Biomedicines

19 pages, 852 KB

Open AccessEditor’s ChoiceArticle

Autoantibodies Targeting G-Protein-Coupled Receptors and RAS-Related Molecules in Post-Acute COVID Vaccination Syndrome: A Retrospective Case Series Study

by Mauro Mantovani, Paolo Bellavite, Serafino Fazio, Giuseppe Di Fede, Marco Tomasi, Daniele Belli and Elisabetta Zanolin

Biomedicines 2024, 12(12), 2852; https://doi.org/10.3390/biomedicines12122852 - 15 Dec 2024

Cited by 1 | Viewed by 19756

Abstract

Background/Objectives: While post-acute COVID-19 syndrome is well known and extensively studied, the post-acute COVID vaccination syndrome (PACVS) is a more recent nosological entity that is poorly defined at the immunopathological level, although it shares many symptoms with the sequelae of viral infections. [...] Read more.

Background/Objectives: While post-acute COVID-19 syndrome is well known and extensively studied, the post-acute COVID vaccination syndrome (PACVS) is a more recent nosological entity that is poorly defined at the immunopathological level, although it shares many symptoms with the sequelae of viral infections. Methods: This single-center retrospective study reports a case series of 17 subjects vaccinated with mRNA or adenoviral vector vaccines who were healthy before vaccination and had never been infected with SARS-CoV-2 but who presented with symptoms similar to PACVS for a median time of 20 months (min 4, max 32). The medical records of all patients referred to our outpatient clinic over a one-year period were retrospectively analyzed. Results: In this group, serological tests showed that, in addition to positivity for anti-spike protein antibodies, a high percentage of subjects were positive for antibodies against G protein-coupled receptors and molecules involved in the response to SARS-CoV-2. In a panel of 16 autoantibodies tested, a few were positively associated with some of the symptoms reported by patients: anti-ATR1 with lymphadenopathy and/or tonsillitis; anti-ACE2 with skin symptoms such as ecchymosis, skin oedema, and rash; anti-MAS1 with widespread burning sensation; and anti-STAB1 with skin oedema and rash. Anti-ADRA2A were negatively associated with memory loss and/or mental fog. ACE2 correlated with the serum levels of anti-S antibodies, supporting the hypothesis of an anti-idiotype mechanism in the immunopathogenesis of PACVS. Conclusions: This exploratory analysis suggests that the levels of autoantibodies directed against ACE2, and probably also MAS1 and STAB1, may serve as biomarkers for PACVS. Full article

(This article belongs to the Special Issue SARS-CoV-2 Infection: Focus on Pathophysiological Characteristics, Complications and Effects of Vaccinations)

► Show Figures

Graphical abstract

16 pages, 301 KB

Open AccessEditor’s ChoiceReview

Updates on Chimeric Antigen Receptor T-Cells in Large B-Cell Lymphoma

by Khalil Saleh, Nadine Khalife, Ahmadreza Arbab, Rita Khoury, Claude Chahine, Rebecca Ibrahim, Zamzam Tikriti, Nohad Masri, Mohamad Hachem and Axel Le Cesne

Biomedicines 2024, 12(12), 2810; https://doi.org/10.3390/biomedicines12122810 - 11 Dec 2024

Cited by 2 | Viewed by 1752

Abstract

CD19-targeting chimeric antigen receptor (CAR) T-cells have changed the treatment paradigm of patients with large B-cell lymphoma (LBCL). Three CAR T-cells were approved by the Food and Drug Administration (FDA) for patients with relapsed and/or refractory (R/R) LBCL in the third-line setting: tisagenlecleucel [...] Read more.

CD19-targeting chimeric antigen receptor (CAR) T-cells have changed the treatment paradigm of patients with large B-cell lymphoma (LBCL). Three CAR T-cells were approved by the Food and Drug Administration (FDA) for patients with relapsed and/or refractory (R/R) LBCL in the third-line setting: tisagenlecleucel (tisa-cel), axicabtagene ciloleucel (axi-cel), and lisocabtagene maraleucel (liso-cel), with an ORR ranging from 58% to 82%. More recently, axi-cel and liso-cel were approved as second-line treatments for patients with R/R disease up to 12 months after the completion of first-line chemo-immunotherapy. The safety profile was acceptable with cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome being the two most frequent acute adverse events. Potential long-term toxicities of CD19-targeting CAR T-cells have also been described. Overall, 30% to 40% of patients are cured with a single infusion of CAR T-cells. However, 60% to 70% of patients relapse after being treated with CAR T-cells and have a dismal prognosis. The advent of bispecific antibodies (BsAb) offers an additional treatment modality for patients with R/R LBCL. The aim of this review is to describe the clinical efficacy of the three CAR T-cells, as well as their safety profile. We also compare these three CAR T-cells in terms of their efficacy and safety profile as well as evaluating the place of CAR T-cells and BsAb in the treatment arsenal of patients with R/R LBCL. Full article

(This article belongs to the Special Issue Advances in CAR-T Cell Therapy)

12 pages, 1920 KB

Open AccessEditor’s ChoiceArticle

Exploration of Novel Biomarkers for Neurodegenerative Diseases Using Proteomic Analysis and Ligand-Binding Assays

by Annalena Kenzelmann, Christina Boch, Ronny Schmidt, Mario Richter and Michael Schulz

Biomedicines 2024, 12(12), 2794; https://doi.org/10.3390/biomedicines12122794 - 9 Dec 2024

Cited by 1 | Viewed by 1955

Abstract

Background/Objectives: Neurodegenerative diseases are a major cause of morbidity and mortality worldwide, and their public health burden continues to increase. There is an urgent need to develop reliable and sensitive biomarkers to aid the timely diagnosis, disease progression monitoring, and therapeutic development for [...] Read more.

Background/Objectives: Neurodegenerative diseases are a major cause of morbidity and mortality worldwide, and their public health burden continues to increase. There is an urgent need to develop reliable and sensitive biomarkers to aid the timely diagnosis, disease progression monitoring, and therapeutic development for neurodegenerative disorders. Proteomic screening strategies, including antibody microarrays, are a powerful tool for biomarker discovery, but their findings should be confirmed using quantitative assays. The current study explored the feasibility of combining an exploratory proteomic strategy and confirmatory ligand-binding assays to screen for and validate biomarker candidates for neurodegenerative disorders. Methods: It analyzed cerebrospinal fluid (CSF) and plasma samples from patients with Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis and healthy controls using an exploratory antibody microarray and validatory ligand-binding assays. Results: The screening antibody microarray identified differentially expressed proteins between patients with neurodegenerative diseases and healthy controls, including cluster of differentiation 14 (CD14), osteopontin, and vascular endothelial growth factor 165b. Quantitative ligand-binding assays confirmed that CD14 levels were elevated in CSF of patients with Alzheimer’s disease (p = 0.0177), whereas osteopontin levels were increased in CSF of patients with Parkinson’s disease (p = 0.0346). Conclusions: The current study demonstrated the potential utility of combining an exploratory proteomic approach and quantitative ligand-binding assays to identify biomarker candidates for neurodegenerative disorders. To further validate and expand these findings, large-scale analyses using well-characterized samples should be conducted. Full article

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

► Show Figures

Figure 1

16 pages, 638 KB

Open AccessEditor’s ChoiceArticle

Machine Learning for Early Detection of Cognitive Decline in Parkinson’s Disease Using Multimodal Biomarker and Clinical Data

by Raziyeh Mohammadi, Samuel Y. E. Ng, Jayne Y. Tan, Adeline S. L. Ng, Xiao Deng, Xinyi Choi, Dede L. Heng, Shermyn Neo, Zheyu Xu, Kay-Yaw Tay, Wing-Lok Au, Eng-King Tan, Louis C. S. Tan, Ewout W. Steyerberg, William Greene and Seyed Ehsan Saffari

Biomedicines 2024, 12(12), 2758; https://doi.org/10.3390/biomedicines12122758 - 3 Dec 2024

Cited by 3 | Viewed by 2617

Abstract

Background: Parkinson’s disease (PD) is the second most common neurodegenerative disease, primarily affecting the middle-aged to elderly population. Among its nonmotor symptoms, cognitive decline (CD) is a precursor to dementia and represents a critical target for early risk assessment and diagnosis. Accurate [...] Read more.

Background: Parkinson’s disease (PD) is the second most common neurodegenerative disease, primarily affecting the middle-aged to elderly population. Among its nonmotor symptoms, cognitive decline (CD) is a precursor to dementia and represents a critical target for early risk assessment and diagnosis. Accurate CD prediction is crucial for timely intervention and tailored management of at-risk patients. This study used machine learning (ML) techniques to predict the CD risk over five-year in early-stage PD. Methods: Data from the Early Parkinson’s Disease Longitudinal Singapore (2014 to 2018) was used to predict CD defined as a one-unit annual decrease or a one-unit decline in Montreal Cognitive Assessment over two consecutive years. Four ML methods—AutoScore, Random Forest, K-Nearest Neighbors and Neural Network—were applied using baseline demographics, clinical assessments and blood biomarkers. Results: Variable selection identified key predictors of CD, including education year, diastolic lying blood pressure, diastolic standing blood pressure, systolic lying blood pressure, Hoehn and Yahr scale, body mass index, phosphorylated tau at threonine 181, total tau, Neurofilament light chain and suppression of tumorigenicity 2. Random Forest was the most effective, achieving an AUC of 0.93 (95% CI: 0.89, 0.97), using 10-fold cross-validation. Conclusions: Here, we demonstrate that ML-based models can identify early-stage PD patients at high risk for CD, supporting targeted interventions and improved PD management. Full article

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

► Show Figures

Figure 1

13 pages, 699 KB

Open AccessEditor’s ChoiceArticle

Pharmacotherapy from Pre-COVID to Post-COVID: Longitudinal Trends and Predictive Indicators for Long COVID Symptoms

by Nadia Baalbaki, Sien T. Verbeek, Harm Jan Bogaard, Jelle M. Blankestijn, Vera C. van den Brink, Merel E. B. Cornelissen, Jos W. R. Twisk, Korneliusz Golebski and Anke H. Maitland-van der Zee

Biomedicines 2024, 12(12), 2694; https://doi.org/10.3390/biomedicines12122694 - 26 Nov 2024

Viewed by 1279

Abstract

Background/objectives: A significant number of COVID-19 cases experience persistent symptoms after the acute infection phase, a condition known as long COVID or post-acute sequelae of COVID-19. Approved prevention and treatment options for long COVID are currently lacking. Given the heterogeneous nature of long [...] Read more.

Background/objectives: A significant number of COVID-19 cases experience persistent symptoms after the acute infection phase, a condition known as long COVID or post-acute sequelae of COVID-19. Approved prevention and treatment options for long COVID are currently lacking. Given the heterogeneous nature of long COVID, a personalized medicine approach is essential for effective disease management. This study aimed to describe trends in pharmacotherapy from pre-COVID to post-COVID phases to gain insights into COVID-19 treatment strategies and assess whether pre-COVID pharmacotherapy can predict long COVID symptoms as a health status indicator. Methods: In the Precision Medicine for more Oxygen (P4O2) COVID-19 study, 95 long COVID patients were comprehensively evaluated through post-COVID outpatient clinics and study visits. This study focused on descriptive analysis of the pharmacotherapy patterns across different phases: pre-COVID-19, acute COVID, and post-COVID. Furthermore, associations between pre-COVID medication and long COVID outcomes were analyzed with regression analyses. Results: We observed peaks in the use of certain medications during the acute infection phase, including corticosteroids and antithrombotic agents, with a decrease in the use of renin–angiotensin system inhibitors. Consistently high use of alimentary tract medications was found across all phases. Pre-COVID respiratory medications were associated with fatigue symptoms, while antiinfectives and cardiovascular drugs were linked to fewer persisting long COVID symptom categories. Conclusion: Our findings provide longitudinal, descriptive pharmacotherapy insights and suggest that medication history can be a valuable health status indicator in characterizing patients for personalized disease management strategies, considering the heterogeneous nature of long COVID. Full article

(This article belongs to the Special Issue Long COVID: Mechanisms, Biomarkers, and Treatment)

► Show Figures

Figure 1

20 pages, 1363 KB

Open AccessEditor’s ChoiceReview

Metabolic Crossroad Between Macrophages and Cancer Cells: Overview of Hepatocellular Carcinoma

by Anna Santarsiero, Paolo Convertini, Dominga Iacobazzi, Vittoria Infantino and Simona Todisco

Biomedicines 2024, 12(12), 2684; https://doi.org/10.3390/biomedicines12122684 - 25 Nov 2024

Cited by 1 | Viewed by 2000

Abstract

The metabolic interplay between macrophages and cancer cells mirrors the plasticity of both kinds of cells, which adapt to the microenvironment by sustaining cell growth and proliferation. In this way, cancer cells induce macrophage polarization, and, on the other hand, tumor-associated macrophages (TAMs) [...] Read more.

The metabolic interplay between macrophages and cancer cells mirrors the plasticity of both kinds of cells, which adapt to the microenvironment by sustaining cell growth and proliferation. In this way, cancer cells induce macrophage polarization, and, on the other hand, tumor-associated macrophages (TAMs) contribute to the survival of cancer cells. In a simplified manner, macrophages can assume two opposite subtypes: M1, pro-inflammatory and anti-tumor phenotype, and M2, anti-inflammatory and protumor phenotype. How do cancer cells induce macrophage polarization? Any actor involved in tumor growth, including the mitochondria, releases molecules into the tumor microenvironment (TME) that trigger a subtype transition. These metabolic changes are the primary cause of this polarization. Hepatocellular carcinoma (HCC), the prevalent type of liver primary tumor, is characterized by cells with extensive metabolic adaptions due to high flexibility in different environmental conditions. This review focuses on the main metabolic features of M1 and M2 macrophages and HCC cells underlying their metabolic behavior in response to TME. Full article

(This article belongs to the Special Issue Mitochondria and Immunometabolism in Cancer)

► Show Figures

Figure 1

19 pages, 2315 KB

Open AccessEditor’s ChoiceArticle

Role of the Egr2 Promoter Antisense RNA in Modulating the Schwann Cell Chromatin Landscape

by Margot Martinez Moreno, David Karambizi, Hyeyeon Hwang, Kristen Fregoso, Madison J. Michles, Eduardo Fajardo, Andras Fiser and Nikos Tapinos

Biomedicines 2024, 12(11), 2594; https://doi.org/10.3390/biomedicines12112594 - 13 Nov 2024

Viewed by 1911

Abstract

Background: Schwann cells (SCs) and their plasticity contribute to the peripheral nervous system’s capacity for nerve regeneration after injury. The Egr2/Krox20 promoter antisense RNA (Egr2-AS) recruits chromatin remodeling complexes to inhibit Egr2 transcription following peripheral nerve injury. Methods: RNA-seq and ATAC-seq [...] Read more.

Background: Schwann cells (SCs) and their plasticity contribute to the peripheral nervous system’s capacity for nerve regeneration after injury. The Egr2/Krox20 promoter antisense RNA (Egr2-AS) recruits chromatin remodeling complexes to inhibit Egr2 transcription following peripheral nerve injury. Methods: RNA-seq and ATAC-seq were performed on control cells, Lenti-GFP-transduced cells, and cells overexpressing Egr2-AS (Lenti-AS). Egr2 AS-RNA was cloned into the pLVX-DsRed-Express2-N1 lentiviral expression vector (Clontech, Mountain View, CA, USA), and the levels of AS-RNA expression were determined. Ezh2 and Wdr5 were immunoprecipitated from rat SCs and RT-qPCR was performed against AS-Egr2 RNA. ChIP followed by DNA purification columns was used to perform qPCR for relevant promoters. Hi-C, HiC-DC+, R, Bioconductor, and TOBIAS were used for significant and differential loop analysis, identifications of COREs and CORE-promotor loops, comparisons of TF activity at promoter sites, and identification of site-specific TF footprints. OnTAD was used to detect TADs, and Juicer was used to identify A/B compartments. Results: Here we show that a Neuregulin-ErbB2/3 signaling axis mediates binding of the Egr2-AS to YY1^Ser184 and regulates its expression. Egr2-AS modulates the chromatin accessibility of Schwann cells and interacts with two distinct histone modification complexes. It binds to EZH2 and WDR5 and enables targeting of H3K27me3 and H3K4me3 to promoters of Egr2 and C-JUN, respectively. Expression of the Egr2-AS results in reorganization of the global chromatin landscape and quantitative changes in the loop formation and contact frequency at domain boundaries exhibiting enrichment for AP-1 genes. In addition, the Egr2-AS induces changes in the hierarchical TADs and increases transcription factor binding scores on an inter-TAD loop between a super-enhancer regulatory hub and the promoter of mTOR. Conclusions: Our results show that Neuregulin-ErbB2/3-YY1 regulates the expression of Egr2-AS, which mediates remodeling of the chromatin landscape in Schwann cells. Full article

(This article belongs to the Special Issue Epigenetic Regulation and Its Impact for Medicine)

► Show Figures

Figure 1

13 pages, 1208 KB

Open AccessEditor’s ChoiceReview

The Critical Role of Host and Bacterial Extracellular Vesicles in Endometriosis

by Michaela Wagner, Chloe Hicks, Emad El-Omar, Valery Combes and Fatima El-Assaad

Biomedicines 2024, 12(11), 2585; https://doi.org/10.3390/biomedicines12112585 - 12 Nov 2024

Cited by 2 | Viewed by 2209

Abstract

Endometriosis is a chronic, inflammatory, oestrogen-dependent disorder that is defined by the presence of endometrium-like tissue in the extra-uterine environment. It is estimated to affect approximately 10% of women of reproductive age, and the cause is still largely unknown. The heterogenous nature and [...] Read more.

Endometriosis is a chronic, inflammatory, oestrogen-dependent disorder that is defined by the presence of endometrium-like tissue in the extra-uterine environment. It is estimated to affect approximately 10% of women of reproductive age, and the cause is still largely unknown. The heterogenous nature and complex pathophysiology of the disease results in diagnostic and therapeutic challenges. This review examines the emerging role of host extracellular vesicles (EVs) in endometriosis development and progression, with a particular focus on bacterial extracellular vesicles (BEVs). EVs are nano-sized membrane-bound particles that can transport bioactive molecules such as nucleic acids, proteins, and lipids, and therefore play an essential role in intercellular communication. Due to their unique cargo composition, EVs can play a dual role, both in the disease pathogenesis and as biomarkers. Both host and bacterial EVs (HEVs and BEVs) have been implicated in endometriosis, by modulating inflammatory responses, angiogenesis, tissue remodelling, and cellular proliferation within the peritoneal microenvironment. Understanding the intricate mechanisms underlying EVs in endometriosis pathophysiology and modulation of the lesion microenvironment may lead to novel diagnostic tools and therapeutic targets. Future research should focus on uncovering the specific cargo, the inter-kingdom cell-to-cell interactions, and the anti-inflammatory and anti-microbial mechanisms of both HEVs and BEVs in endometriosis in the hope of discovering translational findings that could improve the diagnosis and treatment of the disease. Full article

(This article belongs to the Special Issue Advanced Research in Endometriosis 4.0)

► Show Figures

Figure 1

33 pages, 2029 KB

Open AccessEditor’s ChoiceReview

Heart Failure: A Deficiency of Energy—A Path Yet to Discover and Walk

by Ioannis Paraskevaidis, Christos Kourek, Dimitrios Farmakis and Elias Tsougos

Biomedicines 2024, 12(11), 2589; https://doi.org/10.3390/biomedicines12112589 - 12 Nov 2024

Cited by 4 | Viewed by 2296

Abstract

Heart failure is a complex syndrome and our understanding and therapeutic approach relies mostly on its phenotypic presentation. Notably, the heart is characterized as the most energy-consuming organ, being both a producer and consumer, in order to satisfy multiple cardiac functions: ion exchange, [...] Read more.

Heart failure is a complex syndrome and our understanding and therapeutic approach relies mostly on its phenotypic presentation. Notably, the heart is characterized as the most energy-consuming organ, being both a producer and consumer, in order to satisfy multiple cardiac functions: ion exchange, electromechanical coordination, excitation–contraction coupling, etc. By obtaining further knowledge of the cardiac energy field, we can probably better characterize the basic pathophysiological events occurring in heart disease patients and understand the metabolic substance changes, the relationship between the alteration of energy production/consumption, and hence energetic deficiency not only in the heart as a whole but in every single cardiac territory, which will hopefully provide us with the opportunity to uncover the beginning of the heart failure process. In this respect, using (a) newer imaging techniques, (b) biomedicine, (c) nanotechnology, and (d) artificial intelligence, we can gain a deeper understanding of this complex syndrome. This, in turn, can lead to earlier and more effective therapeutic approaches, ultimately improving human health. To date, the scientific community has not given sufficient attention to the energetic starvation model. In our view, this review aims to encourage scientists and the medical community to conduct studies for a better understanding and treatment of this syndrome. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of CVD: Focus on Atherosclerosis (Volume II))

► Show Figures

Figure 1

10 pages, 4456 KB

Open AccessEditor’s ChoiceArticle

Photobiomodulation Therapy at 660 nm Inhibits Hippocampal Neuroinflammation in a Lipopolysaccharide-Challenged Rat Model

by Tae-Mi Jung, Jong-Ha Lee, Jin-Chul Heo and Chang-Hyun Kim

Biomedicines 2024, 12(11), 2514; https://doi.org/10.3390/biomedicines12112514 - 3 Nov 2024

Cited by 1 | Viewed by 2664

Abstract

Background/Objectives: Neuroinflammation is associated with the progression of various brain diseases, and the management of neuroinflammation-induced neural damage is a crucial aspect of treating neurological disorders. This study investigated the anti-inflammatory efficacy of photobiomodulation therapy (PBMT) using 660 nm phototherapy in a rat [...] Read more.

Background/Objectives: Neuroinflammation is associated with the progression of various brain diseases, and the management of neuroinflammation-induced neural damage is a crucial aspect of treating neurological disorders. This study investigated the anti-inflammatory efficacy of photobiomodulation therapy (PBMT) using 660 nm phototherapy in a rat model with lipopolysaccharide (LPS)-induced neuroinflammation. Methods: We induced inflammation in rat brains via intraperitoneal injection of LPS and subjected the treatment group to 660 nm phototherapy to examine its protective effect against hippocampal damage based on pathological, histological, and immunohistochemical tissue analyses. Results: The 660 nm treated rats showed a significant decrease in hippocampal structural damage and cell death compared to the LPS-treated group. We observed reduced expression of the inflammation markers GFAP, TNF-α, and IL-1β in the hippocampus of the treatment group, and an increase in SIRT1 expression across all hippocampal regions. Conclusions: This study presents a promising method for controlling neuroinflammation and providing neuroprotection and inflammation relief. PBMT represents a non-invasive therapeutic approach with minimal side effects ensured through the proper control of light irradiation. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

► Show Figures

Figure 1

15 pages, 3612 KB

Open AccessEditor’s ChoiceArticle

Neuroprotective Effects of Ascorbic Acid, Vanillic Acid, and Ferulic Acid in Dopaminergic Neurons of Zebrafish

by Fatemeh Hedayatikatouli, Michael Kalyn, Dana Elsaid, Herman Aishi Mbesha and Marc Ekker

Biomedicines 2024, 12(11), 2497; https://doi.org/10.3390/biomedicines12112497 - 31 Oct 2024

Cited by 1 | Viewed by 1899

Abstract

Background/Objectives: Parkinson’s disease (PD) is a debilitating neurodegenerative disease that targets the nigrostriatal dopaminergic (DAnergic) system residing in the human midbrain and is currently incurable. The aim of this study is to investigate the neuroprotective effects of ascorbic acid, vanillic acid, and ferulic [...] Read more.

Background/Objectives: Parkinson’s disease (PD) is a debilitating neurodegenerative disease that targets the nigrostriatal dopaminergic (DAnergic) system residing in the human midbrain and is currently incurable. The aim of this study is to investigate the neuroprotective effects of ascorbic acid, vanillic acid, and ferulic acid in a zebrafish model of PD induced by MPTP by assessing the impact of these compounds on DAnergic neurons, focusing on gene expression, mitochondrial dynamics, and cellular stress responses. Methods/Results: Following exposure and qPCR and immunohistochemical analyses, ascorbic acid enhanced DAnergic function, indicated by an upregulation of the dopamine transporter (dat) gene and increased eGFP+ DAnergic cells, suggesting improved dopamine reuptake and neuroprotection. Ascorbic acid also positively affected mitochondrial dynamics and stress response pathways, countering MPTP-induced dysregulation. Vanillic acid only had modest, if any, neuroprotective effects on DAnergic neurons following MPTP administration. Ferulic acid exhibited the largest neuroprotective effects through the modulation of gene expression related to DAnergic neurons and mitochondrial dynamics. Conclusions: These findings suggest that ascorbic acid and ferulic acid can act as potential protective interventions for DAnergic neuron health, demonstrating various beneficial effects at the molecular and cellular levels. However, further investigation is needed to translate these results into clinical applications. This study enhances the understanding of neuroprotective strategies in neurodegenerative diseases, emphasizing the importance of considering interactions between physiological systems. Full article

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

► Show Figures

Figure 1

19 pages, 7537 KB

Open AccessEditor’s ChoiceReview

Bacterial Meningoencephalitis in Newborns

by Alessia Guarnera, Giulia Moltoni, Francesco Dellepiane, Giulia Lucignani, Maria Camilla Rossi-Espagnet, Francesca Campi, Cinzia Auriti and Daniela Longo

Biomedicines 2024, 12(11), 2490; https://doi.org/10.3390/biomedicines12112490 - 30 Oct 2024

Viewed by 3021

Abstract

Bacterial meningoencephalitis in newborns is a severe and life-threatening pathology, which results from meningeal infection and the subsequent involvement of the brain parenchyma. The severity of the acute onset of symptoms and the risk of neurodevelopmental adverse sequelae in children strongly depend on [...] Read more.

Bacterial meningoencephalitis in newborns is a severe and life-threatening pathology, which results from meningeal infection and the subsequent involvement of the brain parenchyma. The severity of the acute onset of symptoms and the risk of neurodevelopmental adverse sequelae in children strongly depend on the timing of the infection, the immunological protection transmitted by the mother to the fetus during pregnancy, and the neonate’s inflammatory and immune system response after birth. Although the incidence of neonatal meningitis and meningoencephalitis and related mortality declined in the past twenty years with the improvement of prenatal care and with the introduction of intrapartum antibiotic prophylaxis against Streptococcus beta Hemolyticus group B (Streptococcus Agalactiae) in the 1990s, bacterial meningitis remains the most common form of cerebrospinal fluid infection in pediatric patients. To date, the rate of unfavorable neurological outcomes is still from 20% to 60%, and the possibility of containing its rate strongly depends on early diagnosis, therapy, and a multidisciplinary approach, which involves neonatologists, neurologists, neuroradiologists, and physiotherapists. Neonatal meningitis remains difficult to diagnose because the responsible bacteria vary with gestational age at birth, age at presentation, and environmental context. The clinical presentation, especially in the newborn, is very ambiguous. From a clinical point of view, the definitive test for diagnosis is lumbar puncture in patients with symptoms suggestive of neurological involvement. Therefore, neuroimaging is key for raising clinical suspicion of meningitis or corroborating the diagnosis based on clinical and laboratory data. Our pictorial review offers a practical approach to neonatal meningoencephalitis by describing the epidemiology, the pathophysiology of bacterial meningoencephalitis, defining the indications and suggesting optimized protocols for neuroimaging techniques, and showing the main neuroimaging findings to reach the diagnosis and offering proper follow-up of bacterial meningitis. Moreover, we tried identifying some peculiar MRI patterns related to some bacteria. Full article

(This article belongs to the Special Issue Understanding Diseases Affecting the Central Nervous System)

► Show Figures

Figure 1

15 pages, 1415 KB

Open AccessEditor’s ChoiceReview

Amino Acid Deprivation in Glioblastoma: The Role in Survival and the Tumour Microenvironment—A Narrative Review

by Keven Du, Leila Grocott, Giulio Anichini, Kevin O’Neill and Nelofer Syed

Biomedicines 2024, 12(11), 2481; https://doi.org/10.3390/biomedicines12112481 - 29 Oct 2024

Cited by 4 | Viewed by 2284

Abstract

Background: Glioblastoma is the most common and aggressive primary brain tumour, characterised by its invasive nature and complex metabolic profile. Emerging research highlights the role of amino acids (AAs) in glioblastoma metabolism, influencing tumour growth and the surrounding microenvironment. Methods: This narrative review [...] Read more.

Background: Glioblastoma is the most common and aggressive primary brain tumour, characterised by its invasive nature and complex metabolic profile. Emerging research highlights the role of amino acids (AAs) in glioblastoma metabolism, influencing tumour growth and the surrounding microenvironment. Methods: This narrative review synthesises recent pre-clinical studies focusing on the metabolic functions of AAs in glioblastoma. Key areas include the effects of AA deprivation on tumour growth, adaptive mechanisms, and the tumour microenvironment. Results: The effects related to arginine, glutamine, methionine, and cysteine deprivation have been more extensively reported. Arginine deprivation in arginine-auxotrophic glioblastomas induces apoptosis and affects cell adhesion, while glutamine deprivation disrupts metabolic pathways and enhances autophagy. Methionine and cysteine deprivation impact lipid metabolism and ferroptosis. Tumour adaptive mechanisms present challenges, and potential compensatory responses have been identified. The response of the microenvironment to AA deprivation, including immune modulation, is critical to determining therapeutic outcomes. Conclusions: Targeting AA metabolism offers a promising approach for glioblastoma treatment, with potential targeted drugs showing clinical promise. However, the complexity of tumour adaptive mechanisms and their impact on the microenvironment necessitates further research to optimise combination therapies and improve therapeutic efficacy. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Gliomas)

► Show Figures

Figure 1

16 pages, 1053 KB

Open AccessEditor’s ChoiceReview

MicroRNAs as Biomarkers in Spinal Muscular Atrophy

by Maruša Barbo, Damjan Glavač, Gregor Jezernik and Metka Ravnik-Glavač

Biomedicines 2024, 12(11), 2428; https://doi.org/10.3390/biomedicines12112428 - 23 Oct 2024

Cited by 3 | Viewed by 2002

Abstract

Spinal muscular atrophy (SMA) is a severe neurodegenerative disease caused by the loss of the survival motor neuron (SMN) protein, leading to degeneration of anterior motor neurons and resulting in progressive muscle weakness and atrophy. Given that SMA has a single, well-defined genetic [...] Read more.

Spinal muscular atrophy (SMA) is a severe neurodegenerative disease caused by the loss of the survival motor neuron (SMN) protein, leading to degeneration of anterior motor neurons and resulting in progressive muscle weakness and atrophy. Given that SMA has a single, well-defined genetic cause, gene-targeted therapies have been developed, aiming to increase SMN production in SMA patients. The SMN protein is likely involved in the synthesis of microRNAs (miRNAs), and dysregulated miRNA expression is increasingly associated with the pathophysiology of SMA. Currently, there is a lack of reliable biomarkers to monitor SMA; therefore, the search for novel SMA biomarkers, including miRNAs, is crucial as reliable tools are needed to track disease progression, predict the response to therapy and understand the different clinical outcomes of available treatments. In this review, we compile data on miRNAs associated with SMA pathogenesis and their potential use as biomarkers. Based on current knowledge, the most frequently deregulated miRNAs between SMA patients and controls, as well as pre- and post-treatment in SMA patients, include miR-1-3p, miR-133a-3p, miR-133b, and miR-206. These findings offer promising possibilities for improving patient classification and monitoring disease progression and response to treatment. Additionally, these findings provide insights into the broader molecular mechanisms and networks of SMA that could inform the development of future therapeutic strategies. Full article

(This article belongs to the Special Issue Advanced Research on Muscle and Bone Diseases)

► Show Figures

Figure 1

12 pages, 1377 KB

Open AccessEditor’s ChoiceArticle

miRNA in Machine-Learning-Based Diagnostics of Oral Cancer

by Xinghang Li, Valentina L. Kouznetsova and Igor F. Tsigelny

Biomedicines 2024, 12(10), 2404; https://doi.org/10.3390/biomedicines12102404 - 21 Oct 2024

Cited by 1 | Viewed by 1974

Abstract

Background: MicroRNAs (miRNAs) are crucial regulators of gene expression, playing significant roles in various cellular processes, including cancer pathogenesis. Traditional cancer diagnostic methods, such as biopsies and histopathological analyses, while effective, are invasive, costly, and require specialized skills. With the rising global incidence [...] Read more.

Background: MicroRNAs (miRNAs) are crucial regulators of gene expression, playing significant roles in various cellular processes, including cancer pathogenesis. Traditional cancer diagnostic methods, such as biopsies and histopathological analyses, while effective, are invasive, costly, and require specialized skills. With the rising global incidence of cancer, there is a pressing need for more accessible and less invasive diagnostic alternatives. Objective: This research investigates the potential of machine-learning (ML) models based on miRNA attributes as non-invasive diagnostic tools for oral cancer. Methods and Tools: We utilized a comprehensive methodological framework involving the generation of miRNA attributes, including sequence characteristics, target gene associations, and cancer-specific signaling pathways. Results: The miRNAs were classified using various ML algorithms, with the BayesNet classifier demonstrating superior performance, achieving an accuracy of 95% and an area under receiver operating characteristic curve (AUC) of 0.98 during cross-validation. The model’s effectiveness was further validated using independent datasets, confirming its potential clinical utility. Discussion: Our findings highlight the promise of miRNA-based ML models in enhancing early cancer detection, reducing healthcare burdens, and potentially saving lives. Conclusions: This study paves the way for future research into miRNA biomarkers, offering a scalable and adaptable diagnostic approach for various cancers. Full article

(This article belongs to the Special Issue Epigenetic Regulation and Its Impact for Medicine)

► Show Figures

Figure 1

25 pages, 1116 KB

Open AccessEditor’s ChoiceReview

Insights into CSF-1R Expression in the Tumor Microenvironment

by Caterina Tomassetti, Gaia Insinga, Francesca Gimigliano, Andrea Morrione, Antonio Giordano and Emanuele Giurisato

Biomedicines 2024, 12(10), 2381; https://doi.org/10.3390/biomedicines12102381 - 18 Oct 2024

Cited by 15 | Viewed by 4230

Abstract

The colony-stimulating factor 1 receptor (CSF-1R) plays a pivotal role in orchestrating cellular interactions within the tumor microenvironment (TME). Although the CSF-1R has been extensively studied in myeloid cells, the expression of this receptor and its emerging role in other cell types in [...] Read more.

The colony-stimulating factor 1 receptor (CSF-1R) plays a pivotal role in orchestrating cellular interactions within the tumor microenvironment (TME). Although the CSF-1R has been extensively studied in myeloid cells, the expression of this receptor and its emerging role in other cell types in the TME need to be further analyzed. This review explores the multifaceted functions of the CSF-1R across various TME cellular populations, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), cancer-associated fibroblasts (CAFs), endothelial cells (ECs), and cancer stem cells (CSCs). The activation of the CSF-1R by its ligands, colony-stimulating factor 1 (CSF-1) and Interleukin-34 (IL-34), regulates TAM polarization towards an immunosuppressive M2 phenotype, promoting tumor progression and immune evasion. Similarly, CSF-1R signaling influences MDSCs to exert immunosuppressive functions, hindering anti-tumor immunity. In DCs, the CSF-1R alters antigen-presenting capabilities, compromising immune surveillance against cancer cells. CSF-1R expression in CAFs and ECs regulates immune modulation, angiogenesis, and immune cell trafficking within the TME, fostering a pro-tumorigenic milieu. Notably, the CSF-1R in CSCs contributes to tumor aggressiveness and therapeutic resistance through interactions with TAMs and the modulation of stemness features. Understanding the diverse roles of the CSF-1R in the TME underscores its potential as a therapeutic target for cancer treatment, aiming at disrupting pro-tumorigenic cellular crosstalk and enhancing anti-tumor immune responses. Full article

(This article belongs to the Special Issue The Molecular Mechanisms Underlying the Activation and Regulation of Signaling Pathways in Cancer)

► Show Figures

Figure 1

14 pages, 1787 KB

Open AccessEditor’s ChoiceArticle

Systemic Innate Immune System Restoration as a Therapeutic Approach for Neurodegenerative Disease: Effects of NP001 on Amyotrophic Lateral Sclerosis (ALS) Progression

by Michael S. McGrath, Rongzhen Zhang, Paige M. Bracci, Ari Azhir and Bruce D. Forrest

Biomedicines 2024, 12(10), 2362; https://doi.org/10.3390/biomedicines12102362 - 16 Oct 2024

Cited by 2 | Viewed by 3039

Abstract

Background/objective: Amyotrophic lateral sclerosis (ALS) is a diagnosis that incorporates a heterogeneous set of neurodegenerative processes into a single progressive and uniformly fatal disease making the development of a uniformly applicable therapeutic difficult. Recent multinational ALS natural history incidence studies have identified systemic [...] Read more.

Background/objective: Amyotrophic lateral sclerosis (ALS) is a diagnosis that incorporates a heterogeneous set of neurodegenerative processes into a single progressive and uniformly fatal disease making the development of a uniformly applicable therapeutic difficult. Recent multinational ALS natural history incidence studies have identified systemic chronic activation of the innate immune system as a major risk factor for developing ALS. Persistent immune activation in patients with ALS leads to loss of muscle and lowering of serum creatinine. The goal of the current study was to test whether the slowing of nerve and muscle destruction in NP001-treated ALS patients compared with controls in phase 2 studies would lead to extension of survival. Methods: Phase 2 clinical studies with NP001, an intravenously administered form of the innate immune system regulator NaClO₂, are now reporting long-term survival benefits for drug recipients vs. placebo controls after only six months of intermittent treatment. As a prodrug, NP001 is converted by macrophages to taurine chloramine, a long-lived regulator of inflammation. We performed a pooled analysis of all patients who had completed the studies in two six-month NP001 phase 2 trials. Changes in respiratory vital capacity and the muscle mass product, creatinine, defined treated patients who, compared to placebo, had up to a year of extended survival. Conclusions: The observed longer survival in ALS patients with the greatest inflammation-associated muscle loss provides further evidence that ALS is a disease of ongoing innate immune dysfunction and that NP001 is a disease-modifying drug with sustained clinical activity. Full article

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

► Show Figures

Figure 1

32 pages, 1215 KB

Open AccessEditor’s ChoiceReview

Regulation of Airway Epithelial-Derived Alarmins in Asthma: Perspectives for Therapeutic Targets

by Ravneet K. Hansi, Maral Ranjbar, Christiane E. Whetstone and Gail M. Gauvreau

Biomedicines 2024, 12(10), 2312; https://doi.org/10.3390/biomedicines12102312 - 11 Oct 2024

Cited by 2 | Viewed by 4129

Abstract

Asthma is a chronic respiratory condition predominantly driven by a type 2 immune response. Epithelial-derived alarmins such as thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, and IL-25 orchestrate the activation of downstream Th2 cells and group 2 innate lymphoid cells (ILC2s), along with other [...] Read more.

Asthma is a chronic respiratory condition predominantly driven by a type 2 immune response. Epithelial-derived alarmins such as thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, and IL-25 orchestrate the activation of downstream Th2 cells and group 2 innate lymphoid cells (ILC2s), along with other immune effector cells. While these alarmins are produced in response to inhaled triggers, such as allergens, respiratory pathogens or particulate matter, disproportionate alarmin production by airway epithelial cells can lead to asthma exacerbations. With alarmins produced upstream of the type 2 inflammatory cascade, understanding the pathways by which these alarmins are regulated and expressed is critical to further explore new therapeutics for the treatment of asthmatic patients. This review emphasizes the critical role of airway epithelium and epithelial-derived alarmins in asthma pathogenesis and highlights the potential of targeting alarmins as a promising therapeutic to improve outcomes for asthma patients. Full article

(This article belongs to the Special Issue The Role of Alarmins in Human Pathologies: Impact on Diagnostic and Therapeutic Approaches)

► Show Figures

Figure 1

15 pages, 2744 KB

Open AccessEditor’s ChoiceArticle

Machine Learning Reveals Microbial Taxa Associated with a Swim across the Pacific Ocean

by Garry Lewis, Sebastian Reczek, Osayenmwen Omozusi, Taylor Hogue, Marc D. Cook and Jarrad Hampton-Marcell

Biomedicines 2024, 12(10), 2309; https://doi.org/10.3390/biomedicines12102309 - 11 Oct 2024

Viewed by 1424

Abstract

Purpose: This study aimed to characterize the association between microbial dynamics and excessive exercise. Methods: Swabbed fecal samples, body composition (percent body fat), and swimming logs were collected (n = 94) from a single individual over 107 days as he swam across the [...] Read more.

Purpose: This study aimed to characterize the association between microbial dynamics and excessive exercise. Methods: Swabbed fecal samples, body composition (percent body fat), and swimming logs were collected (n = 94) from a single individual over 107 days as he swam across the Pacific Ocean. The V4 region of the 16S rRNA gene was sequenced, generating 6.2 million amplicon sequence variants. Multivariate analysis was used to analyze the microbial community structure, and machine learning (random forest) was used to model the microbial dynamics over time using R statistical programming. Results: Our findings show a significant reduction in percent fat mass (Pearson; p < 0.01, R = −0.89) and daily swim distance (Spearman; p < 0.01, R = −0.30). Furthermore, the microbial community structure became increasingly similar over time (PERMANOVA; p < 0.01, R = −0.27). Decision-based modeling (random forest) revealed the genera Alistipes, Anaerostipes, Bifidobacterium, Butyricimonas, Lachnospira, Lachnobacterium, and Ruminococcus as important microbial biomarkers of excessive exercise for explaining variations observed throughout the swim (OOB; R = 0.893). Conclusions: We show that microbial community structure and composition accurately classify outcomes of excessive exercise in relation to body composition, blood pressure, and daily swim distance. More importantly, microbial dynamics reveal the microbial taxa significantly associated with increased exercise volume, highlighting specific microbes responsive to excessive swimming. Full article

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

► Show Figures

Figure 1

11 pages, 1784 KB

Open AccessEditor’s ChoiceArticle

From Gut to Blood: Redistribution of Zonulin in People Living with HIV

by Max Augustin, Carola Horn, Meryem Seda Ercanoglu, Vincent Bondet, Ute Sandaradura de Silva, Isabelle Suarez, Seung-Hun Chon, Dirk Nierhoff, Alexander Zoufaly, Christoph Wenisch, Elena Knops, Eva Heger, Florian Klein, Darragh Duffy, Michaela Müller-Trutwin and Clara Lehmann

Biomedicines 2024, 12(10), 2316; https://doi.org/10.3390/biomedicines12102316 - 11 Oct 2024

Cited by 1 | Viewed by 1544

Abstract

Background: Gastrointestinal mucosal damage due to human immunodeficiency virus (HIV) infection leads to microbial translocation and immune activation, contributing to the development of non-infectious comorbidities (NICM) in people living with HIV (PLWH). Additionally, persistent proviral HIV-1 in the gut-associated lymphatic tissue (GALT) can [...] Read more.

Background: Gastrointestinal mucosal damage due to human immunodeficiency virus (HIV) infection leads to microbial translocation and immune activation, contributing to the development of non-infectious comorbidities (NICM) in people living with HIV (PLWH). Additionally, persistent proviral HIV-1 in the gut-associated lymphatic tissue (GALT) can trigger immunological changes in the epithelial environment, impacting the mucosal barrier. However, the role of zonulin, a modulator of epithelial tight junctions in GALT during HIV infection, remains poorly understood. Methods: We measured zonulin in serum and intestinal tissue sections from five treatment-naive (HIV⁺_NAIVE) and 10 cART-treated (HIV⁺_cART) HIV⁺ individuals, along with 11 controls (CTRL). We compared zonulin levels with clinical characteristics, inflammatory markers (IFN-α, CXCR3, and PD-1), and the viral reservoir in peripheral blood (PB) and terminal ileum (TI). Results: Upon HIV infection, TI was found to harbor more HIV DNA than PB. Circulating zonulin levels were highest in HIV⁺_NAIVE compared to HIV⁺_cART or CTRL. Surprisingly, in the gut tissue sections, zonulin levels were higher in CTRL than in HIV⁺ individuals. Elevated circulating zonulin levels were found to be correlated with CD4⁺T-cell depletion in PB and TI, and with intestinal IFN-α. Conclusions: The findings of this study indicate a shift in zonulin levels from the gut to the bloodstream in response to HIV infection. Furthermore, elevated systemic zonulin levels are associated with the depletion of intestinal CD4⁺ T cells and increased gut inflammation, suggesting a potential link between systemic zonulin and intestinal damage. Gaining insight into the regulation of gut tight junctions during HIV infection could offer valuable understanding for preventing NICM in PLWH. Full article

(This article belongs to the Special Issue Pathogenesis, Diagnosis, and Therapeutics of Infectious Diseases (2nd Edition))

► Show Figures

Figure 1

17 pages, 3752 KB

Open AccessEditor’s ChoiceArticle

Extracorporeal Magnetotransduction Therapy as a New Form of Electromagnetic Wave Therapy: From Gene Upregulation to Accelerated Matrix Mineralization in Bone Healing

by Lennart Gerdesmeyer, Jutta Tübel, Andreas Obermeier, Norbert Harrasser, Claudio Glowalla, Rüdiger von Eisenhart-Rothe and Rainer Burgkart

Biomedicines 2024, 12(10), 2269; https://doi.org/10.3390/biomedicines12102269 - 7 Oct 2024

Cited by 4 | Viewed by 4780

Abstract

Background: Electromagnetic field therapy is gaining attention for its potential in treating bone disorders, with Extracorporeal Magnetotransduction Therapy (EMTT) emerging as an innovative approach. EMTT offers a higher oscillation frequency and magnetic field strength compared to traditional Pulsed Electromagnetic Field (PEMF) therapy, showing [...] Read more.

Background: Electromagnetic field therapy is gaining attention for its potential in treating bone disorders, with Extracorporeal Magnetotransduction Therapy (EMTT) emerging as an innovative approach. EMTT offers a higher oscillation frequency and magnetic field strength compared to traditional Pulsed Electromagnetic Field (PEMF) therapy, showing promise in enhancing fracture healing and non-union recovery. However, the mechanisms underlying these effects remain unclear. Results: This study demonstrates that EMTT significantly enhances osteoblast bone formation at multiple levels, from gene expression to extracellular matrix mineralization. Key osteoblastogenesis regulators, including SP7 and RUNX2, and bone-related genes such as COL1A1, ALPL, and BGLAP, were upregulated, with expression levels surpassing those of the control group by over sevenfold (p < 0.001). Enhanced collagen synthesis and mineralization were confirmed by von Kossa and Alizarin Red staining, indicating increased calcium and phosphate deposition. Additionally, calcium imaging revealed heightened calcium influx, suggesting a cellular mechanism for EMTT’s osteogenic effects. Importantly, EMTT did not compromise cell viability, as confirmed by live/dead staining and WST-1 assays. Conclusion: This study is the first to show that EMTT can enhance all phases of osteoblastogenesis and improve the production of critical mineralization components, offering potential clinical applications in accelerating fracture healing, treating osteonecrosis, and enhancing implant osseointegration. Full article

(This article belongs to the Section Biomedical Engineering and Materials)

► Show Figures

Figure 1

13 pages, 1073 KB

Open AccessEditor’s ChoiceReview

Current Perspectives on Olfactory Loss in Atypical Parkinsonisms—A Review Article

by Katarzyna Bochniak, Mateusz Soszyński, Natalia Madetko-Alster and Piotr Alster

Biomedicines 2024, 12(10), 2257; https://doi.org/10.3390/biomedicines12102257 - 4 Oct 2024

Cited by 1 | Viewed by 2337

Abstract

Introduction: Atypical parkinsonisms (APs) present various symptoms including motor impairment, cognitive decline, and autonomic dysfunction. Olfactory loss (OL), being a significant non-motor symptom, has emerged as an under-evaluated, yet potentially valuable, feature that might aid in the differential diagnosis of APs. State of [...] Read more.

Introduction: Atypical parkinsonisms (APs) present various symptoms including motor impairment, cognitive decline, and autonomic dysfunction. Olfactory loss (OL), being a significant non-motor symptom, has emerged as an under-evaluated, yet potentially valuable, feature that might aid in the differential diagnosis of APs. State of the art: The most pronounced OL is usually associated with Dementia with Lewy Bodies (DLB). While the view about the normosmic course of Multiple System Atrophy (MSA) remains unchanged, research indicates that mild OL may occur in a subset of patients with Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). This might be linked to the deposition of abnormal protein aggregates in the central nervous system. Clinical significance: The aim of this review is to discuss the role of OL and its degree and pattern in the pathogenesis and course of APs. Olfactory testing could serve as a non-invasive, quick screening tool to differentiate between APs and project disease progression. Future directions: There is a need for further evaluation of this topic. This may lead to the development of standardized olfactory testing protocols that could be implemented in clinical practice, making differential diagnosis of APs more convenient. Understanding differences in the sense of smell could create an avenue for more targeted therapeutic strategies. Full article

(This article belongs to the Special Issue Pathophysiological Mechanisms of Parkinson's Disease)

► Show Figures

Figure 1

10 pages, 2635 KB

Open AccessEditor’s ChoiceArticle

Melatonin Improves Vasogenic Edema via Inhibition to Water Channel Aquaporin-4 (AQP4) and Metalloproteinase-9 (MMP-9) Following Permanent Focal Cerebral Ischemia

by Ai-Hua Lee, Shih-Huang Tai, Sheng-Yang Huang, Li-Der Chang, Liang-Yi Chen, Yu-Ning Chen, Hao-Hsiang Hsu and E-Jian Lee

Biomedicines 2024, 12(10), 2184; https://doi.org/10.3390/biomedicines12102184 - 26 Sep 2024

Cited by 3 | Viewed by 1859

Abstract

Background: The efficacy of melatonin in reducing vasogenic and cytotoxic edema was investigated using a model of permanent middle cerebral artery occlusion (pMCAO). Methods: Rats underwent pMCAO, followed by intravenous administration of either melatonin (5 mg/kg) or a vehicle 10 min post-insult. Brain [...] Read more.

Background: The efficacy of melatonin in reducing vasogenic and cytotoxic edema was investigated using a model of permanent middle cerebral artery occlusion (pMCAO). Methods: Rats underwent pMCAO, followed by intravenous administration of either melatonin (5 mg/kg) or a vehicle 10 min post-insult. Brain infarction and edema were assessed, and Western blot analyses were conducted to examine the expression levels of aquaporin-4 (AQP4), metalloproteinase-9 (MMP-9), and the neurovascular tight-junction protein ZO-1 upon sacrifice. The permeability of the blood–brain barrier (BBB) was measured using spectrophotometric quantification of Evans blue dye leakage. Results: Compared to controls, melatonin-treated rats exhibited a significant reduction in infarct volume by 26.9% and showed improved neurobehavioral outcomes (p < 0.05 for both). Melatonin treatment also led to decreased Evans blue dye extravasation and brain edema (p < 0.05 for both), along with lower expression levels of AQP4 and MMP-9 proteins and better preservation of ZO-1 protein (p < 0.05 for all). Conclusions: Therefore, melatonin offers neuroprotection against brain swelling induced by ischemia, possibly through its modulation of AQP4 and MMP-9 activities in glial cells and the extracellular matrix (ECM) during the early phase of ischemic injury. Full article

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

► Show Figures

Figure 1

18 pages, 2243 KB

Open AccessEditor’s ChoiceArticle

The Relationship between Lipoprotein A and the Prevalence of Multivessel Coronary Artery Disease in Young Patients with Acute Myocardial Infarction: An Observational Study

by Ionut Cezar Buciu, Eugen Nicolae Tieranu, Andreea Stefania Pircalabu, Ovidiu Mircea Zlatian, Ionut Donoiu, Constantin Militaru, Sebastian Militaru and Cristian Militaru

Biomedicines 2024, 12(9), 2159; https://doi.org/10.3390/biomedicines12092159 - 23 Sep 2024

Cited by 6 | Viewed by 2015

Abstract

Introduction: Cardiovascular diseases are the leading cause of mortality worldwide, with a significant impact on socioeconomic aspects. Various biomarkers have been studied in relation to the diagnosis, progression, and prognosis of atherosclerotic disease, with lipoprotein (a) [Lp (a)] standing out as an important [...] Read more.

Introduction: Cardiovascular diseases are the leading cause of mortality worldwide, with a significant impact on socioeconomic aspects. Various biomarkers have been studied in relation to the diagnosis, progression, and prognosis of atherosclerotic disease, with lipoprotein (a) [Lp (a)] standing out as an important predictor of cardiovascular risk. This observational study aimed to clarify the association between Lp (a) levels and the severity of significant multivessel coronary lesions in acute myocardial infarction (AMI) patients. Materials and Methods: Conducted at the Clinical Emergency County Hospital of Craiova, Romania, the study involved 256 young patients divided into two groups based on Lp (a) levels: Group A (Lp (a) < 30 mg/dL) and Group B (Lp (a) ≥ 30 mg/dL). Patients included young adults up to 55 years for males and 60 years for females, excluding those with familial hypercholesterolemia. Results: The study revealed a significant association between elevated Lp (a) levels and the presence of multivessel coronary lesions. Patients with Lp (a) concentrations ≥ 30 mg/dL exhibited a higher prevalence of multivessel disease compared to those with lower levels. Discussion: The findings suggest that elevated Lp (a) levels are a crucial biomarker for the risk of coronary artery disease, particularly in young patients with AMI. The study emphasizes the need for aggressive lipid management strategies and personalized treatment approaches, considering the significant role of Lp (a) in atherosclerosis and AMI. Conclusions: Lipoprotein A levels above 30 mg/dL are associated with a higher prevalence of multivessel coronary lesions. Multivariate analysis revealed that higher Lp (a) levels and lower HDL levels are linked to an increased risk of multivessel coronary lesions. Full article

(This article belongs to the Special Issue Molecular Insights into Myocardial Infarction)

► Show Figures

Figure 1

14 pages, 824 KB

Open AccessEditor’s ChoiceArticle

Metabolic Dysfunction-Associated Steatotic Liver Disease: The Associations between Inflammatory Markers, TLR4, and Cytokines IL-17A/F, and Their Connections to the Degree of Steatosis and the Risk of Fibrosis

by Sorina-Cezara Coste, Olga Hilda Orășan, Angela Cozma, Vasile Negrean, Adela-Viviana Sitar-Tăut, Gabriela Adriana Filip, Adriana Corina Hangan, Roxana Liana Lucaciu, Mihaela Iancu and Lucia Maria Procopciuc

Biomedicines 2024, 12(9), 2144; https://doi.org/10.3390/biomedicines12092144 - 21 Sep 2024

Cited by 9 | Viewed by 2249

Abstract

Background: The pathogenesis of MASLD (metabolic dysfunction-associated steatotic liver disease) is driven by environmental, genetic, metabolic, immune, and inflammatory factors. IL-17 and TLR4 determine hepatic steatosis, inflammation, and finally fibrosis. Objectives: To explore the associations between the plasma levels of inflammatory [...] Read more.

Background: The pathogenesis of MASLD (metabolic dysfunction-associated steatotic liver disease) is driven by environmental, genetic, metabolic, immune, and inflammatory factors. IL-17 and TLR4 determine hepatic steatosis, inflammation, and finally fibrosis. Objectives: To explore the associations between the plasma levels of inflammatory markers, TLR4, and the cytokines IL17A/F, as well as their connections with the degree of hepatic steatosis and the risk of hepatic fibrosis (defined by the FIB-4 score) in MASLD patients. Methods: The study cohort included 80 patients diagnosed with MASLD. The IL-17A/F and TLR4 serum concentrations were determined using the ELISA method. Results: We found a significant difference in the CAR levels (C-reactive protein to albumin ratio) when comparing MASLD patients with severe steatosis to those with mild/moderate steatosis (Student’s t test, t (71) = 2.32, p = 0.023). The PIV (pan-immune inflammatory value) was positively correlated with the SII (systemic immune inflammation index), (r = 0.86, p < 0.0001) and the CAR (r = 0.41, p = 0.033) in MASLD patients with severe steatosis. In contrast, increased values of the LMR (lymphocyte to monocyte ratio) were significantly associated, with decreased levels of the SII (ρ = −0.38, p = 0.045). We also found a positive correlation between the CAR and the SII (r = 0.41, p = 0.028). In patients with mild/moderate steatosis, a significant positive correlation was observed between the SII and IL17A (r = 0.36, p = 0.010), the PIV and the CAR (r = 0.29, p = 0.011), the PIV and the SII (r = 0.87, p < 0.0001) and the PIV and IL17A (r = 0.3, p = 0.036). A negative correlation was observed between the LMR and the SII (r = −0.55, p < 0.0001) and the CAR and IL17F (r = −0.37, p = 0.011). Regarding the inflammatory markers, the PIV (336.4 vs. 228.63, p = 0.0107), and the SII (438.47 vs. 585.39, p = 0.0238) had significantly lower levels in patients with an intermediate–high risk of hepatic fibrosis as compared with the patients with a low risk of hepatic fibrosis. The PNI (prognostic nutritional index) (47.16 vs. 42.41, p = 0.0392) had significantly different levels in patients with the likelihood of hepatic fibrosis than those with a low risk of hepatic fibrosis. Conclusions: Regarding the inflammatory markers, the PIV and the SII hold promise as biomarkers for discriminating between MASLD patients with an intermediate–high risk and those with a low risk of hepatic fibrosis. Our findings underscore the role of IL-17A and its potential relationship with inflammatory markers in MASLD pathogenesis and the progression to hepatic fibrosis. Full article

(This article belongs to the Special Issue Pancreatic, Liver, Biliary Tract and Intestinal Diseases: Pathogenesis, Diagnostics and Therapy)

► Show Figures

Figure 1

17 pages, 5211 KB

Open AccessEditor’s ChoiceArticle

Clinical Features and Survival Analysis of Lupus Nephritis among Patients with Systemic Lupus Erythematosus: A Three-Decade-Long Retrospective Cohort Study

by Bianka Perge, Gábor Papp, Bernadett Bói, Nikolett Nagy, Eszter Gáspár-Kiss and Tünde Tarr

Biomedicines 2024, 12(9), 2117; https://doi.org/10.3390/biomedicines12092117 - 18 Sep 2024

Viewed by 3546

Abstract

Background/Objectives: Lupus nephritis (LN) is one of the most severe organ manifestations of systemic lupus erythematosus (SLE). The aim of our retrospective cohort study was to compare the clinical characteristics, therapy, survival, causes of death, and prognostic factors of LN and non-LN lupus [...] Read more.

Background/Objectives: Lupus nephritis (LN) is one of the most severe organ manifestations of systemic lupus erythematosus (SLE). The aim of our retrospective cohort study was to compare the clinical characteristics, therapy, survival, causes of death, and prognostic factors of LN and non-LN lupus patients. Moreover, we compared a wide spectrum of clinical data of LN patients diagnosed before and since 2005 to determine any changes in disease course and outcomes. Methods: We assessed the clinical and laboratory data of 384 SLE patients, out of whom, 127 patients were diagnosed with LN between 1990 and 2020. Results: Based on our observations, discoid LE, subacute cutaneous LE, antiphospholipid syndrome, Sjögren’s syndrome, and rheumatoid arthritis were more common in non-LN patients, while anemia and anti-RNP positivity were more frequent in LN patients. Development of LN did not affect survival rates; male sex and presence of APS were negative prognostic parameters in the non-LN group while achieving remission was a positive prognostic factor in both groups. Death caused by sepsis was more prevalent in the LN group. Serositis and neurological manifestations occurred less frequently in LN patients diagnosed after 2005. The use of mycophenolate mofetil became more common, and the cumulative corticosteroid dose decreased. The SLICC Damage Index score also decreased. Conclusions: Our study demonstrated that the disease course has changed in recent years, and the main therapeutic goal in both SLE and lupus nephritis should be to achieve remission because this significantly improves long-term prognosis and patient survival. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatment of Rheumatic Diseases)

► Show Figures

Figure 1

12 pages, 1679 KB

Open AccessEditor’s ChoiceArticle

Omega-3 Fatty Acids Modify Drp1 Expression and Activate the PINK1-Dependent Mitophagy Pathway in the Kidney and Heart of Adenine-Induced Uremic Rats

by Dong Ho Choi, Su Mi Lee, Bin Na Park, Mi Hwa Lee, Dong Eun Yang, Young Ki Son, Seong Eun Kim and Won Suk An

Biomedicines 2024, 12(9), 2107; https://doi.org/10.3390/biomedicines12092107 - 15 Sep 2024

Viewed by 1844

Abstract

Mitochondrial homeostasis is controlled by biogenesis, dynamics, and mitophagy. Mitochondrial dysfunction plays a central role in cardiovascular and renal disease and omega-3 fatty acids (FAs) are beneficial for cardiovascular disease. We investigated whether omega-3 fatty acids (FAs) regulate mitochondrial biogenesis, dynamics, and mitophagy [...] Read more.

Mitochondrial homeostasis is controlled by biogenesis, dynamics, and mitophagy. Mitochondrial dysfunction plays a central role in cardiovascular and renal disease and omega-3 fatty acids (FAs) are beneficial for cardiovascular disease. We investigated whether omega-3 fatty acids (FAs) regulate mitochondrial biogenesis, dynamics, and mitophagy in the kidney and heart of adenine-induced uremic rats. Eighteen male Sprague Dawley rats were divided into normal control, adenine control, and adenine with omega-3 FA groups. Using Western blot analysis, the kidney and heart expression of mitochondrial homeostasis-related molecules, including peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), dynamin-related protein 1 (Drp1), and phosphatase and tensin homolog-induced putative kinase 1 (PINK1) were investigated. Compared to normal, serum creatinine and heart weight/body weight in adenine control were increased and slightly improved in the omega-3 FA group. Compared to the normal controls, the expression of PGC-1α and PINK1 in the kidney and heart of the adenine group was downregulated, which was reversed after omega-3 FA supplementation. Drp1 was upregulated in the kidney but downregulated in the heart in the adenine group. Drp1 expression in the heart recovered in the omega-3 FA group. Mitochondrial DNA (mtDNA) was decreased in the kidney and heart of the adenine control group but the mtDNA of the heart was recovered in the omega-3 FA group. Drp1, which is related to mitochondrial fission, may function oppositely in the uremic kidney and heart. Omega-3 FAs may be beneficial for mitochondrial homeostasis by activating mitochondrial biogenesis and PINK1-dependent mitophagy in the kidney and heart of uremic rats. Full article

(This article belongs to the Special Issue Pathophysiology of Chronic Kidney Disease and Its Complications, 2nd Edition)

► Show Figures

Figure 1

14 pages, 13928 KB

Open AccessEditor’s ChoiceArticle

STAT3 Protein–Protein Interaction Analysis Finds P300 as a Regulator of STAT3 and Histone 3 Lysine 27 Acetylation in Pericytes

by Gautam Kundu, Maryam Ghasemi, Seungbin Yim, Ayanna Rohil, Cuiyan Xin, Leo Ren, Shraddha Srivastava, Akinwande Akinfolarin, Subodh Kumar, Gyan P. Srivastava, Venkata S. Sabbisetti, Gopal Murugaiyan and Amrendra K. Ajay

Biomedicines 2024, 12(9), 2102; https://doi.org/10.3390/biomedicines12092102 - 14 Sep 2024

Cited by 1 | Viewed by 2212

Abstract

Background: Signal transducer and activator of transcription 3 (STAT3) is a member of the cytoplasmic inducible transcription factors and plays an important role in mediating signals from cytokines, chemokines, and growth factors. We and others have found that STAT3 directly regulates pro-fibrotic signaling [...] Read more.

Background: Signal transducer and activator of transcription 3 (STAT3) is a member of the cytoplasmic inducible transcription factors and plays an important role in mediating signals from cytokines, chemokines, and growth factors. We and others have found that STAT3 directly regulates pro-fibrotic signaling in the kidney. The STAT3 protein–protein interaction plays an important role in activating its transcriptional activity. It is necessary to identify these interactions to investigate their function in kidney disease. Here, we investigated the protein–protein interaction among three species to find crucial interactions that can be targeted to alleviate kidney disease. Method: In this study, we examined common protein–protein interactions leading to the activation or downregulation of STAT3 among three different species: humans (Homo sapiens), mice (Mus musculus), and rabbits (Oryctolagus cuniculus). Further, we chose to investigate the P300 and STAT3 interaction and performed studies of the activation of STAT3 using IL-6 and inhibition of the P300 by its specific inhibitor A-485 in pericytes. Next, we performed immunoprecipitation to confirm whether A-485 inhibits the binding of P300 to STAT3. Results: Using the STRING application from ExPASy, we found that six proteins, including PIAS3, JAK1, JAK2, EGFR, SRC, and EP300, showed highly confident interactions with STAT3 in humans, mice, and rabbits. We also found that IL-6 treatment increased the acetylation of STAT3 and increased histone 3 lysine acetylation (H3K27ac). Furthermore, we found that the disruption of STAT3 and P300 interaction by the P300 inhibitor A-485 decreased STAT3 acetylation and H3K27ac. Finally, we confirmed that the P300 inhibitor A-485 inhibited the binding of STAT3 with P300, which inhibited its transcriptional activity by reducing the expression of Ccnd1 (Cyclin D1). Conclusions: Targeting the P300 protein interaction with STAT3 may alleviate STAT3-mediated fibrotic signaling in humans and other species. Full article

(This article belongs to the Special Issue Genetics and Genomics of Congenital Diseases)

► Show Figures

Graphical abstract

18 pages, 3595 KB

Open AccessEditor’s ChoiceArticle

Pro-Inflammatory Characteristics of Extracellular Vesicles in the Vitreous of Type 2 Diabetic Patients

by Shengshuai Shan, Abdulaziz H. Alanazi, Yohan Han, Duo Zhang, Yutao Liu, S. Priya Narayanan and Payaningal R. Somanath

Biomedicines 2024, 12(9), 2053; https://doi.org/10.3390/biomedicines12092053 - 10 Sep 2024

Cited by 5 | Viewed by 1850

Abstract

Diabetic retinopathy (DR) is a leading cause of blindness, yet its molecular mechanisms are unclear. Extracellular vesicles (EVs) contribute to dysfunction in DR, but the characteristics and functions of vitreous EVs are unclear. This study investigated the inflammatory properties of type 2 diabetic [...] Read more.

Diabetic retinopathy (DR) is a leading cause of blindness, yet its molecular mechanisms are unclear. Extracellular vesicles (EVs) contribute to dysfunction in DR, but the characteristics and functions of vitreous EVs are unclear. This study investigated the inflammatory properties of type 2 diabetic (db) vitreous EVs. EVs isolated from the vitreous of db and non-db donors were used for nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), immunogold staining, Western blotting, and proteomic analysis by mass spectrometry. Intracellular uptake of vitreous EVs by differentiated macrophages was evaluated using ExoGlow membrane labeling, and the impact of EVs on macrophage (THP-1) activation was assessed by cytokine levels using RT-qPCR. NTA and TEM analysis of db and non-db vitreous EVs showed non-aggregated EVs with a heterogeneous size range below 200 nm. Western blot detected EV markers (Alix, Annexin V, HSP70, and Flotillin 1) and an upregulation of Cldn5 in db EVs. While the db EVs were incorporated into macrophages, treatment of THP-1 cells with db EVs significantly increased mRNA levels of TNFα and IL-1β compared to non-db EVs. Proteomic and gene enrichment analysis indicated pro-inflammatory characteristics of db EVs. Our results suggest a potential involvement of EC-derived Cldn5+ EVs in triggering inflammation, offering a novel mechanism involved and presenting a possible therapeutic avenue for DR. Full article

(This article belongs to the Special Issue Angiogenesis and Related Disorders)

► Show Figures

Figure 1

14 pages, 1661 KB

Open AccessEditor’s ChoiceReview

Succinate Dehydrogenase and Human Disease: Novel Insights into a Well-Known Enzyme

by María J. Esteban-Amo, Patricia Jiménez-Cuadrado, Pablo Serrano-Lorenzo, Miguel Á. de la Fuente and María Simarro

Biomedicines 2024, 12(9), 2050; https://doi.org/10.3390/biomedicines12092050 - 9 Sep 2024

Cited by 10 | Viewed by 7045

Abstract

Succinate dehydrogenase (also known as complex II) plays a dual role in respiration by catalyzing the oxidation of succinate to fumarate in the tricarboxylic acid (TCA) cycle and transferring electrons from succinate to ubiquinone in the mitochondrial electron transport chain (ETC). Owing to [...] Read more.

Succinate dehydrogenase (also known as complex II) plays a dual role in respiration by catalyzing the oxidation of succinate to fumarate in the tricarboxylic acid (TCA) cycle and transferring electrons from succinate to ubiquinone in the mitochondrial electron transport chain (ETC). Owing to the privileged position of SDH/CII, its dysfunction leads to TCA cycle arrest and altered respiration. This review aims to elucidate the widely documented profound metabolic effects of SDH/CII deficiency, along with the newly unveiled survival mechanisms in SDH/CII-deficient cells. Such an understanding reveals exploitable vulnerabilities for strategic targeting, which is crucial for the development of novel and more precise therapies for primary mitochondrial diseases, as well as for familial and sporadic cancers associated with SDH/CII mutations. Full article

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

► Show Figures

Figure 1

14 pages, 683 KB

Open AccessEditor’s ChoiceReview

MicroRNAs in Sepsis

by Asimina Valsamaki, Vasileios Vazgiourakis, Konstantinos Mantzarlis, Rodopi Stamatiou and Demosthenes Makris

Biomedicines 2024, 12(9), 2049; https://doi.org/10.3390/biomedicines12092049 - 9 Sep 2024

Cited by 1 | Viewed by 1947

Abstract

Sepsis is an insidious and frequent condition of severe inflammation due to infections. Several biomarkers have been established for initial screening, but the non-specific nature of the existing biomarkers has led to the investigation of more sensitive and specific tools, such as microRNAs [...] Read more.

Sepsis is an insidious and frequent condition of severe inflammation due to infections. Several biomarkers have been established for initial screening, but the non-specific nature of the existing biomarkers has led to the investigation of more sensitive and specific tools, such as microRNAs (miRs). These non-coding RNAs are involved in several diseases, including sepsis, due to their roles in cellular homeostasis. Herein, a literature overview was attempted to distinguish the most prominent miRs identified in septic conditions and their usefulness in diagnosis, prognosis and even classification of sepsis. miRs implicated in the regulation of pro and anti-inflammatory mechanisms, such as MIR-146a, MIR-155, MIR-181b, MIR-223-5p, MIR-494-3p, MIR-2055b, MIR-150 and MIR-143 have been pinpointed as acceptable testing tools. Furthermore, the use of miRs as screening panels, specific for septic parameters, such as type of causal infection, inflammation immune pathways affected (NF-kB, STAT/JACK), organs inflicted, as well as parallel screening of certain miRs alongside other long non-coding RNAs (LNCs), as co-regulators of sepsis progression. Overall, miRs exhibit benefits in terms of specificity and sensitivity, as well as practical ease of use and test stability. Furthermore, miRs could offer valuable insights into the molecular basis of disease causality and provide valuable therapeutic information. Full article

(This article belongs to the Special Issue Sepsis: Pathophysiology and Early Diagnostics)

► Show Figures

Figure 1

23 pages, 7024 KB

Open AccessEditor’s ChoiceArticle

Investigation of High Frequency Irreversible Electroporation for Canine Spontaneous Primary Lung Tumor Ablation

by Alayna N. Hay, Kenneth N. Aycock, Melvin F. Lorenzo, Kailee David, Sheryl Coutermarsh-Ott, Zaid Salameh, Sabrina N. Campelo, Julio P. Arroyo, Brittany Ciepluch, Gregory Daniel, Rafael V. Davalos and Joanne Tuohy

Biomedicines 2024, 12(9), 2038; https://doi.org/10.3390/biomedicines12092038 - 7 Sep 2024

Cited by 5 | Viewed by 2438

Abstract

In this study, the feasibility of treating canine primary lung tumors with high-frequency irreversible electroporation (H-FIRE) was investigated as a novel lung cancer treatment option. H-FIRE is a minimally invasive tissue ablation modality that delivers bipolar pulsed electric fields to targeted cells, generating [...] Read more.

In this study, the feasibility of treating canine primary lung tumors with high-frequency irreversible electroporation (H-FIRE) was investigated as a novel lung cancer treatment option. H-FIRE is a minimally invasive tissue ablation modality that delivers bipolar pulsed electric fields to targeted cells, generating nanopores in cell membranes and rendering targeted cells nonviable. In the current study, canine patients (n = 5) with primary lung tumors underwent H-FIRE treatment with an applied voltage of 2250 V using a 2-5-2 µs H-FIRE waveform to achieve partial tumor ablation prior to the surgical resection of the primary tumor. Surgically resected tumor samples were evaluated histologically for tumor ablation, and with immunohistochemical (IHC) staining to identify cell death (activated caspase-3) and macrophages (IBA-1, CD206, and iNOS). Changes in immunity and inflammatory gene signatures were also evaluated in tumor samples. H-FIRE ablation was evident by the microscopic observation of discrete foci of acute hemorrhage and necrosis, and in a subset of tumors (n = 2), we observed a greater intensity of cleaved caspase-3 staining in tumor cells within treated tumor regions compared to adjacent untreated tumor tissue. At the study evaluation timepoint of 2 h post H-FIRE, we observed differential gene expression changes in the genes IDO1, IL6, TNF, CD209, and FOXP3 in treated tumor regions relative to paired untreated tumor regions. Additionally, we preliminarily evaluated the technical feasibility of delivering H-FIRE percutaneously under CT guidance to canine lung tumor patients (n = 2). Overall, H-FIRE treatment was well tolerated with no adverse clinical events, and our results suggest H-FIRE potentially altered the tumor immune microenvironment. Full article

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

► Show Figures

Figure 1

12 pages, 474 KB

Open AccessEditor’s ChoiceArticle

Exploring the Role of the TAS2R16 Protein and Its Single Nucleotide Variants in Pituitary Adenoma Development

by Enrika Pileckaite, Alvita Vilkeviciute, Greta Gedvilaite-Vaicechauskiene, Loresa Kriauciuniene and Rasa Liutkeviciene

Biomedicines 2024, 12(9), 2022; https://doi.org/10.3390/biomedicines12092022 - 4 Sep 2024

Cited by 1 | Viewed by 1100

Abstract

Background: Pituitary adenoma (PA) is a common benign tumor that develops in the pituitary gland, causing hormonal imbalances and potential health issues. The TAS2R16 gene codes for a taste receptor and is involved in bitter taste perception, but there is currently no known [...] Read more.

Background: Pituitary adenoma (PA) is a common benign tumor that develops in the pituitary gland, causing hormonal imbalances and potential health issues. The TAS2R16 gene codes for a taste receptor and is involved in bitter taste perception, but there is currently no known direct link between this gene and pituitary adenoma. Methods: This study included 221 healthy controls and 131 patients with pituitary adenoma (PA) from the Lithuanian population. DNA was isolated from peripheral venous blood using the salt precipitation method. Genotyping was performed via RT-PCR. Statistical analysis was conducted with IBM SPSS Statistics 29.0 software, incorporating the Bonferroni correction for multiple comparisons. Results: This study found that the TAS2R16 rs978739 C allele is less common in the non-invasive PA group compared to the control group (p = 0.045). The TAS2R16 rs860170 CT genotype reduces the likelihood of developing non-invasive PA by 1.9-fold under the codominant (p = 0.024) and overdominant (p = 0.030) models. The odds of developing non-invasive PA are reduced by 2-fold under the dominant (p = 0.021) model for TAS2R16 rs860170 CT + CC genotypes and by 2-fold under the additive (p = 0.018) model for each TAS2R16 rs860170 C allele. The PA group had higher serum levels of TAS2R16 than the control group (p < 0.001). The present study found that patients with the TAS2R16 rs978739 TT or CT genotype had higher serum TAS2R16 levels and protein concentrations than healthy individuals (p = 0.025 and p = 0.019, respectively), and those with the AA or AG genotype of TAS2R16 rs1357949 had higher protein concentrations (p = 0.005 and p = 0.007, respectively). Conclusions: The TAS2R16 rs978739 C allele was less common in the non-invasive PA group compared to the control group, while the TAS2R16 rs860170 CT genotype was linked to a reduced likelihood of developing non-invasive PA. Additionally, the PA group showed higher serum levels of TAS2R16, and increased serum protein concentrations were observed in PA patients with specific TAS2R16 variants. Full article

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

► Show Figures

Figure 1

13 pages, 557 KB

Open AccessEditor’s ChoiceArticle

Coronary Arteries Lesions in Kawasaki Disease: Risk Factors in an Italian Cohort

by Elisabetta Morana, Fiorentina Guida, Laura Andreozzi, Leonardo Frazzoni, Lucia Augusta Baselli, Francesca Lami, Elena Corinaldesi, Cristina Cicero, Lorenzo Mambelli, Barbara Bigucci, Andrea Taddio, Chiara Ghizzi, Michela Cappella, Paola Fernicola, Marcello Lanari, Rocco Maurizio Zagari and Marianna Fabi

Biomedicines 2024, 12(9), 2010; https://doi.org/10.3390/biomedicines12092010 - 3 Sep 2024

Cited by 6 | Viewed by 1788

Abstract

Background: Kawasaki disease (KD) is a systemic vasculitis of medium arteries, particularly involving coronary arteries. Coronary artery lesions (CALs) is the most serious complication in the acute stage, potentially leading to ischemic cardiomyopathy, myocardial infarction and sudden death. Environmental factors and genetic [...] Read more.

Background: Kawasaki disease (KD) is a systemic vasculitis of medium arteries, particularly involving coronary arteries. Coronary artery lesions (CALs) is the most serious complication in the acute stage, potentially leading to ischemic cardiomyopathy, myocardial infarction and sudden death. Environmental factors and genetic background contribute to individual susceptibility to develop CALs. The aim of this study was to define the risk factors for CALs in an Italian cohort. Methods: Data of KD patients from 10 Italian sites were registered into a REDCap database where demographic and clinical data, laboratory findings and coronary status were recorded. KD was diagnosed according to AHA definition. We used multiple logistic regression analysis to identify independent risk factors for CALs. Results: A total of 517 patients were enrolled, mainly Caucasians (83.6%). Presentation was complete in 321 patients (62.8%) and IVIG responsiveness in 360 (70%). CALs developed in 136/517 (26.31%). Gender, age, ethnicity, clinical presentation, fever duration, non-coronary cardiac events, Hb, albumin and CRP were significantly different between patients with and without CALs, while seasonality was not. Male gender, age < 18 months, Asian ethnicity, incomplete presentation and fever > 10 days were independent risk factors for CALs. Conclusions: Age younger than 18 months, incomplete KD and longer fever duration are risk factors for CALs. Asian ethnicity also represents a risk factor in our Italian Cohort. Full article

(This article belongs to the Special Issue Kawasaki Disease)

► Show Figures

Figure 1

19 pages, 562 KB

Open AccessEditor’s ChoiceReview

Epigenetic Regulation of DNA Methylation and RNA Interference in Gastric Cancer: A 2024 Update

by Iulia Lupan, Vasile Bintintan, Diana Deleanu and Gabriel Samasca

Biomedicines 2024, 12(9), 2001; https://doi.org/10.3390/biomedicines12092001 - 3 Sep 2024

Cited by 4 | Viewed by 2835

Abstract

Gastric cancer (GC) remains a significant public health concern because of its lethality, underscoring the need for deeper insights into its molecular mechanisms. Recent studies have increasingly highlighted the role of epigenetic modifications as critical players in cancer progression. Despite their importance, research [...] Read more.

Gastric cancer (GC) remains a significant public health concern because of its lethality, underscoring the need for deeper insights into its molecular mechanisms. Recent studies have increasingly highlighted the role of epigenetic modifications as critical players in cancer progression. Despite their importance, research specifically addressing epigenetic factors in GC is relatively scarce. This paper seeks to bridge that gap by examining recent literature that elucidates the epigenetic landscape associated with GC. The investigation of long noncoding RNAs (lncRNAs) has revealed their substantial involvement in gene dysregulation and epigenetic alterations within GC tumors. Notably, lncRNAs such as LINC00853 and LINC01266 have been identified as significant contributors to the epigenetic modulation of gene expression. Furthermore, the overexpression of KAT5 and GPX4 has been shown to mitigate the antiproliferative effects resulting from the depletion of circRHOT1, suggesting a complex interplay between these molecules in GC pathophysiology. Another pivotal aspect of epigenetic regulation in GC involves modifications in N6-methyladenosine (m6A), which play crucial roles in mRNA maturation processes such as splicing, export, degradation, and translation. m6A modifications are known for their influence on various cancer-related pathways, thus presenting a potential avenue for targeted interventions. Our findings indicate that the most pronounced instances of epigenetic dysregulation in GC can be traced back to the effects of long lncRNAs and alterations in m6A modification patterns. This underscores the urgent need for comprehensive investigations into these epigenetic factors, as a deeper understanding could lead to enhanced diagnostic markers and innovative therapeutic strategies. The integration of genetic and epigenetic considerations is essential for advancing the field of GC research. This synthesis of recent findings concerning epigenetic regulation offers valuable insights that could inform future studies and therapeutic developments. There is a critical need for ongoing research to elucidate the complexities of epigenetic modifications in GC, ultimately improving patient outcomes through tailored interventions. Full article

(This article belongs to the Special Issue Epigenetic Regulation in Cancer Progression)

► Show Figures

Figure 1

13 pages, 1923 KB

Open AccessEditor’s ChoiceArticle

Cold Atmospheric Plasma Induces Growth Arrest and Apoptosis in Neurofibromatosis Type 1-Associated Peripheral Nerve Sheath Tumor Cells

by Brian Na, Blake Haist, Shilp R. Shah, Graeme Sabiston, Steven J. Jonas, Jeremie Vitte, Richard E. Wirz and Marco Giovannini

Biomedicines 2024, 12(9), 1986; https://doi.org/10.3390/biomedicines12091986 - 2 Sep 2024

Cited by 1 | Viewed by 1633

Abstract

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder resulting from mutations in the NF1 gene. Patients harboring these mutations are predisposed to a spectrum of peripheral nerve sheath tumors (PNSTs) originating from Schwann cells, of which malignant peripheral nerve sheath tumors (MPNSTs) [...] Read more.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder resulting from mutations in the NF1 gene. Patients harboring these mutations are predisposed to a spectrum of peripheral nerve sheath tumors (PNSTs) originating from Schwann cells, of which malignant peripheral nerve sheath tumors (MPNSTs) are the deadliest, with limited treatment options. Therefore, an unmet need still exists for more effective therapies directed at these aggressive malignancies. Cold atmospheric plasma (CAP) is a reactive oxygen species (ROS) and reactive nitrogen species (RNS) generating ionized gas that has been proposed to be a potential therapeutic modality for cancer. In this study, we sought to determine the effects of CAP on NF1-associated PNSTs. Utilizing established mouse and human cell lines to interrogate the effects of CAP in both in vitro and in vivo settings, we found that NF1-associated PNSTs were highly sensitive to CAP exposure, resulting in cell death. To our knowledge, this is the first application of CAP to NF1-associated PNSTs and provides a unique opportunity to study the complex biology of NF1-associated tumors. Full article

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

► Show Figures

Figure 1

19 pages, 1681 KB

Open AccessEditor’s ChoiceReview

The Biological Clock of Liver Metabolism in Metabolic Dysfunction-Associated Steatohepatitis Progression to Hepatocellular Carcinoma

by Pradeep Kumar Rajan, Utibe-Abasi S. Udoh, Robert Finley, Sandrine V. Pierre and Juan Sanabria

Biomedicines 2024, 12(9), 1961; https://doi.org/10.3390/biomedicines12091961 - 29 Aug 2024

Cited by 4 | Viewed by 2673

Abstract

Circadian rhythms are endogenous behavioral or physiological cycles that are driven by a daily biological clock that persists in the absence of geophysical or environmental temporal cues. Circadian rhythm-related genes code for clock proteins that rise and fall in rhythmic patterns driving biochemical [...] Read more.

Circadian rhythms are endogenous behavioral or physiological cycles that are driven by a daily biological clock that persists in the absence of geophysical or environmental temporal cues. Circadian rhythm-related genes code for clock proteins that rise and fall in rhythmic patterns driving biochemical signals of biological processes from metabolism to physiology and behavior. Clock proteins have a pivotal role in liver metabolism and homeostasis, and their disturbances are implicated in various liver disease processes. Encoded genes play critical roles in the initiation and progression of metabolic dysfunction-associated steatohepatitis (MASH) to hepatocellular carcinoma (HCC) and their proteins may become diagnostic markers as well as therapeutic targets. Understanding molecular and metabolic mechanisms underlying circadian rhythms will aid in therapeutic interventions and may have broader clinical applications. The present review provides an overview of the role of the liver’s circadian rhythm in metabolic processes in health and disease, emphasizing MASH progression and the oncogenic associations that lead to HCC. Full article

(This article belongs to the Special Issue Hepatocellular Carcinoma: From Molecular Mechanisms to Novel Therapeutic Approaches)

► Show Figures

Figure 1

13 pages, 4002 KB

Open AccessEditor’s ChoiceArticle

Calcium-Enhanced Medium-Based Delivery of Splice Modulating Antisense Oligonucleotides in 2D and 3D hiPSC-Derived Neuronal Models

by Ronald A. M. Buijsen, Linda M. van der Graaf, Elsa C. Kuijper, Barry A. Pepers, Elena Daoutsali, Lotte Weel, Vered Raz, David A. Parfitt and Willeke M. C. van Roon-Mom

Biomedicines 2024, 12(9), 1933; https://doi.org/10.3390/biomedicines12091933 - 23 Aug 2024

Cited by 1 | Viewed by 2744

Abstract

Antisense technology demonstrates significant potential for addressing inherited brain diseases, with over a dozen products already available and numerous others in the development pipeline. The versatility of differentiating induced pluripotent stem cells (iPSCs) into nearly all neural cell types proves invaluable for comprehending [...] Read more.

Antisense technology demonstrates significant potential for addressing inherited brain diseases, with over a dozen products already available and numerous others in the development pipeline. The versatility of differentiating induced pluripotent stem cells (iPSCs) into nearly all neural cell types proves invaluable for comprehending the mechanisms behind neurological diseases, replicating cellular phenotypes, and advancing the testing and development of new therapies, including antisense oligonucleotide therapeutics. While delivering antisense oligonucleotides (ASOs) to human iPSC-based neuronal models has posed challenges, this study explores various delivery methods, including lipid-based transfection, gymnotic uptake, Ca⁽²⁺⁾-enhanced medium (CEM)-based delivery, and electroporation, in 2D and 3D hiPSC-derived neuronal models. This study reveals that CEM-based delivery exhibits efficiency and low toxicity in both 2D neuronal cultures and 3D brain organoids. Furthermore, the findings indicate that CEM is slightly more effective in neurons than in astrocytes, suggesting promising avenues for further exploration and optimization of preclinical ASO strategies in the treatment of neurological disorders. Full article

(This article belongs to the Special Issue Applications of 3D Cell Culture in Biomedicines)

► Show Figures

Figure 1

15 pages, 1213 KB

Open AccessEditor’s ChoiceReview

Dendrimers—Novel Therapeutic Approaches for Alzheimer’s Disease

by Magdalena Mroziak, Gracjan Kozłowski, Weronika Kołodziejczyk, Magdalena Pszczołowska, Kamil Walczak, Jan Aleksander Beszłej and Jerzy Leszek

Biomedicines 2024, 12(8), 1899; https://doi.org/10.3390/biomedicines12081899 - 20 Aug 2024

Cited by 2 | Viewed by 2024

Abstract

Dendrimers are covalently bonded globular nanostructures that may be used in the treatment of Alzheimer’s disease (AD). Nowadays, AD therapies are focused on improving cognitive functioning and not causal treatment. However, this may change with the use of dendrimers, which are being investigated [...] Read more.

Dendrimers are covalently bonded globular nanostructures that may be used in the treatment of Alzheimer’s disease (AD). Nowadays, AD therapies are focused on improving cognitive functioning and not causal treatment. However, this may change with the use of dendrimers, which are being investigated as a drug-delivery system or as a drug per se. With their ability to inhibit amyloid formation and their anti-tau properties, they are a promising therapeutic option for AD patients. Studies have shown that dendrimers may inhibit amyloid formation in at least two ways: by blocking fibril growth and by breaking already existing fibrils. Neurofibrillary tangles (NFTs) are abnormal filaments built by tau proteins that can be accumulated in the cell, which leads to the loss of cytoskeletal microtubules and tubulin-associated proteins. Cationic phosphorus dendrimers, with their anti-tau properties, can induce the aggregation of tau into amorphous structures. Drug delivery to mitochondria is difficult due to poor transport across biological barriers, such as the inner mitochondrial membrane, which is highly negatively polarized. Dendrimers may be potential nanocarriers and increase mitochondria targeting. Another considered use of dendrimers in AD treatment is as a drug-delivery system, for example, carbamazepine (CBZ) or tacrine. They can also be used to transport siRNA into neuronal tissue and to carry antioxidants and anti-inflammatory drugs to act protectively on the nervous system. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery 2.0)

► Show Figures

Figure 1

20 pages, 774 KB

Open AccessEditor’s ChoiceReview

The Role of Fecal Microbiota Transplantation (FMT) in the Management of Metabolic Diseases in Humans: A Narrative Review

by Eva Zikou, Chrysi Koliaki and Konstantinos Makrilakis

Biomedicines 2024, 12(8), 1871; https://doi.org/10.3390/biomedicines12081871 - 16 Aug 2024

Cited by 17 | Viewed by 5846

Abstract

The gut microbiota represents a complex ecosystem of trillions of microorganisms residing in the human gastrointestinal tract, which is known to interact with the host physiology and regulate multiple functions. Alterations in gut microbial composition, diversity, and function are referred to as dysbiosis. [...] Read more.

The gut microbiota represents a complex ecosystem of trillions of microorganisms residing in the human gastrointestinal tract, which is known to interact with the host physiology and regulate multiple functions. Alterations in gut microbial composition, diversity, and function are referred to as dysbiosis. Dysbiosis has been associated with a variety of chronic diseases, including Clostridioides difficile infections, but also cardiometabolic diseases, including obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM). The implication of gut microbiota dysbiosis in the pathogenesis of both obesity and T2DM has paved the way to implementing novel therapeutic approaches for metabolic diseases through gut microbial reconfiguration. These interventions include probiotics, prebiotics, and synbiotics, while a more innovative approach has been fecal microbiota transplantation (FMT). FMT is a procedure that delivers healthy human donor stool to another individual through the gastrointestinal tract, aiming to restore gut microbiota balance. Several studies have investigated this approach as a potential tool to mitigate the adverse metabolic effects of gut microbiota aberrations associated with obesity and T2DM. The aim of the present review was to critically summarize the existing evidence regarding the clinical applications of FMT in the management of obesity and T2DM and provide an update on the potential of this method to remodel the entire host microbiota, leading thus to weight loss and sustained metabolic benefits. Safety issues, long-term efficacy, limitations, and pitfalls associated with FMT studies are further discussed, emphasizing the need for further research and standardization in certain methodological aspects in order to optimize metabolic outcomes. Full article

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

► Show Figures

Figure 1

18 pages, 1340 KB

Open AccessEditor’s ChoiceReview

Deep Learning for MRI Segmentation and Molecular Subtyping in Glioblastoma: Critical Aspects from an Emerging Field

by Marta Bonada, Luca Francesco Rossi, Giovanni Carone, Flavio Panico, Fabio Cofano, Pietro Fiaschi, Diego Garbossa, Francesco Di Meco and Andrea Bianconi

Biomedicines 2024, 12(8), 1878; https://doi.org/10.3390/biomedicines12081878 - 16 Aug 2024

Cited by 19 | Viewed by 1984

Abstract

Deep learning (DL) has been applied to glioblastoma (GBM) magnetic resonance imaging (MRI) assessment for tumor segmentation and inference of molecular, diagnostic, and prognostic information. We comprehensively overviewed the currently available DL applications, critically examining the limitations that hinder their broader adoption in [...] Read more.

Deep learning (DL) has been applied to glioblastoma (GBM) magnetic resonance imaging (MRI) assessment for tumor segmentation and inference of molecular, diagnostic, and prognostic information. We comprehensively overviewed the currently available DL applications, critically examining the limitations that hinder their broader adoption in clinical practice and molecular research. Technical limitations to the routine application of DL include the qualitative heterogeneity of MRI, related to different machinery and protocols, and the absence of informative sequences, possibly compensated by artificial image synthesis. Moreover, taking advantage from the available benchmarks of MRI, algorithms should be trained on large amounts of data. Additionally, the segmentation of postoperative imaging should be further addressed to limit the inaccuracies previously observed for this task. Indeed, molecular information has been promisingly integrated in the most recent DL tools, providing useful prognostic and therapeutic information. Finally, ethical concerns should be carefully addressed and standardized to allow for data protection. DL has provided reliable results for GBM assessment concerning MRI analysis and segmentation, but the routine clinical application is still limited. The current limitations could be prospectively addressed, giving particular attention to data collection, introducing new technical advancements, and carefully regulating ethical issues. Full article

(This article belongs to the Special Issue Gliomas: Signaling Pathways, Molecular Mechanisms and Novel Therapies)

► Show Figures

Figure 1

12 pages, 1016 KB

Open AccessEditor’s ChoiceReview

The Contribution of the Brain–Gut Axis to the Human Reward System

by Katerina Karaivazoglou, Ioanna Aggeletopoulou and Christos Triantos

Biomedicines 2024, 12(8), 1861; https://doi.org/10.3390/biomedicines12081861 - 15 Aug 2024

Cited by 3 | Viewed by 2791

Abstract

The human reward network consists of interconnected brain regions that process stimuli associated with satisfaction and modulate pleasure-seeking behaviors. Impairments in reward processing have been implicated in several medical and psychiatric conditions, and there is a growing interest in disentangling the underlying pathophysiological [...] Read more.

The human reward network consists of interconnected brain regions that process stimuli associated with satisfaction and modulate pleasure-seeking behaviors. Impairments in reward processing have been implicated in several medical and psychiatric conditions, and there is a growing interest in disentangling the underlying pathophysiological mechanisms. The brain–gut axis plays a regulatory role in several higher-order neurophysiological pathways, including reward processing. In this context, the aim of the current review was to critically appraise research findings on the contribution of the brain–gut axis to the human reward system. Enteric neuropeptides, which are implicated in the regulation of hunger and satiety, such as ghrelin, PYY_3–36, and glucagon-like peptide 1 (GLP-1), have been associated with the processing of food-related, alcohol-related, and other non-food-related rewards, maintaining a delicate balance between the body’s homeostatic and hedonic needs. Furthermore, intestinal microbiota and their metabolites have been linked to differences in the architecture and activation of brain reward areas in obese patients and patients with attention deficit and hyperactivity disorder. Likewise, bariatric surgery reduces hedonic eating by altering the composition of gut microbiota. Although existing findings need further corroboration, they provide valuable information on the pathophysiology of reward-processing impairments and delineate a novel framework for potential therapeutic interventions. Full article

(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development)

► Show Figures

Figure 1

17 pages, 1293 KB

Open AccessEditor’s ChoiceArticle

Sensory Neurons Release Cardioprotective Factors in an In Vitro Ischemia Model

by Clara Hoebart, Attila Kiss, Bruno K. Podesser, Ammar Tahir, Michael J. M. Fischer and Stefan Heber

Biomedicines 2024, 12(8), 1856; https://doi.org/10.3390/biomedicines12081856 - 15 Aug 2024

Viewed by 1351

Abstract

Sensory neurons densely innervate the myocardium. The role of their sensing and response to acute and prolonged ischemia is largely unclear. In a cellular model of ischemia-reperfusion injury, the presence of sensory neurons increases cardiomyocyte survival. Here, after the exclusion of classical neurotransmitter [...] Read more.

Sensory neurons densely innervate the myocardium. The role of their sensing and response to acute and prolonged ischemia is largely unclear. In a cellular model of ischemia-reperfusion injury, the presence of sensory neurons increases cardiomyocyte survival. Here, after the exclusion of classical neurotransmitter release, and measurement of cytokine release, we modified the experiment from a direct co-culture of primary murine cardiomyocytes and sensory neurons to a transfer of the supernatant. Sensory neurons were exposed to ischemia and the resulting conditioned supernatant was transferred onto cardiomyocytes. This approach largely increased the tolerance of cardiomyocytes to ischemia and reperfusion. Towards the identification of the mechanism, it was demonstrated that after ten-fold dilution, the conditioned solution lost its protective effect. The effect remained after removal of extracellular vesicles by ultracentrifugation, and was not affected by exposure to protease activity, and fractionation pointed towards a hydrophilic agent. Solutions conditioned by HEK293t cells or 3T3 fibroblasts also increase cardiomyocyte survival, but to a lower degree. A metabolomic search identified 64 at least two-fold changed metabolites and lipids. Many of these could be identified and are involved in essential cellular functions. In the presented model for ischemia-reperfusion, sensory neurons secrete one or more cardioprotective substances that can improve cardiomyocyte survival. Full article

(This article belongs to the Special Issue Molecular Insights into Myocardial Infarction)

► Show Figures

Graphical abstract

13 pages, 977 KB

Open AccessEditor’s ChoiceReview

Biologic and Small Molecule Therapy in Atopic Dermatitis

by Mahek Shergill, Barinder Bajwa, Orhan Yilmaz, Karishma Tailor, Naila Bouadi and Ilya Mukovozov

Biomedicines 2024, 12(8), 1841; https://doi.org/10.3390/biomedicines12081841 - 13 Aug 2024

Cited by 6 | Viewed by 5529

Abstract

Atopic dermatitis is a chronic inflammatory dermatosis characterized by pruritic, scaly, erythematous lesions. Its incidence varies but is estimated to be approximately 20% in children and between 7 and 14% in adults, with variation amongst countries. It is a multifactorial condition, with a [...] Read more.

Atopic dermatitis is a chronic inflammatory dermatosis characterized by pruritic, scaly, erythematous lesions. Its incidence varies but is estimated to be approximately 20% in children and between 7 and 14% in adults, with variation amongst countries. It is a multifactorial condition, with a complex interplay between genetic, immunological, and environmental factors. Research into the inflammatory response has identified new therapeutic targets that work to reduce inflammation and subsequently reduce flares. This study explores existing therapeutic agents for atopic dermatitis as well as newer therapies such as biologics and small molecules, drawing upon each agent’s mechanism of action, relevant landmark clinical trials, efficacy, and safety profile. Current therapies include emollients, corticosteroids, cyclosporine A, calcineurin inhibitors, phototherapy, and methotrexate. Biologics described include dupilumab, tralokinumab, lebrikizumab, nemolizumab, and rocatinlimab. Small molecules inhibitors include Janus kinase inhibitors, phosphodiesterase 4 inhibitors, transient receptor potential vanilloid subfamily V member 1 antagonist, and aryl hydrocarbon receptor antagonist. Full article

(This article belongs to the Special Issue Current Molecular Research on Skin Diseases)

► Show Figures

Figure 1

15 pages, 1073 KB

Open AccessEditor’s ChoiceReview

Revisiting the Immunometabolic Basis for the Metabolic Syndrome from an Immunonutritional View

by César Jeri Apaza, Juan Francisco Cerezo, Aurora García-Tejedor, Juan Antonio Giménez-Bastida and José Moisés Laparra-Llopis

Biomedicines 2024, 12(8), 1825; https://doi.org/10.3390/biomedicines12081825 - 12 Aug 2024

Cited by 3 | Viewed by 2053

Abstract

Metabolic syndrome (MetS) implies different conditions where insulin resistance constitutes a major hallmark of the disease. The disease incurs a high risk for the development of cardiovascular complications, and takes its toll in regard to the gut–liver axis (pancreas, primary liver and colorectal)-associated [...] Read more.

Metabolic syndrome (MetS) implies different conditions where insulin resistance constitutes a major hallmark of the disease. The disease incurs a high risk for the development of cardiovascular complications, and takes its toll in regard to the gut–liver axis (pancreas, primary liver and colorectal)-associated immunity. The modulation of immunometabolic responses by immunonutritional factors (IFs) has emerged as a key determinant of the gut–liver axis’ metabolic and immune health. IFs from plant seeds have shown in vitro and pre-clinical effectiveness primarily in dealing with various immunometabolic and inflammatory diseases. Only recently have immunonutritional studies established the engagement of innate intestinal immunity to effectively control immune alterations in inflamed livers preceding the major features of the MetS. However, integrative analyses and the demonstration of causality between IFs and specific gut–liver axis-associated immunometabolic imbalances for the MetS remain ill-defined in the field. Herein, a better understanding of the IFs with a significant role in the MetS, as well as within the dynamic interplay in the functional differentiation of innate immune key effectors (i.e., monocytes/macrophages), worsening or improving the disease, could be of crucial relevance. The development of an adequate intermediary phenotype of these cells can significantly contribute to maintaining the function of T_regs and innate lymphoid cells for the prevention and treatment of MetS and associated comorbidities. Full article

(This article belongs to the Special Issue Immunometabolic Determinants of Gut–Liver Axis Health)

► Show Figures

Figure 1

19 pages, 2133 KB

Open AccessEditor’s ChoiceArticle

Prognostic Significance of Plasma Neutrophil Extracellular Trap Levels in Patients with Non-Small Cell Lung Cancer Treated with Immune Checkpoint Inhibitors

by Shun Horaguchi, Yoshiro Nakahara, Yuka Igarashi, Taku Kouro, Feifei Wei, Kenta Murotani, Seiichi Udagawa, Naoko Higashijima, Norikazu Matsuo, Shuji Murakami, Terufumi Kato, Tetsuro Kondo, Huihui Xiang, Rika Kasajima, Hidetomo Himuro, Kayoko Tsuji, Yasunobu Mano, Mitsuru Komahashi, Yohei Miyagi, Haruhiro Saito, Koichi Azuma, Shuichiro Uehara and Tetsuro Sasada Show full author list Hide full author list

Biomedicines 2024, 12(8), 1831; https://doi.org/10.3390/biomedicines12081831 - 12 Aug 2024

Cited by 4 | Viewed by 2311

Abstract

Neutrophil extracellular traps (NETs) released from neutrophils are related to cancer progression. However, the relationship between the therapeutic effects of immune checkpoint inhibitors (ICIs) such as anti-PD-1 and anti-PD-L1 antibodies and plasma NET concentration in patients with non-small cell lung cancer (NSCLC) is [...] Read more.

Neutrophil extracellular traps (NETs) released from neutrophils are related to cancer progression. However, the relationship between the therapeutic effects of immune checkpoint inhibitors (ICIs) such as anti-PD-1 and anti-PD-L1 antibodies and plasma NET concentration in patients with non-small cell lung cancer (NSCLC) is poorly understood. In this study, concentrations of citrullinated histone H3 (CitH3), a surrogate marker of NETs, in plasma before/after treatment were examined in patients with advanced or recurrent NSCLC undergoing ICI treatment (n = 185). The clinical significances of NET levels before/after treatment and posttreatment changes were statistically evaluated. As a result, multivariate Cox analysis showed that high NET levels before treatment were statistically significant predictors of unfavorable overall survival (OS; p < 0.001, HR 1.702, 95% CI 1.356–2.137) and progression-free survival (PFS; p < 0.001, HR 1.566, 95% CI 1.323–1.855). The Kaplan-Meier curves showed significant separation between the high- and low-NET groups in OS (p = 0.002) and PFS (p < 0.001). Additionally, high NET levels after treatment were also significantly associated with worse OS (p < 0.001) and PFS (p < 0.001) by multivariate Cox analysis. Notably, the pretreatment NET levels were significantly correlated with the plasma levels of NET-related inflammatory cytokines, such as IL-6 and IL-8, and with NET-related gene expression and immune-suppressive profile in peripheral blood mononuclear cells. Our findings suggest that NETs released from activated neutrophils might reduce the clinical efficacy of ICIs in patients with NSCLC. Full article

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

► Show Figures

Figure 1

23 pages, 7967 KB

Open AccessEditor’s ChoiceArticle

Differential Regulation of Wingless-Wnt/c-Jun N-Terminal Kinase Crosstalk via Oxidative Eustress in Primary and Metastatic Colorectal Cancer Cells

by Gitana Maria Aceto, Sara Pagotto, Francesco Domenico Del Pizzo, Concetta Saoca, Federico Selvaggi, Rosa Visone, Roberto Cotellese, M’hammed Aguennouz, Rossano Lattanzio and Teresa Catalano

Biomedicines 2024, 12(8), 1816; https://doi.org/10.3390/biomedicines12081816 - 9 Aug 2024

Cited by 2 | Viewed by 1702

Abstract

In the tumor microenvironment (TME), ROS production affects survival, progression, and therapy resistance in colorectal cancer (CRC). H₂O₂-mediated oxidative stress can modulate Wnt/β-catenin signaling and metabolic reprogramming of the TME. Currently, it is unclear how mild/moderate oxidative stress (eustress) [...] Read more.

In the tumor microenvironment (TME), ROS production affects survival, progression, and therapy resistance in colorectal cancer (CRC). H₂O₂-mediated oxidative stress can modulate Wnt/β-catenin signaling and metabolic reprogramming of the TME. Currently, it is unclear how mild/moderate oxidative stress (eustress) modulates Wnt/β-catenin/APC and JNK signaling relationships in primary and metastatic CRC cells. In this study, we determined the effects of the H₂O₂ concentration inducing eustress on isogenic SW480 and SW620 cells, also in combination with JNK inhibition. We assessed cell viability, mitochondrial respiration, glycolysis, and Wnt/β-catenin/APC/JNK gene and protein expression. Primary CRC cells were more sensitive to H₂O₂ eustress combined with JNK inhibition, showing a reduction in viability compared to metastatic cells. JNK inhibition under eustress reduced both glycolytic and respiratory capacity in SW620 cells, indicating a greater capacity to adapt to TME. In primary CRC cells, H₂O₂ alone significantly increased APC, LEF1, LRP6, cMYC and IL8 gene expression, whereas in metastatic CRC cells, this effect occurred after JNK inhibition. In metastatic but not in primary tumor cells, eustress and inhibition of JNK reduced APC, β-catenin, and pJNK protein. The results showed differential cross-regulation of Wnt/JNK in primary and metastatic tumor cells under environmental eustress conditions. Further studies would be useful to validate these findings and explore their therapeutic potential. Full article

(This article belongs to the Special Issue Molecular Research on Colorectal Cancer)

► Show Figures

Figure 1

19 pages, 3367 KB

Open AccessEditor’s ChoiceArticle

Role of miRNA–mRNA Interactome in Pathophysiology of Arrhythmogenic Cardiomyopathy

by Fernando Bonet, Oscar Campuzano, José Córdoba-Caballero, Mireia Alcalde, Georgia Sarquella-Brugada, Aitana Braza-Boïls, Ramon Brugada, Francisco Hernández-Torres, Maribel Quezada-Feijoo, Monica Ramos, Alipio Mangas, Juan A. G. Ranea and Rocío Toro

Biomedicines 2024, 12(8), 1807; https://doi.org/10.3390/biomedicines12081807 - 9 Aug 2024

Cited by 1 | Viewed by 1751

Abstract

Arrhythmogenic cardiomyopathy is an inherited entity characterized by irregular cell–cell adhesion, cardiomyocyte death and fibro-fatty replacement of ventricular myocytes, leading to malignant ventricular arrythmias, contractile dysfunction and sudden cardiac death. Pathogenic variants in genes that encode desmosome are the predominant cause of arrhythmogenic [...] Read more.

Arrhythmogenic cardiomyopathy is an inherited entity characterized by irregular cell–cell adhesion, cardiomyocyte death and fibro-fatty replacement of ventricular myocytes, leading to malignant ventricular arrythmias, contractile dysfunction and sudden cardiac death. Pathogenic variants in genes that encode desmosome are the predominant cause of arrhythmogenic cardiomyopathy. Moreover, signalling pathways such as Wnt/ß-catenin and transforming growth factor-β have been involved in the disease progression. However, still little is known about the molecular pathophysiological mechanisms that underlie arrhythmogenic cardiomyopathy pathogenesis. We used mRNA and small RNA sequencing to analyse the transcriptome of health and arrhythmogenic cardiomyopathy of autopsied human hearts. Our results showed 697 differentially expressed genes and eight differentially expressed miRNAs. Functional enrichment revealed mitochondrial respiratory-related pathways, impaired response to oxidative stress, apoptotic signalling pathways and inflammatory response-related and extracellular matrix response pathways. Furthermore, analysis of the miRNA–mRNA interactome identified eleven negatively correlated miRNA-target pairs for arrhythmogenic cardiomyopathy. Our finding revealed novel arrhythmogenic cardiomyopathy-related miRNAs with important regulatory function in disease pathogenesis, highlighting their value as potential key targets for therapeutic approaches. Full article

(This article belongs to the Special Issue Disease Biomarkers in the Precision Medicine Era: A Comprehensive Multi-Omics Analysis)

► Show Figures

Figure 1

14 pages, 2972 KB

Open AccessEditor’s ChoiceArticle

Impact of Peripheral Angioplasty on Wound Oxygenation and Healing in Patients with Chronic Limb-Threatening Ischemia Measured by Near-Infrared Spectroscopy

by Johanna Schremmer, Manuel Stern, Sven Baasen, Patricia Wischmann, Ramy Foerster, Miriam Schillings, Kálmán Bódis, Roberto Sansone, Christian Heiss, Malte Kelm and Lucas Busch

Biomedicines 2024, 12(8), 1805; https://doi.org/10.3390/biomedicines12081805 - 8 Aug 2024

Viewed by 2267

Abstract

Managing chronic limb-threatening ischemia (CLTI) is challenging due to difficulties in assessing tissue oxygen saturation in ulcers. Near-infrared spectroscopy (NIRS) is a non-invasive method for measuring tissue oxygen saturation (StO₂). This study evaluated the effects of endovascular treatment (EVT) on StO [...] Read more.

Managing chronic limb-threatening ischemia (CLTI) is challenging due to difficulties in assessing tissue oxygen saturation in ulcers. Near-infrared spectroscopy (NIRS) is a non-invasive method for measuring tissue oxygen saturation (StO₂). This study evaluated the effects of endovascular treatment (EVT) on StO₂ and wound healing in CLTI patients, comparing NIRS to standard ankle–brachial index (ABI) measurements. Using the Duesseldorf PTA Registry, 43 CLTI patients were analyzed: 27 underwent EVT, and 16 received conservative treatment. ABI assessed macrocirculation, while NIRS measured wound, wound area, and mean foot StO₂ at baseline, post-EVT, and four-month follow-up. Wound severity was classified by wound area and wound, ischemia, and foot infection (WIfI) score. Wound StO₂ increased significantly (median (interquartile range (IQR)), 38 (49.3) to 60 (34.5)%, p = 0.004), as did wound area StO₂ (median (IQR), 70.9 (21.6) to 72.8 (18.3)%, p < 0.001), with no significant changes in the control group by four-month follow-up. Wound area decreased significantly after EVT (mean ± SD, 343.1 ± 267.8 to 178.1 ± 268.5 mm², p = 0.01) but not in the control group. Changes in wound StO₂, wound area StO₂, and WIfI score correlated with wound area reduction, unlike ABI. This small exploratory study shows that NIRS-measured StO₂ improvements after EVT correlate with reduced wound area and WIfI scores, highlighting NIRS as a potential enhancement for CLTI wound management in addition to ABI. Full article

(This article belongs to the Special Issue Peripheral Artery Disease and Diabetic Foot Ulcer: From Bench to Clinic (2nd Edition))

► Show Figures

Figure 1

20 pages, 2071 KB

Open AccessEditor’s ChoiceReview

Fourier Transform Ion Cyclotron Resonance Mass Spectrometry Applications for Metabolomics

by Darcy Cochran and Robert Powers

Biomedicines 2024, 12(8), 1786; https://doi.org/10.3390/biomedicines12081786 - 6 Aug 2024

Cited by 6 | Viewed by 3189

Abstract

Metabolomics is an interdisciplinary field that aims to study all metabolites < 1500 Da that are ubiquitously found within all organisms. Metabolomics is experiencing exponential growth and commonly relies on high-resolution mass spectrometry (HRMS). Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) is [...] Read more.

Metabolomics is an interdisciplinary field that aims to study all metabolites < 1500 Da that are ubiquitously found within all organisms. Metabolomics is experiencing exponential growth and commonly relies on high-resolution mass spectrometry (HRMS). Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) is a form of HRMS that is particularly well suited for metabolomics research due to its exceptionally high resolution (10⁵–10⁶) and sensitivity with a mass accuracy in parts per billion (ppb). In this regard, FT-ICR-MS can provide valuable insights into the metabolomics analysis of complex biological systems due to unique capabilities such as the easy separation of isobaric and isomeric species, isotopic fine structure analysis, spatial resolution of metabolites in cells and tissues, and a high confidence (<1 ppm mass error) in metabolite identification. Alternatively, the large and complex data sets, long acquisition times, high cost, and limited access mainly through national mass spectrometry facilities may impede the routine adoption of FT-ICR-MS by metabolomics researchers. This review examines recent applications of FT-ICR-MS metabolomics in the search for clinical and non-human biomarkers; for the analysis of food, beverage, and environmental samples; and for the high-resolution imaging of tissues and other biological samples. We provide recent examples of metabolomics studies that highlight the advantages of FT-ICR-MS for the detailed and reliable characterization of the metabolome. Additionally, we offer some practical considerations for implementing FT-ICR-MS into a research program by providing a list of FT-ICR-MS facilities and by identifying different high-throughput interfaces, varieties of sample types, analysis methods (e.g., van Krevelen diagrams, Kendrick mass defect plot, etc.), and sample preparation and handling protocols used in FT-ICR-MS experiments. Overall, FT-ICR-MS holds great promise as a vital research tool for advancing metabolomics investigations. Full article

(This article belongs to the Collection OMICs and Complex Diseases)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Editor’s Choice Articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI