Biomedicines

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))

16 pages, 763 KiB

Open AccessArticle

Clinical Impact of Stool Polymerase Chain Reaction (PCR) Testing in Hospitalized Patients with Acute Diarrhea: A Retrospective Observational Study

by Crina Fofiu, Daniela Dobru, Adina Andone, Victoria Ancuța Nyulas and Alina Boeriu

Biomedicines 2025, 13(5), 1155; https://doi.org/10.3390/biomedicines13051155 - 9 May 2025

Abstract

Background/Objectives: Acute diarrheal illnesses are a major cause of hospital admissions, particularly in immunocompromised patients. Traditional diagnostic methods are slow and often insensitive, delaying treatment. In contrast, PCR panels provide rapid, sensitive detection of multiple pathogens. This study evaluates stool PCR testing [...] Read more.

Background/Objectives: Acute diarrheal illnesses are a major cause of hospital admissions, particularly in immunocompromised patients. Traditional diagnostic methods are slow and often insensitive, delaying treatment. In contrast, PCR panels provide rapid, sensitive detection of multiple pathogens. This study evaluates stool PCR testing in hospitalized adults and its impact on clinical decisions and antimicrobial stewardship. Methods: We conducted a retrospective study at Bistrița County Hospital, Romania (September 2023–September 2024), including 75 adults with acute diarrhea and negative conventional stool tests. PCR testing (VIASURE panels I and II) detected 11 bacteria, 6 viruses, and 5 parasites. Clinical and therapeutic data were analyzed, and logistic regression identified predictors of PCR positivity and adverse outcomes. Results: PCR was positive in 78% of cases, with Campylobacter spp. (57.6%) and Clostridioides difficile (20.3%) being the most common. Bloody diarrhea independently predicted PCR positivity (OR 9.78, p = 0.047). Immunosuppression and end-stage liver disease were linked to worse outcomes. PCR results led to antimicrobial therapy adjustments in 40 patients (p = 0.001), correcting inappropriate antibiotic use in 66% of those receiving empirical treatment. Targeted therapy significantly reduced antimicrobial duration from 7 to 5 days (p = 0.00001). Conclusions: Stool PCR testing enhances pathogen detection, guides targeted therapy, and reduces inappropriate antibiotic use, supporting antimicrobial stewardship and improving outcomes in selected hospitalized patients. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Gastrointestinal Diseases)

18 pages, 555 KiB

Open AccessReview

Angiogenic Factors and Inflammatory Bowel Diseases

by Zhiru Li, Li Zeng, Wei Huang, Xinxing Zhang, Li Zhang and Qin Xie

Biomedicines 2025, 13(5), 1154; https://doi.org/10.3390/biomedicines13051154 - 9 May 2025

Abstract

Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is characterized by chronic intestinal inflammation and impaired epithelial barrier function. Emerging evidence highlights the critical role of vascular remodeling and angiogenesis in IBD pathogenesis. This review explores the intricate relationship between blood [...] Read more.

Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is characterized by chronic intestinal inflammation and impaired epithelial barrier function. Emerging evidence highlights the critical role of vascular remodeling and angiogenesis in IBD pathogenesis. This review explores the intricate relationship between blood vessels and the intestinal epithelial barrier, emphasizing how aberrant vascularization contributes to barrier dysfunction and disease progression. In IBD, excessive angiogenesis is driven by hypoxia, immune cell infiltration, and pro-inflammatory cytokines, further perpetuating inflammation and tissue damage. Key angiogenic factors, such as vascular endothelial growth factor (VEGF), angiopoietins, and platelet-derived growth factor (PDGF), are upregulated in IBD, promoting pathological vessel formation. These newly formed vessels are often immature and hyperpermeable, exacerbating leukocyte recruitment and inflammatory responses. Given the pivotal role of angiogenesis in IBD, anti-angiogenic therapies have emerged as a potential therapeutic strategy. Preclinical and clinical studies targeting VEGF and other angiogenic pathways have shown promise in reducing inflammation and promoting mucosal healing. This review summarizes current knowledge on vascular–epithelial interactions in IBD, the mechanisms driving pathological angiogenesis, and the therapeutic potential of anti-angiogenic approaches, providing insights for future research and treatment development. Full article

(This article belongs to the Special Issue Advances in Angiogenesis, Inflammation, and Oxidative Stress in Inflammatory Bowel Diseases)

30 pages, 708 KiB

Open AccessReview

HER2-Positive Breast Cancer—Current Treatment Management and New Therapeutic Methods for Brain Metastasis

by Hanna Miski, Kamila Krupa, Michał Piotr Budzik, Andrzej Deptała and Anna Badowska-Kozakiewicz

Biomedicines 2025, 13(5), 1153; https://doi.org/10.3390/biomedicines13051153 - 9 May 2025

Abstract

Background: Breast cancer can be classified based on the immunohistochemistry (IHC) phenotypes, defined by the presence or absence of the main IHC markers. IHC phenotyping is important as it determines the prognosis and guides treatment. For example, human epidermal growth factor receptor [...] Read more.

Background: Breast cancer can be classified based on the immunohistochemistry (IHC) phenotypes, defined by the presence or absence of the main IHC markers. IHC phenotyping is important as it determines the prognosis and guides treatment. For example, human epidermal growth factor receptor 2 (HER2) overexpression, which triggers cell growth and division, is observed in HER2-positive breast cancer. Methods: The standard treatment is based on trastuzumab plus pertuzumab in combination with taxane chemotherapy. The possibility of developing metastases depends on those phenotypes. Approximately 25–50% of patients with HER2-positive breast cancer experience brain metastases. This aspect is especially important, as 20% of those patients die as a result. Results: Through the years, many advanced therapies have been introduced to treat brain metastases, including whole brain radiotherapy, stereotactic radiosurgery, and a tyrosine kinase inhibitor (TKI), neratinib. Nonetheless, this still remains a therapeutic challenge. Conclusions: In this review, we focus on the treatment and efficiency of therapies targeting HER2-positive breast cancer, mainly concentrating on the current and newly developed treatment options for brain metastases, such as trastuzumab deruxtecan and tucatinib. Full article

(This article belongs to the Special Issue Advanced Research in Breast Diseases and Histopathology)

28 pages, 1451 KiB

Open AccessReview

Minor Visual Phenomena in Lewy Body Disease: A Systematic Review

by Elettra Capogna, Virginia Pollarini, Alessia Quinzi, Lucia Guidi, Luisa Sambati, Maria Sasca Criante, Elena Mengoli, Annalena Venneri, Raffaele Lodi, Caterina Tonon and Micaela Mitolo

Biomedicines 2025, 13(5), 1152; https://doi.org/10.3390/biomedicines13051152 - 9 May 2025

Abstract

Minor visual phenomena (MVP), such as visual illusions, pareidolias, feeling of presence, and passage hallucinations, are often experienced by patients with Lewy Body Disease (LBD), in addition to complex visual hallucinations (VH), even in the early stages of the disease. This systematic review [...] Read more.

Minor visual phenomena (MVP), such as visual illusions, pareidolias, feeling of presence, and passage hallucinations, are often experienced by patients with Lewy Body Disease (LBD), in addition to complex visual hallucinations (VH), even in the early stages of the disease. This systematic review aimed to provide an up-to-date literature review of the occurrence and prevalence of MVP in LBD and to assess their potential associations both with VH and visuoperceptual and visuospatial deficits. A systematic literature search was carried out in PubMed, Web of Science, APA PsycInfo, Scopus, and Cochrane Library, and a total of 44 articles were included. The included studies showed significant variability in the occurrence of MVP in the LBD population and in the assessment methods used, such as standardized scales (e.g., the noise pareidolia test), semi-structured interviews (e.g., the North-East Visual Hallucinations Interview), and clinical descriptions. Similarly to VH, MVP appears to be highly specific to LBD, helping in differential diagnosis from Alzheimer’s Disease. The overall relationship between MVP, VH, and visuoperceptual/visuospatial deficits remains unclear. Some studies found that MVP (especially pareidolic responses and presence of hallucinations) was positively correlated with VH, yet it is challenging to determine whether MVP can be considered a precursor of future VH development. Negative associations were reported between MVP (especially pareidolias) and visuoperceptual/visuospatial abilities. However, it is not clear whether these deficits serve as independent, exclusive factors in MVP occurrence or if they interact with VH as a contributing component. Gaining insight into the occurrence of these phenomena could prove beneficial for differential diagnosis, prognosis, and prediction of treatment outcomes in patients with LBD. Full article

(This article belongs to the Special Issue Neurodegeneration in Cognitive Impairment and Mood Disorders for Experimental, Clinical, and Translational Neuropsychiatry—Second Edition)

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14 pages, 1908 KiB

Open AccessArticle

Safety and Efficacy of Regorafenib and 5-Fluorouracil Combination Therapy in Refractory Metastatic Colorectal Cancer After Third-Line Treatment: An Institutional Experience

by Maen Abdelrahim, Abdullah Esmail, Ebtesam Al-Najjar, Bayan Khasawneh, Godsfavour Umoru, Waseem Abdelrahim, Karen Abboud and Veronica B. Ajewole

Biomedicines 2025, 13(5), 1151; https://doi.org/10.3390/biomedicines13051151 - 9 May 2025

Abstract

Background: Colorectal carcinoma (CRC) is one of the most common cancer types along with breast, prostate, and lung cancer. Many patients with CRC present with metastatic disease despite receiving standard first- and second-line therapies; thus emerges the demand for implementing new therapies [...] Read more.

Background: Colorectal carcinoma (CRC) is one of the most common cancer types along with breast, prostate, and lung cancer. Many patients with CRC present with metastatic disease despite receiving standard first- and second-line therapies; thus emerges the demand for implementing new therapies that could improve outcomes among CRC patients. This case series was conducted to assess the efficacy and safety of regorafenib plus 5-fluorouracil (5-FU) in patients with refractory metastatic CRC (mCRC). Methods: We conducted a retrospective analysis of data from adult patients aged 18 and above who were diagnosed with refractory mCRC and received regorafenib plus 5-FU combination therapy at Houston Methodist Hospital between November 2017 and October 2023. Our study focuses on assessing key outcomes, including Overall Survival [OS], Progression-Free Survival [PFS], and safety. Results: Among the 12 patients we included in this study who underwent regorafenib plus 5-FU combination therapy for refractory mCRC after receiving at least three prior lines of treatment, the best response for six patients (50%) was successfully achieved, with disease control within 7–12 weeks from therapy initiation. Patients had an overall good tolerance for this treatment regimen and reported only the most common adverse events, including Hand-Foot Syndrome (HFS), mucositis, and hypertension (HTN), which were mostly resolved with dose adjustment of medications. Conclusions: This study highlights that using a combination of regorafenib plus 5-FU can be a potential treatment option for patients with refractory mCRC. Additional research, including prospective clinical trials, is required to assess the effectiveness and safety of regorafenib and 5-FU combination therapy in comparison to other currently limited treatment options. Full article

(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancers: From Microbiota Modulation to New Therapeutic Approaches)

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12 pages, 722 KiB

Open AccessArticle

Cortical Thickness Changes in Migraine Patients Treated with Anti-Calcitonin Gene-Related Peptide Monoclonal Antibodies: A Prospective Age- and Sex-Matched Controlled Study

by Soohyun Cho

Biomedicines 2025, 13(5), 1150; https://doi.org/10.3390/biomedicines13051150 - 9 May 2025

Abstract

Background: Migraine is associated with structural brain abnormalities, including cortical thickness changes. Anti-calcitonin gene-related peptide monoclonal antibodies (anti-CGRP mAbs) are a novel therapy for migraine prevention, but their effects on cortical structures are poorly understood. Methods: In this prospective age- and sex-matched controlled [...] Read more.

Background: Migraine is associated with structural brain abnormalities, including cortical thickness changes. Anti-calcitonin gene-related peptide monoclonal antibodies (anti-CGRP mAbs) are a novel therapy for migraine prevention, but their effects on cortical structures are poorly understood. Methods: In this prospective age- and sex-matched controlled study, 30 migraine patients receiving either anti-CGRP mAbs (fremanezumab) (n = 15) or oral preventive medications (n = 15) underwent 3T MRI scans before and after treatment. Treatment response was defined as a ≥50% reduction in monthly headache days after 3 months. Cortical thickness was analyzed across 46 cortical regions, comparing patients treated with anti-CGRP mAbs to those receiving oral preventive treatment, as well as responders to non-responders within the anti-CGRP group. Results: Cortical thickness changes did not differ significantly between the anti-CGRP and oral treatment groups. However, among patients receiving anti-CGRP mAbs, responders showed significant decreases in cortical thickness compared to non-responders, particularly in the right caudal anterior cingulate (p = 0.026) and left rostral middle frontal cortex (p = 0.007). These cortical changes correlated with treatment response to anti-CGRP mAbs (β = −0.429, 95% CI [−0.777, −0.081], p = 0.016 in the right caudal anterior cingulate; β = −0.224, 95% CI [−0.390, −0.057], p = 0.008 in the left rostral middle frontal cortex). Conclusions: This exploratory study, based on a small sample size, suggests that cortical thickness changes may be associated with treatment response to anti-CGRP mAbs rather than with CGRP mAb treatment itself. Further studies with larger cohorts are needed to confirm these findings. Full article

(This article belongs to the Special Issue Biomarkers in Pain)

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26 pages, 1879 KiB

Open AccessReview

Redox Balance in Cancer in the Context of Tumor Prevention and Treatment

by Paweł Sutkowy and Przemysław Czeleń

Biomedicines 2025, 13(5), 1149; https://doi.org/10.3390/biomedicines13051149 - 9 May 2025

Abstract

Malignant neoplasms constitute a substantial health concern for the human population, currently ranking as the second leading cause of mortality worldwide. In 2022, approximately 10 million deaths were attributable to cancer, and projections estimate that this number will rise to 35 million in [...] Read more.

Malignant neoplasms constitute a substantial health concern for the human population, currently ranking as the second leading cause of mortality worldwide. In 2022, approximately 10 million deaths were attributable to cancer, and projections estimate that this number will rise to 35 million in 2050. Consequently, the development of effective cancer treatments and prevention strategies remains a primary focus of medical research. In this context, the impacts on the redox balance are being considered. The objective of this study was to present the current knowledge on oxidation and reduction processes in cancer. This review discloses the intricate and multifaceted interplay of oxidoreductive systems during carcinogenesis, which engenders discordant findings in the domain of tumor prevention and treatment. This study also examines the controversies surrounding the use of antioxidants, including their impact on other therapeutic interventions. The review offers a comprehensive overview of the existing knowledge on the subject, concluding that personalized and precise anticancer therapies targeting the redox processes can serve as both effective diagnostic and therapeutic tools. Full article

(This article belongs to the Special Issue Navigating the Tumor Microenvironment: The Role of Reactive Oxygen Species in Cancer Progression and Therapy)

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15 pages, 2656 KiB

Open AccessArticle

Endothelial–Mesenchymal Transition and Possible Role of Cytokines in Streptozotocin-Induced Diabetic Heart

by Hsu Lin Kang, Ákos Várkonyi, Ákos Csonka, András Szász, Tamás Várkonyi, Anikó Pósa and Krisztina Kupai

Biomedicines 2025, 13(5), 1148; https://doi.org/10.3390/biomedicines13051148 - 9 May 2025

Abstract

Background: Although endothelial mesenchymal transition (EndMT) has been characterized as a basic process in embryogenesis, EndMT is the mechanism that accelerates the development of cardiovascular diseases, including heart failure, aging, and complications of diabetes or hypertension as well. Endothelial cells lose their distinct [...] Read more.

Background: Although endothelial mesenchymal transition (EndMT) has been characterized as a basic process in embryogenesis, EndMT is the mechanism that accelerates the development of cardiovascular diseases, including heart failure, aging, and complications of diabetes or hypertension as well. Endothelial cells lose their distinct markers and take on a mesenchymal phenotype during EndMT, expressing distinct products. Methods: In this study, type 1 Diabetes mellitus (T1DM) was induced in rats with streptozotocin (STZ) by intraperitoneal injection at a 60 mg/kg dose. Diabetic rats were randomly divided into two groups, namely, control and diabetic rats, for 4 weeks. Heart, aorta, and plasma samples were collected at the end of 4 weeks. Sequentially, biochemical parameters, cytokines, reactive oxygen species (ROS), protein expression of EndMT markers (Chemokine C-X-C motif ligand-1 (CXCL-1), vimentin, citrullinated histone H3 (H3Cit), α-smooth muscle actin (α-SMA), and transforming growth factor beta (TGF-β) and versican), components of the extracellular matrix (matrix metalloproteinase 2 (MMP-2), tissue inhibitor of metalloproteinase-1(TIMP-1), and discoidin domain tyrosine kinase receptor 2 (DDR-2)) were detected by ELISA or Western blot, respectively. Results: Cytokines and ROS were increased in diabetic hearts, which induced partial EndMT. Among EndMT markers, histone citrullination, α-SMA, and CXCL-1 were increased; vimentin was decreased in DM. The endothelial marker endothelin-1 was significantly higher in the aortas of DM rats. Interestingly, TGF-β showed a significant decrease in the diabetic heart, plasma, and aorta. Additionally, MMP-2/TIMP-1 levels also decreased in DM. Conclusions: To sum up, the identification of molecules and regulatory pathways involved in EndMT provided novel therapeutic approaches for cardiac pathophysiological conditions. Full article

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

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13 pages, 456 KiB

Open AccessArticle

Association Between Body Self-Perception and the Incidence of Hypertension: The SUN “Seguimiento Universidad de Navarra” Cohort 1999–2022

by Patricia Caro, Carmen De La Fuente-Arrillaga, Vanessa Bullón-Vela, Rafael Pérez-Araluce, Miguel Ángel Martínez-González and Maira Bes-Rastrollo

Biomedicines 2025, 13(5), 1147; https://doi.org/10.3390/biomedicines13051147 - 9 May 2025

Abstract

Objective: This study aims to analyze the association between self-perceived body image and the incidence of hypertension. Methods: A prospective cohort study was conducted, classifying body image perception into three categories: adequate, underestimation, and overestimation, based on Stunkard’s Figure Rating Scale [...] Read more.

Objective: This study aims to analyze the association between self-perceived body image and the incidence of hypertension. Methods: A prospective cohort study was conducted, classifying body image perception into three categories: adequate, underestimation, and overestimation, based on Stunkard’s Figure Rating Scale and self-reported nutritional status. Cox proportional hazards models were used to determine the association between body image perception and the risk of developing hypertension, adjusting for potential confounders. Results: During a mean follow-up period of 12.7 years, 2359 incident cases of hypertension were identified. In the main adjusted model, body image underestimation was significantly associated with an increased risk of hypertension among women (HR 1.25; 95% CI 1.01–1.55). This association lost statistical significance when adjusting for baseline BMI in the sensitivity analysis. Conclusions: Self-perception of body image may influence health behaviors that impact weight control, potentially leading to higher BMI and, consequently, greater cardiometabolic risk. Although further research is needed to clarify its role, body image perception should begin to be considered in clinical practice as a relevant factor in chronic disease prevention. Full article

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

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21 pages, 2474 KiB

Open AccessReview

Exploring Protein Misfolding in Amyotrophic Lateral Sclerosis: Structural and Functional Insights

by Ouliana Ivantsik, Themis P. Exarchos, Aristidis G. Vrahatis, Panagiotis Vlamos and Marios G. Krokidis

Biomedicines 2025, 13(5), 1146; https://doi.org/10.3390/biomedicines13051146 (registering DOI) - 9 May 2025

Abstract

Protein functionality depends on its proper folding, making protein misfolding crucial for the function of proteins and, by extension, cells and the whole organism. Increasing evidence supports the role of protein misfolding in the pathogenesis of neurodegenerative diseases, such as amyotrophic lateral sclerosis [...] Read more.

Protein functionality depends on its proper folding, making protein misfolding crucial for the function of proteins and, by extension, cells and the whole organism. Increasing evidence supports the role of protein misfolding in the pathogenesis of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). ALS is a rapidly progressive disease diagnosed at a prevalence of 5 cases per 100,000, with approximately 2–3 patients per 100,000 diagnosed each year. To date, there is no cure, and the disease usually leads to death within 2 to 5 years from diagnosis. There are two types of the disorder: familial ALS (fALS), accounting for approximately 10% of cases, and sporadic (sALS), accounting for the remaining 90%. The hallmark of ALS, regardless of type, is the protein aggregates found in patients’ tissues. This suggests that the disruption of proteostasis plays a critical role in the development of the disease. Herein, we stress the distinct factors that lead to protein misfolding and aggregate formation in ALS. Specifically, we highlight several triggering factors affecting protein misfolding, namely mutations, errors in the processes of protein production and trafficking, and failures of folding and chaperone machinery. Gaining a deeper understanding of protein aggregation will improve our comprehension of disease pathogenesis and potentially uncover new therapeutic approaches. Full article

(This article belongs to the Special Issue Protein Misfolding and Functional Impairment in Neurodegenerative Diseases)

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17 pages, 2058 KiB

Open AccessReview

Targeting Metabolic Reprogramming in Bladder Cancer Immunotherapy: A Precision Medicine Approach

by Fuyang Liu, Kai Li and Qingyi Zhu

Biomedicines 2025, 13(5), 1145; https://doi.org/10.3390/biomedicines13051145 - 9 May 2025

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Abstract

Bladder cancer, as a highly heterogeneous malignant tumor of the urinary system, is significantly affected by tumor metabolic reprogramming in its response to immunotherapy. This review systematically elaborates on the molecular mechanisms of abnormal glucose and lipid metabolism in the bladder cancer microenvironment [...] Read more.

Bladder cancer, as a highly heterogeneous malignant tumor of the urinary system, is significantly affected by tumor metabolic reprogramming in its response to immunotherapy. This review systematically elaborates on the molecular mechanisms of abnormal glucose and lipid metabolism in the bladder cancer microenvironment and immune escape, and discusses precision treatment strategies based on metabolic regulation. In the future, it will be necessary to combine spatiotemporal omics and artificial intelligence technologies to construct a multi-target intervention system for the metabolic–immune interaction network, promoting a paradigm shift in precision treatment for bladder cancer. Full article

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

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15 pages, 3224 KiB

Open AccessArticle

Quantitative Real-Time RT-PCR Verifying Gene Expression Profile of Cavitations Within Human Jaw Bone

by Shahram Ghanaati, Eva Dohle, Fabian Schick and Johann Lechner

Biomedicines 2025, 13(5), 1144; https://doi.org/10.3390/biomedicines13051144 - 8 May 2025

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Abstract

Background/Objectives: Immune cells are integral to bone homeostasis, including the repair and remodeling of bone tissue. Chronic dysregulation within this osteoimmune network can lead to bone marrow defects of the jaw (BMDJ), particularly fatty degenerative osteonecrosis of the jaw (FDOJ). These localized pathologies [...] Read more.

Background/Objectives: Immune cells are integral to bone homeostasis, including the repair and remodeling of bone tissue. Chronic dysregulation within this osteoimmune network can lead to bone marrow defects of the jaw (BMDJ), particularly fatty degenerative osteonecrosis of the jaw (FDOJ). These localized pathologies are implicated in systemic immune dysfunctions. Methods: This study is designed to determine whether BMDJ/FDOJ samples are indicative of medullary bone pathology by evaluating FDOJ gene expression patterns using quantitative real-time PCR. Results: Comparative analyses between pathological and healthy samples evaluated the dysregulation of key molecular pathways. BMDJ/FDOJ samples showed significant upregulation of inflammatory mediators, including CCL5/RANTES, VEGF, IGF and KOR, and downregulation of structural proteins, such as collagen types I, II and IV, and osteogenesis-associated factors, such as SP7. Conclusions: The study provides new insights into the molecular mechanisms of BMDJ/FDOJ by identifying potential molecular changes suggesting a pro-inflammatory state in the affected jawbone which may contribute to systemic immune dysregulation. The findings are consistent with morphologic observations of BMDJ/FDOJ in degenerated jawbone and underscore the need for integrative approaches in dentistry and medicine while highlighting BMDJ/FDOJ as a potential target for therapeutic and preventive strategies against systemic diseases and emphasizing its clinical significance. Full article

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

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12 pages, 1350 KiB

Open AccessArticle

Factors Predicting Myocardial Recovery After Hospitalization for De Novo Heart Failure with Reduced Left Ventricular Ejection Fraction: Results from the COMFE Registry

by Víctor Donoso-Trenado, Óscar Otero-García, Raquel López-Vilella, Pablo de la Fuente López, Julia Martínez-Solé, Carlos Yebra-Pimentel Brea, Borja Guerrero-Cervera, Javier Adarraga Gómez, Sara Huélamo-Montoro, Guillermo Gallego-Latorre, David García-Vega, Inés Gómez-Otero, Luis Martínez-Dolz, Jose Ramón González-Juanatey and Luis Almenar Bonet

Biomedicines 2025, 13(5), 1143; https://doi.org/10.3390/biomedicines13051143 - 8 May 2025

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Abstract

Background/Objectives: Patients hospitalized for de novo heart failure with reduced ejection fraction (HFrEF) may experience improvement in left ventricular function, a phenomenon associated with improved morbidity and mortality outcomes. However, the factors influencing this improvement remain unclear. This study aimed to investigate [...] Read more.

Background/Objectives: Patients hospitalized for de novo heart failure with reduced ejection fraction (HFrEF) may experience improvement in left ventricular function, a phenomenon associated with improved morbidity and mortality outcomes. However, the factors influencing this improvement remain unclear. This study aimed to investigate the association between clinical and therapeutic factors and short-term improvement or recovery of left ventricular ejection fraction (LVEF) in patients hospitalized with newly diagnosed heart failure with reduced ejection fraction (HFrEF). Methods: This was a prospective observational study conducted in two referral centers in Spain. All patients admitted with de novo HFrEF between March 2021 and December 2023 were included. Improved myocardial function (HFimpEF) was defined as an initial LVEF ≤ 40% and a follow-up echocardiogram showing LVEF > 40%, with an increase of ≥10 points from baseline. Results: In total, 157 patients (63.3%) met the criteria for HFimpEF. Among the various etiologies of heart failure, significant differences were found between groups for tachycardiomyopathy (HFimpEF: 29.3% vs. non-HFimpEF: 13.1%, p = 0.006), valvular (HFimpEF: 7.6% vs. non-HFimpEF: 1.1%, p = 0.05), and ischemic (HFimpEF: 17.2% vs. non-HFimpEF: 43.9%, p < 0.0001) etiologies. Multivariate analysis showed that non-ischemic etiologies significantly favored myocardial improvement compared to ischemic cardiomyopathy. NT-proBNP values were consistently higher in the non-HFimpEF group at all time points measured with statistically significant differences, except at admission. Event-free survival curves (hospitalization for HF, worsening HF, and all-cause mortality) diverged early, showing statistically significant differences between groups. Conclusions: Overall, 63% of patients hospitalized for de novo HFrEF achieved myocardial improvement within an average of 3–4 months, with improvement favored by valvular and tachycardiomyopathy etiologies. This improvement has a significant prognostic impact. Full article

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

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18 pages, 1537 KiB

Open AccessArticle

Reduced Expression of UPRmt Proteins HSP10, HSP60, HTRA2, OMA1, SPG7, and YME1L Is Associated with Accelerated Heart Failure in Humans

by Petra Bakovic, Vid Mirosevic, Tomo Svagusa, Ana Sepac, Ana Kulic, Davor Milicic, Hrvoje Gasparovic, Igor Rudez, Marjan Urlic, Suncana Sikiric, Sven Seiwerth, Drazen Belina, Matija Bakos, Monika Karija Vlahovic, Rea Taradi, Rado Zic, Ivana Ilic, Borislav Belev, Bosko Skoric, Dora Fabijanovic, Ivo Planinc, Maja Cikes and Filip Sedlic Show full author list Hide full author list

Biomedicines 2025, 13(5), 1142; https://doi.org/10.3390/biomedicines13051142 - 8 May 2025

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Abstract

Background/Objectives: The mitochondrial unfolded protein response (UPRmt) is one of the mitochondrial quality control mechanisms that is responsible for reparation and removal of damaged proteins in mitochondria. Methods: Here we investigated the role of the UPRmt in the myocardium of humans with [...] Read more.

Background/Objectives: The mitochondrial unfolded protein response (UPRmt) is one of the mitochondrial quality control mechanisms that is responsible for reparation and removal of damaged proteins in mitochondria. Methods: Here we investigated the role of the UPRmt in the myocardium of humans with and without heart failure and in the cell culture model. Results: The analysis of myocardial samples by ELISA from patients with ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM), as well as healthy donors, revealed a significantly reduced expression of the UPRmt proteins HSP10, CLPP, LONP1, OMA1, and SPG7 in patients with DCM and ICM. Furthermore, patients with DCM and ICM exhibited elevated levels of myocardial reactive oxygen species (ROS, tested by 4-hydroxynonenal) compared to controls, and a positive correlation between ROS production and mt-HSP70, OMA1, and SPG7 protein expression. The correlation analysis indicated a negative correlation between cardiomyocyte hypertrophy and the expression of several UPRmt genes. The inhibition of four tested UPRmt effector proteins exacerbated the injury of cultured cells under oxidative stress. The patients with ICM, DCM, or both, who showed lower myocardial expression of HSP10, HSP60, HTRA2, OMA1, SPG7, and YME1L, underwent heart transplantation or implantation of a left ventricular assist device earlier in life compared to those with the higher protein expression. Conclusions: In conclusion, our findings indicate that the reduced expression of several UPRmt effector proteins is associated with accelerated heart failure in patients, which, together with other results, indicates that impaired UPRmt may contribute to the pathogenesis of heart failure in humans. Full article

(This article belongs to the Special Issue Advanced Research on Heart Failure and Heart Transplantation)

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17 pages, 2338 KiB

Open AccessArticle

The Effect of Probiotics on Preterm Birth Rates in Pregnant Women After a Threatened Preterm Birth Episode (The PROPEV Trial)

by Ester del Barco, Leidy-Alejandra G. Molano, Mireia Vargas, Marta Miserachs, Linda Puerto, Carmen Garrido-Giménez, Zaida Soler, Begoña Muñoz, Laia Pratcorona, Sonia Rimbaut, Mercè Vidal, Marta Dalmau, Alba Casellas, Elena Carreras, Chaysavanh Manichanh and Maria Goya

Biomedicines 2025, 13(5), 1141; https://doi.org/10.3390/biomedicines13051141 - 8 May 2025

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Abstract

Introduction: Preterm birth is the leading cause of perinatal mortality worldwide, with prevalence rates showing little reduction. Although mortality rates have decreased, morbidity rates remain concerningly high. In recent years, there has been a surge in studies examining the etiology, risk factors, [...] Read more.

Introduction: Preterm birth is the leading cause of perinatal mortality worldwide, with prevalence rates showing little reduction. Although mortality rates have decreased, morbidity rates remain concerningly high. In recent years, there has been a surge in studies examining the etiology, risk factors, and management of preterm birth. The use of vaginal probiotics in pregnant women at risk of preterm birth has garnered attention as a potential approach for improving perinatal outcomes and modulating the vaginal microbiota. However, the efficacy of this intervention remains unclear. Therefore, this study explored the impact of vaginal probiotics on perinatal outcomes and vaginal microbiota composition in pregnant women at risk of preterm birth. Materials and Methods: This was a randomized, prospective, longitudinal, double-blind, placebo-controlled, multicentric trial conducted across seven maternities in Spain from October 2017 to August 2022 in pregnant women at risk of preterm birth. Participants were randomly assigned to receive vaginal probiotics containing four lactobacilli strains or a placebo. The primary outcome was to explore a potential correlation between probiotic use among pregnant women at risk of preterm birth and the actual rate of preterm birth before 37 gestational weeks. Secondary outcomes included an evaluation of preterm birth rates, neonatal morbidity, the vaginal microbiota, and changes in the vaginal microbiota after receiving probiotics. Other secondary outcomes were identifying vaginal microbiota patterns associated with preterm birth and exploring potential therapeutic mechanisms involving probiotics. Trial registration: Clinicaltrials.gov, identifier: NCT03689166. Results: A total of 200 participants were included. Of those, birth data were obtained for 181 women. Demographics were similar between both groups. An analysis of perinatal outcomes found no significant differences in preterm birth rates, prematurity rates, gestational weeks at delivery, neonatal complications, time to birth, or latency time to delivery. Microbiota analysis showed no significant differences in vaginal microbiota changes between groups. No serious or unexpected adverse reactions were reported. Conclusions: There were no statistically significant differences for spontaneous preterm birth between pregnant women receiving probiotics and pregnant women receiving the placebo. Full article

(This article belongs to the Special Issue Gynecological Diseases in Cellular and Molecular Perspectives)

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8 pages, 220 KiB

Open AccessEditorial

Editorial to the Special Issue “Glycine-(and D-Serine)-Related Neurotransmission: Promising Therapeutic Targets with Still Unsolved Problems”

by Luca Raiteri

Biomedicines 2025, 13(5), 1140; https://doi.org/10.3390/biomedicines13051140 - 8 May 2025

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Abstract

Glycine (Gly) is a peculiar neurotransmitter (NT) in the Central Nervous System (CNS) exhibiting dual functions: it is mostly inhibitory, in different CNS areas, when it activates the ionotropic Gly receptors (GlyRs) [...] Full article

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

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Biomedicines, Volume 13, Issue 5 (May 2025) – 161 articles

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