Biomedicines

17 pages, 3109 KiB

Open AccessEditor’s ChoiceArticle

by Marina Khodanovich, Mikhail Svetlik, Anna Naumova, Daria Kamaeva, Anna Usova, Marina Kudabaeva, Tatyana Anan’ina, Irina Wasserlauf, Valentina Pashkevich, Marina Moshkina, Victoria Obukhovskaya, Nadezhda Kataeva, Anastasia Levina, Yana Tumentceva and Vasily Yarnykh

Biomedicines 2024, 12(1), 61; https://doi.org/10.3390/biomedicines12010061 - 27 Dec 2023

Viewed by 1713

Abstract

Age-related myelination decrease is considered one of the likely mechanisms of cognitive decline. The present preliminary study is based on the longitudinal assessment of global and regional myelination of the normal adult human brain using fast macromolecular fraction (MPF) mapping. Additional markers were [...] Read more.

Age-related myelination decrease is considered one of the likely mechanisms of cognitive decline. The present preliminary study is based on the longitudinal assessment of global and regional myelination of the normal adult human brain using fast macromolecular fraction (MPF) mapping. Additional markers were age-related changes in white matter (WM) hyperintensities on FLAIR-MRI and the levels of anti-myelin autoantibodies in serum. Eleven healthy subjects (33–60 years in the first study) were scanned twice, seven years apart. An age-related decrease in MPF was found in global WM, grey matter (GM), and mixed WM–GM, as well as in 48 out of 82 examined WM and GM regions. The greatest decrease in MPF was observed for the frontal WM (2–5%), genu of the corpus callosum (CC) (4.0%), and caudate nucleus (5.9%). The age-related decrease in MPF significantly correlated with an increase in the level of antibodies against myelin basic protein (MBP) in serum (r = 0.69 and r = 0.63 for global WM and mixed WM–GM, correspondingly). The volume of FLAIR hyperintensities increased with age but did not correlate with MPF changes and the levels of anti-myelin antibodies. MPF mapping showed high sensitivity to age-related changes in brain myelination, providing the feasibility of this method in clinics. Full article

(This article belongs to the Special Issue Neuroimaging: Current Position and Future Directions)

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28 pages, 5110 KiB

Open AccessEditor’s ChoiceSystematic Review

Mercury and Autism Spectrum Disorder: Exploring the Link through Comprehensive Review and Meta-Analysis

by Aleksandar Stojsavljević, Novak Lakićević and Slađan Pavlović

Biomedicines 2023, 11(12), 3344; https://doi.org/10.3390/biomedicines11123344 - 18 Dec 2023

Cited by 4 | Viewed by 2174

Abstract

Mercury (Hg) is a non-essential trace metal with unique neurochemical properties and harmful effects on the central nervous system. In this study, we present a comprehensive review and meta-analysis of peer-reviewed research encompassing five crucial clinical matrices: hair, whole blood, plasma, red blood [...] Read more.

Mercury (Hg) is a non-essential trace metal with unique neurochemical properties and harmful effects on the central nervous system. In this study, we present a comprehensive review and meta-analysis of peer-reviewed research encompassing five crucial clinical matrices: hair, whole blood, plasma, red blood cells (RBCs), and urine. We assess the disparities in Hg levels between gender- and age-matched neurotypical children (controls) and children diagnosed with autism spectrum disorder (ASD) (cases). After applying rigorous selection criteria, we incorporated a total of 60 case-control studies into our meta-analysis. These studies comprised 25 investigations of Hg levels in hair (controls/cases: 1134/1361), 15 in whole blood (controls/cases: 1019/1345), 6 in plasma (controls/cases: 224/263), 5 in RBCs (controls/cases: 215/293), and 9 in urine (controls/cases: 399/623). This meta-analysis did not include the data of ASD children who received chelation therapy. Our meta-analysis revealed no statistically significant differences in Hg levels in hair and urine between ASD cases and controls. In whole blood, plasma, and RBCs, Hg levels were significantly higher in ASD cases compared to their neurotypical counterparts. This indicates that ASD children could exhibit reduced detoxification capacity for Hg and impaired mechanisms for Hg excretion from their bodies. This underscores the detrimental role of Hg in ASD and underscores the critical importance of monitoring Hg levels in ASD children, particularly in early childhood. These findings emphasize the pressing need for global initiatives aimed at minimizing Hg exposure, thus highlighting the critical intersection of human–environment interaction and neurodevelopment health. Full article

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

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24 pages, 846 KiB

Open AccessEditor’s ChoiceReview

Advances of Genome Editing with CRISPR/Cas9 in Neurodegeneration: The Right Path towards Therapy

by Aleksandr Klinkovskij, Mikhail Shepelev, Yuri Isaakyan, Denis Aniskin and Ilya Ulasov

Biomedicines 2023, 11(12), 3333; https://doi.org/10.3390/biomedicines11123333 - 17 Dec 2023

Viewed by 1609

Abstract

The rate of neurodegenerative disorders (NDDs) is rising rapidly as the world’s population ages. Conditions such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia are becoming more prevalent and are now the fourth leading cause of death, following heart disease, cancer, and [...] Read more.

The rate of neurodegenerative disorders (NDDs) is rising rapidly as the world’s population ages. Conditions such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia are becoming more prevalent and are now the fourth leading cause of death, following heart disease, cancer, and stroke. Although modern diagnostic techniques for detecting NDDs are varied, scientists are continuously seeking new and improved methods to enable early and precise detection. In addition to that, the present treatment options are limited to symptomatic therapy, which is effective in reducing the progression of neurodegeneration but lacks the ability to target the root cause—progressive loss of neuronal functioning. As a result, medical researchers continue to explore new treatments for these conditions. Here, we present a comprehensive summary of the key features of NDDs and an overview of the underlying mechanisms of neuroimmune dysfunction. Additionally, we dive into the cutting-edge treatment options that gene therapy provides in the quest to treat these disorders. Full article

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

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23 pages, 1237 KiB

Open AccessEditor’s ChoiceReview

Rodent Models of Huntington’s Disease: An Overview

by Giulio Nittari, Proshanta Roy, Ilenia Martinelli, Vincenzo Bellitto, Daniele Tomassoni, Enea Traini, Seyed Khosrow Tayebati and Francesco Amenta

Biomedicines 2023, 11(12), 3331; https://doi.org/10.3390/biomedicines11123331 - 16 Dec 2023

Cited by 1 | Viewed by 1761

Abstract

Huntington’s disease (HD) is an autosomal-dominant inherited neurological disorder caused by a genetic mutation in the IT15 gene. This neurodegenerative disorder is caused by a polyglutamine repeat expansion mutation in the widely expressed huntingtin (HTT) protein. HD is characterized by the degeneration of [...] Read more.

Huntington’s disease (HD) is an autosomal-dominant inherited neurological disorder caused by a genetic mutation in the IT15 gene. This neurodegenerative disorder is caused by a polyglutamine repeat expansion mutation in the widely expressed huntingtin (HTT) protein. HD is characterized by the degeneration of basal ganglia neurons and progressive cell death in intrinsic neurons of the striatum, accompanied by dementia and involuntary abnormal choreiform movements. Animal models have been extensively studied and have proven to be extremely valuable for therapeutic target evaluations. They reveal the hallmark of the age-dependent formation of aggregates or inclusions consisting of misfolded proteins. Animal models of HD have provided a therapeutic strategy to treat HD by suppressing mutant HTT (mHTT). Transgenic animal models have significantly increased our understanding of the molecular processes and pathophysiological mechanisms underlying the HD behavioral phenotype. Since effective therapies to cure or interrupt the course of the disease are not yet available, clinical research will have to make use of reliable animal models. This paper reviews the main studies of rodents as HD animal models, highlighting the neurological and behavioral differences between them. The choice of an animal model depends on the specific aspect of the disease to be investigated. Toxin-based models can still be useful, but most experimental hypotheses depend on success in a genetic model, whose choice is determined by the experimental question. There are many animal models showing similar HD symptoms or pathologies. They include chemical-induced HDs and genetic HDs, where cell-free and cell culture, lower organisms (such as yeast, Drosophila, C. elegans, zebrafish), rodents (mice, rats), and non-human primates are involved. These models provide accessible systems to study molecular pathogenesis and test potential treatments. For developing more effective pharmacological treatments, better animal models must be available and used to evaluate the efficacy of drugs. Full article

(This article belongs to the Special Issue Application of Animal Models and New Therapeutic Approaches in Neurological Diseases)

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32 pages, 405 KiB

Open AccessEditor’s ChoiceReview

Neuromodulation for Craniofacial Pain and Headaches

by Ray J. Pak, Jun B. Ku and Alaa Abd-Elsayed

Biomedicines 2023, 11(12), 3328; https://doi.org/10.3390/biomedicines11123328 - 16 Dec 2023

Cited by 1 | Viewed by 1283

Abstract

Headaches and facial pain are highly prevalent diseases but are often difficult to treat. Though there have been significant advances in medical management, many continue to suffer from refractory pain. Neuromodulation has been gaining interest for its therapeutic purposes in many chronic pain [...] Read more.

Headaches and facial pain are highly prevalent diseases but are often difficult to treat. Though there have been significant advances in medical management, many continue to suffer from refractory pain. Neuromodulation has been gaining interest for its therapeutic purposes in many chronic pain conditions, including headaches and facial pain. There are many potential targets of neuromodulation for headache and facial pain, and some have more robust evidence in favor of their use than others. Despite the need for more high-quality research, the available evidence for the use of neuromodulation in treating headaches and facial pain is promising. Considering the suffering that afflicts patients with intractable headache, neuromodulation may be an appropriate tool to improve not only pain but also disability and quality of life. Full article

(This article belongs to the Special Issue Recent Advances in Craniofacial Pain and Headaches)

14 pages, 2281 KiB

Open AccessEditor’s ChoiceArticle

Early Effects of Alpha-Synuclein Depletion by Pan-Neuronal Inactivation of Encoding Gene on Electroencephalogram Coherence between Different Brain Regions in Mice

by Vasily Vorobyov, Alexander Deev, Olga Morozova, Zoya Oganesyan, Anastasia M. Krayushkina, Tamara A. Ivanova and Kirill Chaprov

Biomedicines 2023, 11(12), 3282; https://doi.org/10.3390/biomedicines11123282 - 12 Dec 2023

Viewed by 1144

Abstract

Inactivation of the Snca gene in young mice by chronic injections of tamoxifen (TAM), a selective estrogen receptor modifier, has been shown to decrease the level of alpha-synuclein, a key peptide in the pathogenesis of Parkinson’s disease. In young mice, different time courses [...] Read more.

Inactivation of the Snca gene in young mice by chronic injections of tamoxifen (TAM), a selective estrogen receptor modifier, has been shown to decrease the level of alpha-synuclein, a key peptide in the pathogenesis of Parkinson’s disease. In young mice, different time courses of the effect were observed in different brain areas, meaning associated disturbances in the intracerebral relations, namely in brain function after TAM-induced synucleinopathy. Methods: We analyzed electroencephalogram (EEG) coherence (“functional connectivity”) between the cortex (MC), putamen (Pt), and dopamine-producing brain regions (ventral tegmental area, VTA, and substantia nigra, SN) in two groups of two-month-old male mice. We compared EEG coherences in the conditional knockout Snca^flox/flox mice with those in their genetic background (C57Bl6J) one, two, and three months after chronic (for five days) intraperitoneal injections of TAM or the vehicle (corn oil). The EEG coherences in the TAM-treated group were compared with those in the alpha-synuclein knockout mice. Results: A significant suppression of EEG coherence in the TAM-treated mice versus the vehicle group was observed in all inter-structural relations, with the exception of MC-VTA at one and three months and VTA-SN at two months after the injections. Suppressive changes in EEG coherence were observed in the alpha-synuclein knockout mice as well; the changes were similar to those in TAM-treated mice three months after treatment. Conclusion: our data demonstrate a combined time-dependent suppressive effect induced by TAM on intracerebral EEG coherence. Full article

(This article belongs to the Special Issue Recent Advances in Understanding of the Role of Synuclein Family Members in Health and Disease Volume II)

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11 pages, 1208 KiB

Open AccessEditor’s ChoiceArticle

Predicting Histologic Grade of Meningiomas Using a Combined Model of Radiomic and Clinical Imaging Features from Preoperative MRI

by Jae Hyun Park, Le Thanh Quang, Woong Yoon, Byung Hyun Baek, Ilwoo Park and Seul Kee Kim

Biomedicines 2023, 11(12), 3268; https://doi.org/10.3390/biomedicines11123268 - 10 Dec 2023

Cited by 1 | Viewed by 1392

Abstract

Meningiomas are common primary brain tumors, and their accurate preoperative grading is crucial for treatment planning. This study aimed to evaluate the value of radiomics and clinical imaging features in predicting the histologic grade of meningiomas from preoperative MRI. We retrospectively reviewed patients [...] Read more.

Meningiomas are common primary brain tumors, and their accurate preoperative grading is crucial for treatment planning. This study aimed to evaluate the value of radiomics and clinical imaging features in predicting the histologic grade of meningiomas from preoperative MRI. We retrospectively reviewed patients with intracranial meningiomas from two hospitals. Preoperative MRIs were analyzed for tumor and edema volumes, enhancement patterns, margins, and tumor–brain interfaces. Radiomics features were extracted, and machine learning models were employed to predict meningioma grades. A total of 212 patients were included. In the training group (Hospital 1), significant differences were observed between low-grade and high-grade meningiomas in terms of tumor volume (p = 0.012), edema volume (p = 0.004), enhancement (p = 0.001), margin (p < 0.001), and tumor–brain interface (p < 0.001). Five radiomics features were selected for model development. The prediction model for radiomics features demonstrated an average validation accuracy of 0.74, while the model for clinical imaging features showed an average validation accuracy of 0.69. When applied to external test data (Hospital 2), the radiomics model achieved an area under the receiver operating characteristics curve (AUC) of 0.72 and accuracy of 0.69, while the clinical imaging model achieved an AUC of 0.82 and accuracy of 0.81. An improved performance was obtained from the model constructed by combining radiomics and clinical imaging features. In the combined model, the AUC and accuracy for meningioma grading were 0.86 and 0.73, respectively. In conclusion, this study demonstrates the potential value of radiomics and clinical imaging features in predicting the histologic grade of meningiomas. The combination of both radiomics and clinical imaging features achieved the highest AUC among the models. Therefore, the combined model of radiomics and clinical imaging features may offer a more effective tool for predicting clinical outcomes in meningioma patients. Full article

(This article belongs to the Special Issue Artificial Intelligence in Neurobiology and Neurologic Diseases)

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22 pages, 1338 KiB

Open AccessEditor’s ChoiceReview

Advancements in Understanding and Classifying Chronic Orofacial Pain: Key Insights from Biopsychosocial Models and International Classifications (ICHD-3, ICD-11, ICOP)

by Federica Canfora, Giulia Ottaviani, Elena Calabria, Giuseppe Pecoraro, Stefania Leuci, Noemi Coppola, Mattia Sansone, Katia Rupel, Matteo Biasotto, Roberto Di Lenarda, Michele Davide Mignogna and Daniela Adamo

Biomedicines 2023, 11(12), 3266; https://doi.org/10.3390/biomedicines11123266 - 9 Dec 2023

Cited by 1 | Viewed by 2598

Abstract

In exploring chronic orofacial pain (COFP), this review highlights its global impact on life quality and critiques current diagnostic systems, including the ICD-11, ICOP, and ICHD-3, for their limitations in addressing COFP’s complexity. Firstly, this study outlines the global burden of chronic pain [...] Read more.

In exploring chronic orofacial pain (COFP), this review highlights its global impact on life quality and critiques current diagnostic systems, including the ICD-11, ICOP, and ICHD-3, for their limitations in addressing COFP’s complexity. Firstly, this study outlines the global burden of chronic pain and the importance of distinguishing between different pain types for effective treatment. It then delves into the specific challenges of diagnosing COFP, emphasizing the need for a more nuanced approach that incorporates the biopsychosocial model. This review critically examines existing classification systems, highlighting their limitations in fully capturing COFP’s multifaceted nature. It advocates for the integration of these systems with the DSM-5’s Somatic Symptom Disorder code, proposing a unified, multidisciplinary diagnostic approach. This recommendation aims to improve chronic pain coding standardization and acknowledge the complex interplay of biological, psychological, and social factors in COFP. In conclusion, here, we highlight the need for a comprehensive, universally applicable classification system for COFP. Such a system would enable accurate diagnosis, streamline treatment strategies, and enhance communication among healthcare professionals. This advancement holds potential for significant contributions to research and patient care in this challenging field, offering a broader perspective for scientists across disciplines. Full article

(This article belongs to the Special Issue Crosstalk between Depression, Anxiety, Dementia, and Chronic Pain: Comorbidity in Behavioral Neurology and Neuropsychiatry Volume III)

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18 pages, 1700 KiB

Open AccessEditor’s ChoiceReview

Bridging Retinal and Cerebral Neurodegeneration: A Focus on Crosslinks between Alzheimer–Perusini’s Disease and Retinal Dystrophies

by Luigi Donato, Domenico Mordà, Concetta Scimone, Simona Alibrandi, Rosalia D’Angelo and Antonina Sidoti

Biomedicines 2023, 11(12), 3258; https://doi.org/10.3390/biomedicines11123258 - 8 Dec 2023

Viewed by 1391

Abstract

In the early stages of Alzheimer–Perusini’s disease (AD), individuals often experience vision-related issues such as color vision impairment, reduced contrast sensitivity, and visual acuity problems. As the disease progresses, there is a connection with glaucoma and age-related macular degeneration (AMD) leading to retinal [...] Read more.

In the early stages of Alzheimer–Perusini’s disease (AD), individuals often experience vision-related issues such as color vision impairment, reduced contrast sensitivity, and visual acuity problems. As the disease progresses, there is a connection with glaucoma and age-related macular degeneration (AMD) leading to retinal cell death. The retina’s involvement suggests a link with the hippocampus, where most AD forms start. A thinning of the retinal nerve fiber layer (RNFL) due to the loss of retinal ganglion cells (RGCs) is seen as a potential AD diagnostic marker using electroretinography (ERG) and optical coherence tomography (OCT). Amyloid beta fragments (Aβ), found in the eye’s vitreous and aqueous humor, are also present in the cerebrospinal fluid (CSF) and accumulate in the retina. Aβ is known to cause tau hyperphosphorylation, leading to its buildup in various retinal layers. However, diseases like AD are now seen as mixed proteinopathies, with deposits of the prion protein (PrP) and α-synuclein found in affected brains and retinas. Glial cells, especially microglial cells, play a crucial role in these diseases, maintaining immunoproteostasis. Studies have shown similarities between retinal and brain microglia in terms of transcription factor expression and morphotypes. All these findings constitute a good start to achieving better comprehension of neurodegeneration in both the eye and the brain. New insights will be able to bring the scientific community closer to specific disease-modifying therapies. Full article

(This article belongs to the Special Issue State of the Art: Prerequisites, Prevention and Treatment of Neurodegenerative Diseases)

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17 pages, 398 KiB

Open AccessEditor’s ChoiceReview

Review of Piezoelectrical Materials Potentially Useful for Peripheral Nerve Repair

by Diogo Casal, Maria Helena Casimiro, Luís M. Ferreira, João Paulo Leal, Gabriela Rodrigues, Raquel Lopes, Diogo Lino Moura, Luís Gonçalves, João B. Lago, Diogo Pais and Pedro M. P. Santos

Biomedicines 2023, 11(12), 3195; https://doi.org/10.3390/biomedicines11123195 - 1 Dec 2023

Cited by 3 | Viewed by 1851

Abstract

It has increasingly been recognized that electrical currents play a pivotal role in cell migration and tissue repair, in a process named “galvanotaxis”. In this review, we summarize the current evidence supporting the potential benefits of electric stimulation (ES) in the physiology of [...] Read more.

It has increasingly been recognized that electrical currents play a pivotal role in cell migration and tissue repair, in a process named “galvanotaxis”. In this review, we summarize the current evidence supporting the potential benefits of electric stimulation (ES) in the physiology of peripheral nerve repair (PNR). Moreover, we discuss the potential of piezoelectric materials in this context. The use of these materials has deserved great attention, as the movement of the body or of the external environment can be used to power internally the electrical properties of devices used for providing ES or acting as sensory receptors in artificial skin (e-skin). The fact that organic materials sustain spontaneous degradation inside the body means their piezoelectric effect is limited in duration. In the case of PNR, this is not necessarily problematic, as ES is only required during the regeneration period. Arguably, piezoelectric materials have the potential to revolutionize PNR with new biomedical devices that range from scaffolds and nerve-guiding conduits to sensory or efferent components of e-skin. However, much remains to be learned regarding piezoelectric materials, their use in manufacturing of biomedical devices, and their sterilization process, to fine-tune their safe, effective, and predictable in vivo application. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Recent Advances and Future Perspectives)

27 pages, 2062 KiB

Open AccessEditor’s ChoiceReview

Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders

by Fabiola De Marchi, Ivana Munitic, Lea Vidatic, Eliša Papić, Valentino Rački, Jerneja Nimac, Igor Jurak, Gabriela Novotni, Boris Rogelj, Vladimira Vuletic, Rajka M. Liscic, Jason R. Cannon, Emanuele Buratti, Letizia Mazzini and Silva Hecimovic

Biomedicines 2023, 11(10), 2793; https://doi.org/10.3390/biomedicines11102793 - 14 Oct 2023

Cited by 9 | Viewed by 2548

Abstract

Many potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases, such as Alzheimer’s (AD) disease, Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), as well as in a seemingly distinct Niemann–Pick type C disease with primarily juvenile onset. [...] Read more.

Many potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases, such as Alzheimer’s (AD) disease, Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), as well as in a seemingly distinct Niemann–Pick type C disease with primarily juvenile onset. This strongly argues for an overlap in pathogenic mechanisms. The commonly researched immune targets include various immune cell subsets, such as microglia, peripheral macrophages, and regulatory T cells (Tregs); the complement system; and other soluble factors. In this review, we compare these neurodegenerative diseases from a clinical point of view and highlight common pathways and mechanisms of protein aggregation, neurodegeneration, and/or neuroinflammation that could potentially lead to shared treatment strategies for overlapping immune dysfunctions in these diseases. These approaches include but are not limited to immunisation, complement cascade blockade, microbiome regulation, inhibition of signal transduction, Treg boosting, and stem cell transplantation. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: “Amyotrophic Lateral Sclerosis: The Present and the Future of the Research”)

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52 pages, 2123 KiB

Open AccessEditor’s ChoiceReview

Mitochondria and Brain Disease: A Comprehensive Review of Pathological Mechanisms and Therapeutic Opportunities

by Vicente Javier Clemente-Suárez, Laura Redondo-Flórez, Ana Isabel Beltrán-Velasco, Domingo Jesús Ramos-Campo, Pedro Belinchón-deMiguel, Ismael Martinez-Guardado, Athanasios A. Dalamitros, Rodrigo Yáñez-Sepúlveda, Alexandra Martín-Rodríguez and José Francisco Tornero-Aguilera

Biomedicines 2023, 11(9), 2488; https://doi.org/10.3390/biomedicines11092488 - 7 Sep 2023

Cited by 15 | Viewed by 6401

Abstract

Mitochondria play a vital role in maintaining cellular energy homeostasis, regulating apoptosis, and controlling redox signaling. Dysfunction of mitochondria has been implicated in the pathogenesis of various brain diseases, including neurodegenerative disorders, stroke, and psychiatric illnesses. This review paper provides a comprehensive overview [...] Read more.

Mitochondria play a vital role in maintaining cellular energy homeostasis, regulating apoptosis, and controlling redox signaling. Dysfunction of mitochondria has been implicated in the pathogenesis of various brain diseases, including neurodegenerative disorders, stroke, and psychiatric illnesses. This review paper provides a comprehensive overview of the intricate relationship between mitochondria and brain disease, focusing on the underlying pathological mechanisms and exploring potential therapeutic opportunities. The review covers key topics such as mitochondrial DNA mutations, impaired oxidative phosphorylation, mitochondrial dynamics, calcium dysregulation, and reactive oxygen species generation in the context of brain disease. Additionally, it discusses emerging strategies targeting mitochondrial dysfunction, including mitochondrial protective agents, metabolic modulators, and gene therapy approaches. By critically analysing the existing literature and recent advancements, this review aims to enhance our understanding of the multifaceted role of mitochondria in brain disease and shed light on novel therapeutic interventions. Full article

(This article belongs to the Special Issue Mitochondria and Brain Disease 2.0)

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25 pages, 1188 KiB

Open AccessEditor’s ChoiceReview

Development of Antiepileptic Drugs throughout History: From Serendipity to Artificial Intelligence

by María Gabriela Corrales-Hernández, Sebastián Kurt Villarroel-Hagemann, Isabella Esther Mendoza-Rodelo, Leonardo Palacios-Sánchez, Mariana Gaviria-Carrillo, Natalia Buitrago-Ricaurte, Santiago Espinosa-Lugo, Carlos-Alberto Calderon-Ospina and Jesús Hernán Rodríguez-Quintana

Biomedicines 2023, 11(6), 1632; https://doi.org/10.3390/biomedicines11061632 - 3 Jun 2023

Cited by 6 | Viewed by 5197

Abstract

This article provides a comprehensive narrative review of the history of antiepileptic drugs (AEDs) and their development over time. Firstly, it explores the significant role of serendipity in the discovery of essential AEDs that continue to be used today, such as phenobarbital and [...] Read more.

This article provides a comprehensive narrative review of the history of antiepileptic drugs (AEDs) and their development over time. Firstly, it explores the significant role of serendipity in the discovery of essential AEDs that continue to be used today, such as phenobarbital and valproic acid. Subsequently, it delves into the historical progression of crucial preclinical models employed in the development of novel AEDs, including the maximal electroshock stimulation test, pentylenetetrazol-induced test, kindling models, and other animal models. Moving forward, a concise overview of the clinical advancement of major AEDs is provided, highlighting the initial milestones and the subsequent refinement of this process in recent decades, in line with the emergence of evidence-based medicine and the implementation of increasingly rigorous controlled clinical trials. Lastly, the article explores the contributions of artificial intelligence, while also offering recommendations and discussing future perspectives for the development of new AEDs. Full article

(This article belongs to the Special Issue Epilepsy: From Physiopathology to Improvements in Diagnosis and Therapy)

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19 pages, 3085 KiB

Open AccessEditor’s ChoiceArticle

Metabolomic Investigation of Blood and Urinary Amino Acids and Derivatives in Patients with Type 2 Diabetes Mellitus and Early Diabetic Kidney Disease

by Maria Mogos, Carmen Socaciu, Andreea Iulia Socaciu, Adrian Vlad, Florica Gadalean, Flaviu Bob, Oana Milas, Octavian Marius Cretu, Anca Suteanu-Simulescu, Mihaela Glavan, Silvia Ienciu, Lavinia Balint, Dragos Catalin Jianu and Ligia Petrica

Biomedicines 2023, 11(6), 1527; https://doi.org/10.3390/biomedicines11061527 - 25 May 2023

Cited by 1 | Viewed by 1890

Abstract

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease; however, few biomarkers of its early identification are available. The aim of the study was to assess new biomarkers in the early stages of DKD in type 2 diabetes mellitus (DM) [...] Read more.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease; however, few biomarkers of its early identification are available. The aim of the study was to assess new biomarkers in the early stages of DKD in type 2 diabetes mellitus (DM) patients. This cross-sectional pilot study performed an integrated metabolomic profiling of blood and urine in 90 patients with type 2 DM, classified into three subgroups according to albuminuria stage from P1 to P3 (30 normo-, 30 micro-, and 30 macroalbuminuric) and 20 healthy controls using high-performance liquid chromatography and mass spectrometry (UPLC-QTOF-ESI* MS). From a large cohort of separated and identified molecules, 33 and 39 amino acids and derivatives from serum and urine, respectively, were selected for statistical analysis using Metaboanalyst 5.0. online software. The multivariate and univariate algorithms confirmed the relevance of some amino acids and derivatives as biomarkers that are responsible for the discrimination between healthy controls and DKD patients. Serum molecules such as tiglylglycine, methoxytryptophan, serotonin sulfate, 5-hydroxy lysine, taurine, kynurenic acid, and tyrosine were found to be more significant in the discrimination between group C and subgroups P1–P2–P3. In urine, o-phosphothreonine, aspartic acid, 5-hydroxy lysine, uric acid, methoxytryptophan, were among the most relevant metabolites in the discrimination between group C and DKD group, as well between subgroups P1–P2–P3. The identification of these potential biomarkers may indicate their involvement in the early DKD and 2DM progression, reflecting kidney injury at specific sites along the nephron, even in the early stages of DKD. Full article

(This article belongs to the Special Issue Pathophysiology and Treatment of Nephropathies)

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17 pages, 2717 KiB

Open AccessEditor’s ChoiceArticle

Influence of Chronic Fatigue Syndrome Codiagnosis on the Relationship between Perceived and Objective Psychoneuro-Immunoendocrine Disorders in Women with Fibromyalgia

by Eduardo Otero, Isabel Gálvez, Eduardo Ortega and María Dolores Hinchado

Biomedicines 2023, 11(5), 1488; https://doi.org/10.3390/biomedicines11051488 - 20 May 2023

Cited by 2 | Viewed by 3151

Abstract

Although the predominant symptom in fibromyalgia (FM) is muscle pain, and fatigue in chronic fatigue syndrome (CFS), differential diagnosis is very difficult. This research investigates the psychoneuroimmunoendocrine disorders of FM patients and ascertains whether a previous CFS diagnosis affected them. Through accelerometry objective [...] Read more.

Although the predominant symptom in fibromyalgia (FM) is muscle pain, and fatigue in chronic fatigue syndrome (CFS), differential diagnosis is very difficult. This research investigates the psychoneuroimmunoendocrine disorders of FM patients and ascertains whether a previous CFS diagnosis affected them. Through accelerometry objective parameters, physical activity/sedentarism levels in relation to fatigue are studied, as well as whether perceived levels of stress, anxiety, and pain correspond to objective biomarkers, all of these with respect to a reference group (RG) of women without FM. FM patients have a worse psychological state and perceived quality of life than those with RG. These perceived outcomes are consistent with impaired objective levels of a sedentary lifestyle, higher systemic levels of cortisol and noradrenaline, and lower levels of serotonin. However, FM patients with a previous CFS diagnosis had lower systemic levels of IL-8, cortisol, oxytocin, and higher levels of adrenaline and serotonin than FM patients without diagnosed CFS. In conclusion, while perceived health parameters do not detect differences, when objective neuroimmunoendocrine parameters related to stress, inflammation, pain, and fatigue are used, people with CFS could be overdiagnosed with FM. This reinforces the need for objective biomarker assessment of these patients for better diagnostic discrimination between both syndromes. Full article

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

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23 pages, 4818 KiB

Open AccessEditor’s ChoiceReview

Cerebrospinal Fluid–Basic Concepts Review

by Natalia Czarniak, Joanna Kamińska, Joanna Matowicka-Karna and Olga Martyna Koper-Lenkiewicz

Biomedicines 2023, 11(5), 1461; https://doi.org/10.3390/biomedicines11051461 - 17 May 2023

Cited by 8 | Viewed by 8403

Abstract

Cerebrospinal fluid plays a crucial role in protecting the central nervous system (CNS) by providing mechanical support, acting as a shock absorber, and transporting nutrients and waste products. It is produced in the ventricles of the brain and circulates through the brain and [...] Read more.

Cerebrospinal fluid plays a crucial role in protecting the central nervous system (CNS) by providing mechanical support, acting as a shock absorber, and transporting nutrients and waste products. It is produced in the ventricles of the brain and circulates through the brain and spinal cord in a continuous flow. In the current review, we presented basic concepts related to cerebrospinal fluid history, cerebrospinal fluid production, circulation, and its main components, the role of the blood–brain barrier and the blood–cerebrospinal fluid barrier in the maintenance of cerebrospinal fluid homeostasis, and the utility of Albumin Quotient (Q_Alb) evaluation in the diagnosis of CNS diseases. We also discussed the collection of cerebrospinal fluid (type, number of tubes, and volume), time of transport to the laboratory, and storage conditions. Finally, we briefly presented the role of cerebrospinal fluid examination in CNS disease diagnosis of various etiologies and highlighted that research on identifying cerebrospinal fluid biomarkers indicating disease presence or severity, evaluating treatment effectiveness, and enabling understanding of pathogenesis and disease mechanisms is of great importance. Thus, in our opinion, research on cerebrospinal fluid is still necessary for both the improvement of CNS disease management and the discovery of new treatment options. Full article

(This article belongs to the Special Issue Cerebrospinal Fluid: The Potential for Molecular Disease-Related and Drug-Related Biomarkers)

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26 pages, 1404 KiB

Open AccessEditor’s ChoiceReview

Adipokines as Clinically Relevant Therapeutic Targets in Obesity

by Marleen Würfel, Matthias Blüher, Michael Stumvoll, Thomas Ebert, Peter Kovacs, Anke Tönjes and Jana Breitfeld

Biomedicines 2023, 11(5), 1427; https://doi.org/10.3390/biomedicines11051427 - 11 May 2023

Cited by 14 | Viewed by 2838

Abstract

Adipokines provide an outstanding role in the comprehensive etiology of obesity and may link adipose tissue dysfunction to further metabolic and cardiovascular complications. Although several adipokines have been identified in terms of their physiological roles, many regulatory circuits remain unclear and translation from [...] Read more.

Adipokines provide an outstanding role in the comprehensive etiology of obesity and may link adipose tissue dysfunction to further metabolic and cardiovascular complications. Although several adipokines have been identified in terms of their physiological roles, many regulatory circuits remain unclear and translation from experimental studies to clinical applications has yet to occur. Nevertheless, due to their complex metabolic properties, adipokines offer immense potential for their use both as obesity-associated biomarkers and as relevant treatment strategies for overweight, obesity and metabolic comorbidities. To provide an overview of the current clinical use of adipokines, this review summarizes clinical studies investigating the potential of various adipokines with respect to diagnostic and therapeutic treatment strategies for obesity and linked metabolic disorders. Furthermore, an overview of adipokines, for which a potential for clinical use has been demonstrated in experimental studies to date, will be presented. In particular, promising data revealed that fibroblast growth factor (FGF)-19, FGF-21 and leptin offer great potential for future clinical application in the treatment of obesity and related comorbidities. Based on data from animal studies or other clinical applications in addition to obesity, adipokines including adiponectin, vaspin, resistin, chemerin, visfatin, bone morphogenetic protein 7 (BMP-7) and tumor necrosis factor alpha (TNF-α) provide potential for human clinical application. Full article

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

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26 pages, 6049 KiB

Open AccessEditor’s ChoiceArticle

Blood pH Analysis in Combination with Molecular Medical Tools in Relation to COVID-19 Symptoms

by Hans-Christian Siebert, Thomas Eckert, Anirban Bhunia, Nele Klatte, Marzieh Mohri, Simone Siebert, Anna Kozarova, John W. Hudson, Ruiyan Zhang, Ning Zhang, Lan Li, Konstantinos Gousias, Dimitrios Kanakis, Mingdi Yan, Jesús Jiménez-Barbero, Tibor Kožár, Nikolay E. Nifantiev, Christian Vollmer, Timo Brandenburger, Detlef Kindgen-Milles, Thomas Haak and Athanasios K. Petridis Show full author list Hide full author list

Biomedicines 2023, 11(5), 1421; https://doi.org/10.3390/biomedicines11051421 - 11 May 2023

Cited by 1 | Viewed by 2845

Abstract

The global outbreak of SARS-CoV-2/COVID-19 provided the stage to accumulate an enormous biomedical data set and an opportunity as well as a challenge to test new concepts and strategies to combat the pandemic. New research and molecular medical protocols may be deployed in [...] Read more.

The global outbreak of SARS-CoV-2/COVID-19 provided the stage to accumulate an enormous biomedical data set and an opportunity as well as a challenge to test new concepts and strategies to combat the pandemic. New research and molecular medical protocols may be deployed in different scientific fields, e.g., glycobiology, nanopharmacology, or nanomedicine. We correlated clinical biomedical data derived from patients in intensive care units with structural biology and biophysical data from NMR and/or CAMM (computer-aided molecular modeling). Consequently, new diagnostic and therapeutic approaches against SARS-CoV-2 were evaluated. Specifically, we tested the suitability of incretin mimetics with one or two pH-sensitive amino acid residues as potential drugs to prevent or cure long-COVID symptoms. Blood pH values in correlation with temperature alterations in patient bodies were of clinical importance. The effects of biophysical parameters such as temperature and pH value variation in relation to physical-chemical membrane properties (e.g., glycosylation state, affinity of certain amino acid sequences to sialic acids as well as other carbohydrate residues and lipid structures) provided helpful hints in identifying a potential Achilles heel against long COVID. In silico CAMM methods and in vitro NMR experiments (including ³¹P NMR measurements) were applied to analyze the structural behavior of incretin mimetics and SARS-CoV fusion peptides interacting with dodecylphosphocholine (DPC) micelles. These supramolecular complexes were analyzed under physiological conditions by ¹H and ³¹P NMR techniques. We were able to observe characteristic interaction states of incretin mimetics, SARS-CoV fusion peptides and DPC membranes. Novel interaction profiles (indicated, e.g., by ³¹P NMR signal splitting) were detected. Furthermore, we evaluated GM1 gangliosides and sialic acid-coated silica nanoparticles in complex with DPC micelles in order to create a simple virus host cell membrane model. This is a first step in exploring the structure–function relationship between the SARS-CoV-2 spike protein and incretin mimetics with conserved pH-sensitive histidine residues in their carbohydrate recognition domains as found in galectins. The applied methods were effective in identifying peptide sequences as well as certain carbohydrate moieties with the potential to protect the blood–brain barrier (BBB). These clinically relevant observations on low blood pH values in fatal COVID-19 cases open routes for new therapeutic approaches, especially against long-COVID symptoms. Full article

(This article belongs to the Section Immunology and Immunotherapy)

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19 pages, 3658 KiB

Open AccessEditor’s ChoiceReview

Epidural and Intrathecal Drug Delivery in Rats and Mice for Experimental Research: Fundamental Concepts, Techniques, Precaution, and Application

by Md. Mahbubur Rahman, Ji Yeon Lee, Yong Ho Kim and Chul-Kyu Park

Biomedicines 2023, 11(5), 1413; https://doi.org/10.3390/biomedicines11051413 - 10 May 2023

Cited by 3 | Viewed by 8083

Abstract

Epidural and intrathecal routes are the most effective drug administration methods for pain management in clinical and experimental medicine to achieve quick results, reduce required drug dosages, and overcome the adverse effects associated with the oral and parenteral routes. Beyond pain management with [...] Read more.

Epidural and intrathecal routes are the most effective drug administration methods for pain management in clinical and experimental medicine to achieve quick results, reduce required drug dosages, and overcome the adverse effects associated with the oral and parenteral routes. Beyond pain management with analgesics, the intrathecal route is more widely used for stem cell therapy, gene therapy, insulin delivery, protein therapy, and drug therapy with agonist, antagonist, or antibiotic drugs in experimental medicine. However, clear information regarding intrathecal and epidural drug delivery in rats and mice is lacking, despite differences from human medicine in terms of anatomical space and proximity to the route of entry. In this study, we discussed and compared the anatomical locations of the epidural and intrathecal spaces, cerebrospinal fluid volume, dorsal root ganglion, techniques and challenges of epidural and intrathecal injections, dosage and volume of drugs, needle and catheter sizes, and the purpose and applications of these two routes in different disease models in rats and mice. We also described intrathecal injection in relation to the dorsal root ganglion. The accumulated information about the epidural and intrathecal delivery routes could contribute to better safety, quality, and reliability in experimental research. Full article

(This article belongs to the Special Issue Neuropathic Pain: From Mechanisms to Therapeutic Approaches)

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16 pages, 2864 KiB

Open AccessEditor’s ChoiceArticle

Anionic Phospholipids Shift the Conformational Equilibrium of the Selectivity Filter in the KcsA Channel to the Conductive Conformation: Predicted Consequences on Inactivation

by María Lourdes Renart, Ana Marcela Giudici, Carlos Coll-Díez, José M. González-Ros and José A. Poveda

Biomedicines 2023, 11(5), 1376; https://doi.org/10.3390/biomedicines11051376 - 5 May 2023

Cited by 1 | Viewed by 1364

Abstract

Here, we report an allosteric effect of an anionic phospholipid on a model K⁺ channel, KcsA. The anionic lipid in mixed detergent–lipid micelles specifically induces a change in the conformational equilibrium of the channel selectivity filter (SF) only when the channel inner [...] Read more.

Here, we report an allosteric effect of an anionic phospholipid on a model K⁺ channel, KcsA. The anionic lipid in mixed detergent–lipid micelles specifically induces a change in the conformational equilibrium of the channel selectivity filter (SF) only when the channel inner gate is in the open state. Such change consists of increasing the affinity of the channel for K⁺, stabilizing a conductive-like form by maintaining a high ion occupancy in the SF. The process is highly specific in several aspects: First, lipid modifies the binding of K⁺, but not that of Na⁺, which remains unperturbed, ruling out a merely electrostatic phenomenon of cation attraction. Second, no lipid effects are observed when a zwitterionic lipid, instead of an anionic one, is present in the micelles. Lastly, the effects of the anionic lipid are only observed at pH 4.0, when the inner gate of KcsA is open. Moreover, the effect of the anionic lipid on K⁺ binding to the open channel closely emulates the K⁺ binding behaviour of the non-inactivating E71A and R64A mutant proteins. This suggests that the observed increase in K⁺ affinity caused by the bound anionic lipid should result in protecting the channel against inactivation. Full article

(This article belongs to the Special Issue Fiftieth Anniversary of the Fluid Mosaic Model of Cell Membranes: From Lipid Structure to Biomedicines)

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10 pages, 436 KiB

Open AccessEditor’s ChoiceCommunication

Prognostic Value of the Selected Polymorphisms in the CD36 Gene in the Domain-Encoding Lipid-Binding Region at a 10-Year Follow-Up for Early-Onset CAD Patients

by Michał Bartoszewicz and Monika Rać

Biomedicines 2023, 11(5), 1332; https://doi.org/10.3390/biomedicines11051332 - 30 Apr 2023

Viewed by 1204

Abstract

The polymorphism of the CD36 gene may have a decisive impact on the formation and progression of atherosclerotic changes. The aim of the study was to confirm the prognostic values of the previously studied polymorphisms in the CD36 gene within a 10-year follow-up [...] Read more.

The polymorphism of the CD36 gene may have a decisive impact on the formation and progression of atherosclerotic changes. The aim of the study was to confirm the prognostic values of the previously studied polymorphisms in the CD36 gene within a 10-year follow-up period. This is the first published report confirming the long-term observation of patients with CAD. The study group covered 100 early-onset CAD patients. It included 26 women not older than 55 years and 74 men not older than 50 years, tested in a ten-year study as a long-term follow-up after the first cardiovascular episode. There are no notable differences between the CD36 variants and the number of fatalities during observation, fatalities due to cardiological reasons, cases of myocardial infarction within a ten-year observation period, hospitalizations for cardiovascular issues, all cardiovascular occurrences, and the number of months lived. We have shown that the CD36 variants analyzed in this study do not appear to be related to the risk of early CAD occurrence in the Caucasian population in long-term observation. Full article

(This article belongs to the Special Issue Cellular Mechanisms of Cardiovascular Disease 2.0)

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27 pages, 1854 KiB

Open AccessEditor’s ChoiceReview

Targeted DNA Demethylation: Vectors, Effectors and Perspectives

by Naohiro Yano and Alexey V. Fedulov

Biomedicines 2023, 11(5), 1334; https://doi.org/10.3390/biomedicines11051334 - 30 Apr 2023

Cited by 5 | Viewed by 3285

Abstract

Aberrant DNA hypermethylation at regulatory cis-elements of particular genes is seen in a plethora of pathological conditions including cardiovascular, neurological, immunological, gastrointestinal and renal diseases, as well as in cancer, diabetes and others. Thus, approaches for experimental and therapeutic DNA demethylation have a [...] Read more.

Aberrant DNA hypermethylation at regulatory cis-elements of particular genes is seen in a plethora of pathological conditions including cardiovascular, neurological, immunological, gastrointestinal and renal diseases, as well as in cancer, diabetes and others. Thus, approaches for experimental and therapeutic DNA demethylation have a great potential to demonstrate mechanistic importance, and even causality of epigenetic alterations, and may open novel avenues to epigenetic cures. However, existing methods based on DNA methyltransferase inhibitors that elicit genome-wide demethylation are not suitable for treatment of diseases with specific epimutations and provide a limited experimental value. Therefore, gene-specific epigenetic editing is a critical approach for epigenetic re-activation of silenced genes. Site-specific demethylation can be achieved by utilizing sequence-dependent DNA-binding molecules such as zinc finger protein array (ZFA), transcription activator-like effector (TALE) and clustered regularly interspaced short palindromic repeat-associated dead Cas9 (CRISPR/dCas9). Synthetic proteins, where these DNA-binding domains are fused with the DNA demethylases such as ten-eleven translocation (Tet) and thymine DNA glycosylase (TDG) enzymes, successfully induced or enhanced transcriptional responsiveness at targeted loci. However, a number of challenges, including the dependence on transgenesis for delivery of the fusion constructs, remain issues to be solved. In this review, we detail current and potential approaches to gene-specific DNA demethylation as a novel epigenetic editing-based therapeutic strategy. Full article

(This article belongs to the Special Issue Molecular Tools for Epigenetic Engineering)

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41 pages, 1567 KiB

Open AccessEditor’s ChoiceReview

The Role of Adipokines in Health and Disease

by Vicente Javier Clemente-Suárez, Laura Redondo-Flórez, Ana Isabel Beltrán-Velasco, Alexandra Martín-Rodríguez, Ismael Martínez-Guardado, Eduardo Navarro-Jiménez, Carmen Cecilia Laborde-Cárdenas and José Francisco Tornero-Aguilera

Biomedicines 2023, 11(5), 1290; https://doi.org/10.3390/biomedicines11051290 - 27 Apr 2023

Cited by 55 | Viewed by 9399

Abstract

Adipokines are cell-signaling proteins secreted by adipose tissue that has been related to a low-grade state of inflammation and different pathologies. The present review aims to analyze the role of adipokines in health and disease in order to understand the important functions and [...] Read more.

Adipokines are cell-signaling proteins secreted by adipose tissue that has been related to a low-grade state of inflammation and different pathologies. The present review aims to analyze the role of adipokines in health and disease in order to understand the important functions and effects of these cytokines. For this aim, the present review delves into the type of adipocytes and the cytokines produced, as well as their functions; the relations of adipokines in inflammation and different diseases such as cardiovascular, atherosclerosis, mental diseases, metabolic disorders, cancer, and eating behaviors; and finally, the role of microbiota, nutrition, and physical activity in adipokines is discussed. This information would allow for a better understanding of these important cytokines and their effects on body organisms. Full article

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

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14 pages, 26769 KiB

Open AccessEditor’s ChoiceArticle

A Combination of an Angiotensin II Receptor and a Neprilysin Inhibitor Attenuates Liver Fibrosis by Preventing Hepatic Stellate Cell Activation

by Junya Suzuki, Kosuke Kaji, Norihisa Nishimura, Takahiro Kubo, Fumimasa Tomooka, Akihiko Shibamoto, Satoshi Iwai, Yuki Tsuji, Yukihisa Fujinaga, Koh Kitagawa, Tadashi Namisaki, Takemi Akahane and Hitoshi Yoshiji

Biomedicines 2023, 11(5), 1295; https://doi.org/10.3390/biomedicines11051295 - 27 Apr 2023

Cited by 3 | Viewed by 1652

Abstract

The renin–angiotensin–aldosterone system has gained attention due to its role as a mediator of liver fibrosis and hepatic stellate cell (HSC) activation. Meanwhile, the natriuretic peptide (NP) system, including atrial NP (ANP) and C-type NP (CNP), is a counter-regulatory hormone regulated by neprilysin. [...] Read more.

The renin–angiotensin–aldosterone system has gained attention due to its role as a mediator of liver fibrosis and hepatic stellate cell (HSC) activation. Meanwhile, the natriuretic peptide (NP) system, including atrial NP (ANP) and C-type NP (CNP), is a counter-regulatory hormone regulated by neprilysin. Although the combination of an angiotensin receptor and a neprilysin inhibitor (sacubitril/valsartan: SAC/VAL) has shown clinical efficacy in patients with heart failure, its potential effects on hepatic fibrosis have not been clarified. This study assessed the effects of SAC/VAL in carbon tetrachloride (CCl₄)-induced murine liver fibrosis as well as the in vitro phenotypes of HSCs. Treatment with SAC and VAL markedly attenuated CCl₄-induced liver fibrosis while reducing α-SMA⁺-HSC expansion and decreasing hepatic hydroxyproline and mRNA levels of pro-fibrogenic markers. Treatment with SAC increased plasma ANP and CNP levels in CCl₄-treated mice, and ANP effectively suppressed cell proliferation and TGF-β-stimulated MMP2 and TIMP2 expression in LX-2 cells by activating guanylate cyclase-A/cGMP/protein kinase G signaling. Meanwhile, CNP did not affect the pro-fibrogenic activity of LX-2 cells. Moreover, VAL directly inhibited angiotensin II (AT-II)-stimulated cell proliferation and the expression of TIMP1 and CTGF through the blockade of the AT-II type 1 receptor/protein kinase C pathway. Collectively, SAC/VAL may be a novel therapeutic treatment for liver fibrosis. Full article

(This article belongs to the Special Issue Liver Fibrosis: Molecular Mechanisms, Potential Therapeutic Targets and Clinical Biomarkers)

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15 pages, 2262 KiB

Open AccessEditor’s ChoiceReview

Degradation and Failure Phenomena at the Dentin Bonding Interface

by Lamia Sami Mokeem, Isadora Martini Garcia and Mary Anne Melo

Biomedicines 2023, 11(5), 1256; https://doi.org/10.3390/biomedicines11051256 - 23 Apr 2023

Cited by 10 | Viewed by 4560

Abstract

Damage in the bonding interface is a significant factor that leads to premature failure of dental bonded restorations. The imperfectly bonded dentin-adhesive interface is susceptible to hydrolytic degradation and bacterial and enzyme attack, severely jeopardizing restorations’ longevity. Developing caries around previously made restorations, [...] Read more.

Damage in the bonding interface is a significant factor that leads to premature failure of dental bonded restorations. The imperfectly bonded dentin-adhesive interface is susceptible to hydrolytic degradation and bacterial and enzyme attack, severely jeopardizing restorations’ longevity. Developing caries around previously made restorations, also called “recurrent or secondary caries,” is a significant health problem. The replacement of restorations is the most prevailing treatment in dental clinics, leading to the so-called “tooth death spiral”. In other words, every time a restoration is replaced, more tooth tissue is removed, increasing the size of the restorations until the tooth is eventually lost. This process leads to high financial costs and detriment to patients’ quality of life. Since the complexity of the oral cavity makes prevention a challenging task, novel strategies in Dental Materials and Operative fields are required. This article briefly overviews the physiological dentin substrate, features of dentin bonding, challenges and clinical relevance. We discussed the anatomy of the dental bonding interface, aspects of the degradation at the resin-dentin interface, extrinsic and intrinsic factors affecting dental bonding longevity, perspectives on resin and collagen degradation and how these subjects are connected. In this narrative review, we also outlined the recent progress in overcoming dental bonding challenges through bioinspiration, nanotechnology and advanced techniques to reduce degradation and improve dental bonding longevity. Full article

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

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27 pages, 4077 KiB

Open AccessEditor’s ChoiceArticle

MicroRNA Signatures in Cartilage Ageing and Osteoarthritis

by Panagiotis Balaskas, Katarzyna Goljanek-Whysall, Peter D. Clegg, Yongxiang Fang, Andy Cremers, Aibek Smagul, Tim J. M. Welting and Mandy J. Peffers

Biomedicines 2023, 11(4), 1189; https://doi.org/10.3390/biomedicines11041189 - 17 Apr 2023

Cited by 7 | Viewed by 1959

Abstract

Osteoarthritis is the most common degenerative joint disorder. MicroRNAs are gene expression regulators that act post-transcriptionally to control tissue homeostasis. Microarray analysis was undertaken in osteoarthritic intact, lesioned and young intact cartilage. Principal component analysis showed that young intact cartilage samples were clustered [...] Read more.

Osteoarthritis is the most common degenerative joint disorder. MicroRNAs are gene expression regulators that act post-transcriptionally to control tissue homeostasis. Microarray analysis was undertaken in osteoarthritic intact, lesioned and young intact cartilage. Principal component analysis showed that young intact cartilage samples were clustered together; osteoarthritic samples had a wider distribution; and osteoarthritic intact samples were separated into two subgroups, osteoarthritic-Intact-1 and osteoarthritic-Intact-2. We identified 318 differentially expressed microRNAs between young intact and osteoarthritic lesioned cartilage, 477 between young intact and osteoarthritic-Intact-1 cartilage and 332 between young intact and osteoarthritic-Intact-2 cartilage samples. For a selected list of differentially expressed microRNAs, results were verified in additional cartilage samples using qPCR. Of the validated DE microRNAs, four—miR-107, miR-143-3p, miR-361-5p and miR-379-5p—were selected for further experiments in human primary chondrocytes treated with IL-1β. Expression of these microRNAs decreased in human primary chondrocytes treated with IL-1β. For miR-107 and miR-143-3p, gain- and loss-of-function approaches were undertaken and associated target genes and molecular pathways were investigated using qPCR and mass spectrometry proteomics. Analyses showed that WNT4 and IHH, predicted targets of miR-107, had increased expression in osteoarthritic cartilage compared to young intact cartilage and in primary chondrocytes treated with miR-107 inhibitor, and decreased expression in primary chondrocytes treated with miR-107 mimic, suggesting a role of miR-107 in chondrocyte survival and proliferation. In addition, we identified an association between miR-143-3p and EIF2 signalling and cell survival. Our work supports the role of miR-107 and miR-143-3p in important chondrocyte mechanisms regulating proliferation, hypertrophy and protein translation. Full article

(This article belongs to the Special Issue Non-coding RNAs in Health and Disease 2.0)

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10 pages, 1242 KiB

Open AccessEditor’s ChoiceArticle

Dihydrotestosterone, and Not Testosterone, Enhances the LPS-Induced Inflammatory Cytokine Gene Expression in Human Adipocytes

by Angelo Di Vincenzo, Marnie Granzotto, Marika Crescenzi, Vincenzo Vindigni, Roberto Vettor and Marco Rossato

Biomedicines 2023, 11(4), 1194; https://doi.org/10.3390/biomedicines11041194 - 17 Apr 2023

Cited by 2 | Viewed by 1898

Abstract

Background: The development of obesity-related complications lies in the low-grade inflammatory state consequent to adipocyte dysfunction. The direct involvement of sex hormones in adipose tissue inflammation has been previously suggested, but the evidence is scarce. In this study, we evaluated the effects of [...] Read more.

Background: The development of obesity-related complications lies in the low-grade inflammatory state consequent to adipocyte dysfunction. The direct involvement of sex hormones in adipose tissue inflammation has been previously suggested, but the evidence is scarce. In this study, we evaluated the effects of sex steroids on the in-vitroexpression of inflammatory mediators in human-derived adipocytes before and after lipopolysaccharide (LPS) exposure. Methods: Human adipocytes were differentiated from the vascular stromal fraction of adipose tissue samples of subjects undergoing abdominoplasty. We evaluated MCP-1, IL-1β, IL-6, and TNF-α gene expression in the presence of the main sex steroids, testosterone (T), and 17β-estradiol (E). Furthermore, we analyzed the effects of adipocytes exposure to the non-aromatizable androgen dihydrotestosterone (DHT), together with the effects of adipocytes pre-incubation with the aromatase inhibitor anastrozole alone (A), and in combination with T (A/T) before incubation with LPS. Results: DHT, but not T, significantly enhanced the LPSinduction of MCP-1, IL-1β, IL-6, and TNF-α. Intriguingly, the exposure of adipocytes with A/T dramatically increased the LPS-induced expression of all considered inflammatory cytokines, even more than a hundred-fold. Conclusions: DHT and A/T dramatically enhance LPS-induced inflammatory cytokine expression in human-derived adipocytes. These results confirm the involvement of sex hormones in adipose tissue inflammation, suggesting a specific role for non-aromatizable androgens as the amplificatory sex hormones of the inflammatory response. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Recent Advances on Adipokines)

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9 pages, 1258 KiB

Open AccessEditor’s ChoiceBrief Report

Long-Term Benefit of Perlingual Polybacterial Vaccines in Patients with Systemic Autoimmune Diseases and Active Immunosuppression

by Inés Pérez-Sancristóbal, Eduardo de la Fuente, María Paula Álvarez-Hernández, Kissy Guevara-Hoyer, Concepción Morado, Cristina Martínez-Prada, Dalifer Freites-Nuñez, Virginia Villaverde, Miguel Fernández-Arquero, Benjamín Fernández-Gutiérrez, Silvia Sánchez-Ramón and Gloria Candelas

Biomedicines 2023, 11(4), 1168; https://doi.org/10.3390/biomedicines11041168 - 13 Apr 2023

Cited by 1 | Viewed by 1771

Abstract

Introduction: We have previously shown that trained-immunity-based vaccines, namely TIbV, significantly reduce the rate of recurrent infections, both of the respiratory tract (RRTI) and urinary tract infections (RUTI) in SAD patients on disease-modifying drugs (DMARDs). Objective: We evaluated the frequency of RRTI and [...] Read more.

Introduction: We have previously shown that trained-immunity-based vaccines, namely TIbV, significantly reduce the rate of recurrent infections, both of the respiratory tract (RRTI) and urinary tract infections (RUTI) in SAD patients on disease-modifying drugs (DMARDs). Objective: We evaluated the frequency of RRTI and RUTI from 2018 to 2021 in those SAD patients that received TIbV until 2018. Secondarily, we evaluated the incidence and clinical course of COVID-19 in this cohort. Methods: A retrospective observational study was conducted in a cohort of SAD patients under active immunosuppression immunized with TIbV (MV130 for RRTI and MV140 for RUTI, respectively). Results: Forty-one SAD patients on active immunosuppression that were given TIbV up to 2018 were studied for RRTI and RUTI during the 2018–2021 period. Approximately half of the patients had no infections during 2018–2021 (51.2% no RUTI and 43.5% no RRTI at all). When we compared the 3-year period with the 1-year pre-TIbV, RRTI (1.61 ± 2.26 vs. 2.76 ± 2.57; p = 0.002) and RUTI (1.56 ± 2.12 vs. 2.69 ± 3.07; p = 0.010) episodes were still significantly lower. Six SAD patients (four RA; one SLE; one MCTD) with RNA-based vaccines were infected with SARS-CoV-2, with mild disease. Conclusions: Even though the beneficial protective effects against infections of TIbV progressively decreased, they remained low for up to 3 years, with significantly reduced infections compared to the year prior to vaccination, further supporting a long-term benefit of TIbV in this setting. Moreover, an absence of infections was observed in almost half of patients. Full article

(This article belongs to the Special Issue Disease Biomarkers in Immunomediated Diseases)

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25 pages, 1336 KiB

Open AccessEditor’s ChoiceReview

Increased Risk of Aging-Related Neurodegenerative Disease after Traumatic Brain Injury

by Sarah Barker, Bindu D. Paul and Andrew A. Pieper

Biomedicines 2023, 11(4), 1154; https://doi.org/10.3390/biomedicines11041154 - 11 Apr 2023

Cited by 11 | Viewed by 3242

Abstract

Traumatic brain injury (TBI) survivors frequently suffer from chronically progressive complications, including significantly increased risk of developing aging-related neurodegenerative disease. As advances in neurocritical care increase the number of TBI survivors, the impact and awareness of this problem are growing. The mechanisms by [...] Read more.

Traumatic brain injury (TBI) survivors frequently suffer from chronically progressive complications, including significantly increased risk of developing aging-related neurodegenerative disease. As advances in neurocritical care increase the number of TBI survivors, the impact and awareness of this problem are growing. The mechanisms by which TBI increases the risk of developing aging-related neurodegenerative disease, however, are not completely understood. As a result, there are no protective treatments for patients. Here, we review the current literature surrounding the epidemiology and potential mechanistic relationships between brain injury and aging-related neurodegenerative disease. In addition to increasing the risk for developing all forms of dementia, the most prominent aging-related neurodegenerative conditions that are accelerated by TBI are amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson’s disease (PD), and Alzheimer’s disease (AD), with ALS and FTD being the least well-established. Mechanistic links between TBI and all forms of dementia that are reviewed include oxidative stress, dysregulated proteostasis, and neuroinflammation. Disease-specific mechanistic links with TBI that are reviewed include TAR DNA binding protein 43 and motor cortex lesions in ALS and FTD; alpha-synuclein, dopaminergic cell death, and synergistic toxin exposure in PD; and brain insulin resistance, amyloid beta pathology, and tau pathology in AD. While compelling mechanistic links have been identified, significantly expanded investigation in the field is needed to develop therapies to protect TBI survivors from the increased risk of aging-related neurodegenerative disease. Full article

(This article belongs to the Special Issue Feature Reviews in Neurodegenerative Diseases and Environmental Factors)

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13 pages, 747 KiB

Open AccessEditor’s ChoiceArticle

The Relationship between Type 1 Diabetes Mellitus, TNF-α, and IL-10 Gene Expression

by Jesselina Francisco dos Santos Haber, Sandra Maria Barbalho, Jose Augusto Sgarbi, Rafael Santos de Argollo Haber, Roger William de Labio, Lucas Fornari Laurindo, Eduardo Federighi Baisi Chagas and Spencer Luiz Marques Payão

Biomedicines 2023, 11(4), 1120; https://doi.org/10.3390/biomedicines11041120 - 7 Apr 2023

Cited by 8 | Viewed by 2437

Abstract

Type 1 diabetes mellitus (T1DM) is one of the major chronic diseases in children worldwide. This study aimed to investigate interleukin-10 (IL-10) gene expression and tumor necrosis factor-alpha (TNF-α) in T1DM. A total of 107 patients were included, 15 were T1DM in ketoacidosis, [...] Read more.

Type 1 diabetes mellitus (T1DM) is one of the major chronic diseases in children worldwide. This study aimed to investigate interleukin-10 (IL-10) gene expression and tumor necrosis factor-alpha (TNF-α) in T1DM. A total of 107 patients were included, 15 were T1DM in ketoacidosis, 30 patients had T1DM and HbA1c ≥ 8%; 32 patients had T1DM and presented HbA1c < 8%; and 30 were controls. The expression of peripheral blood mononuclear cells was performed using the reverse transcriptase–polymerase chain reaction in real time. The cytokines gene expression was higher in patients with T1DM. The IL-10 gene expression increased substantially in patients with ketoacidosis, and there was a positive correlation with HbA1c. A negative correlation was found for IL-10 expression and the age of patients with diabetes, and the time of diagnosis of the disease. There was a positive correlation between TNF-α expression with age. The expression of IL-10 and TNF-α genes showed a significant increase in DM1 patients. Once current T1DM treatment is based on exogenous insulin, there is a need for other therapies, and inflammatory biomarkers could bring new possibilities to the therapeutic approach of the patients. Full article

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

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23 pages, 755 KiB

Open AccessEditor’s ChoiceReview

Non-Alcoholic Fatty Liver Disease or Type 2 Diabetes Mellitus—The Chicken or the Egg Dilemma

by Marcin Kosmalski, Agnieszka Śliwińska and Józef Drzewoski

Biomedicines 2023, 11(4), 1097; https://doi.org/10.3390/biomedicines11041097 - 4 Apr 2023

Cited by 15 | Viewed by 5410

Abstract

In clinical practice, we often deal with patients who suffer from non-alcoholic fatty liver disease (NAFLD) concurrent with type 2 diabetes mellitus (T2DM). The etiopathogenesis of NAFLD is mainly connected with insulin resistance (IR) and obesity. Similarly, the latter patients are in the [...] Read more.

In clinical practice, we often deal with patients who suffer from non-alcoholic fatty liver disease (NAFLD) concurrent with type 2 diabetes mellitus (T2DM). The etiopathogenesis of NAFLD is mainly connected with insulin resistance (IR) and obesity. Similarly, the latter patients are in the process of developing T2DM. However, the mechanisms of NAFLD and T2DM coexistence have not been fully elucidated. Considering that both diseases and their complications are of epidemic proportions and significantly affect the length and quality of life, we aimed to answer which of these diseases appears first and thereby highlight the need for their diagnosis and treatment. To address this question, we present and discuss the epidemiological data, diagnoses, complications and pathomechanisms of these two coexisting metabolic diseases. This question is difficult to answer due to the lack of a uniform procedure for NAFLD diagnosis and the asymptomatic nature of both diseases, especially at their beginning stages. To conclude, most researchers suggest that NAFLD appears as the first disease and starts the sequence of circumstances leading ultimately to the development of T2DM. However, there are also data suggesting that T2DM develops before NAFLD. Despite the fact that we cannot definitively answer this question, it is very important to bring the attention of clinicians and researchers to the coexistence of NAFLD and T2DM in order to prevent their consequences. Full article

(This article belongs to the Special Issue Advanced Research in Metabolic Syndrome)

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13 pages, 467 KiB

Open AccessEditor’s ChoiceReview

Antifungal Drug Resistance: An Emergent Health Threat

by Antonio Vitiello, Francesco Ferrara, Mariarosaria Boccellino, Annarita Ponzo, Carla Cimmino, Emilio Comberiati, Andrea Zovi, Salvatore Clemente and Michela Sabbatucci

Biomedicines 2023, 11(4), 1063; https://doi.org/10.3390/biomedicines11041063 - 31 Mar 2023

Cited by 31 | Viewed by 6358

Abstract

Fungal infections, named mycosis, can cause severe invasive and systemic diseases that can even lead to death. In recent years, epidemiological data have recorded an increase in cases of severe fungal infections, caused mainly by a growing number of immunocompromised patients and the [...] Read more.

Fungal infections, named mycosis, can cause severe invasive and systemic diseases that can even lead to death. In recent years, epidemiological data have recorded an increase in cases of severe fungal infections, caused mainly by a growing number of immunocompromised patients and the emergence of fungal pathogenic forms that are increasingly resistant to antimycotic drug treatments. Consequently, an increase in the incidence of mortality due to fungal infections has also been observed. Among the most drug-resistant fungal forms are those belonging to the Candida and Aspergillus spp. Some pathogens are widespread globally, while others are endemic in some areas only. In addition, some others may represent a health threat for some specific subpopulations and not for the general public. In contrast to the extensive therapeutic armamentarium available for the antimicrobial chemotherapeutic treatment of bacteria, for fungal infections there are only a few classes of antimycotic drugs on the market, such as polyenes, azoles, echinocandins, and a few molecules are under trial. In this review, we focused on the systemic mycosis, highlighted the antifungal drug compounds available in the pipeline, and analyzed the main molecular mechanisms for the development of antifungal resistance to give a comprehensive overview and increase awareness on this growing health threat. Full article

(This article belongs to the Special Issue Antimicrobial Resistance: A Global Challenge)

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20 pages, 5312 KiB

Open AccessEditor’s ChoiceArticle

3D Spheroid Cultivation Alters the Extent and Progression of Osteogenic Differentiation of Mesenchymal Stem/Stromal Cells Compared to 2D Cultivation

by Anne Wolff, Marcus Frank, Susanne Staehlke, Armin Springer, Olga Hahn, Juliane Meyer and Kirsten Peters

Biomedicines 2023, 11(4), 1049; https://doi.org/10.3390/biomedicines11041049 - 29 Mar 2023

Cited by 5 | Viewed by 2256

Abstract

Mesenchymal stem/stromal cells (MSC) are capable of progenitor cell fraction renewal or tissue-specific differentiation. These properties are maintained during in vitro cultivation, making them an interesting model system for testing biological and pharmacological compounds. Cell cultivation in 2D is commonly used to study [...] Read more.

Mesenchymal stem/stromal cells (MSC) are capable of progenitor cell fraction renewal or tissue-specific differentiation. These properties are maintained during in vitro cultivation, making them an interesting model system for testing biological and pharmacological compounds. Cell cultivation in 2D is commonly used to study cellular responses, but the 2D environment does not reflect the structural situation of most cell types. Therefore, 3D culture systems have been developed to provide a more accurate physiological environment in terms of cell–cell interactions. Since knowledge about the effects of 3D culture on specific differentiation processes is limited, we studied the effects on osteogenic differentiation and the release of factors affecting bone metabolism for up to 35 days and compared them with the effects in 2D culture. We demonstrated that the selected 3D model allowed the rapid and reliable formation of spheroids that were stable over several weeks and both accelerated and enhanced osteogenic differentiation compared with the 2D culture. Thus, our experiments provide new insights into the effects of cell arrangement of MSC in 2D and 3D. However, due to the different culture dimensions, various detection methods had to be chosen, which in principle limits the explanatory power of the comparison between 2D and 3D cultures. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—3D In Vitro Models as an Alternative to Animal Experimentation: Advantages and Pitfalls)

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10 pages, 255 KiB

Open AccessEditor’s ChoiceReview

Mesenchymal Stem Cell-Derived Exosomes Modulate Angiogenesis in Gastric Cancer

by Fawzy Akad, Veronica Mocanu, Sorin Nicolae Peiu, Viorel Scripcariu, Bogdan Filip, Daniel Timofte, Florin Zugun-Eloae, Magdalena Cuciureanu, Monica Hancianu, Teodor Oboroceanu, Laura Condur and Radu Florin Popa

Biomedicines 2023, 11(4), 1031; https://doi.org/10.3390/biomedicines11041031 - 27 Mar 2023

Cited by 9 | Viewed by 2524

Abstract

Individualized gastric cancer (GC) treatment aims at providing targeted therapies that translate the latest research into improved management strategies. Extracellular vesicle microRNAs have been proposed as biomarkers for GC prognosis. Helicobacter pylori infection influences the therapeutic response to and the drivers of malignant [...] Read more.

Individualized gastric cancer (GC) treatment aims at providing targeted therapies that translate the latest research into improved management strategies. Extracellular vesicle microRNAs have been proposed as biomarkers for GC prognosis. Helicobacter pylori infection influences the therapeutic response to and the drivers of malignant changes in chronic gastritis. The successful use of transplanted mesenchymal stem cells (MSCs) for gastric ulcer healing has raised interest in studying their effects on tumor neovascularization and in potential antiangiogenic therapies that could use mesenchymal stem cell secretion into extracellular vesicles—such as exosomes—in GC cells. The use of MSCs isolated from bone marrow in order to achieve angiogenic modulation in the tumor microenvironment could exploit the inherent migration of MSCs into GC tissues. Bone marrow-derived MSCs naturally present in the stomach have been reported to carry a malignancy risk, but their effect in GC is still being researched. The pro- and antiangiogenic effects of MSCs derived from various sources complement their role in immune regulation and tissue regeneration and provide further understanding into the heterogeneous biology of GC, the aberrant morphology of tumor vasculature and the mechanisms of resistance to antiangiogenic drugs. Full article

(This article belongs to the Special Issue Angiogenesis and Lymphangiogenesis in Gastrointestinal Tumor Microenvironment: From Molecular to Clinical Aspects)

14 pages, 2425 KiB

Open AccessEditor’s ChoiceArticle

In Vitro Effects of PTH (1-84) on Human Skeletal Muscle-Derived Satellite Cells

by Cecilia Romagnoli, Roberto Zonefrati, Elena Lucattelli, Marco Innocenti, Roberto Civinini, Teresa Iantomasi and Maria Luisa Brandi

Biomedicines 2023, 11(4), 1017; https://doi.org/10.3390/biomedicines11041017 - 27 Mar 2023

Cited by 4 | Viewed by 1599

Abstract

Parathyroid hormone (PTH) is a hormone secreted by the parathyroid glands. Despite its well-known characterized anabolic and catabolic actions on the skeleton, the in vitro effects of PTH on skeletal muscle cells are limited and generally performed on animal models. The aim of [...] Read more.

Parathyroid hormone (PTH) is a hormone secreted by the parathyroid glands. Despite its well-known characterized anabolic and catabolic actions on the skeleton, the in vitro effects of PTH on skeletal muscle cells are limited and generally performed on animal models. The aim of this study was to evaluate the effects of a short impulse of PTH (1-84) on the proliferation and the differentiation of skeletal muscle satellite cells isolated from human biopsies. The cells were exposed for 30 min to different concentrations of PTH (1-84), from 10⁻⁶ mol/L to 10⁻¹² mol/L. ELISA was used to assay cAMP and the myosin heavy-chain (MHC) protein. The proliferation was assayed by BrdU and the differentiation by RealTime-qPCR. A statistical analysis was performed by ANOVA followed by Bonferroni’s test. No significant variations in cAMP and the proliferation were detected in the isolated cells treated with PTH. On the other hand, 10⁻⁷ mol/L PTH on differentiated myotubes has shown significant increases in cAMP (p ≤ 0.05), in the expression of myogenic differentiation genes (p ≤ 0.001), and in the MHC protein (p ≤ 0.01) vs. untreated controls. This work demonstrates for the first time the in vitro effects of PTH (1-84) on human skeletal muscle cells and it opens new fields of investigation in muscle pathophysiology. Full article

(This article belongs to the Special Issue Musculoskeletal Diseases: From Molecular Basis to Therapy)

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62 pages, 2744 KiB

Open AccessEditor’s ChoiceReview

NLRP3 Inflammasome’s Activation in Acute and Chronic Brain Diseases—An Update on Pathogenetic Mechanisms and Therapeutic Perspectives with Respect to Other Inflammasomes

by Anna Chiarini, Li Gui, Chiara Viviani, Ubaldo Armato and Ilaria Dal Prà

Biomedicines 2023, 11(4), 999; https://doi.org/10.3390/biomedicines11040999 - 23 Mar 2023

Cited by 9 | Viewed by 6078

Abstract

Increasingly prevalent acute and chronic human brain diseases are scourges for the elderly. Besides the lack of therapies, these ailments share a neuroinflammation that is triggered/sustained by different innate immunity-related protein oligomers called inflammasomes. Relevant neuroinflammation players such as microglia/monocytes typically exhibit a [...] Read more.

Increasingly prevalent acute and chronic human brain diseases are scourges for the elderly. Besides the lack of therapies, these ailments share a neuroinflammation that is triggered/sustained by different innate immunity-related protein oligomers called inflammasomes. Relevant neuroinflammation players such as microglia/monocytes typically exhibit a strong NLRP3 inflammasome activation. Hence the idea that NLRP3 suppression might solve neurodegenerative ailments. Here we review the recent Literature about this topic. First, we update conditions and mechanisms, including RNAs, extracellular vesicles/exosomes, endogenous compounds, and ethnic/pharmacological agents/extracts regulating NLRP3 function. Second, we pinpoint NLRP3-activating mechanisms and known NLRP3 inhibition effects in acute (ischemia, stroke, hemorrhage), chronic (Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, MS, ALS), and virus-induced (Zika, SARS-CoV-2, and others) human brain diseases. The available data show that (i) disease-specific divergent mechanisms activate the (mainly animal) brains NLRP3; (ii) no evidence proves that NLRP3 inhibition modifies human brain diseases (yet ad hoc trials are ongoing); and (iii) no findings exclude that concurrently activated other-than-NLRP3 inflammasomes might functionally replace the inhibited NLRP3. Finally, we highlight that among the causes of the persistent lack of therapies are the species difference problem in disease models and a preference for symptomatic over etiologic therapeutic approaches. Therefore, we posit that human neural cell-based disease models could drive etiological, pathogenetic, and therapeutic advances, including NLRP3’s and other inflammasomes’ regulation, while minimizing failure risks in candidate drug trials. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Translational Laboratory and Experimental Medicine for the Sake of Neurological Diseases and Mental Illnesses)

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18 pages, 5639 KiB

Open AccessEditor’s ChoiceArticle

In Silico Identification of Lead Compounds for Pseudomonas Aeruginosa PqsA Enzyme: Computational Study to Block Biofilm Formation

by Muhammad Shahab, Muhammad Danial, Taimur Khan, Chaoqun Liang, Xiuyuan Duan, Daixi Wang, Hanzi Gao and Guojun Zheng

Biomedicines 2023, 11(3), 961; https://doi.org/10.3390/biomedicines11030961 - 21 Mar 2023

Cited by 8 | Viewed by 2130

Abstract

Pseudomonas aeruginosa is an opportunistic Gram-negative bacterium implicated in acute and chronic nosocomial infections and a leading cause of patient mortality. Pseudomonas aeruginosa infections are frequently associated with the development of biofilms, which give the bacteria additional drug resistance and increase their virulence. [...] Read more.

Pseudomonas aeruginosa is an opportunistic Gram-negative bacterium implicated in acute and chronic nosocomial infections and a leading cause of patient mortality. Pseudomonas aeruginosa infections are frequently associated with the development of biofilms, which give the bacteria additional drug resistance and increase their virulence. The goal of this study was to find strong compounds that block the Anthranilate-CoA ligase enzyme made by the pqsA gene. This would stop the P. aeruginosa quorum signaling system. This enzyme plays a crucial role in the pathogenicity of P. aeruginosa by producing autoinducers for cell-to-cell communication that lead to the production of biofilms. Pharmacophore-based virtual screening was carried out utilizing a library of commercially accessible enzyme inhibitors. The most promising hits obtained during virtual screening were put through molecular docking with the help of MOE. The virtual screening yielded 7/160 and 10/249 hits (ZINC and Chembridge). Finally, 2/7 ZINC hits and 2/10 ChemBridge hits were selected as potent lead compounds employing diverse scaffolds due to their high pqsA enzyme binding affinity. The results of the pharmacophore-based virtual screening were subsequently verified using a molecular dynamic simulation-based study (MDS). Using MDS and post-MDS, the stability of the complexes was evaluated. The most promising lead compounds exhibited a high binding affinity towards protein-binding pocket and interacted with the catalytic dyad. At least one of the scaffolds selected will possibly prove useful for future research. However, further scientific confirmation in the form of preclinical and clinical research is required before implementation. Full article

(This article belongs to the Special Issue Drug Discovery for Infectious Diseases)

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13 pages, 3068 KiB

Open AccessEditor’s ChoiceReview

Updates on Lymphovascular Invasion in Breast Cancer

by Elisabetta Kuhn, Donatella Gambini, Luca Despini, Dario Asnaghi, Letterio Runza and Stefano Ferrero

Biomedicines 2023, 11(3), 968; https://doi.org/10.3390/biomedicines11030968 - 21 Mar 2023

Cited by 11 | Viewed by 9078

Abstract

Traditionally, lymphovascular invasion (LVI) has represented one of the foremost pathological features of malignancy and has been associated with a worse prognosis in different cancers, including breast carcinoma. According to the most updated reporting protocols, the assessment of LVI is required in the [...] Read more.

Traditionally, lymphovascular invasion (LVI) has represented one of the foremost pathological features of malignancy and has been associated with a worse prognosis in different cancers, including breast carcinoma. According to the most updated reporting protocols, the assessment of LVI is required in the pathology report of breast cancer surgical specimens. Importantly, strict histological criteria should be followed for LVI assessment, which nevertheless is encumbered by inconsistency in interpretation among pathologists, leading to significant interobserver variability and scarce reproducibility. Current guidelines for breast cancer indicate biological factors as the main determinants of oncological and radiation therapy, together with TNM staging and age. In clinical practice, the widespread use of genomic assays as a decision-making tool for hormone receptor-positive, HER2-negative breast cancer and the subsequent availability of a reliable prognostic predictor have likely scaled back interest in LVI’s predictive value. However, in selected cases, the presence of LVI impacts adjuvant therapy. This review summarizes current knowledge on LVI in breast cancer with regard to definition, histopathological assessment, its biological understanding, clinicopathological association, and therapeutic implications. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Target through Emerging In Vitro Approaches)

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29 pages, 4972 KiB

Open AccessEditor’s ChoiceReview

G-Quadruplexes in c-MYC Promoter as Targets for Cancer Therapy

by Bárbara Bahls, Israa M. Aljnadi, Rita Emídio, Eduarda Mendes and Alexandra Paulo

Biomedicines 2023, 11(3), 969; https://doi.org/10.3390/biomedicines11030969 - 21 Mar 2023

Cited by 14 | Viewed by 3153

Abstract

Cancer is a societal burden demanding innovative approaches. A major problem with the conventional chemotherapeutic agents is their strong toxicity and other side effects due to their poor selectivity. Uncontrolled proliferation of cancer cells is due to mutations, deletions, or amplifications in genes [...] Read more.

Cancer is a societal burden demanding innovative approaches. A major problem with the conventional chemotherapeutic agents is their strong toxicity and other side effects due to their poor selectivity. Uncontrolled proliferation of cancer cells is due to mutations, deletions, or amplifications in genes (oncogenes) encoding for proteins that regulate cell growth and division, such as transcription factors, for example, c-MYC. The direct targeting of the c-MYC protein has been attempted but so far unsuccessfully, as it lacks a definite binding site for the modulators. Meanwhile, another approach has been explored since the discovery that G-quadruplex secondary DNA structures formed in the guanine-rich sequences of the c-MYC promoter region can downregulate the transcription of this oncogene. Here, we will overview the major achievements made in the last decades towards the discovery of a new class of anticancer drugs targeting G-quadruplexes in the c-MYC promoter of cancer cells. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series in Drug Discovery)

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15 pages, 8815 KiB

Open AccessEditor’s ChoiceArticle

Polycrystalline Diamond as a Potential Material for the Hard-on-Hard Bearing of Total Hip Prosthesis: Von Mises Stress Analysis

by Muhammad Imam Ammarullah, Rachmad Hartono, Toto Supriyono, Gatot Santoso, S. Sugiharto and Muki Satya Permana

Biomedicines 2023, 11(3), 951; https://doi.org/10.3390/biomedicines11030951 - 20 Mar 2023

Cited by 85 | Viewed by 3960

Abstract

Due to polymeric wear debris causing osteolysis from polymer, metal ions causing metallosis from metal, and brittle characteristic causing fracture failure from ceramic in the application on bearing of total hip prosthesis requires the availability of new material options as a solution to [...] Read more.

Due to polymeric wear debris causing osteolysis from polymer, metal ions causing metallosis from metal, and brittle characteristic causing fracture failure from ceramic in the application on bearing of total hip prosthesis requires the availability of new material options as a solution to these problems. Polycrystalline diamond (PCD) has the potential to become the selected material for hard-on-hard bearing in view of its advantages in terms of mechanical properties and biocompatibility. The present study contributes to confirming the potential of PCD to replace metals and ceramics for hard-on-hard bearing through von Mises stress investigations. A computational simulation using a 2D axisymmetric finite element model of hard-on-hard bearing under gait loading has been performed. The percentage of maximum von Mises stress to respective yield strength from PCD-on-PCD is the lowest at 2.47%, with CoCrMo (cobalt chromium molybdenum)-on-CoCrMo at 10.79%, and Al₂O₃ (aluminium oxide)-on-Al₂O₃ at 13.49%. This confirms that the use of PCD as a hard-on-hard bearing material is the safest option compared to the investigated metal and ceramic hard-on-hard bearings from the mechanical perspective. Full article

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

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44 pages, 1355 KiB

Open AccessEditor’s ChoiceReview

Developmental Pharmacokinetics of Antibiotics Used in Neonatal ICU: Focus on Preterm Infants

by Olga I. Butranova, Elena A. Ushkalova, Sergey K. Zyryanov and Mikhail S. Chenkurov

Biomedicines 2023, 11(3), 940; https://doi.org/10.3390/biomedicines11030940 - 17 Mar 2023

Cited by 7 | Viewed by 4037

Abstract

Neonatal Infections are among the most common reasons for admission to the intensive care unit. Neonatal sepsis (NS) significantly contributes to mortality rates. Empiric antibiotic therapy of NS recommended by current international guidelines includes benzylpenicillin, ampicillin/amoxicillin, and aminoglycosides (gentamicin). The rise of antibacterial [...] Read more.

Neonatal Infections are among the most common reasons for admission to the intensive care unit. Neonatal sepsis (NS) significantly contributes to mortality rates. Empiric antibiotic therapy of NS recommended by current international guidelines includes benzylpenicillin, ampicillin/amoxicillin, and aminoglycosides (gentamicin). The rise of antibacterial resistance precipitates the growth of the use of antibiotics of the Watch (second, third, and fourth generations of cephalosporines, carbapenems, macrolides, glycopeptides, rifamycins, fluoroquinolones) and Reserve groups (fifth generation of cephalosporines, oxazolidinones, lipoglycopeptides, fosfomycin), which are associated with a less clinical experience and higher risks of toxic reactions. A proper dosing regimen is essential for effective and safe antibiotic therapy, but its choice in neonates is complicated with high variability in the maturation of organ systems affecting drug absorption, distribution, metabolism, and excretion. Changes in antibiotic pharmacokinetic parameters result in altered efficacy and safety. Population pharmacokinetics can help to prognosis outcomes of antibiotic therapy, but it should be considered that the neonatal population is heterogeneous, and this heterogeneity is mainly determined by gestational and postnatal age. Preterm neonates are common in clinical practice, and due to the different physiology compared to the full terms, constitute a specific neonatal subpopulation. The objective of this review is to summarize the evidence about the developmental changes (specific for preterm and full-term infants, separately) of pharmacokinetic parameters of antibiotics used in neonatal intensive care units. Full article

(This article belongs to the Special Issue Pharmacokinetics of Biomedicines: Impact on Pre-clinical Development and Clinical Use)

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12 pages, 1602 KiB

Open AccessEditor’s ChoiceArticle

An Observational Study on Chronic Pain Biomarkers in Fibromyalgia and Osteoarthritis Patients: Which Role for Mu Opioid Receptor’s Expression on NK Cells?

by Valentina Malafoglia, Sara Ilari, Chiara Gioia, Laura Vitiello, Michael Tenti, Cristina Iannuccelli, Costanza Maria Cristiani, Cinzia Garofalo, Lucia Carmela Passacatini, Giuseppe Viglietto, Antonio Sili Scavalli, Carlo Tomino, Vincenzo Mollace, William Raffaeli, Manuela Di Franco and Carolina Muscoli

Biomedicines 2023, 11(3), 931; https://doi.org/10.3390/biomedicines11030931 - 17 Mar 2023

Cited by 6 | Viewed by 2014

Abstract

The evaluation of chronic pain is challenging because of the lack of specific biomarkers. We identified the Mu opioid receptor-positive (Mu+) B cell percentage of expression, named Mu-Lympho-Marker (MLM), as a candidate marker for chronic pain in fibromyalgia (FM) and osteoarthritis (OA) patients. [...] Read more.

The evaluation of chronic pain is challenging because of the lack of specific biomarkers. We identified the Mu opioid receptor-positive (Mu+) B cell percentage of expression, named Mu-Lympho-Marker (MLM), as a candidate marker for chronic pain in fibromyalgia (FM) and osteoarthritis (OA) patients. Here, we investigate the role of MLM on natural killer (NK) cells in the same patients. Twenty-nine FM and twelve OA patients were analyzed, and twenty-three pain-free subjects were considered as the control group. Blood samples were collected to perform immunophenotyping and Western blot analysis. Biological and clinical data were statistically analyzed. The final results showed that the percentage of NK cells expressing Mu was statistically lower in FM and OA patients than in pain-free subjects, as already demonstrated for B cells. A Western blot analysis was performed in order to detect NK cells’ functional status. Moreover, the correlation analysis of MLM expression with pharmacological therapy did not show any significant results. In conclusion, here, we confirm the role of MLM as a suitable marker for chronic pain and underline NK cells as a new possible immune cell type involved in the “Mu opioid receptor reserve theory”. Full article

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

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11 pages, 1713 KiB

Open AccessEditor’s ChoiceArticle

The Effects of the Levosimendan Metabolites OR-1855 and OR-1896 on Endothelial Pro-Inflammatory Responses

by Hannah Kipka, Rebecca Schaflinger, Roland Tomasi, Kristin Pogoda and Hanna Mannell

Biomedicines 2023, 11(3), 918; https://doi.org/10.3390/biomedicines11030918 - 16 Mar 2023

Cited by 2 | Viewed by 1540

Abstract

The calcium sensitizer levosimendan is used for the treatment of acute decompensated heart failure. A small portion (4–7%) of levosimendan is metabolized to the pharmacologically active metabolite OR-1896 via the inactive intermediate OR-1855. In addition, levosimendan has been shown to exert positive effects [...] Read more.

The calcium sensitizer levosimendan is used for the treatment of acute decompensated heart failure. A small portion (4–7%) of levosimendan is metabolized to the pharmacologically active metabolite OR-1896 via the inactive intermediate OR-1855. In addition, levosimendan has been shown to exert positive effects on the endothelium in vitro antagonizing vascular dysfunction and inflammation. However, the function of the levosimendan metabolites within this context is still unknown. In this study, we thus investigated the impact of the metabolites OR-1896 and OR-1855 on endothelial inflammatory processes in vitro. We observed a reduction of IL-1β-dependent endothelial adhesion molecule ICAM-1 and VCAM-1 as well as interleukin (IL) -6 expression upon levosimendan treatment but not after treatment with OR-1855 or OR-1896, as assessed by western blotting, flow cytometry, and qRT-PCR. Instead, the metabolites impaired IL-1β-induced ROS formation via inactivation of the MAPK p38, ERK1/2, and JNK. Our results suggest that the levosimendan metabolites OR-1896 and OR-1855 have certain anti-inflammatory properties, partly other than levosimendan. Importantly, they additionally show that the intermediate metabolite OR-1855 does, in fact, have pharmacological effects in the endothelium. This is interesting, as the metabolites are responsible for the long-term therapeutic effects of levosimendan, and heart failure is associated with vascular dysfunction and inflammation. Full article

(This article belongs to the Special Issue Vascular Diseases and Therapeutics)

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20 pages, 37650 KiB

Open AccessEditor’s ChoiceArticle

Nicotine Exerts a Stronger Immunosuppressive Effect Than Its Structural Analogs and Regulates Experimental Colitis in Rats

by Kohki Okada and Kano Matsuo

Biomedicines 2023, 11(3), 922; https://doi.org/10.3390/biomedicines11030922 - 16 Mar 2023

Cited by 3 | Viewed by 4389

Abstract

Ulcerative colitis (UC) is an intractable disease that causes persistent colonic inflammation. Numerous studies have reported that smoking can afford clinical benefits in UC. This study aimed to elucidate whether nicotine, the main component in cigarettes, can exert pharmacological effects against experimental UC. [...] Read more.

Ulcerative colitis (UC) is an intractable disease that causes persistent colonic inflammation. Numerous studies have reported that smoking can afford clinical benefits in UC. This study aimed to elucidate whether nicotine, the main component in cigarettes, can exert pharmacological effects against experimental UC. To achieve this objective, we compared the effects of nicotine with those of structural nicotine analogs in a UC rodent model (Slc: Wistar rats, male, 9-week-old, and 220–250 g/rat). Nicotine, or a respective structural analog (nornicotine, cotinine, anabasine, myosmine, and anatabine), was administered intraperitoneally daily to rats (n = 6/group) exhibiting dextran sulfate sodium-induced experimental colitis. Examining the colon tissues of model rats, we compared disease severity, cytokine secretion, and α7 nicotine acetylcholine receptor (nAChR7) expression. We observed that nicotine administration induced weight loss at 2.35% in 10 days. Notably, the reduction in histological severity (score) of UC was more pronounced in rats treated with nicotine (score = 4.83, p = 0.042) than in untreated rats (score = 8.17). Nicotine administration increased nAChR7 expression 6.88-fold (p = 0.022) in inflammatory sites of the colon, mainly by suppressing the production of interleukin (IL)-1β and IL-6. Moreover, the secretion of these cytokines was suppressed in lipopolysaccharide-stimulated rat macrophages (MΦ) treated with nicotine. In conclusion, nicotine better alleviates experimental UC than the examined structural analogs by activating nAChR7 expression and suppressing proinflammatory cytokines in MΦ. Full article

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

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15 pages, 2986 KiB

Open AccessEditor’s ChoiceArticle

Knockdown SENP1 Suppressed the Angiogenic Potential of Mesenchymal Stem Cells by Impacting CXCR4-Regulated MRTF-A SUMOylation and CCN1 Expression

by Rui Zhang, Qingxi Liu, Cuicui Lyu, Xing Gao and Wenjian Ma

Biomedicines 2023, 11(3), 914; https://doi.org/10.3390/biomedicines11030914 - 15 Mar 2023

Cited by 1 | Viewed by 1649

Abstract

The angiogenic potential of mesenchymal stem cells (MSCs) is critical for adult vascular regeneration and repair, which is regulated by various growth factors and cytokines. In the current study, we report that knockdown SUMO-specific peptidase 1 (SENP1) stimulated the SUMOylation of MRTF-A and [...] Read more.

The angiogenic potential of mesenchymal stem cells (MSCs) is critical for adult vascular regeneration and repair, which is regulated by various growth factors and cytokines. In the current study, we report that knockdown SUMO-specific peptidase 1 (SENP1) stimulated the SUMOylation of MRTF-A and prevented its translocation into the nucleus, leading to downregulation of the cytokine and angiogenic factor CCN1, which significantly impacted MSC-mediated angiogenesis and cell migration. Further studies showed that SENP1 knockdown also suppressed the expression of a chemokine receptor CXCR4, and overexpression of CXCR4 could partially abrogate MRTF-A SUMOylation and reestablish the CCN1 level. Mutation analysis confirmed that SUMOylation occurred on three lysine residues (Lys-499, Lys-576, and Lys-624) of MRTF-A. In addition, SENP1 knockdown abolished the synergistic co-activation of CCN1 between MRTF-A and histone acetyltransferase p300 by suppressing acetylation on histone3K9, histone3K14, and histone4. These results revealed an important signaling pathway to regulate MSC differentiation and angiogenesis by MRTF-A SUMOylation involving cytokine/chemokine activities mediated by CCN1 and CXCR4, which may potentially impact a variety of cellular processes such as revascularization, wound healing, and progression of cancer. Full article

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

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36 pages, 1395 KiB

Open AccessEditor’s ChoiceReview

Novel Oxidative Stress Biomarkers with Risk Prognosis Values in Heart Failure

by Mei Li Ng, Xu Ang, Kwan Yi Yap, Jun Jie Ng, Eugene Chen Howe Goh, Benjamin Bing Jie Khoo, Arthur Mark Richards and Chester Lee Drum

Biomedicines 2023, 11(3), 917; https://doi.org/10.3390/biomedicines11030917 - 15 Mar 2023

Cited by 14 | Viewed by 3162

Abstract

Oxidative stress (OS) is mediated by reactive oxygen species (ROS), which in cardiovascular and other disease states, damage DNA, lipids, proteins, other cellular and extra-cellular components. OS is both initiated by, and triggers inflammation, cardiomyocyte apoptosis, matrix remodeling, myocardial fibrosis, and neurohumoral activation. [...] Read more.

Oxidative stress (OS) is mediated by reactive oxygen species (ROS), which in cardiovascular and other disease states, damage DNA, lipids, proteins, other cellular and extra-cellular components. OS is both initiated by, and triggers inflammation, cardiomyocyte apoptosis, matrix remodeling, myocardial fibrosis, and neurohumoral activation. These have been linked to the development of heart failure (HF). Circulating biomarkers generated by OS offer potential utility in patient management and therapeutic targeting. Novel OS-related biomarkers such as NADPH oxidases (sNox2-dp, Nrf2), advanced glycation end-products (AGE), and myeloperoxidase (MPO), are signaling molecules reflecting pathobiological changes in HF. This review aims to evaluate current OS-related biomarkers and their associations with clinical outcomes and to highlight those with greatest promise in diagnosis, risk stratification and therapeutic targeting in HF. Full article

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

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19 pages, 571 KiB

Open AccessEditor’s ChoiceReview

Pancreatic Cancer Organoids: An Emerging Platform for Precision Medicine?

by Evangelia Sereti, Irida Papapostolou and Konstantinos Dimas

Biomedicines 2023, 11(3), 890; https://doi.org/10.3390/biomedicines11030890 - 14 Mar 2023

Cited by 7 | Viewed by 3126

Abstract

Despite recent therapeutic advances, pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies, with remarkable resistance to treatment, poor prognosis, and poor clinical outcome. More efficient therapeutic approaches are urgently needed to improve patients’ survival. Recently, the development of organoid culture [...] Read more.

Despite recent therapeutic advances, pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies, with remarkable resistance to treatment, poor prognosis, and poor clinical outcome. More efficient therapeutic approaches are urgently needed to improve patients’ survival. Recently, the development of organoid culture systems has gained substantial attention as an emerging preclinical research model. PDAC organoids have been developed to study pancreatic cancer biology, progression, and treatment response, filling the translational gap between in vitro and in vivo models. Here, we review the rapidly evolving field of PDAC organoids and their potential as powerful preclinical tools that could pave the way towards precision medicine for pancreatic cancer. Full article

(This article belongs to the Special Issue Pancreatic Ductal Adenocarcinoma: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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13 pages, 1319 KiB

Open AccessEditor’s ChoiceArticle

The Influence of Ultra-Low Tidal Volume Ventilation during Cardiopulmonary Resuscitation on Renal and Hepatic End-Organ Damage in a Porcine Model

by Katja Mohnke, Victoria Buschmann, Thomas Baller, Julian Riedel, Miriam Renz, René Rissel, Alexander Ziebart, Erik K. Hartmann and Robert Ruemmler

Biomedicines 2023, 11(3), 899; https://doi.org/10.3390/biomedicines11030899 - 14 Mar 2023

Cited by 1 | Viewed by 1157

Abstract

The optimal ventilation strategy during cardiopulmonary resuscitation (CPR) has eluded scientists for years. This porcine study aims to validate the hypothesis that ultra-low tidal volume ventilation (tidal volume 2–3 mL kg⁻¹; ULTVV) minimizes renal and hepatic end-organ damage when compared to [...] Read more.

The optimal ventilation strategy during cardiopulmonary resuscitation (CPR) has eluded scientists for years. This porcine study aims to validate the hypothesis that ultra-low tidal volume ventilation (tidal volume 2–3 mL kg⁻¹; ULTVV) minimizes renal and hepatic end-organ damage when compared to standard intermittent positive pressure ventilation (tidal volume 8–10 mL kg⁻¹; IPPV) during CPR. After induced ventricular fibrillation, the animals were ventilated using an established CPR protocol. Upon return of spontaneous circulation (ROSC), the follow-up was 20 h. After sacrifice, kidney and liver samples were harvested and analyzed histopathologically using an Endothelial, Glomerular, Tubular, and Interstitial (EGTI) scoring system for the kidney and a newly developed scoring system for the liver. Of 69 animals, 5 in the IPPV group and 6 in the ULTVV group achieved sustained ROSC and were enlisted, while 4 served as the sham group. Creatinine clearance was significantly lower in the IPPV-group than in the sham group (p < 0.001). The total EGTI score was significantly higher for ULTVV than for the sham group (p = 0.038). Aminotransferase levels and liver score showed no significant difference between the intervention groups. ULTVV may be advantageous when compared to standard ventilation during CPR in the short-term ROSC follow-up period. Full article

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

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20 pages, 10903 KiB

Open AccessEditor’s ChoiceArticle

25-Hydroxycholecalciferol Inhibits Cell Growth and Induces Apoptosis in SiHa Cervical Cells via Autocrine Vitamin D Metabolism

by Rivak Punchoo, Greta Dreyer and Tahir S. Pillay

Biomedicines 2023, 11(3), 871; https://doi.org/10.3390/biomedicines11030871 - 13 Mar 2023

Cited by 4 | Viewed by 2025

Abstract

Preclinical studies show that the anticancer actions of vitamin D metabolites are mediated by apoptosis, inhibition of cell proliferation and induction of cell cycle arrest. Cervical cancer cells express an autocrine vitamin D metabolising system (VDMS) comprised of a vitamin D receptor, vitamin [...] Read more.

Preclinical studies show that the anticancer actions of vitamin D metabolites are mediated by apoptosis, inhibition of cell proliferation and induction of cell cycle arrest. Cervical cancer cells express an autocrine vitamin D metabolising system (VDMS) comprised of a vitamin D receptor, vitamin D catabolic enzyme (CYP24A1), and the activating enzyme of 25-hydroxycholecalciferol (25(OH)D3), CYP27B1. We assessed the anticancer effects of 25(OH)D3 at clinically relevant concentrations on a cervical squamous cell cancer cell line, SiHa. We evaluated cell health parameters (cell count, viability, and cell cycle), cell death modes (apoptosis, autophagic-dependent death, and necrosis by flow cytometry and transmission electron microscopy), and autocrine VDMS gene and protein expression by qPCR and Western blot, respectively. Our study demonstrates that physiological and supraphysiological doses of 25(OH)D3 inhibit cell growth and viability and induce biochemical and morphological apoptosis in SiHa cells. These growth effects are mediated by alteration in the VDMS gene and protein expression, with prominent negative feedback at supraphysiological treatment dose. These data identify promising therapeutic potential of 25(OH)D3 in cervical cancer, which warrants further clinical translational investigations. Full article

(This article belongs to the Special Issue Recent Advances in Vitamin D)

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23 pages, 1085 KiB

Open AccessEditor’s ChoiceReview

The Impact of Artificial Intelligence in the Odyssey of Rare Diseases

by Anna Visibelli, Bianca Roncaglia, Ottavia Spiga and Annalisa Santucci

Biomedicines 2023, 11(3), 887; https://doi.org/10.3390/biomedicines11030887 - 13 Mar 2023

Cited by 19 | Viewed by 10453

Abstract

Emerging machine learning (ML) technologies have the potential to significantly improve the research and treatment of rare diseases, which constitute a vast set of diseases that affect a small proportion of the total population. Artificial Intelligence (AI) algorithms can help to quickly identify [...] Read more.

Emerging machine learning (ML) technologies have the potential to significantly improve the research and treatment of rare diseases, which constitute a vast set of diseases that affect a small proportion of the total population. Artificial Intelligence (AI) algorithms can help to quickly identify patterns and associations that would be difficult or impossible for human analysts to detect. Predictive modeling techniques, such as deep learning, have been used to forecast the progression of rare diseases, enabling the development of more targeted treatments. Moreover, AI has also shown promise in the field of drug development for rare diseases with the identification of subpopulations of patients who may be most likely to respond to a particular drug. This review aims to highlight the achievements of AI algorithms in the study of rare diseases in the past decade and advise researchers on which methods have proven to be most effective. The review will focus on specific rare diseases, as defined by a prevalence rate that does not exceed 1–9/100,000 on Orphanet, and will examine which AI methods have been most successful in their study. We believe this review can guide clinicians and researchers in the successful application of ML in rare diseases. Full article

(This article belongs to the Special Issue Artificial Intelligence in the Detection of Diseases)

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