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 1133

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 1665

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 1206

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

Viewed by 1190

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

Viewed by 970

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 922

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

Viewed by 983

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 - 09 Dec 2023

Cited by 1 | Viewed by 2061

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 - 08 Dec 2023

Viewed by 924

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 - 01 Dec 2023

Cited by 2 | Viewed by 1288

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 4 | Viewed by 1972

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 - 07 Sep 2023

Cited by 7 | Viewed by 4663

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 - 03 Jun 2023

Cited by 2 | Viewed by 4032

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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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 7 | Viewed by 6567

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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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 2 | Viewed by 6569

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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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 6 | Viewed by 2671

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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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 7 | Viewed by 5028

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 Illness)

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12 pages, 744 KiB

Open AccessEditor’s ChoiceReview

Novel Therapeutic Targets for Migraine

by Areeba Nisar, Zubair Ahmed and Hsiangkuo Yuan

Biomedicines 2023, 11(2), 569; https://doi.org/10.3390/biomedicines11020569 - 15 Feb 2023

Cited by 6 | Viewed by 5360

Abstract

Migraine, a primary headache disorder involving a dysfunctional trigeminal vascular system, remains a major debilitating neurological condition impacting many patients’ quality of life. Despite the success of multiple new migraine therapies, not all patients achieve significant clinical benefits. The success of CGRP pathway-targeted [...] Read more.

Migraine, a primary headache disorder involving a dysfunctional trigeminal vascular system, remains a major debilitating neurological condition impacting many patients’ quality of life. Despite the success of multiple new migraine therapies, not all patients achieve significant clinical benefits. The success of CGRP pathway-targeted therapy highlights the importance of translating the mechanistic understanding toward effective therapy. Ongoing research has identified multiple potential mechanisms in migraine signaling and nociception. In this narrative review, we discuss several potential emerging therapeutic targets, including pituitary adenylate cyclase-activating polypeptide (PACAP), adenosine, δ-opioid receptor (DOR), potassium channels, transient receptor potential ion channels (TRP), and acid-sensing ion channels (ASIC). A better understanding of these mechanisms facilitates the discovery of novel therapeutic targets and provides more treatment options for improved clinical care. Full article

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

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15 pages, 3139 KiB

Open AccessEditor’s ChoiceReview

Converging Evidence of Similar Symptomatology of ME/CFS and PASC Indicating Multisystemic Dyshomeostasis

by David F. Marks

Biomedicines 2023, 11(1), 180; https://doi.org/10.3390/biomedicines11010180 - 11 Jan 2023

Cited by 9 | Viewed by 13523

Abstract

The purpose of this article is to review the evidence of similar symptomatology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-acute sequelae of SARS-CoV-2 infection (PASC). Reanalysis of data from a study by Jason comparing symptom reports from two groups of ME/CFS and [...] Read more.

The purpose of this article is to review the evidence of similar symptomatology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-acute sequelae of SARS-CoV-2 infection (PASC). Reanalysis of data from a study by Jason comparing symptom reports from two groups of ME/CFS and PASC patients shows a notably similar symptomatology. Symptom scores of the PASC group and the ME/CFS group correlated 0.902 (p < 0.0001) across items. The hypothesis is presented that ME/CFS and PASC are caused by a chronic state of multisystemic disequilibrium including endocrinological, immunological, and/or metabolic changes. The hypothesis holds that a changed set point persistently pushes the organism towards a pathological dysfunctional state which fails to reset. To use an analogy of a thermostat, if the ‘off switch’ of a thermostat intermittently stops working, for periods the house would become warmer and warmer without limit. The hypothesis draws on recent investigations of the Central Homeostasis Network showing multiple interconnections between the autonomic system, central nervous system, and brain stem. The hypothesis helps to explain the shared symptomatology of ME/CFS and PASC and the unpredictable, intermittent, and fluctuating pattern of symptoms of ME/CFS and PASC. The current theoretical approach remains speculative and requires in-depth investigation before any definite conclusions can be drawn. Full article

(This article belongs to the Special Issue Feature Review Papers on Brain and Nervous Related Diseases)

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20 pages, 2029 KiB

Open AccessEditor’s ChoiceReview

Stem Cell Therapy for Alzheimer’s Disease: A Scoping Review for 2017–2022

by Yunxiao Duan, Linshuoshuo Lyu and Siyan Zhan

Biomedicines 2023, 11(1), 120; https://doi.org/10.3390/biomedicines11010120 - 03 Jan 2023

Cited by 3 | Viewed by 5226

Abstract

Alzheimer’s disease (AD) has been a major causal factor for mortality among elders around the world. The treatments for AD, however, are still in the stage of development. Stem cell therapy, compared to drug therapies and many other therapeutic options, has many advantages [...] Read more.

Alzheimer’s disease (AD) has been a major causal factor for mortality among elders around the world. The treatments for AD, however, are still in the stage of development. Stem cell therapy, compared to drug therapies and many other therapeutic options, has many advantages and is very promising in the future. There are four major types of stem cells used in AD therapy: neural stem cells, mesenchymal stem cells, embryonic stem cells, and induced pluripotent stem cells. All of them have applications in the treatments, either at the (1) cellular level, in an (2) animal model, or at the (3) clinical level. In general, many more types of stem cells were studied on the cellular level and animal model, than the clinical level. We suggest for future studies to increase research on various types of stem cells and include cross-disciplinary research with other diseases. In the future, there could also be improvements in the timeliness of research and individualization for stem cell therapies for AD. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines: Neuroinflammation and Neuroprotection)

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20 pages, 813 KiB

Open AccessEditor’s ChoiceReview

How the Tumor Micromilieu Modulates the Recruitment and Activation of Colorectal Cancer-Infiltrating Lymphocytes

by Imke Atreya and Markus F. Neurath

Biomedicines 2022, 10(11), 2940; https://doi.org/10.3390/biomedicines10112940 - 15 Nov 2022

Cited by 4 | Viewed by 2705

Abstract

The successful treatment of advanced colorectal cancer disease still represents an insufficiently solved clinical challenge, which is further complicated by the fact that the majority of malignant colon tumors show only relatively low immunogenicity and therefore have only limited responsiveness to immunotherapeutic approaches, [...] Read more.

The successful treatment of advanced colorectal cancer disease still represents an insufficiently solved clinical challenge, which is further complicated by the fact that the majority of malignant colon tumors show only relatively low immunogenicity and therefore have only limited responsiveness to immunotherapeutic approaches, such as, for instance, the use of checkpoint inhibitors. As it has been well established over the past two decades that the local tumor microenvironment and, in particular, the quantity, quality, and activation status of intratumoral immune cells critically influence the clinical prognosis of patients diagnosed with colorectal cancer and their individual benefits from immunotherapy, the enhancement of the intratumoral accumulation of cytolytic effector T lymphocytes and other cellular mediators of the antitumor immune response has emerged as a targeted objective. For the future identification and clinical validation of novel therapeutic target structures, it will thus be essential to further decipher the molecular mechanisms and cellular interactions in the intestinal tumor microenvironment, which are crucially involved in immune cell recruitment and activation. In this context, our review article aims at providing an overview of the key chemokines and cytokines whose presence in the tumor micromilieu relevantly modulates the numeric composition and antitumor capacity of tumor-infiltrating lymphocytes. Full article

(This article belongs to the Special Issue The Role of Inflammatory Cytokines in Cancer Progression)

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11 pages, 1558 KiB

Open AccessEditor’s ChoiceArticle

Sorafenib versus Lenvatinib Causes Stronger Oxidative Damage to Membrane Lipids in Noncancerous Tissues of the Thyroid, Liver, and Kidney: Effective Protection by Melatonin and Indole-3-Propionic Acid

by Jan Stępniak, Joanna Krawczyk-Lipiec, Andrzej Lewiński and Małgorzata Karbownik-Lewińska

Biomedicines 2022, 10(11), 2890; https://doi.org/10.3390/biomedicines10112890 - 11 Nov 2022

Cited by 7 | Viewed by 1554

Abstract

Sorafenib and lenvatinib are multi-targeted tyrosine kinase inhibitors which are currently approved to treat advanced hepatocellular carcinoma, renal cell carcinoma and radioiodine-refractory differentiated thyroid carcinoma. However this treatment is often limited due to common adverse events which may occur via oxidative stress. The [...] Read more.

Sorafenib and lenvatinib are multi-targeted tyrosine kinase inhibitors which are currently approved to treat advanced hepatocellular carcinoma, renal cell carcinoma and radioiodine-refractory differentiated thyroid carcinoma. However this treatment is often limited due to common adverse events which may occur via oxidative stress. The study aims to compare sorafenib- and lenvatinib-induced oxidative damage to membrane lipids (lipid peroxidation, LPO) in homogenates of porcine noncancerous tissues of the thyroid, the liver, and the kidney and to check if it can be prevented by antioxidants melatonin and indole-3-propionic acid (IPA). Homogenates of individual tissues were incubated in the presence of sorafenib or lenvatinib (1 mM, 100 µM, 10 µM, 1 µM, 100 nM, 10 nM, 1 nM, 100 pM) together with/without melatonin (5.0 mM) or IPA (5.0 mM). The concentration of malondialdehyde + 4-hydroxyalkenals, as the LPO index, was measured spectrophotometrically. The incubation of tissue homogenates with sorafenib resulted in a concentration-dependent increase in LPO (statistically significant for concentrations of 1mM and 100 µM in the thyroid and the liver, and of 1 mM, 100 µM, and 10 µM in the kidney). The incubation of thyroid homogenates with lenvatinib did not change LPO level. In case of the liver and the kidney, lenvatinib increased LPO but only in its highest concentration of 1 mM. Melatonin and IPA reduced completely (to the level of control) sorafenib- and lenvatinib-induced LPO in all examined tissues regardless of the drug concentration. In conclusion, sorafenib comparing to lenvatinib is a stronger damaging agent of membrane lipids in noncancerous tissues of the thyroid, the liver, and the kidney. The antioxidants melatonin and IPA can be considered to be used in co-treatment with sorafenib and lenvatinib to prevent their undesirable toxicity occurring via oxidative stress. Full article

(This article belongs to the Special Issue State-of-the-Art Endocrinology and Metabolism Research in Poland)

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21 pages, 3483 KiB

Open AccessEditor’s ChoiceArticle

osr1 Maintains Renal Progenitors and Regulates Podocyte Development by Promoting wnt2ba via the Antagonism of hand2

by Bridgette E. Drummond, Brooke E. Chambers, Hannah M. Wesselman, Shannon Gibson, Liana Arceri, Marisa N. Ulrich, Gary F. Gerlach, Paul T. Kroeger, Ignaty Leshchiner, Wolfram Goessling and Rebecca A. Wingert

Biomedicines 2022, 10(11), 2868; https://doi.org/10.3390/biomedicines10112868 - 09 Nov 2022

Cited by 10 | Viewed by 2107

Abstract

Knowledge about the genetic pathways that control nephron development is essential for better understanding the basis of congenital malformations of the kidney. The transcription factors Osr1 and Hand2 are known to exert antagonistic influences to balance kidney specification. Here, we performed a forward [...] Read more.

Knowledge about the genetic pathways that control nephron development is essential for better understanding the basis of congenital malformations of the kidney. The transcription factors Osr1 and Hand2 are known to exert antagonistic influences to balance kidney specification. Here, we performed a forward genetic screen to identify nephrogenesis regulators, where whole genome sequencing identified an osr1 lesion in the novel oceanside (ocn) mutant. The characterization of the mutant revealed that osr1 is needed to specify not renal progenitors but rather their maintenance. Additionally, osr1 promotes the expression of wnt2ba in the intermediate mesoderm (IM) and later the podocyte lineage. wnt2ba deficiency reduced podocytes, where overexpression of wnt2ba was sufficient to rescue podocytes and osr1 deficiency. Antagonism between osr1 and hand2 mediates podocyte development specifically by controlling wnt2ba expression. These studies reveal new insights about the roles of Osr1 in promoting renal progenitor survival and lineage choice. Full article

(This article belongs to the Special Issue Zebrafish Models for Development and Disease 3.0)

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16 pages, 3475 KiB

Open AccessEditor’s ChoiceArticle

Clinical Outcomes of 3D-Printed Bioresorbable Scaffolds for Bone Tissue Engineering—A Pilot Study on 126 Patients for Burrhole Covers in Subdural Hematoma

by Emma M. S. Toh, Ashiley A. Thenpandiyan, Aaron S. C. Foo, John J. Y. Zhang, Mervyn J. R. Lim, Chun Peng Goh, Nivedh Dinesh, Srujana V. Vedicherla, Ming Yang, Kejia Teo, Tseng Tsai Yeo and Vincent D. W. Nga

Biomedicines 2022, 10(11), 2702; https://doi.org/10.3390/biomedicines10112702 - 26 Oct 2022

Cited by 7 | Viewed by 2233

Abstract

Burrhole craniostomy is commonly performed for subdural hematoma (SDH) evacuation, but residual scalp depressions are often cosmetically suboptimal for patients. Osteoplug^TM, a bioresorbable polycaprolactone burrhole cover, was introduced by the National University Hospital, Singapore, in 2006 to cover these defects, allowing [...] Read more.

Burrhole craniostomy is commonly performed for subdural hematoma (SDH) evacuation, but residual scalp depressions are often cosmetically suboptimal for patients. Osteoplug^TM, a bioresorbable polycaprolactone burrhole cover, was introduced by the National University Hospital, Singapore, in 2006 to cover these defects, allowing osseous integration and vascular ingrowth. However, the cosmetic and safety outcomes of Osteoplug^TM-C—the latest (2017) iteration, with a chamfered hole for subdural drains—remain unexplored. Data were collected from a single institution from April 2017 to March 2021. Patient-reported aesthetic outcomes (Aesthetic Numeric Analog (ANA)) and quality of life (EQ-5D-3L including Visual Analog Scale (VAS)) were assessed via telephone interviews. Clinical outcomes included SDH recurrence, postoperative infections, and drain complications. Osteoplug^TM-C patients had significantly higher satisfaction and quality of life compared to those without a burrhole cover (ANA: 9 [7, 9] vs. 7 [5, 8], p = 0.019; VAS: 85 [75, 90] vs. 70 [50, 80], p = 0.021), and the absence of a burrhole cover was associated with poorer aesthetic outcomes after multivariable adjustment (adjusted OR: 4.55, 95% CI: 1.09–22.68, p = 0.047). No significant differences in other clinical outcomes were observed between Osteoplug^TM-C, Osteoplug^TM, or no burrhole cover. Our pilot study supports Osteoplug^TM-C and its material polycaprolactone as suitable adjuncts to burrhole craniostomy, improving cosmetic outcomes while achieving comparable safety outcomes. Full article

(This article belongs to the Special Issue Scaffolds for Bone Tissue Engineering)

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8 pages, 220 KiB

Open AccessEditor’s ChoiceArticle

Predictive Risk Factors Associated with Severe Radiation-Induced Mucositis in Nasopharyngeal or Oropharyngeal Cancer Patients: A Retrospective Study

by Yumiko Kawashita, Sakiko Soutome, Masahiro Umeda and Toshiyuki Saito

Biomedicines 2022, 10(10), 2661; https://doi.org/10.3390/biomedicines10102661 - 21 Oct 2022

Cited by 5 | Viewed by 1773

Abstract

Radiation-induced mucositis in head and neck cancer patients generates difficulties in eating and swallowing, and may influence treatment tolerance, compliance, and quality of life. However, predictive factors have not been studied in detail. Thus, the aim of this study was to describe the [...] Read more.

Radiation-induced mucositis in head and neck cancer patients generates difficulties in eating and swallowing, and may influence treatment tolerance, compliance, and quality of life. However, predictive factors have not been studied in detail. Thus, the aim of this study was to describe the association between pre-radiotherapy clinical factors and the incidence of severe radiation-induced mucositis in nasopharyngeal or oropharyngeal cancer patients. This retrospective study included all patients with definitive radiotherapy or chemoradiotherapy for nasopharyngeal or oropharyngeal cancer between July 2011 and June 2021 in a single center. The eligibility criteria included patients who received oral management during radiotherapy. Exclusion criteria was patients who received postoperative radiotherapy. The data were acquired from the medical records of patients. One hundred patients were included in this retrospective study. Grade 3 radiation-induced mucositis occurred in 47 patients (47%). Lymphocyte count was significantly associated with grade 3 mucositis (OR = 0.40; 95% CI = 0.19–0.86; p = 0.018). It is suggested that pre-radiation lower lymphocyte counts are a predictive risk factor for severe mucositis in patients who undergo definitive radiotherapy or chemoradiotherapy for nasopharyngeal or oropharyngeal cancer Full article

(This article belongs to the Special Issue State-of-the-Art Cancer Biology, Biodiagnostics and Therapeutics in Japan)

17 pages, 1031 KiB

Open AccessEditor’s ChoiceArticle

Bronchial Asthma as a Cardiovascular Risk Factor: A Prospective Observational Study

by Marcela Kreslová, Olga Kirchnerová, Daniel Rajdl, Vendula Sudová, Jiří Blažek, Aneta Sýkorová, Petr Jehlička, Ladislav Trefil, Jan Schwarz, Renata Pomahačová and Josef Sýkora

Biomedicines 2022, 10(10), 2614; https://doi.org/10.3390/biomedicines10102614 - 18 Oct 2022

Cited by 5 | Viewed by 7126

Abstract

Introduction: Asthma as a chronic inflammatory disorder has been suggested as a risk factor for endothelial dysfunction (ED), but studies on the association between asthma and cardiovascular disease (CVD) risk are limited. Background: We assessed associations of ED with the severity of asthma, [...] Read more.

Introduction: Asthma as a chronic inflammatory disorder has been suggested as a risk factor for endothelial dysfunction (ED), but studies on the association between asthma and cardiovascular disease (CVD) risk are limited. Background: We assessed associations of ED with the severity of asthma, eosinophilic inflammation, lung function, and asthma control. Methods: 52 young asthmatics (median age of 25.22 years) and 45 healthy individuals were included. Demographic, clinical, and laboratory findings were recorded. We evaluated microvascular responsiveness by recording the reactive hyperemia index (RHI) indicating post-occlusive peripheral endothelium-dependent changes in vascular tone using the Itamar Medical EndoPAT2000. VCAM-1, ADMA, high-sensitive CRP (hsCRP), and E-selectin were measured. Results: Asthmatics had considerably lower RHI values (p < 0.001) with a dynamic decreasing trend by asthma severity and higher hsCRP levels (p < 0.001). A substantial increase in hsCRP and E-selectin with asthma severity (p < 0.05) was also observed. We confirmed a higher body mass index (BMI) in asthmatics (p < 0.001), especially in women and in severe asthma. Conclusions: We demonstrated the progression of CVD in asthmatics and the association of the ongoing deterioration of ED with the inflammatory severity, suggesting that the increased risk of CVD in young asthmatics is dependent on disease severity. The underlying mechanisms of risk factors for CVD and disease control require further study. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Advances in Endothelial Dysfunction)

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20 pages, 1052 KiB

Open AccessEditor’s ChoiceReview

Role of Extracellular Vesicles in Thyroid Physiology and Diseases: Implications for Diagnosis and Treatment

by Ophélie Delcorte, Jonathan Degosserie and Christophe E. Pierreux

Biomedicines 2022, 10(10), 2585; https://doi.org/10.3390/biomedicines10102585 - 15 Oct 2022

Cited by 4 | Viewed by 4651

Abstract

Extracellular vesicles are spherical subcellular structures delimited by a lipid bilayer and released by most cells in the human body. They are loaded with a myriad of molecules (i.e., nucleic acids and proteins) depending on their cell of origin and provide the ability [...] Read more.

Extracellular vesicles are spherical subcellular structures delimited by a lipid bilayer and released by most cells in the human body. They are loaded with a myriad of molecules (i.e., nucleic acids and proteins) depending on their cell of origin and provide the ability to transmit a message to surrounding or distant target cells. In several organs, including the thyroid, abundant recent literature reports that extracellular vesicles are responsible for intercellular communication in physiological and pathological processes, and that their utilization as a potential biomarker of pathological states (i.e., cancer, autoimmune diseases) or as therapeutic delivery vehicles promise clinical options. In this review, we present the current knowledge and understanding regarding the role of extracellular vesicles in developing thyroid diseases and diagnosis. Full article

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

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12 pages, 3112 KiB

Open AccessEditor’s ChoiceArticle

Prognostic Significance of STING Immunoexpression in Relation to HPV16 Infection in Patients with Squamous Cell Carcinomas of Oral Cavity and Oropharynx

by Beata Biesaga, Ryszard Smolarczyk, Anna Mucha-Małecka, Justyna Czapla, Janusz Ryś and Krzysztof Małecki

Biomedicines 2022, 10(10), 2538; https://doi.org/10.3390/biomedicines10102538 - 12 Oct 2022

Cited by 3 | Viewed by 1953

Abstract

Infection with HPV16 in cancers of the oral cavity (OCSCC) and oropharynx (OPSCC) is, today, an important etiological and prognostic factor. Patients with HPV-positive OPSCC have a better prognosis than uninfected patients. However, in over 40% of these patients, cancer progression is noticed. [...] Read more.

Infection with HPV16 in cancers of the oral cavity (OCSCC) and oropharynx (OPSCC) is, today, an important etiological and prognostic factor. Patients with HPV-positive OPSCC have a better prognosis than uninfected patients. However, in over 40% of these patients, cancer progression is noticed. Their identification is particularly important due to the ongoing clinical trials regarding the possibility of de-escalation of anticancer treatment in patients with HPV-positive OPSCC. Some studies suggest that there is possibility to differentiate prognosis of HPV16-positive patients by STING (Stimulator of Interferon Genes) immunoexpression. The aim of the present study was to analyze the influence of STING immunoexpression on overall (OS) and disease-free survival (DFS) of patients with HPV16-positive and -negative OCSCC and OPSCC. The study was performed in a group of 87 patients with OCSCC and OPSCC for which in our earlier study active HPV16 infection was assessed by P16 expression followed by HPV DNA detection. To analyze STING immunoexpression in tumor area (THS) and in adjacent stromal tissues (SHS) H score (HS) was applied. In the subgroup with HPV16, active infection patients with tumors with THS had significantly better DFS (p = 0.047) than those without THS. In this subgroup, TSH did not significantly influence OS, and SHS did not significantly correlate with OS and DFS. In the subgroup of patients without active HPV16 infection, THS and SHS also did not significantly influence patients’ survival. Presented results indicated prognostic potential of tumor STING immunoexpression in patients with active HPV16 infection in cancers of oral cavity and oropharynx. Full article

(This article belongs to the Special Issue State-of-the-Art Cancer Biology and Therapeutics in Poland)

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9 pages, 1194 KiB

Open AccessEditor’s ChoiceArticle

Adalimumab Originator vs. Biosimilar in Hidradenitis Suppurativa: A Multicentric Retrospective Study

by Martina Burlando, Gabriella Fabbrocini, Claudio Marasca, Paolo Dapavo, Andrea Chiricozzi, Dalma Malvaso, Valentina Dini, Anna Campanati, Annamaria Offidani, Annunziata Dattola, Raffaele Dante Caposiena Caro, Luca Bianchi, Marina Venturini, Paolo Gisondi, Claudio Guarneri, Giovanna Malara, Caterina Trifirò, Piergiorigio Malagoli, Maria Concetta Fargnoli, Stefano Piaserico, Luca Carmisciano, Riccardo Castelli and Aurora Parodi Show full author list Hide full author list

Biomedicines 2022, 10(10), 2522; https://doi.org/10.3390/biomedicines10102522 - 09 Oct 2022

Cited by 6 | Viewed by 2520

Abstract

This study aimed to compare adalimumab originator vs. biosimilar in HS patients, and to evaluate the effect of a switch to a biosimilar, or a switch back to the originator, in terms of treatment ineffectiveness. Patients with a diagnosis of HS were enrolled [...] Read more.

This study aimed to compare adalimumab originator vs. biosimilar in HS patients, and to evaluate the effect of a switch to a biosimilar, or a switch back to the originator, in terms of treatment ineffectiveness. Patients with a diagnosis of HS were enrolled from 14 Italian sites. Treatment ineffectiveness was measured using Hurley score. The major analyses were 1) comparison between the two treatment groups (non-switcher analysis), and 2) the cross-over trend of Hurley score between treatment switchers (switcher analysis). Cox and Poisson regression models were used to compare the treatment ineffectiveness between groups. A total of 326 patients were divided into four groups: 171 (52.5%) taking originator; 61 (18.7%) patients taking biosimilar; 66 (20.2%) switchers; 28 (8.6%) switchers from originator to biosimilar and switched. A greater loss of efficacy was observed in the group allocated to the biosimilar than the originator group. The switcher analysis showed an effectiveness loss in the biosimilar compared to the originator. These results seem to indicate that a switch from one drug to the other may lead to a greater risk of inefficacy. A return to the previous treatment also does not ensure efficaciousness. Full article

(This article belongs to the Special Issue Immune-Mediated Skin Diseases: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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31 pages, 1015 KiB

Open AccessEditor’s ChoiceReview

Immune Checkpoint Inhibitors and Other Immune Therapies in Breast Cancer: A New Paradigm for Prolonged Adjuvant Immunotherapy

by Andrea Nicolini, Paola Ferrari and Angelo Carpi

Biomedicines 2022, 10(10), 2511; https://doi.org/10.3390/biomedicines10102511 - 08 Oct 2022

Cited by 10 | Viewed by 4512

Abstract

Background: Breast cancer is the most common form of cancer in women worldwide. Advances in the early diagnosis and treatment of cancer in the last decade have progressively decreased the cancer mortality rate, and in recent years, immunotherapy has emerged as a relevant [...] Read more.

Background: Breast cancer is the most common form of cancer in women worldwide. Advances in the early diagnosis and treatment of cancer in the last decade have progressively decreased the cancer mortality rate, and in recent years, immunotherapy has emerged as a relevant tool against cancer. HER2+ and triple-negative breast cancers (TNBCs) are considered more immunogenic and suitable for this kind of treatment due to the higher rate of tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression. In TNBC, genetic aberrations further favor immunogenicity due to more neo-antigens in cancer cells. Methods: This review summarizes the principal ongoing conventional and investigational immunotherapies in breast cancer. Particularly, immune checkpoint inhibitors (ICIs) and their use alone or combined with DNA damage repair inhibitors (DDRis) are described. Then, the issue on immunotherapy with monoclonal antibodies against HER-2 family receptors is updated. Other investigational immunotherapies include a new schedule based on the interferon beta-interleukin-2 sequence that was given in ER+ metastatic breast cancer patients concomitant with anti-estrogen therapy, which surprisingly showed promising results. Results: Based on the scientific literature and our own findings, the current evaluation of tumor immunogenicity and the conventional model of adjuvant chemotherapy (CT) are questioned. Conclusions: A novel strategy based on additional prolonged adjuvant immunotherapy combined with hormone therapy or alternated with CT is proposed. Full article

(This article belongs to the Special Issue Immune Checkpoints and Autoimmunity)

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32 pages, 1786 KiB

Open AccessEditor’s ChoiceReview

The Complex Roles of Adipokines in Polycystic Ovary Syndrome and Endometriosis

by Susanne Schüler-Toprak, Olaf Ortmann, Christa Buechler and Oliver Treeck

Biomedicines 2022, 10(10), 2503; https://doi.org/10.3390/biomedicines10102503 - 07 Oct 2022

Cited by 16 | Viewed by 3707

Abstract

Polycystic ovary syndrome (PCOS) and endometriosis are frequent diseases of the female reproductive tract causing high morbidity as they can significantly affect fertility and quality of life. Adipokines are pleiotropic signaling molecules secreted by white or brown adipose tissues with a central role [...] Read more.

Polycystic ovary syndrome (PCOS) and endometriosis are frequent diseases of the female reproductive tract causing high morbidity as they can significantly affect fertility and quality of life. Adipokines are pleiotropic signaling molecules secreted by white or brown adipose tissues with a central role in energy metabolism. More recently, their involvement in PCOS and endometriosis has been demonstrated. In this review article, we provide an update on the role of adipokines in both diseases and summarize previous findings. We also address the results of multi-omics approaches in adipokine research to examine the role of single nucleotide polymorphisms (SNPs) in genes coding for adipokines and their receptors, the secretome of adipocytes and to identify epigenetic alterations of adipokine genes that might be conferred from mother to child. Finally, we address novel data on the role of brown adipose tissue (BAT), which seems to have notable effects on PCOS. For this review, original research articles on adipokine actions in PCOS and endometriosis are considered, which are listed in the PubMed database. Full article

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

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13 pages, 977 KiB

Open AccessEditor’s ChoiceReview

Vericiguat in Heart Failure: Characteristics, Scientific Evidence and Potential Clinical Applications

by Francesca Vannuccini, Alessandro Campora, Maria Barilli and Alberto Palazzuoli

Biomedicines 2022, 10(10), 2471; https://doi.org/10.3390/biomedicines10102471 - 03 Oct 2022

Cited by 11 | Viewed by 6864

Abstract

Despite recent advances in heart failure (HF) management, the risk of death and hospitalizations remains high in the long term. HF is characterized by endothelial dysfunction, inflammation and increased oxidative stress, due to a reduction in the activity of the nitric oxide (NO)-soluble [...] Read more.

Despite recent advances in heart failure (HF) management, the risk of death and hospitalizations remains high in the long term. HF is characterized by endothelial dysfunction, inflammation and increased oxidative stress, due to a reduction in the activity of the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling pathway. All these factors contribute to direct damage at the myocardial, vascular and renal level. Vericiguat restores the deficiency in this signaling pathway, through stimulation and activation of sGC, aiming to increase cGMP levels, with a reduction in HF-related oxidative stress and endothelial dysfunction. Two main clinical trials were developed in this setting: the SOCRATES-REDUCED phase II study and the VICTORIA phase III study. They found that vericiguat is safe, well tolerated and effective with an absolute event-rate reduction in patients affected by HF with reduced ejection fraction (HFrEF) and recent cardiac decompensation. In patients with HF with preserved ejection fraction (HfpEF), the SOCRATES-PRESERVED trial demonstrated an improvement in quality of life and health status, but the proven beneficial effects with vericiguat are still limited. Further studies are needed to correctly define the role of this drug in heart failure syndromes. Our paper reviews the potential applications and pharmacological characteristics of vericiguat in HFrEF and HFpEF. Full article

(This article belongs to the Special Issue Advances in Therapy for Heart Failure)

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13 pages, 2362 KiB

Open AccessEditor’s ChoiceArticle

Study on Tissue Homogenization Buffer Composition for Brain Mass Spectrometry-Based Proteomics

by Adam Aleksander Karpiński, Julio Cesar Torres Elguera, Anne Sanner, Witold Konopka, Leszek Kaczmarek, Dominic Winter, Anna Konopka and Ewa Bulska

Biomedicines 2022, 10(10), 2466; https://doi.org/10.3390/biomedicines10102466 - 02 Oct 2022

Cited by 2 | Viewed by 2908

Abstract

Mass spectrometry-based proteomics aims to study the proteome both qualitatively and quantitatively. A key step in proteomic analysis is sample preparation, which is crucial for reliable results. We investigated the effect of the composition of the homogenization buffer used to extract proteins from [...] Read more.

Mass spectrometry-based proteomics aims to study the proteome both qualitatively and quantitatively. A key step in proteomic analysis is sample preparation, which is crucial for reliable results. We investigated the effect of the composition of the homogenization buffer used to extract proteins from brain tissue on the yield of protein extraction and the number and type of extracted proteins. Three different types of buffers were compared—detergent-based buffer (DB), chaotropic agent-based buffer (CAB) and buffer without detergent and chaotropic agent (DFB). Based on label-free quantitative protein analysis, detergent buffer was identified as the most suitable for global proteomic profiling of brain tissue. It allows the most efficient extraction of membrane proteins, synaptic and synaptic membrane proteins along with ribosomal, mitochondrial and myelin sheath proteins, which are of particular interest in the field of neurodegenerative disorders research. Full article

(This article belongs to the Special Issue Mass Spectrometry Based Proteomics in Medical Research)

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10 pages, 303 KiB

Open AccessEditor’s ChoiceArticle

Plasma and Peritoneal Fluid ZEB Levels in Patients with Endometriosis and Infertility

by Paweł Bartnik, Joanna Kacperczyk-Bartnik, Ksawery Goławski, Janusz Sierdziński, Grzegorz Mańka, Mariusz Kiecka, Michał Lipa, Damian Warzecha, Robert Spaczyński, Piotr Piekarski, Beata Banaszewska, Artur J. Jakimiuk, Tadeusz Issat, Wojciech Rokita, Jakub Młodawski, Maria Szubert, Piotr Sieroszewski, Grzegorz Raba, Kamil Szczupak, Tomasz Kluz, Marek Kluza, Krzysztof Czajkowski, Mirosław Wielgoś, Ewa Koc-Żórawska, Marcin Żórawski and Piotr Laudański Show full author list Hide full author list

Biomedicines 2022, 10(10), 2460; https://doi.org/10.3390/biomedicines10102460 - 01 Oct 2022

Cited by 6 | Viewed by 1977

Abstract

Zinc finger E-box-binding homeobox 1 (ZEB1) and zinc finger E-box-binding homeobox 2 (ZEB2) are transcription factors that regulate epithelial–mesenchymal transformation (EMT). The aim of this study was to compare levels of ZEB1 and ZEB2 in the peritoneal fluid and plasma between patients with [...] Read more.

Zinc finger E-box-binding homeobox 1 (ZEB1) and zinc finger E-box-binding homeobox 2 (ZEB2) are transcription factors that regulate epithelial–mesenchymal transformation (EMT). The aim of this study was to compare levels of ZEB1 and ZEB2 in the peritoneal fluid and plasma between patients with and without endometriosis in order to assess their utility in the diagnostic process. Plasma and peritoneal fluid samples were collected from 50 patients with and 48 without endometriosis during planned surgical procedures in eight clinical centers. Quantitative ZEB1 and ZEB2 levels analyses were performed using a double-antibody sandwich enzyme-linked immunosorbent assay (ELISA). No significant differences were observed in ZEB1 levels in any of the subanalyses nor any differences regarding ZEB2 levels between patients with and without endometriosis. Plasma ZEB2 levels were significantly higher among patients with infertility compared to fertile women (16.07 ± 12.70 ng/L vs. 12.07 ± 11.92 ng/L; p < 0.04). Both ZEB1 and ZEB2 do not seem to have a significant value in the initial diagnosis of endometriosis as a single marker. The differences in ZEB2 plasma levels between patients with and without infertility indicate the possibility of EMT dysregulation in the pathogenesis of adverse fertility outcomes. Full article

(This article belongs to the Special Issue Advanced Research in Endometriosis 3.0)

12 pages, 1958 KiB

Open AccessEditor’s ChoiceArticle

The Role of [¹⁸F]F-Choline PET/CT in the Initial Management and Outcome Prediction of Prostate Cancer: A Real-World Experience from a Multidisciplinary Approach

by Luca Urso, Giovanni Christian Rocca, Francesca Borgia, Federica Lancia, Antonio Malorgio, Mauro Gagliano, Mauro Zanetto, Licia Uccelli, Corrado Cittanti, Carmelo Ippolito, Laura Evangelista and Mirco Bartolomei

Biomedicines 2022, 10(10), 2463; https://doi.org/10.3390/biomedicines10102463 - 01 Oct 2022

Cited by 5 | Viewed by 1907

Abstract

Initial staging of prostate cancer (PCa) is usually performed with conventional imaging (CI), involving computed tomography (CT) and bone scanning (BS). The aim of this study was to analyze the role of [¹⁸F]F-choline positron emission tomography (PET)/CT in the initial management [...] Read more.

Initial staging of prostate cancer (PCa) is usually performed with conventional imaging (CI), involving computed tomography (CT) and bone scanning (BS). The aim of this study was to analyze the role of [¹⁸F]F-choline positron emission tomography (PET)/CT in the initial management and outcome prediction of PCa patients by analyzing data from a multidisciplinary approach. We retrospectively analyzed 82 patients who were discussed by the uro-oncology board of the University Hospital of Ferrara for primary staging newly diagnosed PCa (median age 72 (56–86) years; median baseline prostate specific antigen (PSA) equal to 8.73 ng/mL). Patients were divided into three groups based on the imaging performed: group A = only CI; group B = CI + [¹⁸F]F-choline PET/CT; group C = only [¹⁸F]F-choline PET/CT. All data on imaging findings, therapy decisions and patient outcomes were retrieved from hospital information systems. Moreover, we performed a sub-analysis of semiquantitative parameters extracted from [¹⁸F]F-choline PET/CT to search any correlation with patient outcomes. The number of patients included in each group was 35, 35 and 12, respectively. Patients with higher values of initial PSA were subjected to CI + PET/CT (p = 0.005). Moreover, the use of [¹⁸F]F-choline PET/CT was more frequent in patients with higher Gleason score (GS) or ISUP grade (p = 0.013). The type of treatment performed (surgery n = 33; radiation therapy n = 22; surveillance n = 6; multimodality therapy n = 6; systemic therapy n = 13; not available n = 2) did not show any relationship with the modality adopted to stage the disease. [¹⁸F]F-choline PET/CT induced a change of planned therapy in 5/35 patients in group B (14.3%). Moreover, patients investigated with [¹⁸F]F-choline PET/CT alone demonstrated longer biochemical recurrence (BCR)-free survival (30.8 months) in comparison to patients of groups A and B (15.5 and 23.5 months, respectively, p = 0.006), probably due to a more accurate selection of primary treatment. Finally, total lesion choline kinase activity (TLCKA) of the primary lesion, calculated by multiplying metabolic tumor volume and mean standardized uptake value (SUVmean), was able to more effectively discriminate patients who had recurrence after therapy compared to those without (p = 0.03). In our real-world experience [¹⁸F]F-choline PET/CT as a tool for the initial management of PCa had a relevant impact in terms of therapy selection and was associated with longer BCR-free survival. Moreover, TLCKA of the primary lesion looks a promising parameter for predicting recurrence after curative therapy. Full article

(This article belongs to the Special Issue Prostate Cancer: from Molecular Imaging to Immunological and Target Therapies II)

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10 pages, 1288 KiB

Open AccessEditor’s ChoiceArticle

High Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios Are Associated with a Higher Risk of Hemodialysis Vascular Access Failure

by Edoardo Pasqui, Gianmarco de Donato, Elisa Lazzeri, Cecilia Molino, Giuseppe Galzerano, Michele Giubbolini and Giancarlo Palasciano

Biomedicines 2022, 10(9), 2218; https://doi.org/10.3390/biomedicines10092218 - 07 Sep 2022

Cited by 13 | Viewed by 1729

Abstract

Our aim was to determine the predictive role of the preoperative neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in vascular access malfunctioning in patients who had undergone their first native arterio-venous fistula (AVF) for hemodialysis. Methods: This was a single-center retrospective observational study. [...] Read more.

Our aim was to determine the predictive role of the preoperative neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in vascular access malfunctioning in patients who had undergone their first native arterio-venous fistula (AVF) for hemodialysis. Methods: This was a single-center retrospective observational study. All patients who underwent the procedure of the creation of a first native AVF for hemodialysis from January 2019 to December 2020 were considered eligible to be part of this study. Reinterventions for AVF malfunctioning were registered and the population was subdivided into two groups with respect to AVF malfunctioning. ROC curves were obtained to find the appropriate cut-off values for the NLR and PLR. A multivariate analysis was used to identify the independent predictors for an AVF malfunction. Kaplan–Meier curves were used to evaluate the AVF patency rates. A total of 178 patients were enrolled in the study, of them 70% (n = 121) were male. The mean age was 67.5 ± 12 years. Reinterventions for AVF malfunctioning were performed on 102 patients (57.3%). An NLR > 4.21 and a PLR > 208.8 was selected as the cut-off for AVF malfunctioning. The study population was divided into two groups depending on the NLR and PLR values of the individual. For the NLR < 4.21 group, the AVF patency rates were 90.7%, 85.3%, and 84% at the 3-, 6-, and 12-month follow-up, respectively, and 77.5%, 65.8%, and 39.3% at 3, 6, and 12 months for the NLR > 4.21 group, respectively (p < 0.0001). For the PLR < 208.8 group, the patency rates were 85.6%, 76.7%, and 67.7% at the 3-, 6-, and 12-month follow-up. For the PLR > 208.28 group, the patency rates were 80.8%, 71.2%, and 50.7% for the 3-, 6-, and 12-month follow-up, respectively (p = 0.014). The multivariate analysis highlighted that diabetes mellitus, the neutrophil count, the lymphocyte count, and the NLR were independent risk factors for an AVF failure. In our experience, the NLR and PLR are useful markers for the stratification of vascular access failure in hemodialysis patients. The inexpensive nature and ready availability of the values of these biomarkers are two points of strength for everyday clinical practice. Full article

(This article belongs to the Special Issue Neutrophils, Fast and Strong 2.0)

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25 pages, 1731 KiB

Open AccessEditor’s ChoiceReview

Lipid Nanoparticles as Delivery Vehicles for Inhaled Therapeutics

by Ellenmae W. X. Leong and Ruowen Ge

Biomedicines 2022, 10(9), 2179; https://doi.org/10.3390/biomedicines10092179 - 02 Sep 2022

Cited by 34 | Viewed by 6300

Abstract

Lipid nanoparticles (LNPs) have emerged as a powerful non-viral carrier for drug delivery. With the prevalence of respiratory diseases, particularly highlighted by the current COVID-19 pandemic, investigations into applying LNPs to deliver inhaled therapeutics directly to the lungs are underway. The progress in [...] Read more.

Lipid nanoparticles (LNPs) have emerged as a powerful non-viral carrier for drug delivery. With the prevalence of respiratory diseases, particularly highlighted by the current COVID-19 pandemic, investigations into applying LNPs to deliver inhaled therapeutics directly to the lungs are underway. The progress in LNP development as well as the recent pre-clinical studies in three main classes of inhaled encapsulated drugs: small molecules, nucleic acids and proteins/peptides will be discussed. The advantages of the pulmonary drug delivery system such as reducing systemic toxicity and enabling higher local drug concentration in the lungs are evaluated together with the challenges and design considerations for improved formulations. This review provides a perspective on the future prospects of LNP-mediated delivery of inhaled therapeutics for respiratory diseases. Full article

(This article belongs to the Special Issue Advances in Nanomedicine for Disease Treatment and Diagnosis)

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16 pages, 1390 KiB

Open AccessEditor’s ChoiceReview

Lipid-Based Drug Delivery Systems for Diseases Managements

by Douweh Leyla Gbian and Abdelwahab Omri

Biomedicines 2022, 10(9), 2137; https://doi.org/10.3390/biomedicines10092137 - 31 Aug 2022

Cited by 14 | Viewed by 3017

Abstract

Liposomes are tiny lipid-based vesicles composed of one or more lipid bilayers, which facilitate the encapsulation of hydrophilic, lipophilic, and amphiphilic biological active agents. The description of the physicochemical properties, formulation methods, characteristics, mechanisms of action, and large-scale manufacturing of liposomes as delivery [...] Read more.

Liposomes are tiny lipid-based vesicles composed of one or more lipid bilayers, which facilitate the encapsulation of hydrophilic, lipophilic, and amphiphilic biological active agents. The description of the physicochemical properties, formulation methods, characteristics, mechanisms of action, and large-scale manufacturing of liposomes as delivery systems are deeply discussed. The benefits, toxicity, and limitations of the use of liposomes in pharmacotherapeutics including in diagnostics, brain targeting, eye and cancer diseases, and in infections are provided. The experimental approaches that may reduce, or even bypass, the use of liposomal drug drawbacks is described. The application of liposomes in the treatment of numerous diseases is discussed. Full article

(This article belongs to the Special Issue Advances in Nanomedicine for Disease Treatment and Diagnosis)

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15 pages, 631 KiB

Open AccessEditor’s ChoiceReview

Inflammatory Cytokine: An Attractive Target for Cancer Treatment

by Hyang-Mi Lee, Hye-Jin Lee and Ji-Eun Chang

Biomedicines 2022, 10(9), 2116; https://doi.org/10.3390/biomedicines10092116 - 29 Aug 2022

Cited by 20 | Viewed by 2933

Abstract

The relationship between inflammation and cancer has attracted attention for a long time. The inflammatory tumor microenvironment consists of inflammatory cells, chemokines, cytokines, and signaling pathways. Among them, inflammatory cytokines play an especially pivotal role in cancer development, prognosis, and treatment. Interleukins, tumor [...] Read more.

The relationship between inflammation and cancer has attracted attention for a long time. The inflammatory tumor microenvironment consists of inflammatory cells, chemokines, cytokines, and signaling pathways. Among them, inflammatory cytokines play an especially pivotal role in cancer development, prognosis, and treatment. Interleukins, tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β), interferons, and vascular endothelial growth factor (VEGF) are the representative inflammatory cytokines in various cancers, which may promote or inhibit cancer progression. The pro-inflammatory cytokines are associated with advanced cancer stages, resistance to immunotherapy, and poor prognoses, such as in objective response and disease control rates, and progression-free and overall survival. In this review, we selected colorectal, pancreatic, breast, gastric, lung, and prostate cancers, which are well-reported for an association between cancer and inflammatory cytokines. The related cytokines and their effects on each cancer’s development and prognosis were summarized. In addition, the treatment strategies targeting inflammatory cytokines in each carcinoma were also described here. By understanding the biological roles of cancer-related inflammatory cytokines, we may modulate the inflammatory tumor microenvironment for potential cancer treatment. Full article

(This article belongs to the Special Issue The Role of Inflammatory Cytokines in Cancer Progression)

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33 pages, 2235 KiB

Open AccessEditor’s ChoiceReview

Bioavailability Enhancement Techniques for Poorly Aqueous Soluble Drugs and Therapeutics

by Dixit V. Bhalani, Bhingaradiya Nutan, Avinash Kumar and Arvind K. Singh Chandel

Biomedicines 2022, 10(9), 2055; https://doi.org/10.3390/biomedicines10092055 - 23 Aug 2022

Cited by 91 | Viewed by 13857

Abstract

The low water solubility of pharmacoactive molecules limits their pharmacological potential, but the solubility parameter cannot compromise, and so different approaches are employed to enhance their bioavailability. Pharmaceutically active molecules with low solubility convey a higher risk of failure for drug innovation and [...] Read more.

The low water solubility of pharmacoactive molecules limits their pharmacological potential, but the solubility parameter cannot compromise, and so different approaches are employed to enhance their bioavailability. Pharmaceutically active molecules with low solubility convey a higher risk of failure for drug innovation and development. Pharmacokinetics, pharmacodynamics, and several other parameters, such as drug distribution, protein binding and absorption, are majorly affected by their solubility. Among all pharmaceutical dosage forms, oral dosage forms cover more than 50%, and the drug molecule should be water-soluble. For good therapeutic activity by the drug molecule on the target site, solubility and bioavailability are crucial factors. The pharmaceutical industry’s screening programs identified that around 40% of new chemical entities (NCEs) face various difficulties at the formulation and development stages. These pharmaceuticals demonstrate less solubility and bioavailability. Enhancement of the bioavailability and solubility of drugs is a significant challenge in the area of pharmaceutical formulations. According to the Classification of Biopharmaceutics, Class II and IV drugs (APIs) exhibit poor solubility, lower bioavailability, and less dissolution. Various technologies are discussed in this article to improve the solubility of poorly water-soluble drugs, for example, the complexation of active molecules, the utilization of emulsion formation, micelles, microemulsions, cosolvents, polymeric micelle preparation, particle size reduction technologies, pharmaceutical salts, prodrugs, the solid-state alternation technique, soft gel technology, drug nanocrystals, solid dispersion methods, crystal engineering techniques and nanomorph technology. This review mainly describes several other advanced methodologies for solubility and bioavailability enhancement, such as crystal engineering, micronization, solid dispersions, nano sizing, the use of cyclodextrins, solid lipid nanoparticles, colloidal drug delivery systems and drug conjugates, referring to a number of appropriate research reports. Full article

(This article belongs to the Special Issue Topical Drug Delivery: Challenges, Opportunities, Novel Approaches and Recent Advances)

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51 pages, 13524 KiB

Open AccessEditor’s ChoiceArticle

Arc Regulates Transcription of Genes for Plasticity, Excitability and Alzheimer’s Disease

by How-Wing Leung, Gabriel Foo and Antonius VanDongen

Biomedicines 2022, 10(8), 1946; https://doi.org/10.3390/biomedicines10081946 - 11 Aug 2022

Cited by 12 | Viewed by 4608

Abstract

The immediate early gene Arc is a master regulator of synaptic function and a critical determinant of memory consolidation. Here, we show that Arc interacts with dynamic chromatin and closely associates with histone markers for active enhancers and transcription in cultured rat hippocampal [...] Read more.

The immediate early gene Arc is a master regulator of synaptic function and a critical determinant of memory consolidation. Here, we show that Arc interacts with dynamic chromatin and closely associates with histone markers for active enhancers and transcription in cultured rat hippocampal neurons. Both these histone modifications, H3K27Ac and H3K9Ac, have recently been shown to be upregulated in late-onset Alzheimer’s disease (AD). When Arc induction by pharmacological network activation was prevented using a short hairpin RNA, the expression profile was altered for over 1900 genes, which included genes associated with synaptic function, neuronal plasticity, intrinsic excitability, and signalling pathways. Interestingly, about 100 Arc-dependent genes are associated with the pathophysiology of AD. When endogenous Arc expression was induced in HEK293T cells, the transcription of many neuronal genes was increased, suggesting that Arc can control expression in the absence of activated signalling pathways. Taken together, these data establish Arc as a master regulator of neuronal activity-dependent gene expression and suggest that it plays a significant role in the pathophysiology of AD. Full article

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

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31 pages, 2309 KiB

Open AccessEditor’s ChoiceReview

Therapeutic Strategies in Huntington’s Disease: From Genetic Defect to Gene Therapy

by Anamaria Jurcau and Maria Carolina Jurcau

Biomedicines 2022, 10(8), 1895; https://doi.org/10.3390/biomedicines10081895 - 05 Aug 2022

Cited by 11 | Viewed by 4290

Abstract

Despite the identification of an expanded CAG repeat on exon 1 of the huntingtin gene located on chromosome 1 as the genetic defect causing Huntington’s disease almost 30 years ago, currently approved therapies provide only limited symptomatic relief and do not influence the [...] Read more.

Despite the identification of an expanded CAG repeat on exon 1 of the huntingtin gene located on chromosome 1 as the genetic defect causing Huntington’s disease almost 30 years ago, currently approved therapies provide only limited symptomatic relief and do not influence the age of onset or disease progression rate. Research has identified various intricate pathogenic cascades which lead to neuronal degeneration, but therapies interfering with these mechanisms have been marked by many failures and remain to be validated. Exciting new opportunities are opened by the emerging techniques which target the mutant protein DNA and RNA, allowing for “gene editing”. Although some issues relating to “off-target” effects or immune-mediated side effects need to be solved, these strategies, combined with stem cell therapies and more traditional approaches targeting specific pathogenic cascades, such as excitotoxicity and bioavailability of neurotrophic factors, could lead to significant improvement of the outcomes of treated Huntington’s disease patients. Full article

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

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16 pages, 1723 KiB

Open AccessEditor’s ChoiceArticle

GLUT3 Promotes Epithelial–Mesenchymal Transition via TGF-β/JNK/ATF2 Signaling Pathway in Colorectal Cancer Cells

by Moon-Young Song, Da-Young Lee, Sun-Mi Yun and Eun-Hee Kim

Biomedicines 2022, 10(8), 1837; https://doi.org/10.3390/biomedicines10081837 - 29 Jul 2022

Cited by 10 | Viewed by 2166

Abstract

Glucose transporter (GLUT) 3, a member of the GLUTs family, is involved in cellular glucose utilization and the first step in glycolysis. GLUT3 is highly expressed in colorectal cancer (CRC) and it leads to poor prognosis to CRC patient outcome. However, the molecular [...] Read more.

Glucose transporter (GLUT) 3, a member of the GLUTs family, is involved in cellular glucose utilization and the first step in glycolysis. GLUT3 is highly expressed in colorectal cancer (CRC) and it leads to poor prognosis to CRC patient outcome. However, the molecular mechanisms of GLUT3 on the epithelial–mesenchymal transition (EMT) process in metastatic CRC is not yet clear. Here, we identified that activation of the c-Jun N-terminal kinase (JNK)/activating transcription factor-2 (ATF2) signaling pathway by transforming growth factor-β (TGF-β) promotes GLUT3-induced EMT in CRC cells. The regulation of GLUT3 expression was significantly associated with EMT-related markers such as E-cadherin, α- smooth muscle actin (α-SMA), plasminogen activator inhibitor-1 (PAI-1), vimentin and zinc finger E-box binding homeobox 1 (ZEB1). We also found that GLUT3 accelerated the invasive ability of CRC cells. Mechanistically, TGF-β induced the expression of GLUT3 through the phosphorylation of JNK/ATF2, one of the SMAD-independent pathways. TGF-β induced the expression of GLUT3 by increasing the phosphorylation of JNK, the nuclear translocation of the ATF2 transcription factor, and the binding of ATF2 to the promoter region of GLUT3, which increased EMT in CRC cells. Collectively, our results provide a new comprehensive mechanism that GLUT3 promotes EMT process through the TGF-β/JNK/ATF2 signaling pathway, which could be a potential target for the treatment of metastatic CRC. Full article

(This article belongs to the Special Issue The Role of Epithelial-Mesenchymal Transition (EMT) in Cancer Development and Metastasis)

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12 pages, 1772 KiB

Open AccessEditor’s ChoiceArticle

Bioactive Cell-Derived ECM Scaffold Forms a Unique Cellular Microenvironment for Lung Tissue Engineering

by Ali Doryab and Otmar Schmid

Biomedicines 2022, 10(8), 1791; https://doi.org/10.3390/biomedicines10081791 - 26 Jul 2022

Cited by 8 | Viewed by 1984

Abstract

Chronic lung diseases are one of the leading causes of death worldwide. Lung transplantation is currently the only causal therapeutic for lung diseases, which is restricted to end-stage disease and limited by low access to donor lungs. Lung tissue engineering (LTE) is a [...] Read more.

Chronic lung diseases are one of the leading causes of death worldwide. Lung transplantation is currently the only causal therapeutic for lung diseases, which is restricted to end-stage disease and limited by low access to donor lungs. Lung tissue engineering (LTE) is a promising approach to regenerating a replacement for at least a part of the damaged lung tissue. Currently, lung regeneration is limited to a simplified local level (e.g., alveolar–capillary barrier) due to the sophisticated and complex structure and physiology of the lung. Here, we introduce an extracellular matrix (ECM)-integrated scaffold using a cellularization–decellularization–recellularization technique. This ECM-integrated scaffold was developed on our artificial co-polymeric BETA (biphasic elastic thin for air–liquid interface cell culture conditions) scaffold, which were initially populated with human lung fibroblasts (IMR90 cell line), as the main generator of ECM proteins. Due to the interconnected porous structure of the thin (<5 µm) BETA scaffold, the cells can grow on and infiltrate into the scaffold and deposit their own ECM. After a mild decellularization procedure, the ECM proteins remained on the scaffold, which now closely mimicked the cellular microenvironment of pulmonary cells more realistically than the plain artificial scaffolds. We assessed several decellularization methods and found that 20 mM NH₄OH and 0.1% Triton X100 with subsequent DNase treatment completely removed the fibroblasts (from the first cellularization) and maintains collagen I and IV as the key ECM proteins on the scaffold. We also showed the repopulation of the primary fibroblast from human (without chronic lung disease (non-CLD) donors) and human bronchial epithelial (16HBE14o⁻) cells on the ECM-integrated BETA scaffold. With this technique, we developed a biomimetic scaffold that can mimic both the physico-mechanical properties and the native microenvironment of the lung ECM. The results indicate the potential of the presented bioactive scaffold for LTE application. Full article

(This article belongs to the Special Issue Human Extracellular Matrix in Homeostasis and Pathology)

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19 pages, 1888 KiB

Open AccessEditor’s ChoiceReview

Obesity and Endothelial Function

by Masato Kajikawa and Yukihito Higashi

Biomedicines 2022, 10(7), 1745; https://doi.org/10.3390/biomedicines10071745 - 19 Jul 2022

Cited by 18 | Viewed by 3619

Abstract

Obesity is a major public health problem and is related to increasing rates of cardiovascular morbidity and mortality. Over 1.9 billion adults are overweight or obese worldwide and the prevalence of obesity is increasing. Obesity influences endothelial function through obesity-related complications such as [...] Read more.

Obesity is a major public health problem and is related to increasing rates of cardiovascular morbidity and mortality. Over 1.9 billion adults are overweight or obese worldwide and the prevalence of obesity is increasing. Obesity influences endothelial function through obesity-related complications such as hypertension, dyslipidemia, diabetes, metabolic syndrome, and obstructive sleep apnea syndrome. The excess fat accumulation in obesity causes adipocyte dysfunction and induces oxidative stress, insulin resistance, and inflammation leading to endothelial dysfunction. Several anthropometric indices and imaging modalities that are used to evaluate obesity have demonstrated an association between obesity and endothelial function. In the past few decades, there has been great focus on the mechanisms underlying endothelial dysfunction caused by obesity for the prevention and treatment of cardiovascular events. This review focuses on pathophysiological mechanisms of obesity-induced endothelial dysfunction and therapeutic targets of obesity. Full article

(This article belongs to the Special Issue Endothelial Dysfunction: From a Pathophysiological Mechanism to a Potential Therapeutic Target (Volume II))

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28 pages, 6072 KiB

Open AccessEditor’s ChoiceArticle

Diminazene Aceturate Reduces Angiotensin II Constriction and Interacts with the Spike Protein of Severe Acute Respiratory Syndrome Coronavirus 2

by John M. Matsoukas, Laura Kate Gadanec, Anthony Zulli, Vasso Apostolopoulos, Konstantinos Kelaidonis, Irene Ligielli, Kalliopi Moschovou, Nikitas Georgiou, Panagiotis Plotas, Christos T. Chasapis, Graham Moore, Harry Ridgway and Thomas Mavromoustakos

Biomedicines 2022, 10(7), 1731; https://doi.org/10.3390/biomedicines10071731 - 18 Jul 2022

Cited by 8 | Viewed by 2702

Abstract

Diminazene aceturate (DIZE) is a putative angiotensin-converting enzyme 2 (ACE2) activator and angiotensin type 1 receptor antagonist (AT₁R). Its simple chemical structure possesses a negatively charged triazene segment that is homologous to the tetrazole of angiotensin receptor blockers (ARB), which explains [...] Read more.

Diminazene aceturate (DIZE) is a putative angiotensin-converting enzyme 2 (ACE2) activator and angiotensin type 1 receptor antagonist (AT₁R). Its simple chemical structure possesses a negatively charged triazene segment that is homologous to the tetrazole of angiotensin receptor blockers (ARB), which explains its AT₁R antagonistic activity. Additionally, the activation of ACE2 by DIZE converts the toxic octapeptide angiotensin II (AngII) to the heptapeptides angiotensin 1–7 and alamandine, which promote vasodilation and maintains homeostatic balance. Due to DIZE’s protective cardiovascular and pulmonary effects and its ability to target ACE2 (the predominant receptor utilized by severe acute respiratory syndrome coronavirus 2 to enter host cells), it is a promising treatment for coronavirus 2019 (COVID-19). To determine DIZE’s ability to inhibit AngII constriction, in vitro isometric tension analysis was conducted on rabbit iliac arteries incubated with DIZE or candesartan and constricted with cumulative doses of AngII. In silico docking and ligand interaction studies were performed to investigate potential interactions between DIZE and other ARBs with AT₁R and the spike protein/ACE2 complex. DIZE, similar to the other ARBs investigated, was able to abolish vasoconstriction in response to AngII and exhibited a binding affinity for the spike protein/ACE2 complex (PDB 6LZ6). These results support the potential of DIZE as a treatment for COVID-19. Full article

(This article belongs to the Special Issue Cardiovascular Diseases and COVID-19)

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10 pages, 817 KiB

Open AccessEditor’s ChoiceArticle

Urine Oxidative Stress Biomarkers as Novel Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome

by Yuan-Hong Jiang, Jia-Fong Jhang, Han-Chen Ho, Dan-Yun Chiou and Hann-Chorng Kuo

Biomedicines 2022, 10(7), 1701; https://doi.org/10.3390/biomedicines10071701 - 14 Jul 2022

Cited by 13 | Viewed by 1757

Abstract

Both hypoxia and chronic suburothelial inflammation are important pathophysiological findings in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). This study investigated the roles of urine oxidative stress biomarkers and inflammatory cytokines in patients with IC/BPS. Urine samples were collected from 159 IC/BPS patients [...] Read more.

Both hypoxia and chronic suburothelial inflammation are important pathophysiological findings in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). This study investigated the roles of urine oxidative stress biomarkers and inflammatory cytokines in patients with IC/BPS. Urine samples were collected from 159 IC/BPS patients and 28 controls. The targeted analytes included oxidative stress biomarkers (8-OHdG, 8-isoprostane, and total antioxidant capacity) and inflammatory cytokines (MCP-1, RANTES, CXCL10, Eotaxin, MIP-1β, and IL-8). IC/BPS patients were classified into four clinical subgroups, based on the glomerulation grade and the maximal bladder capacity under anesthesia. Patients with IC/BPS had urine oxidative stress biomarkers and inflammatory cytokines profiles that were distinct from those of the controls and among each subgroup. Both 8-OHdG and 8-isoprostane showed a high diagnostic ability to distinguish type 2 IC/BPS patients (as classified by the European Society for the Study of Interstitial Cystitis) from controls. Additionally, they both showed positive and negative correlations with the glomerulation grade and the maximal bladder capacity under anesthesia, respectively. Limitations included intra-individual variation and sex influence. Urine oxidative stress biomarkers might have a role in diagnosing IC/BPS and differentiating its clinical subtypes. In addition to inflammatory cytokines, urine oxidative stress biomarkers have the potential to be novel biomarkers in patients with IC/BPS. Full article

(This article belongs to the Special Issue Bladder Dysfunction: From Molecular Pathology to Therapeutic Approaches)

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18 pages, 1175 KiB

Open AccessEditor’s ChoiceReview

Micro- and Nanosized Carriers for Nose-to-Brain Drug Delivery in Neurodegenerative Disorders

by Radka Boyuklieva and Bissera Pilicheva

Biomedicines 2022, 10(7), 1706; https://doi.org/10.3390/biomedicines10071706 - 14 Jul 2022

Cited by 17 | Viewed by 3367

Abstract

Neurodegenerative disorders (NDs) have become a serious health problem worldwide due to the rapid increase in the number of people that are affected and the constantly aging population. Among all NDs, Alzheimer’s and Parkinson’s disease are the most common, and many efforts have [...] Read more.

Neurodegenerative disorders (NDs) have become a serious health problem worldwide due to the rapid increase in the number of people that are affected and the constantly aging population. Among all NDs, Alzheimer’s and Parkinson’s disease are the most common, and many efforts have been made in the development of effective and reliable therapeutic strategies. The intranasal route of drug administration offers numerous advantages, such as bypassing the blood–brain barrier and providing a direct entrance to the brain through the olfactory and trigeminal neurons. The present review summarizes the available information on recent advances in micro- and nanoscale nose-to-brain drug-delivery systems as a novel strategy for the treatment of Alzheimer’s and Parkinson’s disease. Specifically, polymer- and lipid-base micro- and nanoparticles have been studied as a feasible approach to increase the brain bioavailability of certain drugs. Furthermore, nanocomposites are discussed as a suitable formulation for administration into the nasal cavity. Full article

(This article belongs to the Special Issue Targeted Drug Delivery to Brain)

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16 pages, 2149 KiB

Open AccessEditor’s ChoiceReview

Naringin and Naringenin: Their Mechanisms of Action and the Potential Anticancer Activities

by Jolita Stabrauskiene, Dalia M. Kopustinskiene, Robertas Lazauskas and Jurga Bernatoniene

Biomedicines 2022, 10(7), 1686; https://doi.org/10.3390/biomedicines10071686 - 13 Jul 2022

Cited by 62 | Viewed by 8245

Abstract

Naringin and naringenin are the main bioactive polyphenols in citrus fruits, the consumption of which is beneficial for human health and has been practiced since ancient times. Numerous studies have reported these substances’ antioxidant and antiandrogenic properties, as well as their ability to [...] Read more.

Naringin and naringenin are the main bioactive polyphenols in citrus fruits, the consumption of which is beneficial for human health and has been practiced since ancient times. Numerous studies have reported these substances’ antioxidant and antiandrogenic properties, as well as their ability to protect from inflammation and cancer, in various in vitro and in vivo experimental models in animals and humans. Naringin and naringenin can suppress cancer development in various body parts, alleviating the conditions of cancer patients by acting as effective alternative supplementary remedies. Their anticancer activities are pleiotropic, and they can modulate different cellular signaling pathways, suppress cytokine and growth factor production and arrest the cell cycle. In this narrative review, we discuss the effects of naringin and naringenin on inflammation, apoptosis, proliferation, angiogenesis, metastasis and invasion processes and their potential to become innovative and safe anticancer drugs. Full article

(This article belongs to the Special Issue Anticancer Activity and Metabolic Pathways of Natural Products)

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19 pages, 3474 KiB

Open AccessEditor’s ChoiceArticle

Therapeutic miR-506-3p Replacement in Pancreatic Carcinoma Leads to Multiple Effects including Autophagy, Apoptosis, Senescence, and Mitochondrial Alterations In Vitro and In Vivo

by Hannes Borchardt, Alexander Kogel, Hermann Kalwa, Ulrike Weirauch and Achim Aigner

Biomedicines 2022, 10(7), 1692; https://doi.org/10.3390/biomedicines10071692 - 13 Jul 2022

Cited by 7 | Viewed by 1857

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer mortality. Considering its very poor prognosis, novel treatment options are urgently needed. MicroRNAs (miRNAs) are involved in the regulation of various physiological and pathological processes. In tumors, aberrant downregulation of given miRNAs may [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer mortality. Considering its very poor prognosis, novel treatment options are urgently needed. MicroRNAs (miRNAs) are involved in the regulation of various physiological and pathological processes. In tumors, aberrant downregulation of given miRNAs may result in pathological overexpression of oncogenes, rendering miRNA replacement as a promising therapeutic strategy. In different tumor entities, miRNA-506-3p (miR506-3p) has been ambivalently described as tumor suppressing or oncogenic. In PDAC, miR-506 is mainly considered as a tumor-suppressing miRNA. In this study, we extensively analyze the cellular and molecular effects of miRNA-506-3p replacement in different PDAC cell lines. Beyond profound antiproliferation and induction of cell death and autophagy, we describe new cellular miR506-3p effects, i.e., induction of senescence and reactive oxygen species (ROS), as well as alterations in mitochondrial potential and structure, and identify multiple underlying molecular effects. In a preclinical therapy study, PDAC xenograft-bearing mice were treated with nanoparticle-formulated miRNA-506 mimics. Profound tumor inhibition upon systemic miRNA-506 administration was associated with multiple cellular and molecular effects. This demonstrates miRNA replacement as a potential therapeutic option for PDAC patients. Due to its broad mechanisms of action on multiple relevant target genes, miR506-3p is identified as a particularly powerful tumor-inhibitory miRNA. Full article

(This article belongs to the Special Issue MicroRNA in Solid Tumor and Hematological Diseases 2.0)

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