Biomedicines

22 pages, 1254 KB

Open AccessArticle

Regulatory Variants in the KRAS 3′UTR and Intron 2 Are Associated with Breast Cancer Susceptibility Through Independent and Combinatorial Effects in a Mexican Population

by Asbiel Felipe Garibaldi-Ríos, Luis E. Figuera, Belinda Claudia Gómez-Meda, Guillermo Moisés Zúñiga-González, Ingrid Patricia Dávalos-Rodríguez, Patricia Montserrat García-Verdín, Ana María Puebla-Pérez, Irving Alejandro Carrillo-Dávila and Martha Patricia Gallegos-Arreola

Biomedicines 2026, 14(4), 948; https://doi.org/10.3390/biomedicines14040948 - 21 Apr 2026

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Abstract

Background: Breast cancer (BC) is a leading cause of cancer-related mortality worldwide and a major public health concern in Mexico. Regulatory variants in KRAS, particularly within the 3′UTR and intronic regions, may influence gene expression through microRNA binding and transcriptional regulation. Methods: [...] Read more.

Background: Breast cancer (BC) is a leading cause of cancer-related mortality worldwide and a major public health concern in Mexico. Regulatory variants in KRAS, particularly within the 3′UTR and intronic regions, may influence gene expression through microRNA binding and transcriptional regulation. Methods: Five regulatory single-nucleotide variants (SNVs) in KRAS (rs12228277, rs1137196, rs8720, rs12587, and rs12245) were genotyped in BC patients and cancer-free controls. Associations were evaluated using odds ratios (ORs) with 95% confidence intervals (CIs), adjusting for age, alcohol, and tobacco use. Multiple testing was corrected using the Benjamini–Hochberg false discovery rate (FDR). Linkage disequilibrium (LD), multilocus combinations, and in silico functional analyses were also performed. Results: Variants rs12228277, rs1137196, rs8720, and rs12245 showed significant genotype-level associations with BC susceptibility, all remaining significant after FDR correction (pFDR < 0.05). No clinicopathological associations remained significant after correction in single-variant analyses. Multilocus analysis identified specific high-risk combinations (e.g., involving rs12228277, rs1137196, and rs8720) associated with increased BC susceptibility. At the nominal level, these combinations showed associations with clinicopathological features, including hormone receptor–positive status (PR and ER), proliferation markers, and Luminal B subtype; however, none remained significant after FDR correction. LD analysis indicated weak linkage among variants. In silico analyses suggested potential regulatory effects on microRNA binding and KRAS expression. Conclusions: Regulatory variants in KRAS are associated with BC susceptibility through independent effects and potential combinatorial patterns. These findings support the relevance of non-coding variation in cancer risk and warrant further functional and replication studies. Full article

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

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59 pages, 1548 KB

Open AccessReview

Synergistic Interactions Between Medicinal Plant Bioactive and Standard Chemotherapy in Gastric Cancer: Preclinical Evidence and Translational Pitfalls

by Emilia Daliana Muntean, Daniela-Cornelia Lazăr, Ana-Maria Pah, Christian Banciu, Sorin-Dan Chiriac, Iasmina Denisa Boantă, Florin Muntean, Iulian-Alexandru Blidişel, George-Andrei Drăghici and Radu Jipa

Biomedicines 2026, 14(4), 947; https://doi.org/10.3390/biomedicines14040947 - 21 Apr 2026

Cited by 1 | Viewed by 1099

Abstract

Gastric cancer remains a highly heterogeneous malignancy in which chemotherapy response is limited by intrinsic and acquired resistance, cumulative toxicity, and the restricted predictive value of conventional preclinical models. This review critically synthesizes evidence on selected medicinal plants and their bioactive phytocompounds as [...] Read more.

Gastric cancer remains a highly heterogeneous malignancy in which chemotherapy response is limited by intrinsic and acquired resistance, cumulative toxicity, and the restricted predictive value of conventional preclinical models. This review critically synthesizes evidence on selected medicinal plants and their bioactive phytocompounds as adjuncts to standard chemotherapy for gastric cancer, with an emphasis on mechanistic plausibility, preclinical synergy, and translational barriers. Across the reviewed literature, phytocompounds from Curcuma longa, Scutellaria baicalensis, Camellia sinensis, Syzygium aromaticum, Glycyrrhiza glabra, Allium sativum, Marsdenia tenacissima, and Rhus verniciflua showed anticancer or chemopreventive activity through multitarget effects on apoptosis, proliferation, invasion, inflammation, oxidative stress, and resistance-associated signaling. The most convincing chemosensitizing evidence involved curcumin, wogonin, baicalein, EGCG, which enhanced the activity of fluoropyrimidines, platinum agents, paclitaxel, doxorubicin, or related antitumor regimens in selected gastric cancer models. However, the evidence base remains heterogeneous and is constrained by variable extract standardization, incomplete dose reporting, poor bioavailability, insufficient pharmacokinetic/pharmacodynamic integration, and underuse of clinically relevant model systems. Overall, medicinal plant bioactives remain promising adjunct candidates in gastric cancer. Still, meaningful translation will require chemically defined interventions, rigorous synergy analysis, interaction-aware study design, and validation in advanced preclinical and clinical settings. Full article

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

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17 pages, 4081 KB

Open AccessArticle

Neural Network-Based Prediction of Residual Paravalvular Leak in Bicuspid Aortic Valve TAVI Using CT-Derived Anatomical Features

by Yijun Yao, Weili Jiang, Xinyue Yang, Jianyong Wang, Ruisi Tang, Yuan Feng, Yiming Li and Mao Chen

Biomedicines 2026, 14(4), 946; https://doi.org/10.3390/biomedicines14040946 - 21 Apr 2026

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Abstract

Background/Objectives: Transcatheter aortic valve implantation (TAVI) in patients with bicuspid aortic valve (BAV) remains associated with higher rates of residual paravalvular leak (PVL), which confers a two-fold increase in mortality. Despite procedural optimization including balloon post-dilatation, a subset of patients exhibit residual [...] Read more.

Background/Objectives: Transcatheter aortic valve implantation (TAVI) in patients with bicuspid aortic valve (BAV) remains associated with higher rates of residual paravalvular leak (PVL), which confers a two-fold increase in mortality. Despite procedural optimization including balloon post-dilatation, a subset of patients exhibit residual ≥moderate PVL. Pre-procedural identification of these patients could guide procedural planning. Methods: We retrospectively analyzed 402 BAV patients who underwent TAVI with self-expanding valves and balloon post-dilatation between January 2016 and June 2024. A multi-modal deep learning model (Model B) was developed, integrating a 3D ResNet encoder for computed tomography (CT) imaging features with a multilayer perceptron (MLP) for clinical variables, fused via a cross-attention mechanism. Its performance was compared against a conventional model (Model A) combining clinical variables with manually derived CT measurements. Both models were evaluated on identical test folds using 5-fold stratified cross-validation. Results: Of 402 patients, 36 (9.0%) had residual ≥moderate PVL, associated with significantly larger aortic root dimensions at all anatomical levels and greater aortic valve calcification volume (median 887.6 vs. 559.2 mm³; p = 0.004). Model A achieved a mean AUC of 0.694 (95% CI: 0.596–0.792). Model B achieved a mean AUC of 0.822 (95% CI: 0.680–0.964), with a specificity of 0.971, accuracy of 0.881, and PPV of 0.860, while sensitivity was 0.429, reflecting the limited number of outcome events in this cohort. Conclusions: A multi-modal deep learning model integrating expert-segmented CT imaging with clinical variables demonstrated significantly improved discrimination over the conventional approach in this internal cohort for predicting residual PVL in BAV-TAVI, supporting the integration of segmentation-guided deep learning into pre-procedural TAVI planning. However, given the modest number of outcome events, external validation is required to confirm the generalizability of these findings. Full article

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

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Graphical abstract

11 pages, 534 KB

Open AccessArticle

Autonomic Receptor Autoantibodies in Complex Regional Pain Syndrome and Other Chronic Pain Conditions: A Cross-Sectional Analysis

by Daniël P. C. van der Spek, Renée H. Hoffenkamp, Frank J. P. M. Huygen, Krishna D. Bharwani, Niels Eijkelkamp and Maaike Dirckx

Biomedicines 2026, 14(4), 945; https://doi.org/10.3390/biomedicines14040945 - 21 Apr 2026

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Abstract

Objectives: Complex regional pain syndrome (CRPS) is a heterogeneous pain disorder with incompletely understood immunoinflammatory features. This study investigated whether autonomic receptor autoantibodies differentiate CRPS from other chronic pain conditions and healthy controls. Methods: We conducted a cross-sectional analysis of serum [...] Read more.

Objectives: Complex regional pain syndrome (CRPS) is a heterogeneous pain disorder with incompletely understood immunoinflammatory features. This study investigated whether autonomic receptor autoantibodies differentiate CRPS from other chronic pain conditions and healthy controls. Methods: We conducted a cross-sectional analysis of serum samples from patients referred with suspected CRPS. Patients were subsequently classified as having either CRPS or another chronic pain condition, based on the Budapest criteria. Healthy controls were included for comparison. Serum levels of autoantibodies targeting the muscarinic M2 receptor (M2R), β1-adrenergic receptor (β1AR), and the β2-adrenergic receptor (β2AR) were assessed using enzyme-linked immunosorbent assay. All analyses were performed blinded to group assignment. Results: Seventy participants were analyzed (CRPS = 22, other chronic pain = 25, healthy controls = 23). M2R autoantibody levels were higher in both CRPS and other chronic pain compared with healthy controls (mean difference [MD] = 0.37, 95%CI 0.22–0.51; and MD = 0.31 95%CI 0.19–0.44, respectively). β2AR levels were higher in other chronic pain compared with healthy controls (MD = 0.29, 95%CI 0.04–0.54), whereas no significant difference was observed in CRPS (MD = 0.21 95%CI −0.01–0.42). No meaningful differences were observed between CRPS and other chronic pain for any receptor. β1AR levels did not differ between groups. Seropositivity for any autoantibody was 55% in CRPS, 44% in other chronic pain, and 22% in healthy controls. Conclusions: Elevated autonomic receptor autoantibody levels were observed across chronic pain conditions but were not specific for CRPS. Full article

(This article belongs to the Special Issue Biomarkers in Pain: 2nd Edition)

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21 pages, 1842 KB

Open AccessReview

Fatty Kidney: The Interplay of Lipids and Diabetic Kidney Disease

by Zhiyue Zou, Pan Gao, Qian Yuan, Zhiwen Wang, Pengli Luo and Chun Zhang

Biomedicines 2026, 14(4), 944; https://doi.org/10.3390/biomedicines14040944 - 21 Apr 2026

Cited by 1 | Viewed by 1204

Abstract

Diabetic nephropathy and diabetic atherosclerosis often develop together and share similar metabolic disturbances. Lipid abnormalities are common in diabetes, yet their roles in kidney and vascular injury are not fully understood. In diabetic kidney disease, altered lipid uptake, reduced fatty acid oxidation, and [...] Read more.

Diabetic nephropathy and diabetic atherosclerosis often develop together and share similar metabolic disturbances. Lipid abnormalities are common in diabetes, yet their roles in kidney and vascular injury are not fully understood. In diabetic kidney disease, altered lipid uptake, reduced fatty acid oxidation, and accumulation of harmful lipid species contribute to cellular stress, mitochondrial injury, inflammation, and fibrosis. In parallel, disordered lipid handling in the vasculature promotes endothelial dysfunction and atherosclerotic plaque development. However, not all lipid accumulation appears to be detrimental, and some findings suggest adaptive or context-dependent effects, leading to inconsistent results across studies. In this review, we summarize current evidence on lipid metabolism in diabetic nephropathy and atherosclerosis, compare shared and distinct features, and discuss ongoing controversies. We also briefly address the therapeutic relevance of targeting lipid pathways and highlight areas that require further investigation. Compared with prior reviews that mainly discussed fatty kidney as an emerging concept in chronic kidney disease research, this review specifically focuses on diabetic kidney disease and integrates kidney-specific lipid trafficking, kidney–vessel crosstalk, conflicting evidence, and mechanism-based therapeutic implications. Full article

(This article belongs to the Special Issue Diabetic Nephropathy and Diabetic Atherosclerosis (2nd Edition))

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22 pages, 4098 KB

Open AccessArticle

Single Cell and Bulk RNA-Seq Profiling of Non-Metastatic Versus Bone-Metastatic Prostate Cancer Identifies the CXCL10-CXCR3 Axis as a Key Determinant of Tumor Microenvironment and Treatment Resistance

by Zijian Song, Likai Ren, Hong Wang, Yanqing Wang, Xinxing Du, Wei Zhou, Qi Zhang, Jiyuan Yu, Zaixu Zhao, Linxiong Ye, Kaidi Jin, Ying Liu and Wei Xue

Biomedicines 2026, 14(4), 943; https://doi.org/10.3390/biomedicines14040943 - 21 Apr 2026

Cited by 1 | Viewed by 955

Abstract

Background: Bone metastasis is a major determinant of morbidity and therapeutic failure in advanced prostate cancer (PCa); however, the transcriptional programs and tumor microenvironmental alterations driving metastatic progression remain incompletely understood. This study aimed to systematically characterize transcriptomic differences between non-metastatic and bone-metastatic [...] Read more.

Background: Bone metastasis is a major determinant of morbidity and therapeutic failure in advanced prostate cancer (PCa); however, the transcriptional programs and tumor microenvironmental alterations driving metastatic progression remain incompletely understood. This study aimed to systematically characterize transcriptomic differences between non-metastatic and bone-metastatic PCa and to identify key microenvironmental signaling pathways involved in tumor survival and chemoresistance. Methods: Bulk RNA sequencing was performed on 49 non-metastatic and 28 bone-metastatic PCa specimens. Differential expression analysis was integrated with weighted gene co-expression network analysis (WGCNA), gene set enrichment analysis, and immune/stromal deconvolution. Key findings were validated using in vitro functional assays, including Transwell co-culture models, small interfering RNA (siRNA)-mediated gene silencing, cell viability, apoptosis, and docetaxel resistance analyses. Results: Transcriptomic profiling identified 574 differentially expressed genes. Bone-metastatic tumors were enriched in ribosome-related and translational pathways, whereas non-metastatic tumors displayed immune-associated signatures, including natural killer (NK) cell-mediated cytotoxicity and cytokine signaling. WGCNA revealed immune-related gene modules preferentially enriched in non-metastatic disease. Immune deconvolution demonstrated significantly higher infiltration of NK cells and endothelial cells in non-metastatic tumors. Chemokine-receptor analysis highlighted upregulation of the CXCL10-CXCR3 axis in non-metastatic PCa. In vitro, PCa cells expressed CXCR3, while endothelial cells markedly increased CXCL10 expression upon co-culture. Functional assays showed that endothelial-derived CXCL10 promoted PCa cell survival, suppressed apoptosis, and conferred resistance to docetaxel via CXCR3-dependent signaling; these effects were reversed by CXCL10 or CXCR3 knockdown. Conclusions: These findings uncover a context-dependent endothelial-immune chemokine network distinguishing non-metastatic from bone-metastatic PCa and identify the CXCL10-CXCR3 axis as a critical mediator of tumor survival and chemoresistance, suggesting a potential therapeutic vulnerability in advanced prostate cancer. Full article

(This article belongs to the Special Issue Aging and Decoding Aging)

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17 pages, 3138 KB

Open AccessSystematic Review

Topical Glucocorticosteroids for Proactive Therapy of Acute Radiation-Induced Skin Injury in Head and Neck Cancer: A Systematic Review and Meta-Analysis with Trial Sequential Analysis

by Paweł Głuszak, Julia Woźna, Andrzej Bałoniak, Jakub Pazdrowski, Jan Stępka, Joanna Kaźmierska and Aleksandra Dańczak-Pazdrowska

Biomedicines 2026, 14(4), 942; https://doi.org/10.3390/biomedicines14040942 - 21 Apr 2026

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Abstract

Background: Acute radiation-induced skin injury (aRISI) is one of the most frequent adverse effects of radiotherapy (RT) in patients with head and neck cancer (HNC) and may compromise treatment delivery and quality of life. Topical glucocorticosteroids (GCS) are commonly used in clinical practice [...] Read more.

Background: Acute radiation-induced skin injury (aRISI) is one of the most frequent adverse effects of radiotherapy (RT) in patients with head and neck cancer (HNC) and may compromise treatment delivery and quality of life. Topical glucocorticosteroids (GCS) are commonly used in clinical practice for aRISI management; however, evidence supporting their proactive use remains inconsistent. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of proactive topical GCS therapy during RT for HNC. Methods: A systematic search of PubMed, Embase, and the Cochrane Library was conducted from database inception to July 2025 in accordance with PRISMA 2020 guidelines. Randomized controlled trials comparing topical GCS with placebo or standard skin care in adult patients undergoing curative RT or RChT for HNC were included. The primary outcomes were incidence of clinically significant aRISI (grade ≥ 2) and severe aRISI (grade ≥ 3), assessed using validated grading systems (RTOG or CTCAE). Random-effects meta-analyses were performed to calculate pooled risk ratios (RRs) with 95% confidence intervals (CIs). Risk of bias was assessed using the Cochrane RoB 2 tool. Results: Three randomized controlled trials comprising 459 patients were included. Proactive topical GCS did not significantly reduce the pooled incidence of grade ≥ 2 aRISI compared with placebo or standard skin care (RR 0.87, 95% CI 0.60–1.27). Similarly, no statistically significant reduction in grade ≥ 3 aRISI was observed in pooled analysis (RR 0.81, 95% CI 0.22–3.06). Qualitative synthesis of secondary outcomes reported in individual trials suggested potential benefits of topical GCS, including delayed onset or slower progression of aRISI, and, in one large double-blind study, a reduced risk of severe reactions. No increase in treatment-related adverse events was observed in any included trial. Conclusions: Proactive topical GCS do not significantly reduce the overall incidence of aRISI in pooled analysis. Individual studies showed trend towards delayed onset, slower progression, and reduced severe aRISI without compromising safety. These findings support the judicious use of topical GCS as part of proactive supportive care in HNC RT, while highlighting the need for larger, standardized trials to define optimal regimens and patient selection. Full article

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

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15 pages, 891 KB

Open AccessArticle

Beyond QRS Duration: Myocardial Work Indices for the Assessment of Left Bundle Branch Block

by Magdalena Potapowicz-Krysztofiak, Martyna Dąbrowska, Małgorzata Maciorowska, Zbigniew Orski, Paweł Krzesiński, Marek Kiliszek and Beata Uziębło-Życzkowska

Biomedicines 2026, 14(4), 941; https://doi.org/10.3390/biomedicines14040941 - 21 Apr 2026

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Abstract

Background: Left bundle branch block (LBBB) and QRS prolongation are markers of electrical dyssynchrony in heart failure, but they do not fully reflect its mechanical consequences. Myocardial work (MW)-derived indices may provide a more comprehensive assessment of left ventricular (LV) mechanical dyssynchrony. We [...] Read more.

Background: Left bundle branch block (LBBB) and QRS prolongation are markers of electrical dyssynchrony in heart failure, but they do not fully reflect its mechanical consequences. Myocardial work (MW)-derived indices may provide a more comprehensive assessment of left ventricular (LV) mechanical dyssynchrony. We evaluated associations between LV MW parameters, QRS duration, and LBBB in patients with heart failure with reduced ejection fraction (HFrEF) referred for ICD/CRT implantation. Methods: In this single-centre observational cross-sectional study, 96 consecutive patients referred for ICD or CRT implantation were screened. All patients underwent standardized baseline comprehensive echocardiography followed by advanced MW analysis. Myocardial work index (MWI) dispersion was assessed using two complementary methods. MWI dispersion (SD) was calculated as the standard deviation of segmental MWI values across all LV segments, and MWI dispersion (IQR) was defined as the interquartile range (IQR) of segmental MWI values. We evaluated the associations between QRS duration and MW-derived dyssynchrony parameters (individual and composite), as well as their discriminative performance for LBBB. Seven patients were excluded from further analysis due to inadequate echocardiography image quality. Results: The final study group comprised 89 patients with HFrEF (median age 65.5 years), of whom 67.4% were assigned to CRT. LBBB was present in 41.6%, and the median QRS duration was 142 ms (112–162). All analyzed LV MW indices were significantly associated with QRS duration (all q < 0.01). The strongest correlations were observed for MWI dispersion (IQR) (r = 0.58), peak strain dispersion (PSD) (r = 0.54), lateral–septal work asymmetry (r = 0.53), and MWI dispersion (SD) (r = 0.52) (all q < 0.0001). All MW indices differed significantly between patients with and without LBBB (all q ≤ 0.0001). MWI dispersion (IQR) showed the best single-marker discrimination of LBBB (AUC = 0.852). Composite indices achieved AUC = 0.84 but did not significantly improve discrimination versus MWI dispersion (IQR) alone. Conclusions: Myocardial work-derived indices of left ventricular dyssynchrony are strongly associated with QRS duration and the presence of LBBB in patients with HFrEF. Among them, MWI dispersion (IQR) was shown to be the best-performing MW marker for identifying LBBB. These findings suggest that MW dispersion may serve as a robust echocardiographic marker of mechanical dyssynchrony and warrants further investigation as a potential tool for predicting CRT response. Full article

(This article belongs to the Special Issue Cardiac Arrhythmias and Arrhythmogenic Disorders: Pathomechanisms, Diagnostics and Novel Treatment Options)

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25 pages, 11253 KB

Open AccessArticle

Effects of Infliximab in a Propionic Acid-Induced Experimental Autism Rat Model

by Nur Akman, Ahmet Ufuk Kömüroğlu, Salih Çibuk, Fikret Altındağ, Osman Yılmaz and Ahmet Ateşşahin

Biomedicines 2026, 14(4), 940; https://doi.org/10.3390/biomedicines14040940 - 20 Apr 2026

Cited by 1 | Viewed by 931

Abstract

Background/Objectives: Autism spectrum disorder (ASD) is a neurodevelopmental condition increasingly associated with dysregulated neuroimmune signaling and altered neurotrophic homeostasis. Tumor necrosis factor-alpha (TNF-α) has been implicated in ASD pathophysiology; however, the downstream effects of TNF-α blockade on cytokine–neurotrophin interactions during neurodevelopment remain [...] Read more.

Background/Objectives: Autism spectrum disorder (ASD) is a neurodevelopmental condition increasingly associated with dysregulated neuroimmune signaling and altered neurotrophic homeostasis. Tumor necrosis factor-alpha (TNF-α) has been implicated in ASD pathophysiology; however, the downstream effects of TNF-α blockade on cytokine–neurotrophin interactions during neurodevelopment remain insufficiently characterized. In this study, we evaluated the effects of infliximab (IFX), a monoclonal anti-TNF-α antibody, on behavioral performance, neuroinflammatory cytokine profiles, glial activation, and brain-derived neurotrophic factor (BDNF) signaling in a propionic acid (PPA)-induced experimental ASD rat model. Methods: Experimental ASD was induced by propionic acid administration in rats. Animals were divided into control and treatment groups. Behavioral performance was assessed using the Morris Water Maze, direct social interaction, and three-chamber sociability tests. Levels of TNF-α, interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and BDNF were measured in serum, hippocampal, and cerebellar tissues. Microglial and astrocytic activation were evaluated using CD11 and GFAP immunohistochemistry. Results: PPA administration resulted in pronounced impairments in learning, memory, and social behaviors, accompanied by elevated proinflammatory cytokine levels, increased BDNF expression, and marked glial activation in the hippocampus and cerebellum. Although IFX treatment significantly reduced TNF-α levels in central tissues, it did not improve behavioral deficits and was associated with persistently elevated IL-1β and IL-6 levels, sustained glial reactivity, and further alterations in BDNF levels. Conclusions: These findings suggest that TNF-α suppression alone does not normalize the disrupted cytokine–neurotrophin axis and may differentially modulate BDNF-related neuroplastic signaling during development. In conclusion, this study indicates that non-selective TNF-α blockade during neurodevelopment fails to confer behavioral benefit in experimental ASD and highlights the importance of considering cytokine–BDNF pathway interactions when designing immunomodulatory strategies for neurodevelopmental disorders. Full article

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

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18 pages, 5108 KB

Open AccessArticle

DYRK1B Inhibition by AZ191 Sensitizes High-Grade Serous Ovarian Cancer to Niraparib Through Promoting Apoptosis and Ferroptosis

by Yu Gao, Yuanyuan Cao, Junyao Liu, Fang Tong, Xianlin Liu, Jiahui Wang, Peixuan Liu, Yanting Xu, Lu Feng, Pengxin Zhang, Jingchun Gao and Jiwei Liu

Biomedicines 2026, 14(4), 939; https://doi.org/10.3390/biomedicines14040939 - 20 Apr 2026

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Abstract

Background/Objectives: The clinical challenges of PARP inhibitors in ovarian cancer include the lack of effective maintenance regimens for homologous recombination proficiency (HRP) patients and the emergence of acquired resistance in initially responsive homologous recombination deficiency (HRD) patients. This study aims to explore the [...] Read more.

Background/Objectives: The clinical challenges of PARP inhibitors in ovarian cancer include the lack of effective maintenance regimens for homologous recombination proficiency (HRP) patients and the emergence of acquired resistance in initially responsive homologous recombination deficiency (HRD) patients. This study aims to explore the synergistic effect and molecular mechanism of the bispecific tyrosine phosphorylation-regulated kinase 1B (DYRK1B) inhibitor AZ191 combined with the PARP inhibitor Niraparib on high-grade serous ovarian cancer (HGSOC). Methods: This study first explored the expression and prognostic significance of DYRK1B in ovarian cancer through bioinformatics analysis. Subsequently, the therapeutic effect of the DYRK1B inhibitor AZ191 combined with Niraparib on HGSOC cells and organoids was evaluated by MTT examination. Flow cytometry and Western blot were used to investigate the synergistic mechanism between the two agents. Results: Bioinformatics analysis shows that the high expression of DYRK1B in serous ovarian cancer is associated with poor prognosis of the patients. The experiments in vitro have shown that the DYRK1B inhibitor AZ191 can enhance the therapeutic effect of Niraparib on HGSOC cells and organoids, whether HRD-positive or not. Mechanistic studies have shown that the combination of AZ191 and Niraparib can synergistically increase the accumulation of DNA damage, thereby intensifying the apoptosis of HGSOC cells. In addition, the combination therapy induces ferroptosis by inhibiting the Nrf2/SLC7A11/GPX4 axis, thereby exerting cytotoxic effects. Conclusions: Our results uncover a novel mechanism by which inhibiting DYRK1B enhances the anti-HGSOC efficacy of Niraparib and may offer a promising treatment strategy to improve the maintenance therapy in both HRD and HRP ovarian cancer patients. Full article

(This article belongs to the Special Issue Advances in Cancer Treatment)

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21 pages, 2463 KB

Open AccessArticle

Differential Effects of Donepezil and Tacrine on Recall-Phase Exploration in a Trihexyphenidyl-Induced Cholinergic Impairment Y-Maze Model

by Adrian-Florentin Dragomir, Smaranda Stoleru, Aurelian Zugravu, Elena Poenaru, Maria Carina Dumitrescu, Aurelia Cristiana Barbu, Silvia Fratea, Clara Maria Stoleru, Oana Andreia Coman and Ion Fulga

Biomedicines 2026, 14(4), 938; https://doi.org/10.3390/biomedicines14040938 - 20 Apr 2026

Cited by 3 | Viewed by 618

Abstract

Background/Objectives: Cholinergic dysfunction plays a central role in memory impairment, yet trihexyphenidyl (THP)-based paradigms remain less explored than scopolamine-based models. This study aimed to characterize a THP-induced cholinergic challenge in a two-trial Y-maze with a 24 h interval and to compare the effects [...] Read more.

Background/Objectives: Cholinergic dysfunction plays a central role in memory impairment, yet trihexyphenidyl (THP)-based paradigms remain less explored than scopolamine-based models. This study aimed to characterize a THP-induced cholinergic challenge in a two-trial Y-maze with a 24 h interval and to compare the effects of donepezil and tacrine on recall-phase exploratory allocation. Methods: Male Wistar rats (n = 9/group) were studied in a validation phase including saline, THP 5 mg/kg, and THP 10 mg/kg groups, followed by an intervention phase including control, THP 10 mg/kg, donepezil 1 and 3 mg/kg + THP, and tacrine 3 and 5 mg/kg + THP groups. All treatments were administered intraperitoneally (i.p.). Acquisition- and recall-phase behavior was analyzed. Recall outcomes included arm times, arm entries, the novel-to-familiar arm time ratio (U/K time ratio), the novel-to-familiar arm entry ratio (U/K entry ratio), discrimination indices and time-per-entry indices. Data were analyzed by one-way ANOVA; Tukey’s post hoc test was used in the validation experiment, whereas Dunnett’s test was used in the intervention experiment for comparisons against THP 10. Results: THP at 10 mg/kg produced a robust recall-phase phenotype, with increased familiar-arm exploration, reduced novel-arm exploration and lower normalized indices. Under THP challenge, donepezil was associated with clearer effects at 3 mg/kg, whereas tacrine displayed a broader dose-dependent profile, with the strongest shift in recall-phase exploratory allocation toward the novel arm observed at 5 mg/kg. Conclusions: THP 10 mg/kg produced a robust recall-phase exploratory phenotype in a 24 h two-trial Y-maze paradigm. Under THP challenge, donepezil and tacrine were associated with shifts in recall-phase exploratory allocation. These findings support the potential utility of THP-based paradigms for studying cholinergic disruption in Y-maze settings, while direct comparison with scopolamine-based models remains to be established. Full article

(This article belongs to the Special Issue Animal Models for Neurological Disease Research)

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16 pages, 1012 KB

Open AccessArticle

Coagulation and Blood Factors and Clinical Disease Indicators in Patients with Chronic Angioedema and Urticaria—A Validation Study

by Maja Štrajtenberger, Marinko Artuković, Iva Bešlić, Morana Belovic, Ivica Lokner and Liborija Lugović-Mihić

Biomedicines 2026, 14(4), 937; https://doi.org/10.3390/biomedicines14040937 - 20 Apr 2026

Viewed by 787

Abstract

Background: The interaction between coagulation pathways, inflammatory markers, and hematological parameters has not been sufficiently clarified in patients with chronic angioedema (AE) and urticaria. This study aimed to validate previously observed associations and to further explore their relationship with clinical disease control. Methods: [...] Read more.

Background: The interaction between coagulation pathways, inflammatory markers, and hematological parameters has not been sufficiently clarified in patients with chronic angioedema (AE) and urticaria. This study aimed to validate previously observed associations and to further explore their relationship with clinical disease control. Methods: In this cross-sectional validation study, 102 participants were enrolled and stratified into three groups: isolated AE (n = 33), AE associated with urticaria (AE/Urt; n = 34), and healthy controls (n = 35). Serum levels of coagulation factors (D-dimer, fibrinogen, factor VII), inflammatory markers (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR]), and complete blood count parameters were analyzed. Disease control was assessed using the Angioedema Control Test (AECT). Appropriate non-parametric statistical tests were applied. Results: Only D-dimer values differed significantly between groups and were higher in patients with AE/Urt than in controls. At the same time, D-dimers were significantly more often elevated in both AE groups than in healthy individuals. Additionally, CRP values in both AE groups were significantly more often elevated than in controls, with significantly higher values in both AE groups (in both groups 85%) than in controls (57%). Coagulation markers and CRP demonstrated a positive correlation with age (r = 0.268–0.392; p ≤ 0.007), with fibrinogen of all coagulation markers showing the strongest age dependency (r = 0.334; p = 0.001). Gender-related differences in coagulation parameters were not statistically significant, although elevated fibrinogen levels were more common in male participants (p = 0.030). Disease control did not correlate linearly with any inflammatory markers, coagulation factor, age or gender. Conclusions: The findings support a contributory role of coagulation pathway activation and systemic inflammation in the pathophysiology of chronic angioedema and urticaria. These mechanisms may influence clinical disease expression and could represent potential targets for improved diagnostic stratification and therapeutic approaches. However, the interpretation of the present results should be approached with caution in light of several important study limitations, including demographic heterogeneity between the study groups and the relatively limited sample size. Full article

(This article belongs to the Special Issue Advances in Skin Diseases)

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23 pages, 7269 KB

Open AccessArticle

Low-Dose Vitamin C-Based Electroporation of Solid Tumors: A New Area in Non-Cytotoxic Electrochemotherapy

by Seyed Mojtaba YazdanParast, Navid Manoochehri and Mohammad Abdolahad

Biomedicines 2026, 14(4), 936; https://doi.org/10.3390/biomedicines14040936 - 20 Apr 2026

Cited by 1 | Viewed by 842

Abstract

Background: Electrochemotherapy enhances the intracellular delivery of anticancer agents through electroporation but is traditionally limited to cytotoxic drugs associated with significant side effects. Vitamin C (ascorbic acid) exhibits selective anticancer activity when accumulated at high intracellular concentrations; however, its therapeutic application is [...] Read more.

Background: Electrochemotherapy enhances the intracellular delivery of anticancer agents through electroporation but is traditionally limited to cytotoxic drugs associated with significant side effects. Vitamin C (ascorbic acid) exhibits selective anticancer activity when accumulated at high intracellular concentrations; however, its therapeutic application is restricted by poor membrane permeability and rapid systemic clearance. Methods: In this study, we investigated whether reversible electroporation, applied using a custom-designed variable plate electrode system designed to deliver a uniform electric field, could potentiate the antitumor efficacy of low-dose vitamin C. Numerical simulations were performed to optimize electrode spacing and stimulation voltage, suggesting homogeneous electric field coverage throughout the tumor volume. The proposed approach was evaluated in vitro using MDA-MB-231 and 4T1 breast cancer cell lines and in vivo in a 4T1 murine breast cancer model. Results: Low-dose vitamin C alone produced minimal cytotoxic effects, whereas its combination with electroporation significantly reduced cell viability and increased apoptotic and necrotic cell death in vitro. In vivo, vitamin C–assisted electrochemotherapy resulted in pronounced tumor growth suppression, with tumor volumes reduced to approximately 0.34-fold of baseline by day 15, accompanied by decreased proliferation and marked tissue disruption. Conclusions: These findings demonstrate that uniform-field reversible electroporation markedly enhances the intracellular delivery and antitumor activity of low-dose vitamin C, supporting this technology-driven strategy as a promising, low-toxicity alternative to conventional chemotherapeutic agents in electrochemotherapy for solid tumors. Full article

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

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18 pages, 1165 KB

Open AccessArticle

Characteristics, Risk Stratification, and Outcomes of Upper Gastrointestinal Bleeding in Patients Receiving Antithrombotic Therapy

by Ragaey Ahmad Eid, Michael Nady Naguib, Amr Ahmed Abd El Bary, Mohamed Medhat Mohamed Zaki, Marwa O. Elgendy, Anwar M. Alnakhli, Mohammed Gamal and Mohamed Mohamed Tawfik

Biomedicines 2026, 14(4), 935; https://doi.org/10.3390/biomedicines14040935 - 20 Apr 2026

Viewed by 793

Abstract

Background/Objectives: Non-variceal upper gastrointestinal bleeding (NVUGIB) remains a major clinical emergency, particularly among patients receiving antiplatelet or anticoagulant therapy, whose use has increased substantially in recent years. This study aimed to evaluate the clinical characteristics, endoscopic findings, risk stratification, and [...] Read more.

Background/Objectives: Non-variceal upper gastrointestinal bleeding (NVUGIB) remains a major clinical emergency, particularly among patients receiving antiplatelet or anticoagulant therapy, whose use has increased substantially in recent years. This study aimed to evaluate the clinical characteristics, endoscopic findings, risk stratification, and outcomes of NVUGIB in patients receiving antithrombotic therapy, and to compare the predictive performance of commonly used prognostic scores. Methods: This prospective cohort study included 89 patients receiving antithrombotic therapy who presented with NVUGIB at Beni-Suef University Hospitals between March 2023 and March 2025. Clinical presentation, laboratory findings, and endoscopic characteristics were recorded. Risk stratification was assessed using Glasgow–Blatchford (GBS), Rockall, Baylor, AIMS65, ABC, and PNED scores. The optimal cut-off values for prediction of rebleeding and mortality were determined using receiver operating characteristic (ROC) analysis and the Youden index. Area under the curve (AUC) values were reported with 95% confidence intervals. Results: Endoscopy revealed that peptic ulcers were the most common lesion (41/89, 46%), followed by erosive disease (27/89, 30%), with the stomach being the most frequently involved site (76.5%). Rebleeding occurred in 16 patients (18.0%), while mortality was observed in 2 patients (2.2%). The Glasgow–Blatchford score demonstrated the most consistent performance for predicting rebleeding, with an optimal cutoff value of 5.5 (derived using the Youden index), yielding 92.9% sensitivity and 78.8% specificity. For mortality prediction, AIMS65, ABC, and PNED scores showed very high AUC values, although these findings should be interpreted cautiously due to the small number of mortality events (n = 2). No statistically significant difference in rebleeding or mortality was observed between single and dual antithrombotic therapy, although patients receiving dual therapy required longer hospitalization and more transfusion units. Conclusions: In patients with antithrombotic-related GI bleeding, ulcers and erosions predominate, with minimal differences between single and dual therapy outcomes. Concomitant NSAID use trends toward higher mortality. Glasgow–Blatchford score offers optimal performance for both rebleeding and mortality prediction, with a cutoff of 5.5 providing excellent sensitivity (92.9%) and specificity (78.8%) for rebleeding risk assessment. Full article

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

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41 pages, 794 KB

Open AccessReview

Diffuse Midline Gliomas: Clinical, Diagnostic, and Therapeutic Perspectives

by Sanyukta Bihari, Dia Yang, Devarshi Mukherji and Aya Haggiagi

Biomedicines 2026, 14(4), 934; https://doi.org/10.3390/biomedicines14040934 - 20 Apr 2026

Cited by 1 | Viewed by 4255

Abstract

Diffuse midline gliomas (DMGs) are rare but highly aggressive central nervous system (CNS) tumors that can present in both pediatric and adult populations. These tumors were redefined in the 2016 WHO classification of CNS tumors based on integrated histopathological and molecular features, and [...] Read more.

Diffuse midline gliomas (DMGs) are rare but highly aggressive central nervous system (CNS) tumors that can present in both pediatric and adult populations. These tumors were redefined in the 2016 WHO classification of CNS tumors based on integrated histopathological and molecular features, and were initially designated as “DMG, H3 K27M-mutant”. In the 2021 WHO update, DMGs were incorporated into the newly defined category of primarily pediatric-type diffuse high-grade gliomas, and nomenclature was changed to “DMG, H3 K27-altered” to encompass additional molecular drivers beyond the canonical H3 K27M mutation. Clinically, DMGs arise as expansile, infiltrating tumors within midline structures and may present as non-enhancing or enhancing lesions on imaging. Diagnosis is based on neuroimaging and molecular confirmation by immunohistochemistry or sequencing when tissue is available. DMGs are categorized as WHO grade 4 malignant tumors due to their aggressive biology leading to rapid and infiltrative growth. Owing to their deep and midline location, surgical resection is typically not feasible. Radiation therapy is the backbone of treatment, but there is no standard regimen of chemotherapy that has demonstrated durable efficacy. Recent progress in therapeutic approaches has led to a major breakthrough on 6 August 2025 when the U.S. Food and Drug Administration granted the accelerated approval of dordaviprone (ONC201), marking it as the first systemic therapy for progressive DMG harboring H3 K27M mutation. Other novel approaches, including chimeric antigen receptor (CAR) T-cell directed therapies and convection-enhanced delivery, are actively under investigation. We aim to comprehensively review DMGs, including the recent insights into their biology, the evolving therapeutic landscape, and the opportunities to fuel this new momentum against one of the most formidable gliomas. Full article

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

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13 pages, 1905 KB

Open AccessArticle

Semaglutide Prevents Aortic Rupture and Dissection in the Angiotensin II Mouse Model

by Amanda Balboa Ramilo, Kevin Mani, Anders Wanhainen, Henrik Lodén, Anna Nilsson, Per E. Andrén, Malou Friederich-Persson and Dick Wågsäter

Biomedicines 2026, 14(4), 933; https://doi.org/10.3390/biomedicines14040933 - 20 Apr 2026

Viewed by 1031

Abstract

Background and aims: Abdominal aortic aneurysm (AAA) is a vascular disease characterized by the progressive dilation of the aorta, culminating in rupture. At present, there are no pharmacological treatments to prevent AAA development or reduce rupture rate. A recent study showed that patients [...] Read more.

Background and aims: Abdominal aortic aneurysm (AAA) is a vascular disease characterized by the progressive dilation of the aorta, culminating in rupture. At present, there are no pharmacological treatments to prevent AAA development or reduce rupture rate. A recent study showed that patients prescribed Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have significantly lower risks of mortality, AAA repair, and acute abdominal aortic syndrome. Semaglutide is a GLP-1RA with increased agonist capacity and longer half-life, compared to earlier generations of GLP-1RAs. In this study, we aimed to investigate the role and mechanisms of semaglutide in the prevention of AAA development and rupture in a murine model. Methods: AAA was induced in apolipoprotein-E-deficient mice, by continuous subcutaneous infusion of angiotensin II. Treatment with semaglutide (12 µg/kg) began seven days after disease induction (rescue trial) or simultaneously with disease induction (prophylactic trial). At experimental endpoint, aortic diameter was measured by high-frequency ultrasound and the aortic tissue was collected for histological analysis. Results: Prophylactic treatment with semaglutide drastically reduced mortality by dissection and rupture during the first seven days of disease development, but did not affect AAA formation at 28 days. Histological evaluation of the aorta at day seven showed a normal vessel wall thickness with a trend for a higher content of collagen in the aortic wall in mice treated with semaglutide, compared to controls. Conclusions: Semaglutide prevents aortic rupture and dissection in the early phases of AAA development in the angiotensin II mouse model, likely by promoting the maintenance of an adequate proportion of collagen in the vessel wall. Full article

(This article belongs to the Special Issue Aortic Aneurysm: Mechanisms, Biomarkers, and Therapeutic Strategy)

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3 pages, 146 KB

Open AccessCorrection

Correction: Eldakhakhny et al. Prevalence and Factors Associated with Metabolic Syndrome Among Non-Diabetic Saudi Adults: A Cross-Sectional Study. Biomedicines 2023, 11, 3242

by Basmah Eldakhakhny, Sumia Enani, Hanan Jambi, Ghada Ajabnoor, Jawaher Al-Ahmadi, Rajaa Al-Raddadi, Lubna Alsheikh, Wesam H. Abdulaal, Hoda Gad, Anwar Borai, Suhad Bahijri and Jaakko Tuomilehto

Biomedicines 2026, 14(4), 932; https://doi.org/10.3390/biomedicines14040932 - 20 Apr 2026

Viewed by 471

Abstract

In the original publication [...] Full article

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

13 pages, 869 KB

Open AccessArticle

An Initial Indonesian Genome-Wide SNP-Array Study with Functional Variant Prioritization Reveals NASP and GPR78 Candidate SNVs in Hepatocellular Carcinoma

by Toar Jean Maurice Lalisang, Vania Myralda Giamour Marbun, Linda Erlina, Nathaniel Jason Zacharia, Kezia Nathania Limbong Allo, Fadilah Fadilah and Aisyah Fitriannisa Prawiningrum

Biomedicines 2026, 14(4), 931; https://doi.org/10.3390/biomedicines14040931 - 20 Apr 2026

Viewed by 735

Abstract

Background/Objectives: Population-specific genomic data are essential for understanding hepatocellular carcinoma (HCC) biology, particularly in underrepresented regions. This study aimed to perform exploratory single-nucleotide polymorphism (SNP)-array-based profiling of HCC tumor samples from Indonesian patients and to prioritize candidate functional variants using a systematic [...] Read more.

Background/Objectives: Population-specific genomic data are essential for understanding hepatocellular carcinoma (HCC) biology, particularly in underrepresented regions. This study aimed to perform exploratory single-nucleotide polymorphism (SNP)-array-based profiling of HCC tumor samples from Indonesian patients and to prioritize candidate functional variants using a systematic in silico framework. Methods: This retrospective cross-sectional study included 15 resected HCC cases with available formalin-fixed paraffin-embedded (FFPE) tumor tissue. Genome-wide SNP genotyping was performed using the Illumina Asian Screening Array. Following quality control and filtering, variants were annotated using the Ensembl Variant Effect Predictor. A case-only functional prioritization approach incorporating multiple in silico prediction tools was applied, followed by gene-level burden aggregation. Results: After multistep filtering, 11 samples and 104 prioritized variants were retained for analysis. Variants consisted predominantly of splice-region, missense, and regulatory changes. Gene-level burden analysis identified Nuclear Autoantigenic Sperm Protein (NASP, rs775916096) as the highest-ranked candidate gene, while G protein-coupled receptor 78 (GPR78, rs558447540) emerged as a secondary candidate with predicted functional annotations but currently limited biological evidence in HCC. Given the tumor-only design without matched normal tissue, the prioritized variants cannot be distinguished from rare germline variants. Conclusions: This exploratory SNP-array study provides a hypothesis-generating framework for functional variant prioritization in Indonesian HCC. NASP and GPR78 represent preliminary candidates that require validation in larger cohorts with matched normal tissue and sequencing-based confirmation. Full article

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

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16 pages, 1297 KB

Open AccessArticle

CytoSorb^® Hemoadsorption in Post-Cardiac Arrest Syndrome After Out-of-Hospital Cardiac Arrest: A Propensity Score-Matched Cohort Study

by Julian Kreutz, Klevis Mihali, Vivien Sievertsen, Lukas Harbaum, Georgios Chatzis, Styliani Syntila, Bernhard Schieffer and Birgit Markus

Biomedicines 2026, 14(4), 930; https://doi.org/10.3390/biomedicines14040930 - 19 Apr 2026

Viewed by 650

Abstract

Background: Post-cardiac arrest syndrome (PCAS) following out-of-hospital cardiac arrest (OHCA) is driven by global ischemia–reperfusion injury, endothelial dysfunction, and a dysregulated inflammatory response. This cascade frequently culminates in profound vasoplegia and multiorgan failure, even when guideline-directed post-resuscitation management is applied. Hemoadsorption using [...] Read more.

Background: Post-cardiac arrest syndrome (PCAS) following out-of-hospital cardiac arrest (OHCA) is driven by global ischemia–reperfusion injury, endothelial dysfunction, and a dysregulated inflammatory response. This cascade frequently culminates in profound vasoplegia and multiorgan failure, even when guideline-directed post-resuscitation management is applied. Hemoadsorption using the CytoSorb device may attenuate hyperinflammation and vasoplegia by removing circulating inflammatory and injury-related mediators. Methods: This single-centre, retrospective cohort study compared adults with PCAS following OHCA who received hemoadsorption with propensity score-matched controls (1:1 matching; n = 50 per group). For patients treated with hemoadsorption, data were analyzed within predefined intervals covering the 24 h preceding therapy initiation (T1) and the 24 h following the completion of the hemoadsorption treatment period (T2). Controls were evaluated at time points aligned to those of their matched hemoadsorption counterparts. Hemodynamic, metabolic, respiratory, and organ injury markers were assessed. Results: Formal between-group comparisons of temporal change between T1 and T2 showed no statistically significant differences between hemoadsorption-treated patients and matched controls across key parameters, including VIS (Δ −18.7 vs. −7.7; p = 0.183) and lactate (Δ −1.8 vs. −1.25 mmol/L; p = 0.780), as well as markers of organ injury, pH, and oxygenation. In exploratory ANCOVA models, only base excess was associated with treatment group (p = 0.035). Survival to hospital discharge was comparable (48% vs. 40%; p = 0.423), with similar neurological outcomes. Within the hemoadsorption group, pre–post comparisons around hemoadsorption initiation (T1–T2) demonstrated marked improvements, including reduced vasoactive support (VIS 70.0 to 12.1; p = 0.039), substantial lactate clearance (4.1 to 1.1 mmol/L; p < 0.001), and declines in organ injury markers (AST, ALT, LDH, myoglobin), alongside more pronounced platelet reduction compared with controls (129 to 57 × 10³/µL vs. 189 to 123 × 10³/µL). However, adjusted analyses indicated that these changes were primarily driven by baseline shock severity rather than a treatment-specific effect. Conclusions: In this propensity score-matched cohort of PCAS patients after OHCA, hemoadsorption was associated with within-group physiological changes but showed no detectable advantage over matched controls, with similar survival. These findings are hypothesis-generating and warrant prospective studies with standardized timing and phenotype-guided patient selection. Full article

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

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18 pages, 4124 KB

Open AccessArticle

IGF2BP2 Overexpression Predicts Poor Prognosis and Correlates with PD-L1 Expression in Intrahepatic Cholangiocarcinoma

by Jianan Shen, Aihua Yang, Xintao He, Tianyi Dai, Zexuan Hui, Youxiang Ding, Li Zhao and Jun Chen

Biomedicines 2026, 14(4), 929; https://doi.org/10.3390/biomedicines14040929 - 19 Apr 2026

Viewed by 778

Abstract

Background: The immunologically cold nature and immunosuppressive tumor microenvironment (TME) of intrahepatic cholangiocarcinoma (ICC) contribute to its poor prognosis. This study aims to identify novel biomarkers related to prognosis and TME in ICC. Methods: We first identified the high expression of [...] Read more.

Background: The immunologically cold nature and immunosuppressive tumor microenvironment (TME) of intrahepatic cholangiocarcinoma (ICC) contribute to its poor prognosis. This study aims to identify novel biomarkers related to prognosis and TME in ICC. Methods: We first identified the high expression of m6A reader insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) in ICC through bioinformatics screening. Subsequently, a retrospective study was conducted on 224 ICC patients who had undergone radical resection. The expression levels of IGF2BP2 and programmed death ligand 1 (PD-L1) were detected in a tissue microarray (TMA) using immunohistochemistry (IHC). The co-localization of IGF2BP2, PD-L1, programmed cell death protein 1 (PD-1), and CD8⁺T cells was evaluated by multiple immunofluorescence techniques. Results: IHC confirmed a significant upregulation of IGF2BP2 in tumor tissues compared with normal bile duct epithelia (p < 0.05). IGF2BP2 expression was positively correlated with PD-L1 expression (TPS R = 0.215, p = 0.016; CPS R = 0.295, p = 0.008). High IGF2BP2 expression was associated with increased PD-L1/PD-1 positivity and reduced CD8⁺T cell infiltration. Kaplan–Meier analysis revealed significantly worse 3-year overall survival (OS: 20.56% vs. 29.91%, p = 0.0291) and recurrence-free survival (RFS: 9.72% vs. 18.56%, p = 0.0372) in the IGF2BP2-high group. Multivariate analysis identified IGF2BP2 as an independent risk factor for both OS (HR = 1.683, p = 0.044) and RFS (HR = 1.946, p = 0.042). Conclusions: IGF2BP2, as a potential biomarker and independent prognostic factor for ICC, is associated with increased PD-L1 expression. Full article

(This article belongs to the Special Issue Drug Resistance and Tumor Microenvironment in Human Cancers)

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39 pages, 3908 KB

Open AccessReview

DSS Colitis Model: Traps, Tricks, and Reporting Recommendations

by Martina Perše

Biomedicines 2026, 14(4), 928; https://doi.org/10.3390/biomedicines14040928 - 18 Apr 2026

Cited by 4 | Viewed by 2408

Abstract

The dextran sodium sulfate (DSS) colitis model is the most widely used experimental model of inflammatory bowel disease (IBD) due to its simplicity and versatility, with over 7000 PubMed entries in the last decade and an exponential rise in recent years. Since its [...] Read more.

The dextran sodium sulfate (DSS) colitis model is the most widely used experimental model of inflammatory bowel disease (IBD) due to its simplicity and versatility, with over 7000 PubMed entries in the last decade and an exponential rise in recent years. Since its initial description in 1985, DSS colitis has been extensively evaluated across species, most notably in mice and rats, and has yielded substantial insights into IBD pathogenesis. However, the model’s multifactorial nature poses a dual challenge: it offers an opportunity but complicates study design, interpretation, and translational relevance. This complexity is worsened by inconsistent reporting, which hampers reproducibility and comparability across studies. The broad use of the DSS-induced colitis model yields numerous insights about the model, which help better understand its complexity, characteristics and limitations. Although DSS colitis is induced locally, inflammation in the colon and gut barrier destruction may also affect other organs (such as the liver and brain) and their metabolism and molecular responses, which, in turn, may interfere with colitis-underlying mechanisms and drug response, and may influence the interpretation of results. These intrinsic (intra-experimental) characteristics of the DSS model are summarised in the paper (colitis, gut–brain axis, gut–liver axis). In addition, the DSS model is heavily influenced by numerous extrinsic (inter-experimental) factors (environmental, microbiological, genetic), which may further complicate the colitis model, the study outcomes, and data interpretation, and these are also discussed in the paper. As science advances and new data accumulate, understanding the intricate interplay among internal mechanisms, external factors, and technical variables becomes increasingly essential for the accurate interpretation of DSS outcomes. This review synthesises the complexity and interdependence of factors shaping the DSS model, emphasising the need for meticulous reporting and consideration of methodological nuances to enhance reproducibility, interpretation, and translational value in DSS colitis research. In addition, the review provides practical guidance through a “traps and tricks” subsection and checklist table designed to provide a framework and practical recommendations to better understand, apply, and interpret DSS model results in the context of broader systemic and methodological considerations. Full article

(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements (4th Edition))

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17 pages, 9284 KB

Open AccessArticle

Synergistic Effects of Multi-Kinase Inhibition on LRRK2-G2019S and Alpha-Synuclein Pathologies in Models of Parkinson’s Disease

by Xiaoguang Liu, Sean Baxley, Michaeline L. Hebron and Charbel Moussa

Biomedicines 2026, 14(4), 927; https://doi.org/10.3390/biomedicines14040927 - 18 Apr 2026

Viewed by 807

Abstract

Introduction: Pathogenic mutations in leucine-rich repeat protein kinase-2 (LRRK2), particularly G2019S, constitute the most common cause of autosomal dominant PD. Methods: Mouse models encoding human mutant alpha-synuclein (SNCA A53T) and LRRK2 G2019S were treated with a brain-penetrant [...] Read more.

Introduction: Pathogenic mutations in leucine-rich repeat protein kinase-2 (LRRK2), particularly G2019S, constitute the most common cause of autosomal dominant PD. Methods: Mouse models encoding human mutant alpha-synuclein (SNCA A53T) and LRRK2 G2019S were treated with a brain-penetrant kinase inhibitor (BK40196). Behavior, nigrostriatal and mesolimbic dopamine (DA) pathways were examined. Results: Mice harboring LRRK2 G2019S do not show age-dependent motor symptoms, but mice encoding SNCA A53T display motor deficits, while both strains exhibit anxiety-like behavior and BK40196 improves motor and behavioral defects. BK40196, a multi-kinase inhibitor of Abelson (Abl), Discoidin domain receptor (DDR)-1, c-KIT and FYN, alters microglial morphology and alpha-synuclein levels in SNCA A53T mice and improves DA neurotransmission, primarily via the nigrostriatal system. BK40196 inhibits brain LRRK2 G2019S (IC₅₀ of 89nM) and does not affect phosphorylated or total peripheral LRRK2 levels (lungs, kidneys, liver, etc.). LRRK2 G2019S mice treated with BK40196 exhibit distinct increases in DA in mesolimbic neurons such as the nucleus accumbens (NAcc), suggesting differential mechanisms of DA neurotransmission in mutant alpha-synuclein and LRRK2 models of PD. Conclusions: LRRK2 G2019S may primarily involve mesolimbic pathways leading to nonmotor symptoms independent of the motor and behavioral manifestations associated with alpha-synuclein via the nigrostriatal system. BK40196 may provide a comprehensive and synergistic therapeutic approach that addresses multiple mechanisms to reduce the pathologies related to LRRK2 G2019S and/or SNCA in PD. The multiple pathologies of PD necessitate a holistic approach that simultaneously targets inflammation and autophagy and LRRK2 inhibition. Full article

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

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24 pages, 21494 KB

Open AccessPerspective

The Wound Healing: A Mystery Still to Be Solved—What Is the Future?

by Montserrat Fernández-Guarino, María Luisa Hernández Bule and Stefano Bacci

Biomedicines 2026, 14(4), 926; https://doi.org/10.3390/biomedicines14040926 - 18 Apr 2026

Viewed by 964

Abstract

This perspective contains the current understanding of the cellular and molecular mechanisms involved in wound healing (the articles taken into consideration relate to the three-year period 2023–2025). Nevertheless, these biological pathways remain inadequately characterized; this is seen by the modifications leading to pathological [...] Read more.

This perspective contains the current understanding of the cellular and molecular mechanisms involved in wound healing (the articles taken into consideration relate to the three-year period 2023–2025). Nevertheless, these biological pathways remain inadequately characterized; this is seen by the modifications leading to pathological conditions, such as keloids, chronic wounds, or hypertrophic scars and diabetic wounds. Focus is also directed to novel therapy suggested for these types of conditions. Understanding these scientific issues is crucial for professionals across many fields who see such presentations often. Full article

(This article belongs to the Special Issue Wound Healing: From Mechanisms to Therapeutic Approaches (2nd Edition))

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13 pages, 1193 KB

Open AccessReview

The Role of Laboratory Markers in Primary Biliary Cholangitis: A Clinical Review and a Case Report

by Raffaele Radice, Giulia Pollaroli, Michela Salvatici, Chiara Corrado, Francesca Rispoli, Stefania Pacchetti and Lorenzo Drago

Biomedicines 2026, 14(4), 925; https://doi.org/10.3390/biomedicines14040925 - 18 Apr 2026

Cited by 1 | Viewed by 1120

Abstract

Background: Primary biliary cholangitis (PBC) is a rare autoimmune liver disease characterized by marked clinical and serological heterogeneity. Although diagnosis is mainly based on antimitochondrial antibodies (AMAs) and alkaline phosphatase (ALP), non-classical presentations remain a relevant cause of diagnostic delay. In this context, [...] Read more.

Background: Primary biliary cholangitis (PBC) is a rare autoimmune liver disease characterized by marked clinical and serological heterogeneity. Although diagnosis is mainly based on antimitochondrial antibodies (AMAs) and alkaline phosphatase (ALP), non-classical presentations remain a relevant cause of diagnostic delay. In this context, laboratory medicine plays a pivotal role in both diagnosis and long-term disease management. Methods: This manuscript represents a structured clinical review of laboratory biomarkers relevant to the diagnosis, monitoring, and prognostic stratification of PBC, integrated with a representative atypical case with long-term follow-up to illustrate the practical application of laboratory-driven diagnostic. Results: The analysis confirms the central role of immunological and biochemical markers in treatment monitoring and prognostic assessment, while highlighting their limitations in selected clinical scenarios. The reported case, characterized by persistent AMA negativity and consistently normal ALP levels, illustrates how expanded laboratory testing can support the identification of non-standard disease phenotypes. In this setting, parallel testing for AMA- and PBC-specific autoantibodies was essential to achieve a correct diagnosis. Moreover, alternative biomarkers, including gamma-glutamyl transferase (GGT) and selected immunological markers, provided clinically meaningful information when conventional markers were not informative. Conclusions: By integrating current evidence with a long-term clinical case, this work moves beyond a descriptive overview and proposes a practical, laboratory-driven diagnostic and follow-up framework for PBC. It highlights laboratory opportunities to facilitate timely diagnosis, appropriate prognostic stratification, and disease monitoring, including the assessment of associated comorbidities. Full article

(This article belongs to the Topic Hepatobiliary and Pancreatic Diseases: Novel Strategies of Diagnosis and Treatments—Second Edition)

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15 pages, 793 KB

Open AccessSystematic Review

Revisiting the Role of Lorazepam as an Adjunct in the Management of Chemotherapy-Induced Nausea and Vomiting: A Systematic Review and Meta-Analysis

by Tzu-Rong Peng, Hung-Hong Lin, Ta-Wei Wu and Chin-Yu Hsu

Biomedicines 2026, 14(4), 924; https://doi.org/10.3390/biomedicines14040924 - 17 Apr 2026

Viewed by 1110

Abstract

Background/Objectives: While standard antiemetic regimens have evolved, breakthrough symptoms and anticipatory nausea persist. Lorazepam has historically been used as an adjunct, yet a comprehensive re-evaluation of its efficacy across historical trials is lacking. This study provides a synthesis of clinical evidence to [...] Read more.

Background/Objectives: While standard antiemetic regimens have evolved, breakthrough symptoms and anticipatory nausea persist. Lorazepam has historically been used as an adjunct, yet a comprehensive re-evaluation of its efficacy across historical trials is lacking. This study provides a synthesis of clinical evidence to re-evaluate the adjunctive therapeutic value of lorazepam, potentially addressing persistent gaps in emesis control, such as anticipatory and refractory symptoms. Methods: Following PRISMA guidelines, we analyzed eight randomized controlled trials (n = 864) published between 1989 and 1997. Primary endpoints included complete and improved responses for emesis and nausea. Results: Eight trials (n = 864), published between 1989 and 1997, met the inclusion criteria. Lorazepam-containing regimens significantly increased the complete response rate for overall emesis (OR = 1.55; 95% CI, 1.12–2.14; p = 0.008) and improved the response rate (OR = 1.50; 95% CI, 1.03–2.19; p = 0.04). Subgroup analysis of acute emesis showed consistent benefits (complete response OR = 1.77; 95% CI 1.23–2.55; p = 0.002). Nausea control also favored lorazepam, although the differences were not statistically significant. Sedation was more frequent with lorazepam (RR = 2.67; 95% CI 1.54–4.63), although no serious adverse events were reported. Conclusions: By revisiting decades of clinical evidence, this meta-analysis confirms that lorazepam provides a significant therapeutic advantage in controlling chemotherapy-related vomiting, particularly during the acute phase. While its direct efficacy alongside modern agents like NK1 receptor antagonists remains to be fully elucidated, the anxiolytic and amnestic properties of lorazepam remain a potential adjunct for managing complex CINV profiles. Careful dose titration is necessary to balance efficacy with sedation. Full article

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

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21 pages, 3234 KB

Open AccessArticle

The Effects of Past COVID-19 and Vaccination on Antibody Levels, Cellular Immunity, and Cytokine Production by Peripheral Blood Mononuclear Cells

by Yulia A. Desheva, Tatiana V. Gupalova, Polina A. Kudar, Galina F. Leontieva, Igor V. Kudryavtsev, Andrey S. Trulioff, Danila S. Guzenkov, Victoria A. Matyushenko, Elena A. Bormotova, Daniil D. Sokolovsky, Georgy A. Matveev, Boris P. Nikolaev and Alexander N. Suvorov

Biomedicines 2026, 14(4), 923; https://doi.org/10.3390/biomedicines14040923 - 17 Apr 2026

Cited by 1 | Viewed by 956

Abstract

Background/Objective: This study is a cross-sectional investigation of long-term immune responses measured at different time intervals after COVID-19 infections, vaccinations, or combined exposure. The focus is on immune reactivity against recombinant spike (S) and nucleocapsid (N) protein antigens. Materials and Methods: Serum antibody [...] Read more.

Background/Objective: This study is a cross-sectional investigation of long-term immune responses measured at different time intervals after COVID-19 infections, vaccinations, or combined exposure. The focus is on immune reactivity against recombinant spike (S) and nucleocapsid (N) protein antigens. Materials and Methods: Serum antibody levels were assessed up to four to four and a half years after infection or immunization, including virus-specific immunoglobulin G (IgG), IgA and IgM antibodies, as well as neutralizing antibodies against the S-protein. Cellular immunity was assessed by analyzing peripheral blood mononuclear cells (PBMC; n = 43 in first cohort, n = 32 in second cohort), including T-helper memory and cytotoxic subsets, and cytokine production after in vitro stimulation with recombinant SARS-CoV-2 proteins. A multiplex cytokine assay was used to analyze effector and regulatory immune responses. Results: Virus-specific IgG antibodies persisted for years after exposure to SARS-CoV-2, with IgG against the receptor-binding domain (RBD) correlating most strongly with neutralizing activity. Vaccinated individuals demonstrated higher IgA responses, whereas antibodies to the N-protein were associated with previous infection. No IgM antibodies were detected in any subjects, suggesting an immune response based on memory rather than ongoing infection. PBMCs from individuals with a history of both COVID-19 exposure and vaccination exhibited enhanced responsiveness, characterized by increased frequencies of memory T cells compared to vaccination alone. Stimulating with the S-protein induces higher cytokine production, including IFN-gamma, TNF-alfa, and IL-12(p70), compared with stimulation by the N-protein. Cytokines such as IL-10 and TGF-beta are also elevated, suggesting immune regulation rather than persistent inflammation. Conclusions: SARS-CoV-2 infection and vaccination are associated with persistent humoral and cellular immune responses detectable several years after exposure. Individuals with hybrid immunity exhibit broader and functionally enhanced immune reactivity, indicating more robust long-term immune memory. Future studies should focus on the long-term consequences of hybrid immunity and optimize other vaccine strategies, including recombinant antigen vaccines. Full article

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

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19 pages, 810 KB

Open AccessSystematic Review

TNF-α Polymorphisms in Major Depressive Disorder in Patients with and Without Cardiovascular Disease: A Systematic Review

by Antonio Avelino Ferreira Soares, Yago Rodrigues Gontijo, Dante Mafra Tourino Teixeira, Bruna Rodrigues Gontijo, Alexandre Sampaio Rodrigues Pereira, Larissa Sousa Silva Bonasser, Caroline Ferreira Fratelli, Calliandra Maria de Souza Silva and Izabel Cristina Rodrigues da Silva

Biomedicines 2026, 14(4), 922; https://doi.org/10.3390/biomedicines14040922 - 17 Apr 2026

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Abstract

Introduction: Major Depressive Disorder (MDD) has been increasingly associated with inflammatory dysregulation, particularly involving tumor necrosis factor-alpha (TNF-α). Genetic polymorphisms within the TNFA promoter region have been investigated as potential modulators of depressive susceptibility, symptom expression, treatment response, and inflammatory comorbidity. However, findings [...] Read more.

Introduction: Major Depressive Disorder (MDD) has been increasingly associated with inflammatory dysregulation, particularly involving tumor necrosis factor-alpha (TNF-α). Genetic polymorphisms within the TNFA promoter region have been investigated as potential modulators of depressive susceptibility, symptom expression, treatment response, and inflammatory comorbidity. However, findings remain inconsistent across populations and clinical contexts. Methods: This systematic review adhered to PRISMA 2020 guidelines and was registered in PROSPERO (CRD420251242724). Observational and interventional studies evaluating associations between TNFA polymorphisms—specifically rs1800629 (−308 G/A), rs1799724 (−857 C/T), and rs1799964 (−1031 T/C)—and MDD-related outcomes in adults were included. Data extraction and methodological quality assessment were performed independently using an adapted GRIPS framework. Results: Eleven studies met the inclusion criteria, with eight investigating MDD without cardiovascular comorbidity and three assessing cardiovascular populations. Across diverse cohorts, rs1800629 and rs1799724 did not demonstrate consistent associations with MDD susceptibility. Although isolated population-specific findings were reported, genotype and allele distributions were generally comparable between cases and controls. Rs1799724 was associated with symptom dimensions and altered TNF-α expression in two cohorts. Rs1799964 was not linked to disease occurrence but showed potential association with antidepressant response and adverse cardiovascular outcomes in patients with chronic heart failure and comorbid depression. Overall, findings were heterogeneous and influenced by population characteristics, sample size, and clinical context. Conclusions: Current evidence does not support a robust etiological role for TNFA promoter polymorphisms in major depressive disorder. These variants may exert context-dependent modulatory effects on symptom expression, treatment response, or inflammatory-cardiovascular interactions rather than serving as primary susceptibility determinants. Larger, ethnically diverse studies integrating genetic, inflammatory, and clinical data are required to clarify the contribution of inflammatory genetic variability in depressive disorders. Full article

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

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30 pages, 1291 KB

Open AccessReview

Nanocarrier-Based Therapeutic Strategies in Myocardial Ischemia–Reperfusion Injury: A Systematic Review of Preclinical Evidence

by Michał Porada, Bartosz Pawełczak, Karolina Barańska-Pawełczak and Krzysztof Marciniec

Biomedicines 2026, 14(4), 921; https://doi.org/10.3390/biomedicines14040921 - 17 Apr 2026

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Abstract

Background/Objectives: Myocardial ischemia–reperfusion injury (MIRI) remains an ever-growing threat in the field of cardiology, as it has become a major risk factor for unfavorable outcomes following reperfusion therapies. Oxidative stress and inflammation remain the key pathophysiological mechanisms underlying MIRI, and the presently [...] Read more.

Background/Objectives: Myocardial ischemia–reperfusion injury (MIRI) remains an ever-growing threat in the field of cardiology, as it has become a major risk factor for unfavorable outcomes following reperfusion therapies. Oxidative stress and inflammation remain the key pathophysiological mechanisms underlying MIRI, and the presently available treatments fail to prevent this process effectively. This systematic review aimed to summarize and critically assess the latest preclinical research (2020–2026) on nanocarrier-based interventions targeting oxidative stress in MIRI, highlighting the potential of the new nanostructures in cardioprotection. Methods: A total of 24 studies meeting the PRISMA criteria have been found through a literature search of PubMed, Embase, and Web of Science databases published between 2020 and 2026. The studies eligible for inclusion had focused on the efficacy of nanocarrier-based interventions in preclinical studies of MIRI. Results: Of the 24 included studies, all investigated nanocarrier-based interventions in preclinical models of MIRI. In vitro, ex vivo, and in vivo models were diverse, with most studies being a combination of both in vitro and in vivo models. Commonly studied were lipid-based nanocarriers, polymeric nanoparticles, and biomimetic nanocarriers. Across studies assessed for this review, treatments with nanocarriers were seen to suppress inflammatory and oxidative stress pathways, with a few studies showing a suppression of cardiomyocyte apoptosis. Cardiac function was restored as determined by echocardiography analyses or ex vivo models of the myocardium, thus validating that the nanocarrier-mediated therapies are effective against MIRI. Conclusions: The analyzed preclinical studies indicate that the described therapies could provide a promising basis for future clinical trials in the treatment of MIRI, provided their safety and efficacy are confirmed in clinical trials. Full article

(This article belongs to the Special Issue State-of-the-Art Drug Discovery and Development in Poland (3rd Edition))

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13 pages, 1916 KB

Open AccessArticle

Valosin-Containing Protein (VCP)/p97 Expression Correlation of Prognosis of Clear Cell Renal Cell Carcinomas

by Akgül Arıcı, Elif Akçay, Seda Ocaklı, Osman Demir and Fikret Erdemir

Biomedicines 2026, 14(4), 920; https://doi.org/10.3390/biomedicines14040920 - 17 Apr 2026

Viewed by 603

Abstract

Background/Objectives: Although certain established prognostic factors may occasionally fail to provide precise risk prediction in renal cell carcinoma (RCC), valosin-containing protein (VCP)/p97 has been implicated in a poor prognosis in various cancers, while its prognostic value in clear cell renal cell carcinoma [...] Read more.

Background/Objectives: Although certain established prognostic factors may occasionally fail to provide precise risk prediction in renal cell carcinoma (RCC), valosin-containing protein (VCP)/p97 has been implicated in a poor prognosis in various cancers, while its prognostic value in clear cell renal cell carcinoma (ccRCC) remains unknown. This study aimed to determine the independent prognostic value of VCP/p97 expression in ccRCC. Methods: This retrospective study included 137 ccRCC patients, and VCP/p97 expression was analyzed by immunohistochemistry and classified into either low or high expression based on the intensity of the staining in relation to the expression in endothelial cells. Results: High expression of VCP/p97 was significantly correlated with large tumor size (p < 0.001), Fuhrman nuclear grade (p = 0.003), advanced TNM stage (p < 0.001), and distant metastasis (p < 0.001). Kaplan–Meier analysis showed that the survival of patients with high expression of VCP/p97 was significantly reduced, and multivariate analysis revealed that high expression of VCP/p97 independently predicted poor survival (HR 2.09, 95% CI 1.06–4.15, p = 0.034) in addition to age, Fuhrman grade, and TNM stage. Conclusions: This study demonstrated that VCP/p97 expression, a newly identified prognostic factor, independently predicted a poor prognosis in ccRCC, and its expression may be a useful tool in identifying ccRCC patients with a poor prognosis. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches (3rd Edition))

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19 pages, 3197 KB

Open AccessArticle

Paracrine Induction of Cardiomyogenic Differentiation in Patient-Specific MSCs Using Conditioned Medium from iPSC-CMs

by Veronika Litvinenko, Rose Alkhateeb, Serafima Romanova, Sandaara Kovalenko, Vitalii Dzhabrailov, Mikhail A. Popov, Mikhail Slotvitsky, Evgeniy G. Agafonov, Vladislav V. Dontsov, Sheida Frolova, Dmitriy I. Zybin, Dmitriy V. Shumakov, Alexander Romanov, Konstantin Agladze and Valeriya A. Tsvelaya

Biomedicines 2026, 14(4), 919; https://doi.org/10.3390/biomedicines14040919 - 17 Apr 2026

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Abstract

Background/Objectives: Patient-derived mesenchymal stem cells (MSCs) represent a promising avenue for myocardial regeneration, yet therapeutic application remains limited by inconsistent differentiation capacity and the absence of standardized cardiogenic induction protocols. This study demonstrates a proof-of-concept for guiding patient-specific bone marrow MSCs toward [...] Read more.

Background/Objectives: Patient-derived mesenchymal stem cells (MSCs) represent a promising avenue for myocardial regeneration, yet therapeutic application remains limited by inconsistent differentiation capacity and the absence of standardized cardiogenic induction protocols. This study demonstrates a proof-of-concept for guiding patient-specific bone marrow MSCs toward a functional cardiomyocyte phenotype using paracrine signals from differentiating iPSC-derived cardiomyocytes (iPSC-CMs). Materials and Methods: MSCs were maintained in conditioned medium from a concurrent, validated iPSC-CM differentiation protocol, with evaluation via immunocytochemistry, optical mapping, and whole-cell patch-clamp recordings. Results: Differentiated MSCs acquired organized sarcomeric architecture with cross-striations and displayed spontaneous calcium oscillations with decay kinetics matching source iPSC-CMs (CaT50 ≈ 283 ms vs. 301 ms). In co-culture, MSC-derived cells exhibited synchronized calcium dynamics with iPSC-CMs, confirming functional coupling, while patch-clamp detected hallmark cardiac ion currents (INa, ICa,L, and IKv). Morphologically, MSC-CMs displayed more mature, elongated rod-like shapes. Conclusions: Although current densities indicate partial immaturity, their reproducible detection validates successful cardiomyogenic commitment. This “parallel differentiation” platform eliminates donor-specific protocol tuning, providing a streamlined, paracrine-mediated approach to generate autologous cardiomyocyte-like cells for disease modeling, pharmacological testing, and future regenerative applications. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Bioengineering Tools to Pharmacological Therapies)

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Biomedicines, Volume 14, Issue 4 (April 2026) – 212 articles

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