Biomedicines

12 pages, 244 KB

Open AccessViewpoint

From Biomarker Discovery to Targeted Clinical Application: Addressing Translational Gaps in Early Cancer Detection

by Mohamad Adam Bujang

Biomedicines 2026, 14(6), 1292; https://doi.org/10.3390/biomedicines14061292 (registering DOI) - 5 Jun 2026

Despite extensive progress in breast cancer biomarker research, only a limited proportion of candidate biomarkers successfully transition from early discovery to clinically validated tools for targeted early detection. This article examines the key translational barriers that impede this progression across the biomarker development [...] Read more.

Despite extensive progress in breast cancer biomarker research, only a limited proportion of candidate biomarkers successfully transition from early discovery to clinically validated tools for targeted early detection. This article examines the key translational barriers that impede this progression across the biomarker development continuum. Five major gaps are identified: (i) discovery-to-clinical relevance, (ii) methodological and analytical validation, (iii) regulatory and administrative complexity, (iv) translational performance and real-world integration, and (v) equity and deployment challenges. Collectively, these gaps highlight limitations not only in scientific and methodological rigor but also in validation frameworks, regulatory alignment, implementation feasibility, and healthcare system equity. This article emphasizes that successful biomarker translation requires more than analytical validity. Finally, it requires a supportive ecosystem that enables effective breast cancer early detection strategies and improves population-level outcomes in breast cancer care. Full article

(This article belongs to the Special Issue Breast Cancer Research: Charting Future Directions)

17 pages, 1382 KB

Open AccessArticle

Iridis tectori Rhizome Alleviates LPS-Triggered Inflammatory Responses Through Inhibiting NF-κB Signaling in Macrophages

by Yi-Lin Guo, Wen-Jing Li, Xin Huang, Yu-Lin Lin, Yu Liu, Min Cai, Qian Chen, Mu-Qing Wang, Cong-Yu Wu, Yuan Gao and Yun Qi

Biomedicines 2026, 14(6), 1291; https://doi.org/10.3390/biomedicines14061291 (registering DOI) - 5 Jun 2026

Abstract

Objectives: The rhizome of Iris tectorum Maxim. (Chuan She Gan), commonly used as a substitute for She Gan in Sichuan and other regions, is traditionally applied for inflammation-related disorders. This study aimed to evaluate the anti-inflammatory activity of Chuan She Gan ethanolic extract [...] Read more.

Objectives: The rhizome of Iris tectorum Maxim. (Chuan She Gan), commonly used as a substitute for She Gan in Sichuan and other regions, is traditionally applied for inflammation-related disorders. This study aimed to evaluate the anti-inflammatory activity of Chuan She Gan ethanolic extract (CSG) and elucidate its molecular mechanism. Methods: CSG was prepared by 85% ethanol extraction and analyzed by HPLC to identify representative constituents. In LPS-stimulated RAW264.7 macrophages, nitrite accumulation and iNOS activity, cytokine production and inflammatory gene expression were evaluated using Griess assays, ELISA, and qRT-PCR, respectively. NF-κB and AP-1/MAPK signaling were determined using luciferase reporter assays and Wwestern blotting. Serum inflammatory cytokine levels of endotoxemic mice were measured by ELISA. Results: Four characteristic isoflavones/glycosides in CSG were identified, including tectoridin, iridin, tectorigenin, and irigenin. In LPS-activated RAW264.7 macrophages, CSG not only dose-dependently suppressed supernatant NO by inhibiting iNOS activity and downregulating iNOS expression, but also reduced IL-6, MCP-1, and intracellular pro-IL-1β at the protein and mRNA levels. Mechanistic analyses indicated that CSG attenuated NF-κB activation by reducing IκBα phosphorylation and limiting p65 nuclear accumulation, while AP-1/MAPK signaling remained largely unchanged. In endotoxemic mice, a single oral gavage of CSG (50–200 mg/kg) significantly lowered serum IL-6, MCP-1, and TNF-α levels. Conclusions: CSG showed anti-inflammatory activity in LPS-stimulated macrophages and endotoxemic mice. In LPS-stimulated macrophages, CSG suppressed inflammatory mediator production primarily through the inhibition of NF-κB signaling. In endotoxemic mice, CSG reduced the serum levels of pro-inflammatory cytokines. These findings provide pharmacological basis for the traditional use of Chuan She Gan. Full article

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

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16 pages, 4501 KB

Open AccessArticle

Metagenomic Profiling of the Gut Microbiome in Age-Related Macular Degeneration—A Pilot Study

by Andreea-Talida Tîrziu, Mirabela Romanescu, Paula Diana Ciordas, Nadina Mercea, Mihnea Munteanu, Florin George Horhat, Aimee Rodica Chis and Maria-Alexandra Preda

Biomedicines 2026, 14(6), 1290; https://doi.org/10.3390/biomedicines14061290 (registering DOI) - 5 Jun 2026

Abstract

Background/Objectives: Age-related macular degeneration (AMD) is a multifactorial retinal disease involving inflammatory, metabolic, and genetic factors. Increasing evidence suggests that the gut microbiome may contribute to systemic pathways involved in retinal homeostasis. This exploratory pilot study investigated gut microbiome alterations in AMD patients [...] Read more.

Background/Objectives: Age-related macular degeneration (AMD) is a multifactorial retinal disease involving inflammatory, metabolic, and genetic factors. Increasing evidence suggests that the gut microbiome may contribute to systemic pathways involved in retinal homeostasis. This exploratory pilot study investigated gut microbiome alterations in AMD patients and controls using long-read whole-genome sequencing. Methods: Bacterial DNA was extracted from fecal samples and analyzed using Oxford Nanopore sequencing, followed by taxonomic profiling, alpha and beta diversity analyses, and differential abundance testing. Results: AMD patients showed significantly reduced microbial diversity, reflected by lower richness, Shannon and Simpson indices. Species-level beta diversity analyses revealed significant differences in microbial community composition, particularly with Bray-Curtis metrics, alongside increased inter-individual microbial heterogeneity in AMD samples. Differential abundance analyses identified the depletion of several potentially beneficial commensal taxa, including Faecalibacterium prausnitzii and Parabacteriodes distasonis, whereas Staphylococcus aureus was enriched in AMD patients. Comparisons between wet and dry subtypes showed no significant differences in alpha or beta diversity. Conclusions: Overall, the findings support the presence of gut microbial dysbiosis in AMD characterized by reduced diversity, abundance-driven community shifts, and increased microbiome heterogeneity. Given the small cohort size, cross-sectional design and lack of functional analysis, these results should be considered preliminary and hypothesis-generating. Full article

(This article belongs to the Special Issue Molecular Research in Ocular Pathology)

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19 pages, 12935 KB

Open AccessReview

Across Clinical Profiles of Cardiorenal–Metabolic (CKM) Syndrome: A Phenotype-Driven Therapeutic Approach

by Irene Carlino, Sonia Di Franco, Nicola Colalillo, Stefania Bisogno, Luigi Gennari and Alberto Palazzuoli

Biomedicines 2026, 14(6), 1289; https://doi.org/10.3390/biomedicines14061289 (registering DOI) - 5 Jun 2026

Abstract

Cardiorenal–metabolic (CKM) syndrome has emerged as a unifying condition describing the interplay between metabolic dysfunction, chronic kidney disease, and cardiovascular disease. To address this concept, the American Heart Association, in a 2023 Presidential Advisory, presented an official statement to capture the transition from [...] Read more.

Cardiorenal–metabolic (CKM) syndrome has emerged as a unifying condition describing the interplay between metabolic dysfunction, chronic kidney disease, and cardiovascular disease. To address this concept, the American Heart Association, in a 2023 Presidential Advisory, presented an official statement to capture the transition from metabolic risk and subtle cardiorenal dysfunction to overt cardiovascular and renal disease. Although this framework provides a structured representation of disease burden and facilitates risk stratification, emerging evidence suggests that it is primarily focused on the progressive nature, whereas high-risk patients may experience sudden cardiac or renal events. While staging systems provide important tools for risk stratification, they remain primarily descriptive and do not adequately reflect the dynamic and non-linear interactions underlying disease progression. Importantly, patients exhibit substantial heterogeneity in dominant pathophysiological drivers, related to various baseline risk factors and primitive cardio–kidney disorders, that is not fully captured by stage-based classifications. Notably, we propose a phenotype-oriented approach to CKM syndrome based on the recognition that its clinical expression reflects heterogeneous and evolving pathophysiological mechanisms rather than a uniform disease trajectory. According to this strategy, the paradigm of management shifts from an evolutive concept to a more appropriate use of disease modifying agents with cross-organ effects. Sodium–glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1a), and non-steroidal mineralocorticoid receptor antagonists (MRA) have demonstrated the ability to modulate key biological pathways across the cardiovascular, renal, and metabolic axes. Therefore, personalized management that identifies a specific strategy according to CKM phenotypes must be assessed. Full article

(This article belongs to the Special Issue Acute and Chronic Heart Failure: Pathophysiology and New Therapeutic Developments, 3rd Edition)

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23 pages, 9709 KB

Open AccessArticle

Lack of Galectin-3 Disturbs Gut–Adipose–Liver Axis in High-Fat-Diet Mice Model

by Flávia R. S. Corrêa, Natália G. Mação, Felipe S. Lemos, Victor F. S. Ferreira, Vinícius F. Carvalho and Felipe L. Oliveira

Biomedicines 2026, 14(6), 1288; https://doi.org/10.3390/biomedicines14061288 (registering DOI) - 5 Jun 2026

Abstract

Background/Objectives: A high-fat diet (HFD) promotes hepatic steatosis, inflammation, and systemic metabolic imbalance. Notably, HFDs can affect the gut–liver axis and adipose tissue homeostasis. Galectin-3 (Gal-3) binds to β-galactosides and plays regulatory roles in the gut–liver axis, connecting metabolic stress with inflammation [...] Read more.

Background/Objectives: A high-fat diet (HFD) promotes hepatic steatosis, inflammation, and systemic metabolic imbalance. Notably, HFDs can affect the gut–liver axis and adipose tissue homeostasis. Galectin-3 (Gal-3) binds to β-galactosides and plays regulatory roles in the gut–liver axis, connecting metabolic stress with inflammation and tissue remodelling. The objective of this study was to investigate whether Gal-3 affects the gut–liver axis and adipose tissue biology after HFD supplementation. Methods: Six-week-old C57BL/6 mice were randomly divided into either wild-type (Lgals3^+/+) or knockout (Lgals3^−/−) groups. Both groups received an HFD orally for 12 weeks, along with their respective control groups. Physiological measurements and microscopic examination of the gut, liver, and fat tissue were conducted using optical microscopy. Results: The HFD induced obesity in Lgals3^+/+ mice, but not in Lgals3^−/− mice, which exhibited lower weight gain, food intake, daily energy intake, and energy efficiency than Lgals3^+/+ mice. Moreover, Lgals3^−/− HFD mice had hyperglycaemia and hyperinsulinemia. Histological analysis revealed hypertrophied adipose tissue in Lgals3^+/+ HFD mice with abundant Gal-3⁺ crown-like structures, rarely observed in Lgals3^−/− HFD mice. In the jejunum, Lgals3^+/+ HFD mice showed a significant reduction in Gal-3 expression in intestinal epithelial cells, whereas inflammatory signals were increased in Lgals3^−/− HFD mice. In the liver, Lgals3^+/+ HFD mice showed significant steatosis and macrophages expressing Gal-3. In contrast, Lgals3^−/− HFD mice showed pronounced hepatocyte ballooning, suggesting a more progressive stage of metabolic dysfunction-associated steatotic liver disease (MASLD). Conclusions: Together, these data suggest that Gal-3 protects the gut–liver axis and adipose tissue against cytotoxic effects caused by HFD. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Gastrointestinal Tract Disease: 2nd Edition)

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15 pages, 835 KB

Open AccessReview

MicroRNAs in Aneurysmal Subarachnoid Hemorrhage: A Stage-Specific Model Linking Rupture, Vasospasm, and Outcome

by Emre Ozkara, Ebru Erzurumluoglu Gokalp, Ozlem Aykac, Zehra Uysal Kocabas, Sinem Kocagil, Oguz Cilingir, Beyhan Durak Aras, Sevilhan Artan and Atilla Ozcan Ozdemir

Biomedicines 2026, 14(6), 1287; https://doi.org/10.3390/biomedicines14061287 - 4 Jun 2026

Abstract

Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening cerebrovascular condition characterized by a dynamic clinical course spanning distinct pathophysiological stages, including aneurysm rupture, early brain injury (EBI), delayed cerebral vasospasm, and long-term neurological outcome. Despite extensive research, no clinically applicable molecular biomarkers exist to [...] Read more.

Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening cerebrovascular condition characterized by a dynamic clinical course spanning distinct pathophysiological stages, including aneurysm rupture, early brain injury (EBI), delayed cerebral vasospasm, and long-term neurological outcome. Despite extensive research, no clinically applicable molecular biomarkers exist to predict disease trajectory across these stages. MicroRNAs (miRNAs), small non-coding RNA molecules detectable in blood and cerebrospinal fluid (CSF), have emerged as promising candidates due to their stability and close association with vascular, inflammatory, and neuronal processes. However, existing studies have largely evaluated miRNAs in isolation, without integrating findings into a unified temporal framework. This review provides a structured, translational synthesis of miRNA dynamics in aSAH and proposes a stage-specific conceptual model integrating prospective clinical evidence with the broader literature. Dual-biofluid profiling has identified miR-29a, miR-200a-3p, and miR-451a as robust rupture-associated biomarkers, with distinct compartment-specific expression patterns. CSF-based profiling has demonstrated that miR-221-3p, miR-9-3p, and miR-183-5p predict vasospasm within 24 h of hemorrhage, while miR-24 and miR-21-5p correlate with disease severity and poor outcome. Integrating these findings with the broader literature, we categorize miRNA signatures across four stages: rupture discrimination, early brain injury, vasospasm prediction, and outcome stratification. This stage-specific framework highlights the biological continuum linking endothelial injury, vascular dysfunction, and secondary brain damage. The proposed model provides a foundation for multi-marker biomarker development, prospective validation studies, and future precision medicine strategies in aSAH. Full article

(This article belongs to the Special Issue Advanced Research of Non-Coding RNAs in Health and Disease)

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14 pages, 2607 KB

Open AccessArticle

ATP and Liv-52 Ameliorate Linezolid-Induced Liver Injury via Modulation of NF-κB/NLRP3 Pathways

by Serkan Cerrah, Ahmed Ramiz Baykan, Esra Tuba Sezgin, Gulbaniz Huseynova, Elif Karabacak, Serdar Tanas, Emine Kartal Baykan, Murat Gunay, Ali Gungor and Halis Suleyman

Biomedicines 2026, 14(6), 1286; https://doi.org/10.3390/biomedicines14061286 - 4 Jun 2026

Abstract

Objective: Linezolid (LZD), an oxazolidinone antibiotic widely used against Gram-positive infections, has been associated with mitochondrial dysfunction and hepatotoxicity, particularly during prolonged use. This study aimed to investigate the protective effects of adenosine triphosphate (ATP) and Liv-52 against LZD-induced liver injury, with a [...] Read more.

Objective: Linezolid (LZD), an oxazolidinone antibiotic widely used against Gram-positive infections, has been associated with mitochondrial dysfunction and hepatotoxicity, particularly during prolonged use. This study aimed to investigate the protective effects of adenosine triphosphate (ATP) and Liv-52 against LZD-induced liver injury, with a focus on oxidative stress, inflammation, and necroptosis pathways. Methods: Twenty-four male Wistar rats were randomly assigned to four groups: healthy control (HG), LZD-treated (LZDG), Liv-52 + LZD (LVLZ), and ATP + LZD (ATLZ). Liv-52 (50 mg/kg, orally) and ATP (5 mg/kg, intraperitoneally) were administered prior to LZD (125 mg/kg, orally) for 14 days. Results: Following LZD administration, malondialdehyde (MDA) levels markedly increased, indicating oxidative stress, while total glutathione (tGSH), superoxide dismutase (SOD), and catalase (CAT) activities significantly decreased. Histopathological examination revealed pronounced hepatocellular damage accompanied by increased NF-κB, NLRP3, RIPK3, and MLKL expression, indicating activation of inflammatory and necroptotic pathways. Treatment with ATP and Liv-52 significantly ameliorated these biochemical, histopathological, and molecular alterations. Conclusions: Treatment with ATP and Liv-52 significantly attenuated oxidative stress, improved histopathological alterations, and suppressed the expression of inflammatory and necroptotic markers. Notably, ATP exhibited a more pronounced protective effect compared to Liv-52. In conclusion, LZD induces hepatotoxicity through oxidative stress-mediated inflammatory and necroptotic mechanisms, while ATP and Liv-52 confer hepatoprotection, with ATP showing superior efficacy. Full article

(This article belongs to the Special Issue Advanced Research in Liver Diseases)

15 pages, 5482 KB

Open AccessSystematic Review

Effects of Resveratrol on MCP-1/CCL2-Related Readouts in Preclinical Animal Models: A Systematic Review and Meta-Analysis

by Yi-Lin Chiu, Shiue-Wei Lai, Sheng-Cheng Wu, Hsing-Fan Lai, Yi-Ying Wu and Tsung-Neng Tsai

Biomedicines 2026, 14(6), 1285; https://doi.org/10.3390/biomedicines14061285 - 4 Jun 2026

Abstract

Background: Resveratrol is a plant-derived polyphenol with reported anti-inflammatory activity, and the MCP-1/CCL2 axis is a key mediator of monocyte recruitment and inflammatory tissue remodeling. Although individual preclinical studies have examined resveratrol effects on MCP-1/CCL2-related outcomes, the overall in vivo evidence has [...] Read more.

Background: Resveratrol is a plant-derived polyphenol with reported anti-inflammatory activity, and the MCP-1/CCL2 axis is a key mediator of monocyte recruitment and inflammatory tissue remodeling. Although individual preclinical studies have examined resveratrol effects on MCP-1/CCL2-related outcomes, the overall in vivo evidence has not been quantitatively synthesized. This systematic review and meta-analysis evaluated whether resveratrol treatment is associated with reduced MCP-1/CCL2-related inflammatory readouts in animal models. Methods: The protocol was registered in PROSPERO (CRD420261339126), and reporting followed the PRISMA 2020 statement. PubMed was searched from inception to 12 March 2026, with additional reference-list screening. Eligible studies were in vivo animal experiments comparing resveratrol-treated and control groups with extractable quantitative MCP-1/CCL2-related outcomes. Effect sizes were calculated as Hedges’ g with 95% confidence intervals and pooled using random-effects models fitted by restricted maximum likelihood. Subgroup, sensitivity, cumulative, influence, funnel-plot, dose meta-regression, and SYRCLE-based risk-of-bias analyses were conducted. Results: Twenty-seven studies contributing 29 analyzable datasets were included. The overall pooled effect was −3.74 (95% confidence interval, −4.50 to −2.98), indicating lower MCP-1/CCL2-related readouts in resveratrol-treated groups than in controls, with substantial heterogeneity (I2 = 78.9%). The negative association was driven mainly by rat and mouse datasets, whereas the piglet estimate was directionally opposite and the rabbit estimate came from a single dataset. Funnel-plot inspection suggested asymmetry, and dose meta-regression did not significantly explain between-study variation (slope = −0.17, p = 0.482). Leave-one-out and cumulative analyses indicated directional stability but did not resolve the underlying heterogeneity. Conclusions: These preclinical data indicate lower MCP-1/CCL2-related readouts after resveratrol treatment, but high heterogeneity, PubMed-only retrieval, and pharmacokinetic limitations limit direct clinical inference. Full article

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

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22 pages, 1740 KB

Open AccessArticle

Exploring Biomarkers and Regulatory Mechanisms Associated with Lytic Cell Death in Allergic Rhinitis Based on Transcriptome Analysis

by Rui Dong, Zhishan Dong, Zhigang Geng, Lei Lu, Yongjin Ji and Jinmei Xue

Biomedicines 2026, 14(6), 1284; https://doi.org/10.3390/biomedicines14061284 - 4 Jun 2026

Abstract

Background: Allergic rhinitis (AR) is a common inflammatory disorder with an unclear role of lytic cell death (LCD). This study aimed to identify LCD-associated genes associated with AR and investigate their underlying regulatory pathways. Methods: Transcriptomic data from AR patients (GSE19187, GSE206149) were [...] Read more.

Background: Allergic rhinitis (AR) is a common inflammatory disorder with an unclear role of lytic cell death (LCD). This study aimed to identify LCD-associated genes associated with AR and investigate their underlying regulatory pathways. Methods: Transcriptomic data from AR patients (GSE19187, GSE206149) were retrieved from public repositories, and LCD-associated genes were collected from the literature. A combination of differential expression analysis, machine learning techniques, validation of expression levels, and ROC curve analysis was employed to screen for biomarkers. These biomarkers were then subjected to comprehensive functional characterization via GSEA, subcellular localization prediction, immune infiltration profiling, construction of molecular regulatory networks, and drug prediction. Finally, clinical relevance was confirmed through expression levels in patient specimens. Results: Two key indicators, ALOX15 and TIMP1, were successfully pinpointed. GSEA revealed significant enrichment of ALOX15 and TIMP1 in several biological processes, specifically chromatin organization, immune system response, and extracellular substance transport. Subcellular distribution studies showed that ALOX15 predominantly localized in the cytosol and plasma membrane, while TIMP1 was mainly detected extracellularly. Immune infiltration studies demonstrated notable modifications in seven immune cell populations, with significant associations with megakaryocyte–erythroid progenitors and conventional dendritic cells. Based on these findings, a regulatory network composed of transcription factors and microRNAs was established, and several potential therapeutic candidates (e.g., quercetin) were identified through prediction. Consistent with predictions, mRNA expression levels of both genes were significantly upregulated in the AR group compared to controls (p < 0.01), confirming reliability. Conclusions: In summary, ALOX15 and TIMP1 were identified as exploratory biomarkers associated with AR, providing preliminary insights into its molecular mechanisms and potential therapeutic implications. Full article

(This article belongs to the Section Immunology and Immunotherapy)

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14 pages, 1020 KB

Open AccessArticle

Vitamin D Status and Reproductive Hormonal Profiles in Early Versus Physiological Menopause: A Comparative Observational Study

by Anamaria Ardelean, Cristian Furău, Oana Toduț, Nicoleta Mirica, Florina Buleu, Simona Ioana Sipos, Ion Petre, Izabella Petre, Tiberiu Buleu, Mircea Iurciuc, Oana Suciu and Roxana Furău

Biomedicines 2026, 14(6), 1283; https://doi.org/10.3390/biomedicines14061283 - 4 Jun 2026

Abstract

Background: An early menopause (by definition, menopause that occurs at a woman’s age 40 through 45) is often associated with certain changes in the body that can result in risks for health-related conditions, an extended period later. Thus, scientists have begun examining how [...] Read more.

Background: An early menopause (by definition, menopause that occurs at a woman’s age 40 through 45) is often associated with certain changes in the body that can result in risks for health-related conditions, an extended period later. Thus, scientists have begun examining how vitamin D has been suggested to be associated with endocrine function regulating both hormones and reproductive function during this time. However, it is not yet clear as to whether or not vitamin D provides any benefit to women who have experienced an early menopause. Material and Methods: The data was collected from 272 women in this retrospective, observational study at The County Hospital, Department of Obstetrics and Gynecology, Arad. The method of grouping the sample included two stratifications into early and physiological menopause categories based on amenorrhoea for a minimum of 12 consecutive months. 25-hydroxyvitamin D (25(OH)D) levels were classified into three categories: deficiency (<20 ng/mL), insufficiency (21–29 ng/mL), or adequacy (≥30 ng/mL). Estradiol, progesterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) hormone parameters were measured using standard immunoassays. The analysis employed correlation and regression to evaluate potential relationships between 25(OH)D levels and hormone parameters. Results: A significant proportion of the study group had a vitamin D deficiency. This was supported by the fact that only 24.27% of women were identified as having adequate levels of vitamin D, while the rest (62.03%) did not. Women in the early menopause group had a statistically significant negative relationship between estradiol and FSH (i.e., r = −0.29, p = 0.0016), as well as between progesterone and LH (i.e., r = −0.207, p = 0.026). There was not a statistically significant relationship between total sample vitamin D and estradiol (i.e., r = −0.038, p = 0.686) nor between vitamin D and progesterone (i.e., r = 0.031, p = 0.744). Women with vitamin D blood levels of 30 ng/mL or more showed a strong negative relationship between vitamin D and estradiol (r = −0.780; p = 0.0016) and a moderate positive relationship with progesterone (r = 0.534; p = 0.0104). However, these relationships were inconsistent in other groups. All group comparative analyses showed that women in the early menopause group had much lower estradiol levels than those in the physiological menopause group, regardless of whether they were classified based on their vitamin D levels (p < 0.0001). Conclusions: Women experiencing early or physiological menopause are at risk of having low vitamin D levels. However, our study results do not show a consistent relationship between serum 25(OH)D concentrations and serum estradiol or progesterone concentrations among the study population, suggesting that vitamin D is not a major factor influencing hormonal changes during menopause. These findings were inconsistent across analyses and should be interpreted cautiously. Overall, the results do not support a significant association between serum 25(OH)D concentrations and reproductive hormone levels in our study population. Full article

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

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3 pages, 192 KB

Open AccessReply

Reply to Yavuz, S. Comment on “Martire et al. Prognostic Role of High-Sensitivity C-Reactive Protein/Albumin Ratio in Heart Failure Patients. Biomedicines 2026, 14, 748”

by Domenico Martire, Giuseppe Armentaro, Giandomenico Severini, Carlo Alberto Pastura, Maria Rosangela Scarcelli, Velia Cassano, Martina Crasà, Ilaria Gareri, Gianluca Cortese, Valentino Condoleo, Raffaele Maio, Giorgio Sesti, Francesco Andreozzi and Angela Sciacqua

Biomedicines 2026, 14(6), 1282; https://doi.org/10.3390/biomedicines14061282 - 4 Jun 2026

Abstract

We would like to thank the author for the careful evaluation of our manuscript and for the thoughtful comments [...] Full article

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

2 pages, 168 KB

Open AccessComment

Comment on Martire et al. Prognostic Role of High-Sensitivity C-Reactive Protein/Albumin Ratio in Heart Failure Patients. Biomedicines 2026, 14, 748

by Samet Yavuz

Biomedicines 2026, 14(6), 1281; https://doi.org/10.3390/biomedicines14061281 - 4 Jun 2026

Abstract

We read with great interest the retrospective cohort study by Martire and colleagues [...] Full article

(This article belongs to the Section Immunology and Immunotherapy)

21 pages, 1764 KB

Open AccessArticle

APOE ε4 Allele Dose and Time to Clinical Conversion from Mild Cognitive Impairment to Alzheimer’s Disease Dementia: An ADNI Survival Analysis

by Faizaan Fazal Khan and Goo-Rak Kwon

Biomedicines 2026, 14(6), 1280; https://doi.org/10.3390/biomedicines14061280 - 4 Jun 2026

Abstract

Background/Objectives: Existing Alzheimer’s disease (AD) prediction studies often treat APOE ε4 as a binary carrier variable and emphasize classification rather than time-to-event progression. This study evaluated whether APOE ε4 allele dose predicts clinical conversion from mild cognitive impairment (MCI) to AD dementia/probable AD [...] Read more.

Background/Objectives: Existing Alzheimer’s disease (AD) prediction studies often treat APOE ε4 as a binary carrier variable and emphasize classification rather than time-to-event progression. This study evaluated whether APOE ε4 allele dose predicts clinical conversion from mild cognitive impairment (MCI) to AD dementia/probable AD in a longitudinal survival framework adjusted for hippocampal volume and baseline cognition. Methods: We analyzed 1115 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants with baseline MCI, APOE genotype data, and at least one follow-up visit, grouped by APOE ε4 allele count (0, 1, or 2). Kaplan–Meier curves, Bonferroni-corrected log-rank tests, nested Cox models, interaction testing, and twelve sensitivity and robustness analyses were performed. Results: During 3.73 ± 3.38 years of mean follow-up, 399 participants (35.8%) clinically converted. Median conversion-free survival was 18.47 years for non-carriers, 4.32 years for heterozygotes, and 3.41 years for homozygotes, although the non-carrier median occurred late in follow-up. In the fully adjusted Cox model, APOE ε4 dose remained associated with conversion hazard (HR = 1.580, 95% CI 1.362–1.834, p < 0.0001). Intracranial Volume (ICV)-adjusted hippocampal volume was protective (HR = 0.620, 95% CI 0.566–0.680, p < 0.0001), and the model achieved a Concordance Index (C-index) of 0.805. The APOE ε4 × hippocampal volume interaction was not significant (likelihood ratio test p = 0.098). Sensitivity analyses supported robustness, although the APOE ε4 association was attenuated in the exploratory amyloid-positive CSF subgroup. Conclusions: These findings support APOE ε4 allele dose as a statistical marker of clinical progression risk in ADNI, not as evidence of biomarker-confirmed AD progression or distinct mechanisms. Full article

(This article belongs to the Special Issue Applications of Biomedical Engineering and Biomaterials in Human Diseases)

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21 pages, 1320 KB

Open AccessArticle

Treatment of Leukemic Blood Samples with Granulocyte-Macrophage-Colony-Stimulating-Factor Combined with Prostaglandin E1 Is Associated with Reduced Frequencies of Tolerogenic Dendritic Cells and Increased Cytotoxicity Against Autologous Blasts

by Anne Hartz, Lin Li, Hazal Aslan Rejeski, Elena Pepeldjiyska, Elias Rackl, Tobias Baudrexler, Peter Bojko, Jörg Schmohl, Andreas Rank, Christoph Schmid and Helga Schmetzer

Biomedicines 2026, 14(6), 1279; https://doi.org/10.3390/biomedicines14061279 - 4 Jun 2026

Abstract

Background: Acute myeloid leukemia (AML) is characterized by reduced antileukemic effector cells and increased immunosuppressive cell populations. Leukemia-derived dendritic cells (DC_leu), generated from 18 leukemic whole blood (WB) ex vivo using ‘Kit-M’ (clinically approved: GM-CSF + PGE1), lead to improved cytotoxicity [...] Read more.

Background: Acute myeloid leukemia (AML) is characterized by reduced antileukemic effector cells and increased immunosuppressive cell populations. Leukemia-derived dendritic cells (DC_leu), generated from 18 leukemic whole blood (WB) ex vivo using ‘Kit-M’ (clinically approved: GM-CSF + PGE1), lead to improved cytotoxicity against autologous blasts after mixed lymphocyte culture (MLC) with patients’ T-cells. Methods: We studied Kit-M-mediated effects on frequencies of tolerogenic, immunosuppressive DC (DC_tol) and correlated findings with ex vivo-achieved antileukemic effects (increased intracellular IFNγ production/degranulation, blast lysis) and patients’ clinical characteristics. Results: We show significantly decreased frequencies of DC_tol (and increased frequencies of mature DC_leu) without induced blast proliferation in Kit-M treated vs. untreated WB samples. After T-cell-enriched MLC with Kit-M pretreated vs. not pretreated, WB frequencies of regulatory (CD152+ T-cells) were significantly decreased, while ‘activated’ (IFNγ+, degranulating) non-naive, proliferating, memory, CD154+) T-cells, as well as NK and CIK-cells were (significantly) increased. We found a (significant) positive correlation of achieved improved blast lysis, frequencies of DC_leu and ‘activated’ (IFNγ+/degranulating) T- or NK/CIK cells, and a (significant) negative correlation with frequencies of DC_tol and regulatory (CD152+ T-cells). Kit-M treatment of leukemic WB increases DC_leu and decreases DC_tol, correlating with improved immune reactions/improved cytotoxicity against autologous blasts, and downregulated suppressive T-cells in samples before or after MLC. Conclusions: These findings demonstrate the potential of Kit-M (using clinically approved drug compositions) to treat AML patients to potentially overcome the immunosuppressive tumor microenvironment, leading to improved antileukemic responses—thereby stabilizing remission of the disease in AML patients. Full article

(This article belongs to the Section Immunology and Immunotherapy)

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18 pages, 12640 KB

Open AccessArticle

Echocardiographic Global Longitudinal Strain and Myocardial Fibrosis in Patients with Left Ventricular Hypertrophy and Hypertrophic Cardiomyopathy

by Monika Matla-Hajzyk, Mariusz Balys, Aleksander Olejnik, Patrycja Brzoska and Maciej Haberka

Biomedicines 2026, 14(6), 1278; https://doi.org/10.3390/biomedicines14061278 - 4 Jun 2026

Abstract

Background: Myocardial fibrosis is an important pathological feature of hypertrophic cardiomyopathy (HCM) and is associated with ventricular arrhythmias, disease progression, and adverse clinical outcomes. Cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) is the reference non-invasive technique for myocardial fibrosis assessment; however, [...] Read more.

Background: Myocardial fibrosis is an important pathological feature of hypertrophic cardiomyopathy (HCM) and is associated with ventricular arrhythmias, disease progression, and adverse clinical outcomes. Cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) is the reference non-invasive technique for myocardial fibrosis assessment; however, its availability may be limited. Global longitudinal strain (GLS) derived from transthoracic echocardiography (TTE) has emerged as a sensitive marker of myocardial dysfunction and may provide complementary information regarding myocardial involvement. Aim: The aim of our study was to evaluate the diagnostic value of transthoracic echocardiography (TTE) with 2D global longitudinal strain (GLS) to detect the degree of myocardial fibrosis (LGE) in patients with LV hypertrophy (LVH). Methods: A total of 95 consecutive patients referred for cardiovascular magnetic resonance (CMR) because of suspected hypertrophic cardiomyopathy or left ventricular hypertrophy were screened for eligibility. After applying exclusion criteria and excluding patients with alternative diagnoses or inadequate image quality, 83 patients were included in the final analysis. All the participants underwent both CMR and transthoracic echocardiography with GLS assessment. Results: The final study population included 83 patients (57.5 ± 13 years; 66% males). CMR confirmed HCM in 58 (70%) patients, including 23 with left ventricular outflow tract obstruction (LVOTO). The remaining patients demonstrated varying degrees of left ventricular hypertrophy that did not fulfill established diagnostic criteria for hypertrophic cardiomyopathy. Cardiovascular magnetic resonance studies (58 cases; 69%) showed a non-ischemic LGE in LV (23% of segments with LGE). GLS in patients with LGE was significantly lower than those without LGE (−13.9 ± 3.6 vs. −15.9 ± 2.7%, p = 0.01). The mean GLS was −14.52 ± 3.5% and showed a moderate positive correlation with the extent of myocardial fibrosis (LGE%LV; r = 0.45, p < 0.01). This relationship remained significant in multivariable regression analysis (standardized coefficient = 0.683; p < 0.05). Moreover, the transthoracic echocardiography GLS showed a significant association for LV LGE (−14.3%; AUC 0.658; p = 0.01, sensitivity 39%, specificity 90%) with a better diagnostic performance for LGE in more than four LV segments (−12.1%; AUC 0.867; p < 0.001, sensitivity 72%, specificity 87%). Conclusions: GLS was independently associated with myocardial fibrotic burden assessed by CMR. Although it cannot replace CMR for tissue characterization, GLS may provide adjunctive information and may help identify patients with greater fibrotic burden. Prospective studies are needed to validate its clinical utility. Full article

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

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13 pages, 248 KB

Open AccessArticle

Vitamin D Deficiency and Markers of Liver Disease in American Indian Adolescents: The Strong Heart Family Study (SHFS)

by Jessica A. Reese, Erin Davis, Pryce Holloway, Amanda M. Fretts, Tauqeer Ali, Elisa T. Lee, Jason G. Umans, Jason F. Deen, Michael S. Middleton, Rohit Loomba, Claude B. Sirlin, Shelley A. Cole, Ying Zhang and Jennifer D. Peck

Biomedicines 2026, 14(6), 1277; https://doi.org/10.3390/biomedicines14061277 - 3 Jun 2026

Abstract

Background: Vitamin D deficiency (VDD) may be associated with chronic health issues, including markers of liver disease; however, evidence in American Indian adolescents is limited. Therefore, we aimed to evaluate the relationship between VDD in American Indian adolescents and markers of liver disease, [...] Read more.

Background: Vitamin D deficiency (VDD) may be associated with chronic health issues, including markers of liver disease; however, evidence in American Indian adolescents is limited. Therefore, we aimed to evaluate the relationship between VDD in American Indian adolescents and markers of liver disease, including both serum and magnetic resonance imaging (MRI) markers. Methods: The Strong Heart Family Study (SHFS) is a multicenter, family-based, prospective cohort study among American Indians. We evaluated SHFS participants who were <20 years old at baseline (2001–2003; n = 308), defined VDD as hydroxyvitamin-D (25[OH]D) ≤ 20 ng/mL and calculated the Hepatic Steatosis Index (HSI). In 2006–2009, we measured follow-up serum markers (n = 269, median follow-up = 5.8 years, range = 3.0–8.5), and in 2018–2020, we collected MRI markers of hepatic steatosis and fibrosis (n = 33, median follow-up = 16.7 years, range = 15.3–18.1). Results: At baseline, a greater proportion of those with VDD had HSI > 36 (64.5% with VDD; p = 0.002). For participants who reported consuming alcohol, serum alkaline phosphate (ALP) increased at follow-up, which was higher for those with versus without VDD (beta = 12.24, 95% CI = 1.23–23.24). For participants who reported not consuming alcohol, ALP decreased but was not different between the VDD groups. The MRI-proton density fat fraction was higher in those with (median = 11.0%, IQR = 7.7–19.2%) versus without (median = 4.4, IQR = 1.8–6.3%) VDD at baseline (p < 0.001). Conclusions: VDD may be associated with markers of liver disease in American Indian adolescents. After 5.5 years, VDD was associated with increasing ALP in those who consume alcohol, while controlling for adiposity and other covariates. After 17 years of follow-up, VDD was associated with increased liver MRI-PDFF. Full article

(This article belongs to the Special Issue Vitamin D: Latest Scientific Discoveries in Health and Disease)

27 pages, 2765 KB

Open AccessReview

In Vivo mRNA-Lipid Nanoparticle CAR-T Cell Engineering: Advances, Challenges, and Clinical Translation

by Vipin K. Yadav, Priyanka Yadav, Sreevidya Mallappa and Praveen Neeli

Biomedicines 2026, 14(6), 1276; https://doi.org/10.3390/biomedicines14061276 - 3 Jun 2026

Abstract

Chimeric antigen receptor T (CAR-T) cell therapy has transformed the treatment of hematologic malignancies, yet its broader application, particularly in solid tumors, remains constrained by high cost, labor-intensive manufacturing, limited production capacity, and variable clinical performance, as well as barriers such as poor [...] Read more.

Chimeric antigen receptor T (CAR-T) cell therapy has transformed the treatment of hematologic malignancies, yet its broader application, particularly in solid tumors, remains constrained by high cost, labor-intensive manufacturing, limited production capacity, and variable clinical performance, as well as barriers such as poor trafficking, antigen heterogeneity, and an immunosuppressive tumor microenvironment. In vivo CAR-T cell engineering, in which CAR-T cells are generated directly within the patient, offers a paradigm shift by eliminating the need for ex vivo cell processing and complex logistical infrastructure. Among emerging approaches, messenger RNA (mRNA)-loaded lipid nanoparticles (LNPs) have emerged as a promising and clinically tractable platform for in vivo CAR-T cell generation, enabling direct reprogramming of T lymphocytes within the patient and thereby circumventing the need for leukapheresis, viral vector production, and prolonged ex vivo culture, effectively transforming the patient into their own cell therapy factory. This review synthesizes advances in mRNA-LNP-mediated in vivo CAR-T cell generation, encompassing ionizable lipid chemistry and emerging T cell-targeted delivery strategies, including surface functionalization approaches. We discuss the implications of transient CAR expression for immune activation, safety, and therapeutic durability, alongside CAR design optimization through co-stimulatory domains and safety switches. Preclinical evidence from murine tumor models and non-human primates is integrated with current regulatory considerations, and key barriers to clinical translation are highlighted. Collectively, progress in nucleic acid delivery, synthetic immunology, and precision medicine positions in vivo mRNA-CAR-T therapy as a promising modality for oncology and beyond. Full article

(This article belongs to the Special Issue mRNA Personalized Cancer Vaccines and Immune-Oncology)

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16 pages, 1187 KB

Open AccessArticle

Association of Sleep Quality, Nutritional Factors, and Salivary Melatonin and Cortisol Levels with Oral Lichen Planus: A Case–Control Study

by Éverton Adriano Wegner, Julia de Salles Teixeira, Gabriel Rübensam, Catieli Gobetti Lindholz, Fernanda Gonçalves Salum and Karen Cherubini

Biomedicines 2026, 14(6), 1275; https://doi.org/10.3390/biomedicines14061275 - 3 Jun 2026

Abstract

Background/Objectives: The etiology of oral lichen planus (OLP) is unknown, and the treatment is palliative. Considering the possible influence of factors related to lifestyle on the etiopathogenesis and behavior of OLP, the aim of the present study was to investigate the association [...] Read more.

Background/Objectives: The etiology of oral lichen planus (OLP) is unknown, and the treatment is palliative. Considering the possible influence of factors related to lifestyle on the etiopathogenesis and behavior of OLP, the aim of the present study was to investigate the association of sleep quality, nutritional profile, and salivary melatonin and cortisol levels with OLP. Methods: Thirty-two OLP patients and 31 controls completed the Pittsburgh sleep quality index (PSQI), Epworth sleepiness scale, and 24 h dietary recall survey. Saliva was collected to determine melatonin and cortisol levels by liquid chromatography coupled to mass spectrometry. Results: The OLP patients showed higher scores in the sleep disturbances component of PSQI (p = 0.021) and lower salivary melatonin levels (p = 0.015), whereas salivary cortisol did not differ between the groups (p = 0.402). The Control group had higher prevalence of coffee drinkers (p = 0.045), whereas the OLP group had higher consumption of protein (p = 0.011), lipids (p = 0.043), calories (p = 0.022), monounsaturated fat (p = 0.030), polyunsaturated fat (p = 0.007), saturated fat (p = 0.027), cholesterol (p = 0.041), iron (p = 0.014), zinc (p = 0.048), magnesium (p = 0.025), sodium (p = 0.008), and vitamin E (p = 0.016) compared to controls. Conclusions: The results suggest that OLP is associated with lifestyle factors related to sleep and diet, as well as with lower levels of salivary melatonin. Given the exploratory nature of the study, further research is needed to better understand these findings. Full article

(This article belongs to the Special Issue Oral Oncology and Potentially Malignant Disorders)

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25 pages, 6897 KB

Open AccessReview

Where Does Liquid Biopsy Add Value in Thyroid Cancer? Biological Rationale, Technological Innovation, and Clinical Utility

by María Alonso-Chamorro, Ainhoa Palacios Mejorada and Garcilaso Riesco-Eizaguirre

Biomedicines 2026, 14(6), 1274; https://doi.org/10.3390/biomedicines14061274 - 2 Jun 2026

Abstract

Thyroid cancer comprises biologically diverse entities ranging from largely indolent differentiated thyroid cancer (DTC) to aggressive poorly differentiated/anaplastic thyroid cancer and medullary thyroid cancer, generating a need for minimally invasive biomarkers that can be repeatedly sampled. This review summarizes recent advances in liquid [...] Read more.

Thyroid cancer comprises biologically diverse entities ranging from largely indolent differentiated thyroid cancer (DTC) to aggressive poorly differentiated/anaplastic thyroid cancer and medullary thyroid cancer, generating a need for minimally invasive biomarkers that can be repeatedly sampled. This review summarizes recent advances in liquid biopsy for thyroid cancer, focusing on analytes and technologies spanning circulating tumor DNA (ctDNA)/cell-free DNA, circulating microRNAs (miRNAs), extracellular vesicles (EVs), and circulating tumor cells (CTCs). For ctDNA, we contrast qPCR/ddPCR and next-generation sequencing, tumor-informed versus tumor-agnostic strategies, the impact of low tumor fraction in DTC, clonal hematopoiesis confounding, and emerging methylation-based multi-cancer detection paradigms. For miRNAs, we highlight that bulk serum/plasma and EV-enriched compartments are not interchangeable and that regulated EV loading supports fraction-resolved biomarker development. We review recent translational EV-miRNA studies, including externally validated classifiers for metastatic disease and follicular-patterned/indeterminate nodules, and summarize the evolution of CTC research from enumeration to preoperative risk stratification and postoperative or radioiodine-related kinetics. We conclude with an indications-first framework that pairs analyte choice with clinical intent (preoperative diagnosis, initial risk stratification, response to treatment and minimal residual disease and identification of actionable alterations and resistance mechanisms) and prioritizes standardized workflows and prospective multicenter validation. Multi-analyte integration, epigenetic/fragmentomic cfDNA signals, and higher-resolution EV analytics are likely to accelerate clinical adoption, particularly in advanced thyroid cancer where circulating signal and therapeutic actionability are highest. Full article

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

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