of RBP4 in ageing, as well as its mechanisms and effects across organs and systems. Results: Circulating RBP4 levels increase with age and have been related to the onset of various processes like sarcopenia, elevated neurodegenerative markers in the brain, and an increase in TSH levels. Furthermore, it appears that in ageing, the rise in RBP4 is related to the development of atherogenesis, chronic kidney disease, and osteoarthritis. These effects appear to be mediated by chronic inflammation along with the development of insulin resistance, increased oxidative stress and mitochondrial dysfunction, inhibition of autophagy, and intestinal dysbiosis. Conclusions: RBP4 is a factor to be taken into account in the ageing process, as it has been shown that elevated circulating serum levels in older individuals lead to and accelerate deterioration across different organs or systems. Full article

(This article belongs to the Special Issue The Aging Metabolism: Diabetes, Obesity, and Lifespan Insights)

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24 pages, 9444 KB

Open AccessArticle

Sex-Specific Metabolic Footprint of Ketogenic Diet in C57BL/6J Mice

by Marko Sablić, Viktoria Čurila, Barbara Viljetić, Lovro Mihajlović, Zeljka Korade, Károly Mirnics, Irena Labak, Leonarda Murvaj, Senka Blažetić, Vedrana Ivić, Željko Debeljak, Marta Balog and Marija Heffer

Biomedicines 2026, 14(2), 462; https://doi.org/10.3390/biomedicines14020462 - 19 Feb 2026

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Abstract

Background/Objectives: The ketogenic diet (KD) induces profound metabolic shifts, yet the sex-specific long-term effects on skeletal muscle metabolism and sterol homeostasis across tissues remain insufficiently characterized. This study tested the hypothesis that a prolonged KD would elicit distinct, sex-dependent metabolic and sterol [...] Read more.

Background/Objectives: The ketogenic diet (KD) induces profound metabolic shifts, yet the sex-specific long-term effects on skeletal muscle metabolism and sterol homeostasis across tissues remain insufficiently characterized. This study tested the hypothesis that a prolonged KD would elicit distinct, sex-dependent metabolic and sterol adaptations in mice. Methods: We examined how a 12-week KD, compared with a standard diet, affected body mass, the skeletal muscle metabolome, hepatic lipid and collagen content, and sterol profiles in the skeletal muscle, liver, spleen, and serum in male and female C57BL/6J mice. Three-month-old mice of both sexes were randomized to a KD or standard diet and evaluated using the histological quantification of hepatic steatosis and collagen deposition, matrix-assisted laser desorption/ionization time-of-flight imaging mass spectrometry (MALDI-TOF IMS) of skeletal muscle, and LC-MS/MS-based sterol profiling. Results: The KD induced rapid body mass gain in males and delayed weight gain in females, promoted hepatic steatosis in both sexes, and generated clearly segregated, sex- and diet-specific skeletal muscle metabolomic signatures. These signatures included reduced tricarboxylic acid cycle precursors and a marked decrease in S-adenosylmethionine in KD-fed females. Across tissues, the KD consistently suppressed precursor sterols, including 7-dehydrocholesterol and desmosterol in the skeletal muscle, liver, and spleen, while elevating serum cholesterol and desmosterol (male-biased), with changes generally more pronounced in males. Conclusions: Collectively, these findings demonstrate that a long-term KD drives sex- and organ-specific metabolic remodeling, with evidence of greater metabolic flexibility but a shared risk of hepatic steatosis in females. These results underscore the importance of personalized, sex-stratified approaches when considering long-term ketogenic interventions. Full article

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

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14 pages, 619 KB

Open AccessArticle

Tissue Cytomegalovirus DNA Detection by PCR Is Associated with Increased Endoscopic Activity in Ulcerative Colitis: A Retrospective Cohort Study

by Omer Kucukdemirci, Hasan Eruzun, Berk Bas, Muge Ustaoglu, Ufuk Avcioglu, Elfag Isgandarov and Ahmet Bektas

Biomedicines 2026, 14(2), 461; https://doi.org/10.3390/biomedicines14020461 - 19 Feb 2026

Viewed by 664

Abstract

Background: Cytomegalovirus (CMV) reactivation is frequently observed in patients with moderate-to-severe ulcerative colitis (UC), particularly in steroid-refractory cases; however, the clinical significance of tissue CMV DNA detection by polymerase chain reaction (PCR) in the absence of classical histopathological findings remains controversial. Methods: This [...] Read more.

Background: Cytomegalovirus (CMV) reactivation is frequently observed in patients with moderate-to-severe ulcerative colitis (UC), particularly in steroid-refractory cases; however, the clinical significance of tissue CMV DNA detection by polymerase chain reaction (PCR) in the absence of classical histopathological findings remains controversial. Methods: This retrospective cohort study included 110 patients with moderate-to-severe UC who underwent colonoscopy between January 2021 and April 2024 at a tertiary referral center. Tissue and serum samples were analyzed for CMV DNA using PCR. Tissue CMV DNA positivity was defined as ≥250 copies. Endoscopic disease activity was assessed using the Mayo clinical score, Mayo endoscopic score, and the Rachmilewitz Endoscopic Activity Index. Associations between tissue CMV DNA positivity, endoscopic activity scores, inflammatory markers, recent immunosuppressive therapy, and serum CMV PCR results were evaluated. Sensitivity analyses using different tissue CMV DNA thresholds and receiver operating characteristic (ROC) curve analysis for serum CMV PCR were also performed. Results: Tissue CMV DNA positivity was detected in 37.3% of patients. Patients with tissue CMV DNA positivity had significantly higher Mayo clinical scores and Rachmilewitz Endoscopic Activity Index scores compared with CMV-negative patients, whereas Mayo endoscopic scores did not differ significantly between groups. Serum CMV PCR levels were markedly higher in patients with tissue CMV DNA positivity (p < 0.001). Tissue CMV DNA copy number showed a strong correlation with serum CMV PCR levels but did not demonstrate a consistent linear association with endoscopic activity scores. In multivariable logistic regression analysis, recent corticosteroid use was independently associated with tissue CMV DNA positivity, while anti-TNF therapy and endoscopic activity indices were not independent predictors. ROC analysis demonstrated good diagnostic performance of serum CMV PCR for predicting tissue CMV DNA positivity (AUC = 0.82). Conclusions: In patients with moderate-to-severe UC, tissue CMV DNA positivity (≥250 copies) is associated with increased clinical and endoscopic disease activity, even in the absence of classical histopathological evidence of CMV infection. These findings suggest that molecular detection of CMV in colonic tissue may provide clinically relevant information in selected patient populations, particularly those with recent corticosteroid exposure. However, tissue CMV DNA positivity should be interpreted as a molecular association rather than definitive evidence of causality or an indication for antiviral therapy. Prospective multicenter studies are warranted to further clarify the clinical implications of tissue CMV DNA detection in UC. Full article

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

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26 pages, 2240 KB

Open AccessReview

Cutaneous Dendritic Cells: Structure, Function and Immune Role

by Ioana Cristina Alexandru, Mariana Grigore and Olga Simionescu

Biomedicines 2026, 14(2), 460; https://doi.org/10.3390/biomedicines14020460 - 19 Feb 2026

Viewed by 1412

Abstract

Cutaneous antigen-presenting cells (APCs), particularly dendritic cells (DCs) and Langerhans cells (LCs), are a diverse population of cells that play a vital role in immune surveillance by initiating and shaping skin immune responses. They link innate and adaptive immunity by presenting antigens, migrating, [...] Read more.

Cutaneous antigen-presenting cells (APCs), particularly dendritic cells (DCs) and Langerhans cells (LCs), are a diverse population of cells that play a vital role in immune surveillance by initiating and shaping skin immune responses. They link innate and adaptive immunity by presenting antigens, migrating, and activating T lymphocytes, thereby acting as orchestrators of tissue immunity. This review provides an updated overview of the morphofunctional diversity of cutaneous APCs, ranging from epidermal LCs and DCs, to dermal conventional DCs (DC1/DC2), plasmacytoid DCs (pDCs), including newly defined subsets such as DC3, Axl⁺Siglec-6⁺ DCs (ASDCs) and LAMP3⁺ mature regulatory DCs (mRegDCs). Dynamic differences in APC composition and function between homeostatic and inflamed skin are discussed, with particular emphasis on inflammatory and autoimmune conditions such as psoriasis, lupus erythematosus and chronic atopic dermatitis, in which distinct DC subsets contribute to Th1 and Th17 immune circuits. This review is the first skin-related approach that extensively discusses the cutaneous role of APCs in the neuro-immune-cutaneous axis, as well as their interactions with the local microenvironment. Ongoing controversies regarding the classification and stability of certain DC populations are discussed. A better understanding of the diversity, migration mechanisms and microenvironmental interactions of cutaneous APCs could lead to the identification of new biomarkers and therapeutic targets for inflammatory, autoimmune, and oncological skin diseases. Full article

(This article belongs to the Special Issue Dermatology: From Fundamental to Clinical Research)

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Biomedicines, Volume 14, Issue 2 (February 2026) – 233 articles

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