Biomedicines

21 pages, 6168 KiB

Open AccessEditor’s ChoiceArticle

Cell-Free Genic Extrachromosomal Circular DNA Profiles of DNase Knockouts Associated with Systemic Lupus Erythematosus and Relation with Common Fragile Sites

by Daniela Gerovska, Patricia Fernández Moreno, Aitor Zabala and Marcos J. Araúzo-Bravo

Biomedicines 2024, 12(1), 80; https://doi.org/10.3390/biomedicines12010080 - 28 Dec 2023

Viewed by 1471

Abstract

Cell-free extrachromosomal circular DNA (cf-eccDNA) has been proposed as a promising early biomarker for disease diagnosis, progression and drug response. Its established biomarker features are changes in the number and length distribution of cf-eccDNA. Another novel promising biomarker is a set of eccDNA [...] Read more.

Cell-free extrachromosomal circular DNA (cf-eccDNA) has been proposed as a promising early biomarker for disease diagnosis, progression and drug response. Its established biomarker features are changes in the number and length distribution of cf-eccDNA. Another novel promising biomarker is a set of eccDNA excised from a panel of genes specific to a condition compared to a control. Deficiencies in two endonucleases that specifically target DNA, Dnase1 and Dnase1l3, are associated with systemic lupus erythematosus (SLE). To study the genic eccDNA profiles in the case of their deficiencies, we mapped sequenced eccDNA data from plasma, liver and buffy coat from Dnase1 and Dnase1l3 knockouts (KOs), and wild type controls in mouse. Next, we performed an eccDNA differential analysis between KO and control groups using our DifCir algorithm. We found a specific genic cf-eccDNA fingerprint of the Dnase1l3 group compared to the wild type controls involving 131 genes; 26% of them were associated with human chromosomal fragile sites (CFSs) and with a statistically significant enrichment of CFS-associated genes. We found six genes in common with the genic cf-eccDNA profile of SLE patients with DNASE1L3 deficiency, namely Rorb, Mvb12b, Osbpl10, Fto, Tnik and Arhgap10; all of them were specific and present in all human plasma samples, and none of them were associated with CFSs. A not so distinctive genic cf-eccDNA difference involving only seven genes was observed in the case of the Dnase1 group compared to the wild type. In tissue—liver and buffy coat—we did not detect the same genic eccDNA difference observed in the plasma samples. These results point to a specific role of a set of genic eccDNA in plasma from DNase KOs, as well as a relation with CFS genes, confirming the promise of the genic cf-eccDNA in studying diseases and the need for further research on the relationship between eccDNA and CFSs. Full article

(This article belongs to the Special Issue Systemic Lupus Erythematosus: From Molecular Mechanisms to Therapies)

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11 pages, 1485 KiB

Open AccessEditor’s ChoiceArticle

Luteinizing Hormone Surge-Induced Krüppel-like Factor 4 Inhibits Cyp17A1 Expression in Preovulatory Granulosa Cells

by Yuri Choi, Okto Lee, Kiyoung Ryu and Jaesook Roh

Biomedicines 2024, 12(1), 71; https://doi.org/10.3390/biomedicines12010071 - 27 Dec 2023

Viewed by 1144

Abstract

Previous in vivo and in vitro studies have demonstrated a dramatic up-regulation of Krüppel-like factor 4 (Klf4) in rat preovulatory granulosa cells (GCs) after LH/hCG treatment and its role in regulating Cyp19A1 expression during the luteal shift in steroidogenesis. In this [...] Read more.

Previous in vivo and in vitro studies have demonstrated a dramatic up-regulation of Krüppel-like factor 4 (Klf4) in rat preovulatory granulosa cells (GCs) after LH/hCG treatment and its role in regulating Cyp19A1 expression during the luteal shift in steroidogenesis. In this study, we examined whether Klf4 also mediates the LH-induced repression of Cyp17A1 expression in primary rat preovulatory GCs. In response to LH treatment of GCs in vitro, Cyp17A1 expression declined to less than half of its initial value by 1 h, remaining low for 24 h of culture. Overexpression of Klf4 decreased basal and Sf1-induced Cyp17A1 expressions and increased progesterone secretion. Reduction of endogenous Klf4 by siRNA elevated basal Cyp17A1 expression but did not affect LH-stimulated progesterone production. Overexpression of Klf4 also significantly attenuated Sf1-induced Cyp17A1 promoter activity. On the other hand, mutation of the conserved Sp1/Klf binding motif in the promoter revealed that this motif is not required for Klf4-mediated repression. Taken together, these data indicate that the Cyp17A1 gene may be one of the downstream targets of Klf4, which is induced by LH in preovulatory GCs. This information may help in identifying potential targets for preventing the molecular changes occurring in hyperandrogenic disorders. Full article

(This article belongs to the Special Issue Reproductive Medicine: Focus on Cell and Molecule 2.0)

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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 5 | Viewed by 2387

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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23 pages, 1237 KiB

Open AccessEditor’s ChoiceReview

Rodent Models of Huntington’s Disease: An Overview

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

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

Cited by 2 | Viewed by 1978

Abstract

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

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

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

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32 pages, 405 KiB

Open AccessEditor’s ChoiceReview

Neuromodulation for Craniofacial Pain and Headaches

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

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

Cited by 1 | Viewed by 1429

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)

11 pages, 1208 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 2 | Viewed by 1590

Abstract

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

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

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

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22 pages, 1338 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 1 | Viewed by 2869

Abstract

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

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

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

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18 pages, 1700 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 1 | Viewed by 1529

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, 5016 KiB

Open AccessEditor’s ChoiceArticle

The Na/K-ATPase α1/Src Signaling Axis Regulates Mitochondrial Metabolic Function and Redox Signaling in Human iPSC-Derived Cardiomyocytes

by Liquan Cai, Marco T. Pessoa, Yingnyu Gao, Sidney Strause, Moumita Banerjee, Jiang Tian, Zijian Xie and Sandrine V. Pierre

Biomedicines 2023, 11(12), 3207; https://doi.org/10.3390/biomedicines11123207 - 2 Dec 2023

Viewed by 1696

Abstract

Na/K-ATPase (NKA)-mediated regulation of Src kinase, which involves defined amino acid sequences of the NKA α1 polypeptide, has emerged as a novel regulatory mechanism of mitochondrial function in metazoans. Mitochondrial metabolism ensures adequate myocardial performance and adaptation to physiological demand. It is also [...] Read more.

Na/K-ATPase (NKA)-mediated regulation of Src kinase, which involves defined amino acid sequences of the NKA α1 polypeptide, has emerged as a novel regulatory mechanism of mitochondrial function in metazoans. Mitochondrial metabolism ensures adequate myocardial performance and adaptation to physiological demand. It is also a critical cellular determinant of cardiac repair and remodeling. To assess the impact of the proposed NKA/Src regulatory axis on cardiac mitochondrial metabolic function, we used a gene targeting approach in human cardiac myocytes. Human induced pluripotent stem cells (hiPSC) expressing an Src-signaling null mutant (A420P) form of the NKA α1 polypeptide were generated using CRISPR/Cas9-mediated genome editing. Total cellular Na/K-ATPase activity remained unchanged in A420P compared to the wild type (WT) hiPSC, but baseline phosphorylation levels of Src and ERK1/2 were drastically reduced. Both WT and A420P mutant hiPSC readily differentiated into cardiac myocytes (iCM), as evidenced by marker gene expression, spontaneous cell contraction, and subcellular striations. Total NKA α1-3 protein expression was comparable in WT and A420P iCM. However, live cell metabolism assessed functionally by Seahorse extracellular flux analysis revealed significant reductions in both basal and maximal rates of mitochondrial respiration, spare respiratory capacity, ATP production, and coupling efficiency. A significant reduction in ROS production was detected by fluorescence imaging in live cells, and confirmed by decreased cellular protein carbonylation levels in A420P iCM. Taken together, these data provide genetic evidence for a role of NKA α1/Src in the tonic stimulation of basal mitochondrial metabolism and ROS production in human cardiac myocytes. This signaling axis in cardiac myocytes may provide a new approach to counteract mitochondrial dysfunction in cardiometabolic diseases. Full article

(This article belongs to the Special Issue The Role of Na,K-ATPase in Human Health: From Structure to Function)

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10 pages, 1777 KiB

Open AccessEditor’s ChoiceArticle

Application of a Receptor-Binding-Domain-Based Simple Immunoassay for Assessing Humoral Immunity against Emerging SARS-CoV-2 Virus Variants

by Orsolya Mózner, Judit Moldvay, Kata Sára Szabó, Dorottya Vaskó, Júlia Domján, Dorottya Ács, Zoltán Ligeti, Csaba Fehér, Edit Hirsch, László Puskás, Cordula Stahl, Manfred Frey and Balázs Sarkadi

Biomedicines 2023, 11(12), 3193; https://doi.org/10.3390/biomedicines11123193 - 1 Dec 2023

Cited by 1 | Viewed by 1556

Abstract

We have developed a simple, rapid, high-throughput RBD-based ELISA to assess the humoral immunity against emerging SARS-CoV-2 virus variants. The cDNAs of the His-tagged RBD proteins of the virus variants were stably engineered into HEK cells secreting the protein into the supernatant, and [...] Read more.

We have developed a simple, rapid, high-throughput RBD-based ELISA to assess the humoral immunity against emerging SARS-CoV-2 virus variants. The cDNAs of the His-tagged RBD proteins of the virus variants were stably engineered into HEK cells secreting the protein into the supernatant, and RBD purification was performed by Ni-chromatography and buffer exchange by membrane filtration. The simplified assay uses single dilutions of sera from finger-pricked native blood samples, purified RBD in 96-well plates, and a chromogenic dye for development. The results of this RBD-ELISA were confirmed to correlate with those of a commercial immunoassay measuring antibodies against the Wuhan strain, as well as direct virus neutralization assays assessing the cellular effects of the Wuhan and the Omicron (BA.5) variants. Here, we document the applicability of this ELISA to assess the variant-specific humoral immunity in vaccinated and convalescent patients, as well as to follow the time course of selective vaccination response. This simple and rapid assay, easily modified to detect humoral immunity against emerging SARS-CoV-2 virus variants, may help to assess the level of antiviral protection after vaccination or infection. Full article

(This article belongs to the Special Issue The End of the COVID-19 Pandemic—What Is Currently Known and What Could Have Been Useful Four Years Ago?)

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17 pages, 398 KiB

Open AccessEditor’s ChoiceReview

Review of Piezoelectrical Materials Potentially Useful for Peripheral Nerve Repair

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

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

Cited by 6 | Viewed by 2042

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)

11 pages, 553 KiB

Open AccessEditor’s ChoiceReview

MRI Methods to Visualize and Quantify Adipose Tissue in Health and Disease

by Katerina Nikiforaki and Kostas Marias

Biomedicines 2023, 11(12), 3179; https://doi.org/10.3390/biomedicines11123179 - 29 Nov 2023

Viewed by 1223

Abstract

MRI is the modality of choice for a vast range of pathologies but also a sensitive probe into human physiology and tissue function. For this reason, several methodologies have been developed and continuously evolve in order to non-invasively monitor underlying phenomena in human [...] Read more.

MRI is the modality of choice for a vast range of pathologies but also a sensitive probe into human physiology and tissue function. For this reason, several methodologies have been developed and continuously evolve in order to non-invasively monitor underlying phenomena in human adipose tissue that were difficult to assess in the past through visual inspection of standard imaging modalities. To this end, this work describes the imaging methodologies used in medical practice and lists the most important quantitative markers related to adipose tissue physiology and pathology that are currently supporting diagnosis, longitudinal evaluation and patient management decisions. The underlying physical principles and the resulting markers are presented and associated with frequently encountered pathologies in radiology in order to set the frame of the ability of MRI to reveal the complex role of adipose tissue, not as an inert tissue but as an active endocrine organ. Full article

(This article belongs to the Special Issue Adipose Tissue in Health and Diseases)

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24 pages, 1541 KiB

Open AccessEditor’s ChoiceSystematic Review

Enteroscopy versus Video Capsule Endoscopy for Automatic Diagnosis of Small Bowel Disorders—A Comparative Analysis of Artificial Intelligence Applications

by Stefan Lucian Popa, Bogdan Stancu, Abdulrahman Ismaiel, Daria Claudia Turtoi, Vlad Dumitru Brata, Traian Adrian Duse, Roxana Bolchis, Alexandru Marius Padureanu, Miruna Oana Dita, Atamyrat Bashimov, Victor Incze, Edoardo Pinna, Simona Grad, Andrei-Vasile Pop, Dinu Iuliu Dumitrascu, Mihai Alexandru Munteanu, Teodora Surdea-Blaga and Florin Vasile Mihaileanu

Biomedicines 2023, 11(11), 2991; https://doi.org/10.3390/biomedicines11112991 - 7 Nov 2023

Viewed by 1322

Abstract

Background: Small bowel disorders present a diagnostic challenge due to the limited accessibility of the small intestine. Accurate diagnosis is made with the aid of specific procedures, like capsule endoscopy or double-ballon enteroscopy, but they are not usually solicited and not widely accessible. [...] Read more.

Background: Small bowel disorders present a diagnostic challenge due to the limited accessibility of the small intestine. Accurate diagnosis is made with the aid of specific procedures, like capsule endoscopy or double-ballon enteroscopy, but they are not usually solicited and not widely accessible. This study aims to assess and compare the diagnostic effectiveness of enteroscopy and video capsule endoscopy (VCE) when combined with artificial intelligence (AI) algorithms for the automatic detection of small bowel diseases. Materials and methods: We performed an extensive literature search for relevant studies about AI applications capable of identifying small bowel disorders using enteroscopy and VCE, published between 2012 and 2023, employing PubMed, Cochrane Library, Google Scholar, Embase, Scopus, and ClinicalTrials.gov databases. Results: Our investigation discovered a total of 27 publications, out of which 21 studies assessed the application of VCE, while the remaining 6 articles analyzed the enteroscopy procedure. The included studies portrayed that both investigations, enhanced by AI, exhibited a high level of diagnostic accuracy. Enteroscopy demonstrated superior diagnostic capability, providing precise identification of small bowel pathologies with the added advantage of enabling immediate therapeutic intervention. The choice between these modalities should be guided by clinical context, patient preference, and resource availability. Studies with larger sample sizes and prospective designs are warranted to validate these results and optimize the integration of AI in small bowel diagnostics. Conclusions: The current analysis demonstrates that both enteroscopy and VCE with AI augmentation exhibit comparable diagnostic performance for the automatic detection of small bowel disorders. Full article

(This article belongs to the Special Issue New Technologies in Digestive Endoscopy)

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15 pages, 2120 KiB

Open AccessEditor’s ChoiceArticle

Whole Genome Expression Profiling of Semitendinosus Tendons from Children with Diplegic and Tetraplegic Cerebral Palsy

by Simona Nemska, Simone Serio, Veronica Larcher, Giulia Beltrame, Nicola Marcello Portinaro and Marie-Louise Bang

Biomedicines 2023, 11(11), 2918; https://doi.org/10.3390/biomedicines11112918 - 28 Oct 2023

Cited by 3 | Viewed by 1217

Abstract

Cerebral palsy (CP) is the most common movement disorder in children, with a prevalence ranging from 1.5 to 4 per 1000 live births. CP is caused by a non-progressive lesion of the developing brain, leading to progressive alterations of the musculoskeletal system, including [...] Read more.

Cerebral palsy (CP) is the most common movement disorder in children, with a prevalence ranging from 1.5 to 4 per 1000 live births. CP is caused by a non-progressive lesion of the developing brain, leading to progressive alterations of the musculoskeletal system, including spasticity, often leading to the development of fixed contractures, necessitating tendon lengthening surgery. Total RNA-sequencing analysis was performed on semitendinosus tendons from diplegic and tetraplegic CP patients subjected to tendon lengthening surgery compared to control patients undergoing anterior cruciate ligament reconstructive surgery. Tetraplegic CP patients showed increased expression of genes implicated in collagen synthesis and extracellular matrix (ECM) turnover, while only minor changes were observed in diplegic CP patients. In addition, tendons from tetraplegic CP patients showed an enrichment for upregulated genes involved in vesicle-mediated transport and downregulated genes involved in cytokine and apoptotic signaling. Overall, our results indicate increased ECM turnover with increased net synthesis of collagen in tetraplegic CP patients without activation of inflammatory and apoptotic pathways, similar to observations in athletes where ECM remodeling results in increased tendon stiffness and tensile strength. Nevertheless, the resulting increased tendon stiffness is an important issue in clinical practice, where surgery is often required to restore joint mobility. Full article

(This article belongs to the Special Issue From Pathophysiology to Novel Therapeutic Approaches in Musculoskeletal System 2.0)

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14 pages, 3822 KiB

Open AccessEditor’s ChoiceArticle

Role of Pericytes in Cardiomyopathy-Associated Myocardial Infarction Revealed by Multiple Single-Cell Sequencing Analysis

by Yanqiao Lu, Huanhuan Huo, Feng Liang, Jieyuan Xue, Liang Fang, Yutong Miao, Lan Shen and Ben He

Biomedicines 2023, 11(11), 2896; https://doi.org/10.3390/biomedicines11112896 - 26 Oct 2023

Viewed by 1523

Abstract

Acute myocardial infarction (AMI) is one of the leading causes of cardiovascular death worldwide. AMI with cardiomyopathy is accompanied by a poor long-term prognosis. However, limited studies have focused on the mechanism of cardiomyopathy associated with AMI. Pericytes are important to the microvascular [...] Read more.

Acute myocardial infarction (AMI) is one of the leading causes of cardiovascular death worldwide. AMI with cardiomyopathy is accompanied by a poor long-term prognosis. However, limited studies have focused on the mechanism of cardiomyopathy associated with AMI. Pericytes are important to the microvascular function in the heart, yet little attention has been paid to their function in myocardial infarction until now. In this study, we integrated single-cell data from individuals with cardiomyopathy and myocardial infarction (MI) GWAS data to reveal the potential function of pericytes in cardiomyopathy-associated MI. We found that pericytes were concentrated in the left atrium and left ventricle tissues. DLC1/GUCY1A2/EGFLAM were the top three uniquely expressed genes in pericytes (p < 0.05). The marker genes of pericytes were enriched in renin secretion, vascular smooth muscle contraction, gap junction, purine metabolism, and diabetic cardiomyopathy pathways (p < 0.05). Among these pathways, the renin secretion and purine metabolism pathways were also found in the process of MI. In cardiomyopathy patients, the biosynthesis of collagen, modulating enzymes, and collagen formation were uniquely negatively regulated in pericytes compared to other cell types (p < 0.05). COL4A2/COL4A1/SMAD3 were the hub genes in pericyte function involved in cardiomyopathy and AMI. In conclusion, this study provides new evidence about the importance of pericytes in the pathogenesis of cardiomyopathy-associated MI. DLC1/GUCY1A2/EGFLAM were highly expressed in pericytes. The hub genes COL4A2/COL4A1/SMAD3 may be potential research targets for cardiomyopathy-associated MI. Full article

(This article belongs to the Special Issue Acute and Chronic Heart Failure: Pathophysiology and New Therapeutic Developments)

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15 pages, 1939 KiB

Open AccessEditor’s ChoiceArticle

Stratification of Amniotic Fluid Cells and Amniotic Fluid by Sex Opens Up New Perspectives on Fetal Health

by Ilaria Campesi, Giampiero Capobianco, Antonella Cano, Valeria Lodde, Sara Cruciani, Margherita Maioli, Giovanni Sotgiu, Maria Laura Idda, Mariangela Valentina Puci, Margherita Ruoppolo, Michele Costanzo, Marianna Caterino, Francesca Cambosu, Andrea Montella and Flavia Franconi

Biomedicines 2023, 11(10), 2830; https://doi.org/10.3390/biomedicines11102830 - 18 Oct 2023

Cited by 2 | Viewed by 1541

Abstract

Amniotic fluid is essential for fetus wellbeing and is used to monitor pregnancy and predict fetal outcomes. Sex affects health and medicine from the beginning of life, but knowledge of its influence on cell-depleted amniotic fluid (AF) and amniotic fluid cells (AFCs) is [...] Read more.

Amniotic fluid is essential for fetus wellbeing and is used to monitor pregnancy and predict fetal outcomes. Sex affects health and medicine from the beginning of life, but knowledge of its influence on cell-depleted amniotic fluid (AF) and amniotic fluid cells (AFCs) is still neglected. We evaluated sex-related differences in AF and in AFCs to extend personalized medicine to prenatal life. AFCs and AF were obtained from healthy Caucasian pregnant women who underwent amniocentesis at the 16th–18th week of gestation for advanced maternal age. In the AF, inflammation biomarkers (TNFα, IL6, IL8, and IL4), malondialdehyde, nitrites, amino acids, and acylcarnitines were measured. Estrogen receptors and cell fate (autophagy, apoptosis, senescence) were measured in AFCs. TNFα, IL8, and IL4 were higher in female AF, whereas IL6, nitrites, and MDA were similar. Valine was higher in male AF, whereas several acylcarnitines were sexually different, suggesting a mitochondrial involvement in establishing sex differences. Female AFCs displayed higher expression of ERα protein and a higher ERα/ERβ ratio. The ratio of LC3II/I, an index of autophagy, was higher in female AFCs, while LC3 gene was similar in both sexes. No significant sex differences were found in the expression of the lysosomal protein LAMP1, while p62 was higher in male AFCs. LAMP1 gene was upregulated in male AFCs, while p62 gene was upregulated in female ones. Finally, caspase 9 activity and senescence linked to telomeres were higher in female AFCs, while caspase 3 and β-galactosidase activities were similar. This study supports the idea that sex differences start very early in prenatal life and influence specific parameters, suggesting that it may be relevant to appreciate sex differences to cover knowledge gaps. This might lead to improving the diagnosis of risk prediction for pregnancy complications and achieving a more satisfactory monitoring of fetus health, even preventing future diseases in adulthood. Full article

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

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12 pages, 1910 KiB

Open AccessEditor’s ChoiceArticle

Identifying Potent Nonsense-Mediated mRNA Decay Inhibitors with a Novel Screening System

by Julie Carrard, Fiona Ratajczak, Joséphine Elsens, Catherine Leroy, Rebekah Kong, Lucie Geoffroy, Arnaud Comte, Guy Fournet, Benoît Joseph, Xiubin Li, Sylvie Moebs-Sanchez and Fabrice Lejeune

Biomedicines 2023, 11(10), 2801; https://doi.org/10.3390/biomedicines11102801 - 16 Oct 2023

Viewed by 1950

Abstract

Nonsense-mediated mRNA decay (NMD) is a quality control mechanism that degrades mRNAs carrying a premature termination codon. Its inhibition, alone or in combination with other approaches, could be exploited to develop therapies for genetic diseases caused by a nonsense mutation. This, however, requires [...] Read more.

Nonsense-mediated mRNA decay (NMD) is a quality control mechanism that degrades mRNAs carrying a premature termination codon. Its inhibition, alone or in combination with other approaches, could be exploited to develop therapies for genetic diseases caused by a nonsense mutation. This, however, requires molecules capable of inhibiting NMD effectively without inducing toxicity. We have built a new screening system and used it to identify and validate two new molecules that can inhibit NMD at least as effectively as cycloheximide, a reference NMD inhibitor molecule. These new NMD inhibitors show no cellular toxicity at tested concentrations and have a working concentration between 6.2 and 12.5 µM. We have further validated this NMD-inhibiting property in a physiopathological model of lung cancer in which the TP53 gene carries a nonsense mutation. These new molecules may potentially be of interest in the development of therapies for genetic diseases caused by a nonsense mutation. Full article

(This article belongs to the Special Issue Nonsense-Mediated mRNA Decay: From Molecular Mechanism to Therapeutic Perspectives 2.0)

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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 13 | Viewed by 2833

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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13 pages, 2614 KiB

Open AccessEditor’s ChoiceArticle

Transcriptional Activity of Metalloproteinase 9 (MMP-9) and Tissue Metalloproteinase 1 (TIMP-1) Genes as a Diagnostic and Prognostic Marker of Heart Failure Due to Ischemic Heart Disease

by Dariusz Korzeń, Oskar Sierka and Józefa Dąbek

Biomedicines 2023, 11(10), 2776; https://doi.org/10.3390/biomedicines11102776 - 13 Oct 2023

Cited by 5 | Viewed by 979

Abstract

The most common cause of heart failure (HF) is coronary artery disease (CAD). The aim of this study was to evaluate the transcriptional activity of the metalloproteinase 9 (MMP-9) and tissue metalloproteinase inhibitor 1 (TIMP-1) genes in a study [...] Read more.

The most common cause of heart failure (HF) is coronary artery disease (CAD). The aim of this study was to evaluate the transcriptional activity of the metalloproteinase 9 (MMP-9) and tissue metalloproteinase inhibitor 1 (TIMP-1) genes in a study group of patients with HF due to CAD and in the control group, as well as assess the transcriptional activity of the examined genes, taking into account the number of affected coronary arteries and the severity of heart failure. The study group consisted of a total of 150 (100%) patients. The material for the study was peripheral blood, and molecular tests were performed using the quantitative QRT-PCR technique. The transcriptional activity of the MMP-9 gene was significantly higher in the group of patients with CAD and HF. It was also significantly higher with the progression of heart failure. TIMP-1 gene transcriptional activity was significantly lower with the advancement of heart failure. The transcriptional activity of the MMP-9 and TIMP-1 genes differentiated the examined patients. The severity of HF, and a significant increase in the QRT-PCR transcriptional activity of the MMP-9 gene with a simultaneous decrease in the activity of the TIMP-1 gene, makes them useful diagnostic and prognostic markers in clinical practice. Full article

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

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16 pages, 2169 KiB

Open AccessEditor’s ChoiceArticle

Metabolic Fingerprinting for the Diagnosis of Clinically Similar Long COVID and Fibromyalgia Using a Portable FT-MIR Spectroscopic Combined with Chemometrics

by Kevin V. Hackshaw, Siyu Yao, Haona Bao, Silvia de Lamo Castellvi, Rija Aziz, Shreya Madhav Nuguri, Lianbo Yu, Michelle M. Osuna-Diaz, W. Michael Brode, Katherine R. Sebastian, M. Monica Giusti and Luis Rodriguez-Saona

Biomedicines 2023, 11(10), 2704; https://doi.org/10.3390/biomedicines11102704 - 5 Oct 2023

Cited by 4 | Viewed by 3351

Abstract

Post Acute Sequelae of SARS-CoV-2 infection (PASC or Long COVID) is characterized by lingering symptomatology post-initial COVID-19 illness that is often debilitating. It is seen in up to 30–40% of individuals post-infection. Patients with Long COVID (LC) suffer from dysautonomia, malaise, fatigue, and [...] Read more.

Post Acute Sequelae of SARS-CoV-2 infection (PASC or Long COVID) is characterized by lingering symptomatology post-initial COVID-19 illness that is often debilitating. It is seen in up to 30–40% of individuals post-infection. Patients with Long COVID (LC) suffer from dysautonomia, malaise, fatigue, and pain, amongst a multitude of other symptoms. Fibromyalgia (FM) is a chronic musculoskeletal pain disorder that often leads to functional disability and severe impairment of quality of life. LC and FM share several clinical features, including pain that often makes them indistinguishable. The aim of this study is to develop a metabolic fingerprinting approach using portable Fourier-transform mid-infrared (FT-MIR) spectroscopic techniques to diagnose clinically similar LC and FM. Blood samples were obtained from LC (n = 50) and FM (n = 50) patients and stored on conventional bloodspot protein saver cards. A semi-permeable membrane filtration approach was used to extract the blood samples, and spectral data were collected using a portable FT-MIR spectrometer. Through the deconvolution analysis of the spectral data, a distinct spectral marker at 1565 cm⁻¹ was identified based on a statistically significant analysis, only present in FM patients. This IR band has been linked to the presence of side chains of glutamate. An OPLS-DA algorithm created using the spectral region 1500 to 1700 cm⁻¹ enabled the classification of the spectra into their corresponding classes (Rcv > 0.96) with 100% accuracy and specificity. This high-throughput approach allows unique metabolic signatures associated with LC and FM to be identified, allowing these conditions to be distinguished and implemented for in-clinic diagnostics, which is crucial to guide future therapeutic approaches. Full article

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

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17 pages, 3227 KiB

Open AccessEditor’s ChoiceArticle

Cannabidiol Modulates M-Type K⁺ and Hyperpolarization-Activated Cation Currents

by Yen-Chin Liu, Edmund Cheung So and Sheng-Nan Wu

Biomedicines 2023, 11(10), 2651; https://doi.org/10.3390/biomedicines11102651 - 27 Sep 2023

Cited by 3 | Viewed by 1046

Abstract

Cannabidiol (CBD) is a naturally occurring compound found in the Cannabis plant that is known for its potential therapeutic effects. However, its impact on membrane ionic currents remains a topic of debate. This study aimed to investigate how CBD modifies various types of [...] Read more.

Cannabidiol (CBD) is a naturally occurring compound found in the Cannabis plant that is known for its potential therapeutic effects. However, its impact on membrane ionic currents remains a topic of debate. This study aimed to investigate how CBD modifies various types of ionic currents in pituitary GH₃ cells. Results showed that exposure to CBD led to a concentration-dependent decrease in M-type K⁺ currents (I_K(M)), with an IC₅₀ of 3.6 μM, and caused the quasi-steady-state activation curve of the current to shift to a more depolarized potential with no changes in the curve’s steepness. The CBD-mediated block of I_K(M) was not reversed by naloxone, suggesting that it was not mediated by opioid receptors. The I_K(M) elicited by pulse-train stimulation was also decreased upon exposure to CBD. The magnitude of erg-mediated K⁺ currents was slightly reduced by adding CBD (10 μM), while the density of voltage-gated Na⁺ currents elicited by a short depolarizing pulse was not affected by it. Additionally, CBD decreased the magnitude of hyperpolarization-activated cation currents (I_h) with an IC₅₀ of 3.3 μM, and the decrease was reversed by oxaliplatin. The quasi-steady-state activation curve of I_h was shifted in the leftward direction with no changes in the slope factor of the curve. CBD also diminished the strength of voltage-dependent hysteresis on I_h elicited by upright isosceles-triangular ramp voltage. Collectively, these findings suggest that CBD’s modification of ionic currents presented herein is independent of cannabinoid or opioid receptors and may exert a significant impact on the functional activities of excitable cells occurring in vitro or in vivo. Full article

(This article belongs to the Special Issue Actions of Small Molecules on Varying Type of Membrane Ion Channels 2.0)

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15 pages, 1919 KiB

Open AccessEditor’s ChoiceArticle

Effect of Probiotic Therapy on Neuropsychiatric Manifestations in Children with Multiple Neurotransmitter Disorders: A Study

by Loredana Matiș, Bogdana Ariana Alexandru, Radu Fodor, Lucia Georgeta Daina, Timea Claudia Ghitea and Silviu Vlad

Biomedicines 2023, 11(10), 2643; https://doi.org/10.3390/biomedicines11102643 - 26 Sep 2023

Cited by 3 | Viewed by 1229

Abstract

Probiotics, also known as psychobiotics, have been linked to cognitive functions, memory, learning, and behavior, in addition to their positive effects on the digestive tract. The purpose of this study is to examine the psychoemotional effects and cognitive functioning in children with gastrointestinal [...] Read more.

Probiotics, also known as psychobiotics, have been linked to cognitive functions, memory, learning, and behavior, in addition to their positive effects on the digestive tract. The purpose of this study is to examine the psychoemotional effects and cognitive functioning in children with gastrointestinal disorders who undergo psychobiotherapy. A total of 135 participants, aged 5–18 years, were divided into three groups based on the pediatrician’s diagnosis: Group I (Control) consisted of 37 patients (27.4%), Group II included 65 patients (48.1%) with psychoanxiety disorders, and Group III comprised 33 individuals (24.4%) with psychiatric disorders. The study monitored neurotransmitter levels such as serotonin, GABA, glutamate, cortisol, and DHEA, as well as neuropsychiatric symptoms including headaches, fatigue, mood swings, hyperactivity, aggressiveness, sleep disorders, and lack of concentration in patients who had gastrointestinal issues such as constipation, diarrhea, and other gastrointestinal problems. The results indicate that psychobiotics have a significant impact on reducing hyperactivity and aggression, and improving concentration. While further extensive studies are needed, these findings offer promising insights into the complexity of a child’s neuropsychic behavior and the potential for balancing certain behaviors through psychobiotics. Full article

(This article belongs to the Special Issue State-of-the-Art and Novel Approaches in Molecular and Translational Medicine in Europe)

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10 pages, 539 KiB

Open AccessEditor’s ChoiceArticle

Cerebrospinal Fluid Metabolomics Identified Ongoing Analgesic Medication in Neuropathic Pain Patients

by Emmanuel Bäckryd, Katarina Thordeman, Björn Gerdle and Bijar Ghafouri

Biomedicines 2023, 11(9), 2525; https://doi.org/10.3390/biomedicines11092525 - 13 Sep 2023

Viewed by 1160

Abstract

Background: Cerebrospinal fluid (CSF) can reasonably be hypothesized to mirror central nervous system pathophysiology in chronic pain conditions. Metabolites are small organic molecules with a low molecular weight. They are the downstream products of genes, transcripts and enzyme functions, and their levels can [...] Read more.

Background: Cerebrospinal fluid (CSF) can reasonably be hypothesized to mirror central nervous system pathophysiology in chronic pain conditions. Metabolites are small organic molecules with a low molecular weight. They are the downstream products of genes, transcripts and enzyme functions, and their levels can mirror diseased metabolic pathways. The aim of this metabolomic study was to compare the CSF of patients with chronic neuropathic pain (n = 16) to healthy controls (n = 12). Methods: Nuclear magnetic resonance spectroscopy was used for analysis of the CSF metabolome. Multivariate data analysis by projection discriminant analysis (OPLS-DA) was used to separate information from noise and minimize the multiple testing problem. Results: The significant OPLS-DA model identified 26 features out of 215 as important for group separation (R² = 0.70, Q² = 0.42, p = 0.017 by CV-ANOVA; 2 components). Twenty-one out of twenty-six features were statistically significant when comparing the two groups by univariate statistics and remained significant at a false discovery rate of 10%. For six out of the top ten metabolite features, the features were absent in all healthy controls. However, these features were related to medication, mainly acetaminophen (=paracetamol), and not to pathophysiological processes. Conclusion: CSF metabolomics was a sensitive method to detect ongoing analgesic medication, especially acetaminophen. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Biomarkers in Pain)

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52 pages, 2123 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 25 | Viewed by 7256

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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13 pages, 2420 KiB

Open AccessEditor’s ChoiceArticle

Ghrelin Amplifies the Nicotine-Induced Release of Dopamine in the Bed Nucleus of Stria Terminalis (BNST)

by Jázmin Ayman, Miklós Palotai, Roberta Dochnal and Zsolt Bagosi

Biomedicines 2023, 11(9), 2456; https://doi.org/10.3390/biomedicines11092456 - 4 Sep 2023

Cited by 1 | Viewed by 2203

Abstract

Ghrelin is an orexigenic neuropeptide that is known for stimulating the release of growth hormone (GH) and appetite. In addition, ghrelin has been implicated in addiction to drugs such as nicotine. Nicotine is the principal psychoactive component in tobacco and is responsible for [...] Read more.

Ghrelin is an orexigenic neuropeptide that is known for stimulating the release of growth hormone (GH) and appetite. In addition, ghrelin has been implicated in addiction to drugs such as nicotine. Nicotine is the principal psychoactive component in tobacco and is responsible for the reward sensation produced by smoking. In our previous in vitro superfusion studies, it was demonstrated that ghrelin and nicotine stimulate equally the dopamine release in the rat amygdala, and ghrelin amplifies the nicotine-induced dopamine release in the rat striatum. However, less attention was paid to the actions of ghrelin and nicotine in the bed nucleus of the stria terminalis (BNST). Therefore, in the present study, nicotine and ghrelin were superfused to the BNST of male Wistar rats, and the dopamine release from the BNST was measured in vitro. In order to determine which receptors mediate these effects, mecamylamine, a non-selective nicotinic acetylcholine receptor (nAchR) antagonist, and GHRP-6, a selective growth hormone secretagogue receptor (GHS-R1A) antagonist, were also superfused to the rat BNST. Nicotine significantly increased the release of dopamine, and this effect was significantly inhibited by mecamylamine. Ghrelin increased dopamine release even more significantly than nicotine did, and this effect was significantly inhibited by GHRP-6. Moreover, when administered together, ghrelin significantly amplified the nicotine-induced release of dopamine in the BNST, and this additive effect was reversed partly by mecamylamine and partly by GHRP-6. Therefore, the present study provides a new base of evidence for the involvement of ghrelin in dopamine signaling implicated in nicotine addiction. Full article

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

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18 pages, 488 KiB

Open AccessEditor’s ChoiceArticle

Is the Development of Ascites in Alcoholic Liver Patients Influenced by Specific KIR/HLA Gene Profiles?

by Isabel Legaz, Raquel Morales, José Miguel Bolarín, Aurelia Collados-Ros, José Antonio Pons and Manuel Muro

Biomedicines 2023, 11(9), 2405; https://doi.org/10.3390/biomedicines11092405 - 28 Aug 2023

Viewed by 1452

Abstract

Decompensated cirrhosis is the most common cause of ascites due to hemodynamic and renal alteration by continuous fluid leakage from the hepatic sinusoids and splanchnic capillaries into the interstitial space. Then, fluid leakage exceeds lymphatic return, leading to progressive fluid accumulation directly into [...] Read more.

Decompensated cirrhosis is the most common cause of ascites due to hemodynamic and renal alteration by continuous fluid leakage from the hepatic sinusoids and splanchnic capillaries into the interstitial space. Then, fluid leakage exceeds lymphatic return, leading to progressive fluid accumulation directly into the peritoneal cavity. Alcohol consumption is one of the main risks of developing alcoholic cirrhosis (AC), but not all AC patients develop ascites. Avoiding the development of ascites is crucial, given that it deteriorates prognosis and increases the patient mortality patient. The innate immune system plays a crucial role in cirrhosis through natural killer cells, which are abundant in the liver. The aim of this study was to analyze the KIR/HLA-C genetic profile in AC patients with and without ascites to understand this pathology and find predictive clinical susceptibility biomarkers that can help to establish risks and prevent the development of ascites in AC patients. A total of 281 AC patients with and without ascites were analyzed and compared with 319 healthy controls. Genomic DNA was extracted from peripheral blood in all groups. A PCR-SSO assay was performed for KIR/HLA genotyping analysis. A total of 16 activating and inhibitor KIR genes and their corresponding known ligands, epitopes of HLA-C, and their genotypes were analyzed. According to our analysis, C1 epitopes were statistically significantly decreased in AC patients with and without ascites. When comparing AC patients with ascites and healthy controls, a significant decrease in C1 epitope frequency was also observed. A statistically significant decrease was also found when comparing the C1C2 genotype in AC patients without ascites with controls. In conclusion, the absence of KIR2DL2 and KIR3DL1 genes may be a predisposing factor for the development of ascites in AC patients. The KIR2DS2/KIR2DL2 may could be involved in grade I ascites development, and the presence of the C1+ epitope and the homozygous C2C2 genotype may be protective genetic factors against ascites development in AC patients. Full article

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

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10 pages, 2339 KiB

Open AccessEditor’s ChoiceArticle

Clot Retraction and Its Correlation with the Function of Platelet Integrin α_IIbβ₃

by Daniel Gao, Caroline W. Sun, Angela B. Woodley and Jing-fei Dong

Biomedicines 2023, 11(9), 2345; https://doi.org/10.3390/biomedicines11092345 - 23 Aug 2023

Cited by 2 | Viewed by 1977

Abstract

Clot retraction results from retractions of platelet filopodia and fibrin fibers and requires the functional platelet α_IIbβ₃ integrin. This assay is widely used to test the functions of platelets and fibrinogen as well as the efficacy of fibrinolysis. Changes in [...] Read more.

Clot retraction results from retractions of platelet filopodia and fibrin fibers and requires the functional platelet α_IIbβ₃ integrin. This assay is widely used to test the functions of platelets and fibrinogen as well as the efficacy of fibrinolysis. Changes in clot retraction have been found in a variety of hemostatic abnormalities and, more recently, in arterial thrombosis. Despite its broad clinical use and low cost, many aspects of clot retraction are poorly understood. In the present study, we performed two clinical standard clot retraction assays using whole-blood and platelet-rich plasma (PRP) samples to determine how clot retraction correlates with platelet counts and mean volume, the density of α_IIbβ₃ integrin and PLA genotypes, and plasma fibrinogen levels. We found that clot retraction was affected by platelet counts, but not mean platelet volume. It correlated with the surface density of the integrin α_Iibβ₃, but not PLA genotypes. These results indicate that clot retraction measures a unique aspect of platelet function and can serve as an additional means to detect functional changes in platelets. Full article

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

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26 pages, 4055 KiB

Open AccessEditor’s ChoiceArticle

Drug-Delivery Silver Nanoparticles: A New Perspective for Phenindione as an Anticoagulant

by Stoyanka Nikolova, Miglena Milusheva, Vera Gledacheva, Mehran Feizi-Dehnayebi, Lidia Kaynarova, Deyana Georgieva, Vassil Delchev, Iliyana Stefanova, Yulian Tumbarski, Rositsa Mihaylova, Emiliya Cherneva, Snezhana Stoencheva and Mina Todorova

Biomedicines 2023, 11(8), 2201; https://doi.org/10.3390/biomedicines11082201 - 4 Aug 2023

Cited by 22 | Viewed by 2648

Abstract

Anticoagulants prevent the blood from developing the coagulation process, which is the primary cause of death in thromboembolic illnesses. Phenindione (PID) is a well-known anticoagulant that is rarely employed because it totally prevents coagulation, which can be a life-threatening complication. The goal of [...] Read more.

Anticoagulants prevent the blood from developing the coagulation process, which is the primary cause of death in thromboembolic illnesses. Phenindione (PID) is a well-known anticoagulant that is rarely employed because it totally prevents coagulation, which can be a life-threatening complication. The goal of the current study is to synthesize drug-loaded Ag NPs to slow down the coagulation process. Methods: A rapid synthesis and stabilization of silver nanoparticles as drug-delivery systems for phenindione (PID) were applied for the first time. Results: Several methods are used to determine the size of the resulting Ag NPs. Additionally, the drug-release capabilities of Ag NPs were established. Density functional theory (DFT) calculations were performed for the first time to indicate the nature of the interaction between PID and nanostructures. DFT findings supported that galactose-loaded nanostructure could be a proper delivery system for phenindione. The drug-loaded Ag NPs were characterized in vitro for their antimicrobial, cytotoxic, and anticoagulant activities, and ex vivo for spasmolytic activity. The obtained data confirmed the drug-release experiments. Drug-loaded Ag NPs showed that prothrombin time (PT, sec) and activated partial thromboplastin time (APTT, sec) are approximately 1.5 times longer than the normal values, while PID itself stopped coagulation at all. This can make the PID-loaded Ag NPs better therapeutic anticoagulants. PID was compared to PID-loaded Ag NPs in antimicrobial, spasmolytic activity, and cytotoxicity. All the experiments confirmed the drug-release results. Full article

(This article belongs to the Special Issue Novel Drug Delivery Systems: Design, Evaluation and Application)

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13 pages, 6004 KiB

Open AccessEditor’s ChoiceArticle

Evaluation of Five Mammalian Models for Human Disease Research Using Genomic and Bioinformatic Approaches

by Sankarasubramanian Jagadesan, Pinaki Mondal, Mark A. Carlson and Chittibabu Guda

Biomedicines 2023, 11(8), 2197; https://doi.org/10.3390/biomedicines11082197 - 4 Aug 2023

Cited by 1 | Viewed by 1618

Abstract

The suitability of an animal model for use in studying human diseases relies heavily on the similarities between the two species at the genetic, epigenetic, and metabolic levels. However, there is a lack of consistent data from different animal models at each level [...] Read more.

The suitability of an animal model for use in studying human diseases relies heavily on the similarities between the two species at the genetic, epigenetic, and metabolic levels. However, there is a lack of consistent data from different animal models at each level to evaluate this suitability. With the availability of genome sequences for many mammalian species, it is now possible to compare animal models based on genomic similarities. Herein, we compare the coding sequences (CDSs) of five mammalian models, including rhesus macaque, marmoset, pig, mouse, and rat models, with human coding sequences. We identified 10,316 conserved CDSs across the five organisms and the human genome based on sequence similarity. Mapping the human-disease-associated single-nucleotide polymorphisms (SNPs) from these conserved CDSs in each species has identified species-specific associations with various human diseases. While associations with a disease such as colon cancer were prevalent in multiple model species, the rhesus macaque showed the most model-specific human disease associations. Based on the percentage of disease-associated SNP-containing genes, marmoset models are well suited to study many human ailments, including behavioral and cardiovascular diseases. This study demonstrates a genomic similarity evaluation of five animal models against human CDSs that could help investigators select a suitable animal model for studying their target disease. Full article

(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements 2.0)

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17 pages, 4757 KiB

Open AccessEditor’s ChoiceArticle

Integrating Chinese Herbs and Western Medicine for New Wound Dressings through Handheld Electrospinning

by Jianfeng Zhou, Liangzhe Wang, Wenjian Gong, Bo Wang, Deng-Guang Yu and Yuanjie Zhu

Biomedicines 2023, 11(8), 2146; https://doi.org/10.3390/biomedicines11082146 - 30 Jul 2023

Cited by 22 | Viewed by 2411

Abstract

In this nanotechnology era, nanostructures play a crucial role in the investigation of novel functional nanomaterials. Complex nanostructures and their corresponding fabrication techniques provide powerful tools for the development of high-performance functional materials. In this study, advanced micro-nanomanufacturing technologies and composite micro-nanostructures were [...] Read more.

In this nanotechnology era, nanostructures play a crucial role in the investigation of novel functional nanomaterials. Complex nanostructures and their corresponding fabrication techniques provide powerful tools for the development of high-performance functional materials. In this study, advanced micro-nanomanufacturing technologies and composite micro-nanostructures were applied to the development of a new type of pharmaceutical formulation, aiming to achieve rapid hemostasis, pain relief, and antimicrobial properties. Briefly, an approach combining a electrohydrodynamic atomization (EHDA) technique and reversed-phase solvent was employed to fabricate a novel beaded nanofiber structure (BNS), consisting of micrometer-sized particles distributed on a nanoscale fiber matrix. Firstly, Zein-loaded Yunnan Baiyao (YB) particles were prepared using the solution electrospraying process. Subsequently, these particles were suspended in a co-solvent solution containing ciprofloxacin (CIP) and hydrophilic polymer polyvinylpyrrolidone (PVP) and electrospun into hybrid structural microfibers using a handheld electrospinning device, forming the EHDA product E3. The fiber-beaded composite morphology of E3 was confirmed through scanning electron microscopy (SEM) images. Fourier-transform infrared (FTIR) spectroscopy and X-ray diffraction (XRD) analysis revealed the amorphous state of CIP in the BNS membrane due to the good compatibility between CIP and PVP. The rapid dissolution experiment revealed that E3 exhibits fast disintegration properties and promotes the dissolution of CIP. Moreover, in vitro drug release study demonstrated the complete release of CIP within 1 min. Antibacterial assays showed a significant reduction in the number of adhered bacteria on the BNS, indicating excellent antibacterial performance. Compared with the traditional YB powders consisting of Chinese herbs, the BNS showed a series of advantages for potential wound dressing. These advantages include an improved antibacterial effect, a sustained release of active ingredients from YB, and a convenient wound covering application, which were resulted from the integration of Chinese herbs and Western medicine. This study provides valuable insights for the development of novel multiscale functional micro-/nano-composite materials and pioneers the developments of new types of medicines from the combination of herbal medicines and Western medicines. Full article

(This article belongs to the Special Issue Novel Drug Delivery Systems: Design, Evaluation and Application)

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10 pages, 3158 KiB

Open AccessEditor’s ChoiceArticle

Effects of Mesenchymal Stem Cell Injection into Healed Myocardial Infarction Scar Border Zone on the Risk of Ventricular Tachycardia

by Eun-Hye Park, Jin-Moo Kim, EunHwa Seong, Eunmi Lee, Kiyuk Chang and Young Choi

Biomedicines 2023, 11(8), 2141; https://doi.org/10.3390/biomedicines11082141 - 29 Jul 2023

Cited by 1 | Viewed by 1047

Abstract

The scar border zone is a main source of reentry responsible for ischemic ventricular tachycardia (VT). We evaluated the effects of mesenchymal stem cell (MSC) injection into the scar border zone on arrhythmic risks in a post-myocardial infarction (MI) animal model. Rabbit MI [...] Read more.

The scar border zone is a main source of reentry responsible for ischemic ventricular tachycardia (VT). We evaluated the effects of mesenchymal stem cell (MSC) injection into the scar border zone on arrhythmic risks in a post-myocardial infarction (MI) animal model. Rabbit MI models were generated by left descending coronary artery ligation. Surviving rabbits after 4 weeks underwent left thoracotomy and autologous MSCs or phosphate-buffered saline (PBS) was administered to scar border zones in two rabbits in each group. Another rabbit without MI underwent a sham procedure (control). An implantable loop recorder (ILR) was implanted in the left chest wall in all animals. Four weeks after cell injections, ventricular fibrillation was induced in 1/2 rabbit in the PBS group by electrophysiologic study, and no ventricular arrhythmia was induced in the MSC group or control. Spontaneous VT was not detected during ILR analysis in any animal for 4 weeks. Histologic examination showed restoration of connexin 43 (Cx43) expression in the MSC group, which was higher than in the PBS group and comparable to the control. In conclusion, MSC injections into the MI scar border zone did not increase the risk of VT and were associated with favorable Cx43 expression and arrangement. Full article

(This article belongs to the Special Issue Recent Advances in Ischemic Heart Diseases)

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13 pages, 1341 KiB

Open AccessEditor’s ChoiceArticle

Transcutaneous Spinal Cord Stimulation Improves Respiratory Muscle Strength and Function in Subjects with Cervical Spinal Cord Injury: Original Research

by Hatice Kumru, Loreto García-Alén, Aina Ros-Alsina, Sergiu Albu, Margarita Valles and Joan Vidal

Biomedicines 2023, 11(8), 2121; https://doi.org/10.3390/biomedicines11082121 - 27 Jul 2023

Cited by 3 | Viewed by 1732

Abstract

(1) Background: Respiratory muscle weakness is common following cervical spinal cord injury (cSCI). Transcutaneous spinal cord stimulation (tSCS) promotes the motor recovery of the upper and lower limbs. tSCS improved breathing and coughing abilities in one subject with tetraplegia. Objective: We therefore hypothesized [...] Read more.

(1) Background: Respiratory muscle weakness is common following cervical spinal cord injury (cSCI). Transcutaneous spinal cord stimulation (tSCS) promotes the motor recovery of the upper and lower limbs. tSCS improved breathing and coughing abilities in one subject with tetraplegia. Objective: We therefore hypothesized that tSCS applied at the cervical and thoracic levels could improve respiratory function in cSCI subjects; (2) Methods: This study was a randomized controlled trial. Eleven cSCI subjects received inspiratory muscle training (IMT) alone. Eleven cSCI subjects received tSCS combined with IMT (six of these subjects underwent IMT alone first and then they were given the opportunity to receive tSCS + IMT). The subjects evaluated their sensation of breathlessness/dyspnea and hypophonia compared to pre-SCI using a numerical rating scale. The thoracic muscle strength was assessed by maximum inspiratory (MIP), expiratory pressure (MEP), and spirometric measures. All assessments were conducted at baseline and after the last session. tSCS was applied at C3-4 and Th9-10 at a frequency of 30 Hz for 30 min on 5 consecutive days; (3) Results: Following tSCS + IMT, the subjects reported a significant improvement in breathlessness/dyspnea and hypophonia (p < 0.05). There was also a significant improvement in MIP, MEP, and forced vital capacity (p < 0.05). Following IMT alone, there were no significant changes in any measurement; (4) Conclusions: Current evidence supports the potential of tSCS as an adjunctive therapy to accelerate and enhance the rehabilitation process for respiratory impairments following SCI. However, further research is needed to validate these results and establish the long-term benefits of tSCS in this population. Full article

(This article belongs to the Special Issue Combined Treatments and Therapies to Cure Spinal Cord Injury)

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12 pages, 966 KiB

Open AccessEditor’s ChoiceArticle

Effects of Progestin on Modulation of the Expression of Biomarkers in Endometriosis

by Daniela Roxana Matasariu, Alexandra Irma Gabriela Bausic, Cristina Elena Mandici, Iuliana Elena Bujor, Alexandra Elena Cristofor, Elvira Bratila, Ludmila Lozneanu, Lucian Vasile Boiculese, Mihaela Grigore and Alexandra Ursache

Biomedicines 2023, 11(7), 2036; https://doi.org/10.3390/biomedicines11072036 - 20 Jul 2023

Viewed by 1205

Abstract

Background: Our study aimed to examine the osteopontin (OPN) serum levels and tissue expression of CD44 and OPN in endometriosis-affected women both undergoing and not undergoing progestin treatment, and also to determine their involvement in the pathogenesis of endometriosis. Methods: Using an ELISA [...] Read more.

Background: Our study aimed to examine the osteopontin (OPN) serum levels and tissue expression of CD44 and OPN in endometriosis-affected women both undergoing and not undergoing progestin treatment, and also to determine their involvement in the pathogenesis of endometriosis. Methods: Using an ELISA kit, we evaluated the OPN serum levels of healthy and endometriosis-affected women both undergoing and not undergoing progestin treatment. Immunohistochemical (IHC) analyses were used to assess the endometriotic tissue expressions of CD44 and OPN. Results: There were statistically significant higher OPN serum levels in the healthy control group compared to the women with endometriosis. Furthermore, there were higher OPN serum levels in the endometriosis-affected women undergoing the progestin treatment, but the difference did not reach statistical significance. In comparison to OPN, CD44 expression was significantly higher in all the endometriotic tissue glands and stroma, regardless of the patient’s treatment status. Compared to the group receiving therapy, the OPN levels were higher in the endometriosis group not receiving therapy. OPN’s robust cytoplasmic expression seemed to be associated with the non-treatment group. Conclusion: Endometriosis, CD44, and OPN appear to be closely related. This study suggests that endometriosis that has not been treated has an immunological profile distinct to endometriosis that has received treatment. Full article

(This article belongs to the Special Issue Biomarkers of Endometriosis)

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11 pages, 1032 KiB

Open AccessEditor’s ChoiceArticle

Metabolic Syndrome: A Strange Companion of Atrial Fibrillation; A Blessing in Disguise from the Neuropsychiatric Point of View

by Ciprian Ilie Rosca, Daniel Florin Lighezan, Daniel-Dumitru Nisulescu, Abhinav Sharma, Marioara Nicula Neagu, Daciana Nistor, Doina Georgescu and Nilima Rajpal Kundnani

Biomedicines 2023, 11(7), 2012; https://doi.org/10.3390/biomedicines11072012 - 17 Jul 2023

Cited by 2 | Viewed by 1190

Abstract

Background: The concept of metabolic syndrome (MetSy) brings together components that individually represent a risk factor for cardiovascular diseases, which over time can prove to be more harmful if a combined effect of these is exhibited. Method: A single-centre retrospective study in [...] Read more.

Background: The concept of metabolic syndrome (MetSy) brings together components that individually represent a risk factor for cardiovascular diseases, which over time can prove to be more harmful if a combined effect of these is exhibited. Method: A single-centre retrospective study in an academic medical unit was conducted. We analysed the link between the MetSy and the occurrence of neuropsychic complications among atrial fibrillation (AF) patients. We sifted through the files of the patients admitted during 2015–2016 to the Municipal Emergency University Hospital Timisoara, Romania, with the diagnosis of AF. We divided these AF patients into two groups: the first group comprised patients with atrial fibrillation and MetSy (267 patients), while the second group comprised AF patients without MetSy (843 patients). We analysed the occurrence of neuropsychic changes (stroke, Parkinson’s disease, dementia, cognitive impairment, and silent lacunar infarction) among the two groups. Results: Cognitive impairment (p-value = 0.0081) and dementia (p-value < 0.0001) were less frequent in patients with AF and MetSy than in those with AF without MetSy. Regarding the presence of stroke and Parkinson’s disease (PD), we could not demonstrate the existence of any statistically significant difference between the two groups. Using logistic regression (enter test), we found that MetSy might have a protective effect (OR = 0.4040, 95% CI [0.2132; 0.7654], p-value = 0.0054) for the occurrence of dementia in those patients. Furthermore, obesity was the only factor with a possible protective effect from all the constituents of the MetSy when analysed together (with a significance level of p-value = 0.0004 for the logistic regression). The protective effect of MetSy against stroke occurrence was supplementarily proven by a longer period of survival without stroke from the AF diagnosis (3.521 years, p = 0.0304) compared to patients with AF without MetSy (3.286 years to first stroke occurrence). Conclusions: Metabolic syndrome might offer protection against the occurrence of dementia among patients with AF, but no effect was noted when compared with the presence of stroke. Further studies on larger cohorts can help us reach a conclusion regarding the positive effects of the metabolic syndrome. Full article

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

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12 pages, 3252 KiB

Open AccessEditor’s ChoiceBrief Report

Senescence-Driven Inflammatory and Trophic Microenvironment Imprints Mesenchymal Stromal/Stem Cells in Osteoarthritic Patients

by Giuseppe Fusi, Michael Constantinides, Christina Fissoun, Lydiane Pichard, Yves-Marie Pers, Rosanna Ferreira-Lopez, Veronique Pantesco, Christophe Poulet, Olivier Malaise, Dominique De Seny, Jean-Marc Lemaitre, Christian Jorgensen and Jean-Marc Brondello

Biomedicines 2023, 11(7), 1994; https://doi.org/10.3390/biomedicines11071994 - 14 Jul 2023

Cited by 1 | Viewed by 1366

Abstract

Senescent cells promote progressive tissue degeneration through the establishment of a combined inflammatory and trophic microenvironment. The cellular senescence state has therefore emerged as a central driving mechanism of numerous age-related diseases, including osteoarthritis (OA), the most common rheumatic disease. Senescence hallmarks are [...] Read more.

Senescent cells promote progressive tissue degeneration through the establishment of a combined inflammatory and trophic microenvironment. The cellular senescence state has therefore emerged as a central driving mechanism of numerous age-related diseases, including osteoarthritis (OA), the most common rheumatic disease. Senescence hallmarks are detectable in chondrocytes, synoviocytes and sub-chondral bone cells. This study investigates how the senescence-driven microenvironment could impact the cell fate of resident osteoarticular mesenchymal stromal/stem cells (MSCs) that are hence contributing to OA disease progression. For that purpose, we performed a comparative gene expression analysis of MSCs isolated from healthy donors that were in vitro chronically exposed either to interferon-gamma (IFN-γ) or Transforming Growth Factor beta 1 (TGFβ1), two archetypical factors produced by senescent cells. Both treatments reduced MSC self-renewal capacities by upregulating different senescence-driven cycle-dependent kinase inhibitors. Furthermore, a common set of differentially expressed genes was identified in both treated MSCs that was also found enriched in MSCs isolated from OA patients. These findings highlight an imprinting of OA MSCs by the senescent joint microenvironment that changes their matrisome gene expression. Altogether, this research gives new insights into OA etiology and points to new innovative therapeutic opportunities to treat OA patients. Full article

(This article belongs to the Special Issue Inflammation and Immunosenescence in Age-Related Diseases)

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15 pages, 2915 KiB

Open AccessEditor’s ChoiceArticle

Pregnancy Zone Protein Serves as a Prognostic Marker and Favors Immune Infiltration in Lung Adenocarcinoma

by Kehong Chen, Taihao Zheng, Cai Chen, Liangzhong Liu, Zhengjun Guo, Yuan Peng, Xiaoyue Zhang and Zhenzhou Yang

Biomedicines 2023, 11(7), 1978; https://doi.org/10.3390/biomedicines11071978 - 13 Jul 2023

Cited by 3 | Viewed by 1440

Abstract

Lung adenocarcinoma (LUAD) is a public enemy with a very high incidence and mortality rate, for which there is no specific detectable biomarker. Pregnancy zone protein (PZP) is an immune-related protein; however, the functions of PZP in LUAD are unclear. In this study, [...] Read more.

Lung adenocarcinoma (LUAD) is a public enemy with a very high incidence and mortality rate, for which there is no specific detectable biomarker. Pregnancy zone protein (PZP) is an immune-related protein; however, the functions of PZP in LUAD are unclear. In this study, a series of bioinformatics methods, combined with immunohistochemistry (IHC), four-color multiplex fluorescence immunohistochemistry (mIHC), quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA), were utilized to explore the prognostic value and potential role of PZP in LUAD. Our data revealed that PZP expression was markedly reduced in LUAD tissues, tightly correlated with clinical stage and could be an independent unfavorable prognostic factor. In addition, pathway analysis revealed that high expression of PZP in LUAD was mainly involved in immune-related molecules. Tumor immune infiltration analysis by CIBERSORT showed a significant correlation between PZP expression and several immune cell infiltrations, and IHC further confirmed a positive correlation with CD4+ T-cell infiltration and a negative correlation with CD68+ M0 macrophage infiltration. Furthermore, mIHC demonstrated that PZP expression gave rise to an increase in CD86+ M1 macrophages and a decrease in CD206+ M2 macrophages. Therefore, PZP can be used as a new biomarker for the prediction of prognosis and may be a promising immune-related molecular target for LUAD. Full article

(This article belongs to the Section Immunology and Immunotherapy)

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12 pages, 554 KiB

Open AccessEditor’s ChoiceArticle

Identification of Healthy Tissue from Malignant Tissue in Surgical Margin Using Raman Spectroscopy in Oral Cancer Surgeries

by Mukta Sharma, Ying-Chang Li, S. N. Manjunatha, Chia-Lung Tsai, Ray-Ming Lin, Shiang-Fu Huang and Liann-Be Chang

Biomedicines 2023, 11(7), 1984; https://doi.org/10.3390/biomedicines11071984 - 13 Jul 2023

Cited by 5 | Viewed by 1724

Abstract

Accurate identification of tissue types in surgical margins is essential for ensuring the complete removal of cancerous cells and minimizing the risk of recurrence. The objective of this study was to explore the clinical utility of Raman spectroscopy for the detection of oral [...] Read more.

Accurate identification of tissue types in surgical margins is essential for ensuring the complete removal of cancerous cells and minimizing the risk of recurrence. The objective of this study was to explore the clinical utility of Raman spectroscopy for the detection of oral squamous cell carcinoma (OSCC) in both tumor and healthy tissues obtained from surgical resection specimens during surgery. This study enrolled a total of 64 patients diagnosed with OSCC. Among the participants, approximately 50% of the cases were classified as the most advanced stage, referred to as T4. Raman experiments were conducted on cryopreserved tissue samples collected from patients diagnosed with OSCC. Prominent spectral regions containing key oral biomarkers were analyzed using the partial least squares–support vector machine (PLS–SVM) method, which is a powerful multivariate analysis technique for discriminant analysis. This approach effectively differentiated OSCC tissue from non-OSCC tissue, achieving a sensitivity of 95.7% and a specificity of 93.3% with 94.7% accuracy. In the current study, Raman analysis of fresh tissue samples showed that OSCC tissues contained significantly higher levels of nucleic acids, proteins, and several amino acids compared to the adjacent healthy tissues. In addition to differentiating between OSCC and non-OSCC tissues, we have also explored the potential of Raman spectroscopy in classifying different stages of OSCC. Specifically, we have investigated the classification of T1, T2, T3, and T4 stages based on their Raman spectra. These findings emphasize the importance of considering both stage and subsite factors in the application of Raman spectroscopy for OSCC analysis. Future work will focus on expanding our tissue sample collection to better comprehend how different subsites influence the Raman spectra of OSCC at various stages, aiming to improve diagnostic accuracy and aid in identifying tumor-free margins during surgical interventions. Full article

(This article belongs to the Special Issue Progress in Oral Microbiome Related to Oral Diseases)

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12 pages, 871 KiB

Open AccessEditor’s ChoiceArticle

Residual Aneurysmal Sac Shrinkage Post-Endovascular Aneurysm Repair: The Role of Preoperative Inflammatory Markers

by Edoardo Pasqui, Gianmarco de Donato, Cecilia Molino, Mustafa Abu Leil, Manfredi Giuseppe Anzaldi, Giuseppe Galzerano and Giancarlo Palasciano

Biomedicines 2023, 11(7), 1920; https://doi.org/10.3390/biomedicines11071920 - 6 Jul 2023

Cited by 4 | Viewed by 1238

Abstract

Introduction: In this study, we evaluated the role of preoperative inflammatory markers as Neutrophil-to-Lymphocyte (NLR) and Platelet-to-Lymphocyte (PLR) ratios in relation to post-endovascular aneurysm repair (EVAR) sac shrinkage, which is known to be an important factor for abdominal aortic aneurysm (AAA) healing. Methods: [...] Read more.

Introduction: In this study, we evaluated the role of preoperative inflammatory markers as Neutrophil-to-Lymphocyte (NLR) and Platelet-to-Lymphocyte (PLR) ratios in relation to post-endovascular aneurysm repair (EVAR) sac shrinkage, which is known to be an important factor for abdominal aortic aneurysm (AAA) healing. Methods: This was a single-center retrospective observational study. All patients who underwent the EVAR procedure from January 2017 to December 2020 were eligible for this study. Pre-operative blood samples of all patients admitted were used to calculate NLR and PLR. Sac shrinkage was defined as a decrease of ≥5 mm in the maximal sac diameter. The optimal NLR and PLR cut-offs for aneurysmal sac shrinkage were obtained from ROC curves. Stepwise multivariate analysis was performed in order to identify independent risk and protective factors for the absence of AAA shrinkage. Kaplan–Meier curves were used to evaluate survival rates with respect to the AAA shrinkage. Results: A total of 184 patients were finally enrolled. The mean age was 75.8 ± 8.3 years, and 85.9% were male (158/184). At a mean follow-up of 43 ± 18 months, sac shrinkage was registered in 107 patients (58.1%). No-shrinking AAA patients were more likely to be older, to have a higher level of NLR and PLR, and be an active smoker. Kaplan–Meier curves highlighted a higher rate of survival for shrinking AAA patients with respect to their counterparts (p < 0.03). Multivariate analysis outlined active smoking and NLR as independent risk factors for no-shrinking AAA. Conclusions: Inflammation emerged as a possible causative factor for no-shrinking AAA, playing a role in aneurysmal sac remodeling. This study revealed that inflammatory biomarkers, such as NLR and PLR, can be used as a preoperative index of AAA sac behavior after EVAR procedures. Full article

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

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9 pages, 1633 KiB

Open AccessEditor’s ChoiceArticle

The Evaluation of SWEEPS Plus Antimicrobial Photodynamic Therapy with Indocyanine Green in Eliminating Enterococcus faecalis Biofilm from Infected Root Canals: An In Vitro Study

by Golriz Rostami, Shima Afrasiabi, Stefano Benedicenti, Antonio Signore and Nasim Chiniforush

Biomedicines 2023, 11(7), 1850; https://doi.org/10.3390/biomedicines11071850 - 28 Jun 2023

Cited by 3 | Viewed by 1243

Abstract

Objectives: This study aimed to assess the efficacy of shockwave-enhanced emission photoacoustic streaming (SWEEPS) plus antimicrobial photodynamic therapy (aPDT) using indocyanine green (ICG) for the elimination of Enterococcus faecalis biofilm from infected root canals. Materials and Methods: thirty sound human single-canal teeth were [...] Read more.

Objectives: This study aimed to assess the efficacy of shockwave-enhanced emission photoacoustic streaming (SWEEPS) plus antimicrobial photodynamic therapy (aPDT) using indocyanine green (ICG) for the elimination of Enterococcus faecalis biofilm from infected root canals. Materials and Methods: thirty sound human single-canal teeth were chosen and standardized to have 12 mm of root length. The root canals were shaped and prepared by means of ProTaper rotary files. After sterilization of the teeth, the canals were inoculated with E. faecalis for 2 weeks. The teeth were then randomly divided into six groups (n = five) of control, ICG, ICG + 808 nm diode laser, ICG + SWEEPS, ICG + 808 nm diode laser + SWEEPS, and 5.25% sodium hypochlorite (NaOCl). Following treatment, the number of colony-forming units (CFUs)/mL were calculated for each group. Statistical analysis was carried out using one-way ANOVA. For multiple comparisons, Tukey’s test was used as the post hoc test. Results: NaOCl alone showed the highest efficacy (p < 0.001). The ICG + 808 nm diode laser + SWEEPS group displayed significantly lower amounts of bacteria than either the ICG + 808 nm diode laser or SWEEPS (p < 0.001). There was a statistically significant difference detected between the ICG + 808 nm diode laser and ICG + SWEEPS (p = 0.035). Conclusions: SWEEPS can effectively increase the photosensitizer distribution in the root canal space, and its application along with irrigants can bring about promising results. Full article

(This article belongs to the Special Issue Photodynamic Therapy 2.0)

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12 pages, 749 KiB

Open AccessEditor’s ChoiceArticle

Vitamin D Supplementation and Adherence to World Cancer Research Fund (WCRF) Diet Recommendations for Colorectal Cancer Prevention: A Nested Prospective Cohort Study of a Phase II Randomized Trial

by Davide Serrano, Federica Bellerba, Harriet Johansson, Debora Macis, Valentina Aristarco, Chiara A. Accornero, Aliana Guerrieri-Gonzaga, Cristina M. Trovato, Maria Giulia Zampino, Emanuela Omodeo Salè, Bernardo Bonanni, Sara Gandini and Patrizia Gnagnarella

Biomedicines 2023, 11(6), 1766; https://doi.org/10.3390/biomedicines11061766 - 20 Jun 2023

Cited by 2 | Viewed by 1472

Abstract

Vitamin D and a healthy diet, based on World Cancer Research Fund (WCRF) recommendations, are considered key elements for colorectal cancer (CRC) prevention. In a CRC case-control study, we observed that CRC cases were often significantly Vitamin D deficient while subjects following WCRF [...] Read more.

Vitamin D and a healthy diet, based on World Cancer Research Fund (WCRF) recommendations, are considered key elements for colorectal cancer (CRC) prevention. In a CRC case-control study, we observed that CRC cases were often significantly Vitamin D deficient while subjects following WCRF recommendations significantly decreased their risk of developing CRC. We conducted a randomized phase-II trial (EudraCT number-2015-000467-14) where 74 CRC patients showed differences in response to Vitamin D supplementation, 2000 IU in average per day, according to gender and microbiota. The aim of this nested study is to correlate Vitamin D (supplementation, serum level and receptor polymorphisms), circulating biomarkers, and events (polyp/adenoma, CRC relapse and other cancers) in concomitant to WCRF recommendation adherence. Vitamin D supplementation did not modulate circulating biomarkers or follow-up events. FokI and TaqI VDR were associated with 25-hydroxyvitamin D (25OHD) levels. Patients following the WCRF recommendations had significantly lower leptin, significantly lower IL-6 (only in females), and significantly lower risk of events (HR = 0.41, 95%CI: 0.18–0.92; p = 0.03; median follow-up 2.6 years). Interestingly, no WCRF adherents had significantly more events if they were in the placebo (p < 0.0001), whereas no influence of WCRF was observed in the Vitamin D arm. While one-year Vitamin D supplementation might be too short to show significant preventive activity, a healthy diet and lifestyle should be the first step for preventive programs. Full article

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

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23 pages, 46660 KiB

Open AccessEditor’s ChoiceArticle

Arsenic Inhibits Proliferation and Induces Autophagy of Tumor Cells in Pleural Effusion of Patients with Non-Small Cell Lung Cancer Expressing EGFR with or without Mutations via PI3K/AKT/mTOR Pathway

by Jianhua Mao, Xiaoqian Shi, Li Hua, Menghang Yang, Yan Shen, Zheng Ruan, Bing Li and Xiaodong Xi

Biomedicines 2023, 11(6), 1721; https://doi.org/10.3390/biomedicines11061721 - 15 Jun 2023

Cited by 6 | Viewed by 1455

Abstract

To clarify whether arsenic could exert inhibitory effects on tumor cells in pleural effusions of patients with non-small cell lung cancer (NSCLC), 36 NSCLC pleural effusion samples were collected from Changzheng Hospital and Ruijin Hospital, from 2019 to 2022. The genotype of epidermal [...] Read more.

To clarify whether arsenic could exert inhibitory effects on tumor cells in pleural effusions of patients with non-small cell lung cancer (NSCLC), 36 NSCLC pleural effusion samples were collected from Changzheng Hospital and Ruijin Hospital, from 2019 to 2022. The genotype of epidermal growth factor receptor (EGFR) was identified. Tumor cells were isolated and treated with arsenic trioxide (ATO) or/and gefitinib. Additionally, six patients were intrapleurally administrated with ATO. Results showed that 25 samples bore EGFR wild type (WT) and 11 harbored EGFR mutations, including 6 with L858R, 3 with ΔE746-A750, and 2 with T790M. ATO diminished the number of tumor cells from patients with WT and mutant EGFR, down-regulated the expression or phosphorylation of EGFR, pmTOR, PI3K, PTEN, and p4E-BP1, and up-regulated the expression of LC3. Immunofluorescent experiments showed that ATO enhanced LC3 and P62. By contrast, gefitinib was only effective in those harboring EGFR sensitizing mutations. Notably, in patients with intrapleural ATO injection, the pleural effusion underwent a bloody to pale yellow color change, the volume of the pleural effusion was reduced, and the number of the tumor cells was significantly reduced. In conclusion, arsenic is effective against NSCLC with various EGFR genotypes in vitro and in vivo, and potentially circumvents gefitinib resistance. Full article

(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy)

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13 pages, 885 KiB

Open AccessEditor’s ChoiceArticle

MR-proADM as Prognostic Factor of Outcome in COVID-19 Patients

by Paolo Cameli, Elena Pordon, Miriana d’Alessandro, Maria Laura Marzi, Lucrezia Galasso, Cesare Biuzzi, Laura Bergantini, Elena Bargagli, Sabino Scolletta and Federico Franchi

Biomedicines 2023, 11(6), 1680; https://doi.org/10.3390/biomedicines11061680 - 9 Jun 2023

Viewed by 1028

Abstract

Background: Serum mid-regional proadrenomedullin (MR-proADM) has emerged as a marker of organ failure (mainly lungs and kidneys) and poor prognosis in patients admitted to intensive care (IC); some reports also suggest it and other markers, such as Krebs von den Lungen-6 (KL-6) and [...] Read more.

Background: Serum mid-regional proadrenomedullin (MR-proADM) has emerged as a marker of organ failure (mainly lungs and kidneys) and poor prognosis in patients admitted to intensive care (IC); some reports also suggest it and other markers, such as Krebs von den Lungen-6 (KL-6) and interleukin-6 (IL-6), as a prognostic biomarker of COVID-19. The aim of the study was to evaluate the performance MR-proADM in hospitalized COVID-19 patients for predicting in-hospital mortality and need for non-invasive or invasive respiratory support. Methods: We enrolled 74 patients hospitalized in the COVID Unit of Siena Hospital from March to May 2020, for whom serum samples were available on admission for assay of MR-proADM, KL-6 and IL-6. Demographic data, comorbidities, medical history and clinical laboratory data on days 1–3 of admission and Simplified Acute Physiology Score and Simplified Organ Failure Assessment scores calculated at day 1 were collected retrospectively, as well as mortality and IC admission data. Results: 12 patients died in hospital (16%) and 14 patients were admitted to IC (19%). Serum concentrations of MR-proADM on admission and on day 1 were higher among non-survivors than among survivors (p = 0.015 and p = 0.045, respectively), while those on day 3 were not significantly different. Patients needing respiratory support had higher MR-proADM concentrations on admission than the others (p = 0.046), and those requiring invasive mechanical ventilation had higher MR-proADM on day 1 (p = 0.017). Serum concentrations of KL-6 and IL-6 were significantly higher in non-survivors (p = 0.03 and p = 0.004, respectively). ROC curve analysis showed that serum MR-proADM on day 1 had the best accuracy in predicting death and/or IC admission (AUC = 0.9583, p = 0.0006); the combination of all three biomarkers further improved the accuracy of prediction of death or IC admission (AUC = 0.9793; p = 0.00004). Conclusions: Our data sustain the potential of serum MR-proADM as a reliable prognostic biomarker of hospitalized COVID-19 patients and confirms the utility of the three markers in the management and risk stratification of hospitalized patients. The markers are collected mini-invasively and are quick to analyze and cost-effective. Full article

(This article belongs to the Special Issue Past, Present and Future of COVID-19 2.0)

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23 pages, 870 KiB

Open AccessEditor’s ChoiceReview

Pathogenesis, Intervention, and Current Status of Drug Development for Sarcopenia: A Review

by Jung Yoon Jang, Donghwan Kim and Nam Deuk Kim

Biomedicines 2023, 11(6), 1635; https://doi.org/10.3390/biomedicines11061635 - 4 Jun 2023

Cited by 18 | Viewed by 5820

Abstract

Sarcopenia refers to the loss of muscle strength and mass in older individuals and is a major determinant of fall risk and impaired ability to perform activities of daily living, often leading to disability, loss of independence, and death. Owing to its impact [...] Read more.

Sarcopenia refers to the loss of muscle strength and mass in older individuals and is a major determinant of fall risk and impaired ability to perform activities of daily living, often leading to disability, loss of independence, and death. Owing to its impact on morbidity, mortality, and healthcare expenditure, sarcopenia in the elderly has become a major focus of research and public policy debates worldwide. Despite its clinical importance, sarcopenia remains under-recognized and poorly managed in routine clinical practice, partly owing to the lack of available diagnostic testing and uniform diagnostic criteria. Since the World Health Organization and the United States assigned a disease code for sarcopenia in 2016, countries worldwide have assigned their own disease codes for sarcopenia. However, there are currently no approved pharmacological agents for the treatment of sarcopenia; therefore, interventions for sarcopenia primarily focus on physical therapy for muscle strengthening and gait training as well as adequate protein intake. In this review, we aimed to examine the latest information on the epidemiology, molecular mechanisms, interventions, and possible treatments with new drugs for sarcopenia. Full article

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

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25 pages, 1188 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 7 | Viewed by 5775

Abstract

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

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

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

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19 pages, 3085 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 3 | Viewed by 2043

Abstract

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

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

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

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12 pages, 2575 KiB

Open AccessEditor’s ChoiceArticle

Hyperpolarized Xenon-129: A New Tool to Assess Pulmonary Physiology in Patients with Pulmonary Fibrosis

by Kun Qing, Talissa A. Altes, John P. Mugler III, Jaime F. Mata, Nicholas J. Tustison, Kai Ruppert, Juliana Bueno, Lucia Flors, Yun M. Shim, Li Zhao, Joanne Cassani, William G. Teague, John S. Kim, Zhixing Wang, Iulian C. Ruset, F. William Hersman and Borna Mehrad

Biomedicines 2023, 11(6), 1533; https://doi.org/10.3390/biomedicines11061533 - 25 May 2023

Cited by 1 | Viewed by 1774

Abstract

Purpose: The existing tools to quantify lung function in interstitial lung diseases have significant limitations. Lung MRI imaging using inhaled hyperpolarized xenon-129 gas (¹²⁹Xe) as a contrast agent is a new technology for measuring regional lung physiology. We sought to assess [...] Read more.

Purpose: The existing tools to quantify lung function in interstitial lung diseases have significant limitations. Lung MRI imaging using inhaled hyperpolarized xenon-129 gas (¹²⁹Xe) as a contrast agent is a new technology for measuring regional lung physiology. We sought to assess the utility of the ¹²⁹Xe MRI in detecting impaired lung physiology in usual interstitial pneumonia (UIP). Materials and methods: After institutional review board approval and informed consent and in compliance with HIPAA regulations, we performed chest CT, pulmonary function tests (PFTs), and ¹²⁹Xe MRI in 10 UIP subjects and 10 healthy controls. Results: The ¹²⁹Xe MRI detected highly heterogeneous abnormalities within individual UIP subjects as compared to controls. Subjects with UIP had markedly impaired ventilation (ventilation defect fraction: UIP: 30 ± 9%; healthy: 21 ± 9%; p = 0.026), a greater amount of ¹²⁹Xe dissolved in the lung interstitium (tissue-to-gas ratio: UIP: 1.45 ± 0.35%; healthy: 1.10 ± 0.17%; p = 0.014), and impaired ¹²⁹Xe diffusion into the blood (RBC-to-tissue ratio: UIP: 0.20 ± 0.06; healthy: 0.28 ± 0.05; p = 0.004). Most MRI variables had no correlation with the CT and PFT measurements. The elevated level of ¹²⁹Xe dissolved in the lung interstitium, in particular, was detectable even in subjects with normal or mildly impaired PFTs, suggesting that this measurement may represent a new method for detecting early fibrosis. Conclusion: The hyperpolarized ¹²⁹Xe MRI was highly sensitive to regional functional changes in subjects with UIP and may represent a new tool for understanding the pathophysiology, monitoring the progression, and assessing the effectiveness of treatment in UIP. Full article

(This article belongs to the Special Issue Phenotypes and Endotypes in Interstitial Lung Diseases)

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17 pages, 2717 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 3 | Viewed by 3267

Abstract

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

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

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

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23 pages, 4818 KiB

Open AccessEditor’s ChoiceReview

Cerebrospinal Fluid–Basic Concepts Review

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

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

Cited by 16 | Viewed by 9944

Abstract

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

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

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

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26 pages, 1404 KiB

Open AccessEditor’s ChoiceReview

Adipokines as Clinically Relevant Therapeutic Targets in Obesity

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

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

Cited by 18 | Viewed by 3099

Abstract

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

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

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

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26 pages, 6049 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 4 | Viewed by 3015

Abstract

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

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

(This article belongs to the Section Immunology and Immunotherapy)

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