Biomedicines

13 pages, 2296 KiB

Open AccessCase Report

A Novel Bradycardia-Associated Variant in HCN4 as a Candidate Modifier in Type 3 Long QT Syndrome: Case Report and Deep In Silico Analysis

by Anna A. Bukaeva, Anastasia V. Blokhina, Maria S. Kharlap, Marija Zaicenoka, Evgenia D. Zotova, Anna V. Petukhova, Elizaveta V. Garbuzova, Anastasia A. Zharikova, Mikhail G. Divashuk, Anna V. Kiseleva, Alexandra I. Ershova, Alexey N. Meshkov and Oxana M. Drapkina

Biomedicines 2025, 13(4), 1008; https://doi.org/10.3390/biomedicines13041008 - 21 Apr 2025

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Abstract

Background: Genetic testing for long QT syndrome (LQTS) is straightforward in many families; however, in severe and complex cases, a single disease-causing variant may not be enough to explain all clinical features. In such cases, the search for genetic modifiers may be beneficial [...] Read more.

Background: Genetic testing for long QT syndrome (LQTS) is straightforward in many families; however, in severe and complex cases, a single disease-causing variant may not be enough to explain all clinical features. In such cases, the search for genetic modifiers may be beneficial for precise diagnosis and management. Case presentation: We describe a three-generational family affected with clinically heterogeneous LQTS type 3 and bradycardia in which a novel missense variant p.V642M in HCN4 was identified in addition to the known pathogenic variant p.E1784K in SCN5A. We performed the detailed clinical investigation of the family and a deep in silico analysis of the discovered variants, showing the causal role of a new HCN4 variant in sinus bradycardia and its possible contribution to the phenotypic heterogeneity of LQTS type 3. Conclusions: This case is the first description of a functional variant in HCN4 as a candidate modifier in LQTS type 3 and demonstrates the importance of analyzing additional genetic variations in families with complex LQTS phenotypes. Full article

(This article belongs to the Special Issue Cardiovascular Diseases in the Era of Precision Medicine)

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14 pages, 2090 KiB

Open AccessSystematic Review

The Clinicopathological and Prognostic Value of CCR7 Expression in Breast Cancer Throughout the Literature: A Systematic Review and Meta-Analysis

by Mohamed Elhadary, Basel Elsayed, Amgad Mohamed Elshoeibi, Omar Karen, Ibrahim Elmakaty, Jehad Alhmoud, Ahmad Hamdan and Mohammed Imad Malki

Biomedicines 2025, 13(4), 1007; https://doi.org/10.3390/biomedicines13041007 - 21 Apr 2025

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Abstract

Background/Objective: This study aimed to determine the clinicopathological findings and prognostic value of chemokine receptor 7 (CCR7) expression in patients with breast cancer (BC). Methods: Up to the 25th of March 2025, a search was conducted using five databases: PubMed, Embase, Scopus, Medline, [...] Read more.

Background/Objective: This study aimed to determine the clinicopathological findings and prognostic value of chemokine receptor 7 (CCR7) expression in patients with breast cancer (BC). Methods: Up to the 25th of March 2025, a search was conducted using five databases: PubMed, Embase, Scopus, Medline, and Web of Science. The methodological standards for the epidemiological research scale were used to assess the quality of the included articles, and Stata software (Stata 19) was used to synthesize the meta-analysis. Results: We considered 12 of 853 studies that included 3119 patients with BC. High CCR7 expression was not associated with age (odds ratio [OR] 0.82, 95% confidence interval [CI] 0.66–1.03); clinicopathological findings, including tumor size (OR 1.062, 95% CI 0.630–1.791); clinical stage (OR 1.753, 95% CI 0.231–13.304); nodal metastasis (OR 1.252, 95% CI 0.571–2.741); or histological differentiation (OR 1.167, 95% CI 0.939–1.450). CCR7 expression did not affect overall survival (hazard ratio 0.996, 95% CI 0.659–1.505). Conclusions: Our quantitative analysis did not reveal an association between CCR7 expression and poor clinicopathological or prognostic features in BC patients. Because of the high heterogeneity and potential publication bias, large high-quality studies are required to further confirm these findings. Full article

(This article belongs to the Special Issue The Role of Cytokines in Health and Disease: 2nd Edition)

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14 pages, 2415 KiB

Open AccessArticle

Prostate Tissue-Induced Platelet Activation and Platelet–Neutrophil Aggregation Following Transurethral Resection of the Prostate Surgery: An In Vitro Study

by Po-An Lin, Hsiang-Han Huang, Mei-Hua Hu, Go-Shine Huang, En Meng, Yi-Lin Chiu, Yung-Chi Hsu and Wei-Hung Chan

Biomedicines 2025, 13(4), 1006; https://doi.org/10.3390/biomedicines13041006 - 21 Apr 2025

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Abstract

Background: This study aimed to investigate the effects of prostate tissue on platelet activation markers, primarily assessed through P-selectin expression, and to assess the formation of platelet–leukocyte aggregations in response to prostate tissue exposure. Furthermore, we compared platelet activation induced by prostate [...] Read more.

Background: This study aimed to investigate the effects of prostate tissue on platelet activation markers, primarily assessed through P-selectin expression, and to assess the formation of platelet–leukocyte aggregations in response to prostate tissue exposure. Furthermore, we compared platelet activation induced by prostate tissue homogenates with that induced by thrombin stimulation. These processes may play a role in the development of disseminated intravascular coagulation (DIC) following transurethral resection of the prostate (TURP). Methods: We collected prostate tissue samples from 12 patients undergoing TURP. The samples were homogenized and used to stimulate platelet-rich plasma in vitro. Flow cytometry was used to measure platelet P-selectin expression and platelet–leukocyte aggregation. Additionally, four experimental groups were established: (A) saline control, (B) thrombin stimulation, (C) phosphate-buffered saline (PBS) control, and (D) prostate tissue homogenate. Data were analyzed to assess the impact of prostate tissue and thrombin on platelet activation and platelet–leukocyte interactions. Results: Prostate tissue homogenates significantly increased platelet P-selectin expression and platelet–neutrophil aggregation compared with the control groups (p < 0.05). Overall, platelet–leukocyte aggregation was not significantly different between the thrombin and prostate tissue groups. However, prostate tissue exposure did not significantly affect platelet–monocyte and platelet–lymphocyte aggregations. Conclusions: Prostate tissue exposure during TURP induces platelet activation, particularly platelet P-selectin expression and platelet–neutrophil aggregation, suggesting a potential mechanism for DIC development. These findings highlight the importance of monitoring platelet activity in patients undergoing TURP and indicate that interventions targeting platelet P-selectin expression and platelet–neutrophil interactions may help mitigate DIC risk. Full article

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

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11 pages, 427 KiB

Open AccessArticle

Temporal Patterns of Holter-Detected Arrhythmias in Hypertrophic Cardiomyopathy Patients Treated with Mavacamten

by Amro Badr, Kaitlin Roehl, Mustafa Suppah, Humam Abo Abdullah, Reza Arsanjani, Konstantinos C. Siontis, Jeffrey B. Geske, Steve R. Ommen, John R. Giudicessi and Said Alsidawi

Biomedicines 2025, 13(4), 1005; https://doi.org/10.3390/biomedicines13041005 - 21 Apr 2025

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Abstract

Background: Hypertrophic cardiomyopathy (HCM) is a genetic cardiomyopathy marked by increased left ventricular wall thickness, leading in some cases to left ventricular outflow tract (LVOT) obstruction, heart failure, and arrhythmias. Mavacamten, a selective allosteric inhibitor of cardiac myosin, has demonstrated benefits in improving [...] Read more.

Background: Hypertrophic cardiomyopathy (HCM) is a genetic cardiomyopathy marked by increased left ventricular wall thickness, leading in some cases to left ventricular outflow tract (LVOT) obstruction, heart failure, and arrhythmias. Mavacamten, a selective allosteric inhibitor of cardiac myosin, has demonstrated benefits in improving hemodynamics and reducing LVOT obstruction. However, its impact on arrhythmic burden remains unclear, with reports of early atrial fibrillation (AF) risk contrasting with long-term reductions in arrhythmias. This study assesses the temporal patterns of Holter-detected arrhythmias in HCM patients treated with mavacamten. Methods: This retrospective study included HCM patients from three Mayo Clinic sites. Baseline demographic, clinical, and echocardiographic data were collected. Holter monitoring was performed at baseline, short-term (<6 months), and long-term (>6 months) follow-up. Arrhythmic events, including premature atrial contractions (PACs), premature ventricular contractions (PVCs), and supraventricular tachycardia (SVT), were analyzed using standardized rates per 24 h. Statistical comparisons utilized the Wilcoxon signed-rank test. Results: Twenty-seven patients (56% female, median age 66 years) were included. PACs, PVCs, and SVT duration transiently but not significantly increased at short-term follow-up but returned to baseline at long-term follow-up. No sustained or high-risk ventricular arrhythmias were observed. Conclusions: Mavacamten is associated with transient arrhythmic fluctuations early in treatment, followed by stabilization. These findings support its long-term electrophysiological safety and underscore the need for early rhythm monitoring. Further research should explore its role in arrhythmic risk stratification in HCM patients. Full article

(This article belongs to the Special Issue Advanced Research in Hypertrophic Cardiomyopathy)

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15 pages, 2112 KiB

Open AccessArticle

The Cellular and Molecular Characteristics of Postnatal Human Thymus Stromal Stem Cells

by Josipa Skelin Ilic, Ildikó Bódi, Lidija Milkovic, Zsolt Prodan, Dražen Belina, Darko Heckel, Lipa Cicin-Sain, Danka Grčević, Domenico Vittorio Delfino, Delfa Radic Kristo, Maja Matulić and Mariastefania Antica

Biomedicines 2025, 13(4), 1004; https://doi.org/10.3390/biomedicines13041004 - 21 Apr 2025

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Abstract

Background: The thymus is the central hub of T-cell differentiation, where epithelial cells guide the process of their maturation. Objective: Our goal was to identify and describe progenitor cells within the human thymus that can differentiate into epithelial cells. Methods: [...] Read more.

Background: The thymus is the central hub of T-cell differentiation, where epithelial cells guide the process of their maturation. Objective: Our goal was to identify and describe progenitor cells within the human thymus that can differentiate into epithelial cells. Methods: When we plated enriched thymic cells in 3D culture conditions, rare individual cells capable of self-renewal and differentiation formed spheroids. Results: Both neonatal and adult thymuses produced similar numbers of spheroids, suggesting that progenitor potential remains consistent across age groups. Some cells within the spheres express genes typical of mature epithelial cells, while others express genes associated with the immature compartment active during thymic organogenesis. However, there were also cells expressing PDGFRβ. We treated the tissues with 2-deoxyguanosine before digestion, which improved the yield of progenitor cells. We also cultured the enriched stromal thymocytes with Cyr61 and Interleukin-22, which affected the spheroid size. Conclusions: Our efforts towards thymic reconstitution are ongoing, but our research uncovers previously unknown characteristics of the elusive epithelial progenitor population. Full article

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

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16 pages, 1716 KiB

Open AccessReview

Immunological Avalanches in Renal Immune Diseases

by Davide Viggiano, Pietro Iulianiello, Antonio Mancini, Candida Iacuzzo, Luca Apicella, Renata Angela Di Pietro, Sarah Hamzeh, Giovanna Cacciola, Eugenio Lippiello, Andrea Gigliotti, Carmine Secondulfo, Giancarlo Bilancio and Giuseppe Gigliotti

Biomedicines 2025, 13(4), 1003; https://doi.org/10.3390/biomedicines13041003 - 21 Apr 2025

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Abstract

The complex nature of immune system behavior in both autoimmune diseases and transplant rejection can be understood through the lens of avalanche dynamics in critical-point systems. This paper introduces the concept of the “immunological avalanche” as a framework for understanding unpredictable patterns of [...] Read more.

The complex nature of immune system behavior in both autoimmune diseases and transplant rejection can be understood through the lens of avalanche dynamics in critical-point systems. This paper introduces the concept of the “immunological avalanche” as a framework for understanding unpredictable patterns of immune activity in both contexts. Just as avalanches represent sudden releases of accumulated potential energy, immune responses exhibit periods of apparent stability followed by explosive flares triggered by seemingly minor stimuli. The model presented here draws parallels between immune system behavior and other complex systems such as earthquakes, forest fires, and neuronal activity, where localized events can propagate into large-scale disruptions. In autoimmune conditions like systemic lupus erythematosus (SLE), which affects multiple organ systems including the kidneys in approximately 50% of patients, these dynamics manifest as alternating periods of remission and flares. Similarly, in transplant recipients, the immune system exhibits metastable behavior under constant allograft stimulation. This critical-point dynamics framework is characterized by threshold-dependent activation, positive feedback loops, and dynamic non-linearity. In autoimmune diseases, triggers such as UV light exposure, infections, or stress can initiate cascading immune responses. In transplant patients, longitudinal analysis reveals how monitoring oscillatory patterns in blood parameters and biological age markers can predict rejection risk. In a preliminary study on kidney transplant, all measured variables showed temporal instability. Proteinuria exhibited precise log–log linearity in power law analysis, confirming near-critical-point system behavior. Two distinct dynamic patterns emerged: large oscillations in eGFR, proteinuria, or biological age predicted declining function, while small oscillations indicated stability. During avalanche events, biological age increased dramatically, with partial reversal leaving persistent elevation after acute episodes. Understanding these dynamics has important implications for therapeutic approaches in both contexts. Key findings suggest that monitoring parameter oscillations, rather than absolute values, better indicates system instability and potential avalanche events. Additionally, biological age calculations provide valuable prognostic information, while proteinuria measurements offer efficient sampling for system dynamics assessment. This conceptual model provides a unifying framework for understanding the pathogenesis of both autoimmune and transplant-related immune responses, potentially leading to new perspectives in disease management and rejection prediction. Full article

(This article belongs to the Section Immunology and Immunotherapy)

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38 pages, 6259 KiB

Open AccessReview

Recent Advancements Towards the Use of Vitamin D Isoforms and the Development of Their Synthetic Analogues as New Therapeutics

by Rajiv Patel, Nandini, Harsha Kharkwal, Moumita Saha, Murugesan Sankaranarayanan, Saurabh Sharma and Subhash Chander

Biomedicines 2025, 13(4), 1002; https://doi.org/10.3390/biomedicines13041002 - 21 Apr 2025

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Abstract

Vitamin D and its metabolites are essential in various physiological processes, including muscle strength, metabolism, antifibrotic activity, and immune regulation. Researchers are focusing on developing vitamin D derivatives with optimized receptor selectivity and reduced systemic toxicity, enhancing their therapeutic efficacy against cancer, autoimmune [...] Read more.

Vitamin D and its metabolites are essential in various physiological processes, including muscle strength, metabolism, antifibrotic activity, and immune regulation. Researchers are focusing on developing vitamin D derivatives with optimized receptor selectivity and reduced systemic toxicity, enhancing their therapeutic efficacy against cancer, autoimmune disorders, and inflammatory diseases. Several analogues, such as alfacalcidol, paricalcitol, and falecalcitriol, are used for managing CKD-related bone disorders, while eldecalcitol is effective for osteoporosis, and calcipotriol against psoriasis. Recent studies have explored their impact on metabolic pathways, parathyroid hormone secretion, asthma, and liver fibrosis, revealing their broad clinical potential. Despite enormous efforts in the past decades, translations of vitamin D-drugs are disproportionately limited, mainly due to toxicity due to calcemic effects and undesirable metabolic profile. This review discusses structural modifications in vitamin D3, their influence on VDR binding, transcriptional activity, and calcium homeostasis, along with their role in targeting pathways like EGFR, KRAS, and Hedgehog in cancers. Advanced analytical techniques such as LC/ESI-MS/MS facilitate precise detection of vitamin D metabolites, further improving pharmacokinetic profiling. Future research may enable the clinical approval of novel vitamin D-based therapeutics with minimal disruption to calcium–phosphorus balance. Full article

(This article belongs to the Special Issue Medicinal Chemistry in Drug Design and Discovery, 2nd Edition)

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13 pages, 2040 KiB

Open AccessArticle

Electroencephalography Alpha Traveling Waves as Early Predictors of Treatment Response in Major Depressive Episodes: Insights from Intermittent Photic Stimulation

by Xiaojing Guo, Haifeng Zhang, Biyu Zeng, Aoling Cai, Junjie Zheng, Jingshuai Zhou, Yongquan Gu, Minya Wu, Guanhui Wu, Li Zhang and Fei Wang

Biomedicines 2025, 13(4), 1001; https://doi.org/10.3390/biomedicines13041001 - 21 Apr 2025

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Abstract

Background: Early evaluation of treatment efficacy in adolescents and young adults with major depressive episodes (MDEs) remains a clinical challenge, often delaying timely therapeutic adjustments. Electroencephalography (EEG) alpha traveling waves, particularly those elicited by intermittent photic stimulation (IPS), may serve as biomarkers reflecting [...] Read more.

Background: Early evaluation of treatment efficacy in adolescents and young adults with major depressive episodes (MDEs) remains a clinical challenge, often delaying timely therapeutic adjustments. Electroencephalography (EEG) alpha traveling waves, particularly those elicited by intermittent photic stimulation (IPS), may serve as biomarkers reflecting neural dynamics. This study aimed to investigate whether IPS-induced alpha traveling waves could predict early treatment outcomes in transitional-aged youth with MDEs. Methods: We recorded EEG signals from 119 patients aged 16–24 years at admission, prior to a standardized two-week treatment regimen. IPS was applied using multiple stimulus frequencies, and alpha traveling waves were analyzed in terms of directionality (forward vs. backward) and hemispheric lateralization. Results: Alpha traveling wave amplitudes varied across individuals, depending on stimulus frequency and hemisphere. Notably, a higher amplitude of backward alpha traveling waves at 10 Hz IPS in the left hemisphere significantly predicted positive early treatment response. In contrast, forward waves and right hemisphere responses did not show predictive value. Conclusions: IPS-induced backward alpha traveling waves in the left hemisphere may represent promising EEG biomarkers for early prediction of treatment efficacy in youth with MDEs. These findings offer a potential neurophysiological tool to support personalized treatment strategies and inform future clinical applications in adolescent and young adult depression. Full article

(This article belongs to the Special Issue Brain Imaging and Cognitive Deficits in Psychiatric Disorders, 2nd Edition)

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19 pages, 4270 KiB

Open AccessArticle

Metagenomic Microbial Signatures for Noninvasive Detection of Pancreatic Cancer

by Yueying Chen, Fulin Nian, Jia Chen, Qiuyu Jiang, Tianli Yuan, Haokang Feng, Xizhong Shen and Ling Dong

Biomedicines 2025, 13(4), 1000; https://doi.org/10.3390/biomedicines13041000 - 21 Apr 2025

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Abstract

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with poor early detection rates owing to the limited sensitivity and specificity of the current biomarker CA19-9. Gut microbiota dysbiosis plays a key role in PDAC pathogenesis. This study aimed to evaluate the [...] Read more.

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with poor early detection rates owing to the limited sensitivity and specificity of the current biomarker CA19-9. Gut microbiota dysbiosis plays a key role in PDAC pathogenesis. This study aimed to evaluate the noninvasive approach we developed, combining metagenome-derived microbial signatures with CA19-9, to improve PDAC detection. Methods: This study included 50 treatment-naïve patients with PDAC and their matched controls. Fecal samples were analyzed using shotgun metagenomic sequencing. Machine learning algorithms were used to develop and validate a diagnostic panel integrating microbial signatures and CA19-9 levels. Subgroup analyses were used to confirm the robustness of the microbial markers. Results: The combined models at both species and genus levels effectively distinguished patients with PDAC from healthy individuals, and their strong diagnostic efficacy and accuracy were demonstrated through rigorous validation. Conclusions: In conclusion, the combination of gut microbiome profiling and CA19-9 improves PDAC detection accuracy compared to the use of CA19-9 alone, showing promise for early and noninvasive diagnosis. Full article

(This article belongs to the Collection Feature Papers in Microbiology in Human Health and Disease)

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12 pages, 893 KiB

Open AccessArticle

A Retrospective Single-Center Analysis from Southern Italy on the Use of T2 Magnetic Resonance Assays as a Point-of-Care Method for Patients with Sepsis

by Mariarita Margherita Bona, Vincenza Maria Carelli, Nicola Serra, Salvatore Amico, Roberta Bartolini, Anna Giammanco, Paola Di Carlo, Teresa Fasciana and Maria Andriolo

Biomedicines 2025, 13(4), 999; https://doi.org/10.3390/biomedicines13040999 - 20 Apr 2025

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Abstract

Background: The rapid and accurate identification of the pathogens responsible for sepsis is essential for prompt and effective antimicrobial therapy. The T2Bacteria^® Panel (T2B) and T2Candida^® Panel (T2C) are rapid molecular tests performed on whole blood that exploit T2 Magnetic [...] Read more.

Background: The rapid and accurate identification of the pathogens responsible for sepsis is essential for prompt and effective antimicrobial therapy. The T2Bacteria^® Panel (T2B) and T2Candida^® Panel (T2C) are rapid molecular tests performed on whole blood that exploit T2 Magnetic Resonance (T2MRsup^®) technology. Objectives: This study evaluates the impact of the T2MR system as a point-of-care device for managing sepsis and septic shock patients. Methods: This single-center retrospective study was conducted at the Sant’ Elia Hospital of Caltanissetta from 1 January 2023 to 31 July 2023. The study population was composed of patients with suspected sepsis and septic shock according to the Sepsis-3 criteria and for whom concurrent T2MR and BC samples were requested for diagnosis. Results: A total of 81 consecutive patients were enrolled in this study. Concordant T2/BC results were obtained in 69/81 (85.2%) patients; 58/81 (71.6%) were concordant-negative and 11/81 (13.6%) were concordant-positive. Discordant T2MR+/BC− results were observed in 9/81 patients (11.1%), while T2MR−/BC+ results were detected in 3/81 patients (3.7%). Furthermore, the median time for reporting positive T2MR test results (5.2 h) was significantly shorter than that for BC (122 h). Conclusions: Due to its high reliability, faster detection time, and simple workflow, T2MR in combination with BC improved the etiological diagnosis of sepsis in the enrolled patients. Full article

(This article belongs to the Special Issue Microbial Infections and Sepsis: Pathophysiological Mechanisms and Therapeutic Approaches)

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15 pages, 413 KiB

Open AccessSystematic Review

The Use of Hyaluronic Acid in the Non-Surgical Treatment of Periodontitis—An Umbrella Review

by Wojciech Niemczyk, Jacek Matys, Rafał Wiench, Jacek Żurek and Marzena Dominiak

Biomedicines 2025, 13(4), 998; https://doi.org/10.3390/biomedicines13040998 - 20 Apr 2025

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Abstract

Background: Periodontitis is a prevalent inflammatory condition that destroys periodontal tissues. Scaling and root planing (SRP) is the gold standard for non-surgical treatment; however, its efficacy may be limited in cases with complex dental issues. This umbrella review aims to evaluate the [...] Read more.

Background: Periodontitis is a prevalent inflammatory condition that destroys periodontal tissues. Scaling and root planing (SRP) is the gold standard for non-surgical treatment; however, its efficacy may be limited in cases with complex dental issues. This umbrella review aims to evaluate the effectiveness of hyaluronic acid (HA) as an adjunct to scaling and root planing (SRP) in enhancing clinical outcomes for periodontitis management. Methods: A comprehensive review of five systematic reviews, including meta-analyses where available, was conducted to synthesize evidence on the adjunctive use of HA with SRP. The studies were evaluated using the AMSTAR-2 quality assessment tool to determine methodological rigor. Data on clinical parameters such as probing depth (PD), clinical attachment level (CAL), bleeding on probing (BOP), gingival index (GI), and plaque index (PI) were extracted and analyzed. Results: The findings indicate that HA supplementation leads to moderate improvements in PD, CAL, BOP, GI, and PI compared to SRP alone. Notable reductions in PD and gains in CAL were observed, with some meta-analyses showing statistically significant benefits. However, the heterogeneity in HA concentrations (0.2–1.4%), application methods, treatment frequencies, and follow-up durations (1 week to 12 months) limits definitive conclusions. Additionally, HA did not significantly affect the reduction in P. gingivalis prevalence. Conclusions: The use of HA in conjunction with SRP shows promise in enhancing the efficacy of non-surgical periodontal therapy. However, the heterogeneity in the quality and methodologies of the studies indicates the necessity for high-quality, standardized randomized controlled trials to establish clear clinical guidelines for the application of HA in the treatment of periodontitis. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapeutic Approaches for Oral Disorders)

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12 pages, 1983 KiB

Open AccessArticle

Effect of CBC-Derived Inflammatory Indicators in Predicting Chronic Kidney Disease Risk in Hypertrophic Cardiomyopathy Patients

by Changying Zhao, Luqin Yan, Yong Liu, Siyuan Chen, Beidi Lan, Ruohan Liu, Jinqi Xin, Tao Shi and Xiaohong Yang

Biomedicines 2025, 13(4), 997; https://doi.org/10.3390/biomedicines13040997 - 20 Apr 2025

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Abstract

Background: Hypertrophic cardiomyopathy (HCM) is a prevalent condition that often coexists with chronic kidney disease (CKD), significantly impacting patient prognosis. This study aimed to investigate the predictive value of complete blood cell counts derived inflammatory indicators in assessing CKD risk in HCM patients. [...] Read more.

Background: Hypertrophic cardiomyopathy (HCM) is a prevalent condition that often coexists with chronic kidney disease (CKD), significantly impacting patient prognosis. This study aimed to investigate the predictive value of complete blood cell counts derived inflammatory indicators in assessing CKD risk in HCM patients. Methods: This study enrolled HCM patients and categorized them into CKD and non-CKD group based on discharge diagnoses. Analyzed indicators included systemic inflammation response index (SIRI), systemic immune inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR). Least absolute shrinkage and selection operator (LASSO) logistic and multivariable logistic regression were employed to identified independent risk factors for CKD, which were subsequently utilized to develop a nomogram. Results: A total of 1795 HCM patients were included, including 112 (6.24%) individuals assigned to the CKD group. In univariate analyses, NLR (AUC: 0.755; 95%CI: 0.711–0.800) demonstrated superior accuracy compared to others. Eighteen baseline characteristics exhibiting statistical difference were incorporated into LASSO-logistic regression. Six factors were further selected by multivariable logistic regression. The results identified male gender (OR: 2.622; 95% CI: 1.565–4.393, p < 0.001), Hb (OR: 0.972; 95% CI: 0.962–0.981, p < 0.001), Pro-BNP (OR: 1.000; 95% CI: 1.000–1.000, p < 0.001), SIRI (OR: 1.037; 95% CI: 1.026–1.049, p < 0.001), and SII (OR: 1.000; 95% CI: 1.000–1.001, p = 0.003) as risk factors. These five factors were used to construct a nomogram, which exhibited good accuracy and consistency. Conclusions: Male gender, Hb, Pro-BNP, SIRI, and SII were identified as risk factors for CKD risk in HCM patients. A nomogram was developed using these factors, which may facilitate early identification and management of high-risk individuals. Full article

(This article belongs to the Special Issue Advanced Research in Hypertrophic Cardiomyopathy)

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15 pages, 9862 KiB

Open AccessArticle

Label-Free Electrochemical Cell-Based Biosensor for Toxicity Assay of Water-Soluble Form of Phosphatidylcholine

by Veronica V. Pronina, Lyubov V. Kostryukova, Sergey V. Ivanov, Elena G. Tichonova, Alexander I. Archakov and Victoria V. Shumyantseva

Biomedicines 2025, 13(4), 996; https://doi.org/10.3390/biomedicines13040996 - 20 Apr 2025

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Abstract

Background/Objectives: Our study brings a new method to properly evaluating drug efficacy at the non-invasive in vitro level. Methods: In this work, the electrochemical mediator-free and reagent-free analysis of cell lines based on the registration of electrochemical profiles of membrane proteins was developed. [...] Read more.

Background/Objectives: Our study brings a new method to properly evaluating drug efficacy at the non-invasive in vitro level. Methods: In this work, the electrochemical mediator-free and reagent-free analysis of cell lines based on the registration of electrochemical profiles of membrane proteins was developed. We studied the specificity of cell lines Wi-38 and HepG2 and the toxic effects of drugs on cell-on-electrode systems. Results: A linear dependence of the peak current on the concentration of cells applied to the electrode in the range from 1 × 10⁵ to 6 × 10⁵ cells/electrode was registered (R² 0.932 for Wi-38 and R² 0.912 for HepG2). The water-soluble form of phosphatidylcholine (wPC) nanoparticles recommended for atherosclerosis treatment and prevention of cardiovascular diseases did not show a toxic effect on the human fibroblast cells, Wi-38, or the human hepatocellular carcinoma cells, HepG2, at sufficiently high concentrations (such as 0.1–1 mg/mL). The antitumor drug doxorubicin, at concentrations of 3 and 10 μg/mL, showed a pronounced toxic effect on the tested cell lines, where the percentage of living cells was 50–55%. Conclusions: A comparative analysis of the cytotoxicity of wPC (0.1–1 mg/mL) and doxorubicin (3–10 μg/mL) on the cell lines Wi-38 and HepG2 using the MTT test and electrochemical approach for the registration of cells showed their clear adequacy. Full article

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

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19 pages, 11196 KiB

Open AccessArticle

WNT Signaling Factors as Potential Synovial Inflammation Moderators in Patients with Hip Osteoarthritis

by Ivana Jurić, Nela Kelam, Anita Racetin, Natalija Filipović, Davor Čarić, Matko Rošin and Katarina Vukojević

Biomedicines 2025, 13(4), 995; https://doi.org/10.3390/biomedicines13040995 - 19 Apr 2025

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Abstract

Background: The main feature of osteoarthritis (OA) is the deterioration of articular cartilage, but numerous studies have demonstrated the role of synovial inflammation in the early stages of the disease, leading to further progression of OA. The WNT signaling pathway is involved in [...] Read more.

Background: The main feature of osteoarthritis (OA) is the deterioration of articular cartilage, but numerous studies have demonstrated the role of synovial inflammation in the early stages of the disease, leading to further progression of OA. The WNT signaling pathway is involved in numerous activities in joint tissue, but there is a lack of evidence considering the role of WNT in OA synovitis. Our research aims to investigate the expression of WNT Family Member 5A/B (WNT5A/B), β-catenin, acetyl-α-tubulin, Dishevelled-1 (DVL-1), and Inversin (INV) in the synovial membrane of osteoarthritis (OA) hips. Methods: The immunohistochemical expressions of the aforementioned proteins in the synovial membrane were analyzed and compared with samples of control group participants with fractured femoral necks. Results: The immunoexpression of acetyl-α-tubulin was significantly increased in the intima (p < 0.0001) and subintima (p < 0.0001) of the group with OA compared with the intima and subintima of the control group. At the same time, acetyl-α-tubulin was also more highly expressed in the intima of the OA group than in the subintima of the OA group (p < 0.05); we found the same expression pattern in the control group (p < 0.0001). The differential analysis of the GEO dataset did not show significant differences between the osteoarthritis (OA) and control groups in the expression of TUBA1A. β-catenin was significantly increased in the subintima (p < 0.01) of the group with OA compared to the subintima of the control group. WNT expression has significantly higher positivity in the subintima than in the intima, especially in the control group (p < 0.01). WNT5A and WNT5B were significantly down-regulated in OA compared to the control in the differential analysis of the GEO dataset. The expression of INV and DVL-1 in our study and the differential analysis of the GEO dataset did not differ significantly between the osteoarthritis (OA) and control groups. Conclusions: Based on our results, we suggest that acetyl-α-tubulin and β-catenin might be involved in synovial membrane inflammation in OA and serve as potential therapeutic targets. Full article

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21 pages, 2631 KiB

Open AccessReview

Critical Review of the Benefit from Early Pharmacological and Dietary Support for Patients with Moderate-to-Severe (Non-Terminal) Chronic Kidney Disease

by Charline Danneel, Camille Sauvage, Mohamed Nabil Hayef, Véronique Desmet, Murielle Surquin, Joëlle Nortier and Carine De Vriese

Biomedicines 2025, 13(4), 994; https://doi.org/10.3390/biomedicines13040994 - 19 Apr 2025

Viewed by 119

Abstract

Moderate-to-severe chronic kidney disease (CKD) is a public health problem affecting hundreds of millions of people around the world. Started early, nephroprotection measures are able to prevent the degradation of renal function and are a major issue in CKD management. This approach consists [...] Read more.

Moderate-to-severe chronic kidney disease (CKD) is a public health problem affecting hundreds of millions of people around the world. Started early, nephroprotection measures are able to prevent the degradation of renal function and are a major issue in CKD management. This approach consists of a combination of pharmacological and non-pharmacological treatments aimed at slowing down the decline in renal filtration capacity and improving patient well-being. Drugs such as angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, and sodium–glucose cotransport type 2 inhibitors play a crucial role in reducing intraglomerular pressure and renal inflammation. Their beneficial effects are potentiated when they are combined with non-pharmacological approaches, such as salt and protein restriction. This present review provides a critical overview of the current pharmacological and nutritional therapies that may slow down the progression of CKD. Recently, many pharmacological treatments have opened up new perspectives for managing this condition. Nevertheless, prevention remains the cornerstone of effective disease management. Actually, very few studies include both pharmacists and dietitians in their interdisciplinary team mainly represented by nephrologists, nurses, and social workers. However, their specific collaboration may significantly improve the knowledge and skills to help patients in their own CKD management. Future research is required to assess the benefit of collaboration in supporting patients with moderate-to-severe CKD before any concern of renal replacement therapy (RRT). Full article

(This article belongs to the Special Issue Pharmaceutical Treatments for Typical CKD Comorbidities)

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16 pages, 4230 KiB

Open AccessArticle

Malignancy in Systemic Sclerosis: A Multicenter Retrospective Study

by Dóra Nemes-Tömöri, Dávid Kurszán Jász, Dóra Tari, Bernadett Bói, Ágnes Ágoston-Szabó, Gabriella Szűcs and Gyöngyike Emese Majai

Biomedicines 2025, 13(4), 993; https://doi.org/10.3390/biomedicines13040993 - 19 Apr 2025

Viewed by 157

Abstract

Background/Objectives: Systemic sclerosis (SSc) is associated with high malignancy risk. With improving SSc management, tumor risk could change, therefore re-evaluating the possibility of neoplasms is necessary. Our aim was to observe malignancy prevalence and its risk factors in the Hungarian SSc population, [...] Read more.

Background/Objectives: Systemic sclerosis (SSc) is associated with high malignancy risk. With improving SSc management, tumor risk could change, therefore re-evaluating the possibility of neoplasms is necessary. Our aim was to observe malignancy prevalence and its risk factors in the Hungarian SSc population, comparing them to our previous and international results. Methods: We retrospectively collected the data of SSc patients followed by and admitted to three Hungarian clinical centers between 2018 and 2024. The collected data included the characteristics of SSc and neoplasms, autoantibody positivities, immunosuppressive treatments, pregnancy and environmental factors. Results: Out of 541 patients, 85 had malignancy and, in total, 96 tumors were registered. Skin cancer was the most common (n = 24), followed by breast (n = 14) and lung cancer (n = 14). Among skin cancers, almost one-third was melanoma. Tumors mostly appeared in two peaks: around the time of SSc diagnosis and 10 years later. The occurrence of anti-RNA Polymerase III (anti-RNAPIII) was significantly higher in cancerous patients. Tumor risk was higher with anti-RNAPIII (Odds Ratio (OR) 4.33, 95% Confidence Interval (95% CI) 1.08, 15.1) and anti-topoisomerase I (ATA) (OR 2.34, 95% CI 0.94, 5.84) positivity. Women and patients with diffuse cutaneous SSc (dcSSc) were more likely to have malignancy. Smoking (OR 1.27, 95% CI 0.53, 3.00) also raised the possibility of carcinogenesis. Cancerous patients were older (p-value = 0.003), and their mortality was worse compared to non-cancerous patients (Hazard Ratio (HR) 4.75, 95% CI 2.12, 10.62). Pregnancy did not provide a protective effect against breast cancer. Conclusions: Malignancy significantly contributes to the increased mortality in SSc. Female gender, dcSSc, anti-RNAPIII positivity, smoking and older age represent a higher risk of tumors. Dermatological cancer screening is necessary for all patients with SSc. Full article

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

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23 pages, 9420 KiB

Open AccessArticle

Druggability Studies of Benzene Sulfonamide Substituted Diarylamide (E3) as a Novel Diuretic

by Hang Zhang, Shuyuan Wang, Nannan Li, Yue Xu, Zhizhen Huang, Yukun Zhang, Jing Li, Yinglin Zuo, Min Li, Runtao Li and Baoxue Yang

Biomedicines 2025, 13(4), 992; https://doi.org/10.3390/biomedicines13040992 - 18 Apr 2025

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Abstract

Background/Objectives: Urea transporters (UTs) play an important role in the urine-concentrating mechanism and have been regarded as a novel drug target for developing salt-sparing diuretics. Our previous studies found that diarylamides 1H and 25a are specific UT inhibitors and have oral diuretic [...] Read more.

Background/Objectives: Urea transporters (UTs) play an important role in the urine-concentrating mechanism and have been regarded as a novel drug target for developing salt-sparing diuretics. Our previous studies found that diarylamides 1H and 25a are specific UT inhibitors and have oral diuretic activity. However, these compounds necessitate further optimization and comprehensive druggability studies. Methods: The optimal compound was identified through structural optimization. Experiments were conducted to investigate its UT inhibitory activity and evaluate its diuretic effect. Furthermore, disease models were utilized to assess the compound’s efficacy in treating hyponatremia. Pharmacokinetic studies were performed to examine its metabolic stability, and toxicity tests were conducted to evaluate its safety. Results: Based on the chemical structure of compound 25a, we synthesized a novel diarylamide compound, E3, by introducing a benzenesulfonamide group into its side chain. E3 exhibited dose-dependent inhibition of UT at the nanomolar level and demonstrated oral diuretic activity without causing electrolyte excretion disorders in both mice and rats. Experiments on UT-B^−/− and UT-A1^−/− mice indicated that E3 enhances the diuretic effect primarily by inhibiting UT-A1 more effectively than UT-B. Furthermore, E3 displayed good metabolic stability and favorable pharmacokinetic characteristics. E3 significantly ameliorated hyponatremia through diuresis in a rat model. Importantly, E3 did not induce acute oral toxicity, subacute oral toxicity, genotoxicity, or cardiotoxicity. Conclusions: Our study confirms that E3 exerts a diuretic effect by specifically inhibiting UTs and has good druggability, which offers potential for E3 to be developed into a new diuretic for the treatment of hyponatremia. Full article

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

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22 pages, 4129 KiB

Open AccessArticle

Active Forms of Chemerin Are Elevated in Human and Mouse Ovarian Carcinoma

by Lei Zhao, Qin Zhou, Venkatesh Krishnan, Justine Chan, Simone Sasse, Supreeti Tallapragada, Dan Eisenberg, Lawrence Leung, Oliver Dorigo and John Morser

Biomedicines 2025, 13(4), 991; https://doi.org/10.3390/biomedicines13040991 - 18 Apr 2025

Viewed by 190

Abstract

Background: Chemerin is a small adipokine that is activated and inactivated by proteolysis of its C-terminus with a role in regulating metabolism, immunity, and inflammation. Significant levels of chemerin are found in circulation and ascitic fluid of ovarian carcinoma patients. Methods: We investigated [...] Read more.

Background: Chemerin is a small adipokine that is activated and inactivated by proteolysis of its C-terminus with a role in regulating metabolism, immunity, and inflammation. Significant levels of chemerin are found in circulation and ascitic fluid of ovarian carcinoma patients. Methods: We investigated the levels of different chemerin forms in three cohorts: people with BMI < 25, with BMI > 40, and ovarian carcinoma ascites with ELISAs specific for different chemerin forms. Ascites from a mouse model of ovarian carcinoma were also analyzed, and the model was compared between wild-type and chemerin-deficient mice. Results: Conversion of plasma to serum increased the levels of processed chemerin with lower increases in samples from people with BMI < 25 than in people with BMI > 40. High levels of total chemerin and processed forms of chemerin were found in ascitic fluid from both patients who had a mean BMI of 29 and the mouse model. In chemerin-deficient mice the tumors grew slower than in wild-type mice. Conclusions: Serum has more processed and active chemerin than plasma irrespective of source. Ascites of ovarian carcinoma patients contained high levels of active chemerin, which, based on the mouse data, enhance tumor growth. Full article

(This article belongs to the Special Issue The Role of Chemerin in Human Disease—2nd Edition)

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28 pages, 4089 KiB

Open AccessReview

Anticancer Potential of Prebiotics: Targeting Estrogen Receptors and PI3K/AKT/mTOR in Breast Cancer

by Hussein Sabit, Sama Abouelnour, Bassel M. Hassen, Salma Magdy, Ahmed Yasser, Al-Hassan Soliman Wadan, Shaimaa Abdel-Ghany, Faisal Radwan, Amany I. Alqosaibi, Hala Hafiz, Ohaad F. A. Awlya and Borros Arneth

Biomedicines 2025, 13(4), 990; https://doi.org/10.3390/biomedicines13040990 - 18 Apr 2025

Viewed by 385

Abstract

Estrogen receptors (ERs) play a critical role in breast cancer (BC) development and progression, with ERα being oncogenic and ERβ exhibiting tumor-suppressive properties. The interaction between ER signaling and other molecular pathways, such as PI3K/AKT/mTOR, influences tumor growth and endocrine resistance. Emerging research [...] Read more.

Estrogen receptors (ERs) play a critical role in breast cancer (BC) development and progression, with ERα being oncogenic and ERβ exhibiting tumor-suppressive properties. The interaction between ER signaling and other molecular pathways, such as PI3K/AKT/mTOR, influences tumor growth and endocrine resistance. Emerging research highlights the role of prebiotics in modulating gut microbiota, which may influence estrogen metabolism, immune function, and therapeutic responses in BC. This review explores the impact of prebiotics on estrogen receptor modulation, gut microbiota composition, immune regulation, and metabolic pathways in breast cancer. The potential of prebiotics as adjunctive therapies to enhance treatment efficacy and mitigate chemotherapy-related side effects is discussed. A comprehensive analysis of recent preclinical and clinical studies was conducted, examining the role of prebiotics in gut microbiota modulation, immune regulation, and metabolic reprogramming in breast cancer. The impact of short-chain fatty acids (SCFAs) derived from prebiotic fermentation on epigenetic regulation and endocrine resistance was also evaluated. Prebiotics were found to modulate the gut microbiota-estrogen axis, reduce inflammation, and influence immune responses. SCFAs demonstrated selective estrogen receptor downregulation and metabolic reprogramming, suppressing tumor growth. Synbiotic interventions mitigate chemotherapy-related side effects, improving the quality of life in breast cancer patients. Prebiotics offer a promising avenue for breast cancer prevention and therapy by modulating estrogen metabolism, immune function, and metabolic pathways. Future clinical trials are needed to validate their efficacy as adjunctive treatments in breast cancer management. Full article

(This article belongs to the Special Issue Breast Cancer: New Diagnostic and Therapeutic Approaches)

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13 pages, 4655 KiB

Open AccessArticle

Pirfenidone Alleviates Against Fine Particulate Matter-Induced Pulmonary Fibrosis Modulating via TGF-β1/TAK1/MKK3/p38 MAPK Signaling Pathway in Rats

by Jun-Seok Sung, Il-Gyu Ko, Lakkyong Hwang, Sang-Hoon Kim, Jin Hee Han, Jung Won Jeon, Sae Rom Kim, Jeong Mi Lee and Cheon Woong Choi

Biomedicines 2025, 13(4), 989; https://doi.org/10.3390/biomedicines13040989 - 17 Apr 2025

Viewed by 242

Abstract

Increased exposure to particulate matter (PM) from air pollution causes lung inflammation and increases morbidity and mortality due to respiratory diseases. Pirfenidone is an anti-fibrotic agent used to treat idiopathic pulmonary fibrosis. Background/Objectives: In this experiment, we studied the therapeutic effects of [...] Read more.

Increased exposure to particulate matter (PM) from air pollution causes lung inflammation and increases morbidity and mortality due to respiratory diseases. Pirfenidone is an anti-fibrotic agent used to treat idiopathic pulmonary fibrosis. Background/Objectives: In this experiment, we studied the therapeutic effects of pirfenidone on PM-induced pulmonary fibrosis. Methods: Pulmonary fibrosis was induced by the intratracheal application of 100 μg/kg PM10 mixed with 200 μL saline. After 42 days of PM10 infusion, 0.2 mL of distilled water with pirfenidone was orally administered to the pirfenidone-treated groups (200 and 400 mg/kg) every other day for a total of 15 times over 30 days. Results: The intratracheal administration of PM resulted in lung injury and a significant decrease in the number of bronchoalveolar lavage fluid cells. PM administration increased the lung injury score, level of lung fibrosis, and production of pro-inflammatory cytokines. Pirfenidone treatment effectively suppressed transforming growth factor-β-activated kinase 1 in PM-induced pulmonary fibrosis. The present changes inhibited the expressions of mitogen-activated protein kinase kinase 3 and p38, which suppressed transforming growth factor-β, ultimately alleviating lung fibrosis. PM exposure upregulated the expressions of fibronectin and type 1 collagen. PM exposure enhanced connective tissue growth factor and hydroxyproline levels in the lung tissue. The levels of these fibrosis-related factors were inhibited by pirfenidone treatment. Conclusions: These results suggest that pirfenidone is therapeutically effective against PM-induced pulmonary fibrosis. Full article

(This article belongs to the Section Immunology and Immunotherapy)

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17 pages, 668 KiB

Open AccessReview

Quantitative Sensory Testing in Fibromyalgia Syndrome: A Scoping Review

by Adriana Munhoz Carneiro, Marina de Góes Salvetti, Camila Squarzoni Dale and Valquíria Aparecida da Silva

Biomedicines 2025, 13(4), 988; https://doi.org/10.3390/biomedicines13040988 - 17 Apr 2025

Viewed by 269

Abstract

Background/Objectives: Quantitative sensory testing (QST) is one of the most reliable methods for assessing Fibromyalgia Syndrome (FMS). Despite its importance, there are still controversies regarding the correct interpretation of evoked responses, as they may vary depending on the protocol, individual characteristics, disease [...] Read more.

Background/Objectives: Quantitative sensory testing (QST) is one of the most reliable methods for assessing Fibromyalgia Syndrome (FMS). Despite its importance, there are still controversies regarding the correct interpretation of evoked responses, as they may vary depending on the protocol, individual characteristics, disease severity, and other factors. This study aims to examine how QST has been applied as an outcome measure in FMS. Methods: We considered three databases (Medline, Embase, and Web of Science) until June 2024. From a total of 2512 studies, 126 (39 RCTs and 87 non-RCTs) were selected for full reading after assessment for risk of bias and eligibility criteria. These criteria included at least one type of QST and a clear diagnosis of fibromyalgia (FMS). Results: The results highlighted a lack of standardization in QST, as no reported protocols were followed and there was no specific number of tender points tested for FMS. Additionally, there was inconsistency in the selection of sites and types of tests conducted. Conclusions: This heterogeneity in methodology may affect the comparability and interpretation of results, underscoring the urgent need for standardized guidelines for conducting QST in fibromyalgia studies. A clear understanding of how QST has been measured could prompt a reevaluation of current approaches to FMS assessment, leading to more accurate interpretations and, ultimately, improved management of this complex condition. Full article

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

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18 pages, 1438 KiB

Open AccessArticle

Nanosurgery and Bioengineered Regenerative Protocols for the Treatment of Hip Osteoarthritis: A Double-Blind Randomized Controlled Trial as an Alternative to Surgical Hip Replacement

by Cezary Wasilczyk and Bartosz Wasilczyk

Biomedicines 2025, 13(4), 987; https://doi.org/10.3390/biomedicines13040987 - 17 Apr 2025

Viewed by 163

Abstract

Introduction: Hip osteoarthritis (HOA) significantly affects mobility and quality of life, with total hip arthroplasty (THA) being a common treatment. However, complications and increasing revision rates highlight the need for alternative approaches. This study evaluates the efficacy of ultrasound-guided nanosurgery and bioengineering treatment [...] Read more.

Introduction: Hip osteoarthritis (HOA) significantly affects mobility and quality of life, with total hip arthroplasty (THA) being a common treatment. However, complications and increasing revision rates highlight the need for alternative approaches. This study evaluates the efficacy of ultrasound-guided nanosurgery and bioengineering treatment (NSBT) compared to non-standardized platelet-rich plasma (PRP) treatment for patients with symptomatic HOA. Methods: A double-blind, randomized trial included 38 patients referred for THA, divided into two groups. The study group received NSBT with modified PRP enriched with somatotropin and Strophanthus kombe, while the control group received PRP and hyaluronic acid injections without a standardized protocol. Treatments were guided by ultrasound, and outcomes were assessed using the Visual Analog Scale (VAS), Western Ontario and McMaster Universities Arthritis Index (WOMAC), Harris Hip Score (HHS), and range of motion (RoM) evaluations over 12 months. Results: The study group showed significant improvements in all clinical outcomes, including reductions in VAS scores from 7.8 to 0.2 (p < 0.0001) and WOMAC scores from 76.2 to 10.5 (p < 0.0001). The HHS improved from 56.4 to 93.0, and RoM showed substantial gains in flexion, external rotation, and internal rotation (all p < 0.001). The control group demonstrated less pronounced improvements. Conclusions: NSBT offers a safe and effective alternative for managing HOA, significantly reducing pain and improving joint function while potentially delaying or avoiding the need for THA. Further long-term studies are warranted to confirm these findings. Full article

(This article belongs to the Special Issue Progress in Nanotechnology-Based Therapeutic Strategies)

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31 pages, 3553 KiB

Open AccessReview

Ferroptosis: An Energetic Villain of Age-Related Macular Degeneration

by Na Zhao, Siyu Li, Hao Wu, Dong Wei, Ning Pu, Kexin Wang, Yashuang Liu, Ye Tao and Zongming Song

Biomedicines 2025, 13(4), 986; https://doi.org/10.3390/biomedicines13040986 - 17 Apr 2025

Viewed by 147

Abstract

Iron homeostasis plays an important role in maintaining cellular homeostasis; however, excessive iron can promote the production of reactive oxygen species (ROS). Ferroptosis is iron-dependent programmed cell death that is characterized by excessive iron accumulation, elevated lipid peroxides, and the overproduction of ROS. [...] Read more.

Iron homeostasis plays an important role in maintaining cellular homeostasis; however, excessive iron can promote the production of reactive oxygen species (ROS). Ferroptosis is iron-dependent programmed cell death that is characterized by excessive iron accumulation, elevated lipid peroxides, and the overproduction of ROS. The maintenance of iron homeostasis is contingent upon the activity of the transferrin receptor (TfR), ferritin (Ft), and ferroportin (FPn). In the retina, iron accumulation and lipid peroxidation can contribute to the development of age-related macular degeneration (AMD). This phenomenon can be explained by the occurrence of the Fenton reaction, in which the interaction between divalent iron and hydrogen peroxide leads to the generation of highly reactive hydroxyl radicals. The hydroxyl radicals exhibit a propensity to attack proteins, lipids, nucleic acids, and carbohydrates, thereby instigating oxidative damage and promoting lipid peroxidation. Ultimately, these processes culminate in cell death and retinal degeneration. In this context, a comprehensive understanding of the exact mechanisms underlying ferroptosis may hold significant importance for developing therapeutic interventions. This review summarizes recent findings on iron metabolism, cellular ferroptosis, and lipid metabolism in the aging retina. We also introduce developments in the therapeutic strategies using iron chelating agents. Further refinements of these knowledges would deepen our comprehension of the pathophysiology of AMD and advance the clinical management of degenerative retinopathy. A comprehensive search strategy was employed to identify relevant studies on the role of ferroptosis in AMD. We performed systematic searches of the PubMed and Web of Science electronic databases from inception to the current date. The keywords used in the search included “ferroptosis”, “AMD”, “age-related macular degeneration”, “iron metabolism”, “oxidative stress”, and “ferroptosis pathways”. Peer-reviewed articles, including original research, reviews, meta-analyses, and clinical studies, were included in this paper, with a focus on the molecular mechanisms of ferroptosis in AMDs. Studies not directly related to ferroptosis, iron metabolism, or oxidative stress in the context of AMD were excluded. Furthermore, articles that lacked sufficient data or were not peer-reviewed (e.g., conference abstracts, editorials, or opinion pieces) were not considered. Full article

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

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7 pages, 878 KiB

Open AccessPerspective

Shifting Paradigms in Bronchopulmonary Dysplasia: From Treatment to Etiology/Pathophysiology-Based Classification

by Fumihiko Namba and Hidehiko Nakanishi

Biomedicines 2025, 13(4), 985; https://doi.org/10.3390/biomedicines13040985 - 17 Apr 2025

Viewed by 208

Abstract

Bronchopulmonary dysplasia (BPD) is a severe chronic respiratory disease linked to preterm births. A scoping review was performed to identify risk factors for moderate and severe BPD to develop an evidence-based, early prognostic, globally recognized, and etiology/pathophysiology-based classification. The findings were then validated [...] Read more.

Bronchopulmonary dysplasia (BPD) is a severe chronic respiratory disease linked to preterm births. A scoping review was performed to identify risk factors for moderate and severe BPD to develop an evidence-based, early prognostic, globally recognized, and etiology/pathophysiology-based classification. The findings were then validated against a Japanese national database, the Neonatal Research Network Japan. After identifying histological chorioamnionitis, bubbly/cystic appearance on chest X-ray, and small-for-gestational-age infants as risk factors for severe BPD, BPD was divided into nine categories based on the presence or absence of these three risk factors. After consensus was reached using the Delphi method, public comments were requested, and the classification of BPD was finalized. This perspective introduces the new etiology/pathophysiology-based BPD classification, which should be used in research to better understand the respiratory prognosis and pathophysiology of BPD. Full article

(This article belongs to the Special Issue State-of-the-Art Neonatal Medicine in Japan)

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20 pages, 4305 KiB

Open AccessArticle

Breast Cancer Surgical Specimens: A Marking Challenge and a Novel Solution—A Prospective, Randomized Study

by András Drozgyik, Noémi Kránitz, Tamás Szabó, Dániel Kollár, István Á. Harmati, Renáta Rajnai and Tamás F. Molnár

Biomedicines 2025, 13(4), 984; https://doi.org/10.3390/biomedicines13040984 - 17 Apr 2025

Viewed by 154

Abstract

Background: Accurate orientation of resected breast specimens is essential for proper pathological evaluation and margin assessment. Misorientation may compromise analysis, lead to imprecise re-excisions, and increase the risk of local recurrence. This study aims to evaluate a novel specimen plate designed to maintain [...] Read more.

Background: Accurate orientation of resected breast specimens is essential for proper pathological evaluation and margin assessment. Misorientation may compromise analysis, lead to imprecise re-excisions, and increase the risk of local recurrence. This study aims to evaluate a novel specimen plate designed to maintain consistent tissue orientation and compares its effectiveness to traditional suture marking. Methods: In a single-center, prospective, randomized two-arm trial, 56 specimens were oriented with the new plate and 54 with conventional sutures. Outcomes included intraoperative imaging interpretation, specimen handling, and pathological assessment, with a focus on orientation accuracy and margin evaluation. Results: The specimen plate significantly reduced misorientation (p < 0.01) and improved interpretation during intraoperative imaging. Pathologists reported greater ease in identifying direction and tumor-free zones, leading to a more accurate margin assessment. Non-R0 resections requiring re-excision were fewer with the specimen plate (8.9%) compared to suture marking (22.2%). Conclusions: The newly developed specimen plate can offer a reliable solution for improving specimen orientation in breast cancer surgery; however, further validation in multicenter studies is needed to confirm its applicability across diverse surgical settings. By ensuring consistent orientation and enhancing diagnostic interpretation, it may help reduce re-excisions and improve patient safety. Full article

(This article belongs to the Special Issue New Insights into the Diagnosis and Treatment of Breast Cancer)

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13 pages, 2782 KiB

Open AccessArticle

Exploring the Non-Toxic Therapeutic Potential of Dioscorea communis in Combating Oral Pathogenic Bacteria and Their Effects on Hard and Soft Oral Tissues

by Anastasia-Ioanna Papantonaki, Eleni Georgakopoulou, Christina Barda, Panagiota Loumou, Ioannis Sfiniadakis, Jane Anastassopoulou, Andreas Vitsos and Michail Christou Rallis

Biomedicines 2025, 13(4), 983; https://doi.org/10.3390/biomedicines13040983 - 17 Apr 2025

Viewed by 245

Abstract

Background/Objectives: Gingivitis and dental caries are oral diseases resulting from bacterial accumulation in dental plaque, leading to inflammation, tissue destruction and the demineralization of tooth structures. Dioscorea communis, due to its anti-inflammatory and antimicrobial properties, could be a new treatment candidate. Methods: [...] Read more.

Background/Objectives: Gingivitis and dental caries are oral diseases resulting from bacterial accumulation in dental plaque, leading to inflammation, tissue destruction and the demineralization of tooth structures. Dioscorea communis, due to its anti-inflammatory and antimicrobial properties, could be a new treatment candidate. Methods: This study evaluated the preventive and therapeutic effect of a D. communis berry juice paste, formulated at 3% and 7% concentrations, on gingivitis and dental caries, in 55 male SKH-hr2 hairless mice. Gingivitis and dental caries were induced by ligation of the upper left incisor and the paste was applied topically three times daily, five days a week. Treatment efficacy was assessed through clinical examinations, photo-documentation, histopathological analysis and FT-IR spectroscopy. Results/Conclusions: Preventive administration of D. communis 7% significantly delayed disease onset, while therapeutic effects on established conditions were limited. Both concentrations were non-toxic to gingival tissues and dental structures. Full article

(This article belongs to the Special Issue Advancements in Understanding and Treating Oral Pathologies: From Dry Mouth to Oral Cancer)

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20 pages, 1787 KiB

Open AccessArticle

HSP₇₀ Modulators for the Correction of Cognitive, Mnemonic, and Behavioral Disorders After Prenatal Hypoxia

by Olena Aliyeva, Igor F. Belenichev, Ivan Bilai, Iryna Duiun, Lyudmyla Makyeyeva, Valentyn Oksenych and Oleksandr Kamyshnyi

Biomedicines 2025, 13(4), 982; https://doi.org/10.3390/biomedicines13040982 - 17 Apr 2025

Viewed by 150

Abstract

Background/Objectives: Prenatal hypoxia (PH) is a leading cause of nervous system disorders in early childhood and subsequently leads to a decline in the cognitive and mnemonic functions of the central nervous system (such as memory impairment, reduced learning ability, and information processing). It [...] Read more.

Background/Objectives: Prenatal hypoxia (PH) is a leading cause of nervous system disorders in early childhood and subsequently leads to a decline in the cognitive and mnemonic functions of the central nervous system (such as memory impairment, reduced learning ability, and information processing). It also increases anxiety and the risk of brain disorders in adulthood. Compensatory–adaptive mechanisms of the mother–placenta–fetus system, which enhance the fetus’s CNS resilience, are known, including the activation of endogenous neuroprotection in response to hypoxic brain injury through the pharmacological modulation of HSP₇₀. Methods: To evaluate the effect of HSP₇₀ modulators—Cerebrocurin, Angiolin, Tamoxifen, Glutaredoxin, Thiotriazoline, and HSF-1 (heat shock factor 1 protein), as well as Mildronate and Mexidol—on the motor skills, exploratory behaviors, psycho-emotional activities, learning, and memories of offspring after PH. Experimental PH was induced by daily intraperitoneal injections of sodium nitrite solution into pregnant female rats from the 16th to the 21st day of pregnancy at a dose of 50 mg/kg. The newborns received intraperitoneal injections of Angiolin (50 mg/kg), Thiotriazoline (50 mg/kg), Mexidol (100 mg/kg), Cerebrocurin (150 µL/kg), L-arginine (200 mg/kg), Glutaredoxin (200 µg/kg), HSF-1 (50 mg/kg), or Mildronate (50 mg/kg) for 30 days. At 1 month, the rats were tested in the open field test, and at 2 months, they were trained and tested for working and spatial memory in the radial maze. Results: Modeling PH led to persistent impairments in exploratory activity, psycho-emotional behavior, and a decrease in the cognitive–mnestic functions of the CNS. It was found that Angiolin and Cerebrocurin had the most pronounced effects on the indicators of exploratory activity and psycho-emotional status in 1-month-old animals after PH. They also exhibited the most significant cognitive-enhancing and memory-supporting effects during the training and evaluation of skill retention in the maze in 2-month-old offspring after PH. Conclusions: for the first time, we obtained experimental data on the effects of HSP₇₀ modulators on exploratory activity, psycho-emotional behavior, and cognitive–mnestic functions of the central nervous system in offspring following intrauterine hypoxia. Based on the results of this study, we identified the pharmacological agents Angiolin and Cerebrocurin as promising neuroprotective agents after perinatal hypoxia. Full article

(This article belongs to the Special Issue Brain Injury and Neurodegeneration: Molecular, Functional, and Translational Approach 3.0)

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25 pages, 1732 KiB

Open AccessReview

Pt(IV) Complexes as Anticancer Drugs and Their Relationship with Oxidative Stress

by Vlad Iova, Radu Ciprian Tincu, Ioana Scrobota and Mihail Silviu Tudosie

Biomedicines 2025, 13(4), 981; https://doi.org/10.3390/biomedicines13040981 - 17 Apr 2025

Viewed by 201

Abstract

Despite continuous research, cancer is still a leading cause of death worldwide; therefore, new methods of cancer management improvement are emerging. It is well known that in the pathophysiology of cancer, oxidative stress (OS) is a significant factor. Nevertheless, there is currently no [...] Read more.

Despite continuous research, cancer is still a leading cause of death worldwide; therefore, new methods of cancer management improvement are emerging. It is well known that in the pathophysiology of cancer, oxidative stress (OS) is a significant factor. Nevertheless, there is currently no quick or easy way to identify OS in cancer patients using blood tests. Currently, in cancer treatments, Pt(IV) complexes are preferred to Pt(II) complexes in terms of adverse effects, drug resistance, and administration methods. Intracellular reductants convert Pt(IV) complexes to their Pt(II) analogs, which are Pt compounds with anti-carcinogenic effects. Our aim was to find out if Pt(IV) complexes could be used to assess blood oxidative stress indicators and, consequently, monitor the development of cancer. In this review, we analyzed previous research using the PubMed and Google Scholar public databases to verify the potential use of Pt(IV) complexes in cancer management. We found that two main serum antioxidants, glutathione and ascorbic acid, which are easily measured using conventional methods, react favorably with Pt(IV) complexes. Our research results suggest Pt(IV) complexes as therapeutic anticancer drugs and potential diagnosis agents. However, further research must be conducted to verify this hypothesis. Full article

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

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17 pages, 4714 KiB

Open AccessArticle

Thiamine and METTL14 in Diabetes Management with Intensive Insulin Therapy

by Miaoguan Peng, Yingying Zhang, Xiaoshi Weng, Jianfeng Wu, Taizhen Luo, Yanmei Dong, Shiyun Wen, Naifeng Liang, Liangying Zhong, Yaojie Zhai, Yijuan Xie, Yingjun Xie and Yuyi Chen

Biomedicines 2025, 13(4), 980; https://doi.org/10.3390/biomedicines13040980 - 17 Apr 2025

Viewed by 160

Abstract

Background/Objectives: Epigenetic regulation plays a critical role in diabetes research, with N6-methyladenosine (m6A) modification emerging as a key factor in disease progression. METTL14, an essential epigenetic regulator, may influence the effects of thiamine on intensive insulin therapy in diabetic patients. Methods: [...] Read more.

Background/Objectives: Epigenetic regulation plays a critical role in diabetes research, with N6-methyladenosine (m6A) modification emerging as a key factor in disease progression. METTL14, an essential epigenetic regulator, may influence the effects of thiamine on intensive insulin therapy in diabetic patients. Methods: Blood samples from twenty diabetic patients were collected before and after intensive insulin therapy for MeRIP-seq and RNA-seq analysis. Genes with m6A modifications and corresponding mRNAs were identified and functionally analyzed using Gene Ontology (GO) and KEGG pathway analysis. RT-qPCR was used to confirm the overexpression of METTL14, PIK3R1, TPK1, and IPMK, while METTL14 overexpression was further validated in THP1 cells. Results: GO analysis revealed a significant enrichment of overlapping genes in metabolic pathways. A reduction in m6A modification levels was observed post intensive insulin therapy, indicating METTL14’s involvement in regulating TPK1, IPMK, and PIK3R1 expression. TPK1 levels showed a positive correlation with thiamine levels. Clinical validation demonstrated that combining thiamine with insulin therapy significantly reduced glucose and triglyceride levels compared to insulin alone. Conclusions: Thiamine supplementation alongside intensive insulin therapy offers therapeutic potential by downregulating TPK1 expression and mitigating lipid-related complications in diabetic patients. These findings highlight the pivotal role of METTL14-mediated m6A modification in regulating key metabolic genes during diabetes treatment. Full article

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

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Open AccessArticle

Amburana cearensis (Cumaru) and Its Active Principles as Source of Anti-Leishmania Drugs: Immunomodulatory Activity of Coumarin (1,2-Benzopyrone)

by Naya Lúcia de Castro Rodrigues, Elizama Shirley Silveira, Francisco Rafael Marciano Fonseca, Ticiana Monteiro Abreu, Edilberto Rocha Silveira, Ana Bruna de Araújo, Maria Jania Teixeira and Luzia Kalyne Almeida Moreira Leal

Biomedicines 2025, 13(4), 979; https://doi.org/10.3390/biomedicines13040979 - 17 Apr 2025

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Abstract

Background/Objectives: In Brazil, Leishmania braziliensis is the main etiological agent of cutaneous leishmaniasis and represents an important public health problem. The actual pharmacotherapy of leishmaniasis has several disadvantages, making the development of new therapeutic options essential. The present study aimed to carry [...] Read more.

Background/Objectives: In Brazil, Leishmania braziliensis is the main etiological agent of cutaneous leishmaniasis and represents an important public health problem. The actual pharmacotherapy of leishmaniasis has several disadvantages, making the development of new therapeutic options essential. The present study aimed to carry out the bioprospecting and selection of products of Amburana cearensis, including extracts and active principles with a leishmanicidal effect and to evaluate its possible mechanism of action. Methods: A dry extract of A. cearensis (DEAC) was characterized by HPLC, with the following active markers: coumarin (CM), amburoside A (AMR), and vanillic acid (VA). The leishmanicidal effect of DEAC was assessed, and the in vitro inhibitory action of the phenolic fraction, including CM, AMR, and VA, on promastigote and amastigote forms were determined. Results: CM showed the best reductions (maximal inhibition: 57%) of the promastigote form of L. braziliensis, followed by the plant extract (40% inhibition) and other test drugs (maximal reduction: 29%). The treatment of macrophages infected by L. brasiliensis with CM (10 μg/mL) reduced the intracellular parasite load (amastigote form, maximal reduction: 50%), increased the production of nitric oxide, TNF-α, IL-12, and IL-10, and decreased the production of IL-4. These effects were not related to cytotoxicity (MTT test). Glucantime (4 mg/mL, standard drug) reduced the amastigote form by 65%. Conclusions: CM showed promising leishmanicidal activity against both forms of L. brasiliensis, and this effect seems to be associated, at least in part, to its immunomodulatory action by tilting the Th1/Th2 imbalance in favor of Th1. Full article

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

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Biomedicines, Volume 13, Issue 4 (April 2025) – 247 articles

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