Biomedicines

21 pages, 3868 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 (registering DOI) - 11 May 2025

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)

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 (registering DOI) - 11 May 2025

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 (registering DOI) - 11 May 2025

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 (registering DOI) - 11 May 2025

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 (registering DOI) - 11 May 2025

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, 1048 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 (registering DOI) - 10 May 2025

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)

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 (registering DOI) - 10 May 2025

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, 1696 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 (registering DOI) - 10 May 2025

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)

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 (registering DOI) - 10 May 2025

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 (registering DOI) - 10 May 2025

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 (registering DOI) - 10 May 2025

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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14 pages, 574 KiB

Open AccessArticle

Associations Between Inflammatory and Bone Turnover Markers and Mortality in Hemodialysis Patients

by Alexandru Florin Sircuța, Iulia Dana Grosu, Adalbert Schiller, Ligia Petrica, Viviana Ivan, Oana Schiller, Felix-Mihai Maralescu, Marcel Palamar, Monica-Nicoleta Mircea, Daniel Nișulescu, Ionuț Goleț and Flaviu Bob

Biomedicines 2025, 13(5), 1163; https://doi.org/10.3390/biomedicines13051163 (registering DOI) - 10 May 2025

Abstract

Background/Objectives: Chronic kidney disease–mineral and bone disorder (CKD-MBD) and systemic inflammation contribute to mortality in hemodialysis (HD) patients. The primary aim of this study was to determine whether specific CKD-MBD markers and inflammatory biomarkers are associated with increased mortality risk in HD patients. [...] Read more.

Background/Objectives: Chronic kidney disease–mineral and bone disorder (CKD-MBD) and systemic inflammation contribute to mortality in hemodialysis (HD) patients. The primary aim of this study was to determine whether specific CKD-MBD markers and inflammatory biomarkers are associated with increased mortality risk in HD patients. Methods: We conducted a retrospective cohort study on 63 stage 5D CKD patients undergoing maintenance HD. Serum intact parathyroid hormone (iPTH), soluble Klotho, calcium, phosphorus, 25(OH)D (25-hydroxyvitamin D), transforming growth factor-beta (TGF-β), vascular endothelial growth factor (VEGF), C-reactive protein (CRP), and interleukin-6 (IL-6) were analyzed. A Cox regression analysis assessed mortality predictors, and linear regression analysis evaluated CKD-MBD–inflammation correlations. Results: Lower iPTH (<329.3 pg/mL) levels were the only significant mortality predictor (p = 0.042). Other CKD-MBD markers (calcium, phosphorus, 25(OH)D, VEGF, TGF-β) did not impact survival. Soluble Klotho correlated positively with IL-6 (r = 0.57, p < 0.001), suggesting a compensatory inflammatory response. Conclusions: Our findings demonstrate that low iPTH levels and advanced age are independent predictors of mortality in hemodialysis patients. The positive association between soluble Klotho and IL-6 suggests a potential compensatory inflammatory response. These results highlight the need for further research to clarify underlying mechanisms and to explore novel therapeutic strategies. Full article

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

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15 pages, 1909 KiB

Open AccessArticle

Early Immunological and Inflammation Proteomic Changes in Elderly COVID-19 Patients Predict Severe Disease Progression

by Shiyang Liu, Wen Xu, Bo Tu, Zhiqing Xiao, Xue Li, Lei Huang, Xin Yuan, Juanjuan Zhou, Xinxin Yang, Junlian Yang, De Chang, Weiwei Chen and Fu-Sheng Wang

Biomedicines 2025, 13(5), 1162; https://doi.org/10.3390/biomedicines13051162 (registering DOI) - 10 May 2025

Abstract

Background: Elderly patients infected with SARS-CoV-2 are at higher risk of developing cytokine storm and severe outcomes; however, specific immunological and proteomic biomarkers for early prediction remain unclear in this vulnerable group. Methods: We enrolled 182 elderly COVID-19 patients from the Chinese PLA [...] Read more.

Background: Elderly patients infected with SARS-CoV-2 are at higher risk of developing cytokine storm and severe outcomes; however, specific immunological and proteomic biomarkers for early prediction remain unclear in this vulnerable group. Methods: We enrolled 182 elderly COVID-19 patients from the Chinese PLA General Hospital between November 2022 and April 2023, categorizing them based on progression to respiratory failure requiring mechanical ventilation (defined as severe progression). Olink proteomic analysis was performed on admission serum from 40 propensity score-matched samples, with differentially expressed proteins (DEPs) validated by cytometric bead array (CBA) in 178 patients. To predict severe progression, a model was developed using a 70% training set and validated on a 30% validation set. LASSO regression screened features followed by logistic regression and receiver operating characteristic (ROC) analysis to optimize the model by incrementally incorporating features ranked by random forest importance. Results: Elderly patients progressing to severe COVID-19 exhibited early immune dysregulation, including neutrophilia, lymphopenia, monocytopenia, elevated procalcitonin (PCT), C-reactive protein (CRP), interleukin-6 (IL-6), neutrophil-to-lymphocyte ratio (NLR), and systemic immune-inflammation index (SII), as well as coagulation dysfunction and multi-organ injury. Proteomics identified a set of biomarkers, including tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and revealed disruptions in signaling pathways, including the mTOR and VEGF signaling pathways. The optimal predictive model, which incorporated PCT, IL-6, monocyte percentage, lymphocyte count, and TRAIL, achieved an area under curve (AUC) of 0.870 (0.729–1.000) during validation. TRAIL levels negatively correlated with fibrinogen (p < 0.05). Conclusions: Elderly COVID-19 patients with severe progression demonstrate early immune dysregulation, hyperinflammation, coagulation dysfunction, and multi-organ injury. The model we proposed effectively predicts disease progression in elderly COVID-19 patients, providing potential biomarkers for early clinical risk stratification in this vulnerable population. Full article

(This article belongs to the Section Immunology and Immunotherapy)

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12 pages, 221 KiB

Open AccessReview

Comparative Analysis of 5-ALA and Fluorescent Techniques in High-Grade Glioma Treatment

by José E. Valerio, Guillermo de Jesús Aguirre Vera, Jorge Zumaeta, Noe Santiago Rea, Maria P. Fernandez Gomez, Penelope Mantilla-Farfan, Laurel Valente and Andrés M. Alvarez-Pinzon

Biomedicines 2025, 13(5), 1161; https://doi.org/10.3390/biomedicines13051161 (registering DOI) - 10 May 2025

Abstract

Background: 5-Aminolevulinic acid (5-ALA) serves as a precursor in the heme biosynthesis pathway, resulting in the selective accumulation of protoporphyrin IX (PpIX) within glioma cells. This property facilitates fluorescence-guided resection (FGR) in high-grade gliomas (HGGs), enhancing surgical precision and oncological results. Nonetheless, its [...] Read more.

Background: 5-Aminolevulinic acid (5-ALA) serves as a precursor in the heme biosynthesis pathway, resulting in the selective accumulation of protoporphyrin IX (PpIX) within glioma cells. This property facilitates fluorescence-guided resection (FGR) in high-grade gliomas (HGGs), enhancing surgical precision and oncological results. Nonetheless, its clinical implementation is restricted by factors such as accessibility, cost, and technical limitations. Methods: A systematic review of PubMed literature (2019–2024) was conducted to assess the efficacy of 5-ALA in HGG surgery compared to conventional white light microscopy. Studies focusing on non-neurosurgical applications, pediatric populations, and non-HGG indications were excluded. Results: Nineteen articles met the criteria. Recent studies indicate that 5-ALA-guided resection significantly enhances gross total resection (GTR) rates compared to white light surgery (75.4% vs. 54.3%, p < 0.001). Patients receiving 5-ALA-assisted resection exhibit enhanced progression-free survival (PFS) at 6 months (median 8.1 months compared to 5.4 months, p = 0.002) and overall survival (OS) (median 15.2 months versus 12.3 months, p = 0.008). The necessity for specialized neurosurgical microscopes equipped with blue light filters restricts accessibility, especially in low-resource environments. Recent advancements in fluorescence-enhancing technologies, particularly loupe-based systems, have demonstrated increases in fluorescence intensity by up to tenfold through direct emission. Sodium fluorescein, originally designed for ophthalmological use, has been adapted for enhancing contrast in intracranial tumors; however, its non-specific binding to serum albumin restricts its accuracy in glioma resection. Conclusions: Recent publications demonstrate that 5-ALA fluorescence-guided surgery significantly improves gross total resection rates and survival outcomes in patients with high-grade gliomas. Although it offers clinical advantages, cost and equipment constraints continue to pose substantial obstacles to broad implementation. Additional research is required to enhance fluorescence-guided techniques and increase accessibility in resource-constrained environments. Full article

(This article belongs to the Special Issue Advanced Cancer Diagnosis and Treatment: Second Edition)

41 pages, 5959 KiB

Open AccessReview

Biomarker-Driven Approaches to Bone Metastases: From Molecular Mechanisms to Clinical Applications

by Youssef Elshimy, Abdul Rahman Alkhatib, Bilal Atassi and Khalid S. Mohammad

Biomedicines 2025, 13(5), 1160; https://doi.org/10.3390/biomedicines13051160 (registering DOI) - 10 May 2025

Abstract

Bone metastases represent a critical complication in oncology, frequently indicating advanced malignancy and substantially reducing patient quality of life. This review provides a comprehensive analysis of the complex interactions between tumor cells and the bone microenvironment, emphasizing the relevance of the “seed and [...] Read more.

Bone metastases represent a critical complication in oncology, frequently indicating advanced malignancy and substantially reducing patient quality of life. This review provides a comprehensive analysis of the complex interactions between tumor cells and the bone microenvironment, emphasizing the relevance of the “seed and soil” hypothesis, the RANK/RANKL/OPG signaling axis, and Wnt signaling pathways that collectively drive metastatic progression. The molecular and cellular mechanisms underlying the formation of osteolytic and osteoblastic lesions are examined in detail, with a particular focus on their implications for bone metastases associated with breast, prostate, lung, and other cancers. A central component of this review is the categorization of pathological biomarkers into four types: diagnostic, prognostic, predictive, and monitoring. We provide a comprehensive evaluation of circulating tumor cells (CTCs), bone turnover markers (such as TRACP-5b and CTX), advanced imaging biomarkers (including PET/CT and MRI), and novel genomic signatures. These biomarkers offer valuable insights for early detection, enhanced risk stratification, and optimized therapeutic decision-making. Furthermore, emerging strategies in immunotherapy and bone-targeted treatments are discussed, highlighting the potential of biomarker-guided precision medicine to enhance personalized patient care. The distinctiveness of this review lies in its integrative approach, combining fundamental pathophysiological insights with the latest developments in biomarker discovery and therapeutic innovation. By synthesizing evidence across various cancer types and biomarker categories, we provide a cohesive framework aimed at advancing both the scientific understanding and clinical management of bone metastases. Full article

(This article belongs to the Special Issue Pathological Biomarkers in Precision Medicine)

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10 pages, 375 KiB

Open AccessArticle

Changes in Gingival Crevicular Fluid Endocan (ESM-1) Levels as a Potential Biomarker After Non-Surgical Periodontal Treatment in Periodontitis Patients

by Bilge Karci and Kevser Sokmen

Biomedicines 2025, 13(5), 1159; https://doi.org/10.3390/biomedicines13051159 - 9 May 2025

Abstract

Background: This study aimed to investigate endocan (ESM-1) levels in periodontitis patients before and after non-surgical periodontal treatment by analyzing the relationship between vascular endothelial growth factor A (VEGF-A) and tumor necrosis factor-alpha (TNF-α) in gingival crevicular fluid (GCF). Methods: This [...] Read more.

Background: This study aimed to investigate endocan (ESM-1) levels in periodontitis patients before and after non-surgical periodontal treatment by analyzing the relationship between vascular endothelial growth factor A (VEGF-A) and tumor necrosis factor-alpha (TNF-α) in gingival crevicular fluid (GCF). Methods: This study included 26 periodontally healthy people as controls (Group 1) and 27 patients with Stage III-Grade B periodontitis (Group 2). Demographic and periodontal variables were assessed. GCF samples were collected from every subject both before and 6 weeks following non-surgical periodontal therapy (NSPT). Using an enzyme-linked immunosorbent test, biomarker levels were determined. Results: The periodontitis patients showed higher ESM-1 levels than the controls, although the difference was not significant (p > 0.005). The ESM-1 levels decreased significantly after treatment (p = 0.001). The VEGF-A levels did not differ significantly between the periodontitis patients and controls (p > 0.005) and decreased non-significantly following treatment (p > 0.005). The TNF-α levels were significantly higher in the periodontitis patients than the controls (p = 0.000) and decreased significantly after treatment (p = 0.000). A significant correlation was found between TNF-α and both probing depth (PD) and interproximal clinical attachment level (iCAL) in the control group (p < 0.05). In the periodontitis group, the VEGF levels were significantly correlated with the gingival index (GI) (p < 0.05). Significant correlations were identified between ESM-1 and VEGF-A and ESM-1 and TNF-α, as well as VEGF-A and TNF-α, in both the control group and following treatment (p < 0.05). Conclusions: ESM-1 and TNF-α levels decreased with non-surgical periodontal treatment in GCF. Within the limits of the study, the findings suggest that ESM-1 levels in periodontal tissues may be an indicator of periodontal disease. Full article

(This article belongs to the Special Issue Periodontal Disease and Periodontal Tissue Regeneration)

28 pages, 1422 KiB

Open AccessSystematic Review

Experimental Models of Type 2 Diabetes Mellitus Induced by Combining Hyperlipidemic Diet (HFD) and Streptozotocin Administration in Rats: An Integrative Review

by Ana Karolinne da Silva Brito, Ana Victória da Silva Mendes, Boris Timah Acha, Amanda Suellenn da Silva Santos Oliveira, Joyce Lopes Macedo, Akemi Suzuki Cruzio, Maria das Graças Prianti, Raquel Rodrigues de Abreu, Massimo Lucarini, Alessandra Durazzo, Maria do Carmo de Carvalho e Martins and Daniel Dias Rufino Arcanjo

Biomedicines 2025, 13(5), 1158; https://doi.org/10.3390/biomedicines13051158 - 9 May 2025

Abstract

Type 2 diabetes mellitus (DM2) is a metabolic disorder characterized by chronic hyperglycemia associated with low insulin production and/or insulin resistance. A high-fat diet (HFD) combined with a low dose of streptozotocin (STZ) in an animal model produces a disease that mimics type [...] Read more.

Type 2 diabetes mellitus (DM2) is a metabolic disorder characterized by chronic hyperglycemia associated with low insulin production and/or insulin resistance. A high-fat diet (HFD) combined with a low dose of streptozotocin (STZ) in an animal model produces a disease that mimics type 2 diabetes mellitus in humans. However, there is wide variation in the methods of inducing diabetes in terms of the dose of STZ, the duration of the induction period, and the composition of the diet used, all of which could result in biological responses that are not typical of the disease. This review aims to investigate the characteristics of an experimental model of type 2 diabetes mellitus by combining a high-fat diet with low doses of streptozotocin in Wistar rats. This is an integrative review conducted by searching in the Medline, Lilacs, and Embase databases using the keywords “type 2 diabetes mellitus”, “high-fat diet”, “streptozotocin” and “Wistar rats”. Articles published in English between 2018 and 2025 were included. The induction of DM2 in young male rats with a high-fat HFD for a period of at least 3 weeks followed by a low dose of STZ resulted in metabolic, histological, inflammatory, and oxidative changes, and alterations in the signaling pathways of glycemic and lipid metabolism in different tissues, replicating the characteristics observed in humans. HFD-fed + STZ-induced Wistar rats constitute an effective animal model for studying DM2. Full article

(This article belongs to the Special Issue Animal Models for the Study of Cardiovascular Physiology)

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10 pages, 503 KiB

Open AccessArticle

Accuracy of Imaging Scoring Indexes in Pediatric Crohn’s Disease Patients

by Goran Hauser, Goran Palčevski, Barbara Čandrlić, Pero Hrabač and Damir Miletić

Biomedicines 2025, 13(5), 1157; https://doi.org/10.3390/biomedicines13051157 - 9 May 2025

Abstract

Background: Crohn’s disease (CD) is a chronic inflammatory condition that can affect the gastrointestinal tract and cause significant extraintestinal manifestations. Diagnosing and monitoring disease activity, especially in pediatric patients, remains a challenge due to the variable clinical presentations and limitations of traditional imaging [...] Read more.

Background: Crohn’s disease (CD) is a chronic inflammatory condition that can affect the gastrointestinal tract and cause significant extraintestinal manifestations. Diagnosing and monitoring disease activity, especially in pediatric patients, remains a challenge due to the variable clinical presentations and limitations of traditional imaging methods. Objective: This study aimed to evaluate and compare the diagnostic accuracy and clinical utility of small bowel capsule endoscopy (SBCE) versus magnetic resonance enterography (MRE) for assessing disease activity and extent in pediatric Crohn’s disease using the Pediatric Crohn’s Disease Activity Index (PCDAI) and Simple Endoscopic Score for Crohn’s Disease (SES-CD) as reference standards. Methods: In this prospective study, 52 pediatric patients with newly diagnosed CD underwent upper and lower endoscopy, MRE, and SBCE. The SBCE images were analyzed using the Capsule Endoscopy Crohn’s Disease Activity Index (CECDAI), while the MRE images were scored using the Crohn’s Disease MRI Index (CDMI). Correlations of these findings with PCDAI and SES-CD were statistically analyzed. Results: CECDAI and CDMI demonstrated strong correlations with PCDAI (r = 0.517 and r = 0.525, respectively; p < 0.001). The correlations between CECDAI and SES-CD were less pronounced but significant. SBCE and MRE showed comparable efficacy in detecting small bowel lesions, with both methods offering valuable insights into the disease status. Conclusion: SBCE is a reliable, non-invasive tool for diagnosing and monitoring pediatric CD, comparable to MRE. While SBCE offers higher resolution for mucosal evaluation, it requires additional expertise for optimal interpretation. The adoption of SBCE alongside MRE could enhance diagnostic accuracy and early therapeutic interventions for pediatric CD. Full article

(This article belongs to the Special Issue Digestive Disorders: Translation and Bridging the Gap Between Research, Diagnosis, and Treatment)

25 pages, 1919 KiB

Open AccessArticle

Molecular Ancestry Across Allelic Variants of SLC22A1, SLC22A2, SLC22A3, ABCB1, CYP2C8, CYP2C9, and CYP2C19 in Mexican-Mestizo DMT2 Patients

by Adiel Ortega-Ayala, Carla González de la Cruz, Pedro Dorado, Fernanda Rodrigues-Soares, Fernando Castillo-Nájera, Adrián LLerena Ruiz and Juan Molina-Guarneros

Biomedicines 2025, 13(5), 1156; https://doi.org/10.3390/biomedicines13051156 - 9 May 2025

Abstract

Background/Aims: across protein-coding genes, single nucleotide allelic variants (SNVs) affect antidiabetic drug pharmacokinetics, thus contributing to interindividual variability in drug response. SNV frequencies vary across different populations. Studying ancestry proportions among SNV genotypes is particularly important for personalising diabetes mellitus type 2 [...] Read more.

Background/Aims: across protein-coding genes, single nucleotide allelic variants (SNVs) affect antidiabetic drug pharmacokinetics, thus contributing to interindividual variability in drug response. SNV frequencies vary across different populations. Studying ancestry proportions among SNV genotypes is particularly important for personalising diabetes mellitus type 2 (DMT2) treatment. Methods: a sample of 249 Mexican DMT2 patients was gathered. SNVs were determined through real-time PCR (RT-PCR). Molecular ancestries were determined as 3 clusters (Native-American, European, and African) based upon 90 ancestry markers (AIMS). Statistical inference tests were performed to analyse ancestry across 23 SNV genotypes. Allele and ancestry distributions were analysed through Spearman’s correlation. Results: ancestry medians were 65.48% Native-American (NATAM), 28.34% European (EUR), and 4.8% African (AFR). CYP2C8*3 and CYP2C8*4 were negatively correlated to NATAM, whereas positively to EUR. The activity score of CYP2C9 was correlated to NATAM (Rho = 0.131, p = 0.042). CYP2C19*17 and the activity score of CYP2C19 were negatively correlated to NATAM. The correlation throughout SLC22A1 variants, such as GAT in rs72552763, was positive by EUR, while A in rs594709 was negative thereby and positive by NATAM. SLC22A3 variant C in rs2076828 was positively correlated to NATAM. NATAM patients present higher HbA1c levels with respect to Mestizo patients (p = 0.037). Uncontrolled patients (HbA1c ≥ 7%) have a larger NATAM ancestry (p = 0.018) and lower EUR (p = 0.022) as compared to controlled patients (HbA1c < 7%). Conclusions: there is a correlation between ancestry and some pharmacokinetically relevant alleles among Mexican DMT2 patients. Ethnicity is relevant for personalised medicine across different populations. Full article

(This article belongs to the Special Issue Diabetes: Comorbidities, Therapeutics and Insights (2nd Edition))

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