Biomedicines

13 pages, 2312 KiB

Open AccessArticle

Mechanotransductive Activation of PPAR-γ by Low-Intensity Pulsed Ultrasound Induces Contractile Phenotype in Corpus Spongiosum Smooth Muscle Cells

by Huan Yu, Jianying Li, Zihan Xu, Zhiwei Peng, Min Wu, Yiqing Lv, Fang Chen, Mingming Yu and Yichen Huang

Biomedicines 2025, 13(7), 1701; https://doi.org/10.3390/biomedicines13071701 - 11 Jul 2025

Abstract

Background: Previously, we found that the pathological changes in the corpus spongiosum (CS) in hypospadias were mainly localized within smooth muscle tissue, presenting as a transformation from the contraction phenotype to synthesis. The role of low-intensity pulsed ultrasound (LIPUS) in regulating smooth muscle [...] Read more.

Background: Previously, we found that the pathological changes in the corpus spongiosum (CS) in hypospadias were mainly localized within smooth muscle tissue, presenting as a transformation from the contraction phenotype to synthesis. The role of low-intensity pulsed ultrasound (LIPUS) in regulating smooth muscle cells (SMCs) and angiogenesis has been confirmed. Objectives: To demonstrate the feasibility of regulating the phenotypic transformation of corpus spongiosum smooth muscle cells (CSSMCs) in hypospadias using LIPUS and to explore the potential mechanisms. Materials and Methods: The CSSMCs were extracted from CS in patients with proximal hypospadias. In vitro experiments were conducted to explore the appropriate LIPUS irradiation intensity and duration which could promote the phenotypic transformation of CSSMCs. A total of 71 patients with severe hypospadias were randomly divided into a control group and a LIPUS group to verify the in vivo transition effect of LIPUS. Consequently, the potential mechanisms by which LIPUS regulates the phenotypic transformation of CSSMCs were explored in vitro. Results: In vitro experiments showed that LIPUS with an intensity of 100 mW/cm² and a duration of 10 min could significantly increase the expression of contraction markers in CSSMCs and decrease the expression of synthesis markers. Moreover, LIPUS stimulation could alter the phenotype of CSSMCs in patients with proximal hypospadias. RNA sequencing results revealed that peroxisome proliferator-activated receptor gamma (PPAR-γ) significantly increased after LIPUS stimulation. Overexpression of PPAR-γ significantly increased the expression of contraction markers in CSSMCs, and the knockdown of PPAR-γ blocked this effect. Conclusions: LIPUS can regulate the transition of CSSMCs from a synthetic to a contractile phenotype in hypospadias. The PPAR-γ-mediated signaling pathway is a possible mechanism involved in this process. Full article

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

12 pages, 2024 KiB

Open AccessArticle

Effectiveness and Safety of Endovascular Treatment in Large Vessel Occlusion Stroke with an NIHSS Score of ≤5 Exhibiting Predominant Cortical Signs

by Chulho Kim, Seung Joon Oh, Jae Jun Lee, Jong-Hee Sohn, Joo Hye Sung, Yerim Kim, Minwoo Lee, Mi Sun Oh, Kyung-Ho Yu, Hee Jung Mo and Sang-Hwa Lee

Biomedicines 2025, 13(7), 1700; https://doi.org/10.3390/biomedicines13071700 - 11 Jul 2025

Abstract

Background: Our study aimed to evaluate the impact of EVT on stroke outcomes in patients with LVO with a National Institute of Health Stroke Scale (NIHSS) score of ≤5, exhibiting primarily cortical signs. Methods: We conducted a multicenter registry-based analysis of [...] Read more.

Background: Our study aimed to evaluate the impact of EVT on stroke outcomes in patients with LVO with a National Institute of Health Stroke Scale (NIHSS) score of ≤5, exhibiting primarily cortical signs. Methods: We conducted a multicenter registry-based analysis of patients with acute ischemic stroke with LVO who arrived within 12 h of onset. Among these, patients with low NIHSS scores and prominent cortical signs (Items 2, 3, 9, or 11) were included. Patients were divided into two groups: those who underwent EVT and those treated with the best medical therapy (BMT), which included intravenous thrombolysis where appropriate. The primary outcome measure was a modified Rankin scale (mRS) score of 0–1 at 3 months and symptomatic hemorrhagic transformation (SHT). We performed logistic regression analysis to evaluate the impact of EVT on the outcomes. Results: Of the 970 patients with LVO, 291 met the inclusion criteria, with 95 and 196 undergoing EVT and BMT, respectively. The EVT group demonstrated a significantly higher rate of 3-month mRS score of 0–1 (65.3% vs. 39.3%, p < 0.001) and a lower incidence of SHT than the BMT group (3.2% vs. 12.8%, p = 0.01). Multivariate analysis confirmed that EVT was associated with improved functional recovery (mRS score, 0–1; odds ratio [OR], 3.61; 95% confidence interval [CI], 1.82–7.06; p < 0.001) and reduced risk of SHT (OR, 0.19; 95% CI, 0.05–0.74; p = 0.02). Notably, patients with specific cortical signs, such as aphasia and spatial neglect, exhibited better outcomes with EVT. Conclusions: EVT may significantly improve the functional outcomes in patients with mild LVO stroke who present with cortical signs, despite low NIHSS scores. These findings suggest that cortical signs should be a key factor in EVT decision-making for mild stroke cases, thereby advocating for a more individualized approach in acute stroke management. Full article

(This article belongs to the Special Issue Advances in Stroke Neuroprotection and Repair)

14 pages, 349 KiB

Open AccessArticle

Cognitive Impairment in Rheumatoid Arthritis: The Role of Pain, Inflammation, and Multimorbidity in Neuropsychological Outcomes

by Agnieszka Pigłowska-Juhnke, Maia Stanisławska-Kubiak, Piotr Kalmus, Marzena Waszczak-Jeka, Włodzimierz Samborski and Ewa Mojs

Biomedicines 2025, 13(7), 1699; https://doi.org/10.3390/biomedicines13071699 - 11 Jul 2025

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease that may affect the central nervous system, leading to cognitive impairment associated with chronic inflammation and pain. Objective: To assess the relationship between cognitive function, disease progression, pain intensity, and clinical parameters in patients with [...] Read more.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that may affect the central nervous system, leading to cognitive impairment associated with chronic inflammation and pain. Objective: To assess the relationship between cognitive function, disease progression, pain intensity, and clinical parameters in patients with RA. Materials and Methods: This study included 62 RA patients, including individuals with comorbid conditions. Cognitive performance was assessed using the Automated Neuropsychological Assessment Metrics (ANAM) battery. Associations between cognitive function and pain intensity (VAS), inflammatory markers (ESR), number of disease flares, and surgical interventions were analyzed. Results: Patients with isolated RA demonstrated better performance in visuospatial memory and cognitive flexibility compared to those with comorbidities. Increased pain intensity and the number of disease flares were associated with impaired attention, memory, and psychomotor speed. Conclusions: Chronic pain and high disease activity in RA negatively impact cognitive functions. Routine neuropsychological assessment should be considered in the comprehensive clinical management of RA patients. Full article

(This article belongs to the Special Issue Pathogenesis, Diagnostics, and Therapeutics for Rheumatic Diseases)

2 pages, 136 KiB

Open AccessCorrection

Correction: Nocini et al. Improving Nasal Protection for Preventing SARS-CoV-2 Infection. Biomedicines 2022, 10, 2966

by Riccardo Nocini, Brandon Michael Henry, Camilla Mattiuzzi and Giuseppe Lippi

Biomedicines 2025, 13(7), 1698; https://doi.org/10.3390/biomedicines13071698 - 11 Jul 2025

Abstract

In the original publication [...] Full article

(This article belongs to the Section Microbiology in Human Health and Disease)

15 pages, 271 KiB

Open AccessReview

Modic Changes as Biomarkers for Treatment of Chronic Low Back Pain

by Jeffrey Zhang, Emily Bellow, Jennifer Bae, Derek Johnson, Sandi Bajrami, Andrew Torpey and William Caldwell

Biomedicines 2025, 13(7), 1697; https://doi.org/10.3390/biomedicines13071697 - 11 Jul 2025

Abstract

Background: Chronic low back pain (CLBP) is the leading cause of disability both within the United States and globally. However, reliable diagnosis and treatment remains limited due to a lack of objective and image-based biomarkers. Modic changes (MCs) are visible vertebral endplate and [...] Read more.

Background: Chronic low back pain (CLBP) is the leading cause of disability both within the United States and globally. However, reliable diagnosis and treatment remains limited due to a lack of objective and image-based biomarkers. Modic changes (MCs) are visible vertebral endplate and bone marrow changes in signal intensity seen on MRI. MCs have emerged as promising correlates with degenerative disc disease and CLBP. Methods: This is a non-systematic literature review. Results: This review synthesizes current evidence on the classification, pathophysiology, and imaging of MCs, with a particular focus on their associations with patient-reported outcomes, including pain (Visual Analog Scale), functional status (Oswestry disability index and Roland-Morris Disability Questionnaire), and health-related quality of life (Short Form-36 and EuroQol 5-Dimension 5 Level). MC type 1 and 2 show significant correlations with symptom severity and predict positive response to basi-vertebral nerve (BVN) ablation, a minimally invasive intervention inhibiting the nerves’ ability to transmit pain signals. Conclusions: Across multiple trials, BVN ablation has shown significant sustained improvements in patient-reported outcomes among patients with MC, reinforcing their role as both a diagnostic and therapeutic biomarker. Full article

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

4 pages, 134 KiB

Open AccessEditorial

Urothelial Carcinoma: Role of Biomarkers in Diagnosis, Prognosis and Treatment

by Ioannis Zachos

Biomedicines 2025, 13(7), 1696; https://doi.org/10.3390/biomedicines13071696 - 11 Jul 2025

Abstract

Urothelial carcinoma (UC), also known as transitional cell carcinoma (TCC), is the second most frequently diagnosed urological tumor worldwide, and typically involves the bladder [...] Full article

(This article belongs to the Special Issue Urothelial Carcinoma: Role of Biomarkers in Diagnosis, Prognosis and Treatment)

11 pages, 2180 KiB

Open AccessArticle

Ornidazole-Induced Liver Injury: The Clinical Characterization of a Rare Adverse Reaction and Its Implications from a Multicenter Study

by Ali Rıza Çalışkan, Ilker Turan, Sezgin Vatansever, Jasmin Weninger, Emine Türkmen Şamdancı, Ayşe Nur Akatli, Elvan Işık, Esra Durmazer, Ayşenur Arslan, Nilay Danış, Hüseyin Kaçmaz, Sedat Cicek, Osman Sağlam, Dilara Turan Gökçe, Derya Arı, Sevinç Tuğçe Güvenir, Serkan Yaraş, Cumali Efe, Meral Akdoğan Kayhan, Murat Harputluoğlu, Ali Canbay, Ulus Salih Akarca, Zeki Karasu, Ramazan Idilman and Fulya Günşar Show full author list Hide full author list

Biomedicines 2025, 13(7), 1695; https://doi.org/10.3390/biomedicines13071695 - 11 Jul 2025

Abstract

Background and Aims: Ornidazole, a nitroimidazole antibiotic, is widely used for protozoal and anaerobic infections and is generally considered safe. However, ornidazole-induced liver injury (OILI) is an underrecognized yet potentially severe adverse reaction. This multicenter study aims to characterize the clinical features, histopathology, [...] Read more.

Background and Aims: Ornidazole, a nitroimidazole antibiotic, is widely used for protozoal and anaerobic infections and is generally considered safe. However, ornidazole-induced liver injury (OILI) is an underrecognized yet potentially severe adverse reaction. This multicenter study aims to characterize the clinical features, histopathology, and outcomes of OILI to improve the awareness and management of this rare entity worldwide. Methods: We conducted a retrospective analysis of 101 patients with OILI from eight tertiary centers between 2006 and 2023. Cases were included based on liver enzyme elevations temporally linked to ornidazole and the exclusion of other causes. Causality was assessed using the Roussel Uclaf Causality Assessment Method (RUCAM) score. Clinical data, laboratory parameters, autoantibody profiles, histology, treatments, and outcomes were evaluated. Results: OILI was classified as highly probable in 42.6% of cases (n = 43), probable in 51.5% of cases (n = 52), and possible in 5.9% (n = 6) of cases. The predominant pattern was acute hepatocellular injury (83.2%) (n = 84). Autoimmune-like hepatitis occurred in 5% of cases (n = 5), with ANA positivity in 16.8% of cases (n = 17). Corticosteroids were used in 24.8% of cases (n = 25) and were associated with higher ANA positivity and a 20% (n = 5) relapse rate post-discontinuation. Recovery was achieved in 87.7% of cases (n = 88), while 7.9% of cases (n = 8) required liver transplantation and 4% (n = 4) died. Conclusions: Ornidazole can cause serious idiosyncratic liver injury, including autoimmune phenotypes, and should be considered in the differential diagnosis of acute hepatitis. Given the notable risk of liver failure and death, early recognition, drug discontinuation, and close monitoring are essential. In select cases, corticosteroids and plasmapheresis may be beneficial, though the evidence remains limited. Full article

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

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12 pages, 385 KiB

Open AccessArticle

Psychological Profiles in Ulcerative Colitis and Crohn’s Disease: Distinct Emotional and Behavioral Patterns

by Antonio Maria D’Onofrio, Eleonora Maggio, Valentina Milo, Gaspare Filippo Ferrajoli, Daniele Ferrarese, Daniela Pia Rosaria Chieffo, Massimiliano Luciani, Antonio Gasbarrini, Gabriele Sani, Franco Scaldaferri, Rosaria Calia and Giovanni Camardese

Biomedicines 2025, 13(7), 1694; https://doi.org/10.3390/biomedicines13071694 - 10 Jul 2025

Abstract

Background/Objectives: Ulcerative colitis (UC) and Crohn’s disease (CD) are two forms of inflammatory bowel disease (IBD), which, despite their shared inflammatory nature, differ markedly in clinical presentation and disease course. In this study, we aimed to explore whether these clinical differences are [...] Read more.

Background/Objectives: Ulcerative colitis (UC) and Crohn’s disease (CD) are two forms of inflammatory bowel disease (IBD), which, despite their shared inflammatory nature, differ markedly in clinical presentation and disease course. In this study, we aimed to explore whether these clinical differences are also reflected at the psychological level. Specifically, we sought to delineate the personality characteristics of a sample of patients with IBD and to investigate psychological and psychopathological differences between individuals with UC and CD. Methods: We enrolled 29 (44.61%) UC patients and 36 (55.39%) CD patients, all aged 18 years or older. Each participant completed the Minnesota Multiphasic Personality Inventory-2 (MMPI-2), which was subsequently scored and interpreted by trained psychologists. The MMPI-2 is a 567-item inventory with dichotomous answers (true/false), providing measures of a wide range of symptoms, beliefs, attitudes, and personality traits. Results: The total sample showed clinically significant elevations on hypochondriasis (Hs), health concerns (HEA), general health concerns (HEA₃), and physical malfunctioning (D₃) scales. UC patients had statistically significant higher scores on hypomania (p = 0.043), lack of ego mastery—defective inhibition (p = 0.006), and fears (p = 0.038) scales than CD patients. On the other hand, CD patients showed statistically significant higher scores on the Overcontrolled Hostility scale (p = 0.043). Conclusions: Both groups of patients experience emotional difficulties related to their clinical conditions, leading to an increased preoccupation with bodily symptoms and illness. These aspects appear to be accompanied by shifts in mood towards a more depressive state. Notably, the UC group demonstrates a greater degree of impairment compared to the CD group, with experiences of anxiety, stress, difficulties in emotional control, and emerging relational challenges. Full article

(This article belongs to the Special Issue Crohn’s Disease and Ulcerative Colitis: From Pathophysiology to Novel Therapeutic Approaches (3rd Edition))

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17 pages, 1003 KiB

Open AccessReview

Current Application of Mineralocorticoid Antagonist (MRA) in Heart Failure and CKD: Does Non-Steroidal Drug Add Novel Insights

by Irene Carlino, Filippo Pirrotta, Luigi Gennari and Alberto Palazzuoli

Biomedicines 2025, 13(7), 1693; https://doi.org/10.3390/biomedicines13071693 - 10 Jul 2025

Abstract

Heart failure (HF) treatment evolved in the last 5 years with the introduction of new agents capable of reducing HF hospitalization and HF-related mortality. However, some categories such as patients with renal dysfunction tend to be excluded from larger randomized clinical trials. Additionally, [...] Read more.

Heart failure (HF) treatment evolved in the last 5 years with the introduction of new agents capable of reducing HF hospitalization and HF-related mortality. However, some categories such as patients with renal dysfunction tend to be excluded from larger randomized clinical trials. Additionally, most patients with HF experienced unavoidable glomerular filtration rate (GFR) deterioration during the clinical course. This is related to both cardio–renal interaction pathways and common cardiovascular risk factors that affect HF and chronic kidney disease (CKD). However, mineralocorticoid antagonists (MRAs) remain a cornerstone of HF therapy regardless of left ventricular ejection fraction (LVEF) values; some concerns remain about their utilization in CKD. Nevertheless, three studies (FIDELIO, FIGARO, and FINEARTS) have recently showed beneficial effects in both patients with HF and CKD associated with diabetes. Notably, finerenone a new non-steroidal MRA represents a significant step forward in cardiovascular therapy; its application spans a wide spectrum of HF phenotypes and CKD stages, and ongoing investigations will further elucidate its role in combination regimens and in broader patient populations. Further study may investigate the role of the drug in patients with heart failure with reduced ejection fraction (HFrEF) and in the severe CKD stage of non-diabetic etiology. In the current review paper, we provide a chronological overview of major trials evaluating the renal outcomes of MRAs, culminating in the emergence of finerenone as a novel therapeutic option for high-risk CKD populations, particularly those with type 2 diabetes mellitus (T2DM). Full article

(This article belongs to the Special Issue Hypertension and Chronic Renal Failure)

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17 pages, 5502 KiB

Open AccessArticle

Distinct Roles of apoE Receptor-2 Cytoplasmic Domain Splice Variants in Cardiometabolic Disease Modulation

by Anja Jaeschke, April Haller and David Y. Hui

Biomedicines 2025, 13(7), 1692; https://doi.org/10.3390/biomedicines13071692 - 10 Jul 2025

Abstract

Background/Objectives: Apolipoprotein E receptor-2 (apoER2) exists in various alternatively spliced forms, including variants that express apoER2 with or without exon 19 in the cytoplasmic domain. This study compared vascular response to endothelial denudation, as well as diet-induced atherosclerotic and metabolic diseases, between [...] Read more.

Background/Objectives: Apolipoprotein E receptor-2 (apoER2) exists in various alternatively spliced forms, including variants that express apoER2 with or without exon 19 in the cytoplasmic domain. This study compared vascular response to endothelial denudation, as well as diet-induced atherosclerotic and metabolic diseases, between genetically modified mice that exclusively expressed the apoER2 splice variant with or without exon 19 to determine the impact of apoER2 exon 19 motif in cardiometabolic disease modulation. Methods: Vascular response to injury was assessed by measuring neointima area of the carotid arteries after endothelial denudation. The genetically modified mice were also fed a high-fat high-cholesterol diet for 16 weeks for the determination of body weight gain, glucose and insulin levels, glucose tolerance and insulin secretion. Additionally, adipose tissue inflammation was assessed by analysis of adipose gene expression, and atherosclerosis was characterized by measuring fatty lesion size in the whole aorta, as well as in the aortic roots. Results: The results showed that whereas the expression of either splice variant is sufficient to impede denudation-induced fibrotic neointima formation and complex necrotic atherosclerotic lesions, the expression of the apoER2 splice variant containing exon 19 is necessary for the complete protection of injury-induced neointima formation in the vessel wall. However, exclusive expression of either apoER2 cytoplasmic splice variant does not influence the early phase of atherogenesis. Additionally, the exclusive expression of apoER2 without exon 19 promotes adipocyte inflammation and accelerates diet-induced insulin resistance and glucose intolerance. Conclusions: These results indicate that the apoER2 cytoplasmic variants have distinct and cell type-specific roles in influencing cardiometabolic disease development. Full article

(This article belongs to the Special Issue Molecular and Cellular Research in Diabetes and Metabolic Diseases)

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30 pages, 4867 KiB

Open AccessReview

Targeting Resistance Pathways in Breast Cancer Through Precision Oncology: Nanotechnology and Immune Modulation Approaches

by Hussein Sabit, Sanaa Rashwan, Yasser Albrahim, Al-Hassan Soliman Wadan, Faisal Radwan, Amany I. Alqosaibi, Shaimaa Abdel-Ghany and Borros Arneth

Biomedicines 2025, 13(7), 1691; https://doi.org/10.3390/biomedicines13071691 - 10 Jul 2025

Abstract

According to the WHO, in 2022, there were 2.3 million women diagnosed with breast cancer (BC) and 670,000 deaths globally. BC remains the leading cause of cancer-related mortality, with therapeutic resistance representing a significant barrier to effective treatment, particularly in aggressive subtypes like [...] Read more.

According to the WHO, in 2022, there were 2.3 million women diagnosed with breast cancer (BC) and 670,000 deaths globally. BC remains the leading cause of cancer-related mortality, with therapeutic resistance representing a significant barrier to effective treatment, particularly in aggressive subtypes like triple-negative breast cancer (TNBC). This review article discusses emerging strategies to overcome resistance by integrating precision oncology, nanotechnology-based drug delivery, and immune modulation. Resistance mechanisms—such as metabolic reprogramming, tumor heterogeneity, immune evasion, autophagy, and the role of cancer stem cells—are critically examined. We highlight cutting-edge nanoplatforms that co-deliver chemotherapeutics and immune stimulants with spatiotemporal precision, including sonodynamic and photothermal systems, ADCs, and targeted nanoparticles. Moreover, advances in tumor microenvironment (TME) modulation, photoimmunotherapy, and exosomal miRNA targeting offer promising avenues to enhance immunogenicity and therapeutic durability. The integration of molecular profiling with advanced computational approaches, including artificial intelligence and biomimetic models, holds significant promise for the future development of personalized resistance-mitigating interventions, though a detailed exploration is beyond the current scope. Collectively, these strategies reflect a paradigm shift from conventional monotherapies toward multifaceted, precision-guided treatment approaches. This review aims to provide a comprehensive overview of current innovations and propose future directions for overcoming drug resistance in BC. Full article

(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy—Second Edition)

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11 pages, 1584 KiB

Open AccessArticle

Investigation into the Effects of Tramadol, Citalopram, Tianeptine, and Their Combinations on Rat Brain Tissue

by Irem Ates, Bahar Isik, Fusun Gozen, Gulce Naz Yazici, Mine Gulaboglu, Renad Mammadov, Gulbeniz Huseynova, Durdu Altuner and Halis Suleyman

Biomedicines 2025, 13(7), 1690; https://doi.org/10.3390/biomedicines13071690 - 10 Jul 2025

Abstract

Background: Tramadol binds to opioid receptors and inhibits norepinephrine and serotonin reuptake, causing serotonin syndrome. Tianeptine stimulates serotonin reuptake and reduces serotonin levels. The aim of this study was to investigate whether tianeptine is effective against serotonin syndrome that may occur with [...] Read more.

Background: Tramadol binds to opioid receptors and inhibits norepinephrine and serotonin reuptake, causing serotonin syndrome. Tianeptine stimulates serotonin reuptake and reduces serotonin levels. The aim of this study was to investigate whether tianeptine is effective against serotonin syndrome that may occur with serotoninergic drugs such as tramadol and citalopram. Methods: Rats were divided into eight groups (n = 6) that received tramadol (50 mg/kg), citalopram (10 mg/kg), or tianeptine (5 mg/kg) alone or a combination of tramadol + citalopram, tramadol + tianeptine, citalopram + tianeptine or tramadol + citalopram + tianeptine at the same doses administered to the stomach by oral gavage for 3 weeks. The healthy control group was given saline. Malondialdehyde, total glutathione, superoxide dismutase, and catalase levels were measured in removed brain tissues. The tissues were also examined histopathologically. Results: In the tramadol, tramadol + citalopram, and tramadol + citalopram + tianeptine groups, malondialdehyde levels were found to be higher compared to the control group, while glutathione, superoxide dismutase, and catalase levels were found to be lower. In other groups, values close to the control group were measured. Morphological degeneration was observed in neurons in the tramadol + citalopram group. The swelling of astrocytes and pericellular edema in oligodendrocytes were also observed. A significant population increase was noted in microglial cells. Blood vessels belonging to the tissue were observed to be severely dilated and congested. Histopathological damage was partially resolved in the group given tramadol + citalopram + tianeptine. Conclusions: The tramadol + citalopram combination caused severe oxidative stress in brain tissue. Tramadol alone caused mild damage in brain tissue, whereas tianeptine prevented the brain damage caused by tramadol. Full article

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

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16 pages, 9169 KiB

Open AccessArticle

Impact of Acute and Chronic Stressors on the Morphofunctional Characteristics of Long Bones in Spontaneously Hypertensive Rats: A Pilot Study Using Histological and Microtomographic Analysis

by Marina Ribeiro Paulini, Dimitrius Leonardo Pitol, Sara Feldman, Camila Aparecida Ribeiro, Daniela Vieira Buchaim, Rogerio Leone Buchaim and João Paulo Mardegan Issa

Biomedicines 2025, 13(7), 1689; https://doi.org/10.3390/biomedicines13071689 - 10 Jul 2025

Abstract

Background/Objectives: Hypertension is a major contributor to cardiovascular diseases and is often intensified by psychological stress, which can also affect bone metabolism. Although both conditions independently compromise bone health, their combined impact—particularly under acute and chronic stress—remains unclear. This pilot study aimed to [...] Read more.

Background/Objectives: Hypertension is a major contributor to cardiovascular diseases and is often intensified by psychological stress, which can also affect bone metabolism. Although both conditions independently compromise bone health, their combined impact—particularly under acute and chronic stress—remains unclear. This pilot study aimed to assess the effects of such stressors on bone structure in spontaneously hypertensive rats (SHRs). Methods: Forty male rats, both normotensive and SHRs, were randomly assigned to control, acute stress, or chronic stress groups. Acute stress involves a single 2 h physical restraint. Chronic stress was induced over 10 days using alternating stressors: agitation, forced swimming, physical restraint, cold exposure, and water deprivation. Tibial bones were analyzed by microcomputed tomography (micro-CT), and histology was performed using Hematoxylin and Eosin and Masson’s Trichrome stains. Results: Micro-CT showed increased trabecular bone volume in normotensive rats under chronic stress, whereas SHRs displayed impaired remodeling under both stress types. Histological analysis revealed preserved connective tissue overall but evident changes in growth plate structure among stressed rats. SHRs exhibited exacerbated trabecular formation and cartilage abnormalities, including necrotic zones. Conclusions: Both acute and chronic stress, especially in the context of hypertension, negatively affect bone remodeling and maturation. Despite the absence of overt inflammation, structural bone changes were evident, indicating potential long-term risks. These findings highlight the importance of further studies on stress–hypertension interactions in bone health as well as the exploration of therapeutic approaches to mitigate skeletal damage under such conditions. Full article

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

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17 pages, 1693 KiB

Open AccessArticle

Overcoming Challenges in the Determination of Fatty Acid Ethyl Esters in Post-Mortem Plasma Samples with the Use of Targeted Metabolomics and the Quality by Design Approach

by Joanna Dawidowska, Julia Jacyna-Gębala, Renata Wawrzyniak, Michał Kaliszan and Michał Jan Markuszewski

Biomedicines 2025, 13(7), 1688; https://doi.org/10.3390/biomedicines13071688 - 10 Jul 2025

Abstract

Background: Excessive alcohol consumption constitutes a serious cause of death worldwide. Fatty acid ethyl esters, as metabolites of the non-oxidative elimination pathway of ethanol, have been recognized as mediators of alcohol-induced organ damage. These metabolites serve as potential biomarkers for the assessment of [...] Read more.

Background: Excessive alcohol consumption constitutes a serious cause of death worldwide. Fatty acid ethyl esters, as metabolites of the non-oxidative elimination pathway of ethanol, have been recognized as mediators of alcohol-induced organ damage. These metabolites serve as potential biomarkers for the assessment of ethanol intake and might be also used in post-mortem studies. Methods: In this study, the development and optimization of a simple, fast, precise, accurate, and cost-effective method with the use of gas chromatography coupled with tandem mass spectrometry for quantitative analysis of six fatty acid ethyl esters, namely ethyl laurate, myristate, palmitate, linoleate, oleate, and stearate, were conducted. Results: The optimized method was fully validated according to ICH guidelines. Additionally, identification of critical method parameters was possible by using the quality by design approach. By carrying out analyses according to the Plackett–Burman plan (design of experiments methodology), the robustness of the analytical method developed was confirmed for four (ethyl palmitate, linoleate, oleate, and stearate) ethyl esters. In the case of ethyl myristate, the variable significantly affecting the results appeared to be the temperature of solvent evaporation after the deproteinization step. Conclusions: Biochemical interpretation of the obtained results with available medical records suggests that plasma concentrations of selected fatty acid ethyl esters are valuable indicators of pre-mortem alcohol consumption and may be one of the key factors helpful in determining the cause and mechanism of death. Full article

(This article belongs to the Special Issue Pathophysiology of Fatty Acid Metabolism)

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19 pages, 5784 KiB

Open AccessArticle

Identification of Exosome-Associated Biomarkers in Diabetic Foot Ulcers: A Bioinformatics Analysis and Experimental Validation

by Tianbo Li, Lei Gao and Jiangning Wang

Biomedicines 2025, 13(7), 1687; https://doi.org/10.3390/biomedicines13071687 - 10 Jul 2025

Abstract

Background: Diabetic foot ulcers (DFUs) are a severe complication of diabetes and are characterized by impaired wound healing and a high amputation risk. Exosomes—which are nanovesicles carrying proteins, RNAs, and lipids—mediate intercellular communication in wound microenvironments, yet their biomarker potential in DFUs remains [...] Read more.

Background: Diabetic foot ulcers (DFUs) are a severe complication of diabetes and are characterized by impaired wound healing and a high amputation risk. Exosomes—which are nanovesicles carrying proteins, RNAs, and lipids—mediate intercellular communication in wound microenvironments, yet their biomarker potential in DFUs remains underexplored. Methods: We analyzed transcriptomic data from GSE134431 (13 DFU vs. 8 controls) as a training set and validated findings in GSE80178 (6 DFU vs. 3 controls). A sum of 7901 differentially expressed genes (DEGs) of DFUs were detected and intersected with 125 literature-curated exosome-related genes (ERGs) to yield 51 candidates. This was followed by GO/KEGG analyses and a PPI network construction. Support vector machine–recursive feature elimination (SVM-RFE) and the Boruta random forest algorithm distilled five biomarkers (DIS3L, EXOSC7, SDC1, STX11, SYT17). Expression trends were confirmed in both datasets. Analyses included nomogram construction, functional and correlation analyses, immune infiltration, GSEA, gene co-expression and regulatory network construction, drug prediction, molecular docking, and RT-qPCR validation in clinical samples. Results: A nomogram combining these markers achieved an acceptable calibration (Hosmer–Lemeshow p = 0.0718, MAE = 0.044). Immune cell infiltration (CIBERSORT) revealed associations between biomarker levels and NK cell and neutrophil subsets. Gene set enrichment analysis (GSEA) implicated IL-17 signaling, proteasome function, and microbial infection pathways. A GeneMANIA network highlighted RNA processing and vesicle trafficking. Transcription factor and miRNA predictions uncovered regulatory circuits, and DGIdb-driven drug repurposing followed by molecular docking identified Indatuximab ravtansine and heparin as high-affinity SDC1 binders. Finally, RT-qPCR validation in clinical DFU tissues (n = 5) recapitulated the bioinformatic expression patterns. Conclusions: We present five exosome-associated genes as novel DFU biomarkers with diagnostic potential and mechanistic links to immune modulation and vesicular transport. These findings lay the groundwork for exosome-based diagnostics and therapeutic targeting in DFU management. Full article

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

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16 pages, 990 KiB

Open AccessReview

Repurposing Rafoxanide: From Parasite Killer to Cancer Fighter

by Teresa Pacifico, Lorenzo Tomassini, Livia Biancone, Giovanni Monteleone, Carmine Stolfi and Federica Laudisi

Biomedicines 2025, 13(7), 1686; https://doi.org/10.3390/biomedicines13071686 - 9 Jul 2025

Abstract

Rafoxanide, originally developed as a veterinary anthelmintic for the treatment of parasitic infections in livestock, has recently emerged as a promising therapeutic prospect in oncology. This compound has demonstrated notable antineoplastic effects against a variety of cancers, including skin, gastric, colorectal, and lung [...] Read more.

Rafoxanide, originally developed as a veterinary anthelmintic for the treatment of parasitic infections in livestock, has recently emerged as a promising therapeutic prospect in oncology. This compound has demonstrated notable antineoplastic effects against a variety of cancers, including skin, gastric, colorectal, and lung cancers, as well as hematological malignancies such as multiple myeloma. Rafoxanide exerts its anticancer activity through multiple complementary mechanisms, including the induction of endoplasmic reticulum stress, cell cycle arrest, apoptosis, and immunogenic cell death. Furthermore, the drug has been reported to inhibit key oncogenic signaling pathways (e.g., STAT3, NF-κB, c-FLIP, survivin) that contribute to tumor growth and metastasis. Preclinical studies in murine models have demonstrated significant reductions in tumor volume of up to 50% and a tumor-free rate exceeding 80%, with effective doses ranging from 7.5 to 40 mg/kg. This multitargeted mode of action distinguishes rafoxanide from conventional therapies and may help overcome resistance mechanisms that often limit the efficacy of cancer treatments. In this review, we summarize and discuss the growing body of evidence supporting rafoxanide’s therapeutic potential in oncology, as well as its possible applications in cancer treatment. Full article

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

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22 pages, 1381 KiB

Open AccessReview

Artificial Intelligence and ECG: A New Frontier in Cardiac Diagnostics and Prevention

by Dorota Bartusik-Aebisher, Kacper Rogóż and David Aebisher

Biomedicines 2025, 13(7), 1685; https://doi.org/10.3390/biomedicines13071685 - 9 Jul 2025

Abstract

Objectives: With the growing importance of mobile technology and artificial intelligence (AI) in healthcare, the development of automated cardiac diagnostic systems has gained strategic significance. This review aims to summarize the current state of knowledge on the use of AI in the [...] Read more.

Objectives: With the growing importance of mobile technology and artificial intelligence (AI) in healthcare, the development of automated cardiac diagnostic systems has gained strategic significance. This review aims to summarize the current state of knowledge on the use of AI in the analysis of electrocardiographic (ECG) signals obtained from wearable devices, particularly smartwatches, and to outline perspectives for future clinical applications. Methods: A narrative literature review was conducted using PubMed, Web of Science, and Scopus databases. The search focused on combinations of keywords related to AI, ECG, and wearable technologies. After screening and applying inclusion criteria, 152 publications were selected for final analysis. Conclusions: Modern AI algorithms—especially deep neural networks—show promise in detecting arrhythmias, heart failure, prolonged QT syndrome, and other cardiovascular conditions. Smartwatches without ECG sensors, using photoplethysmography (PPG) and machine learning, show potential as supportive tools for preliminary atrial fibrillation (AF) screening at the population level, although further validation in diverse real-world settings is needed. This article explores innovation trends such as genetic data integration, digital twins, federated learning, and local signal processing. Regulatory, technical, and ethical challenges are also discussed, along with the issue of limited clinical evidence. Artificial intelligence enables a significant enhancement of personalized, mobile, and preventive cardiology. Its integration into smartwatch ECG analysis opens a path toward early detection of cardiac disorders and the implementation of population-scale screening approaches. Full article

(This article belongs to the Special Issue Feature Reviews in Cardiovascular Diseases)

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16 pages, 1261 KiB

Open AccessReview

Extracorporeal Cytokine Adsorption in Sepsis: Current Evidence and Future Perspectives

by Matteo Guarino, Anna Costanzini, Francesco Luppi, Martina Maritati, Carlo Contini, Roberto De Giorgio and Michele Domenico Spampinato

Biomedicines 2025, 13(7), 1684; https://doi.org/10.3390/biomedicines13071684 - 9 Jul 2025

Abstract

Background: Sepsis and septic shock are major contributors to global morbidity and mortality. The “cytokine storm,” a hyper-inflammatory response, plays a central role in sepsis pathophysiology, leading to multi-organ failure. Extracorporeal cytokine adsorption therapies, such as CytoSorb, Toraymyxin, Oxiris, HA330/380, and Seraph [...] Read more.

Background: Sepsis and septic shock are major contributors to global morbidity and mortality. The “cytokine storm,” a hyper-inflammatory response, plays a central role in sepsis pathophysiology, leading to multi-organ failure. Extracorporeal cytokine adsorption therapies, such as CytoSorb, Toraymyxin, Oxiris, HA330/380, and Seraph 100 Microbind, aim to mitigate the inflammatory response by removing circulating cytokines and other mediators. Methods: A comprehensive search of Scopus and PubMed was conducted for studies published from January 2020 to May 2025. The search terms included “sepsis,” “septic shock,” and “extracorporeal cytokine adsorption.” Relevant studies, including clinical trials and meta-analyses, were included to assess the efficacy and safety of these therapies. Results: Extracorporeal cytokine adsorption has shown promising results in reducing cytokine levels, improving organ function, and decreasing vasopressor requirements. However, evidence regarding mortality reduction remains inconsistent. Studies have demonstrated benefits in sepsis, ARDS, and cardiogenic shock, improving organ recovery and inflammatory markers. Conclusions: Extracorporeal cytokine adsorption is a potential adjunctive therapy in sepsis management, offering improvements in organ function and inflammatory control. While the mortality benefit remains uncertain, ongoing research and large-scale clinical trials are essential to define its clinical role and optimize its application. Full article

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

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18 pages, 5448 KiB

Open AccessArticle

Glucocorticoid Receptor (GR) Expression in Human Tumors: A Tissue Microarray Study on More than 14,000 Tumors

by Maria Christina Tsourlakis, Simon Kind, Sebastian Dwertmann Rico, Sören Weidemann, Katharina Möller, Ria Schlichter, Martina Kluth, Claudia Hube-Magg, Christian Bernreuther, Guido Sauter, Andreas H. Marx, Ronald Simon, Ahmed Abdulwahab Bawahab, Florian Lutz, Viktor Reiswich, Davin Dum, Stefan Steurer, Eike Burandt, Till S. Clauditz, Till Krech, Christoph Fraune, Seyma Büyücek, Neele Heckmann, Natalia Gorbokon, Maximilian Lennartz, Sarah Minner and Florian Viehweger Show full author list Hide full author list

Biomedicines 2025, 13(7), 1683; https://doi.org/10.3390/biomedicines13071683 - 9 Jul 2025

Abstract

Background: The glucocorticoid receptor (GR) regulates the transcription of thousands of genes. In cancer, both oncogenic and tumor suppressive roles of GR have been proposed. Methods: A tissue microarray containing 18,527 samples from 147 tumor (sub-)types and 608 samples from 76 normal [...] Read more.

Background: The glucocorticoid receptor (GR) regulates the transcription of thousands of genes. In cancer, both oncogenic and tumor suppressive roles of GR have been proposed. Methods: A tissue microarray containing 18,527 samples from 147 tumor (sub-)types and 608 samples from 76 normal tissue types was analyzed for GR expression by immunohistochemistry. Results: GR positivity was found in 76.4% of 14,349 interpretable cancers, including 18.5% with weak, 19.6% with moderate, and 38.3% with strong positivity. GR positivity appeared in all 147 tumor types, with at least one strongly positive tumor in 136 types. Of out tumor entities, 77 of the 147 showed GR positivity in 100% of the cases analyzed. Only six tumor types had less than 50% GR-positive cases, including adenomas with low-/high-grade dysplasia (32.5%/21.7%), adenocarcinomas (17%) and neuroendocrine carcinomas (45.5%) of the colorectum, endometrial carcinomas (25.6%), and rhabdoid tumors (25%). Reduced GR staining was associated with grade progression in pTa (p < 0.0001) and with nodal metastasis in pT2-4 (p = 0.0051) urothelial bladder carcinoma, advanced pT stage (p = 0.0006) in breast carcinomas of no special type (NST), and high grade (p = 0.0066), advanced pT stage (p < 0.0001), and distant metastasis (p = 0.0081) in clear cell renal cell carcinoma. GR expression was unrelated to clinico-pathological parameters in gastric, pancreatic, and colorectal adenocarcinoma, and in serous high-grade carcinoma of the ovary. Conclusions: GR expression is frequent across all cancer types. Associations between reduced GR expression and unfavorable tumor features in certain cancers suggest that the functional importance of GR-regulated genes in cancer progression depends on the cell of tumor origin. Full article

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

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17 pages, 1886 KiB

Open AccessReview

Random Insertion Reporter Gimmicks Powered by Cut-and-Paste DNA Transposons

by Yamato Kasahara, Kentaro Semba, Shinya Watanabe and Kosuke Ishikawa

Biomedicines 2025, 13(7), 1682; https://doi.org/10.3390/biomedicines13071682 - 9 Jul 2025

Abstract

Transposons are mobile genetic elements capable of moving within the genome. Leveraging this property—particularly the cut-and-paste mechanism of DNA transposons—has enabled the development of technologies for inserting exogenous DNA fragments into host genomes. While targeted integration is a key goal for therapeutic applications, [...] Read more.

Transposons are mobile genetic elements capable of moving within the genome. Leveraging this property—particularly the cut-and-paste mechanism of DNA transposons—has enabled the development of technologies for inserting exogenous DNA fragments into host genomes. While targeted integration is a key goal for therapeutic applications, this review highlights the value of their intrinsic randomness. By combining the ability to freely design the DNA cargo with the stochastic nature of transposon integration, it becomes possible to generate highly sensitive reporter cells. These can be used to efficiently identify functional markers, uncover novel signaling pathways, and establish innovative platforms for drug screening. As more subfamilies of transposons become available for research use, their complementary biases may enhance the coverage and diversity of genome-wide screening approaches. Although inherently unpredictable, this strategy embraces randomness as a strength, and we propose that it holds great promise for driving new advances in biology, cellular engineering, and medical research. Full article

(This article belongs to the Special Issue Gene Delivery and Gene Editing)

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9 pages, 216 KiB

Open AccessArticle

Higher Body Mass Index Shows No Evidence of Association with Histopathologic Markers of Aggressiveness in Early-Stage Papillary Thyroid Carcinoma

by Aliki Economides, Demetris Lamnisos, Paris Vogazianos, Konstantinos Giannakou, Savvas Frangos, Vasilis Constantinides, Panagiotis Papageorgis and Panayiotis A. Economides

Biomedicines 2025, 13(7), 1681; https://doi.org/10.3390/biomedicines13071681 - 9 Jul 2025

Abstract

Background: Obesity has been implicated in the pathogenesis and progression of several malignancies, including papillary thyroid carcinoma (PTC), but its role in tumor aggressiveness remains controversial. This study aimed to investigate the association between adiposity, as measured by body mass index (BMI), and [...] Read more.

Background: Obesity has been implicated in the pathogenesis and progression of several malignancies, including papillary thyroid carcinoma (PTC), but its role in tumor aggressiveness remains controversial. This study aimed to investigate the association between adiposity, as measured by body mass index (BMI), and histopathological features of aggressiveness in patients with PTC. Methods: This single-center retrospective study included 298 consecutive adult patients diagnosed with PTC between 2016 and 2021 at an endocrine referral center. Patients were stratified based on BMI into normal weight (<25 kg/m²) and overweight/obese (≥25 kg/m²) groups. Clinical, metabolic, and histopathological data were compared between the two groups. Results: Overweight/obese patients had significantly higher rates of hypertension, type 2 diabetes, fasting glucose, and triglycerides, as well as lower high-density lipoprotein cholesterol (all p < 0.01). Tumor size was similar between groups, with over 85% of tumors measuring ≤ 1 cm (microcarcinomas) and no significant difference in the proportion of tumors > 1 cm (p = 0.582). There were no significant differences in multifocality (p = 0.269) or extrathyroidal extension (ETE) (p = 0.826). Lymph node metastases occurred in 34% of normal weight and 28% of overweight/obese patients, without a statistically significant difference (p = 0.402). Lymph node compartment involvement did not significantly differ between groups (p = 0.160). Conclusions: Despite being associated with adverse metabolic profiles, higher BMI was not linked to tumor aggressiveness in patients with predominantly early-stage PTC. As the incidence of obesity and PTC continues to rise, these findings highlight the need for further research into early-stage PTC biology and more precise risk measures of adiposity beyond BMI alone. Full article

(This article belongs to the Special Issue Advanced Research in Thyroid and Parathyroid Diseases)

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Open AccessArticle

The Role and Mechanism of GSDME-Dependent Pyroptosis in Cochlear Marginal Cells Injury by Cisplatin

by Wenyang Lei, Wenting Yu, Ting Li, Wei Tang, Shimin Zong and Hongjun Xiao

Biomedicines 2025, 13(7), 1680; https://doi.org/10.3390/biomedicines13071680 - 9 Jul 2025

Abstract

Background: Elucidating the mechanisms underlying cisplatin-induced ototoxicity is critical for the clinical management of hearing loss. While cisplatin is known to penetrate the inner ear via the blood-labyrinth barrier in the stria vascularis, its precise damaging effects on marginal cells (MCs) and subsequent [...] Read more.

Background: Elucidating the mechanisms underlying cisplatin-induced ototoxicity is critical for the clinical management of hearing loss. While cisplatin is known to penetrate the inner ear via the blood-labyrinth barrier in the stria vascularis, its precise damaging effects on marginal cells (MCs) and subsequent hearing impairment remain incompletely understood. Pyroptosis, a gasdermin-mediated inflammatory cell death pathway, may play a key role. This study investigated the involvement of gasdermin E (GSDME)-dependent pyroptosis in cisplatin-induced injury to MCs. Methods: An in vitro cisplatin-induced pyroptosis model was established in MCs. GSDME expression was downregulated using small interfering RNA (siRNA), and caspase-3 activity was inhibited pharmacologically. The critical threshold for pyroptosis induction was determined to be 5 μmol/L cisplatin exposure for 24 h, which activated the caspase-3/GSDME signaling pathway. Results: Cisplatin treatment upregulated GSDME and caspase-3 expression in MCs. Both inhibition of GSDME and pharmacological blockade of caspase-3 significantly attenuated cisplatin-induced cellular damage. Notably, caspase-3 suppression reduced GSDME expression, suggesting a positive regulatory relationship between these mediators. Conclusions: GSDME-mediated pyroptosis plays a pivotal role in cisplatin-induced marginal cell injury, with caspase-3 acting as an upstream regulator of GSDME expression. These findings provide a mechanistic foundation for developing novel therapeutic strategies against cisplatin ototoxicity. Full article

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

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13 pages, 845 KiB

Open AccessArticle

Paradox of Low CA-125 in Patients with Decompensated Congestive Heart Failure

by Raquel López-Vilella, Borja Guerrero Cervera, Víctor Donoso Trenado, Julia Martínez-Solé, Sara Huélamo Montoro, Valero Soriano Alfonso, Franco Appiani, Luis Martínez Dolz and Luis Almenar-Bonet

Biomedicines 2025, 13(7), 1679; https://doi.org/10.3390/biomedicines13071679 - 9 Jul 2025

Abstract

Background/Objectives: Patients diagnosed with decompensated congestive heart failure (HF) often have elevated CA-125 levels, attributed to systemic congestion. However, a subgroup of patients presents with normal CA-125 levels. The primary objective of this study was to characterize the clinical, analytical, and echocardiographic [...] Read more.

Background/Objectives: Patients diagnosed with decompensated congestive heart failure (HF) often have elevated CA-125 levels, attributed to systemic congestion. However, a subgroup of patients presents with normal CA-125 levels. The primary objective of this study was to characterize the clinical, analytical, and echocardiographic profiles of patients admitted for decompensated congestive HF according to their CA-125 levels. The secondary objective was to analyze mortality after discharge. Methods: We conducted a retrospective study of patients hospitalized for a decompensated congestive HF episode. Recruitment was consecutive over more than 4 years (December 2019–June 2024), with 3151 patients recruited. Scheduled admissions, transfers from other hospitals, pulmonary congestion patterns, mixed patterns, and low output were the exclusion criteria. The final number of patients included was 166, all with an isolated systemic congestion pattern: CA-125 ≤ 50 U/mL: 38, and CA-125 > 50 U/mL: 128. Results: The comparative analysis between the groups showed that patients with CA-125 ≤ 50 U/mL were more often women (p < 0.05). They also had lower bilirubin and GOT/AST levels (p < 0.05). The percentage of patients with a preserved left ventricular ejection fraction (≥50%) was higher in the CA-125 ≤ 50 U/mL group (p < 0.05). The right ventricular (RV) size and inferior vena cava (IVC) were enlarged in both groups but with no significant differences (p < 0.05). However, the degree of RV dysfunction was greater in the CA-125 > 50 U/mL group, while the proportion of patients with inspiratory collapse of the IVC was higher in the CA-125 ≤ 50 U/mL group (p < 0.05). Survival curves differed from the first month and throughout the follow-up, with higher mortality in the CA-125 > 50 U/mL group. Thus, the probability of being alive at the end of the follow-up was over 50% in the CA-125 ≤ 50 U/mL group, while in the CA-125 > 50 U/mL group, it was around 25% (p < 0.05). Conclusions: The proportion of patients with decompensated congestive HF and systemic congestion who present with a low CA-125 level is close to 25%. These patients are mostly women with a preserved ejection fraction and inspiratory collapse of the IVC of >50%. Moreover, they have a higher survival rate, so a low CA-125 could help identify a subgroup of patients with a better prognosis. Full article

(This article belongs to the Special Issue Acute and Chronic Heart Failure: Pathophysiology and New Therapeutic Developments, 2nd Edition)

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15 pages, 516 KiB

Open AccessReview

Epigenetic Regulation in Wilms Tumor

by Annabelle Bolitho and Hongbing Liu

Biomedicines 2025, 13(7), 1678; https://doi.org/10.3390/biomedicines13071678 - 9 Jul 2025

Abstract

Wilms tumor (nephroblastoma), the most common pediatric renal malignancy, has a complex genetic and epigenetic landscape. While mutations in genes like WT1, CTNNB1, and WTX have been well characterized, accumulating evidence suggests that epigenetic dysregulation plays a pivotal role in WT pathogenesis. This [...] Read more.

Wilms tumor (nephroblastoma), the most common pediatric renal malignancy, has a complex genetic and epigenetic landscape. While mutations in genes like WT1, CTNNB1, and WTX have been well characterized, accumulating evidence suggests that epigenetic dysregulation plays a pivotal role in WT pathogenesis. This review examines the various epigenetic mechanisms implicated in WT, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA-mediated regulation. We discuss how epigenetic mechanisms contribute to tumor initiation, progression, and heterogeneity and their implications for improved diagnosis and targeted therapy. We also highlight recent advances in epigenomic profiling, discuss the interplay between epigenetics and developmental gene expression programs, and evaluate potential therapeutic strategies targeting epigenetic regulators. Full article

(This article belongs to the Special Issue Epigenetic Regulation of Kidney Development)

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11 pages, 805 KiB

Open AccessArticle

Efficacy and Safety of OROSOL Spray for Oral Mucositis in Children: A Randomized, Double-Blind, Placebo-Controlled Trial

by Fatima-Zahra El Barche, Manon D’Almeida, Séverine Dameron and Rémi Shrivastava

Biomedicines 2025, 13(7), 1677; https://doi.org/10.3390/biomedicines13071677 - 9 Jul 2025

Abstract

Background: Oral mucositis (OM) is a common and debilitating complication of cancer therapy, particularly in patients undergoing chemotherapy and radiotherapy. It significantly impairs quality of life and may necessitate the interruption of cancer treatment. This study aimed to evaluate the efficacy and [...] Read more.

Background: Oral mucositis (OM) is a common and debilitating complication of cancer therapy, particularly in patients undergoing chemotherapy and radiotherapy. It significantly impairs quality of life and may necessitate the interruption of cancer treatment. This study aimed to evaluate the efficacy and safety of OROSOL, an oral spray device, in managing oral mucositis in pediatric patients undergoing chemotherapy or radiotherapy. Methods: This randomized, double-blind, placebo-controlled clinical trial compared OROSOL to a placebo in children with oral mucositis aged 3 to 17 years. Participants were followed for 28 days with regular medical visits. The primary endpoints were changes in the Oral Assessment Guide (OAG) scores and key symptoms (mucositis score, difficulty in oral feeding, ulceration and erythema, and pain sensation). Safety was assessed via adverse events and local tolerability. Results: Both groups were demographically balanced at baseline (p > 0.6). OROSOL demonstrated significantly greater improvements in the mucositis score beginning on Day 7 (p = 0.0122) and maintained superiority through Day 28 (p = 0.0007). Notable reductions in mucositis severity were observed, with significantly faster relief in the OROSOL group compared to the placebo (p < 0.001 for most timepoints). Oral feeding difficulty also showed a marked decline, with significant improvements starting from Day 5 (p = 0.0153). Ulceration and erythema scores significantly decreased from Day 14 onwards (p = 0.0188). Pain sensation showed a marked reduction from Day 14 (p = 0.0014). No serious adverse events were reported, and tolerability was consistent across all participants. Conclusions: OROSOL has a significant impact on reducing mucositis severity, oral feeding difficulty, ulceration, erythema, and pain. Coupled with its excellent safety profile, it is a valuable therapeutic option. This treatment is particularly beneficial for pediatric patients, ensuring improved comfort and recovery without notable adverse effects. Full article

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

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18 pages, 569 KiB

Open AccessArticle

Impact of Biologics and Proton Pump Inhibitors on Gastrointestinal Infection Risk in Inflammatory Bowel Disease Patients: A Retrospective Analysis of Pathogen-Specific Outcomes and Treatment Interactions

by Ryan Njeim, Elie Moussa, Chapman Wei, Joelle Sleiman, Reem Dimachkie and Liliane Deeb

Biomedicines 2025, 13(7), 1676; https://doi.org/10.3390/biomedicines13071676 - 8 Jul 2025

Abstract

Background/Objectives: Inflammatory bowel disease (IBD) patients face elevated gastrointestinal (GI) infection risks due to immune dysregulation and gut dysbiosis. While steroids and immunosuppressants are known to increase infection risk, data on biologics and proton pump inhibitors (PPIs) remain limited, particularly for non-Clostridioides [...] Read more.

Background/Objectives: Inflammatory bowel disease (IBD) patients face elevated gastrointestinal (GI) infection risks due to immune dysregulation and gut dysbiosis. While steroids and immunosuppressants are known to increase infection risk, data on biologics and proton pump inhibitors (PPIs) remain limited, particularly for non-Clostridioides difficile (C.diff) infections. Methods: This retrospective cohort study analyzed 9849 hospitalized IBD patients (2013–2023) from the Northwell Inpatient Database. Patients were categorized into four groups: biologics-only, PPIs-only, both, or neither. GI infections were identified via C.diff PCR, GI PCR, and chart review. Multivariate logistic regression adjusted for demographics, BMI, and IBD type. Results: GI infections occurred in 1.75% of patients, with significantly higher odds in those on biologics alone (OR 21.5, 95% CI 11.7–39.4) or with PPIs (OR 16.6, 95% CI 10.2–26.8) versus untreated patients. Non-C.diff infections were strongly associated with biologics (OR 20.7, 95% CI 10.2–41.9). PPIs alone increased slightly the risk of GI infections (OR 1.6, 95% CI 1.1–2.4). Vedolizumab and adalimumab had the highest infection risks among biologics (26.8% and 22.7%, respectively). Bacterial pathogens, such as E. coli and Salmonella, predominated, with no significant difference in causative agents across treatment groups. Conclusions: Biologic therapy greatly increases GI infection risk in IBD patients independent of PPI use. Clinicians should weigh infection risks when prescribing biologics, particularly in high-risk populations. Further studies are needed to assess risks by biologic subtype and the interplay with PPIs. Full article

(This article belongs to the Special Issue Crohn’s Disease and Ulcerative Colitis: From Pathophysiology to Novel Therapeutic Approaches (3rd Edition))

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21 pages, 2230 KiB

Open AccessSystematic Review

Corneal Nerve Morphology in Painful Diabetic Neuropathy: A Meta-Analysis of In Vivo Confocal Microscopy Studies

by Prajna Vidyasagar, Scott F. Farrell, Luisa Holguin Colorado, Samantha Dando and Katie Edwards

Biomedicines 2025, 13(7), 1675; https://doi.org/10.3390/biomedicines13071675 - 8 Jul 2025

Abstract

Background/Objectives: Painful diabetic peripheral neuropathy (pDPN) significantly impacts quality of life, yet its diagnosis remains challenging due to reliance on subjective pain reports and limited objective biomarkers. This meta-analysis evaluated corneal nerve morphology parameters; corneal nerve fibre length (CNFL), corneal nerve fibre density [...] Read more.

Background/Objectives: Painful diabetic peripheral neuropathy (pDPN) significantly impacts quality of life, yet its diagnosis remains challenging due to reliance on subjective pain reports and limited objective biomarkers. This meta-analysis evaluated corneal nerve morphology parameters; corneal nerve fibre length (CNFL), corneal nerve fibre density (CNFD), and corneal nerve branch density (CNBD), measured through in vivo confocal microscopy (IVCM), as potential tools for differentiating painful and painless forms of diabetic neuropathy. Methods: A systematic review was performed comparing corneal nerve morphology across four groups: painful diabetic neuropathy (pDPN), non-painful diabetic neuropathy (npDPN), diabetes without neuropathy (DPN-), and healthy controls. Literature search extended over MEDLINE, EMBASE, Web of Science, and Cochrane Library, focusing on studies published since 2000. Study quality was assessed using the Newcastle–Ottawa Scale, while evidence certainly followed GRADE guidelines. Random-effects meta-analyses calculated mean differences (MDs) with 95% confidence intervals (CIs) for CNFL, CNFD, and CNBD. Results: Seven observational studies comprising 803 participants (213 pDPN, 275 npDPN, 99 DPN-, and 216 controls) revealed no significant differences between pDPN and npDPN groups in CNFL (MD = 0.79, 95% CI −0.64 to 2.22), CNFD (MD = 1.67, 95% CI −0.14 to 3.47), or CNBD (MD = 1.84, 95% CI −4.31 to 7.98). However, all metrics were markedly reduced in pDPN compared to DPN- and healthy controls. Conclusions: While effective in identifying diabetic neuropathy, common corneal nerve morphology parameters cannot reliably distinguish pDPN from npDPN. This highlights the need for research into mechanisms like central sensitization, inflammation, and micro-neuromas, which could refine diagnostic and therapeutic approaches for pDPN. Full article

(This article belongs to the Special Issue Novel Biomarker and Treatments for Diabetic Neuropathy)

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14 pages, 1277 KiB

Open AccessArticle

Experimentally Constrained Mechanistic and Data-Driven Models for Simulating NMDA Receptor Dynamics

by Duy-Tan J. Pham and Jean-Marie C. Bouteiller

Biomedicines 2025, 13(7), 1674; https://doi.org/10.3390/biomedicines13071674 - 8 Jul 2025

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Abstract

Background: The N-methyl-d-aspartate receptor (NMDA-R) is a glutamate ionotropic receptor in the brain that is crucial for synaptic plasticity, which underlies learning and memory formation. Dysfunction of NMDA receptors is implicated in various neurological diseases due to their roles in both normal [...] Read more.

Background: The N-methyl-d-aspartate receptor (NMDA-R) is a glutamate ionotropic receptor in the brain that is crucial for synaptic plasticity, which underlies learning and memory formation. Dysfunction of NMDA receptors is implicated in various neurological diseases due to their roles in both normal cognition and excitotoxicity. However, their dynamics are challenging to capture accurately due to their high complexity and non-linear behavior. Methods: This article presents the elaboration and calibration of experimentally constrained computational models of GluN1/GluN2A NMDA-R dynamics: (1) a nine-state kinetic model optimized to replicate experimental data and (2) a computationally efficient look-up table model capable of replicating the dynamics of the nine-state kinetic model with a highly reduced footprint. Determination of the kinetic model’s parameter values was performed using the particle swarm optimization algorithm. The optimized kinetic model was then used to generate a rich input–output dataset to train the look-up table synapse model and estimate its coefficients. Results: Optimization produced a kinetic model capable of accurately reproducing experimentally found results such as frequency-dependent potentiation and the temporal response due to synaptic release of glutamate. Furthermore, the look-up table synapse model was able to closely mimic the dynamics of the optimized kinetic model. Conclusions: The results obtained with both models indicate that they constitute accurate alternatives for faithfully reproducing the dynamics of NMDA-Rs. High computational efficiency is also achieved with the use of the look-up table synapse model, making this implementation an ideal option for inclusion in large-scale neuronal models. Full article

(This article belongs to the Special Issue Synaptic Function and Modulation in Health and Disease)

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14 pages, 1519 KiB

Open AccessArticle

Efficacy of EA575 as an Antitussive and Mucoactive Agent in Preclinical In Vivo Models

by Matthias Hufnagel, André Rademaekers, Anika Weisert, Hanns Häberlein and Sebastian Franken

Biomedicines 2025, 13(7), 1673; https://doi.org/10.3390/biomedicines13071673 - 8 Jul 2025

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Abstract

Background: The efficacy of EA575 in the treatment of respiratory diseases is described in various clinical studies, improving patients’ disease-related symptoms. However, mechanistic in vivo data proving its beneficial effects are limited. Methods: Focusing on the treatment of acute airway inflammation and accompanying [...] Read more.

Background: The efficacy of EA575 in the treatment of respiratory diseases is described in various clinical studies, improving patients’ disease-related symptoms. However, mechanistic in vivo data proving its beneficial effects are limited. Methods: Focusing on the treatment of acute airway inflammation and accompanying cough, this study aimed to elucidate antitussive and mucoactive properties of EA575, applying two animal models. Animals were treated orally twice daily for 7 days, resulting in 43, 215.2, or 430.5 mg/kg bw/d of EA575. Antitussive effects were investigated within an acute lung inflammation model of bleomycin-treated guinea pigs after citric acid exposure. Hereby, the number of coughs, enhanced pause (penH), and bronchoalveolar lavage fluid (BALF) were investigated. Mucoactivity of EA575 was assessed within a murine model, determining phenol red concentration in BALF. Results: EA575 treatment within the acute lung inflammation model reduced cough events up to 56% while reducing inflammatory cell influx in BALF dose-dependently, e.g., reducing neutrophils in BALF up to 70.9%. This suggests a strong connection between anti-inflammatory and antitussive properties of EA575. Furthermore, penH decreased in a dose-dependent manner, suggesting an ease in respiration. Mucoactivity was shown by a dose-dependent increase in phenol red concentration in BALF up to 38.9%. Notably, EA575/salbutamol co-administration resulted in enhanced phenol red secretion compared to respective single administrations. Conclusions: These data highlight the benefits of EA575 in treating cough-related respiratory diseases, particularly when accompanied by sputum, as EA575 has been shown to obtain mucoactivity. Furthermore, the combinatory effect of EA575/salbutamol treatment provides a foundation for future research in the treatment of chronic respiratory diseases. Full article

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

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16 pages, 2332 KiB

Open AccessArticle

Serum Levels of N^ε-(Carboxymethyl)-Lysine in Chronic Kidney Disease and Type 2 Diabetes Mellitus

by Rositsa Tsekovska, Evan Gatev, Roumyana Mironova, Simona Kerezieva, Siyana Ilieva, Teodora Ilieva, Bilyana Vasileva, Toshimitsu Niwa, Daniela Popova and Vasil Vasilev

Biomedicines 2025, 13(7), 1672; https://doi.org/10.3390/biomedicines13071672 - 8 Jul 2025

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Abstract

Background: N^ε-(carboxymethyl)-lysine (CML) is formed in the human body by non-enzymatically driven reactions including glycation, oxidation, and lipoxidation. CML is a ubiquitous product of normal physiology, but its levels are increased under disease conditions like chronic kidney disease (CKD) and [...] Read more.

Background: N^ε-(carboxymethyl)-lysine (CML) is formed in the human body by non-enzymatically driven reactions including glycation, oxidation, and lipoxidation. CML is a ubiquitous product of normal physiology, but its levels are increased under disease conditions like chronic kidney disease (CKD) and diabetes mellitus (DM). Free CML is eliminated from the human body mainly through kidney excretion, and its accumulation in the kidney tissue is linked to CKD pathogenesis. Aim: The main goal of this study was to evaluate the relative contribution of CKD and Type 2 DM (T2DM) to the accumulation of CML in patients’ sera. Methods: The study included 22 patients with CKD without DM, 55 with CKD and comorbid T2DM, and 21 with T2DM without CKD. Serum CML levels were measured by ELISA. The Kruskal-Wallis test was used to detect differences among groups. Spearman correlation analysis was performed, and the one-tailed Dunn test was considered to indicate statistical significance at p < 0.05. Results: The median serum CML levels (CKD, 658.4 ± 434.3 ng/mL; CKD + T2DM, 431.3 ± 327.9 ng/mL; T2DM, 273.9 ± 134.2 ng/mL) differed significantly (p < 0.05) among the three patient groups. A positive correlation was observed between serum CML and microalbuminuria (p = 0.004; r = 0.58), proteinuria (p = 0.002; r = 0.6), and age (p = 0.007; r = 0.52) only in the CKD patients. In all T2DM patients, independent of CKD status, serum CML correlated negatively (p < 0.05) with postprandial glucose and duration of diabetes, while its correlation with fasting glucose and HbA1c was negative only in the T2DM cohort without CKD. Conclusions: In patients with CKD, higher levels of CML were observed compared to those with T2DM. Serum CML correlated positively with proteinuria, albuminuria, and patient age in non-diabetic CKD patients, and negatively with blood glucose, HbA1c, and DM duration of T2DM in patients without CKD. Full article

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

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Biomedicines, Volume 13, Issue 7 (July 2025) – 193 articles

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