Biomedicines

15 pages, 3147 KiB

Open AccessArticle

Cardiac Phase-Resolved T₂^* Magnetic Resonance Imaging Reveals Differences Between Normal Hearts and a Humanized Mouse Model of Hypertrophic Cardiomyopathy

by Oumaima Laghzali, Shahriar Shalikar, Siqin Liu, Sandra Lehmann, Joao dos Santos Periquito, Andreas Pohlmann, Sonia Waiczies, Lucie Carrier, Hsin-Jung Yang, Thoralf Niendorf and Min-Chi Ku

Biomedicines 2025, 13(5), 1193; https://doi.org/10.3390/biomedicines13051193 (registering DOI) - 14 May 2025

Abstract

Background/Objectives: While T₂^* mapping effectively assesses cerebral blood oxygenation, its utility for capturing cardiac phase-dependent myocardial changes in hypertrophic cardiomyopathy (HCM) is underexplored. This study investigates T₂^* dynamics in an HCM mouse model, to validate T₂^* [...] Read more.

Background/Objectives: While T₂^* mapping effectively assesses cerebral blood oxygenation, its utility for capturing cardiac phase-dependent myocardial changes in hypertrophic cardiomyopathy (HCM) is underexplored. This study investigates T₂^* dynamics in an HCM mouse model, to validate T₂^* as a clinically relevant biomarker for improved HCM diagnosis and treatment monitoring. Methods: A cardiac-specific Mybpc3 genetic mouse model, closely mirroring human HCM, was used with 12 young mice (6–11 weeks old), including both male and female wild-type (WT) and Mybpc3-KI (HCM) groups. The cardiac function was assessed using self-gated multi-slice 2D CINE imaging. To investigate myocardial T₂^* variations across the cardiac cycle, multi-gradient echo (MGE) imaging was employed. This approach used retrospective gating and continuous acquisition synchronization with pulse oximetry at 9.4 T small animal MRI. Results: Mybpc3-KI mice demonstrated left-ventricular (LV) hypertrophy compared to WT (HCM = 50.08 ± 4.68 µm/g vs. WT = 45.80 ± 20.07 µm/g, p < 0.01) and reduced ejection fraction (HCM = 38.55 ± 5.39% vs. WT= 72.53 ± 3.95%, p < 0.01). Myocardial T₂^* was significantly elevated in HCM across all cardiac phases (HCM = 12.14 ± 1.54 ms vs. WT = 7.93 ± 1.57 ms, p = 0.002). Strong correlations were observed between myocardial T₂^* and LV mass (rho = 0.88, p = 0.03). Conclusions: T₂^* was elevated in HCM with increased LV mass, highlighting the potential of T₂^* MRI as a sensitive biomarker for distinguishing healthy mice from those with HCM and revealing possible myocardial abnormalities. Full article

(This article belongs to the Special Issue Pathogenesis, Diagnosis, and Treatment of Cardiomyopathy)

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15 pages, 3402 KiB

Open AccessArticle

Loss of miRNA-Mediated VEGFA Regulation by SNP-Induced Impairment: A Bioinformatic Analysis in Diabetic Complications

by Raquel Freitas, Stela Felipe, Christina Pacheco, Emmanuelle Faria, Jonathan Martins, Jefferson Fortes, Denner Silva, Paulo Oliveira and Vania Ceccatto

Biomedicines 2025, 13(5), 1192; https://doi.org/10.3390/biomedicines13051192 (registering DOI) - 14 May 2025

Abstract

Background/Objectives: MicroRNAs (miRNAs) are molecules involved in biological regulation processes, including type 2 diabetes and its complications development. Single nucleotide polymorphisms (SNPs) can alter miRNA mechanisms, resulting in loss or gain effects. VEGFA is recognized for its role in angiogenesis. However, its [...] Read more.

Background/Objectives: MicroRNAs (miRNAs) are molecules involved in biological regulation processes, including type 2 diabetes and its complications development. Single nucleotide polymorphisms (SNPs) can alter miRNA mechanisms, resulting in loss or gain effects. VEGFA is recognized for its role in angiogenesis. However, its overexpression can lead to deleterious effects, such as disorganized and inefficient vasculature. Under hyperglycemic conditions, VEGFA expression seems to increase, which may contribute to the development of microvascular and macrovascular diabetic complications. Several miRNAs are associated with VEGFA regulation and seem to act in the prevention of dysregulated expression. This study aimed to investigate SNPs in miRNA regions related to the loss effect in VEGFA regulation, examining their frequency and potential physiological effects in the development of diabetic complications. Methods: VEGFA-targeting miRNAs were identified using the R package multimiR, with validated and predicted results. Tissue expression analysis and SNP search were data-mined with Python 3 for miRNASNP-v3 SNP raw databases. Allele frequencies were obtained from dbSNP. The miRNA–mRNA interaction comparison was obtained in the miRmap tool through Python 3. MalaCards were used to infer physiological disease association. Results: The variant rs371699284 was selected in hsa-miR-654-3p among 103 potential VEGFA-targeting miRNAs. This selected SNP demonstrated promising results in bioinformatics predictions, tissue-specific expression, and population frequency, highlighting its potential role in miRNA regulation and the resulting loss in VEGFA-silencing efficiency. Conclusions: Our findings suggest that carriers of rs1238947970 may increase susceptibility to diabetic microvascular and macrovascular complications. Furthermore, in vitro and in silico studies are necessary to better understand these processes. Full article

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

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11 pages, 358 KiB

Open AccessArticle

Preimplantation Testing of Human Blastomeres for Aneuploidy Increases IVF Success in Couples Where Male Partners Had Abnormal Semen Parameters

by Mahira Ismayilova, Aytakin Hasanova and Andrei Semikhodskii

Biomedicines 2025, 13(5), 1191; https://doi.org/10.3390/biomedicines13051191 (registering DOI) - 13 May 2025

Abstract

Background/Objectives: Male infertility is becoming a serious problem affecting about 7% of all men worldwide and is a major or contributory factor in 50% of infertile couples overall. Men with abnormal semen parameters have a significantly increased risk of aneuploidy, presenting a serious [...] Read more.

Background/Objectives: Male infertility is becoming a serious problem affecting about 7% of all men worldwide and is a major or contributory factor in 50% of infertile couples overall. Men with abnormal semen parameters have a significantly increased risk of aneuploidy, presenting a serious concern in programmes of assisted reproductive technologies. Recently, the introduction of preimplantation genetic testing for aneuploidies (PGT-A) has increased the pregnancy rate and live births. We investigated the effect of PGT-A on the success of IVF treatment in couples with the male factor of infertility. Methods: Two experimental groups and one control group were studied: Group A (110 couples)—male partners with abnormal semen parameters, with PGT-A; Group B (110 couples)—male partners with abnormal semen parameters, without PGT-A; and Group C (105 couples)—control, male partners with normal spermograms, with PGT-A. A Day 3 blastomere biopsy was followed by FISH-based PGT-A. A total of 880 embryos from Group A and 890 embryos from Group C was analysed. Results: In patients with abnormal semen parameters, embryonic aneuploidy was twice as common compared to the control (13.6% vs. 5.8%, p < 0.001). Group B had the lowest clinical pregnancy rate (28.2%), with two out of three pregnancies ending in a miscarriage. Only 10% of IVF cycles in this group resulted in live birth compared with 35.5% for Group A and 49.5% for Group C. Conclusions: Our data demonstrate that PGT-A screening as part of IVF treatment drastically increases the clinical pregnancy rate and chances of live birth in couples where male partners have semen abnormality. Full article

(This article belongs to the Special Issue The Art of ART (Assisted Reproductive Technologies))

7 pages, 196 KiB

Open AccessEditorial

Special Issue “Brain Injury: New Insights into Mechanisms and Future Promising Treatments”

by Kristina Pilipović and Petra Dolenec

Biomedicines 2025, 13(5), 1190; https://doi.org/10.3390/biomedicines13051190 (registering DOI) - 13 May 2025

Abstract

This Special Issue of Biomedicines presents 12 published, peer-reviewed articles on the theme of “Brain Injury: New Insights into Mechanisms and Future Promising Treatments”, including 10 original research papers and 2 reviews covering the topics related to the pathophysiology of acquired central nervous [...] Read more.

This Special Issue of Biomedicines presents 12 published, peer-reviewed articles on the theme of “Brain Injury: New Insights into Mechanisms and Future Promising Treatments”, including 10 original research papers and 2 reviews covering the topics related to the pathophysiology of acquired central nervous system (CNS) injuries, as well as biomarker discovery, diagnosis, and potential pharmacological and non-pharmacological approaches in the treatment of these disorders [...] Full article

(This article belongs to the Special Issue Brain Injury: New Insights into Mechanisms and Future Promising Treatments)

44 pages, 840 KiB

Open AccessSystematic Review

MicroRNA Signatures in Endometrial Receptivity—Unlocking Their Role in Embryo Implantation and IVF Success: A Systematic Review

by Charalampos Voros, Antonia Varthaliti, Diamantis Athanasiou, Despoina Mavrogianni, Kyriakos Bananis, Antonia Athanasiou, Aikaterini Athanasiou, Anthi-Maria Papahliou, Constantinos G. Zografos, Panagiota Kondili, Maria Anastasia Daskalaki, Dimitris Mazis Kourakos, Dimitrios Vaitsis, Marianna Theodora, Panagiotis Antsaklis, Dimitrios Loutradis and Georgios Daskalakis

Biomedicines 2025, 13(5), 1189; https://doi.org/10.3390/biomedicines13051189 (registering DOI) - 13 May 2025

Abstract

Background: Endometrial receptivity is crucial for successful embryo implantation in assisted reproductive technologies (ARTs). MicroRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) have emerged as important post-transcriptional regulators of endometrial function, although their diagnostic and molecular functions are poorly understood. Methods: [...] Read more.

Background: Endometrial receptivity is crucial for successful embryo implantation in assisted reproductive technologies (ARTs). MicroRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) have emerged as important post-transcriptional regulators of endometrial function, although their diagnostic and molecular functions are poorly understood. Methods: A systematic review was conducted following PRISMA 2020 principles and registered in PROSPERO (CRD420251001811). We looked at 28 peer-reviewed publications published between 2010 and 2025 that used endometrial tissue, blood, uterine fluid, saliva, and embryo culture medium to study miRNAs and other non-coding RNAs in endometrial receptivity, recurrent implantation failure (RIF), and infertility. Results: MiRNAs like miR-145, miR-30d, miR-223-3p, and miR-125b influence implantation-related pathways such as HOXA10, LIF-STAT3, PI3K-Akt, and Wnt/β-catenin. Dysregulated expression profiles were linked to inadequate decidualization, immunological imbalance, and poor angiogenesis. CeRNA networks that include lncRNAs (e.g., H19 and NEAT1) and circRNAs (e.g., circ_0038383) further regulate miRNA activity. Non-invasive biomarkers derived from plasma, uterine fluid, and embryo media showed high prediction accuracy for implantation outcomes. Conclusions: MiRNA signatures offer a functional and diagnostic blueprint for endometrial receptivity. This systematic review provides a timely and thorough synthesis of the existing literature, with the goal of bridging the gap between molecular discoveries and therapeutic applications. By emphasizing both the mechanistic importance and diagnostic value of certain miRNA signatures, it paves the way for future precision-based techniques in embryo transfer and endometrial assessment in ART. Full article

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

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23 pages, 2218 KiB

Open AccessReview

Epigenetic Therapies in Melanoma—Targeting DNA Methylation and Histone Modification

by Adrian Bogdan Tigu, Andrei Ivancuta, Andrada Uhl, Alexandru Cristian Sabo, Madalina Nistor, Ximena-Maria Mureșan, Diana Cenariu, Tanase Timis, Doru Diculescu and Diana Gulei

Biomedicines 2025, 13(5), 1188; https://doi.org/10.3390/biomedicines13051188 - 13 May 2025

Abstract

Skin cancer prevalence has increased during the last decades, with the last years serving as a pivotal moment for comprehending its epidemiological patterns and its impact on public health. Melanoma is one of the most frequently occurring malignancies, arising from a complex interplay [...] Read more.

Skin cancer prevalence has increased during the last decades, with the last years serving as a pivotal moment for comprehending its epidemiological patterns and its impact on public health. Melanoma is one of the most frequently occurring malignancies, arising from a complex interplay of genetic factors, environmental factors, lifestyle and socio-economic conditions. Epigenetic changes play a critical role in tumor development, influencing progression and aggressiveness. Epigenetic therapies could represent novel therapeutic options, while drug repositioning may serve as a viable strategy for cancer treatment. Demethylating agents, commonly used in hematological malignancies, show promising results on solid tumors, including melanoma. Methylation patterns are responsible for tumor development by modulating gene expression, while histone acetylation influences DNA processes such as transcription, replication, repair, and recombination. This review aims to identify existing potential therapeutical approaches using therapeutic agents that can modulate DNA methylation and histone modification, which can lead to tumor inhibition, cell death initiation and reactivation of tumor suppressor genes. Full article

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

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18 pages, 4023 KiB

Open AccessArticle

Evaluation of Platelet Lysate-Based Medium and Protein Substrate for HUVEC Culture and Expansion

by Juan Manuel Duarte Rojas, Luz Marina Restrepo Múnera and Sergio Estrada Mira

Biomedicines 2025, 13(5), 1187; https://doi.org/10.3390/biomedicines13051187 - 13 May 2025

Abstract

Background/Objectives: Endothelial cell (EC) culture relies on specialized and commercial media with distinct growth supplement compositions. These media are expensive and must be imported, increasing the time to effective use. Human platelet lysate (PL) and platelet lysate serum (PLS) supplemented media are emerging [...] Read more.

Background/Objectives: Endothelial cell (EC) culture relies on specialized and commercial media with distinct growth supplement compositions. These media are expensive and must be imported, increasing the time to effective use. Human platelet lysate (PL) and platelet lysate serum (PLS) supplemented media are emerging alternatives to commercial media. Methods: Umbilical cords were collected, and human umbilical vein endothelial cells (HUVEC) were isolated and cultured using different media formulations, using Endothelial Cell Growth, Promocell^® (ECGM-Promocell^®) commercial medium, and media supplemented with PL and PLS. Results: A mixed medium combining DMEM-F12 + PLS and ECGM-Promocell^® maintained EC viability, adhesion, and proliferation. Introducing a PL-derived protein substrate enhanced cell adhesion and proliferation by simulating an extracellular matrix. Flow cytometry revealed positive CD31, CD144, and CD146 markers in cells cultured with ECGM-Promocell^® and the mixed medium, with or without the PL-protein substrate. Conclusions: These findings suggest that the mixed medium, especially with the PL protein substrate, offers a cost-effective and efficient approach for EC culture and proliferation, holding promise for research and therapeutic applications. Full article

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

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11 pages, 898 KiB

Open AccessArticle

Intracardiac Echo Versus Fluoroscopic Guidance for Pulsed Field Ablation: Single-Center Real-Life Study

by Vivek Joseph Varughese, James Pollock, Chandler Richardson, Dominic Vacca, Hata Mujadzic and Sultan Siddique

Biomedicines 2025, 13(5), 1186; https://doi.org/10.3390/biomedicines13051186 - 13 May 2025

Abstract

Background: Pulsed field ablation (PFA) is a novel non-thermal modality for catheter ablation (CA) in atrial fibrillation (AF) and has been replacing traditional thermal modalities. There have been studies in the past comparing fluoroscopic (FL) versus intracardiac echocardiogram (ICE) guidance for thermal ablation [...] Read more.

Background: Pulsed field ablation (PFA) is a novel non-thermal modality for catheter ablation (CA) in atrial fibrillation (AF) and has been replacing traditional thermal modalities. There have been studies in the past comparing fluoroscopic (FL) versus intracardiac echocardiogram (ICE) guidance for thermal ablation modalities. However, there have not been studies that compare outcomes for PFA performed under ICE versus FL guidance. Methods: This study was designed in a longitudinal cross-sectional format. A total of 196 patients who underwent PFA for AF at Prisma Health Richland were selected for the retrospective analysis. Patients were divided into two groups: those who underwent PFA under FL guidance (103 patients) versus ICE guidance (93 patients). The recurrence of atrial arrhythmias in the six-month follow-up period was studied. Multivariate regression analysis was performed to assess the difference in the association of either modality with recurrence of atrial arrhythmias. Bayesian non-inferiority models were used to analyze the non-inferiority between the modalities. Results: A total of 31 patients (30.1%) in the fluoro group had documented atrial arrhythmias in the six months following ablation. While 23 patients (24.7%) in the ICE group had documented atrial arrhythmias in the six-month follow-up period. The recurrence of AF was noted in 22.3% (22 patients) in the fluoro group and 14% (13 patients) in the ICE group. After running the multivariate regression analysis models, PFA under fluoroscopic guidance did not differ from ICE guidance, in terms of the recurrent atrial arrhythmias in the six-month follow-up (Adjusted Odds Ratio: 0.964; 95% CI: 0.336–2.772). The fluoro and ICE groups also did not differ in terms of six-month atrial fibrillation recurrence (Adjusted Odds Ratio: 2.43; 95% CI: 0.649–9.19). Non-inferiority analysis with Bayesian model was carried out, comparing the fluoro group and the ICE group in terms of freedom from arrhythmias in the six-month follow-up, and no inferiority was proved (95% confidence interval: −0.18–0.053), with a 61.03% chance of ICE-guided PFA being superior to fluoro guidance in terms of recurrence free interval, but statistical significance was not reached. Conclusions: Mean fluoroscopic time in the FL guidance group was 15.9 min, while no radiation exposure was documented in the ICE group. CA performed under FL versus ICE guidance did not differ statistically in terms of six-month recurrence of atrial arrhythmias in general and AF in particular. Full article

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

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17 pages, 2579 KiB

Open AccessArticle

The Effect of Fungal Nutraceutical Supplementation on Postoperative Complications, Inflammatory Factors and Fecal Microbiota in Patients Undergoing Colorectal Cancer Surgery with Curative Intent: A Randomized, Placebo-Controlled, Double-Blind Clinical Trial

by Cristina Regueiro, Astrid Irene Diez Martín, Sonia Pérez, Carlos Daviña-Núñez, Sara Zarraquiños, David Remedios, Cristina Alejandra Sánchez Gómez, Sara Alonso Lorenzo, Romina Fernández Poceiro, María Luisa de Castro Parga, Vicent Hernández Ramírez, Arturo Rodríguez-Blanco, Esteban Sinde, Catalina Fernández-de-Ana and Joaquín Cubiella

Biomedicines 2025, 13(5), 1185; https://doi.org/10.3390/biomedicines13051185 - 13 May 2025

Abstract

Background/Objectives: The combination of different fungal extracts could be beneficial to cancer patients due to their role in gut microbiota modulation and anti-inflammatory activity. The study aimed to evaluate whether fungal extract supplementation reduces postsurgical complications in patients with colorectal cancer undergoing curative [...] Read more.

Background/Objectives: The combination of different fungal extracts could be beneficial to cancer patients due to their role in gut microbiota modulation and anti-inflammatory activity. The study aimed to evaluate whether fungal extract supplementation reduces postsurgical complications in patients with colorectal cancer undergoing curative surgery. Methods: Patients were randomized to receive the nutraceutical Micodigest 2.0 or a placebo until surgery. Surgical complications were evaluated using the Clavien-Dindo classification. We also assessed the effect of the nutraceutical on gut microbiota composition, inflammatory response, nutritional status, and quality of life. A subanalysis based on surgery type (robotic vs. non-robotic) was performed. Results: We included 46 patients who met the inclusion criteria, with 27 randomized to the intervention group and 19 to the placebo group, receiving treatment for three (2–4) weeks. Non-robotic surgery was performed in 35 (76.1%) patients. We found non-significant differences in postoperative complications (Micodigest 2.0: 25.9%, placebo: 26.3%; p = 0.9). In non-robotic surgery, we identified a non-significant reduction in postoperative complications (Micodigest 2.0: 25.0%, placebo: 36.4%; p = 0.7), as well as a significant increase in lymphocyte levels and a reduction in the neutrophil-to-lymphocyte ratio (p = 0.02). Micodigest 2.0 supplementation was also associated with significant changes in gut microbiota composition, as indicated by a decreased relative abundance of the phyla Firmicutes (p = 0.004) and Actinobacteria (p = 0.04). Conclusions: Micodigest 2.0 supplementation was associated with non-significant reductions in postoperative complications and significant modifications in gut microbiota composition. Limitations: The trial did not reach the calculated sample size. Full article

(This article belongs to the Special Issue Colorectal Cancer: Diagnostic, Pathophysiology and Therapeutic Approaches)

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31 pages, 3417 KiB

Open AccessReview

Green Synthesis, Characterization, and Potential Antibacterial and Anticancer Applications of Gold Nanoparticles: Current Status and Future Prospects

by Md. Amdadul Huq, Md. Rasel Rana, Abdus Samad, Md. Shahedur Rahman, M. Mizanur Rahman, Md Ashrafudoulla, Shahina Akter and Jong-Whi Park

Biomedicines 2025, 13(5), 1184; https://doi.org/10.3390/biomedicines13051184 - 13 May 2025

Abstract

Drug resistance is a serious problem for human health worldwide. Day by day this drug resistance is increasing and creating an anxious situation for the treatment of both cancer and infectious diseases caused by pathogenic microorganisms. Researchers are trying to solve this terrible [...] Read more.

Drug resistance is a serious problem for human health worldwide. Day by day this drug resistance is increasing and creating an anxious situation for the treatment of both cancer and infectious diseases caused by pathogenic microorganisms. Researchers are trying to solve this terrible situation to overcome drug resistance. Biosynthesized gold nanoparticles (AuNPs) could be a promising agent for controlling drug-resistant pathogenic microorganisms and cancer cells. AuNPs can be synthesized via chemical and physical approaches, carrying many threats to the ecosystem. Green synthesis of AuNPs using biological agents such as plants and microbes is the most fascinating and attractive alternative to physicochemical synthesis as it offers many advantages, such as simplicity, non-toxicity, cost-effectiveness, and eco-friendliness. Plant extracts contain numerous biomolecules, and microorganisms produce various metabolites that act as reducing, capping, and stabilizing agents during the synthesis of AuNPs. The characterization of green-synthesized AuNPs has been conducted using multiple instruments including UV–Vis spectrophotometry (UV–Vis), transmission electron microscopy (TEM), scanning electron microscopy (SEM), atomic force microscopy (AFM), X-ray diffraction (XRD), DLS, and Fourier transform infrared spectroscopy (FT-IR). AuNPs have detrimental effects on bacterial and cancer cells via the disruption of cell membranes, fragmentation of DNA, production of reactive oxygen species, and impairment of metabolism. The biocompatibility and biosafety of synthesized AuNPs must be investigated using a proper in vitro and in vivo screening model system. In this review, we have emphasized the green, facile, and eco-friendly synthesis of AuNPs using plants and microorganisms and their potential antimicrobial and anticancer applications and highlighted their antibacterial and anticancer mechanisms. This study demonstrates that green-synthesized AuNPs may potentially be used to control pathogenic bacteria as well as cancer cells. Full article

(This article belongs to the Special Issue Next-Generation Nanoparticles: Innovations in Biomedical Applications and Theranostics)

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13 pages, 289 KiB

Open AccessArticle

Association of Genetic Variants, Such as the μ-Opioid Receptor 1 (OPRM1) rs1799971 and Catechol-O-Methyltransferase (COMT) rs4680, with Phenotypic Expression of Fibromyalgia

by Isabel Erenas Ondategui, Julia Gómez Castro, Sandra Estepa Hernández, Celia Chicharro Miguel, Regina Peiró Cárdenas, Ana Fernández-Araque and Zoraida Verde

Biomedicines 2025, 13(5), 1183; https://doi.org/10.3390/biomedicines13051183 - 13 May 2025

Abstract

Background/Objectives: Genetic variants, such as the µ-opioid receptor 1 (OPRM1) rs1799971 and the catechol-O-methyltransferase (COMT) rs4680, have been considered among the potential causes in the development of some chronic pain conditions. In this regard, there are controversial [...] Read more.

Background/Objectives: Genetic variants, such as the µ-opioid receptor 1 (OPRM1) rs1799971 and the catechol-O-methyltransferase (COMT) rs4680, have been considered among the potential causes in the development of some chronic pain conditions. In this regard, there are controversial results regarding their roles in fibromyalgia (FM). We aimed to investigate whether the OPRM1 rs1799971 and COMT rs4680 polymorphisms are associated with the development of or susceptibility to FM, as well as their potential association with syndrome characteristic variables, in a sample of the Spanish population with and without FM. Methods: The present study analysed COMT Val158Met and OPRM1 Asn40Asp genetic variants in 311 FM patients (301 women and 10 men) and 135 non-FM participants (120 women and 15 men). In addition to clinical variables, widespread pain index (WPI), symptom severity scale (SSS) (fatigue, rest quality, and cognitive symptoms), pain, stress episodes, and Borg scale were collected. Results: The main results indicate that women carrying the Val/Val genotype (i.e., high COMT activity) exhibited significantly lower levels of fatigue, cognitive impairment, and total SSS than heterozygote carriers. In addition, Met allele carriers (i.e., lower COMT activity) showed higher probabilities of suffering a stress episode and higher levels of exertion during daily activities. Conclusions: The present research suggests a link between dopaminergic dysfunction and exacerbated, frequently described symptoms in female FM patients. Although further research with wider genetic variants and recruited patients is needed, these results point out the necessity of considering gender as a separate category in chronic pain studies. Full article

(This article belongs to the Special Issue Advanced Research on Fibromyalgia (3rd Edition))

20 pages, 1587 KiB

Open AccessSystematic Review

Normal Weight, Overweight and Obesity Conditions Associated to Prostate Neoplasm Stages—A Systematic Review and Meta-Analysis

by Elsa Vitale, Alessandro Rizzo, Kurvatteppa Halemani, Asha P. Shetty, Omar Cauli, Francesco Massari and Matteo Santoni

Biomedicines 2025, 13(5), 1182; https://doi.org/10.3390/biomedicines13051182 - 13 May 2025

Abstract

Background/Objective: Prostate cancer (PCa) represents the second-most common cancer among men worldwide. Obesity is generally considered as a risk factor for cancer and it has been associated with a 20–30% increased risk of PCa death. The present systematic review and meta-analyses aimed to [...] Read more.

Background/Objective: Prostate cancer (PCa) represents the second-most common cancer among men worldwide. Obesity is generally considered as a risk factor for cancer and it has been associated with a 20–30% increased risk of PCa death. The present systematic review and meta-analyses aimed to highlight any existing trends between prostate neoplasm stages according to normal weight, overweight and obesity conditions. Methods: All interventional records such as randomized clinical trials, quasi-experimental studies and observational studies were included in the present systematic review and meta-analysis which reported PCa stages according to Gleason (GS) or TNM scores according to the BMI-related incidence, as normal weight, overweight and obesity groups. Results: Twenty-nine studies were included in the present study. As regards the GS scoring system, 1.09% of high grade in GS was reported among PCa normal weights. Among PCa overweights, 0.98% of low grade was registered in GS. The same trend was recorded among obese PCa patients, since 0.79% of low grade in GS was also registered. As regards TNM scores, both normal weight, overweight and obese PCa patients registered a significant incidence in non-advanced TNM score, without any significant differences considering higher TNM assessments. Conclusions: Although the literature seemed to be more in favor of associations between BMI and GS, no specific mechanisms were highlighted between obesity and PCa progression. In this regard, the low androgen microenvironment in obese men could play an important role, but further studies will be necessary in this direction. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Steroid Hormone Action—2nd Edition)

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10 pages, 654 KiB

Open AccessArticle

Characterization of Coronary Artery Disease in Sepsis Survivors

by Samuel Malomo, Thomas Oswald, Thomas Alway, Stanislav Hadjivassilev, Steven Coombs, Susan Ellery, Joon Lee, Claire Phillips, Barbara Philips, Rachael James, David Hildick-Smith, Victoria Parish and Alexander Liu

Biomedicines 2025, 13(5), 1181; https://doi.org/10.3390/biomedicines13051181 - 13 May 2025

Abstract

Background: Sepsis survivors are at risk of developing myocardial infarction and heart failure. It remains unclear whether coronary artery disease (CAD) is a major contributor to the development of these complications. This study sought to characterize the burden and distribution of significant CAD [...] Read more.

Background: Sepsis survivors are at risk of developing myocardial infarction and heart failure. It remains unclear whether coronary artery disease (CAD) is a major contributor to the development of these complications. This study sought to characterize the burden and distribution of significant CAD in sepsis survivors. Methods: Sepsis survivors who underwent computed tomography coronary angiography (CTCA) or invasive coronary angiography (ICA) in a UK tertiary cardiac center for suspected ischemic heart disease were retrospectively studied. Results: Of the 30 sepsis survivors (age 57 ± 12 years; 50% males), 21 patients underwent CTCA and 9 patients underwent ICA a median 39 days [IQR 12–152] from the sepsis episode. Eight patients (~27%) had angiographically significant CAD (n = 6 severe [>70%] stenosis; n = 2 moderate [50–70%] stenosis). The CT coronary calcium score was higher in patients with significant CAD compared to patients without significant CAD (638 [368–1015] vs. 4 [1–72]; p < 0.001). Of the 8 patients with significant CAD, 3 patients had LV systolic dysfunction (38%) on echocardiography and 8/21 (38%) patients without significant CAD had LV systolic dysfunction (p = 1.00). Long-term adverse complications (all-cause mortality and/or heart failure hospitalization) occurred 3/8 (38%) patients with significant CAD and 4/22 (18%) patients without significant CAD (p = 0.345). Conclusions: A minority of sepsis survivors have significant CAD. The presence of significant CAD cannot fully explain the occurrence of post-sepsis LV systolic dysfunction and adverse outcomes. The ischemic and non-ischemic mechanisms underlying post-sepsis cardiovascular disease require further investigation. Full article

(This article belongs to the Special Issue Pathogenesis, Diagnosis, and Treatment of Cardiomyopathy)

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14 pages, 624 KiB

Open AccessReview

Merkel Cell Polyomavirus (MCPyV) and Its Possible Role in Head and Neck Cancers

by Sara Passerini, Sara Messina, Ugo Moens and Valeria Pietropaolo

Biomedicines 2025, 13(5), 1180; https://doi.org/10.3390/biomedicines13051180 - 12 May 2025

Abstract

Despite significant progress in its prevention, diagnosis, and treatment, head and neck cancer (HNC) remains a major global health issue due to its multifactorial pathogenesis. Indeed, HNCs have been found to be associated with different environmental and lifestyle factors, as well as with [...] Read more.

Despite significant progress in its prevention, diagnosis, and treatment, head and neck cancer (HNC) remains a major global health issue due to its multifactorial pathogenesis. Indeed, HNCs have been found to be associated with different environmental and lifestyle factors, as well as with infection with oncogenic viruses. To date, seven viruses are recognized for their tumorigenic properties and have been proposed as implicated in HNC development, including Merkel Cell Polyomavirus (MCPyV). MCPyV is well recognized as the major etiological agent of Merkel cell carcinoma (MCC), a rare but rapidly metastasizing skin neoplasm. Specifically, in almost 80% of MCC cases, viral genome integration occurs, and a truncated form of Large T Antigen (tLT) is expressed. Although MCC is a rare cancer, MCPyV is a ubiquitous virus, widely distributed among the human population. Therefore, a plausible role of the virus has been proposed, even for other tumors. The current review provides an overview of the available data describing the presence of MCPyV in non-MCC tumors, such as HNCs, with the aim of elucidating the potential contribution of MCPyV to oral cancer. Understanding the role of viral infections in the etiology of cancer opens up the opportunity for developing preventive measures and targeted therapies that effectively address HNC progression while reducing treatment-related side effects. Full article

(This article belongs to the Special Issue Head and Neck Tumors, 4th Edition)

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25 pages, 3231 KiB

Open AccessReview

Immunomodulation and Immunotherapy for Patients with Prostate Cancer: An Up-to-Date Review

by Nigel P. Murray

Biomedicines 2025, 13(5), 1179; https://doi.org/10.3390/biomedicines13051179 - 12 May 2025

Abstract

Immunotherapy alone or in combination with chemotherapy or radiotherapy is the frontline treatment for melanoma and lung cancer. However, its role in prostate cancer is usually as a fourth-line treatment. It is usually employed in patients with metastasis, after androgen blockade and chemotherapy. [...] Read more.

Immunotherapy alone or in combination with chemotherapy or radiotherapy is the frontline treatment for melanoma and lung cancer. However, its role in prostate cancer is usually as a fourth-line treatment. It is usually employed in patients with metastasis, after androgen blockade and chemotherapy. This article reviews the immunosuppressive effects of prostate cancer and possible uses of various types of immunotherapies. It also considers when would be the optimal time to employ this type of therapy. Full article

(This article belongs to the Special Issue Feature Reviews in Precision Oncology)

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13 pages, 565 KiB

Open AccessArticle

Linking Dietary Patterns to Autism Severity and Developmental Outcomes: A Correlational Study Using Food Frequency Questionnaires; The Childhood Autism Rating Scale, Second Edition; And Developmental Profile 3

by Dimitar Marinov, Sevdzhihan Eyubova, Albena Toneva, Rositsa Chamova, Rozalina Braykova, Stanislava Hadzhieva and Ruzha Pancheva

Biomedicines 2025, 13(5), 1178; https://doi.org/10.3390/biomedicines13051178 - 12 May 2025

Abstract

Background/Objectives: Autism Spectrum Disorder (ASD) is characterized by social communication challenges and repetitive behaviors. Children with ASD often exhibit selective eating habits that may result in nutritional deficiencies and exacerbate developmental issues. While food frequency questionnaires (FFQs) are effective for dietary assessment, [...] Read more.

Background/Objectives: Autism Spectrum Disorder (ASD) is characterized by social communication challenges and repetitive behaviors. Children with ASD often exhibit selective eating habits that may result in nutritional deficiencies and exacerbate developmental issues. While food frequency questionnaires (FFQs) are effective for dietary assessment, the links between food preferences, ASD severity, and developmental outcomes remain underexplored, particularly in Bulgaria. This study examines these relationships using validated tools. Methods: The present report constitutes a pilot, hypothesis-generating substudy of the broader NutriLect project. This substudy involved 49 children aged 2–12 years diagnosed with ASD. Dietary patterns were evaluated with a modified FFQ, while ASD severity and developmental profiles were assessed using the Childhood Autism Rating Scale, Second Edition (CARS-2) and the Developmental Profile 3 (DP-3). Results: Among 49 ASD children (mean age = 6.89 ± 2.15 years; 86% boys), 73.4% consumed grains/potatoes daily. Only 34.7% met combined fruit and vegetable recommendations. Only 36.7% met the recommendation for daily milk or other dairy product consumption. Fish was consumed at least twice weekly by only 22,4%. Furthermore, children with more severe autism were approximately 9.4 times more likely to consume grains daily (χ² = 14.319, p = 0.006). Logistic regression analyses indicated that higher cognitive scores were strongly associated with lower grain (OR ≈ 0.044) and other dairy products consumption (OR ≈ 0.337), yet with greater fish intake (OR ≈ 3.317). In contrast, better communication skills corresponded to increased milk consumption (OR ≈ 5.76), and higher physical development scores predicted more frequent egg consumption (OR ≈ 4.40). Conclusions: The pronounced preference for grain and meat products, which are frequently ultra-processed, and avoidance of nutrient-dense foods in children with severe ASD symptoms underscore the need for tailored dietary interventions. These interventions must address sensory sensitivities, nutritional inadequacies, and the risks that selective nutrition can have on the nutritional status and development of the children. Full article

(This article belongs to the Special Issue Progress in Neurodevelopmental Disorders Research)

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15 pages, 4496 KiB

Open AccessArticle

Transposable Element Is Predictive of Chemotherapy- and Immunotherapy-Related Overall Survival in Glioma

by Bi Peng, Fan Shen, Ziqi Chen, Yongkai Yu, Rundong Liu, Yiling Zhang, Guoxian Long, Guangyuan Hu and Yuanhui Liu

Biomedicines 2025, 13(5), 1177; https://doi.org/10.3390/biomedicines13051177 - 12 May 2025

Abstract

Background: Glioma is the most common type of malignant brain tumor. Temozolomide (TMZ) is a limited systematic treatment option for glioma, including low-grade glioma (LGG) and glioblastoma (GBM). However, not all patients benefit from TMZ and some develop resistance to it. MGMT methylation [...] Read more.

Background: Glioma is the most common type of malignant brain tumor. Temozolomide (TMZ) is a limited systematic treatment option for glioma, including low-grade glioma (LGG) and glioblastoma (GBM). However, not all patients benefit from TMZ and some develop resistance to it. MGMT methylation has been used to identify patients who may benefit from TMZ, but it is not effective in all cases. Objectives: There is an urgent need for new biomarkers to predict the survival of patients who receive TMZ. Methods: We utilized a recently developed method called REdiscoverTE to precisely measure the expression of transposable elements (TE). We performed Cox regression analysis to assess the predictive ability for prognosis and conducted a series of correlation studies to uncover potential mechanisms. Results: We identified three TEs, LTR81B, LTR27B, and MER39B, that were strongly predictive of longer survival in glioma patients receiving chemotherapy. We discovered that the expression of these TEs was positively associated with immune cells that enhance the immune system and negatively associated with immune cells suppressing the immune response, as well as molecules that control immune checkpoints. These three TEs were also found to predict better survival in patients receiving immunotherapy. Conclusions: In conclusion, we demonstrate that the expression of TEs can serve as a novel biomarker for the overall survival of glioma patients who receive TMZ chemotherapy or immunotherapy. Full article

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

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13 pages, 601 KiB

Open AccessArticle

Early Renal Dysfunction and Reduced Retinal Vascular Density Assessed by Angio-OCT in Hypertensive Patients

by Caterina Carollo, Maria Vadalà, Alessandra Sorce, Emanuele Cirafici, Miriam Bennici, Massimo Castellucci, Vincenza Maria Elena Bonfiglio, Giuseppe Mulè and Giulio Geraci

Biomedicines 2025, 13(5), 1176; https://doi.org/10.3390/biomedicines13051176 - 12 May 2025

Abstract

Background: The eye and kidney share embryological, structural, and pathophysiological similarities, suggesting potential interconnections between retinal and renal microvascular changes. Hypertension, a major risk factor for renal impairment, also affects retinal microvasculature. This study investigates the relationship between retinal vascular density, assessed by [...] Read more.

Background: The eye and kidney share embryological, structural, and pathophysiological similarities, suggesting potential interconnections between retinal and renal microvascular changes. Hypertension, a major risk factor for renal impairment, also affects retinal microvasculature. This study investigates the relationship between retinal vascular density, assessed by Optical Coherence Tomography Angiography (OCT-A), and early renal dysfunction in hypertensive patients. Methods: A total of 142 hypertensive patients (mean age 47 ± 13 years; 74% male) were enrolled from the Nephrology and Hypertension Unit at the University of Palermo. Retinal vascular density was measured using OCT-A, and renal function was assessed using estimated glomerular filtration rate (eGFR). Clinical and hemodynamic parameters, including 24-h aortic blood pressure, were also analyzed. Results: Patients with eGFR < 60 mL/min/1.73 m² exhibited significantly lower retinal vascular densities, particularly in the parafoveal region. Superficial parafoveal density was inversely associated with aortic pulse pressure (p = 0.012) and directly correlated with eGFR (p = 0.012). Deep parafoveal density was independently associated with eGFR (p = 0.001). Multiple linear regression confirmed that lower retinal vascular density was significantly linked to reduced renal function, independent of age and blood pressure. Conclusions: Retinal vascular density, particularly in the parafoveal region, is associated with renal function decline in hypertensive patients. These findings suggest that retinal microvascular changes could serve as a non-invasive biomarker for kidney dysfunction, with potential applications in early risk stratification and disease monitoring. Further research is needed to establish causality and clinical utility. Full article

(This article belongs to the Special Issue Retinal Diseases: Pathogenetic, Diagnostic and Therapeutic Perspectives)

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15 pages, 1701 KiB

Open AccessArticle

Real-World Outcomes of First-Line Pembrolizumab Monotherapy in Metastatic NSCLC with High PD-L1 Expression (TPS ≥ 50%): A Multicenter Study from Serbia

by Filip Marković, Mihailo Stjepanović, Milan Rančić, Marina Cekić and Milica Kontić

Biomedicines 2025, 13(5), 1175; https://doi.org/10.3390/biomedicines13051175 - 11 May 2025

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Abstract

Background: Pembrolizumab monotherapy is the standard first-line treatment for metastatic non-small cell lung cancer (NSCLC) patients whose tumors express a PD-L1 tumor proportion score (TPS) of ≥50%. However, real-world data regarding its effectiveness outside of clinical trials, particularly in Eastern European populations, are [...] Read more.

Background: Pembrolizumab monotherapy is the standard first-line treatment for metastatic non-small cell lung cancer (NSCLC) patients whose tumors express a PD-L1 tumor proportion score (TPS) of ≥50%. However, real-world data regarding its effectiveness outside of clinical trials, particularly in Eastern European populations, are limited. Methods: We conducted a retrospective, multicenter study including 225 patients with metastatic NSCLC and PD-L1 TPS ≥ 50% who received first-line pembrolizumab monotherapy in Serbia between 2019 and 2022. Patient demographics, clinical characteristics, and treatment outcomes were collected. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method, and multivariable Cox proportional hazards regression was performed to identify predictors of outcomes. Results: The median PFS was 9.7 months (95% CI: 7.979–11.421), and the median OS was 17.0 months (95% CI: 12.813–20.187) at a median follow-up of 18.1 months. The overall response rate (ORR) was 36.4%, and the disease control rate (DCR) was 73.4%. Multivariable analysis identified good performance status (ECOG PS 0–1), PD-L1 TPS ≥ 90%, and the occurrence of immune-related adverse events (irAEs) as independent predictors of improved PFS and OS. Conclusions: Our study highlights the efficacy and safety of first-line pembrolizumab monotherapy in a real-world Serbian population with metastatic NSCLC and high PD-L1 expression. Furthermore, it confirms the prognostic value of ECOG PS, high PD-L1 expression, and the development of irAEs in predicting favorable clinical outcomes. Full article

(This article belongs to the Special Issue Advances in Lung Cancer: From Bench to Bedside)

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21 pages, 4865 KiB

Open AccessArticle

Therapeutic Potential of Umbilical Cord MSC-Derived Exosomes in a Severe Dry Eye Rat Model: Enhancing Corneal Protection and Modulating Inflammation

by Sze-Min Chan, Chris Tsai, Tai-Ping Lee, Zih-Rou Huang, Wei-Hsiang Huang and Chung-Tien Lin

Biomedicines 2025, 13(5), 1174; https://doi.org/10.3390/biomedicines13051174 - 11 May 2025

Viewed by 90

Abstract

Background/Objectives: Dry eye disease (DED) is a multifactorial inflammatory disease that disrupts the ocular surface, causing tear film instability, epithelial damage, and chronic inflammation. Mesenchymal stem cell-derived exosomes (MSC-exos) are promising therapeutics with immunomodulatory and regenerative properties. This study investigates the therapeutic [...] Read more.

Background/Objectives: Dry eye disease (DED) is a multifactorial inflammatory disease that disrupts the ocular surface, causing tear film instability, epithelial damage, and chronic inflammation. Mesenchymal stem cell-derived exosomes (MSC-exos) are promising therapeutics with immunomodulatory and regenerative properties. This study investigates the therapeutic effects of umbilical cord MSC-derived exosomes (UCMSC-exos) in a severe dry eye model, induced by a surgical resection of the infra-orbital (ILG) and extra-orbital lacrimal gland (ELG) in rats. Methods: Clinical evaluations, including tear volume measurement, slit lamp biomicroscopy, fluorescein staining, and spectral domain optical coherence tomography (SD-OCT), were performed to assess corneal neovascularization, corneal abrasion, and epithelial/stromal thickness. Histopathological analysis, immunohistochemistry, and mRNA gene expression were conducted to evaluate corneal tissue changes and inflammatory marker expression. Results: The results show that the treatment group exhibited significantly reduced corneal neovascularization compared to the control group (p = 0.030). During the first month, the Exo group also had a significantly lower corneal fluorescein staining area (p = 0.032), suggesting accelerated wound healing. SD-OCT analysis revealed that the corneal epithelial thickness in the treatment group was closer to normal levels compared to the control group (p = 0.02 and p = 0.006, respectively). UCMSC-exos treatment also modulated the expression of α-SMA and apoptosis in the cornea. Additionally, the gene expression of inflammatory cytokines (IL-1β and TNF-α) were downregulated. Conclusions: These findings suggest that MSC-exosome therapy offers a novel, cell-free regenerative approach for managing severe DED, modulating inflammatory response. Full article

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

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19 pages, 3261 KiB

Open AccessReview

The Role of Tregs in the Tumor Microenvironment

by Yohei Sato

Biomedicines 2025, 13(5), 1173; https://doi.org/10.3390/biomedicines13051173 - 11 May 2025

Viewed by 67

Abstract

The tumor microenvironment (TME) is a unique ecosystem that surrounds tumor tissues. The TME is composed of extracellular matrix, immune cells, blood vessels, stromal cells, and fibroblasts. These environments enhance cancer development, progression, and metastasis. Recent success in immune checkpoint blockade also supports [...] Read more.

The tumor microenvironment (TME) is a unique ecosystem that surrounds tumor tissues. The TME is composed of extracellular matrix, immune cells, blood vessels, stromal cells, and fibroblasts. These environments enhance cancer development, progression, and metastasis. Recent success in immune checkpoint blockade also supports the importance of the TME and immune cells residing in the tumor niche. Although the TME can be identified in almost all cancer types, the role of the TME may not be similar among different cancer types. Regulatory T cells (Tregs) play a pivotal role in immune homeostasis and are frequently found in the TME. Owing to their suppressive function, Tregs are often considered unfavorable factors that allow the immune escape of cancer cells. However, the presence of Tregs is not always linked to an unfavorable phenotype, which can be explained by the heterogeneity and plasticity of Tregs. In this review, the current understanding of the role of Tregs in TME is addressed for each cancer cell type. Moreover, recently a therapeutic approach targeting Tregs infiltrating in the TME has been developed including drug antibody conjugate, immunotoxin, and FOXP3 inhibiting peptide. Thus, understanding the role of Tregs in the TME may lead to the development of novel therapies that directly target the TME. Full article

(This article belongs to the Special Issue Feature Reviews in Tumor Immunology)

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12 pages, 697 KiB

Open AccessReview

Co-Occurrence of Helicobacter pylori and Candida spp. Infections in the Pathogenesis of Gastrointestinal Diseases

by Joanna Braksator, Anna Kofla-Dłubacz, Katarzyna Antosz-Popiołek, Hubert Szyller, Joanna Koga-Batko, Martyna Wrześniewska, Maciej Dyda and Tomasz Pytrus

Biomedicines 2025, 13(5), 1172; https://doi.org/10.3390/biomedicines13051172 - 11 May 2025

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Abstract

Helicobacter pylori and Candida spp. are widespread microorganisms found in the human gastrointestinal tract, often coexisting in the same ecological niche. H. pylori, a Gram-negative bacterium, is a well-known pathogen responsible for gastritis, peptic ulcers, and gastric cancer. In contrast, Candida fungi, [...] Read more.

Helicobacter pylori and Candida spp. are widespread microorganisms found in the human gastrointestinal tract, often coexisting in the same ecological niche. H. pylori, a Gram-negative bacterium, is a well-known pathogen responsible for gastritis, peptic ulcers, and gastric cancer. In contrast, Candida fungi, often detected in food, particularly Candida albicans, are generally considered commensal organisms, but can become opportunistic pathogens under certain conditions. Recent studies suggest a possible link between these microorganisms, highlighting a new survival strategy of H. pylori, that is, its ability to internalize in Candida vacuoles. This phenomenon, confirmed by various microscopic and molecular techniques, may provide H. pylori with protection against adverse environmental conditions, especially clinically important antibiotic therapy. The basic premise of this theory is the ability of H. pylori to penetrate vacuoles in fungal cells, which then become a reservoir of infection, allowing the infection to recur. Understanding the interaction between H. pylori and Candida may offer new insights into the pathogenesis of gastrointestinal diseases and may lead to the development of treatments targeting both organisms simultaneously. The purpose of this article is to review the literature, considering the first observations on this problem in the literature and the current state of knowledge, and to suggest a direction for further research. Full article

(This article belongs to the Special Issue The Interplay between Immunity and Microbiota in Human Health and Diseases (2nd Edition))

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24 pages, 6932 KiB

Open AccessArticle

Circular Nucleic Acids Act as an Oncogenic MicroRNA Sponge to Inhibit Hepatocellular Carcinoma Progression

by Qianyi Zhang, Pengcheng Sun, Guang Hu, Xuanyao Yu, Wen Zhang, Xuan Feng, Lan Yu and Pengfei Zhang

Biomedicines 2025, 13(5), 1171; https://doi.org/10.3390/biomedicines13051171 - 11 May 2025

Viewed by 132

Abstract

Background: Aberrant expression of microRNAs in neoplastic lesions may serve as potential personalized therapeutic targets. To inhibit oncogenic microRNAs (oncomiRs) expression and restore tumor suppressor proteins, linear miRNA sponges have been developed, leading to several drugs in clinical trials. Despite their efficacy, chemically [...] Read more.

Background: Aberrant expression of microRNAs in neoplastic lesions may serve as potential personalized therapeutic targets. To inhibit oncogenic microRNAs (oncomiRs) expression and restore tumor suppressor proteins, linear miRNA sponges have been developed, leading to several drugs in clinical trials. Despite their efficacy, chemically synthesized miRNA inhibitors face challenges with sustained inhibition and high production costs, hindering widespread clinical adoption. Additionally, single-stranded circular RNAs (circRNAs) act as miRNA sponges, enhancing protein expression and demonstrating stability and therapeutic potential in cancer treatment. Our approach involves the use of synthetic single-stranded circular nucleic acids, including circDNA and circRNA, to selectively target and inhibit a variety of aberrantly overexpressed oncomiRs in tumors. The objective of this strategy is to restore the expression levels of multiple tumor suppressor factors and to suppress the malignant progression of tumors. Methods: Our methodology comprises a two-step process. First, we identified tumor suppressor genes (TSGs) with abnormally low expression in hepatocellular carcinoma (HCC) tumor cells by transcriptomic analysis and targeted the upstream cancer miRNA clusters of these TSGs. Second, we designed and validated a fully complementary circDNA or circRNA construct, ligated by T4 DNA ligase or T4 RNA ligase, respectively, that specifically targets the sponge oncomiRs both in vitro and in vivo to inhibit the malignant progression of HCC. Results: CircNAs demonstrated superior, long-lasting therapeutic efficacy against HCC compared to inhibitors. Furthermore, we compared the immune effects in vivo of three different nucleic acid adsorption carriers, including commercial miRNA inhibitor, circDNA, and circRNA. We found that the miRNA inhibitor activates a more robust inflammatory response compared to circDNA and circRNA. Conclusions: These findings underscore the substantial therapeutic potential of circDNA in tumorigenesis and provide novel insights for the formulation of personalized treatment plans for malignant tumors, such as HCC. Full article

(This article belongs to the Special Issue MicroRNA and Its Role in Human Health, 2nd Edition)

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18 pages, 1376 KiB

Open AccessReview

Emerging Epigenetic Therapies for the Treatment of Cardiac Fibrosis

by Nerea Garitano, Laura Pilar Aguado-Alvaro and Beatriz Pelacho

Biomedicines 2025, 13(5), 1170; https://doi.org/10.3390/biomedicines13051170 - 11 May 2025

Viewed by 160

Abstract

Fibrosis is a pathological process characterized by excessive extracellular matrix (ECM) deposition, leading to tissue stiffening and organ dysfunction. It is a major contributor to chronic diseases affecting various organs, with limited therapeutic options available. Among the different forms of fibrosis, cardiac fibrosis [...] Read more.

Fibrosis is a pathological process characterized by excessive extracellular matrix (ECM) deposition, leading to tissue stiffening and organ dysfunction. It is a major contributor to chronic diseases affecting various organs, with limited therapeutic options available. Among the different forms of fibrosis, cardiac fibrosis is particularly relevant due to its impact on cardiovascular diseases (CVDs), which remain the leading cause of morbidity and mortality worldwide. This process is driven by activated cardiac fibroblasts (CFs), which promote ECM accumulation in response to chronic stressors. Epigenetic mechanisms, including DNA methylation, histone modifications, and chromatin remodeling, are key regulators of fibroblast activation and fibrotic gene expression. Enzymes such as DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), histone acetyltransferases (HATs), and histone deacetylases (HDACs) have emerged as potential therapeutic targets, and epigenetic inhibitors have shown promise in modulating these enzymes to attenuate fibrosis by controlling fibroblast function and ECM deposition. These small-molecule compounds offer advantages such as reversibility and precise temporal control, making them attractive candidates for therapeutic intervention. This review aims to provide a comprehensive overview of the mechanisms by which epigenetic regulators influence cardiac fibrosis and examines the latest advances in preclinical epigenetic therapies. By integrating recent data from functional studies, single-cell profiling, and drug development, it highlights key molecular targets, emerging therapeutic strategies, and current limitations, offering a critical framework to guide future research and clinical translation. Full article

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

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9 pages, 2102 KiB

Open AccessArticle

Engagement of CD300c by a Novel Monoclonal Antibody Ameliorates Behavioral Deficits in a 5xFAD Mouse Model of Alzheimer’s Disease

by Suin Lee, Chang Ki Lim, Jongyeob Kim, Joon Kim, Hee Kyung Jin, Jae-sung Bae and Jae-Won Jeon

Biomedicines 2025, 13(5), 1169; https://doi.org/10.3390/biomedicines13051169 - 10 May 2025

Viewed by 128

Abstract

Background: Current treatment modalities for Alzheimer’s disease (AD), which is characterized by the accumulation of amyloid β (Aβ), have limitations with regard to their efficacy and safety, posing significant challenges for advances in healthcare. However, recent studies indicated that AD can be [...] Read more.

Background: Current treatment modalities for Alzheimer’s disease (AD), which is characterized by the accumulation of amyloid β (Aβ), have limitations with regard to their efficacy and safety, posing significant challenges for advances in healthcare. However, recent studies indicated that AD can be treated using monocyte-derived macrophages (MDMs). Reportedly, the protein CD300c regulates monocyte differentiation, indicating that targeting CD300c could offer a treatment for AD. Methods: To confirm this, we developed CB201, a fully human anti-CD300c antibody, and demonstrated its strong and specific binding to CD300c using surface plasmon resonance and binding ELISAs. Results: Treatment of THP-1 and human peripheral blood mononuclear cells with CB201 led to increased levels of pro-inflammatory cytokines and the differentiation of macrophages to MDMs. Moreover, the CB201-differentiated macrophages expressed cytokines and chemokines in a pattern that alleviates AD symptoms. In a 5xFAD mouse model, CB201 treatment improved memory and behavior in both the early and late stages of AD and reduced cerebral Aβ plaque load. Conclusions: These results indicate that CB201 promotes the differentiation of macrophages to MDMs and modulates AD-related inflammatory responses, thereby ameliorating the pathological features of AD. These findings identify CD300c as a potential therapeutic target for AD and indicate that CB201 is a promising candidate for its treatment. Full article

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

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23 pages, 1040 KiB

Open AccessReview

Juvenile Primary Fibromyalgia Syndrome: Advances in Etiopathogenesis, Clinical Assessment and Treatment: A Narrative Review

by Claudio Lavarello, Silvana Ancona and Clara Malattia

Biomedicines 2025, 13(5), 1168; https://doi.org/10.3390/biomedicines13051168 - 10 May 2025

Viewed by 122

Abstract

Juvenile Primary Fibromyalgia Syndrome (JPFS) is a complex, multifactorial condition characterized by widespread musculoskeletal pain, often accompanied by sleep disturbances, headaches, cognitive and mood disorders, and fatigue, resulting in a significant impact on the quality of life for affected children, adolescents, and their [...] Read more.

Juvenile Primary Fibromyalgia Syndrome (JPFS) is a complex, multifactorial condition characterized by widespread musculoskeletal pain, often accompanied by sleep disturbances, headaches, cognitive and mood disorders, and fatigue, resulting in a significant impact on the quality of life for affected children, adolescents, and their families. Although recent advances have improved the understanding of the underlying pathophysiological mechanisms and therapeutic approaches, its etiology and optimal treatments remain largely unknown. In this review, we summarize recent advances in the etiopathogenesis, clinical assessment, and treatment of JPFS. Our aim is to support clinicians in the diagnosis and management of JPFS patients, while also highlighting key areas that require further research to improve diagnostic accuracy and therapeutic outcomes. Full article

(This article belongs to the Special Issue Advanced Research on Fibromyalgia (3rd Edition))

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25 pages, 4600 KiB

Open AccessArticle

Cannabidiol-Loaded Retinal Organoid-Derived Extracellular Vesicles Protect Oxidatively Stressed ARPE-19 Cells

by Peggy Arthur, Sangeetha Kandoi, Anil Kalvala, Breana Boirie, Aakash Nathani, Mounika Aare, Santanu Bhattacharya, Tanmay Kulkarni, Li Sun, Deepak A. Lamba, Yan Li and Mandip Singh

Biomedicines 2025, 13(5), 1167; https://doi.org/10.3390/biomedicines13051167 - 10 May 2025

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Abstract

Background/Objectives: Age-related macular degeneration (AMD) is the third leading cause of irreversible blindness in elderly individuals aged over 50 years old. Oxidative stress plays a crucial role in the etiopathogenesis of multifactorial AMD disease. The phospholipid bilayer EVs derived from the culture-conditioned medium [...] Read more.

Background/Objectives: Age-related macular degeneration (AMD) is the third leading cause of irreversible blindness in elderly individuals aged over 50 years old. Oxidative stress plays a crucial role in the etiopathogenesis of multifactorial AMD disease. The phospholipid bilayer EVs derived from the culture-conditioned medium of human induced pluripotent stem cell (hiPSC) differentiated retinal organoids aid in cell-to-cell communication, signaling, and extracellular matrix remodeling. The goal of the current study is to establish and evaluate the encapsulation of a hydrophobic compound, cannabidiol (CBD), into retinal organoid-derived extracellular vesicles (EVs) for potential therapeutic use in AMD. Methods: hiPSC-derived retinal organoid EVs were encapsulated with CBD via sonication (CBD-EVs), and structural features were elucidated using atomic force microscopy, nanoparticle tracking analysis, and small/microRNA (miRNA) sequencing. ARPE-19 cells and oxidative-stressed (H₂O₂) ARPE-19 cells treated with CBD-EVs were assessed for cytotoxicity, apoptosis (MTT assay), reactive oxygen species (DCFDA), and antioxidant proteins (immunohistochemistry and Western blot). Results: Distinct miRNA cargo were identified in early and late retinal organoid-derived EVs, implicating their roles in retinal development, differentiation, and functionality. The therapeutic effects of CBD-loaded EVs on oxidative-stressed ARPE-19 cells showed greater viability, decreased ROS production, downregulated expression of inflammation- and apoptosis-related proteins, and upregulated expression of antioxidants by Western blot and immunocytochemistry. Conclusions: miRNAs are both prognostic and predictive biomarkers and can be a target for developing therapy since they regulate RPE physiology and diseases. Our findings indicate that CBD-EVs could potentially alleviate the course of AMD by activating the targeted proteins linked to the adenosine monophosphate kinase (AMPK) pathway. Implicating the use of CBD-EVs represents a novel frontline to promote long-term abstinence from drugs and pharmacotherapy development in treating AMD. Full article

(This article belongs to the Special Issue Therapeutic Potential for Cannabis and Cannabinoids, 3rd Edition)

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17 pages, 9155 KiB

Open AccessArticle

Long-Term Alterations of Renal Microvasculature in Rats Following Maternal PM_2.5 Exposure: Vitamin D Effects

by Eujin Park, Hyung-Eun Yim, Min-Hwa Son, Yoon-Jeong Nam, Yu-Seon Lee, Sang-Hoon Jeong and Ju-Han Lee

Biomedicines 2025, 13(5), 1166; https://doi.org/10.3390/biomedicines13051166 - 10 May 2025

Viewed by 92

Abstract

Background: This study aimed to investigate the long-term effects of maternal exposure to fine particulate matter (PM_2.5) with or without vitamin D supplementation on the renal microvasculature in adult rat offspring. Methods: Pregnant Sprague–Dawley rats were exposed to normal [...] Read more.

Background: This study aimed to investigate the long-term effects of maternal exposure to fine particulate matter (PM_2.5) with or without vitamin D supplementation on the renal microvasculature in adult rat offspring. Methods: Pregnant Sprague–Dawley rats were exposed to normal saline, PM_2.5, and PM_2.5 with vitamin D for one month during nephrogenesis. Male offspring kidneys were taken for analyses on postnatal day 56. Results: Adult offspring rats exposed to maternal PM_2.5 exhibited lower body weights and greater glomerular and tubular injury scores compared to control rats. Semi-quantitative analysis revealed a significant reduction in glomerular and peritubular capillary endothelial cells, along with a decrease in the number of glomeruli in the PM_2.5 group. Maternal vitamin D supplementation reduced these changes. In offspring rats exposed to maternal PM_2.5, intrarenal expression of renin, angiotensin-converting enzyme (ACE), cytochrome P450 27B1, and vascular endothelial growth factor-A (VEGF-A) increased, while expression of the vitamin D receptor, Klotho, VEGF receptor 2, angiopoietin-1, and Tie-2 decreased. Maternal vitamin D supplementation restored VEGF receptor 2 and angiopoietin-1 activities and reduced ACE and VEGF-A protein expression in adult offspring kidneys. Conclusions: Early-life exposure to PM_2.5 may lead to long-term alterations in renal microvasculature and nephron loss. Maternal vitamin D supplementation during renal development can ameliorate PM_2.5-induced capillary rarefaction and nephron loss in the kidneys of adult offspring. Full article

(This article belongs to the Special Issue New Advances in Chronic Kidney Disease: Biology, Diagnosis and Therapy (2nd Edition))

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6 pages, 1036 KiB

Open AccessOpinion

Strategies for Anticancer Treatment in p53-Mutated Head and Neck Squamous Cell Carcinoma

by Bi-He Cai, Chia-Chi Chen, Yu-Te Sung, Yu-Chen Shih and Ching-Feng Lien

Biomedicines 2025, 13(5), 1165; https://doi.org/10.3390/biomedicines13051165 - 10 May 2025

Viewed by 129

Abstract

This Opinion summarizes the strategies for anticancer treatment in p53-mutated head and neck squamous cell carcinoma (HNSCC). It examines six strategies for anticancer treatment in p53-mutated HNSCC: 1. direct reactivation of mutated p53; 2. activation of p63; 3. activation of p73; 4. degradation [...] Read more.

This Opinion summarizes the strategies for anticancer treatment in p53-mutated head and neck squamous cell carcinoma (HNSCC). It examines six strategies for anticancer treatment in p53-mutated HNSCC: 1. direct reactivation of mutated p53; 2. activation of p63; 3. activation of p73; 4. degradation of mutated p53; 5. blocking the p53-regulated oncogenic microRNA; and 6. blocking the p53-regulated oncogenic long non-coding RNA. Since HNSCC has a high p53 mutation rate compared to other types of cancers, these strategies for combating p53-mutated HNSCC may prove useful for generating new ideas or methods for developing treatments for other cancers with p53 mutations. This article also explores other factors that may impact the effectiveness of anticancer therapies in p53-mutated HNSCC. Full article

(This article belongs to the Special Issue Strategies for Anticancer in p53 Mutated Cancers)

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15 pages, 1487 KiB

Open AccessArticle

The Effect of Early Spironolactone Administration on 2-Year Acute Graft Rejection in Cardiac Transplant Patients

by Dragos-Florin Baba, Alina Danilesco, Horatiu Suciu, Calin Avram, Marius Mihai Harpa, Mircea Stoian, Diana-Andreea Moldovan, Laurentiu Huma, Gabriel Rusu, Tunde Pal, Adina Stoian and Anca-Ileana Sin

Biomedicines 2025, 13(5), 1164; https://doi.org/10.3390/biomedicines13051164 - 10 May 2025

Viewed by 159

Abstract

Background: The objective of our study was to investigate the impact of mineralocorticoid receptor antagonists (MRAs), such as spironolactone, administrated early after cardiac transplantation on the occurrence of acute graft rejection (AGR) in the first 2 years post-transplant. Methods: This retrospective research was [...] Read more.

Background: The objective of our study was to investigate the impact of mineralocorticoid receptor antagonists (MRAs), such as spironolactone, administrated early after cardiac transplantation on the occurrence of acute graft rejection (AGR) in the first 2 years post-transplant. Methods: This retrospective research was conducted in the Emergency Institute for Cardiovascular Diseases and Transplantation of Targu Mures, Romania. After applying the inclusion criteria, between January 2011 and December 2023, 36 patients fit the study design. Using Cox proportional hazards regression and Kaplan–Meier curves, we determined the time-to-event distribution, for which the first episode of AGR was considered an event, with a significance threshold of 0.05. Results: The 1-year rate of AGR was 38.9% and was 47.2% at 2 years, with a 2-year mortality of 11.1%. The interpretation of the Cox regression indicated that early initiation of spironolactone represents a protective factor against the 2-year AGR (HR: 0.263; 95%CI: 0.076–0.922; p = 0.037 by the log-rank test). Conclusions: These results might suggest a possible benefit of the early administration of spironolactone after a heart transplant, but further prospective studies need to be performed for the validation of our findings. Full article

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

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Biomedicines, Volume 13, Issue 5 (May 2025) – 185 articles

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