Biomedicines

19 pages, 1269 KiB

Open AccessReview

Assessment of IL-6 Pathway Inhibition in Gastrointestinal Behçet’s Disease from Immunological and Clinical Perspectives

by Makoto Naganuma, Mitsuhiro Takeno, Aykut Ferhat Çelik, Robert Moots, Philippe Pinton and Tadakazu Hisamatsu

Biomedicines 2025, 13(1), 247; https://doi.org/10.3390/biomedicines13010247 - 20 Jan 2025

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Abstract

Behçet’s disease is an autoinflammatory disorder characterized by relapsing and remitting vasculitis that can manifest in various forms, including gastrointestinal Behçet’s disease (GIBD). Its complications (e.g., intestinal perforation) are among the primary causes of morbidity and mortality. GIBD pathogenesis involves the enhanced production [...] Read more.

Behçet’s disease is an autoinflammatory disorder characterized by relapsing and remitting vasculitis that can manifest in various forms, including gastrointestinal Behçet’s disease (GIBD). Its complications (e.g., intestinal perforation) are among the primary causes of morbidity and mortality. GIBD pathogenesis involves the enhanced production of certain cytokines, e.g., tumor necrosis factor α and interleukin-6 (IL-6), which could serve as a target for potential therapies. This review provides an overview of GIBD, including the diagnosis and immunopathogenesis as it is currently understood, and evaluates the emerging role of the inhibition of IL-6 (classic and trans-signaling) as an alternative treatment option for patients with GIBD. Given the current paucity of data, we reflected on the potential of IL-6 inhibitors such as tocilizumab and olamkicept based on immunopathogenic considerations and available clinical data in patients with inflammatory bowel disease (IBD), in whom clinical response or remission was induced. The selective inhibition of IL-6 trans-signaling may bring new impetus to the development of this drug class, particularly regarding safety. Still, the benefits of IL-6 inhibitors for patients with GIBD need to be evaluated in appropriate proof-of-concept studies. The clinical outcomes of IL-6 inhibitors in IBD are promising and may suggest their potential relevance in GIBD. Full article

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

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20 pages, 2410 KiB

Open AccessReview

The Role of Air Pollution and Olfactory Dysfunction in Alzheimer’s Disease Pathogenesis

by Louise Odendaal, Hazel Quek, Carla Cuní-López, Anthony R. White and Romal Stewart

Biomedicines 2025, 13(1), 246; https://doi.org/10.3390/biomedicines13010246 - 20 Jan 2025

Viewed by 766

Abstract

The escalating issue of air pollution contributes to an alarming number of premature fatalities each year, thereby posing a significant threat to global health. The focus of recent research has shifted towards understanding its potential association with neurodegenerative diseases, specifically Alzheimer’s disease (AD). [...] Read more.

The escalating issue of air pollution contributes to an alarming number of premature fatalities each year, thereby posing a significant threat to global health. The focus of recent research has shifted towards understanding its potential association with neurodegenerative diseases, specifically Alzheimer’s disease (AD). AD is recognised for its characteristic deposition of toxic proteins within the brain, leading to a steady deterioration of cognitive capabilities, memory failure, and, ultimately, death. There is burgeoning evidence implying that air pollution may be a contributing factor to this protein build up, thereby intensifying the course of AD. It has been demonstrated that the olfactory system, responsible for smell perception and processing, acts as a potential gateway for airborne pollutants to inflict brain damage. This review aims to elucidate the relationship between air pollution, olfactory deterioration, and AD. Additionally, this review aims to highlight the potential mechanisms through which pollutants might instigate the development of AD and the role of the olfactory system in disease pathogenesis. Moreover, the diverse model systems employed in exploring the correlation, public health policy ramifications, and prospective directions for future research will be discussed. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: From Mechanisms to Therapeutic Approaches)

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13 pages, 2364 KiB

Open AccessArticle

Bacterial Diversity in Native Heart Valves in Infective Endocarditis

by Anna Sinitskaya, Alexander Kostyunin, Maxim Asanov, Maria Khutornaya, Anastasia Klyueva, Alyona Poddubnyak, Alexey Tupikin, Marsel Kabilov and Maxim Sinitsky

Biomedicines 2025, 13(1), 245; https://doi.org/10.3390/biomedicines13010245 - 20 Jan 2025

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Abstract

Background: Infective endocarditis (IE) is an infectious disease caused by the hematogenous dissemination of bacteria into heart valves. Improving the identification of pathogens that cause IE is important to increase the effectiveness of its therapy and reduce the mortality caused by this pathology. [...] Read more.

Background: Infective endocarditis (IE) is an infectious disease caused by the hematogenous dissemination of bacteria into heart valves. Improving the identification of pathogens that cause IE is important to increase the effectiveness of its therapy and reduce the mortality caused by this pathology. Methods: Ten native heart valves obtained from IE patients undergoing heart valve replacements were analyzed. Bacterial invasion in the heart valves was studied by Gram staining of histological sections. Histopathological changes accompanied with bacterial invasion were studied by immunohistochemical analysis of pan-leukocyte marker CD45, platelet marker CD41, and neutrophil myeloperoxidase. The taxonomic diversity of the bacteria was analyzed using 16S rRNA metabarcoding. Results: Gram staining of the histological sections revealed bacterial cells localized on the atrial surface at the leaflet’s free edge or on the ventricular surface at the leaflet’s base within fibrin deposits in only three of the studied heart valves. Bacterial colonies were co-localized with microthrombi (CD41⁺ cells) containing single leucocytes (CD45⁺ cells), represented by segmented neutrophils. As a result of 16S rRNA metabarcoding, we detected the following bacterial genera: Pseudomonas (70% of the studied heart valves), Roseateles (60%), Acinetobacter (40%), Sphingomonas (40%), Enterococcus (30%), Reyranella (20%), Sphingobium (20%), Streptococcus (20%), Agrobacterium (20%), Ralstonia (10%), and Bacillus (10%). Conclusions: A number of opportunistic microorganisms that could not be detected by routine laboratory tests and were not eliminated during antibiotic therapy were identified in the IE-affected heart valves. The obtained results show the importance of 16S rRNA metabarcoding of heart valves removed due to IE not only as an independent diagnostic method but also as a highly accurate approach that complements routine tests for pathogen identification. Full article

(This article belongs to the Special Issue Mechanisms, Implications, and Therapeutic Targets in Infectious Diseases)

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17 pages, 2313 KiB

Open AccessArticle

Perfusate Liver Arginase 1 Levels After End-Ischemic Machine Perfusion Are Associated with Early Allograft Dysfunction

by Giuseppina Basta, Serena Babboni, Daniele Pezzati, Serena Del Turco, Emanuele Balzano, Gabriele Catalano, Lara Russo, Giovanni Tincani, Paola Carrai, Stefania Petruccelli, Jessica Bronzoni, Caterina Martinelli, Simona Palladino, Arianna Trizzino, Lorenzo Petagna, Renato Romagnoli, Damiano Patrono, Giandomenico Biancofiore, Adriano Peris, Chiara Lazzeri and Davide Ghinolfi Show full author list Hide full author list

Biomedicines 2025, 13(1), 244; https://doi.org/10.3390/biomedicines13010244 - 20 Jan 2025

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Abstract

Background/Objectives: The rising use of liver grafts from donation after circulatory death (DCD) has been enabled by advances in normothermic regional perfusion (NRP) and machine perfusion (MP) technologies. We aimed to identify predictive biomarkers in DCD grafts subjected to NRP, followed by [...] Read more.

Background/Objectives: The rising use of liver grafts from donation after circulatory death (DCD) has been enabled by advances in normothermic regional perfusion (NRP) and machine perfusion (MP) technologies. We aimed to identify predictive biomarkers in DCD grafts subjected to NRP, followed by randomization to either normothermic machine perfusion (NMP) or dual hypothermic oxygenated perfusion (D-HOPE). Methods: Among 57 DCD donors, 32 liver grafts were transplanted, and recipients were monitored for one week post-transplant. Biomarkers linked with oxidative stress, hepatic injury, mitochondrial dysfunction, inflammation, regeneration, and autophagy were measured during NRP, end-ischemic MP, and one week post-transplant. Results: Arginase-1 (ARG-1) levels were consistently higher in discarded grafts and in recipients who later developed early allograft dysfunction (EAD). Specifically, ARG-1 levels at the end of MP correlated with markers of hepatic injury. Receiver operating characteristic analysis indicated that ARG-1 at the end of MP had a good predictive accuracy for EAD (AUC = 0.713; p = 0.02). Lipid peroxidation (TBARS) elevated at the start of NRP, declined over time, with higher levels in D-HOPE than in NMP, suggesting a more oxidative environment in D-HOPE. Metabolites like flavin mononucleotide (FMN) and NADH exhibited significant disparities between perfusion types, due to differences in perfusate compositions. Inflammatory biomarkers rose during NRP and NMP but normalized post-transplantation. Regenerative markers, including osteopontin and hepatocyte growth factor, increased during NRP and NMP and normalized post-transplant. Conclusions: ARG-1 demonstrates strong potential as an early biomarker for assessing liver graft viability during perfusion, supporting timely and effective decision-making in transplantation. Full article

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

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18 pages, 7850 KiB

Open AccessArticle

Palm Tocotrienol Activates the Wnt3a/β-Catenin Signaling Pathway, Protecting MC3T3-E1 Osteoblasts from Cellular Damage Caused by Dexamethasone and Promoting Bone Formation

by Norfarahin Abdullah Sani, Nur Aqilah Kamaruddin, Ima Nirwana Soelaiman, Kok-Lun Pang, Kok-Yong Chin and Elvy Suhana Mohd Ramli

Biomedicines 2025, 13(1), 243; https://doi.org/10.3390/biomedicines13010243 - 20 Jan 2025

Viewed by 490

Abstract

Background and aim: Prolonged glucocorticoid (GC) treatment increases oxidative stress, triggers apoptosis of osteoblasts, and contributes to osteoporosis. Tocotrienol, as an antioxidant, could protect the osteoblasts and preserve bone quality under glucocorticoid treatment. From this study, we aimed to determine the effects of [...] Read more.

Background and aim: Prolonged glucocorticoid (GC) treatment increases oxidative stress, triggers apoptosis of osteoblasts, and contributes to osteoporosis. Tocotrienol, as an antioxidant, could protect the osteoblasts and preserve bone quality under glucocorticoid treatment. From this study, we aimed to determine the effects of tocotrienol on MC3T3-E1 murine pre-osteoblastic cells treated with GC. Methods: MC3T3-E1 cells were exposed to dexamethasone (150 µM), with or without palm tocotrienol (PTT; 0.25, 0.5, and 1 µg/mL). Cell viability was measured by the MTS assay. Alizarin Red staining was performed to detect calcium deposits. Cellular alkaline phosphatase activity was measured to evaluate osteogenic activity. The expression of osteoblastic differentiation markers was measured by an enzyme-linked immunoassay. Results: Enhanced matrix mineralization was observed in the cells treated with 0.5 µg/mL PTT, especially on day 18 (p < 0.05). The expression of Wnt3a, β-catenin, collagen 1α1, alkaline phosphatase, osteocalcin, low-density lipoprotein receptor-related protein 6, and runt-related transcription factor-2 were significantly increased in the PTT-treated groups compared to the vehicle control group, especially at 0.5 µg/mL of PTT (p < 0.05) and on day 6 of treatment. Conclusions: PTT maintains the osteogenic activity of the dexamethasone-treated osteoblasts by promoting their differentiation. Full article

(This article belongs to the Special Issue Molecular Research on Osteoarthritis and Osteoporosis)

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13 pages, 730 KiB

Open AccessArticle

Clinical Characteristics and Prognostic Factors Affecting Clinical Outcomes in Cytomegalovirus Retinitis Following Allogeneic Hematopoietic Stem Cell Transplantation

by Qiaozhu Zeng, Yuou Yao, Jing Hou and Heng Miao

Biomedicines 2025, 13(1), 242; https://doi.org/10.3390/biomedicines13010242 - 20 Jan 2025

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Abstract

Background/Objectives: This study aimed to evaluate the clinical characteristics and identify the prognostic factors affecting visual outcomes, retinal detachment, and recurrence in cytomegalovirus retinitis (CMVR) patients following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: A retrospective analysis of 54 CMVR patients [...] Read more.

Background/Objectives: This study aimed to evaluate the clinical characteristics and identify the prognostic factors affecting visual outcomes, retinal detachment, and recurrence in cytomegalovirus retinitis (CMVR) patients following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: A retrospective analysis of 54 CMVR patients (84 eyes) who underwent allo-HSCT between 2015 and 2024 was conducted. Ophthalmologic and systemic evaluations were performed. The visual outcomes were classified as improvement, stabilization, and deterioration. Logistic regression and LASSO regression models were used to identify the prognostic factors. Results: Improved or stabilized visual outcomes were found in 22 eyes, while 62 eyes suffered from deterioration. Larger lesion areas were independently associated with poorer visual outcomes (OR 0.989, p = 0.002). Eight (9.5%) eyes had rhegmatogenous retinal detachment and thirteen (15.5%) eyes suffered from recurrence. Retinal detachment was significantly predicted by higher baseline aqueous CMV DNA load (OR 5.087, p = 0.026). Macula involvement (OR 5.322, p = 0.032) and more intravitreal injections (IVs) (OR 1.263, p = 0.008) were independent risk factors for recurrence. No systemic factors were found to be associated with the clinical outcome of eyes with CMVR. Conclusions: Ocular characteristics, rather than systemic factors, were more useful to predict the clinical outcome of eyes with CMVR. Routine ophthalmic screening and early intervention are essential to improving outcomes in this vulnerable population. Full article

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

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25 pages, 1615 KiB

Open AccessReview

Environmental Pollutants as Emerging Concerns for Cardiac Diseases: A Review on Their Impacts on Cardiac Health

by Vinay Kumar, Hemavathy S, Lohith Kumar Dasarahally Huligowda, Mridul Umesh, Pritha Chakraborty, Basheer Thazeem and Anand Prakash Singh

Biomedicines 2025, 13(1), 241; https://doi.org/10.3390/biomedicines13010241 - 20 Jan 2025

Viewed by 957

Abstract

Comorbidities related to cardiovascular disease (CVD) and environmental pollution have emerged as serious concerns. The exposome concept underscores the cumulative impact of environmental factors, including climate change, air pollution, chemicals like PFAS, and heavy metals, on cardiovascular health. Chronic exposure to these pollutants [...] Read more.

Comorbidities related to cardiovascular disease (CVD) and environmental pollution have emerged as serious concerns. The exposome concept underscores the cumulative impact of environmental factors, including climate change, air pollution, chemicals like PFAS, and heavy metals, on cardiovascular health. Chronic exposure to these pollutants contributes to inflammation, oxidative stress, and endothelial dysfunction, further exacerbating the global burden of CVDs. Specifically, carbon monoxide (CO), ozone, particulate matter (PM_2.5), nitrogen dioxide (NO₂), sulfur dioxide (SO₂), heavy metals, pesticides, and micro- and nanoplastics have been implicated in cardiovascular morbidity and mortality through various mechanisms. PM_2.5 exposure leads to inflammation and metabolic disruptions. Ozone and CO exposure induce oxidative stress and vascular dysfunction. NO₂ exposure contributes to cardiac remodeling and acute cardiovascular events, and sulfur dioxide and heavy metals exacerbate oxidative stress and cellular damage. Pesticides and microplastics pose emerging risks linked to inflammation and cardiovascular tissue damage. Monitoring and risk assessment play a crucial role in identifying vulnerable populations and assessing pollutant impacts, considering factors like age, gender, socioeconomic status, and lifestyle disorders. This review explores the impact of cardiovascular disease, discussing risk-assessment methods, intervention strategies, and the challenges clinicians face in addressing pollutant-induced cardiovascular diseases. It calls for stronger regulatory policies, public health interventions, and green urban planning. Full article

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

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72 pages, 14427 KiB

Open AccessReview

Natural Cyclic Peptides: Synthetic Strategies and Biomedical Applications

by Devan Buchanan, Shogo Mori, Ahmed Chadli and Siva S. Panda

Biomedicines 2025, 13(1), 240; https://doi.org/10.3390/biomedicines13010240 - 20 Jan 2025

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Abstract

Natural cyclic peptides, a diverse class of bioactive compounds, have been isolated from various natural sources and are renowned for their extensive structural variability and broad spectrum of medicinal properties. Over 40 cyclic peptides or their derivatives are currently approved as medicines, underscoring [...] Read more.

Natural cyclic peptides, a diverse class of bioactive compounds, have been isolated from various natural sources and are renowned for their extensive structural variability and broad spectrum of medicinal properties. Over 40 cyclic peptides or their derivatives are currently approved as medicines, underscoring their significant therapeutic potential. These compounds are employed in diverse roles, including antibiotics, antifungals, antiparasitics, immune modulators, and anti-inflammatory agents. Their unique ability to combine high specificity with desirable pharmacokinetic properties makes them valuable tools in addressing unmet medical needs, such as combating drug-resistant pathogens and targeting challenging biological pathways. Due to the typically low concentrations of cyclic peptides in nature, effective synthetic strategies are indispensable for their acquisition, characterization, and biological evaluation. Cyclization, a critical step in their synthesis, enhances metabolic stability, bioavailability, and receptor binding affinity. Advances in synthetic methodologies—such as solid-phase peptide synthesis (SPPS), chemoenzymatic approaches, and orthogonal protection strategies—have transformed cyclic peptide production, enabling greater structural complexity and precision. This review compiles recent progress in the total synthesis and biological evaluation of natural cyclic peptides from 2017 onward, categorized by cyclization strategies: head-to-tail; head-to-side-chain; tail-to-side-chain; and side-chain-to-side-chain strategies. Each account includes retrosynthetic analyses, synthetic advancements, and biological data to illustrate their therapeutic relevance and innovative methodologies. Looking ahead, the future of cyclic peptides in drug discovery is bright. Emerging trends, including integrating computational tools for rational design, novel cyclization techniques to improve pharmacokinetic profiles, and interdisciplinary collaboration among chemists, biologists, and computational scientists, promise to expand the scope of cyclic peptide-based therapeutics. These advancements can potentially address complex diseases and advance the broader field of biological drug development. Full article

(This article belongs to the Special Issue Peptides and Amino Acids in Drug Development: Here and Now)

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25 pages, 2874 KiB

Open AccessReview

A Biopsychosocial Overview of Speech Disorders: Neuroanatomical, Genetic, and Environmental Insights

by Diya Jaishankar, Tanvi Raghuram, Bhuvanesh Kumar Raju, Divyanka Swarna, Shriya Parekh, Narendra Chirmule and Vikramsingh Gujar

Biomedicines 2025, 13(1), 239; https://doi.org/10.3390/biomedicines13010239 - 20 Jan 2025

Viewed by 803

Abstract

Speech disorders encompass a complex interplay of neuroanatomical, genetic, and environmental factors affecting individuals’ communication ability. This review synthesizes current insights into the neuroanatomy, genetic underpinnings, and environmental influences contributing to speech disorders. Neuroanatomical structures, such as Broca’s area, Wernicke’s area, the arcuate [...] Read more.

Speech disorders encompass a complex interplay of neuroanatomical, genetic, and environmental factors affecting individuals’ communication ability. This review synthesizes current insights into the neuroanatomy, genetic underpinnings, and environmental influences contributing to speech disorders. Neuroanatomical structures, such as Broca’s area, Wernicke’s area, the arcuate fasciculus, and basal ganglia, along with their connectivity, play critical roles in speech production, comprehension, and motor coordination. Advances in the understanding of intricate brain networks involved in language offer insights into typical speech development and the pathophysiology of speech disorders. Genetic studies have identified key genes involved in neural migration and synaptic connectivity, further elucidating the role of genetic mutations in speech disorders, such as stuttering and speech sound disorders. Beyond the biological mechanisms, this review explores the profound impact of psychological factors, including anxiety, depression, and neurodevelopmental conditions, on individuals with speech disorders. Psychosocial comorbidities often exacerbate speech disorders, complicating diagnosis and treatment and underscoring the need for a holistic approach to managing these conditions. Future directions point toward leveraging genetic testing, digital technologies, and personalized therapies, alongside addressing the psychosocial dimensions, to improve outcomes for individuals with speech disorders. This comprehensive overview aims to inform future research and therapeutic advancements, particularly in treating fluency disorders like stuttering. Full article

(This article belongs to the Special Issue Progress in Neurodevelopmental Disorders Research)

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16 pages, 1709 KiB

Open AccessArticle

Intra- and Interspecies Conjugal Transfer of Plasmids in Gram-Negative Bacteria

by Julia R. Savelieva, Daria A. Kondratieva and Maria V. Golikova

Biomedicines 2025, 13(1), 238; https://doi.org/10.3390/biomedicines13010238 - 20 Jan 2025

Viewed by 455

Abstract

Background/Objectives: Plasmid-mediated resistance is a significant mechanism that contributes to the gradual decrease in the efficacy of antibiotics from various classes, including carbapenems. The aim of this study is to investigate the frequency of transfer of carbapenemase-encoding plasmids from K. pneumoniae to E. [...] Read more.

Background/Objectives: Plasmid-mediated resistance is a significant mechanism that contributes to the gradual decrease in the efficacy of antibiotics from various classes, including carbapenems. The aim of this study is to investigate the frequency of transfer of carbapenemase-encoding plasmids from K. pneumoniae to E. coli and P. aeruginosa. Methods: Matings were performed on agar with subsequent isolation of transconjugant, recipient, and donor colonies. The frequency of conjugation (CF) and minimum inhibitory concentrations (MICs) of meropenem were determined for the PCR-confirmed transconjugants. A pharmacodynamic study was conducted using a hollow-fiber infection model on E. coli transconjugant in order to evaluate its viability in the presence of therapeutic concentrations of meropenem. Results: CF for K. pneumoniae-K. pneumoniae was similar to that for K. pneumoniae-E. coli and was higher the higher was meropenem MIC of the K. pneumoniae donor. The meropenem MICs for K. pneumoniae and E. coli transconjugants were higher (0.25–4 μg/mL) compared to recipients (0.03–0.06 μg/mL). P. aeruginosa did not acquire plasmids from K. pneumoniae. In pharmacodynamic experiments, an E. coli transconjugant with MIC of 2 mg/L within the “susceptibility range”, failed to respond to meropenem treatment. Conclusions: The frequency of conjugation between K. pneumoniae and E. coli falls within a similar range. A higher permissiveness of K. pneumoniae for plasmids from K. pneumoniae, i.e., within the same species, was observed. Conjugation did not occur between K. pneumoniae and P. aeruginosa. The transconjugants with meropenem MICs with borderline susceptibility may pose a potential threat to the efficacy of meropenem. Full article

(This article belongs to the Special Issue Infectious Diseases: Prevention, Diagnosis, and Treatment Under Antimicrobial Resistance Global Urgency)

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14 pages, 1581 KiB

Open AccessArticle

Venoarterial Membrane Oxygenation in Cardiogenic Shock Complicated from an Acute Myocardial Infarction: An Overview and Comprehensive Meta-Analysis

by Kiarash Sassani, Styliani Syntila, Christian Waechter, Julian Kreutz, Birgit Markus, Nikolaos Patsalis, Bernhard Schieffer and Georgios Chatzis

Biomedicines 2025, 13(1), 237; https://doi.org/10.3390/biomedicines13010237 - 20 Jan 2025

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Abstract

Background: Cardiogenic shock remains a significant cause of mortality in patients with acute coronary syndrome, despite early interventions, such as coronary revascularization. Mechanical circulatory support devices, particularly venoarterial extracorporeal membrane oxygenation (VA-ECMO), are increasingly being utilized to address this issue. Limited randomized controlled [...] Read more.

Background: Cardiogenic shock remains a significant cause of mortality in patients with acute coronary syndrome, despite early interventions, such as coronary revascularization. Mechanical circulatory support devices, particularly venoarterial extracorporeal membrane oxygenation (VA-ECMO), are increasingly being utilized to address this issue. Limited randomized controlled trials (RCTs) exist to evaluate the efficacy of VA-ECMO in cardiogenic shock related to acute coronary syndrome. Methods: A meta-analysis was conducted to assess the effectiveness of VA-ECMO in adult patients with infarct-related cardiogenic shock. Trials were identified through database searches and selected based on specific inclusion criteria. The primary outcome was 30-day all-cause mortality, with secondary outcomes including bleeding and vascular complications. Results: A total of 24 studies met the inclusion criteria and were included in the meta-analysis, involving 4706 patients. The median age of the patients was 61.8 ± 4.1 years, with 76% of them being males. The analysis revealed that 30-day mortality rates for patients with cardiogenic shock receiving ECMO were still high, with a mortality of 63%. Vascular complications were identified as factors associated with a worse prognosis. Conclusions: The meta-analysis highlights the ongoing challenge of high mortality rates in cardiogenic shock patients despite the use of VA-ECMO. While VA-ECMO shows promise in providing circulatory support, further research is needed to explore ways to improve outcomes and reduce complications associated with the use of these devices. The complexity of patient management in cardiogenic shock cases underscores the need for a multidisciplinary approach to optimize treatment strategies and enhance patient outcomes. Full article

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

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19 pages, 8598 KiB

Open AccessArticle

Identification of Hepatocellular Carcinoma Subtypes Based on Global Gene Expression Profiling to Predict the Prognosis and Potential Therapeutic Drugs

by Cunzhen Zhang, Jiyao Wang, Lin Jia, Qiang Wen, Na Gao and Hailing Qiao

Biomedicines 2025, 13(1), 236; https://doi.org/10.3390/biomedicines13010236 - 20 Jan 2025

Viewed by 685

Abstract

Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous tumor, and distinguishing its subtypes holds significant value for diagnosis, treatment, and the prognosis. Methods: Unsupervised clustering analysis was conducted to classify HCC subtypes. Subtype signature genes were identified using LASSO, SVM, and logistic regression. [...] Read more.

Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous tumor, and distinguishing its subtypes holds significant value for diagnosis, treatment, and the prognosis. Methods: Unsupervised clustering analysis was conducted to classify HCC subtypes. Subtype signature genes were identified using LASSO, SVM, and logistic regression. Survival-related genes were identified using Cox regression, and their expression and function were validated via qPCR and gene interference. GO, KEGG, GSVA, and GSEA were used to determine enriched signaling pathways. ESTIMATE and CIBERSORT were used to calculate the stromal score, tumor purity, and immune cell infiltration. TIDE was employed to predict the patient response to immunotherapy. Finally, drug sensitivity was analyzed using the oncoPredict algorithm. Results: Two HCC subtypes with different gene expression profiles were identified, where subtype S1 exhibited a significantly shorter survival time. A subtype scoring formula and a nomogram were constructed, both of which showed an excellent predictive performance. COL11A1 and ACTL8 were identified as survival-related genes among the signature genes, and the downregulation of COL11A1 could suppress the invasion and migration of HepG2 cells. Subtype S1 was characterized by the upregulation of pathways related to collagen and the extracellular matrix, as well as downregulation associated with the xenobiotic metabolic process and fatty acid degradation. Subtype S1 showed higher stromal scores, immune scores, and ESTIMATE scores and infiltration of macrophages M0 and plasma cells, as well as lower tumor purity and infiltration of NK cells (resting/activated) and resting mast cells. Subtype S2 was more likely to benefit from immunotherapy. Subtype S1 appeared to be more sensitive to BMS-754807, JQ1, and Axitinib, while subtype S2 was more sensitive to SB505124, Pevonedistat, and Tamoxifen. Conclusions: HCC patients can be classified into two subtypes based on their gene expression profiles, which exhibit distinctions in terms of signaling pathways, the immune microenvironment, and drug sensitivity. Full article

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

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12 pages, 540 KiB

Open AccessArticle

Evaluation of Individual Cardiovascular Risk in Pre-Dialysis CKD Patients by Using the Ratio of Calcium–Phosphorus Product to Estimated Glomerular Filtration Rate (Ca × P/eGFR)

by Krasimir Kostov, Tatyana Simeonova, Borislav Ignatov and Tsvetelina Eftimova

Biomedicines 2025, 13(1), 235; https://doi.org/10.3390/biomedicines13010235 - 19 Jan 2025

Viewed by 791

Abstract

Background: Chronic kidney disease (CKD) patients have an increased risk of cardiovascular disease (CVD), necessitating effective risk assessment methods. This study evaluates the calcium–phosphorus product (Ca × P) to estimated glomerular filtration rate (Ca × P/eGFR) ratio as a potential biomarker for predicting [...] Read more.

Background: Chronic kidney disease (CKD) patients have an increased risk of cardiovascular disease (CVD), necessitating effective risk assessment methods. This study evaluates the calcium–phosphorus product (Ca × P) to estimated glomerular filtration rate (Ca × P/eGFR) ratio as a potential biomarker for predicting CV risk in pre-dialysis CKD patients. Methods: Eighty-four CKD patients in stages G1–G4, according to the KDIGO criteria, were classified into CVD (n = 43) and non-CVD (n = 41) groups. Biochemical parameters, including serum creatinine (SCr), blood urea nitrogen (BUN), calcium (Ca), inorganic phosphate (Pi), parathyroid hormone (PTH), alkaline phosphatase (ALP), Ca × P, eGFR, and the Ca × P/eGFR ratio, were measured and calculated. Statistical analyses were performed to identify predictors of CV risk and evaluate the diagnostic reliability of the Ca × P/eGFR ratio for predicting the risk. Results: Significant differences were observed in SCr, BUN, eGFR (p < 0.001), and the Ca × P/eGFR ratio (p = 0.007) between the groups. Regression analysis indicated the Ca × P/eGFR ratio as a significant CVD risk predictor (p = 0.012, OR = 1.206, 95% CI: 1.042–1.395). Receiver Operating Characteristic (ROC) curve analysis revealed an AUC of 0.751 (p < 0.001, 95% CI: 0.645–0.857), with a sensitivity and specificity of the method of 74.4% and 70.7%, respectively. Significant correlations were found between the Ca × P/eGFR ratio and SCr, BUN, UA, Ca, Pi, PTH, and ALP. Conclusions: The Ca × P/eGFR ratio may serve as a significant predictor of CVD risk in pre-dialysis CKD patients, suggesting that its integration into routine evaluations could enhance CV risk stratification and management. Full article

(This article belongs to the Special Issue New Advances in Chronic Kidney Disease: Biology, Diagnosis and Therapy (2nd Edition))

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11 pages, 1313 KiB

Open AccessArticle

Pharmacokinetics of Hydrogen During Hydrogen-Saturated Saline Infusion in Pigs

by Masaki Shibuya, Masafumi Fujinaka, Mako Yonezawa, Natsumi Nishimura, Hitoshi Uchinoumi, Hiroshi Sunahara, Kenji Tani, Eiji Kobayashi and Motoaki Sano

Biomedicines 2025, 13(1), 234; https://doi.org/10.3390/biomedicines13010234 - 19 Jan 2025

Viewed by 571

Abstract

Background: Hydrogen gas (H₂) has been shown to be effective in the treatment of various clinical conditions, from acute illnesses to chronic illnesses. However, its clinical indications and the corresponding appropriate hydrogen delivery methods have yet to be determined. This [...] Read more.

Background: Hydrogen gas (H₂) has been shown to be effective in the treatment of various clinical conditions, from acute illnesses to chronic illnesses. However, its clinical indications and the corresponding appropriate hydrogen delivery methods have yet to be determined. This is due to the fact that the pharmacokinetics and pharmacodynamics of hydrogen in each delivery method have not been experimentally proven. Here, we verified the pharmacokinetics of hydrogen after the infusion of hydrogen-saturated saline. Methods: Hydrogen-saturated saline was prepared and checked for sterility and component specifications. Hydrogen-saturated saline was administered intravenously (125 mL/h) through the left internal jugular vein of pigs, and the blood hydrogen concentration was measured over time. Results: It was confirmed that hydrogen can be safely mixed under pressure into intravenous solutions (pharmaceutical products) without the contamination of foreign substances by using a needle-less vial access cannula. No change in the PH or composition of the solution was observed due to hydrogen filling. The hydrogen concentrations of blood samples collected from the left internal jugular vein 3 cm to the heart from the tip of the infusion line were 6.4 (30 min), 4.7 (60 min), 4.9 (90 min), and 5.3 (120 min) ppb w/w, respectively. The hydrogen concentrations of blood samples collected from the right atrium were 0.7 (30 min), 0.5 (60 min), 0.7 (90 min), and 0.7 (120 min) ppb, respectively. The hydrogen concentration of blood samples collected from the right internal carotid artery were 0.1 (pre), 0.2 (30 min), 0.3 (60 min), 0.0 (90 min), and 0.0 (120 min) ppb w/w, respectively. Conclusions: We confirmed that hydrogen could be safely pressurized and filled into intravenous (pharmaceutical) solution without contamination by foreign objects using a needle-free vial access cannula. When saturated hydrogen saline was dripped intravenously, almost all of the hydrogen was expelled during its passage through the lungs and could not be supplied to the arterial side. Full article

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

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23 pages, 1294 KiB

Open AccessReview

Exosomes in Ocular Health: Recent Insights into Pathology, Diagnostic Applications and Therapeutic Functions

by Noelia Blanco-Agudín, Suhui Ye, Sara González-Fernández, Ignacio Alcalde, Jesús Merayo-Lloves and Luis M. Quirós

Biomedicines 2025, 13(1), 233; https://doi.org/10.3390/biomedicines13010233 - 19 Jan 2025

Viewed by 653

Abstract

Exosomes are extracellular vesicles ranging from 30 to 150 nm in diameter that contain proteins, nucleic acids and other molecules. Produced by virtually all cell types, they travel throughout the body until they reach their target, where they can trigger a wide variety [...] Read more.

Exosomes are extracellular vesicles ranging from 30 to 150 nm in diameter that contain proteins, nucleic acids and other molecules. Produced by virtually all cell types, they travel throughout the body until they reach their target, where they can trigger a wide variety of effects by transferring the molecular cargo to recipient cells. In the context of ocular physiology, exosomes play a very important role in embryological development, the regulation of homeostasis and the immune system, which is crucial for normal vision. Consequently, in pathological situations, exosomes also undergo modifications in terms of quantity, composition and content, depending on the etiology of the disease. However, the mechanisms by which exosomes contribute to ocular pathology has not yet been studied in depth, and many questions remain unanswered. This review aims to summarize the most recent knowledge on the function of exosomes in the ocular system in healthy individuals and the role they play during pathological processes of a degenerative, infectious, neurodegenerative, vascular and inflammatory nature, such as keratoconus, keratitis, glaucoma, diabetic retinopathy and uveitis. Furthermore, given their unique characteristics, their potential as diagnostic biomarkers or therapeutic agents and their application in clinical ophthalmology are also explored, along with the main limitations that researchers face today in the field. Full article

(This article belongs to the Special Issue Exosomes and Their Role in Diseases—2nd Edition)

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22 pages, 7534 KiB

Open AccessArticle

Baicalin Mitigates Cardiac Hypertrophy and Fibrosis by Inhibiting the p85a Subunit of PI3K

by Lu He, Min Zhu, Rui Yin, Liangli Dai, Juan Chen and Jie Zhou

Biomedicines 2025, 13(1), 232; https://doi.org/10.3390/biomedicines13010232 - 19 Jan 2025

Viewed by 386

Abstract

Background: Heart failure (HF) is a serious public health concern. Baicalin is one of the major active ingredients of a traditional Chinese herbal medicine, Huang Qin, which is used to treat patients with chest pain or cardiac discomfort. However, the underlying mechanism(s) of [...] Read more.

Background: Heart failure (HF) is a serious public health concern. Baicalin is one of the major active ingredients of a traditional Chinese herbal medicine, Huang Qin, which is used to treat patients with chest pain or cardiac discomfort. However, the underlying mechanism(s) of the cardioprotective effect of baicalin are still not fully understood. Methods: Isoprenaline injection or transverse aortic constriction-induced animal models and isoprenaline or angiotensin 2 administration-induced cell models of heart failure were established. Baicalin (15 mg/kg/day or 25 mg/kg/day) was administered in vivo, and 10 μM baicalin was administered in vitro. Potential pharmacological targets of baicalin and genes related to heart failure were identified via different databases, which suggested that PI3K–Akt may be involved in the effects of baicalin. Molecular docking was carried out to reveal the effect of baicalin on p85a. Results: We observed significant antihypertrophic and antifibrotic effects of baicalin both in vivo and in vitro. The mean cross-sectional area of cardiomyocytes recovered from 390 μm² in the HF group to 195 μm² in the baicalin-treated group. The area of fibrosis was reduced from 2.8-fold in the HF group to 1.62-fold in the baicalin-treated group. Baicalin displayed a significant cardioprotective effect via the inhibition of the PI3K signaling pathway by binding with five amino acid residues of the p85a regulatory subunit of PI3K. The combination treatment of baicalin and an inhibitor of PI3K p110 demonstrated a stronger cardioprotective effect. The mean ejection fraction increased from 54% in the baicalin-treated group to 67% in the combination treatment group. Conclusions: Our work identified baicalin as a new active herbal ingredient that is able to treat isoprenaline-induced heart dysfunction and suggests that p85a is a pharmacological target. These findings reveal the significant potential of baicalin combined with an inhibitor of PI3K p110 for the treatment of heart failure and support more clinical trials in the future. Full article

(This article belongs to the Special Issue Cardiac and Vascular Diseases: Pathogenesis, Pharmacological Treatments, Advances in Therapies (2nd Edition))

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Graphical abstract

14 pages, 1594 KiB

Open AccessArticle

Mendelian Randomization Reveals Potential Causal Relationships Between DNA Damage Repair-Related Genes and Inflammatory Bowel Disease

by Zhihao Qi, Quan Li, Shuhua Yang, Chun Fu and Burong Hu

Biomedicines 2025, 13(1), 231; https://doi.org/10.3390/biomedicines13010231 - 19 Jan 2025

Viewed by 514

Abstract

DNA damage repair (DDR) plays a key role in maintaining genomic stability and developing inflammatory bowel disease (IBD). However, no report about the causal association between DDR and IBD exists. Whether DDR-related genes are the precise causal association to IBD in etiology remains [...] Read more.

DNA damage repair (DDR) plays a key role in maintaining genomic stability and developing inflammatory bowel disease (IBD). However, no report about the causal association between DDR and IBD exists. Whether DDR-related genes are the precise causal association to IBD in etiology remains unclear. Herein, we employed a multi-omics summary data-based Mendelian randomization (SMR) approach to ascertain the potential causal effects of DDR-related genes in IBD. Methods: Summary statistics from expression quantitative trait loci (eQTL), DNA methylation QTL (mQTL), and protein QTL (pQTL) on European descent were included. The GWAS summarized data for IBD and its two subtypes, Crohn’s disease (CD) and ulcerative colitis (UC), were acquired from the FinnGen study. We elected from genetic variants located within or near 2000 DDR-related genes in cis, which are closely associated with DDR-related gene changes. Variants were selected as instrumental variables (IVs) and assessed for causality with IBD and its subtypes using both SMR and two-sample MR (TSMR) approaches. Colocalization analysis was employed to evaluate whether a single genetic variant simultaneously influences two traits, thereby validating the pleiotropy hypothesis. Results: We identified seven DDR-related genes (Arid5b, Cox5a, Erbb2, Ube2l3, Gpx1, H2bcl2, and Mapk3), 33 DNA methylation genes, and two DDR-related proteins (CD274 and FCGR2A) which were all causally associated with IBD and its subtypes. Beyond causality, we integrated the multi-omics data between mQTL-eQTL and conducted druggability values. We found that DNA methylation of Erbb2 and Gpx1 significantly impacted their gene expression levels offering insights into the potential regulatory mechanisms of risk variants on IBD. Meanwhile, CD247 and FCGR2A could serve as targets for potential pharmacological interventions in IBD. Conclusions: Our study demonstrates the causal role of DDR in IBD based on the data-driven MR. Moreover, we found potential regulatory mechanisms of risk variants on IBD and potential pharmacological targets. Full article

(This article belongs to the Section Molecular Genetics and Genetic Diseases)

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16 pages, 1196 KiB

Open AccessArticle

miRNAs and Hematological Markers in Non-Alcoholic Fatty Liver Disease—A New Diagnostic Path?

by Agata Michalak, Małgorzata Guz, Joanna Kozicka, Marek Cybulski, Witold Jeleniewicz, Ilona Telejko, Karolina Szczygieł, Ewa Tywanek and Halina Cichoż-Lach

Biomedicines 2025, 13(1), 230; https://doi.org/10.3390/biomedicines13010230 - 18 Jan 2025

Viewed by 882

Abstract

Background: Asymptomatic liver steatosis constitutes an emerging issue worldwide. Therefore, we decided to explore relationships between selected types of microRNAs (miRNAs), serological markers of liver fibrosis and hematological parameters in the course of non-alcoholic fatty liver disease (NAFLD). Methods: Two hundred and seven [...] Read more.

Background: Asymptomatic liver steatosis constitutes an emerging issue worldwide. Therefore, we decided to explore relationships between selected types of microRNAs (miRNAs), serological markers of liver fibrosis and hematological parameters in the course of non-alcoholic fatty liver disease (NAFLD). Methods: Two hundred and seven persons were included in the survey: 97 with NAFLD and 110 healthy controls. Serological concentrations of miR-126-3p, miR-197-3p, and miR-1-3p were measured in all participants. Direct indices of liver fibrosis [procollagen I carboxyterminal propeptide (PICP), procollagen III aminoterminal propeptide (PIIINP), platelet-derived growth factor AB (PDGF-AB), transforming growth factor-α (TGF-α) and laminin] together with indirect markers (AAR, APRI, FIB-4 and GPR) were also evaluated. The assessment of hematological parameters concerned: mean platelet volume (MPV), platelet distribution width (PDW), plateletcrit (PCT), red blood cell distribution width (RDW), MPV to platelet (PLT) ratio (MPR), RDW to PLT ratio (RPR), neutrophil to lymphocyte (LYM) ratio (NLR), PLT to LYM ratio (PLR) and RDW to LYM ratio (RLR). Additionally, the NAFLD fibrosis score and BARD score were applied. Results: The concentration of miR-126-3p and miR-1-3p was higher, and miR-197-3p was lower in the NAFLD group (p < 0.0001). miR-197-3p correlated notably with hematological indices: negatively with PDW (p < 0.05) and positively with PLR (p < 0.05). Conclusions: Significant correlations between miRNA molecules and hematological markers in the course of NAFLD indicate inflammation as a potential background and create new possibilities for a diagnostic approach. Full article

(This article belongs to the Special Issue Fatty Liver Disease: From Mechanisms to Therapeutic Approaches)

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14 pages, 540 KiB

Open AccessSystematic Review

Toxicity Associated with Pembrolizumab Monotherapy in Patients with Gastrointestinal Cancers: A Systematic Review of Clinical Trials

by Nikolas Naleid, Amit Mahipal and Sakti Chakrabarti

Biomedicines 2025, 13(1), 229; https://doi.org/10.3390/biomedicines13010229 - 18 Jan 2025

Viewed by 586

Abstract

Background/Objectives: Pembrolizumab, an immune checkpoint inhibitor targeting programmed death 1 (PD-1), is a widely employed therapy for various gastrointestinal (GI) cancers. We conducted a systematic review of clinical trials investigating pembrolizumab monotherapy in GI cancer patients to assess the spectrum and incidence of [...] Read more.

Background/Objectives: Pembrolizumab, an immune checkpoint inhibitor targeting programmed death 1 (PD-1), is a widely employed therapy for various gastrointestinal (GI) cancers. We conducted a systematic review of clinical trials investigating pembrolizumab monotherapy in GI cancer patients to assess the spectrum and incidence of immune-related adverse events (irAEs) associated with pembrolizumab. Methods: A comprehensive search of PubMed/MEDLINE was performed to identify clinical trials investigating pembrolizumab monotherapy in GI cancer patients. Primary endpoints included the incidence of grade 3 or higher irAEs and the rate of treatment discontinuation due to irAEs. Secondary endpoints encompassed the incidence of any-grade irAEs, as well as specific irAEs. Results: Data extraction and analysis were performed on 25 articles. The analysis included 3101 patients with a median age of 62 years (range 53–68), with 30.2% being female. Tumor types encompassed were colorectal (12%), esophagogastric (46%), hepatocellular carcinoma (24%), and other GI tumor types (18%). The rate of treatment discontinuation due to irAEs was 6.8%. The most prevalent grade 3 or higher irAEs were hepatitis (3.6%), pneumonitis (0.8%), and colitis (0.7%). Death attributed to irAEs was infrequent (0.9%). Conclusions: In patients with GI cancers treated with pembrolizumab monotherapy, severe toxicities are infrequent, and irAEs leading to treatment discontinuation or death are uncommon. Full article

(This article belongs to the Special Issue Recent Advances in Immunotherapy for Solid Tumors)

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14 pages, 1373 KiB

Open AccessReview

Effects of Carbon Dioxide Therapy on Skin Wound Healing

by José Prazeres, Ana Lima and Gesiane Ribeiro

Biomedicines 2025, 13(1), 228; https://doi.org/10.3390/biomedicines13010228 - 18 Jan 2025

Viewed by 388

Abstract

Promoting rapid healing is a concern in skin wound treatment, as the increased pain and the loss of functional ability when wounds become chronic create a complex problem to manage. This scoping review aimed to explore the literature and synthesize existing knowledge on [...] Read more.

Promoting rapid healing is a concern in skin wound treatment, as the increased pain and the loss of functional ability when wounds become chronic create a complex problem to manage. This scoping review aimed to explore the literature and synthesize existing knowledge on the therapeutic use of CO₂ in treating cutaneous wounds. The literature was selected using previously defined inclusion and exclusion criteria, and 22 articles were selected for data extraction. The most researched type of injury was chronic wounds located on the extremities of the limbs. Carboxytherapy was performed in five different ways: subcutaneous, intradermal, or intralesional injections; in hot water baths with temperatures ranging from 30 to 42 °C; transcutaneous application; intra-abdominal insufflation; and a paste for transcutaneous local application. The main effects of CO₂ therapy described were as follows: improved blood flow and local oxygenation, reduction of the inflammatory process, increased collagen production, and improved clinical aspects of wounds, with faster healing. Carboxytherapy can be considered a good alternative for treating skin wounds, although further studies should be pursued to elucidate its molecular mechanisms and enhance its efficacy. Full article

(This article belongs to the Special Issue Wound Healing: From Basic to Clinical Research)

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13 pages, 791 KiB

Open AccessArticle

Inflammatory Markers and Severity in COVID-19 Patients with Clostridioides Difficile Co-Infection: A Retrospective Analysis Including Subgroups with Diabetes, Cancer, and Elderly

by Teodor Cerbulescu, Flavia Ignuta, Uma Shailendri Rayudu, Maliha Afra, Ovidiu Rosca, Adrian Vlad and Stana Loredana

Biomedicines 2025, 13(1), 227; https://doi.org/10.3390/biomedicines13010227 - 17 Jan 2025

Viewed by 658

Abstract

Background and Objectives: The interplay of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and Clostridioides difficile infection (CDI) poses a critical clinical challenge. The resultant inflammatory milieu and its impact on outcomes remain incompletely understood, especially among vulnerable subgroups such as elderly [...] Read more.

Background and Objectives: The interplay of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and Clostridioides difficile infection (CDI) poses a critical clinical challenge. The resultant inflammatory milieu and its impact on outcomes remain incompletely understood, especially among vulnerable subgroups such as elderly patients, those with diabetes, and individuals with cancer. This study aimed to characterize inflammatory markers and composite inflammatory severity scores—such as Acute Physiology and Chronic Health Evaluation II (APACHE II), Confusion, Urea, Respiratory rate, Blood pressure, and age ≥ 65 years (CURB-65), National Early Warning Score (NEWS), and the Systemic Immune-Inflammation Index (SII)—in hospitalized Coronavirus Disease 2019 (COVID-19) patients with and without CDI, and to evaluate their prognostic implications across key clinical subgroups. Methods: We conducted a retrospective, single-center study of 240 hospitalized adults with Reverse Transcription Polymerase Chain Reaction (RT-PCR)-confirmed COVID-19 between February 2021 and March 2023. Of these, 98 had concurrent CDI. We collected baseline demographics, comorbidities, and laboratory parameters including C-reactive protein (CRP), Interleukin-6 (IL-6), ferritin, neutrophil and lymphocyte counts, albumin, platelet counts, and calculated indices (C-reactive protein to Albumin Ratio (CAR), Neutrophil-to-Lymphocyte Ratio (NLR), Prognostic Nutritional Index (PNI), SII). Patients were stratified by CDI status and analyzed for inflammatory marker distributions, severity scores (APACHE II, CURB-65, NEWS), and outcomes (Intensive Care Unit (ICU) admission, mechanical ventilation, mortality). Subgroup analyses included diabetes, elderly (≥65 years), and cancer patients. Statistical comparisons employed t-tests, chi-square tests, and logistic regression models. Results: Patients with CDI demonstrated significantly higher CRP, IL-6, SII, and CAR, coupled with lower albumin and PNI (p < 0.05). They also had elevated APACHE II, CURB-65, and NEWS scores. CDI-positive patients experienced increased ICU admission (38.8% vs. 20.5%), mechanical ventilation (24.5% vs. 12.9%), and mortality (22.4% vs. 10.6%, all p < 0.05). Subgroup analyses revealed more pronounced inflammatory derangements and worse outcomes in elderly, diabetic, and cancer patients with CDI. Conclusions: Concurrent CDI intensifies systemic inflammation and adverse clinical trajectories in hospitalized COVID-19 patients. Elevations in inflammatory markers and severity scores predict worse outcomes, especially in high-risk subgroups. Early recognition and targeted interventions, including infection control and supportive measures, may attenuate disease severity and improve patient survival. Full article

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

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11 pages, 1147 KiB

Open AccessArticle

Vibrio cholerae Gut Colonization of Zebrafish Larvae Induces a Dampened Sensorimotor Response

by Isabella Cubillejo, Kevin R. Theis, Jonathan Panzer, Xixia Luo, Shreya Banerjee, Ryan Thummel and Jeffrey H. Withey

Biomedicines 2025, 13(1), 226; https://doi.org/10.3390/biomedicines13010226 - 17 Jan 2025

Viewed by 455

Abstract

Background: Cholera is a diarrheal disease prevalent in populations without access to clean water. Cholera is caused by Vibrio cholerae, which colonizes the upper small intestine in humans once ingested. A growing number of studies suggest that the gut microbiome composition modulates animal [...] Read more.

Background: Cholera is a diarrheal disease prevalent in populations without access to clean water. Cholera is caused by Vibrio cholerae, which colonizes the upper small intestine in humans once ingested. A growing number of studies suggest that the gut microbiome composition modulates animal behavior. Zebrafish are an established cholera model that can maintain a complex, mature gut microbiome during infection. Larval zebrafish, which have immature gut microbiomes, provide the advantage of high-throughput analyses for established behavioral models. Methods: We identified the effects of V. cholerae O1 El Tor C6706 colonization at 5 days post-fertilization (dpf) on larval zebrafish behavior by tracking startle responses at 10 dpf. We also characterized the larval gut microbiome using 16S rRNA sequencing. V. cholerae-infected or uninfected control groups were exposed to either an alternating light/dark stimuli or a single-tap stimulus, and average distance and velocity were tracked. Results: While there was no significant difference in the light/dark trial, we report a significant decrease in distance moved for C6706-colonized larvae during the single-tap trial. Conclusion: This suggests that early V. cholerae colonization of the larval gut microbiome has a dampening effect on sensorimotor function, supporting the idea of a link between the gut microbiome and behavior. Full article

(This article belongs to the Special Issue Zebrafish Models for Development and Disease 4.0)

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15 pages, 2118 KiB

Open AccessReview

Advances in Immunotherapy and Targeted Therapy of Malignant Melanoma

by Xue Wang, Shanshan Ma, Shuting Zhu, Liucun Zhu and Wenna Guo

Biomedicines 2025, 13(1), 225; https://doi.org/10.3390/biomedicines13010225 - 17 Jan 2025

Viewed by 839

Abstract

Malignant melanoma (MM) is a malignant tumor, resulting from mutations in melanocytes of the skin and mucous membranes. Its mortality rate accounts for 90% of all dermatologic tumor mortality. Traditional treatments such as surgery, chemotherapy, and radiotherapy are unable to achieve the expected [...] Read more.

Malignant melanoma (MM) is a malignant tumor, resulting from mutations in melanocytes of the skin and mucous membranes. Its mortality rate accounts for 90% of all dermatologic tumor mortality. Traditional treatments such as surgery, chemotherapy, and radiotherapy are unable to achieve the expected results due to MM’s low sensitivity, high drug resistance, and toxic side effects. As treatment advances, immunotherapy and targeted therapy have made significant breakthroughs in the treatment of MM and have demonstrated promising application prospects. However, the heterogeneity of tumor immune response causes more than half of patients to not benefit from clinical immunotherapy and targeted therapy, which delays the patient’s condition and causes them to suffer adverse immune events’ side effects. The combination of immunotherapy and targeted therapy can help improve therapeutic effects, delay drug resistance, and mitigate adverse effects. This review provides a comprehensive overview of the current development status and research progress of immune checkpoints, targeted genes, and their inhibitors, with a view to providing a reference for the clinical treatment of MM. Full article

(This article belongs to the Special Issue Molecular Research and New Therapy in Melanoma)

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14 pages, 3034 KiB

Open AccessArticle

NF-κB-Specific Suppression in Cardiomyocytes Unveils Aging-Associated Responses in Cardiac Tissue

by Letícia Aparecida Lopes Morgado, Larissa Maria Zacarias Rodrigues, Daiane Cristina Floriano Silva, Bruno Durante da Silva, Maria Claudia Costa Irigoyen and Ana Paula Cremasco Takano

Biomedicines 2025, 13(1), 224; https://doi.org/10.3390/biomedicines13010224 - 17 Jan 2025

Viewed by 580

Abstract

Background/Objectives: Aging is associated with structural and functional changes in the heart, including hypertrophy, fibrosis, and impaired contractility. Cellular mechanisms such as senescence, telomere shortening, and DNA damage contribute to these processes. Nuclear factor kappa B (NF-κB) has been implicated in mediating [...] Read more.

Background/Objectives: Aging is associated with structural and functional changes in the heart, including hypertrophy, fibrosis, and impaired contractility. Cellular mechanisms such as senescence, telomere shortening, and DNA damage contribute to these processes. Nuclear factor kappa B (NF-κB) has been implicated in mediating cellular responses in aging tissues, and increased NF-κB expression has been observed in the hearts of aging rodents. Therefore, NF-κB is suspected to play an important regulatory role in the cellular and molecular processes occurring in the heart during aging. This study investigates the in vivo role of NF-κB in aging-related cardiac alterations, focusing on senescence and associated cellular events. Methods: Young and old wild-type (WT) and transgenic male mice with cardiomyocyte-specific NF-κB suppression (3M) were used to assess cardiac function, morphology, senescence markers, lipofuscin deposition, DNA damage, and apoptosis. Results: Kaplan–Meier analysis revealed reduced survival in 3M mice compared to WT. Echocardiography showed evidence of eccentric hypertrophy, and both diastolic and systolic dysfunction in 3M mice. Both aged WT and 3M mice exhibited cardiac hypertrophy, with more pronounced hypertrophic changes in cardiomyocytes from 3M mice. Additionally, cardiac fibrosis, senescence-associated β-galactosidase activity, p21 protein expression, and DNA damage (marked by phosphorylated H2A.X) were elevated in aged WT and both young and aged 3M mice. Conclusions: The suppression of NF-κB in cardiomyocytes leads to pronounced cardiac remodeling, dysfunction, and cellular damage associated with the aging process. These findings suggest that NF-κB plays a critical regulatory role in cardiac aging, influencing both cellular senescence and molecular damage pathways. This has important implications for the development of therapeutic strategies aimed at mitigating age-related cardiovascular diseases. Full article

(This article belongs to the Special Issue Unraveling the Molecular Mechanisms of Heart and Skeletal Muscle Pathologies)

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27 pages, 951 KiB

Open AccessReview

Bcl-2 and Bcl-xL in Diabetes: Contributions to Endocrine Pancreas Viability and Function

by Atenea A. Perez-Serna, Daniel Guzman-Llorens, Reinaldo S. Dos Santos and Laura Marroqui

Biomedicines 2025, 13(1), 223; https://doi.org/10.3390/biomedicines13010223 - 17 Jan 2025

Viewed by 771

Abstract

Diabetes is a chronic metabolic disorder whose prevalence increases every year, affecting more than 530 million adults worldwide. Type 1 (T1D) and type 2 diabetes (T2D), the most common forms of diabetes, are characterized by the loss of functional pancreatic β-cells, mostly due [...] Read more.

Diabetes is a chronic metabolic disorder whose prevalence increases every year, affecting more than 530 million adults worldwide. Type 1 (T1D) and type 2 diabetes (T2D), the most common forms of diabetes, are characterized by the loss of functional pancreatic β-cells, mostly due to apoptosis. B-cell leukemia/lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xL), two anti-apoptotic proteins belonging to the Bcl-2 family, are crucial for regulating the intrinsic pathway of apoptosis. However, over the years, they have been implicated in many other cellular processes, including intracellular Ca²⁺ homeostasis and the regulation of mitochondrial metabolism. Thus, understanding the biological processes in which these proteins are involved may be crucial to designing new therapeutic targets. This review summarizes the roles of Bcl-2 and Bcl-xL in apoptosis and metabolic homeostasis. It focuses on how the dysregulation of Bcl-2 and Bcl-xL affects pancreatic β-cell function and survival, and the consequences for diabetes development. Full article

(This article belongs to the Special Issue Novel Insights into the Mechanisms Leading to β-Cell Dysfunction and Demise in Type 1 Diabetes)

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12 pages, 870 KiB

Open AccessReview

Detection of Deaths Caused by Hyperkalemia

by Małgorzata Żulicka, Kamila Sobczak, Dominik Kowalczyk, Sylwia Sikorska, Wioletta Arendt and Marta Hałas-Wiśniewska

Biomedicines 2025, 13(1), 222; https://doi.org/10.3390/biomedicines13010222 - 17 Jan 2025

Viewed by 464

Abstract

Under normal conditions, potassium is predominantly found within cells. The concentration gradient of sodium and potassium ions between intracellular and extracellular spaces enables signal transmission through membrane depolarization. The disruption of this transcellular process leads to elevated potassium ion levels in the extracellular [...] Read more.

Under normal conditions, potassium is predominantly found within cells. The concentration gradient of sodium and potassium ions between intracellular and extracellular spaces enables signal transmission through membrane depolarization. The disruption of this transcellular process leads to elevated potassium ion levels in the extracellular space, and thus in the blood, a condition known as hyperkalemia. Clinically, hyperkalemia may present as cardiac arrhythmias, muscle weakness, and palpitations. The post-mortem accumulation of potassium ions in various human tissues and organs, such as the heart, liver, kidneys, lungs, and vitreous body, particularly in cases of overdose, has been an area of research interest for years. Unfortunately, deaths caused by hyperkalemia are difficult to identify due to their non-specific symptoms and are often misinterpreted as cardiovascular-related. Furthermore, most potassium ion concentration tests developed in recent years are non-specific, have limitations, or are based on outdated techniques. Consequently, alternative methods, such as histopathological tissue analysis, potassium concentration assessment in the vitreous body, and aldosterone level measurement, show promise for improving the post-mortem detection of exogenous hyperkalemia. Full article

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

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8 pages, 755 KiB

Open AccessCommunication

Cell Mechanisms of Post-Mortem Excitability of Skeletal Muscle

by H. Stigter, T. Krap and W. L. J. M. Duijst

Biomedicines 2025, 13(1), 221; https://doi.org/10.3390/biomedicines13010221 - 17 Jan 2025

Viewed by 527

Abstract

Background/Objectives: The excitability of skeletal muscle is a less-known post-mortem supravital phenomenon in human bodies, and it can be used to estimate the post-mortem interval. We conducted a field study in the Netherlands to investigate the applicability of muscle excitability (SMR) by mechanical [...] Read more.

Background/Objectives: The excitability of skeletal muscle is a less-known post-mortem supravital phenomenon in human bodies, and it can be used to estimate the post-mortem interval. We conducted a field study in the Netherlands to investigate the applicability of muscle excitability (SMR) by mechanical stimulation for estimating the post-mortem interval in daily forensic practice. Knowledge concerning the post-mortem cell mechanisms accounting for the post-mortem excitability of skeletal muscle is lacking. Cell mechanisms are the specific intracellular and biochemical processes responsible for post-mortem muscle excitability. Methods: We have studied the theoretical backgrounds of the cell mechanisms that might be responsible for post-mortem muscle excitability, by performing literature research via the databank PubMed. Results: Based on the current available literature, in our opinion the intracellular changes in muscle cells that are responsible for SMR resemble the intracellular processes responsible for muscle fatigue due to energy exhaustion in the living. Conclusions: We hypothesize two pathways, depending on the level of energy in the muscle cell, that could be responsible for post-mortem muscle excitability by mechanical stimulation. Full article

(This article belongs to the Special Issue Advanced Research on Skeletal Muscle Metabolism)

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16 pages, 2695 KiB

Open AccessArticle

Inflammatory Biomarkers and Lipid Parameters May Predict an Increased Risk for Atrial Arrhythmias in Patients with Systemic Sclerosis

by Veronika Sebestyén, Dóra Ujvárosy, Balázs Ratku, Hajnalka Lőrincz, Sára Csiha, Dóra Tari, Gyöngyike Majai, Sándor Somodi, Gabriella Szűcs, Mariann Harangi and Zoltán Szabó

Biomedicines 2025, 13(1), 220; https://doi.org/10.3390/biomedicines13010220 - 16 Jan 2025

Viewed by 468

Abstract

Background/Objectives: Autoimmune inflammation enhances the electrical instability of the atrial myocardium in patients with systemic sclerosis (SSc); thus, atrial arrhythmia risk is increased, which might be predicted by evaluating the P wave interval and dispersion of a 12-lead surface electrocardiogram (ECG). Methods: We [...] Read more.

Background/Objectives: Autoimmune inflammation enhances the electrical instability of the atrial myocardium in patients with systemic sclerosis (SSc); thus, atrial arrhythmia risk is increased, which might be predicted by evaluating the P wave interval and dispersion of a 12-lead surface electrocardiogram (ECG). Methods: We examined 26 SSc patients and 36 healthy controls and measured the P wave interval and P wave dispersion of the 12-lead surface ECG in each patient. Furthermore, echocardiography and 24-h Holter ECG were performed and levels of inflammatory laboratory parameters, including serum progranulin (PGRN), sVCAM-1, sICAM-1, leptin and C-reactive protein (CRP), were determined. Lipid parameters, such as Apo A-I, LDL-cholesterol (LDL-C), oxidized LDL (oxLDL) and the LDL and HDL subfractions were also evaluated. Results: The P wave interval showed a significant positive correlation with the levels of Apo A-I, LDL-C, CRP, sVCAM-1, sICAM-1 and leptin. The oxLDL level correlated positively with P wave dispersion. Of note, significant positive correlation was also found between the large HDL percentage and the P wave interval. Conclusions: Our results suggest that PGRN, sVCAM-1, sICAM-1, leptin, CRP, LDL-C and oxLDL, along with LDL and HDL subfractions, might have a role in atrial arrhythmogenesis in patients with SSc. Full article

(This article belongs to the Special Issue Connective Tissue Disorders: Pathogenetic, Diagnostic and Therapeutic Perspectives)

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24 pages, 3976 KiB

Open AccessArticle

Influence of Mesalazine on Ferroptosis-Related Gene Expression in In Vitro Colorectal Cancer Culture

by Joanna Słoka, Barbara Strzałka-Mrozik, Sebastian Kubica, Ilona Nowak and Celina Kruszniewska-Rajs

Biomedicines 2025, 13(1), 219; https://doi.org/10.3390/biomedicines13010219 - 16 Jan 2025

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Abstract

Background/Objectives: Colorectal cancer (CRC) is one of the most common oncological disorders. Its fundamental treatments include surgery and chemotherapy, predominantly utilizing 5-fluorouracil (5-FU). Despite medical advances, CRC continues to present a high risk of recurrence, metastasis and low survival rates. Consequently, significant emphasis [...] Read more.

Background/Objectives: Colorectal cancer (CRC) is one of the most common oncological disorders. Its fundamental treatments include surgery and chemotherapy, predominantly utilizing 5-fluorouracil (5-FU). Despite medical advances, CRC continues to present a high risk of recurrence, metastasis and low survival rates. Consequently, significant emphasis has been directed towards exploring novel types of cell death, particularly ferroptosis. Ferroptosis is characterized by iron imbalance and the accumulation of lipid peroxides and reactive oxygen species (ROS), leading to cellular damage and death. Thus, the discovery of safe inducers of ferroptosis, offering new hope in the struggle against CRC, remains crucial. In this study, we applied the concept of drug repositioning, selecting mesalazine (MES), a non-steroidal anti-inflammatory drug (NSAID), for investigation. Methods: The study was conducted on the colon cancer cell line DLD-1 and normal intestinal epithelial cells from the CCD 841 CoN cell line. Both cell lines were treated with MES solutions at concentrations of 10, 20, 30, 40, and 50 mM. Cytotoxicity was assessed using the MTT assay, while ferroptosis-related gene expression analysis was performed using oligonucleotide microarrays, with RT-qPCR used for validation. Results: MES effectively reduces the viability of DLD-1 cells while minimally affecting normal intestinal cells. Subsequent oligonucleotide microarray analysis revealed that MES significantly alters the expression of 56 genes associated with ferroptosis. Conclusions: Our results suggest that MES may induce ferroptosis in CRC, providing a foundation for further research in this area. Full article

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

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25 pages, 5173 KiB

Open AccessArticle

Repetitive Mild but Not Single Moderate Brain Trauma Is Associated with TAR DNA-Binding Protein 43 Mislocalization and Glial Activation in the Mouse Spinal Cord

by Tamara Janković, Jelena Rajič Bumber, Nika Gržeta Krpan, Petra Dolenec, Marc Jaeger, Jasna Kriz, Gordana Župan and Kristina Pilipović

Biomedicines 2025, 13(1), 218; https://doi.org/10.3390/biomedicines13010218 - 16 Jan 2025

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Abstract

Background/Objectives: Traumatic brain injury (TBI) occurs after a sudden mechanical force to the skull and represents a significant public health problem. Initial brain trauma triggers secondary pathophysiological processes that induce structural and functional impairment of the central nervous system, even in the [...] Read more.

Background/Objectives: Traumatic brain injury (TBI) occurs after a sudden mechanical force to the skull and represents a significant public health problem. Initial brain trauma triggers secondary pathophysiological processes that induce structural and functional impairment of the central nervous system, even in the regions distant to the lesion site. Later in life, these changes can be manifested as neurodegenerative sequalae that commonly involve proteinopathies, such as transactive DNA-binding protein 43 (TDP-43). The progression of pathophysiological changes to the spinal cord motor neurons has been detected after repetitive TBI, while such changes have been less investigated after single TBI. Methods: Single TBI was applied over the left parietal cortex of mice by using the lateral fluid percussion injury apparatus and a separate cohort of animals received repetitive mild TBI by weight drop apparatus, with two mild injuries daily, for five days in a row. Mice were sacrificed after single moderate or last mild TBI and their spinal cords were prepared for the analyses. For both types of injury, sham-injured mice were used as a control group. Results: Here, we found an early formation of toxic phosphorylated TDP-43 species on the 3rdday post-injury which, together with TDP-43 cytoplasmic translocation, remained present in the subacute period of 14 days after repetitive mild but not single moderate TBI. During the subacute period following a repetitive brain trauma, we found an increased choline acetyltransferase protein expression and significant microgliosis in the cervical part of the spinal cord, which was not detected after single TBI. Astrogliosis presented similarly after both experimental procedures. Conclusions: This study demonstrates the differences in the spinal cord TDP-43 pathology and inflammation, depending on the brain trauma type, and may contribute to the development of targeted therapeutic strategies. Full article

(This article belongs to the Special Issue Brain Injury: New Insights into Mechanisms and Future Promising Treatments)

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Biomedicines, Volume 13, Issue 1 (January 2025) – 247 articles

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