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Biomedicines
Volume 13
Issue 7
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Biomedicines, Volume 13, Issue 7 (July 2025) – 279 articles

Cover Story (view full-size image): Graft-versus-host disease remains one of the most challenging complications following allogeneic stem cell transplantation. In this review, we explore how targeting the JAK2 pathway has transformed the treatment landscape for both acute and chronic GVHD, with particular focus on ruxolitinib and emerging agents under clinical investigation. We also examine the recent FDA approvals of axatilimab and remestemcel-L, which introduce new mechanisms aimed at fibrotic and inflammatory disease biology. Looking ahead, personalized strategies that combine targeted immunomodulation with biomarker-guided care offer promise for improving patient outcomes. This article outlines how evolving therapies are reshaping the field toward more durable, precise, and tolerable GVHD management. View this paper
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18 pages, 2893 KiB  
Article
Amylin Receptor 1 Mutagenesis Revealed a Potential Role of Calcitonin Serine 29 in Receptor Interaction
by Hyeseon Song, Jaehyeok Jang, Minjae Park, Junsu Yun, Jeongwoo Jin and Sangmin Lee
Biomedicines 2025, 13(7), 1787; https://doi.org/10.3390/biomedicines13071787 - 21 Jul 2025
Viewed by 488
Abstract
Background: The amylin receptor is a receptor for the peptide hormone amylin, and its activation is known to reduce body weight. The amylin receptor functions as a heterodimer complex that consists of the calcitonin receptor for peptide hormone calcitonin and an accessary protein. [...] Read more.
Background: The amylin receptor is a receptor for the peptide hormone amylin, and its activation is known to reduce body weight. The amylin receptor functions as a heterodimer complex that consists of the calcitonin receptor for peptide hormone calcitonin and an accessary protein. Although the structural information of amylin receptors is currently available, receptor–ligand binding studies that support the peptide binding mode for amylin receptors remain incomplete. Methods: Here, we introduced mutagenesis to the amylin receptor 1 extracellular domain and examined mutational effects on peptide binding affinity. We focused on several residues mainly from the peptide-binding pocket (D97, D101, E123, N124, and N135 of the calcitonin receptor). Two well-known peptide ligands for amylin receptors were used for this study: a salmon calcitonin fragment and an antagonist amylin analog AC413 fragment with Y25P mutation. Results: Among the introduced mutations, D101A and N135A mutations abolished peptide ligand binding, suggesting that these residues are critical for peptide interaction. The N124A mutation also significantly decreased the peptide binding affinity by more than 8-fold. Intriguingly, the N124D mutation restored the decreased affinity of the salmon calcitonin fragment, while it failed to restore the decreased affinity of the AC413 fragment. Structural analyses suggested that there was a potential role of salmon calcitonin serine 29 in the interaction with aspartate of the N124D mutation. Conclusions: This study validates the critical residues of the amylin receptor 1 extracellular domain for the interaction with C-terminal fragments of peptide ligands. This study also suggests that modulating receptor–ligand interaction is feasible by the modification of receptor amino acids near an interacting peptide ligand. Full article
(This article belongs to the Special Issue Exploring Protein-Ligand Interaction: Key Insights for Drug Discovery)
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15 pages, 2583 KiB  
Review
Multiparametric Ultrasound in the Differential Diagnosis of Soft Tissue Tumors: A Comprehensive Review
by Fabrizio Termite, Linda Galasso, Giacomo Capece, Federica Messina, Giorgio Esposto, Maria Elena Ainora, Irene Mignini, Raffaele Borriello, Raffaele Vitiello, Giulio Maccauro, Antonio Gasbarrini and Maria Assunta Zocco
Biomedicines 2025, 13(7), 1786; https://doi.org/10.3390/biomedicines13071786 - 21 Jul 2025
Viewed by 437
Abstract
Soft tissue tumors (STTs) are a heterogeneous group of mesenchymal neoplasms requiring accurate differentiation for optimal patient management. While histopathology remains the gold standard, imaging plays a crucial role in non-invasive assessment. Multiparametric ultrasound (mpUS) has emerged as a promising, cost-effective alternative to [...] Read more.
Soft tissue tumors (STTs) are a heterogeneous group of mesenchymal neoplasms requiring accurate differentiation for optimal patient management. While histopathology remains the gold standard, imaging plays a crucial role in non-invasive assessment. Multiparametric ultrasound (mpUS) has emerged as a promising, cost-effective alternative to MRI, integrating B-mode, color and power Doppler, shear wave elastography (SWE), and contrast-enhanced ultrasound (CEUS) to provide comprehensive morphological, vascular, and biomechanical insights. Each modality offers distinct yet complementary diagnostic value, enhancing accuracy and potentially reducing unnecessary biopsies. This narrative review aims to serve as a practical guide, providing a readily accessible reference for mpUS parameters useful in the differential diagnosis of soft tissue tumors. Full article
(This article belongs to the Special Issue Applications of Imaging Technology in Human Diseases)
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14 pages, 2459 KiB  
Article
Enhancement of Oral Mucosal Regeneration Using Human Exosomal Therapy in SD Rats
by Chien Ming Lee, Qasim Hussain, Kuo Pin Chuang and Hoang Minh
Biomedicines 2025, 13(7), 1785; https://doi.org/10.3390/biomedicines13071785 - 21 Jul 2025
Viewed by 685
Abstract
Background/Objectives: Oral cavity wound recovery presents unique challenges due to constant moisture exposure and functional mechanical stresses. Nanoscale extracellular vesicles (exosomes) with regenerative properties offer promising therapeutic potential for tissue regeneration, contributing to improved health outcomes. This study evaluated human exosomal preparations in [...] Read more.
Background/Objectives: Oral cavity wound recovery presents unique challenges due to constant moisture exposure and functional mechanical stresses. Nanoscale extracellular vesicles (exosomes) with regenerative properties offer promising therapeutic potential for tissue regeneration, contributing to improved health outcomes. This study evaluated human exosomal preparations in promoting oral mucosal regeneration. Methods: We established standardized full-thickness wounds in the buccal mucosa of SD rats and divided subjects into experimental (receiving 50 billion human exosomes) and control (receiving carrier solution only) groups. Comprehensive wound assessment occurred at predetermined intervals (days 0, 3, 7, and 10) through photographic documentation, histological examination, and quantitative measurement. Results: Exosomal-treated tissues demonstrated statistically significant acceleration in closure rates (p < 0.05), achieving 87.3% reduction by day 10 versus 64.1% in the controls. Microscopic analysis revealed superior epithelial development, reduced inflammatory infiltration, and enhanced collagen architectural organization in exosomal-treated specimens. Semi-quantitative evaluation confirmed consistently superior healing metrics in the experimental group across all assessment timepoints. Conclusions: These findings demonstrate that human exosome preparations significantly enhance oral mucosal regeneration in SD rats, suggesting potential clinical applications for accelerating recovery following oral surgical procedures. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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15 pages, 2272 KiB  
Article
Upregulation of 15-Hydroxyprostaglandin Dehydrogenase by Celecoxib to Reduce Pain After Laparoendoscopic Single-Site Surgery (POPCORN Trial): A Randomized Controlled Trial
by Kyung Hee Han, Sunwoo Park, Seungmee Lee, Jiyeon Ham, Whasun Lim, Gwonhwa Song and Hee Seung Kim
Biomedicines 2025, 13(7), 1784; https://doi.org/10.3390/biomedicines13071784 - 21 Jul 2025
Viewed by 395
Abstract
Background: Peritoneal stretching from CO2 insufflation is a primary mechanism of pain associated with laparoscopy. Cyclooxygenase-2 inhibitors are promising anti-inflammatory and analgesic agents. This study aimed to evaluate the effect of celecoxib on postoperative pain reduction and associated changes in peritoneal [...] Read more.
Background: Peritoneal stretching from CO2 insufflation is a primary mechanism of pain associated with laparoscopy. Cyclooxygenase-2 inhibitors are promising anti-inflammatory and analgesic agents. This study aimed to evaluate the effect of celecoxib on postoperative pain reduction and associated changes in peritoneal gene expression after laparoendoscopic single-site (LESS) surgery for benign gynecologic disease. Methods: In this randomized, double-blind, placebo-controlled pilot study, 70 patients were randomly assigned to receive either celecoxib or placebo (400 mg) 40 min before surgery. Peritoneal tissues were collected before and after CO2 insufflation. We analyzed changes in expressions of prostaglandin I2 synthase, prostaglandin E synthase (PTGES), PTGES3, aldo-keto reductase family 1 member C1, and 15-hydroxyprostaglandin dehydrogenase (HPGD). Numeric Rating Scale (NRS) pain scores were also compared between groups. Results: A total of 62 patients completed the study: 30 in the celecoxib group and 32 in the placebo group. The mean CO2 exposure time was 60.4 min. In a quantitative real-time polymerase chain reaction analysis, HPGD mRNA expression significantly increased after surgery in patients exposed to CO2 for more than 60 min. Patients treated with celecoxib showed a significantly higher rate of grade 3 expression (83.3% vs. 37.5%; p = 0.01) and a level 2 increase in HPGD expression on in situ hybridization (58.3% vs. 12.5%; p = 0.01), despite no significant difference on immunohistochemistry. Moreover, celecoxib effectively reduced NRS pain scores compared to placebo. Conclusions: In this pilot study, celecoxib appeared to reduce postoperative pain and was associated with increased HPGD mRNA expression in the peritoneal tissue of patients with prolonged CO2 exposure during LESS surgery. These exploratory findings warrant confirmation in larger trials with functional validation of HPGD expression (ClinicalTrials.gov, NCT03391570). Full article
(This article belongs to the Section Molecular and Translational Medicine)
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28 pages, 1358 KiB  
Review
Understanding the Borderline Brain: A Review of Neurobiological Findings in Borderline Personality Disorder (BPD)
by Eleni Giannoulis, Christos Nousis, Ioanna-Jonida Sula, Maria-Evangelia Georgitsi and Ioannis Malogiannis
Biomedicines 2025, 13(7), 1783; https://doi.org/10.3390/biomedicines13071783 - 21 Jul 2025
Viewed by 1272
Abstract
Borderline personality disorder (BPD) is a complex and heterogeneous condition characterized by emotional instability, impulsivity, and impaired regulation of interpersonal relationships. This narrative review integrates findings from recent neuroimaging, neurochemical, and treatment studies to identify core neurobiological mechanisms and highlight translational potential. Evidence [...] Read more.
Borderline personality disorder (BPD) is a complex and heterogeneous condition characterized by emotional instability, impulsivity, and impaired regulation of interpersonal relationships. This narrative review integrates findings from recent neuroimaging, neurochemical, and treatment studies to identify core neurobiological mechanisms and highlight translational potential. Evidence from 112 studies published up to 2025 is synthesized, encompassing structural MRI, resting-state and task-based functional MRI, EEG, PET, and emerging machine learning applications. Consistent disruptions are observed across the prefrontal–amygdala circuitry, the default mode network (DMN), and mentalization-related regions. BPD shows a dominant and stable pattern of hyperconnectivity in the precuneus. Transdiagnostic comparisons with PTSD and cocaine use disorder (CUD) suggest partial overlap in DMN dysregulation, though BPD-specific traits emerge in network topology. Machine learning models achieve a classification accuracy of 70–88% and may support the tracking of early treatment responses. Longitudinal fMRI studies indicate that psychodynamic therapy facilitates the progressive normalization of dorsal anterior cingulate cortex (dACC) activity and reductions in alexithymia. We discuss the role of phenotypic heterogeneity (internalizing versus externalizing profiles), the potential of neuromodulation guided by biomarkers, and the need for standardized imaging protocols. Limitations include small sample sizes, a lack of effective connectivity analyses, and minimal multicenter cohort representation. Future research should focus on constructing multimodal biomarker panels that integrate functional connectivity, epigenetics, and computational phenotyping. This review supports the use of a precision psychiatry approach for BPD by aligning neuroscience with scalable clinical tools. Full article
(This article belongs to the Section Neurobiology and Clinical Neuroscience)
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17 pages, 1009 KiB  
Article
Sex-Specific Patterns and Predictors of Reverse Left Ventricular Remodeling and Outcomes in STEMI Patients with LVEF ≤ 50% After Successful Primary Angioplasty
by Bogdan-Flaviu Buz, Sergiu-Florin Arnautu, Mirela-Cleopatra Tomescu, Minodora Andor, Simina Crisan, Dan Gaita, Cristina Vacarescu, Constantin-Tudor Luca, Cristian Mornos, Dragos Cozma and Diana-Aurora Arnăutu
Biomedicines 2025, 13(7), 1782; https://doi.org/10.3390/biomedicines13071782 - 21 Jul 2025
Viewed by 357
Abstract
Background: Sex-related differences in left ventricular (LV) reverse remodeling following ST-segment elevation myocardial infarction (STEMI) remain underexplored. We aimed to investigate predictors of reverse remodeling and its association with clinical outcomes, with a focus on sex-specific differences. Methods: We enrolled 253 [...] Read more.
Background: Sex-related differences in left ventricular (LV) reverse remodeling following ST-segment elevation myocardial infarction (STEMI) remain underexplored. We aimed to investigate predictors of reverse remodeling and its association with clinical outcomes, with a focus on sex-specific differences. Methods: We enrolled 253 STEMI patients (91 women, 28%) and assessed echocardiographic parameters at baseline and six months. LV reverse remodeling was defined as a ≥15% reduction in LV end-diastolic volume (LVEDV). Multivariate logistic regression identified independent predictors of remodeling. Clinical outcomes were evaluated over a median follow-up of 17 months (IQR 14–22 months), including major adverse cardiac events (MACEs). Kaplan–Meier and Cox regression analyses were performed. Results: Reverse remodeling occurred in 43% of patients and was more frequent in men than women (47% vs. 37%, p = 0.04). Male sex (OR 0.30; 95% CI: 0.14–0.65; p < 0.0001) and baseline global work efficiency (GWE) (OR 1.64; 95% CI: 1.45–1.85; p < 0.0001) were independent predictors. Men exhibited greater reductions in LVEDV, greater improvements in LV ejection fraction, and superior myocardial work indices. Over the follow-up, patients with reverse remodeling had significantly lower MACE rates compared to those without (10% vs. 24%, p < 0.01). Cox regression demonstrated that reverse remodeling was associated with a reduced risk of MACEs (HR 0.318; 95% CI: 0.181–0.557; p < 0.0001). Conclusions: LV reverse remodeling after STEMI is associated with improved clinical outcomes and is influenced by sex-specific differences. Baseline myocardial work indices, particularly GWE, are strong predictors of reverse remodeling. Men demonstrated a more favorable remodeling profile and myocardial recovery compared to women. Full article
(This article belongs to the Special Issue Women’s Special Issue Series: Biomedicines (2nd Edition))
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15 pages, 766 KiB  
Article
Photobiomodulation Therapy Reduces Oxidative Stress and Inflammation to Alleviate the Cardiotoxic Effects of Doxorubicin in Human Stem Cell-Derived Ventricular Cardiomyocytes
by Guilherme Rabelo Nasuk, Leonardo Paroche de Matos, Allan Luís Barboza Atum, Bruna Calixto de Jesus, Julio Gustavo Cardoso Batista, Gabriel Almeida da Silva, Antonio Henrique Martins, Maria Laura Alchorne Trivelin, Cinthya Cosme Gutierrez Duran, Ana Paula Ligeiro de Oliveira, Renato de Araújo Prates, Rodrigo Labat Marcos, Stella Regina Zamuner, Ovidiu Constantin Baltatu and José Antônio Silva, Jr.
Biomedicines 2025, 13(7), 1781; https://doi.org/10.3390/biomedicines13071781 - 21 Jul 2025
Viewed by 541
Abstract
Background/Objectives: Doxorubicin (DOX), a widely used anthracycline chemotherapeutic agent, is recognized for its efficacy in treating various malignancies. However, its clinical application is critically limited due to dose-dependent cardiotoxicity, predominantly induced by oxidative stress and compromised antioxidant defenses. Photobiomodulation (PBM), a non-invasive intervention [...] Read more.
Background/Objectives: Doxorubicin (DOX), a widely used anthracycline chemotherapeutic agent, is recognized for its efficacy in treating various malignancies. However, its clinical application is critically limited due to dose-dependent cardiotoxicity, predominantly induced by oxidative stress and compromised antioxidant defenses. Photobiomodulation (PBM), a non-invasive intervention that utilizes low-intensity light, has emerged as a promising therapeutic modality in regenerative medicine, demonstrating benefits such as enhanced tissue repair, reduced inflammation, and protection against oxidative damage. This investigation sought to evaluate the cardioprotective effects of PBM preconditioning in human-induced pluripotent stem cell-derived ventricular cardiomyocytes (hiPSC-vCMs) subjected to DOX-induced toxicity. Methods: Human iPSC-vCMs were allocated into three experimental groups: control cells (untreated), DOX-treated cells (exposed to 2 μM DOX for 24 h), and PBM+DOX-treated cells (preconditioned with PBM, utilizing 660 nm ±10 nm LED light at an intensity of 10 mW/cm2 for 500 s, delivering an energy dose of 5 J/cm2, followed by DOX exposure). Cell viability assessments were conducted in conjunction with evaluations of oxidative stress markers, including antioxidant enzyme activities and malondialdehyde (MDA) levels. Furthermore, transcriptional profiling of 40 genes implicated in cardiac dysfunction was performed using TaqMan quantitative polymerase chain reaction (qPCR), complemented by analyses of protein expression for markers of cardiac stress, inflammation, and apoptosis. Results: Exposure to DOX markedly reduced the viability of hiPSC-vCMs. The cells exhibited significant alterations in the expression of 32 out of 40 genes (80%) after DOX exposure, reflecting the upregulation of markers associated with apoptosis, inflammation, and adverse cardiac remodeling. PBM preconditioning partially restored the cell viability, modulating the expression of 20 genes (50%), effectively counteracting a substantial proportion of the dysregulation induced by DOX. Notably, PBM enhanced the expression of genes responsible for antioxidant defense, augmented antioxidant enzyme activity, and reduced oxidative stress indicators such as MDA levels. Additional benefits included downregulating stress-related mRNA markers (HSP1A1 and TNC) and apoptotic markers (BAX and TP53). PBM also demonstrated gene reprogramming effects in ventricular cells, encompassing regulatory changes in NPPA, NPPB, and MYH6. PBM reduced the protein expression levels of IL-6, TNF, and apoptotic markers in alignment with their corresponding mRNA expression profiles. Notably, PBM preconditioning showed a diminished expression of BNP, emphasizing its positive impact on mitigating cardiac stress. Conclusions: This study demonstrates that PBM preconditioning is an effective strategy for reducing DOX-induced chemotherapy-related cardiotoxicity by enhancing cell viability and modulating signaling pathways associated with oxidative stress, as well as inflammatory and hypertrophic markers. Full article
(This article belongs to the Special Issue Pathological Biomarkers in Precision Medicine)
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21 pages, 594 KiB  
Review
PEDF and Its Role in Metabolic Disease, Angiogenesis, Cardiovascular Disease, and Diabetes
by Crispin R. Dass
Biomedicines 2025, 13(7), 1780; https://doi.org/10.3390/biomedicines13071780 - 21 Jul 2025
Viewed by 485
Abstract
This review highlights recent findings on the potent anti-angiogenic serpin protein, pigment epithelium-derived factor (PEDF) as it relates to metabolic disease, diabetes, angiogenesis and cardiovascular disease (CVD), listing a majority of all the publicly available studies reported to date. PEDF is involved in [...] Read more.
This review highlights recent findings on the potent anti-angiogenic serpin protein, pigment epithelium-derived factor (PEDF) as it relates to metabolic disease, diabetes, angiogenesis and cardiovascular disease (CVD), listing a majority of all the publicly available studies reported to date. PEDF is involved in various physiological roles in the body, and when awry, it triggers various disease states clinically. Biomarkers such as insulin, AMP-activated protein kinase alpha (AMPK-α), and peroxisome proliferator-activated receptor gamma (PPAR-γ) are involved in PEDF effects on metabolism. Wnt, insulin receptor substate (IRS), Akt, extracellular signal-regulated kinase (ERK), and mitogen-activated protein kinase (MAPK) are implicated in diabetes effects displayed by PEDF. For CVD, oxidised LDL, Wnt/β-catenin, and reactive oxygen species (ROS) are players intertwined with PEDF activity. The review also presents an outlook on where efforts could be devoted to bring this serpin closer to clinical trials for these diseases and others in general. Full article
(This article belongs to the Special Issue New Advances in Cardiovascular Drugs: In Memory of Professor Akira Endo)
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19 pages, 1204 KiB  
Review
Immunomodulatory Effects of RAAS Inhibitors: Beyond Hypertension and Heart Failure
by Raluca Ecaterina Haliga, Elena Cojocaru, Oana Sîrbu, Ilinca Hrițcu, Raluca Elena Alexa, Ioana Bianca Haliga, Victorița Șorodoc and Adorata Elena Coman
Biomedicines 2025, 13(7), 1779; https://doi.org/10.3390/biomedicines13071779 - 21 Jul 2025
Viewed by 574
Abstract
The renin–angiotensin–aldosterone system (RAAS) plays a central role in cardiovascular and renal homeostasis and is increasingly recognized for its broad immunomodulatory effects. Pharmacological RAAS inhibition, primarily via angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), has demonstrated therapeutic value beyond its use [...] Read more.
The renin–angiotensin–aldosterone system (RAAS) plays a central role in cardiovascular and renal homeostasis and is increasingly recognized for its broad immunomodulatory effects. Pharmacological RAAS inhibition, primarily via angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), has demonstrated therapeutic value beyond its use in hypertension and heart failure, extending to autoimmune, infectious, oncologic, and neurodegenerative conditions. ACEIs and ARBs modulate both innate and adaptive immune responses through Ang II-dependent and -independent mechanisms, influencing macrophage polarization, T-cell differentiation, cytokine expression, and antigen presentation. Notably, ACEIs exhibit Ang II-independent effects by enhancing antigen processing and regulating amyloid-β metabolism, offering potential neuroprotective benefits in Alzheimer’s disease. ARBs, particularly telmisartan and candesartan, provide additional anti-inflammatory effects via PPARγ activation. In cancer, RAAS inhibition affects tumor growth, angiogenesis, and immune surveillance, with ACEIs and ARBs showing distinct yet complementary impacts on tumor microenvironment modulation and chemotherapy cardioprotection. Moreover, ACEIs have shown promise in autoimmune myocarditis, colitis, and diabetic nephropathy by attenuating inflammatory cytokines. While clinical evidence supports the use of centrally acting ACEIs to treat early cognitive decline, further investigation is warranted to determine the long-term outcomes across disease contexts. These findings highlight the evolving role of RAAS inhibitors as immunomodulatory agents with promising implications across multiple systemic pathologies. Full article
(This article belongs to the Special Issue Renin-Angiotensin System in Cardiovascular Biology, 2nd Edition)
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19 pages, 507 KiB  
Review
Radiomics and Radiogenomics in Differentiating Progression, Pseudoprogression, and Radiation Necrosis in Gliomas
by Sohil Reddy, Tyler Lung, Shashank Muniyappa, Christine Hadley, Benjamin Templeton, Joel Fritz, Daniel Boulter, Keshav Shah, Raj Singh, Simeng Zhu, Jennifer K. Matsui and Joshua D. Palmer
Biomedicines 2025, 13(7), 1778; https://doi.org/10.3390/biomedicines13071778 - 21 Jul 2025
Viewed by 564
Abstract
Over recent decades, significant advancements have been made in the treatment and imaging of gliomas. Conventional imaging techniques, such as MRI and CT, play critical roles in glioma diagnosis and treatment but often fail to distinguish between tumor pseudoprogression (Psp) and radiation necrosis [...] Read more.
Over recent decades, significant advancements have been made in the treatment and imaging of gliomas. Conventional imaging techniques, such as MRI and CT, play critical roles in glioma diagnosis and treatment but often fail to distinguish between tumor pseudoprogression (Psp) and radiation necrosis (RN) versus true progression (TP). Emerging fields like radiomics and radiogenomics are addressing these challenges by extracting quantitative features from medical images and correlating them with genomic data, respectively. This article will discuss several studies that show how radiomic features (RFs) can aid in better patient stratification and prognosis. Radiogenomics, particularly in predicting biomarkers such as MGMT promoter methylation and 1p/19q codeletion, shows potential in non-invasive diagnostics. Radiomics also offers tools for predicting tumor recurrence (rBT), essential for treatment management. Further research is needed to standardize these methods and integrate them into clinical practice. This review underscores radiomics and radiogenomics’ potential to revolutionize glioma management, marking a significant shift towards precision neuro-oncology. Full article
(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Gliomas)
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17 pages, 659 KiB  
Review
Insights into the Molecular Mechanisms and Novel Therapeutic Strategies of Stenosis Fibrosis in Crohn’s Disease
by Yuan Zhou, Huiping Chen, Qinbo Wang, Guozeng Ye, Yingjuan Ou, Lihong Huang, Xia Wu and Jiaxi Fei
Biomedicines 2025, 13(7), 1777; https://doi.org/10.3390/biomedicines13071777 - 21 Jul 2025
Viewed by 488
Abstract
Crohn’s disease (CD), characterized by chronic gastrointestinal inflammation, is complicated by intestinal stenosis resulting from dysregulated fibrogenesis and is marked by excessive extracellular matrix (ECM) deposition, fibroblast activation, and luminal obstruction. While biologics control inflammation, their failure to halt fibrosis underscores a critical [...] Read more.
Crohn’s disease (CD), characterized by chronic gastrointestinal inflammation, is complicated by intestinal stenosis resulting from dysregulated fibrogenesis and is marked by excessive extracellular matrix (ECM) deposition, fibroblast activation, and luminal obstruction. While biologics control inflammation, their failure to halt fibrosis underscores a critical therapeutic void. Emerging evidence highlights the multifactorial nature of stenosis-associated fibrosis, driven by profibrotic mediators and dysregulated crosstalk among immune, epithelial, and mesenchymal cells. Key pathways, including transforming growth factor (TGF-β), drosophila mothers against decapentaplegic protein (Smad) signaling, Wnt/β-catenin activation, epithelial–mesenchymal transition (EMT), and matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinase (TIMP)-mediated ECM remodeling, orchestrate fibrotic progression. Despite the current pharmacological, endoscopic, and surgical interventions for fibrostenotic CD, their palliative nature and inability to reverse fibrosis highlight an unmet need for disease-modifying therapies. This review synthesizes mechanistic insights, critiques therapeutic limitations with original perspectives, and proposes a translational roadmap prioritizing biomarker-driven stratification, combinatorial biologics, and mechanistically targeted antifibrotics. 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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24 pages, 921 KiB  
Review
Neuromodulation of the Cardiac Autonomic Nervous System for Arrhythmia Treatment
by Benjamin Wong, Yuki Kuwabara and Siamak Salavatian
Biomedicines 2025, 13(7), 1776; https://doi.org/10.3390/biomedicines13071776 - 21 Jul 2025
Viewed by 833
Abstract
This review explores current and emerging neuromodulation techniques targeting the cardiac autonomic nervous system for the treatment and prevention of atrial and ventricular arrhythmias. Arrhythmias remain a significant cause of morbidity and mortality, with the autonomic nervous system playing a crucial role in [...] Read more.
This review explores current and emerging neuromodulation techniques targeting the cardiac autonomic nervous system for the treatment and prevention of atrial and ventricular arrhythmias. Arrhythmias remain a significant cause of morbidity and mortality, with the autonomic nervous system playing a crucial role in arrhythmogenesis. Interventions span surgical, pharmacological, and bioelectronic methods. We discuss the range of neuromodulation methods targeting the stellate ganglion, the spinal region, the parasympathetic system, and other promising methods. These include stellate ganglion block, stellate ganglion ablation, cardiac sympathetic denervation, subcutaneous electrical stimulation, thoracic epidural anesthesia, spinal cord stimulation, dorsal root ganglion stimulation, vagus nerve stimulation, baroreflex activation therapy, carotid body ablation, renal denervation, ganglionated plexi ablation, acupuncture, and transcutaneous magnetic stimulation. Both preclinical and clinical studies are presented as evidence for arrhythmia management. Full article
(This article belongs to the Special Issue Cardiac Arrhythmias and Arrhythmogenic Disorders: Technological Frontiers, Drug Development and Future Directions)
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20 pages, 4705 KiB  
Article
GRK5 as a Novel Therapeutic Target for Immune Evasion in Testicular Cancer: Insights from Multi-Omics Analysis and Immunotherapeutic Validation
by Congcong Xu, Qifeng Zhong, Nengfeng Yu, Xuqiang Zhang, Kefan Yang, Hao Liu, Ming Cai and Yichun Zheng
Biomedicines 2025, 13(7), 1775; https://doi.org/10.3390/biomedicines13071775 - 21 Jul 2025
Viewed by 410
Abstract
Background: Personalized anti-tumor therapy that activates the immune response has demonstrated clinical benefits in various cancers. However, its efficacy against testicular cancer (TC) remains uncertain. This study aims to identify suitable patients for anti-tumor immunotherapy and to uncover potential therapeutic targets in TC [...] Read more.
Background: Personalized anti-tumor therapy that activates the immune response has demonstrated clinical benefits in various cancers. However, its efficacy against testicular cancer (TC) remains uncertain. This study aims to identify suitable patients for anti-tumor immunotherapy and to uncover potential therapeutic targets in TC for the development of tailored anti-tumor immunotherapy. Methods: Consensus clustering analysis was conducted to delineate immune subtypes, while weighted gene co-expression network analysis (WGCNA), least absolute shrinkage and selection operator (LASSO) regression, and support vector machine (SVM) algorithms were employed to evaluate the potential efficacy of anti-tumor immunotherapy. Candidate immunotherapy targets were systematically identified through multi-gene panel analyses and subsequently validated using molecular biology assays. A prioritized target emerging from cellular screening was further evaluated for its capacity to potentiate anti-tumor immunity. The therapeutic efficacy of this candidate was rigorously confirmed through a comprehensive suite of immunological experiments. Results: Following systematic screening of five candidate genes (WNT11, FAM181B, GRK5, FSCN1, and ECHS1), GRK5 emerged as a promising therapeutic target for immunotherapy based on its distinct functional and molecular associations with immune evasion mechanisms. Cellular functional assays revealed that GRK5 knockdown significantly attenuated the malignant phenotype of testicular cancer cells, as evidenced by reduced proliferative capacity and invasive potential. Complementary immunological validation established that specific targeting of GRK5 with the selective antagonist GRK5-IN-2 disrupts immune evasion pathways in testicular cancer, as quantified by T-cell-mediated cytotoxicity. Conclusions: These findings position GRK5 as a critical modulator of tumor-immune escape, warranting further preclinical exploration of GRK5-IN-2 as a candidate immunotherapeutic agent. Full article
(This article belongs to the Section Immunology and Immunotherapy)
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29 pages, 15117 KiB  
Article
Reduction in SH-SY5Y Cell Stress Induced by Corticosterone and Attenuation of the Inflammatory Response in RAW 264.7 Cells Using Endomorphin Analogs
by Renata Perlikowska, Angelika Długosz-Pokorska, Małgorzata Domowicz, Sylwia Grabowicz, Mariusz Stasiołek and Małgorzata Zakłos-Szyda
Biomedicines 2025, 13(7), 1774; https://doi.org/10.3390/biomedicines13071774 - 20 Jul 2025
Viewed by 508
Abstract
Background: To identify drug candidates that reduce cellular stress, linear peptides known as endomorphin (EM) analogs containing proline surrogates in position 2 were tested in in vitro injury models induced by corticosterone (CORT). Methods: In this study, neuroblastoma (SH-SY5Y) cells were treated with [...] Read more.
Background: To identify drug candidates that reduce cellular stress, linear peptides known as endomorphin (EM) analogs containing proline surrogates in position 2 were tested in in vitro injury models induced by corticosterone (CORT). Methods: In this study, neuroblastoma (SH-SY5Y) cells were treated with CORT and synthesized peptides, and then the cell viability and morphology, reactive oxygen species production (ROS), mitochondrial membrane potential (ΔΨm), adenosine triphosphate (ATP), and intracellular calcium ion [Ca2+]i levels were evaluated. We also conducted an in-depth analysis of the apoptosis markers using quantitative real-time PCR (qPCR). Finally, we explore the brain-derived neurotrophic factor (BDNF) expression (qPCR) and protein levels (ELI-SA and Western blot). Results: The strongest neuroprotective effect in the CORT-induced stress model was shown by peptide 3 and peptide 7 (in the following sequence Tyr-Inp-Trp-Phe-NH2 and Tyr-Inp-Phe-Phe-NH2, respectively). These peptides significantly improved cell viability and reduced oxidative stress in CORT-treated cells. Conclusions: Their neuroprotective potential appears linked to anti-apoptotic effects, along with in-creased BDNF expression. Moreover, in the lipopolysaccharide (LPS)- and interferon-γ (IFN-γ)-induced damage model in macrophage RAW 264.7 cells, these two peptides reduced the secretion of inflammatory mediators nitric oxide (NO), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). Peptides exhibiting both neuroprotective and anti-inflammatory properties warrant further investigation as potential therapeutic agents. Full article
(This article belongs to the Special Issue New Molecular Insights into the Pathogenesis and Drug Development of Neurodegenerative Diseases: 2nd Edition)
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28 pages, 2909 KiB  
Review
State of the Art in Pulmonary Arterial Hypertension: Molecular Basis, Imaging Modalities, and Right Heart Failure Treatment
by Melika Shafeghat, Yasmin Raza, Roberta Catania, Amir Ali Rahsepar, Blair Tilkens, Michael J. Cuttica, Benjamin H. Freed, Jingbo Dai, You-Yang Zhao and James C. Carr
Biomedicines 2025, 13(7), 1773; https://doi.org/10.3390/biomedicines13071773 - 20 Jul 2025
Viewed by 1004
Abstract
Pulmonary hypertension (PH) is broadly defined as a mean pulmonary arterial pressure (mPAP) exceeding 20 mm Hg at rest. Pulmonary arterial hypertension (PAH) is a specific subset of PH characterized by a normal pulmonary arterial wedge pressure (PAWP), combined with elevated mPAP and [...] Read more.
Pulmonary hypertension (PH) is broadly defined as a mean pulmonary arterial pressure (mPAP) exceeding 20 mm Hg at rest. Pulmonary arterial hypertension (PAH) is a specific subset of PH characterized by a normal pulmonary arterial wedge pressure (PAWP), combined with elevated mPAP and increased pulmonary vascular resistance (PVR), without other causes of pre-capillary hypertension such as lung diseases or chronic thromboembolic pulmonary hypertension. The majority of PAH cases are idiopathic; other common etiologies include connective tissue disease-associated PAH, congenital heart disease, and portopulmonary hypertension. To a lesser extent, genetic and familial forms of PAH can also occur. The pathophysiology of PAH involves the following four primary pathways: nitric oxide, endothelin-1, prostacyclin, and activin/bone morphogenetic protein (BMP). Dysregulation of these pathways leads to a progressive vasculopathy marked by vasoconstriction, vascular proliferation, elevated right heart afterload, and ultimately right-sided heart failure. Diagnosing PAH is challenging and often occurs at advanced stages. The gold standard for diagnosis remains invasive right heart catheterization. Along with invasive hemodynamic measurements, several noninvasive imaging modalities such as echocardiography and ventilation-perfusion scanning are key adjunct techniques. Also, recent advancements in cardiac magnetic resonance (CMR) have opened a new era for PAH management. Additionally, CMR and echocardiography not only enable diagnosis but also aid in evaluating disease severity and monitoring treatment responses. Current PAH treatments focus on targeting molecular pathways, reducing inflammation, and inhibiting right-sided heart failure. Integrating imaging with basic science techniques is crucial for enhanced patient diagnosis, and precision medicine is emerging as a key strategy in PAH management. Additionally, the incorporation of artificial intelligence into both molecular and imaging approaches holds significant potential. There is a growing need to integrate new imaging modalities with high resolution and reduced radiation exposure into clinical practice. In this review, we discuss the molecular pathways involved in PAH, the imaging modalities utilized for diagnosis and monitoring, and current targeted therapies. Advances in molecular understanding and imaging technologies, coupled with precision medicine, could hold promise in improving patient outcomes and revolutionizing the management of PAH patients. Full article
(This article belongs to the Special Issue Pulmonary Arterial Hypertension: From Molecular Basis to Therapeutic Approaches)
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Graphical abstract

11 pages, 1466 KiB  
Communication
Do Rats Have Epicardial Adipose Tissue?
by Magdalena Kleszczewska, Katarzyna Czarzasta, Liana Puchalska, Łukasz Koperski, Agnieszka Cudnoch-Jędrzejewska and Małgorzata Wojciechowska
Biomedicines 2025, 13(7), 1772; https://doi.org/10.3390/biomedicines13071772 - 20 Jul 2025
Viewed by 380
Abstract
The most frequently used laboratory animals for studies on adipose tissue properties and obesity are rodents. However, there are significant differences in the types of visceral fat depots between rodents and humans, including fat depots in the heart area. The large human fat [...] Read more.
The most frequently used laboratory animals for studies on adipose tissue properties and obesity are rodents. However, there are significant differences in the types of visceral fat depots between rodents and humans, including fat depots in the heart area. The large human fat depot of greatest interest in cardiac research is the epicardial adipose tissue (EAT). Its properties are widely investigated, because the EAT lies directly on the heart’s surface and can easily affect myocardial physiology. The major fat depot in rodents‘ chest—pericardial fat—is located on the ventral surface of the parietal lamina of the pericardium and is often incorrectly referred to as the EAT. Further confusion arises from reports claiming that rodents are entirely devoid of the EAT. We decided to verify adipose tissues in the heart area of 16 male Sprague Dawley rats under physiological conditions and in obesity. The animals in the NFD group (n = 8) were fed with a standard diet while these in the HFD group (n = 8) were fed with a high-fat diet (31% fat) starting from 4 weeks after birth. When the animals reached 12 weeks, the presence of fat deposits was verified. Additionally, their blood was collected to characterize carbohydrate and lipid metabolism changes, adipokine profile alterations, and their systemic inflammation status. The obesogenic diet caused significant disturbances in their carbohydrate and lipid metabolism, as well as hyperleptinemia. A high-fat diet primarily promoted the accumulation of pericardial fat, which was absent in the NFD rats and observed in 6 out of the 8 HFD animals. In both groups, adipocytes were also found directly on the hearts’ surfaces (EAT), albeit in very small numbers and limited to the atrioventricular groove on the dorsal side of the hearts. These adipocytes were dispersed among the vessels, making quantitative assessment and separation difficult, however, macroscopic evaluation revealed no noticeable differences in its extent. In conclusion, although rats are not entirely devoid of the EAT, their suitability for studying the properties of the EAT appears to be considerably limited. Full article
(This article belongs to the Section Cell Biology and Pathology)
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15 pages, 785 KiB  
Review
Systemic Sclerosis: A Key Model of Endothelial Dysfunction
by Vincenzo Zaccone, Lorenzo Falsetti, Silvia Contegiacomo, Serena Cataldi, Devis Benfaremo and Gianluca Moroncini
Biomedicines 2025, 13(7), 1771; https://doi.org/10.3390/biomedicines13071771 - 19 Jul 2025
Viewed by 532
Abstract
Systemic sclerosis (SSc) is a heterogeneous disease characterized by vascular alterations, immune dysregulation, and fibrosis. Solid evidence supports the hypothesis that endothelial dysfunction is the key player in SSc vascular injury and a critical factor concurring to the initiation of SSc pathogenesis. This [...] Read more.
Systemic sclerosis (SSc) is a heterogeneous disease characterized by vascular alterations, immune dysregulation, and fibrosis. Solid evidence supports the hypothesis that endothelial dysfunction is the key player in SSc vascular injury and a critical factor concurring to the initiation of SSc pathogenesis. This narrative review reports on persistent endothelial dysfunction, resulting from oxidative stress, autoimmunity, and impaired vascular repair, in the course of SSc, and how it can trigger and sustain fibrotic remodeling of various organs. In this paper, we also analyze the impact on SSc of impaired angiogenesis and vasculogenesis, diminished endothelial progenitor cell function, and endothelial-to-mesenchymal transition, which can collectively disrupt vascular homeostasis and promote myofibroblast activation. These pathologic events underlie the hallmark clinical manifestations, i.e., Raynaud’s phenomenon, digital ulcers, pulmonary arterial hypertension, and scleroderma renal crisis. The review highlights how recognizing SSc as a paradigm of systemic endothelial dysfunction may reframe our understanding of its physiopathology, modify current therapeutic strategies, and unveil new therapeutic targets. Full article
(This article belongs to the Special Issue Role of Endothelial Cells in Cardiovascular Disease—2nd Edition)
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16 pages, 886 KiB  
Perspective
The Effects of Adipose Tissue Dysregulation on Type 2 Diabetes Mellitus
by Jamie Rausch, Kaitlyn E. Horne and Luis Marquez
Biomedicines 2025, 13(7), 1770; https://doi.org/10.3390/biomedicines13071770 - 19 Jul 2025
Viewed by 551
Abstract
Internationally, the prevalence of type 2 diabetes mellitus (T2DM) and obesity rates are increasing significantly. As these epidemics continue to spread, the continuation of further research is paramount given that chronic diseases, such as T2DM, cause strain on both economies and healthcare systems. [...] Read more.
Internationally, the prevalence of type 2 diabetes mellitus (T2DM) and obesity rates are increasing significantly. As these epidemics continue to spread, the continuation of further research is paramount given that chronic diseases, such as T2DM, cause strain on both economies and healthcare systems. Recently, adipose tissue has been identified as an endocrine organ that produces many hormones that influence many bodily processes. Adipose tissue dysregulation (ATD)—when adipokines (adipose tissue hormones) are produced in abnormal amounts—plays an important role in T2DM development, progression, and prognosis. This narrative review focuses on mechanisms linking ATD with T2DM through adipokine actions (specifically, leptin and adiponectin) on insulin resistance and glucose metabolism. Here we show that the adipokines leptin and adiponectin are valuable in monitoring, diagnosing, and treating diseases. Further, their ratio (the leptin-to-adiponectin ratio, or LAR) may be more valuable than either adipokine individually. The LAR may give researchers the ability to utilize a primary prevention approach by utilizing LAR as a biomarker influencing early prognosis and treatment. Targeting ATD through diet, weight loss, physical activity, etc., may improve prevention and management outcomes for patients living with or at risk of T2DM. Full article
(This article belongs to the Special Issue Biomarkers in Metabolic Disorders, Obesity and Type 2 Diabetes Mellitus)
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23 pages, 1654 KiB  
Review
The Small Intestinal Microbiota and the Gut–Brain Axis in Parkinson’s Disease: A Narrative Review
by Gloria Carrossa, Valentina Misenti, Sofia Faggin, Maria Cecilia Giron and Angelo Antonini
Biomedicines 2025, 13(7), 1769; https://doi.org/10.3390/biomedicines13071769 - 19 Jul 2025
Viewed by 849
Abstract
Researchers are increasingly focusing on understanding the microbiota’s influence on disease susceptibility and overall health. The vast number of microorganisms in our gastrointestinal tract and their extensive surface area underscore their undeniable impact on well-being. Viewing the gut microbiome as a distinct pool [...] Read more.
Researchers are increasingly focusing on understanding the microbiota’s influence on disease susceptibility and overall health. The vast number of microorganisms in our gastrointestinal tract and their extensive surface area underscore their undeniable impact on well-being. Viewing the gut microbiome as a distinct pool of microbial genetic information that interacts with the human genome highlights its pivotal role in genetically predisposed diseases. Investigating this complex crosstalk may lead to the development of novel therapeutic strategies—such as targeting dysbiosis—to complement conventional treatments and improve patient care. Parkinson’s disease (PD) is a multifactorial condition originating from a combination of genetic and environmental risk factors. Compelling evidence points to the enteric nervous system as an initial site of pathological processes that later extend to the brain—a pattern known as the ‘body-first’ model. Furthermore, most patients with PD exhibit both qualitative and quantitative alterations in the composition of the gut microbiota, including dysbiosis and small intestinal overgrowth. Nonetheless, the existing literature predominantly addresses fecal microbiota, while knowledge of upper intestinal sections, like the duodenum, remains scarce. Given the potential for microbiota modulation to impact both motor and gastrointestinal symptoms, further research exploring the therapeutic roles of balanced diets, probiotics, and fecal transplants in PD is warranted. Full article
(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development: 2nd Edition)
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12 pages, 433 KiB  
Systematic Review
Advancements in Cervical Cancer Screening: Enhancing HPV Testing and Triage Strategies for Improved Risk Assessment
by Yana Merdzhanova-Gargova, Magdalena Ivanova, Angelina Mollova-Kysebekirova, Anna Mihaylova, Nikoleta Parahuleva-Rogacheva, Ekaterina Uchikova and Mariya Koleva-Ivanova
Biomedicines 2025, 13(7), 1768; https://doi.org/10.3390/biomedicines13071768 - 18 Jul 2025
Viewed by 598
Abstract
Background/Objectives: Cervical cancer remains a significant global health issue, with high incidence and mortality rates, particularly in Eastern Europe. Despite the availability of vaccines against human papillomavirus (HPV), regular screening remains crucial for prevention. Testing for HPV, alone or combined with cytology, has [...] Read more.
Background/Objectives: Cervical cancer remains a significant global health issue, with high incidence and mortality rates, particularly in Eastern Europe. Despite the availability of vaccines against human papillomavirus (HPV), regular screening remains crucial for prevention. Testing for HPV, alone or combined with cytology, has become an alternative to traditional methods. However, since many HPV infections are transient, additional tests are needed to identify high-risk cases. Methods: This study aims to generate detailed statistical data specific to the Bulgarian population, reinforcing the necessity of incorporating updated European methodologies and algorithms for the prophylaxis and prevention of cervical carcinoma. Results: By evaluating epidemiological trends, risk factors, and the effectiveness of current preventive measures, this research seeks to provide a strong foundation for enhancing cervical cancer screening and early detection programs. This method improves triage by identifying women who require further evaluation, ensuring timely referrals for colposcopy or biopsy. Conclusions: While liquid-based cytology (LBC) and HPV genotyping improve detection, the introduction of p16/Ki-67 dual staining has enhanced risk stratification, offering higher sensitivity and specificity for detecting high-grade lesions. These advancements are improving cervical cancer screening and patient outcomes. Full article
(This article belongs to the Section Cancer Biology and Oncology)
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14 pages, 2083 KiB  
Article
GDF-15 Levels in Gouty Arthritis and Correlations with Decreasing Renal Function: A Clinical Study
by Osman Cure, Ertugrul Yigit, Merve Huner Yigit and Hakki Uzun
Biomedicines 2025, 13(7), 1767; https://doi.org/10.3390/biomedicines13071767 - 18 Jul 2025
Viewed by 490
Abstract
Background/Objectives: Gouty arthritis (GA) is a chronic inflammatory disorder frequently linked to systemic inflammation and impaired kidney function. Growth differentiation factor-15 (GDF-15) has been suggested as a potential biomarker involved in both inflammatory responses and renal dysfunction. Studies on GDF-15 serum levels [...] Read more.
Background/Objectives: Gouty arthritis (GA) is a chronic inflammatory disorder frequently linked to systemic inflammation and impaired kidney function. Growth differentiation factor-15 (GDF-15) has been suggested as a potential biomarker involved in both inflammatory responses and renal dysfunction. Studies on GDF-15 serum levels and renal function decline in GA patients are limited. This study aimed to investigate serum GDF-15 levels in patients with GA and to evaluate the relationship between GDF-15 and renal function parameters. Methods: This prospective case–control study included 60 (intercritical group: 30; acute attack group: 30) patients with gout arthritis and 60 healthy controls, matched for body mass index and sex. The enzyme-linked immunosorbent assay measured serum GDF-15, and renal function and inflammatory markers were also assessed. Group comparisons used non-parametric tests, Spearman’s analysis evaluated correlations, and receiver operating characteristic (ROC) analysis assessed diagnostic performance. Results: Serum GDF-15 levels were significantly higher in GA patients than controls (p < 0.001), especially during acute attacks. GDF-15 correlated moderately with renal function markers. ROC analysis showed high diagnostic accuracy for both acute (area under the curve (AUC) = 0.98) and intercritical gout phases (AUC = 0.96). Conclusions: Serum GDF-15 levels are increased in patients with gouty arthritis and are associated with impaired renal function. GDF-15 may serve as a helpful biomarker for disease activity and renal involvement in GA, but its interpretation should be considered in conjunction with other clinical and laboratory parameters. Full article
(This article belongs to the Special Issue Emerging Trends in Kidney Disease)
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19 pages, 1329 KiB  
Review
Autosomal Dominant Polycystic Kidney Disease: From Pathogenesis to Organoid Disease Models
by Alexandru Scarlat, Susanna Tomasoni and Piera Trionfini
Biomedicines 2025, 13(7), 1766; https://doi.org/10.3390/biomedicines13071766 - 18 Jul 2025
Viewed by 715
Abstract
Mutations in PKD1 and PKD2 cause autosomal dominant polycystic kidney disease (ADPKD), the most common renal genetic disease, leading to the dysregulation of renal tubules and the development of cystic growth that compromises kidney function. Despite significant advances in recent decades, there remains [...] Read more.
Mutations in PKD1 and PKD2 cause autosomal dominant polycystic kidney disease (ADPKD), the most common renal genetic disease, leading to the dysregulation of renal tubules and the development of cystic growth that compromises kidney function. Despite significant advances in recent decades, there remains a considerable unmet clinical need, as current therapeutics are not effective at slowing or halting disease progression. Although preclinical animal models have been used extensively, the translatability of such findings is uncertain and human-relevant disease models are urgently needed. The advent of pluripotent stem cells (PSCs) and their ability to more accurately recapitulate organ architecture and function has allowed for the study of renal disease in a more physiological and human-relevant setting. To date, many research groups have studied ADPKD using PSC-derived kidney organoids, identifying many dysregulated pathways and screening drug candidates that may yield effective therapies in the clinic. In this review article, we discuss in detail the development of PSC-derived kidney organoids as ADPKD models and how they have advanced our understanding of the disease’s pathogenesis, as well as their limitations and potential strategies to address them. Full article
(This article belongs to the Special Issue Human Stem Cells in Disease Modelling and Treatment)
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15 pages, 1828 KiB  
Article
The Effect of Anti-Inflammatory Dimethylmalonic Acid on the Neurobehavioral Phenotype of a Neonatal ASD Model Induced by Antiepileptic Valproic Acid
by Xiuwen Zhou, Xiaowen Xu, Lili Li, Yiming Jin, Qing Wang, Xinxin Wang, Meifang Jin and Hong Ni
Biomedicines 2025, 13(7), 1765; https://doi.org/10.3390/biomedicines13071765 - 18 Jul 2025
Viewed by 397
Abstract
Background: Valproic acid (VPA) is a medication used to treat epilepsy, bipolar disorder, and migraine. If taken during pregnancy, it can cause neural tube defects (NTDs) and leads to offspring ASD behavioral phenotype. It has recently been found that early postnatal VPA [...] Read more.
Background: Valproic acid (VPA) is a medication used to treat epilepsy, bipolar disorder, and migraine. If taken during pregnancy, it can cause neural tube defects (NTDs) and leads to offspring ASD behavioral phenotype. It has recently been found that early postnatal VPA exposure can also induce the ASD phenotype, but the details of model production and intervention still need further investigation. Dimethylmalonic acid (DMM), a competitive inhibitor of succinate dehydrogenase, blocks the key element succinate of OXPHOS, decreasing the secretion of anti-inflammatory cytokines and ROS production. However, it is still unclear whether DMM is involved in the repair of developmental brain injuries. Objectives: The aim of this study was to evaluate the intervention effect and optimal dosage of DMM on behavioral phenotypes using a neonatal mouse VPA autism model. Methods: This experiment consists of two parts. The first part observed the effects of different concentrations of VPA on the development and neurobehavioral phenotype of mice. The second part determined the intervention effect of DMM on a developmental VPA autism model and determined the optimal therapeutic dose. Results: We found that the 40 mg/mL concentration had a greater impact on the neural reflex damage in mice. Moreover, DMM treatment can partially improve the neurobehavioral damage in the VPA model, and 20 mg/kg has the best intervention effect. Conclusions: This study provides valuable model construction data for further exploring the mechanism of DMM treatment for an ASD phenotype induced by VPA exposure in neonates. Full article
(This article belongs to the Special Issue Neuroinflammation and Neuroprotection)
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32 pages, 1948 KiB  
Review
Writing the Future: Artificial Intelligence, Handwriting, and Early Biomarkers for Parkinson’s Disease Diagnosis and Monitoring
by Giuseppe Marano, Sara Rossi, Ester Maria Marzo, Alice Ronsisvalle, Laura Artuso, Gianandrea Traversi, Antonio Pallotti, Francesco Bove, Carla Piano, Anna Rita Bentivoglio, Gabriele Sani and Marianna Mazza
Biomedicines 2025, 13(7), 1764; https://doi.org/10.3390/biomedicines13071764 - 18 Jul 2025
Cited by 1 | Viewed by 582
Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that impairs motor function, including the fine motor control required for handwriting. Traditional diagnostic methods often lack sensitivity and objectivity in the early stages, limiting opportunities for timely intervention. There is a growing need for [...] Read more.
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that impairs motor function, including the fine motor control required for handwriting. Traditional diagnostic methods often lack sensitivity and objectivity in the early stages, limiting opportunities for timely intervention. There is a growing need for non-invasive, accessible tools capable of capturing subtle motor changes that precede overt clinical symptoms. Among early PD manifestations, handwriting impairments such as micrographia have shown potential as digital biomarkers. However, conventional handwriting analysis remains subjective and limited in scope. Recent advances in artificial intelligence (AI) and machine learning (ML) enable automated analysis of handwriting dynamics, such as pressure, velocity, and fluency, collected via digital tablets and smartpens. These tools support the detection of early-stage PD, monitoring of disease progression, and assessment of therapeutic response. This paper highlights how AI-enhanced handwriting analysis provides a scalable, non-invasive method to support diagnosis, enable remote symptom tracking, and personalize treatment strategies in PD. This approach integrates clinical neurology with computer science and rehabilitation, offering practical applications in telemedicine, digital health, and personalized medicine. By capturing dynamic features often missed by traditional assessments, AI-based handwriting analysis contributes to a paradigm shift in the early detection and long-term management of PD, with broad relevance across neurology, digital diagnostics, and public health innovation. Full article
(This article belongs to the Section Neurobiology and Clinical Neuroscience)
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18 pages, 5007 KiB  
Article
Integrated Multi-Omics Profiling Reveals That Highly Pyroptotic MDMs Contribute to Psoriasis Progression Through CXCL16
by Liping Jin, Xiaowen Xie, Mi Zhang, Wu Zhu, Guanxiong Zhang and Wangqing Chen
Biomedicines 2025, 13(7), 1763; https://doi.org/10.3390/biomedicines13071763 - 18 Jul 2025
Viewed by 407
Abstract
Background: Psoriasis, an inflammatory skin disorder, involves pyroptosis—a pro-inflammatory cell death process. However, cell-specific pyroptosis dynamics and immune microenvironment interactions remain unclear. Objective: To investigate cell-type-specific pyroptosis patterns in psoriasis and their immunoregulatory mechanisms. Methods: We integrated 21 transcriptomic datasets (from 2007 to [...] Read more.
Background: Psoriasis, an inflammatory skin disorder, involves pyroptosis—a pro-inflammatory cell death process. However, cell-specific pyroptosis dynamics and immune microenvironment interactions remain unclear. Objective: To investigate cell-type-specific pyroptosis patterns in psoriasis and their immunoregulatory mechanisms. Methods: We integrated 21 transcriptomic datasets (from 2007 to 2020) obtained from the GEO database and two single-cell RNA sequencing datasets to quantify pyroptotic activity using Gene Set Variation Analysis and AUCell algorithms. Immune cell infiltration profiles were evaluated via CIBERSORT, while cell-cell communication networks were analyzed by CellChat. In vitro and in vivo experiments were performed to validate key findings. Results: Our analysis revealed that psoriasis patients exhibited significantly elevated levels of pyroptosis compared to healthy controls, with pyroptotic activity reflecting treatment responses. Notably, monocyte-derived macrophages (MDMs) in psoriatic lesions displayed markedly heightened pyroptotic activity. In vitro experiments confirmed that MDMs derived from psoriasis patients overexpressed pyroptosis-related molecules (Caspase 1 and Caspase 4) as well as pro-inflammatory cytokines (TNFα, IL6, IL1β) when compared to healthy controls. Furthermore, these cells showed increased expression of CXCL16, which might potentially activate Th17 cells through CXCR6 signaling, thereby driving skin inflammation. Inhibition of monocyte migration in an imiquimod-induced psoriasiform dermatitis model significantly alleviated skin inflammation and reduced the proportion of M1 macrophages and Th17 cells in lesional skin. Conclusions: This study revealed that MDMs in psoriatic lesions exhibited a hyperactive pyroptotic state, which contributed to disease progression through CXCL16-mediated remodeling of the immune microenvironment. These findings highlight pyroptosis as a potential therapeutic target for psoriasis. Full article
(This article belongs to the Special Issue Skin Diseases: From Molecular Mechanisms to Novel Therapeutic Approaches)
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16 pages, 1624 KiB  
Article
Neurobehavioral and Oxidative Stress Effects of SiO2 Nanoparticles in Zebrafish and the Protective Role of N-Acetylcysteine
by Viorica Rarinca, Irina-Luciana Gurzu, Mircea Nicusor Nicoara, Alin Ciobica, Malina Visternicu, Catalina Ionescu, Ioana Miruna Balmus, Gabriel-Ionut Plavan, Elena Todirascu-Ciornea and Bogdan Gurzu
Biomedicines 2025, 13(7), 1762; https://doi.org/10.3390/biomedicines13071762 - 18 Jul 2025
Viewed by 464
Abstract
Background/Objectives: Silicon dioxide nanoparticles (SiO2NPs) do not exist in isolation in the environment but can interact with other substances, thus influencing their toxic effects on aquatic organisms. We assessed the combined impact of SiO2NPs and N-acetylcysteine (NAC), an antioxidant [...] Read more.
Background/Objectives: Silicon dioxide nanoparticles (SiO2NPs) do not exist in isolation in the environment but can interact with other substances, thus influencing their toxic effects on aquatic organisms. We assessed the combined impact of SiO2NPs and N-acetylcysteine (NAC), an antioxidant with the potential to counteract nanoparticle-induced oxidative stress (OS). Methods: Behavioral assessments, including the social interaction test and color preference test, were performed to evaluate neurobehavioral changes. OS biomarkers, including malondialdehyde (MDA) levels for lipid peroxidation and the activity of key antioxidant enzymes such as glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD), were assessed to evaluate the extent of cellular damage. Results: The results indicate that prolonged exposure to SiO2NPs induces significant behavioral disruptions, including reduced exploratory behavior and increased anxiety-like responses. Furthermore, biochemical analysis revealed increased OS, suggesting nanoparticle-induced cellular toxicity. NAC co-treatment partially reversed these effects, particularly improving locomotor outcomes and antioxidant response, but was less effective on social behavior. Conclusions: These findings highlight the ecological and health risks posed by SiO2NPs and point toward the need for further toxicological studies on their long-term biological effects. Full article
(This article belongs to the Section Neurobiology and Clinical Neuroscience)
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36 pages, 1483 KiB  
Review
Microbial Crosstalk with Therapy: Pharmacomicrobiomics in AML—One Step Closer to Personalized Medicine
by Aneta Nowicka, Hanna Tomczak, Edyta Szałek, Agnieszka Karbownik and Lidia Gil
Biomedicines 2025, 13(7), 1761; https://doi.org/10.3390/biomedicines13071761 - 18 Jul 2025
Viewed by 646
Abstract
Increasing evidence demonstrates the mutualistic connection between the microbiome and acute myeloid leukemia (AML) treatment. Drugs disrupt the microbial balance and, conversely, changes in the microbiome influence therapy. A new field, pharmacomicrobiomics, examines the role of the microbiome in pharmacokinetics, pharmacodynamics, and drug [...] Read more.
Increasing evidence demonstrates the mutualistic connection between the microbiome and acute myeloid leukemia (AML) treatment. Drugs disrupt the microbial balance and, conversely, changes in the microbiome influence therapy. A new field, pharmacomicrobiomics, examines the role of the microbiome in pharmacokinetics, pharmacodynamics, and drug toxicity. The multimodal therapeutic management of AML, along with disease-related immunosuppression, infection, and malnutrition, creates the unique microbial profile of AML patients, in which every delicate modification plays a crucial role in pharmacotherapy. While both preclinical and real-world data have confirmed a bilateral connection between standard chemotherapy and the microbiome, the impact of novel targeted therapies and immunotherapy remains unknown. Multi-omics technologies have provided qualitative and mechanistic insights into specific compositional and functional microbial signatures associated with the outcomes of AML therapy, but require a large-scale investigation to draw reliable conclusions. In this review, we outline the role of the microbiome within the therapeutic landscape of AML, focusing on the determinants of post-treatment dysbiosis and its effects on the therapeutic response and toxicity. We explore emerging strategies for microbiota modulation, highlighting their safety and efficacy. Advances in microbiome-based approaches are an inevitable step toward precision medicine in AML. However, clinical research in a well-defined group of immunocompromised patients is needed to study their variable effects on human health and determine safety issues. Full article
(This article belongs to the Collection Feature Papers in Microbiology in Human Health and Disease)
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16 pages, 2608 KiB  
Article
Small Interfering RNAs Targeting VP4, VP3, 2B, or 3A Coding Regions of Enterovirus A71 Inhibit Viral Replication In Vitro
by Yun Ji Ga, Yun Young Go and Jung-Yong Yeh
Biomedicines 2025, 13(7), 1760; https://doi.org/10.3390/biomedicines13071760 - 18 Jul 2025
Viewed by 403
Abstract
Background: Enterovirus A71 (EV-A71) is considered as the primary causative agent of hand, foot, and mouth disease (HFMD) in young children, leading to severe neurological complications and contributing to substantial mortalities in recent HFMD outbreaks across Asia. Despite this, there is currently [...] Read more.
Background: Enterovirus A71 (EV-A71) is considered as the primary causative agent of hand, foot, and mouth disease (HFMD) in young children, leading to severe neurological complications and contributing to substantial mortalities in recent HFMD outbreaks across Asia. Despite this, there is currently no effective antiviral treatment available for EV-A71. RNA interference (RNAi) is a powerful mechanism of post-transcriptional gene regulation that utilizes small interfering RNA (siRNA) to target and degrade specific RNA sequences. Objectives: The aim of this study was to design various siRNAs targeting EV-A71 genomic regions and evaluate the RNAi efficacy against a novel, previously genetically uncharacterized EV-A71 strain. Methods: A novel EV-A71 strain was first sequenced to design target-specific siRNAs. The viral titers, viral protein expression, cytopathic effects, and cell viability of EV-A71-infected HeLa cells were examined to evaluate the specific viral inhibition by the siRNAs. Results: A substantial reduction in viral titers and viral protein synthesis was observed in EV-A71-infected HeLa cells treated with specific siRNAs targeting the VP4, VP3, 2B, and 3A genes. siRNAs delayed cytopathic effects and increased cell viability of EV-A71-infected HeLa cells. Nonspecific interferon induction caused by siRNAs was not observed in this study. In contrast, replication of coxsackievirus B3, another important member of the Enterovirus genus, remained unaffected. Conclusions: Overall, the findings demonstrate that RNAi targeting genomic regions of EV-A71 VP4, VP3, 2B, or 3A could become a potential strategy for controlling EV-A71 infection, and this promising result can be integrated into future anti-EV-A71 therapy developments. Full article
(This article belongs to the Special Issue Encephalitis and Viral Infection: Mechanisms and Therapies)
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19 pages, 2312 KiB  
Article
Improvement of Blood Flow and Epidermal Temperature in Cold Feet Using Far-Infrared Rays Emitted from Loess Balls Manufactured by Low-Temperature Wet Drying Method: A Randomized Trial
by Yong Il Shin, Min Seok Kim, Yeong Ae Yang, Yun Jeong Lee, Gye Rok Jeon, Jae Ho Kim, Yeon Jin Choi, Woo Cheol Choi and Jae Hyung Kim
Biomedicines 2025, 13(7), 1759; https://doi.org/10.3390/biomedicines13071759 - 18 Jul 2025
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Abstract
Background: Cold feet syndrome is characterized by hypersensitivity of sympathetic nerves to cold stimuli, resulting in vasoconstriction and reduced peripheral blood flow. This condition causes an intense cold sensation, particularly in the extremities. Although hormonal changes (e.g., during childbirth or menopause) and psychological [...] Read more.
Background: Cold feet syndrome is characterized by hypersensitivity of sympathetic nerves to cold stimuli, resulting in vasoconstriction and reduced peripheral blood flow. This condition causes an intense cold sensation, particularly in the extremities. Although hormonal changes (e.g., during childbirth or menopause) and psychological stress have been implicated, the mechanisms and effective treatments remain unclear. Methods: Ninety adult volunteers were randomized into three groups based on the type of heating mat applied to the feet, with surface temperatures gradually increased from 20 °C to 50 °C. Group A (control) used non-FIR electric mats, Group B used carbon FIR mats, and Group C used loess bio-ball FIR mats. Blood flow (mL/min/100 g) and epidermal temperature (°C) in the left big toe (LBT) and right big toe (RBT) were measured before and after heating or FIR exposure using laser Doppler flowmetry and infrared thermometers. Results: No significant changes in blood flow or skin temperature were observed in Group A. In Group B, blood flow increased by 15.07 mL/min/100 g in the LBT (from 4.12 ± 2.22 to 19.19 ± 5.44) and by 14.55 mL/min/100 g in the RBT (from 4.26 ± 2.29 to 18.81 ± 4.29). In Group C, blood flow increased by 32.86 mL/min/100 g in the LBT (from 4.23 ± 1.64 to 37.09 ± 6.04) and by 32.63 mL/min/100 g in the RBT (from 4.20 ± 1.61 to 36.83 ± 6.48). Epidermal temperature also increased significantly in Group C. All changes in Groups B and C were statistically significant (p < 0.05), with Group C showing the most prominent enhancement. Conclusions: The loess bio-ball mat significantly increased both peripheral blood flow and epidermal temperature compared to the electric and carbon mats. These findings suggest that FIR emitted from loess bio-balls may enhance peripheral circulation through hypothalamus thermogenic response and nitric oxide (NO)-dependent pathways and could serve as a complementary and non-invasive intervention for individuals with poor blood flow. Full article
(This article belongs to the Section Biomedical Engineering and Materials)
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Systematic Review
Cardioneuroablation for Vasovagal Syncope: An Updated Systematic Review and Single-Arm Meta-Analysis
by Alexandru Ababei, Cosmin Gabriel Ursu, Mircea Ioan Alexandru Bistriceanu, Darie Ioan Andreescu, Iasmina-Maria Iurea, Beatrice Budeanu, Adriana Elena Dumitrache, Alexandra Hostiuc, Maria-Celina Sturz-Lazar, Cristian-Valentin Toma, Stefan Sebastian Busnatu, Alexandru Deaconu and Stefan Bogdan
Biomedicines 2025, 13(7), 1758; https://doi.org/10.3390/biomedicines13071758 - 18 Jul 2025
Viewed by 571
Abstract
Background: When conservative therapies are insufficient for vasovagal syncope (VVS), procedural options such as permanent pacemakers or catheter ablation of ganglionated plexi (GP) may be considered. This meta-analysis aimed to evaluate the efficacy of GP catheter ablation in patients with VVS. Methods: A [...] Read more.
Background: When conservative therapies are insufficient for vasovagal syncope (VVS), procedural options such as permanent pacemakers or catheter ablation of ganglionated plexi (GP) may be considered. This meta-analysis aimed to evaluate the efficacy of GP catheter ablation in patients with VVS. Methods: A comprehensive literature search was performed in PubMed, Embase, and the Cochrane Library from 15 March 2024 to 10 May 2025. After duplicate removal, two reviewers independently screened studies and assessed full texts based on predefined criteria. A single-arm proportion meta-analysis was conducted. Results: Thirty-seven studies comprising 1585 participants were included. The pooled proportion of VVS recurrence after ablation was 8.9% (95% CI, 6.4–11.4%), but with substantial heterogeneity (I2 = 74.4%, p < 0.001). Sensitivity and subgroup analyses confirmed the robustness of the pooled estimate. A meta-regression was performed to further explore potential effect modifiers, but no covariate reached statistical significance. Conclusions: This meta-analysis suggests that ganglionated plexi catheter ablation may be associated with a reduced recurrence of vasovagal syncope in selected populations. However, the findings are based predominantly on non-randomized observational studies, and the high between-study heterogeneity limits the strength of inference. Future randomized controlled trials with standardized methodologies are needed to confirm the long-term efficacy and safety of this intervention. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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