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Biomedicines, Volume 12, Issue 7 (July 2024) – 183 articles

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19 pages, 772 KiB  
Review
Molecular Changes in the Ischemic Brain as Non-Invasive Brain Stimulation Targets—TMS and tDCS Mechanisms, Therapeutic Challenges, and Combination Therapies
by Aleksandra Markowska and Beata Tarnacka
Biomedicines 2024, 12(7), 1560; https://doi.org/10.3390/biomedicines12071560 (registering DOI) - 13 Jul 2024
Viewed by 152
Abstract
Ischemic stroke is one of the leading causes of death and disability. As the currently used neurorehabilitation methods present several limitations, the ongoing research focuses on the use of non-invasive brain stimulation (NIBS) techniques such as transcranial magnetic stimulation (TMS) and transcranial direct [...] Read more.
Ischemic stroke is one of the leading causes of death and disability. As the currently used neurorehabilitation methods present several limitations, the ongoing research focuses on the use of non-invasive brain stimulation (NIBS) techniques such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). NIBS methods were demonstrated to modulate neural excitability and improve motor and cognitive functioning in neurodegenerative diseases. However, their mechanisms of action are not fully elucidated, and the clinical outcomes are often unpredictable. This review explores the molecular processes underlying the effects of TMS and tDCS in stroke rehabilitation, including oxidative stress reduction, cell death, stimulation of neurogenesis, and neuroprotective phenotypes of glial cells. A highlight is put on the newly emerging therapeutic targets, such as ferroptotic and pyroptotic pathways. In addition, the issue of interindividual variability is discussed, and the role of neuroimaging techniques is investigated to get closer to personalized medicine. Furthermore, translational challenges of NIBS techniques are analyzed, and limitations of current clinical trials are investigated. The paper concludes with suggestions for further neurorehabilitation stroke treatment, putting the focus on combination and personalized therapies, as well as novel protocols of brain stimulation techniques. Full article
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32 pages, 822 KiB  
Review
Embryonic Zebrafish as a Model for Investigating the Interaction between Environmental Pollutants and Neurodegenerative Disorders
by Ji-Hang Yin and Katharine A. Horzmann
Biomedicines 2024, 12(7), 1559; https://doi.org/10.3390/biomedicines12071559 (registering DOI) - 13 Jul 2024
Viewed by 101
Abstract
Environmental pollutants have been linked to neurotoxicity and are proposed to contribute to neurodegenerative disorders. The zebrafish model provides a high-throughput platform for large-scale chemical screening and toxicity assessment and is widely accepted as an important animal model for the investigation of neurodegenerative [...] Read more.
Environmental pollutants have been linked to neurotoxicity and are proposed to contribute to neurodegenerative disorders. The zebrafish model provides a high-throughput platform for large-scale chemical screening and toxicity assessment and is widely accepted as an important animal model for the investigation of neurodegenerative disorders. Although recent studies explore the roles of environmental pollutants in neurodegenerative disorders in zebrafish models, current knowledge of the mechanisms of environmentally induced neurodegenerative disorders is relatively complex and overlapping. This review primarily discusses utilizing embryonic zebrafish as the model to investigate environmental pollutants-related neurodegenerative disease. We also review current applicable approaches and important biomarkers to unravel the underlying mechanism of environmentally related neurodegenerative disorders. We found embryonic zebrafish to be a powerful tool that provides a platform for evaluating neurotoxicity triggered by environmentally relevant concentrations of neurotoxic compounds. Additionally, using variable approaches to assess neurotoxicity in the embryonic zebrafish allows researchers to have insights into the complex interaction between environmental pollutants and neurodegenerative disorders and, ultimately, an understanding of the underlying mechanisms related to environmental toxicants. Full article
(This article belongs to the Special Issue Zebrafish Models for Development and Disease 4.0)
28 pages, 1436 KiB  
Review
Amantadine for Traumatic Brain Injury—Supporting Evidence and Mode of Action
by Andrzej Dekundy, Gerald Pichler, Reda El Badry, Astrid Scheschonka and Wojciech Danysz
Biomedicines 2024, 12(7), 1558; https://doi.org/10.3390/biomedicines12071558 (registering DOI) - 13 Jul 2024
Viewed by 121
Abstract
Traumatic brain injury (TBI) is an important global clinical issue, requiring not only prevention but also effective treatment. Following TBI, diverse parallel and intertwined pathological mechanisms affecting biochemical, neurochemical, and inflammatory pathways can have a severe impact on the patient’s quality of life. [...] Read more.
Traumatic brain injury (TBI) is an important global clinical issue, requiring not only prevention but also effective treatment. Following TBI, diverse parallel and intertwined pathological mechanisms affecting biochemical, neurochemical, and inflammatory pathways can have a severe impact on the patient’s quality of life. The current review summarizes the evidence for the utility of amantadine in TBI in connection to its mechanism of action. Amantadine, the drug combining multiple mechanisms of action, may offer both neuroprotective and neuroactivating effects in TBI patients. Indeed, the use of amantadine in TBI has been encouraged by several clinical practice guidelines/recommendations. Amantadine is also available as an infusion, which may be of particular benefit in unconscious patients with TBI due to immediate delivery to the central nervous system and the possibility of precise dosing. In other situations, orally administered amantadine may be used. There are several questions that remain to be addressed: can amantadine be effective in disorders of consciousness requiring long-term treatment and in combination with drugs approved for the treatment of TBI? Do the observed beneficial effects of amantadine extend to disorders of consciousness due to factors other than TBI? Well-controlled clinical studies are warranted to ultimately confirm its utility in the TBI and provide answers to these questions. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Novel Therapies for Brain Injury)
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9 pages, 2842 KiB  
Article
A Rapid and Reliable Spectrofluorimetric Method to Measure the Urinary Lactulose/Mannitol Ratio for Dysbiosis Assessment
by Lorenzo Marino Cerrato, Elisabetta Schiano, Fortuna Iannuzzo, Gian Carlo Tenore, Vincenzo Summa, Maria Daglia, Ettore Novellino and Mariano Stornaiuolo
Biomedicines 2024, 12(7), 1557; https://doi.org/10.3390/biomedicines12071557 (registering DOI) - 13 Jul 2024
Viewed by 164
Abstract
Gut microbiota plays a crucial role in human health homeostasis, and the result of its alteration, known as dysbiosis, leads to several pathologies (e.g., inflammatory bowel disease, metabolic syndrome, and Crohn’s disease). Traditional methods used to assess dysbiosis include the dual sugar absorption [...] Read more.
Gut microbiota plays a crucial role in human health homeostasis, and the result of its alteration, known as dysbiosis, leads to several pathologies (e.g., inflammatory bowel disease, metabolic syndrome, and Crohn’s disease). Traditional methods used to assess dysbiosis include the dual sugar absorption test and the urinary lactulose/mannitol ratio (LMR) measurement using mass spectrometry. Despite its precision, this approach is costly and requires specialized equipment. Hence, we developed a rapid and reliable spectrofluorimetric method for measuring LMR in urine, offering a more accessible alternative. This spectrofluorimetric assay quantifies the fluorescence of nicotinamide adenine dinucleotide (NADH) and nicotinamide adenine dinucleotide phosphate (NADPH) produced during the enzymatic oxidation of mannitol and lactulose, respectively. The assay requires 100 µL of urine samples and detects LMR values lower (eubiosis) and higher (dysbiosis) than 0.05, ultimately being amenable to high-throughput screening and automatization, making it practical for clinical and research settings. A validation of the method demonstrated its high precision, accuracy, and robustness. Additionally, this study confirmed analyte stability under various storage conditions, ensuring reliable results even with delayed analysis. Overall, this spectrofluorimetric technique reduces costs, time, and the environmental impact associated with traditional mass spectrometry methods, making it a viable option for widespread use in the assessment of dysbiosis. Full article
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12 pages, 1822 KiB  
Article
Spasmolytic Activity of 1,3-Disubstituted 3,4-Dihydroisoquinolines
by Miglena Milusheva, Mihaela Stoyanova, Vera Gledacheva, Iliyana Stefanova, Mina Todorova and Stoyanka Nikolova
Biomedicines 2024, 12(7), 1556; https://doi.org/10.3390/biomedicines12071556 (registering DOI) - 13 Jul 2024
Viewed by 184
Abstract
This article concerns the spasmolytic activities of some novel 1,3-disubstituted 3,4-dihydroisoquinolines. These compounds can be evaluated as potential therapeutic candidates according to Lipinski’s rule of five, showing high gastrointestinal absorption and the ability to cross the blood–brain barrier, which is a very important [...] Read more.
This article concerns the spasmolytic activities of some novel 1,3-disubstituted 3,4-dihydroisoquinolines. These compounds can be evaluated as potential therapeutic candidates according to Lipinski’s rule of five, showing high gastrointestinal absorption and the ability to cross the blood–brain barrier, which is a very important parameter in the drug discovery processes. In silico simulation predicted smooth muscle relaxant activity for all the compounds. Since smooth muscle contractile failure is a characteristic feature of many disorders, in the current paper, we concentrate on the parameters of the spontaneous contractile responses of smooth muscle (SM) cells compared to the well-known drug mebeverine. Two of the newly synthesized substances can be identified as essential modulating regulators and potentially used as therapeutic molecules. One of these molecules also showed significant DPPH antioxidant activity compared to rutin. Full article
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15 pages, 4092 KiB  
Article
Evaluation of Neuroinflammatory Contribution to Neurodegeneration in LRRK2 Drosophila Models
by Hoai Nam Nguyen, Grazia Galleri, Antonio Rassu, Cristina Ciampelli, Roberto Bernardoni, Manuela Galioto, Diego Albani, Claudia Crosio and Ciro Iaccarino
Biomedicines 2024, 12(7), 1555; https://doi.org/10.3390/biomedicines12071555 - 12 Jul 2024
Viewed by 219
Abstract
Pathological mutations in the LRRK2 gene are the major genetic cause of Parkinson’s disease (PD). Although several animal models with either LRRK2 down- or over-expression have been developed, the physiological function of LRRK2 remains elusive. LRRK2 is constitutively expressed in various tissues including [...] Read more.
Pathological mutations in the LRRK2 gene are the major genetic cause of Parkinson’s disease (PD). Although several animal models with either LRRK2 down- or over-expression have been developed, the physiological function of LRRK2 remains elusive. LRRK2 is constitutively expressed in various tissues including neurons and glial cells, but importantly, it is expressed at low levels in dopaminergic neurons, further contributing to the cryptic function of LRRK2. Significant levels of LRRK2 protein and mRNA have been detected in peripheral blood mononuclear cells, lymph nodes, the spleen, and primary microglia, strongly suggesting the contribution of inflammatory cells to neuronal degeneration. In this research article, using Drosophila LRRK2 models, we were able to demonstrate a significant contribution of glial cells to the LRRK2 pathological phenotype. Furthermore, in Drosophila, neurodegeneration is associated with a significant and important increase in specific inflammatory peptides. Finally, levetiracetam, a compound widely used in human therapy to treat epilepsy, was able to rescue both neuronal degeneration and neuroinflammation. Full article
(This article belongs to the Special Issue Pharmacological Targets for Neuroinflammation)
14 pages, 298 KiB  
Review
How General and Inflammatory Status Impacts on the Prognosis of Patients Affected by Lung Cancer: State of the Art
by Antonio Mazzella, Riccardo Orlandi, Sebastiano Maiorca, Clarissa Uslenghi, Matteo Chiari, Luca Bertolaccini, Monica Casiraghi, Giorgio Lo Iacono, Lara Girelli and Lorenzo Spaggiari
Biomedicines 2024, 12(7), 1554; https://doi.org/10.3390/biomedicines12071554 - 12 Jul 2024
Viewed by 250
Abstract
Pulmonary cancer is often associated with systemic inflammation and poor nutritional status and these two aspects are strongly correlated and related to the scarce infiltration of a tumor by immune cells. We reviewed all English literature reviews from 2000 to 2024 from PubMed, [...] Read more.
Pulmonary cancer is often associated with systemic inflammation and poor nutritional status and these two aspects are strongly correlated and related to the scarce infiltration of a tumor by immune cells. We reviewed all English literature reviews from 2000 to 2024 from PubMed, Scopus and Google Scholar, including original articles, review articles, and metanalyses. We excluded non-English language articles and case reports/case series. Generally speaking, nutritional and inflammatory status largely affect medium and long-term prognosis in lung cancer patients. A correct stratification of patients could improve their preoperative general functional nutritional and inflammatory status, minimizing, therefore, possible treatment complications and improving long-term prognosis. Full article
(This article belongs to the Special Issue The Role of Inflammatory Cytokines in Cancer Progression 2.0)
23 pages, 2541 KiB  
Article
Ketosis Suppression and Ageing (KetoSAge) Part 2: The Effect of Suppressing Ketosis on Biomarkers Associated with Ageing, HOMA-IR, Leptin, Osteocalcin, and GLP-1, in Healthy Females
by Isabella D. Cooper, Yvoni Kyriakidou, Lucy Petagine, Kurtis Edwards, Adrian Soto-Mota, Kenneth Brookler and Bradley T. Elliott
Biomedicines 2024, 12(7), 1553; https://doi.org/10.3390/biomedicines12071553 - 12 Jul 2024
Viewed by 523
Abstract
Metabolic dysfunctions are among the best documented hallmarks of ageing. Cardiovascular disease, Alzheimer’s disease, cancer, type 2 diabetes mellitus, metabolic-dysfunction-associated steatosis liver disease, and fragility fractures are diseases of hyperinsulinaemia that reduce life and healthspan. We studied the effect of suppressing ketosis in [...] Read more.
Metabolic dysfunctions are among the best documented hallmarks of ageing. Cardiovascular disease, Alzheimer’s disease, cancer, type 2 diabetes mellitus, metabolic-dysfunction-associated steatosis liver disease, and fragility fractures are diseases of hyperinsulinaemia that reduce life and healthspan. We studied the effect of suppressing ketosis in 10 lean (BMI 20.5 kg/m2 ± 1.4), metabolically healthy, pre-menopausal women (age 32.3 ± 8.9 years) maintaining nutritional ketosis (NK) for an average of 3.9 years (± 2.3) who underwent three 21-day phases: nutritional ketosis (NK; P1), suppressed ketosis (SuK; P2), and returned to NK (P3). Ketosis suppression significantly increased insulin, 1.83-fold (p = 0.0006); glucose, 1.17-fold (p = 0.0088); homeostasis model assessment for insulin resistance (HOMA-IR), 2.13-fold (p = 0.0008); leptin, 3.35-fold (p = 0.0010); total osteocalcin, 1.63-fold (p = 0.0138); and uncarboxylated osteocalcin, 1.98-fold (p = 0.0417) and significantly decreased beta-hydroxybutyrate, 13.50-fold (p = 0.0012) and glucagon-like peptide-1 (GLP-1), 2.40-fold (p = 0.0209). Sustained NK showed no adverse health effects and may mitigate hyperinsulinemia. All biomarkers returned to basal P1 levels after removing the intervention for SuK, indicating that metabolic flexibility was maintained with long-term euketonaemia. Full article
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12 pages, 1836 KiB  
Article
Deciphering the Reactivity of Autoantibodies Directed against the RNP-A, -C and 70 kDa Components of the U1-snRNP Complex: “Double or Nothing”?
by Daniel Bertin, Benjamin Babacci, Alexandre Brodovitch, Cléa Dubrou, Xavier Heim, Jean Louis Mege and Nathalie Bardin
Biomedicines 2024, 12(7), 1552; https://doi.org/10.3390/biomedicines12071552 - 12 Jul 2024
Viewed by 211
Abstract
Background: The positivity of anti-RNP autoantibodies as biological criteria for the diagnosis of mixed connective tissue disease (MCTD) has recently divided the rheumatology community. Autoantigenicity of the U1-snRNP complex tends to generate multiple autoantibodies against RNP-A, -C and -70 KDa or Sm proteins. [...] Read more.
Background: The positivity of anti-RNP autoantibodies as biological criteria for the diagnosis of mixed connective tissue disease (MCTD) has recently divided the rheumatology community. Autoantigenicity of the U1-snRNP complex tends to generate multiple autoantibodies against RNP-A, -C and -70 KDa or Sm proteins. The aim of this study is to identify the most informative autoantibodies in clinical practice, in particular, to contribute to differential diagnosis between MCTD and systemic lupus erythematosus (SLE). Methods: Sera from 74 patients positive for anti-RNP autoantibodies were selected over a period of one year of laboratory practice. Autoantibodies directed against extractable nuclear antigen, RNP proteins (A, C, 70 KDa) and 40 kDa fragments of RNP-70 KDa were investigated by using quantitative fluoroenzymatic assay and Western blot analysis. Results: Among the 74 patients, 40 patients were diagnosed with SLE, 20 with MCTD, six with another autoimmune disease, three with SARS-CoV-2 infection, three with cancer and two were healthy. No preferential clinical association of IgG or IgM autoantibodies directed against each of the RNP proteins was found between SLE and MCTD. In contrast, the proportion of autoantibodies directed against the RNP component within the U1-snRNP complex showed a significantly higher RNP index in patients with MCTD than in those with SLE (p = 0.011), with good performance (sensitivity: 69.2%, specificity: 88.9%). Conclusions: The analysis of the proportion of the different autoantibodies directed against the U1-snRNP complex is more informative than the analysis of each autoantibody separately. A follow-up of patients could be informative about the interest of the RNP index as a predictor of disease evolution. Full article
(This article belongs to the Section Molecular Genetics and Genetic Diseases)
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11 pages, 3611 KiB  
Article
Cannabielsoin (CBE), a CBD Oxidation Product, Is a Biased CB1 Agonist
by Mehdi Haghdoost, Scott Young, Matthew Roberts, Caitlyn Krebs and Marcel O. Bonn-Miller
Biomedicines 2024, 12(7), 1551; https://doi.org/10.3390/biomedicines12071551 - 12 Jul 2024
Viewed by 217
Abstract
Cannabielsoin (CBE) is primarily recognized as an oxidation byproduct of cannabidiol (CBD) and a minor mammalian metabolite of CBD. The pharmacological interactions between CBE and cannabinoid receptors remain largely unexplored, particularly with respect to cannabinoid receptor type 1 (CB1). The present [...] Read more.
Cannabielsoin (CBE) is primarily recognized as an oxidation byproduct of cannabidiol (CBD) and a minor mammalian metabolite of CBD. The pharmacological interactions between CBE and cannabinoid receptors remain largely unexplored, particularly with respect to cannabinoid receptor type 1 (CB1). The present study aimed to elucidate the interaction dynamics of CBE in relation to CB1 by employing cyclic adenosine monophosphate (cAMP) and β-arrestin assays to assess its role as an agonist, antagonist, and positive allosteric modulator (PAM). To our knowledge, this is the first publication to investigate CBE’s receptor activity in vitro. Our findings reveal that S-CBE acts as an agonist to CB1 with EC50 = 1.23 µg/mL (3.7 µM) in the cAMP assay. No agonist activity was observed in the β-arrestin assay in concentrations up to 12 µM, suggesting a noteworthy affinity towards G-protein activation and the cAMP signaling pathway. Furthermore, in silico molecular docking simulations were conducted to provide a structural basis for the interaction between CBE and CB1, offering insights into the molecular determinants of its receptor affinity and functional selectivity. Full article
(This article belongs to the Special Issue Compounds from Natural Products as Sources for Drug Discovery)
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18 pages, 3012 KiB  
Article
CRISPR Base Editing to Create Potential Charcot–Marie–Tooth Disease Models with High Editing Efficiency: Human Induced Pluripotent Stem Cell Harboring SH3TC2 Variants
by Camille Loret, Amandine Pauset, Pierre-Antoine Faye, Valérie Prouzet-Mauleon, Ioanna Pyromali, Angélique Nizou, Federica Miressi, Franck Sturtz, Frédéric Favreau, Béatrice Turcq and Anne-Sophie Lia
Biomedicines 2024, 12(7), 1550; https://doi.org/10.3390/biomedicines12071550 - 12 Jul 2024
Viewed by 234
Abstract
Human induced pluripotent stem cells (hiPSCs) represent a powerful tool to investigate neuropathological disorders in which the cells of interest are inaccessible, such as in the Charcot–Marie–Tooth disease (CMT), the most common inherited peripheral neuropathy. Developing appropriate cellular models becomes crucial in order [...] Read more.
Human induced pluripotent stem cells (hiPSCs) represent a powerful tool to investigate neuropathological disorders in which the cells of interest are inaccessible, such as in the Charcot–Marie–Tooth disease (CMT), the most common inherited peripheral neuropathy. Developing appropriate cellular models becomes crucial in order to both study the disease’s pathophysiology and test new therapeutic approaches. The generation of hiPS cellular models for disorders caused by a single nucleotide variation has been significantly improved following the development of CRISPR-based editing tools. In this study, we efficiently and quickly generated, by CRISPR editing, the two first hiPSCs cellular models carrying alterations involved in CMT4C, also called AR-CMTde-SH3TC2. This subtype of CMT is associated with alterations in the SH3TC2 gene and represents the most prevalent form of autosomal recessive demyelinating CMT. We aimed to develop models for two different SH3TC2 nonsense variants, c.211C>T, p.Gln71* and the most common AR-CMTde-SH3TC2 alteration, c.2860C>T, p.Arg954*. First, in order to determine the best CRISPR strategy to adopt on hiPSCs, we first tested a variety of sgRNAs combined with a selection of recent base editors using the conveniently cultivable and transfectable HEK-293T cell line. The chosen CRISPR base-editing strategy was then applied to hiPSCs derived from healthy individuals to generate isogenic CMT disease models with up to 93% editing efficiency. For point mutation generation, we first recommend to test your strategies on alternative cell line such as HEK-293T before hiPSCs to evaluate a variety of sgRNA-BE combinations, thus boosting the chance of achieving edited cellular clones with the hard-to-culture and to transfect hiPSCs. Full article
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18 pages, 1776 KiB  
Review
Routinely Used and Emerging Diagnostic and Immunotherapeutic Approaches for Wheat Allergy
by Wanqi Zheng, Christine Yee Yan Wai, Jason Ka Chun Sit, Nam Sze Cheng, Christy Wing Man Leung and Ting Fan Leung
Biomedicines 2024, 12(7), 1549; https://doi.org/10.3390/biomedicines12071549 - 12 Jul 2024
Viewed by 209
Abstract
Wheat, a component of the staple diet globally, is a common food allergen in children. The symptoms of wheat allergy (WA) range from skin rash to shortness of breath, significantly impairing quality of life. Following initial clinical suspicion, individuals may undergo routinely used [...] Read more.
Wheat, a component of the staple diet globally, is a common food allergen in children. The symptoms of wheat allergy (WA) range from skin rash to shortness of breath, significantly impairing quality of life. Following initial clinical suspicion, individuals may undergo routinely used allergy tests such as a wheat allergen-specific skin prick test (SPT), a blood test for specific immunoglobulin E (sIgE) levels, or oral food challenge. Conventional management of WA lies in wheat avoidance, yet accidental consumption may be inevitable owing to the ubiquity of wheat in various food products. This article aims to provide an overview of the immunologic pathway of WA, followed by its emerging diagnostic methods, namely alcohol-soluble SPT extracts, component-resolved diagnosis, and the basophil activation test (BAT). The mechanisms underlying wheat allergen-specific oral immunotherapy (OIT) as well as a summary of the efficacy, tolerability, and safety of related clinical trials will then be discussed. Full article
(This article belongs to the Collection Feature Papers in Immunology and Immunotherapy)
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22 pages, 3709 KiB  
Review
Unraveling Chylomicron Retention Disease Enhances Insight into SAR1B GTPase Functions and Mechanisms of Actions, While Shedding Light of Intracellular Chylomicron Trafficking
by Emile Levy, Catherine Fallet-Bianco, Nickolas Auclair, Natalie Patey, Valérie Marcil, Alain Théophile Sané and Schohraya Spahis
Biomedicines 2024, 12(7), 1548; https://doi.org/10.3390/biomedicines12071548 - 12 Jul 2024
Viewed by 277
Abstract
Over the past three decades, significant efforts have been focused on unraveling congenital intestinal disorders that disrupt the absorption of dietary lipids and fat-soluble vitamins. The primary goal has been to gain deeper insights into intra-enterocyte sites, molecular steps, and crucial proteins/regulatory pathways [...] Read more.
Over the past three decades, significant efforts have been focused on unraveling congenital intestinal disorders that disrupt the absorption of dietary lipids and fat-soluble vitamins. The primary goal has been to gain deeper insights into intra-enterocyte sites, molecular steps, and crucial proteins/regulatory pathways involved, while simultaneously identifying novel therapeutic targets and diagnostic tools. This research not only delves into specific and rare malabsorptive conditions, such as chylomicron retention disease (CRD), but also contributes to our understanding of normal physiology through the utilization of cutting-edge cellular and animal models alongside advanced research methodologies. This review elucidates how modern techniques have facilitated the decoding of CRD gene defects, the identification of dysfunctional cellular processes, disease regulatory mechanisms, and the essential role of coat protein complex II-coated vesicles and cargo receptors in chylomicron trafficking and endoplasmic reticulum (ER) exit sites. Moreover, experimental approaches have shed light on the multifaceted functions of SAR1B GTPase, wherein loss-of-function mutations not only predispose individuals to CRD but also exacerbate oxidative stress, inflammation, and ER stress, potentially contributing to clinical complications associated with CRD. In addition to dissecting the primary disease pathology, genetically modified animal models have emerged as invaluable assets in exploring various ancillary aspects, including responses to environmental challenges such as dietary alterations, gender-specific disparities in disease onset and progression, and embryonic lethality or developmental abnormalities. In summary, this comprehensive review provides an in-depth and contemporary analysis of CRD, offering a meticulous examination of the CRD current landscape by synthesizing the latest research findings and advancements in the field. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Gastrointestinal Tract Disease)
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17 pages, 882 KiB  
Review
The Clinical Significance and Application of Heart Rate Variability in Dialysis Patients: A Narrative Review
by Rong-Na Jhen, Ping-Chen Wang, Yu-Ming Chang, Jsun-Liang Kao, Eric Chien-Hwa Wu and Chih-Chung Shiao
Biomedicines 2024, 12(7), 1547; https://doi.org/10.3390/biomedicines12071547 - 11 Jul 2024
Viewed by 281
Abstract
Autonomic nervous system (ANS) dysfunction is prevalent in end-stage kidney disease (ESKD) patients, carrying significant risks for morbidity and mortality. Heart rate variability (HRV) is a simple and non-invasive method to evaluate ANS functions and predict prognoses in specific patient populations. Since there [...] Read more.
Autonomic nervous system (ANS) dysfunction is prevalent in end-stage kidney disease (ESKD) patients, carrying significant risks for morbidity and mortality. Heart rate variability (HRV) is a simple and non-invasive method to evaluate ANS functions and predict prognoses in specific patient populations. Since there is a lack of a clear understanding of the clinical significance of HRV in predicting prognoses in ESKD patients, an updated review on this topic is urgently warranted. The clinical significance of HRV in dialysis patients includes its associations with metabolic syndrome, nutritional status, intradialytic hypotension, vascular access failure, major adverse cardiovascular events, and mortality. These findings underscore the essential role of the autonomic reserve, which might denote the elevation of ANS activity as a response to external stimulus. Patients with a higher level of sympathetic activity at the resting stage, but who are unable to adequately elevate their sympathetic activity under stress might be susceptible to a worse outcome in critical circumstances. Further applications of HRV include HRV biofeedback, risk classification, and real-time HRV monitoring. Overall, HRV is an optimal tool for predicting prognoses in dialysis patients. Further study is encouraged in order to gain a clearer understanding of the clinical significance and application of HRV, and thereby enhance the care of ESKD patients. Full article
37 pages, 4442 KiB  
Review
Forms of Non-Apoptotic Cell Death and Their Role in Gliomas—Presentation of the Current State of Knowledge
by Reinhold Nafe and Elke Hattingen
Biomedicines 2024, 12(7), 1546; https://doi.org/10.3390/biomedicines12071546 - 11 Jul 2024
Viewed by 249
Abstract
In addition to necrosis and apoptosis, the two forms of cell death that have been known for many decades, other non-apoptotic forms of cell death have been discovered, many of which also play a role in tumors. Starting with the description of autophagy [...] Read more.
In addition to necrosis and apoptosis, the two forms of cell death that have been known for many decades, other non-apoptotic forms of cell death have been discovered, many of which also play a role in tumors. Starting with the description of autophagy more than 60 years ago, newer forms of cell death have become important for the biology of tumors, such as ferroptosis, pyroptosis, necroptosis, and paraptosis. In this review, all non-apoptotic and oncologically relevant forms of programmed cell death are presented, starting with their first descriptions, their molecular characteristics, and their role and their interactions in cell physiology and pathophysiology. Based on these descriptions, the current state of knowledge about their alterations and their role in gliomas will be presented. In addition, current efforts to therapeutically influence the molecular components of these forms of cell death will be discussed. Although research into their exact role in gliomas is still at a rather early stage, our review clarifies that all these non-apoptotic forms of cell death show significant alterations in gliomas and that important insight into understanding them has already been gained. Full article
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16 pages, 3948 KiB  
Article
Licofelone, a Dual COX/LOX Inhibitor, Ameliorates Paclitaxel-Induced Mechanical Allodynia in Rats in a Cannabinoid Receptor-Dependent Manner
by Willias Masocha, Esraa Aly, Aisha Albaloushi and Altaf Al-Romaiyan
Biomedicines 2024, 12(7), 1545; https://doi.org/10.3390/biomedicines12071545 - 11 Jul 2024
Viewed by 326
Abstract
The use of paclitaxel as a chemotherapeutic drug is limited by the development of dose-dependent paclitaxel-induced neuropathic pain (PINP). Recently, we observed that the combination of indomethacin plus minocycline (IPM) attenuates PINP in a mouse model in a cannabinoid (CB) receptor-dependent manner. Indomethacin [...] Read more.
The use of paclitaxel as a chemotherapeutic drug is limited by the development of dose-dependent paclitaxel-induced neuropathic pain (PINP). Recently, we observed that the combination of indomethacin plus minocycline (IPM) attenuates PINP in a mouse model in a cannabinoid (CB) receptor-dependent manner. Indomethacin inhibits cyclooxygenase (COX) activity, and minocycline inhibits 5-lipoxygenase (5-LOX) activity. Male Sprague Dawley rats with paclitaxel-induced mechanical allodynia were treated with indomethacin, minocycline, IPM combination, licofelone (a dual COX/LOX inhibitor), or their vehicles. AM251, a CB1 receptor antagonist, and AM630, a CB2 receptor antagonist, were administered before the IPM combination or licofelone. Mechanical allodynia was measured using a dynamic plantar aesthesiometer. Molecular docking was performed using CB-Dock2. Licofelone and IPM combination had antiallodynic effects, which were significantly higher than either indomethacin or minocycline alone. AM251 and AM630 blocked the antiallodynic effects of IPM combination and licofelone. Molecular docking showed that licofelone binds to both CB1 and CB2 receptors with a high affinity similar to the phytocannabinoid 1-trans-delta-9-tetrahydrocannabinol and the synthetic cannabinoid WIN 55,212-2. Licofelone inhibits COX and LOX and/or directly interacts with CB receptors to produce antiallodynic effects in a rat model of PINP. The findings further suggest that licofelone could be a therapeutic agent for managing PINP. Full article
(This article belongs to the Special Issue Therapeutic Potential for Cannabis and Cannabinoids 2.0)
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32 pages, 2361 KiB  
Review
The Categorization of Perinatal Derivatives for Orthopedic Applications
by Amol H. Trivedi, Vicki Z. Wang, Edward J. McClain IV, Praveer S. Vyas, Isaac R. Swink, Edward D. Snell, Boyle C. Cheng and Patrick J. DeMeo
Biomedicines 2024, 12(7), 1544; https://doi.org/10.3390/biomedicines12071544 - 11 Jul 2024
Viewed by 269
Abstract
Musculoskeletal (MSK) pathology encompasses an array of conditions that can cause anything from mild discomfort to permanent injury. Their prevalence and impact on disability have sparked interest in more effective treatments, particularly within orthopedics. As a result, the human placenta has come into [...] Read more.
Musculoskeletal (MSK) pathology encompasses an array of conditions that can cause anything from mild discomfort to permanent injury. Their prevalence and impact on disability have sparked interest in more effective treatments, particularly within orthopedics. As a result, the human placenta has come into focus within regenerative medicine as a perinatal derivative (PnD). These biologics are sourced from components of the placenta, each possessing a unique composition of collagens, proteins, and factors believed to aid in healing and regeneration. This review aims to explore the current literature on PnD biologics and their potential benefits for treating various MSK pathologies. We delve into different types of PnDs and their healing effects on muscles, tendons, bones, cartilage, ligaments, and nerves. Our discussions highlight the crucial role of immune modulation in the healing process for each condition. PnDs have been observed to influence the balance between anti- and pro-inflammatory factors and, in some cases, act as biologic scaffolds for tissue growth. Additionally, we assess the range of PnDs available, while also addressing gaps in our understanding, particularly regarding biologic processing methods. Although certain PnD biologics have varying levels of support in orthopedic literature, further clinical investigations are necessary to fully evaluate their impact on human patients. Full article
22 pages, 2407 KiB  
Review
Fibromyalgia: A Review of the Pathophysiological Mechanisms and Multidisciplinary Treatment Strategies
by Lina Noelia Jurado-Priego, Cristina Cueto-Ureña, María Jesús Ramírez-Expósito and José Manuel Martínez-Martos
Biomedicines 2024, 12(7), 1543; https://doi.org/10.3390/biomedicines12071543 - 11 Jul 2024
Viewed by 372
Abstract
Fibromyalgia is a syndrome characterized by chronic widespread musculoskeletal pain, which may or may not be associated with muscle or joint stiffness, accompanied by other symptoms such as fatigue, sleep disturbances, anxiety, and depression. It is a highly prevalent condition globally, being considered [...] Read more.
Fibromyalgia is a syndrome characterized by chronic widespread musculoskeletal pain, which may or may not be associated with muscle or joint stiffness, accompanied by other symptoms such as fatigue, sleep disturbances, anxiety, and depression. It is a highly prevalent condition globally, being considered the third most common musculoskeletal disorder, following lower back pain and osteoarthritis. It is more prevalent in women than in men, and although it can occur at any age, it is more common between the ages of thirty and thirty-five. Although the pathophysiology and etiopathogenesis remain largely unknown, three underlying processes in fibromyalgia have been investigated. These include central sensitization, associated with an increase in the release of both excitatory and inhibitory neurotransmitters; peripheral sensitization, involving alterations in peripheral nociceptor signaling; and inflammatory and immune mechanisms that develop concurrently with the aforementioned processes. Furthermore, it has been determined that genetic, endocrine, psychological, and sleep disorders may influence the development of this pathology. The accurate diagnosis of fibromyalgia remains challenging as it lacks specific diagnostic biomarkers, which are still under investigation. Nonetheless, diagnostic approaches to the condition have evolved based on the use of scales and questionnaires for pain identification. The complexity associated with this pathology makes it difficult to establish a single effective treatment. Therefore, treatment is multidisciplinary, involving both pharmacological and non-pharmacological interventions aimed at alleviating symptoms. The non-pharmacological treatments outlined in this review are primarily related to physiotherapy interventions. The effectiveness of physical exercise, both on land and in water, as well as the application of electrotherapy combined with transcranial therapy and manual therapy has been highlighted. All of these interventions aim to improve the quality of life of patients highly affected by fibromyalgia. Full article
(This article belongs to the Special Issue Advanced Research on Fibromyalgia (2nd Edition))
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22 pages, 3826 KiB  
Article
Immunoexpression Patterns of Megalin, Cubilin, Caveolin-1, Gipc1 and Dab2IP in the Embryonic and Postnatal Development of the Kidneys in Yotari (Dab1−/−) Mice
by Sani Žužul, Nela Kelam, Anita Racetin, Petra Kovačević, Suzana Konjevoda, Natalija Filipović, Nikola Pavlović and Katarina Vukojević
Biomedicines 2024, 12(7), 1542; https://doi.org/10.3390/biomedicines12071542 - 11 Jul 2024
Viewed by 248
Abstract
Our study examines the immunoexpression patterns of Megalin, Cubilin, Caveolin-1, Gipc1 and Dab2IP in the embryonic development (E) and postnatal (P) mouse kidney, with a focus on differentiating patterns between wild-type (wt) and yotari, Dab1−/− (yot) mice. Immunofluorescence revealed [...] Read more.
Our study examines the immunoexpression patterns of Megalin, Cubilin, Caveolin-1, Gipc1 and Dab2IP in the embryonic development (E) and postnatal (P) mouse kidney, with a focus on differentiating patterns between wild-type (wt) and yotari, Dab1−/− (yot) mice. Immunofluorescence revealed raised immunoexpression of receptors Megalin and Cubilin at the ampulla/collecting ducts and convoluted tubules across all developmental stages, with the most prominent immunoexpression observed in the convoluted tubules and the parietal epithelium of the Bowman’s capsule. Quantitative analysis showed a higher percentage of Megalin and Cubilin in wt compared to yot mice at E13.5. Co-expression of Megalin and Cubilin was observed at the apical membrane of convoluted tubules and the parietal layer of the Bowman’s capsule. The staining intensity of Megalin varied across developmental stages, with the strongest reactivity observed at the ampulla and collecting ducts at embryonic day (E) 13.5 in wt mice. In contrast, Caveolin-1 exhibited high immunoexpression in the metanephric mesenchyme, blood vessels, and the border area between the metanephric mesenchyme and renal vesicle, with a decrease in immunoexpression as development progressed. Gipc1 showed diffuse cytoplasmic staining in metanephric mesenchyme, convoluted tubules and collecting ducts, with significant differences in immunoexpression between wild-type and yot mice at both investigated embryonic time points. Dab2IP immunofluorescent staining was most prominent in renal vesicle/glomeruli and ampulla/collecting ducts at E13.5, with mild staining intensity observed in the distal convoluted tubules postnatally. Our findings elucidate distinct immunoexpression of patterns and potential parts of these proteins in the development and function of the kidney, highlighting the importance of further investigation into their regulatory mechanisms. Full article
(This article belongs to the Section Molecular Genetics and Genetic Diseases)
16 pages, 1345 KiB  
Article
Can We Go beyond Pathology? The Prognostic Role of Risk Scoring Tools for Cancer-Specific Survival of Patients with Bladder Cancer Undergoing Radical Cystectomy
by Aleksander Ślusarczyk, Rafał Wolański, Jerzy Miłow, Hanna Piekarczyk, Piotr Lipiński, Piotr Zapała, Grzegorz Niemczyk, Paweł Kurzyna, Andrzej Wróbel, Waldemar Różański, Piotr Radziszewski and Łukasz Zapała
Biomedicines 2024, 12(7), 1541; https://doi.org/10.3390/biomedicines12071541 - 11 Jul 2024
Viewed by 205
Abstract
Radical cystectomy (RC) remains a mainstay surgical treatment for non-metastatic muscle-invasive and BCG-unresponsive bladder cancer. Various perioperative scoring tools assess comorbidity burden, complication risks, and cancer-specific mortality (CSM) risk. We investigated the prognostic value of these scores in patients who underwent RC between [...] Read more.
Radical cystectomy (RC) remains a mainstay surgical treatment for non-metastatic muscle-invasive and BCG-unresponsive bladder cancer. Various perioperative scoring tools assess comorbidity burden, complication risks, and cancer-specific mortality (CSM) risk. We investigated the prognostic value of these scores in patients who underwent RC between 2015 and 2021. Cox proportional hazards were used in survival analyses. Risk models’ accuracy was assessed with the concordance index (C-index) and area under the curve. Among 215 included RC patients, 63 (29.3%) died, including 53 (24.7%) cancer-specific deaths, with a median follow-up of 39 months. The AJCC system, COBRA score, and Charlson comorbidity index (CCI) predicted CSM with low accuracy (C-index: 0.66, 0.65; 0.59, respectively). Multivariable Cox regression identified the AJCC system and CCI > 5 as significant CSM predictors. Additional factors included the extent of lymph node dissection, histology, smoking, presence of concomitant CIS, and neutrophil-to-lymphocyte ratio, and model accuracy was high (C-index: 0.80). The internal validation of the model with bootstrap samples revealed its slight optimism of 0.06. In conclusion, the accuracy of the AJCC staging system in the prediction of CSM is low and can be improved with the inclusion of other pathological data, CCI, smoking history and inflammatory indices. Full article
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14 pages, 1262 KiB  
Review
Role of ncRNAs in the Pathogenesis of Sjögren’s Syndrome
by Amal Al-Haidose, Sondoss Hassan, Mahmoud Elhassan, Eiman Ahmed, Abdulla Al-Riashi, Yazeed M. Alharbi, Monther Ghunaim, Talal Alhejaili and Atiyeh M. Abdallah
Biomedicines 2024, 12(7), 1540; https://doi.org/10.3390/biomedicines12071540 - 11 Jul 2024
Viewed by 239
Abstract
Sjögren’s syndrome is a multisystemic autoimmune disease that mainly affects the exocrine glands, causing dryness of the eyes and the mouth as the principal symptoms. Non-coding RNAs (ncRNAs), once regarded as genomic “junk”, are now appreciated as important molecular regulators of gene expression, [...] Read more.
Sjögren’s syndrome is a multisystemic autoimmune disease that mainly affects the exocrine glands, causing dryness of the eyes and the mouth as the principal symptoms. Non-coding RNAs (ncRNAs), once regarded as genomic “junk”, are now appreciated as important molecular regulators of gene expression, not least in Sjögren’s syndrome and other autoimmune diseases. Here we review research into the causative roles of microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) on immunological responses, inflammation, and salivary gland epithelial cell function in Sjögren’s syndrome patients. These ncRNAs represent promising new therapeutic targets for treating the disease and possibly as biomarkers for early diagnosis. Full article
(This article belongs to the Special Issue MicroRNA and Its Role in Human Health)
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13 pages, 1830 KiB  
Article
Plasma Neurofilament Light Chain: A Potential Biomarker for Neurological Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
by Naiara Azcue, Beatriz Tijero-Merino, Marian Acera, Raquel Pérez-Garay, Tamara Fernández-Valle, Naia Ayo-Mentxakatorre, Marta Ruiz-López, Jose Vicente Lafuente, Juan Carlos Gómez Esteban and Rocio Del Pino
Biomedicines 2024, 12(7), 1539; https://doi.org/10.3390/biomedicines12071539 - 11 Jul 2024
Viewed by 540
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder characterized by heterogeneous symptoms, which lack specific biomarkers for its diagnosis. This study aimed to investigate plasma neurofilament light chain (NfL) levels as a potential biomarker for ME/CFS and explore associations with cognitive, autonomic, [...] Read more.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder characterized by heterogeneous symptoms, which lack specific biomarkers for its diagnosis. This study aimed to investigate plasma neurofilament light chain (NfL) levels as a potential biomarker for ME/CFS and explore associations with cognitive, autonomic, and neuropathic symptoms. Here, 67 ME/CFS patients and 43 healthy controls (HCs) underwent comprehensive assessments, including neuropsychological evaluation, autonomic nervous system (ANS) testing, and plasma NfL level analysis. ME/CFS patients exhibited significantly higher plasma NfL levels compared to HC (F = 4.30, p < 0.05). Correlations were observed between NfL levels and cognitive impairment, particularly in visuospatial perception (r = −0.42; p ≤ 0.001), verbal memory (r = −0.35, p ≤ 0.005), and visual memory (r = −0.26; p < 0.05) in ME/CFS. Additionally, higher NfL levels were associated with worsened autonomic dysfunction in these patients, specifically in parasympathetic function (F = 9.48, p ≤ 0.003). In ME/CFS patients, NfL levels explained up to 17.2% of the results in cognitive tests. Unlike ME/CFS, in HC, NfL levels did not predict cognitive performance. Elevated plasma NfL levels in ME/CFS patients reflect neuroaxonal damage, contributing to cognitive dysfunction and autonomic impairment. These findings support the potential role of NfL as a biomarker for neurological dysfunction in ME/CFS. Further research is warranted to elucidate underlying mechanisms and clinical implications. Full article
(This article belongs to the Special Issue Biomarkers in Neurological Disorders)
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20 pages, 5648 KiB  
Article
Experimental Insights on the Use of Secukinumab and Magnolol in Acute Respiratory Diseases in Mice
by Andrei Gheorghe Vicovan, Diana Cezarina Petrescu, Daniela Constantinescu, Elena Iftimi, Irina Teodora Cernescu, Codrina Mihaela Ancuta, Cezar-Cătălin Caratașu, Laurențiu Șorodoc, Alexandr Ceasovschih, Carmen Solcan and Cristina Mihaela Ghiciuc
Biomedicines 2024, 12(7), 1538; https://doi.org/10.3390/biomedicines12071538 - 11 Jul 2024
Viewed by 235
Abstract
This study investigates the combined treatment of secukinumab (SECU) and magnolol (MAGN) in a mouse model of LPS-induced ALI overlapped with allergic pulmonary inflammation, aiming to better understand the mechanism behind this pathology and to assess the therapeutic potential of this novel approach [...] Read more.
This study investigates the combined treatment of secukinumab (SECU) and magnolol (MAGN) in a mouse model of LPS-induced ALI overlapped with allergic pulmonary inflammation, aiming to better understand the mechanism behind this pathology and to assess the therapeutic potential of this novel approach in addressing the severity of ALI. The combined treatment reveals intricate immunomodulatory effects. Both treatments inhibit IL-17 and promote M2 macrophage polarization, which enhances anti-inflammatory cytokine production such as IL-4, IL-5, IL-10, and IL-13, crucial for lung repair and inflammation resolution. However, the combination treatment exacerbates allergic responses and increases OVA-specific IgE, potentially worsening ALI outcomes. MAGN pretreatment alone demonstrates higher potency in reducing neutrophils and enhancing IFN-γ, suggesting its potential in mitigating severe asthma symptoms and modulating immune responses. The study highlights the need for careful consideration in therapeutic applications due to the combination treatment’s inability to reduce IL-6 and its potential to exacerbate allergic inflammation. Elevated IL-6 levels correlate with worsened oxygenation and increased mortality in ALI patients, underscoring its critical role in disease severity. These findings offer valuable insights for the advancement of precision medicine within the realm of respiratory illnesses, emphasizing the importance of tailored therapeutic strategies. Full article
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13 pages, 2716 KiB  
Article
Causal Effects and Immune Cell Mediators of Prescription Analgesic Use and Risk of Liver Cancer and Precancerosis in European Population: A Mendelian Randomization Study
by Xuewen Tao, Shuai Mao, Jincheng Wang, Guoqiang Li and Beicheng Sun
Biomedicines 2024, 12(7), 1537; https://doi.org/10.3390/biomedicines12071537 - 11 Jul 2024
Viewed by 271
Abstract
Diverse clinical observations and basic studies have been conducted to explore the implications of analgesic medications in liver diseases. However, the direct causal relationship between prescription analgesic use (PAU) and the risk of liver cancer and precancerosis remains unclear. Thus, we aimed to [...] Read more.
Diverse clinical observations and basic studies have been conducted to explore the implications of analgesic medications in liver diseases. However, the direct causal relationship between prescription analgesic use (PAU) and the risk of liver cancer and precancerosis remains unclear. Thus, we aimed to reveal the conceivable causal effect of PAU on liver cancer and precancerosis, with immune cells as mediating factors. Two-sample Mendelian randomization (MR) analyses were performed to ascertain the causality of PAU on liver cancer and precancerosis. Sensitivity analysis approaches were employed to assess the heterogeneity and pleiotropy of results. Our findings revealed a causal correlation between different PAUs and the risk of liver cancer and alcoholic liver disease (ALD). Specifically, salicylic acid derivatives (SADs) and anilide medications were found to have a protective effect on liver cancer. And non-steroidal anti-inflammatory drugs (NSAIDs) and anilide medications showed a causal impact on ALD. Finally, mediation analyses found that anilide medications influence liver cancer through different immune cell phenotypes. Our research provides new genetic evidence for the causal impact of PAU on liver cancer and precancerosis, with the mediating role of immune cells demonstrated, offering a valuable foundation for researching analgesic medications in liver cancer and precancerosis treatment. Full article
(This article belongs to the Section Immunology and Immunotherapy)
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15 pages, 5814 KiB  
Article
Cerebral Endothelial CXCR2 Promotes Neutrophil Transmigration into Central Nervous System in LPS-Induced Septic Encephalopathy
by Fengjiao Wu, Yuhong Han, Qianqian Xiong, Haitao Tang, Jing Shi, Qingqing Yang, Xuemeng Li, Haoxuan Jia, Jun Qian, Yishu Dong, Tuantuan Li, Yong Gao, Zhongqing Qian, Hongtao Wang and Ting Wang
Biomedicines 2024, 12(7), 1536; https://doi.org/10.3390/biomedicines12071536 - 11 Jul 2024
Viewed by 244
Abstract
Septic encephalopathy (SE) represents a severe inflammatory syndrome linked to elevated septic mortality rates, lacking specific therapeutic interventions, and often resulting in enduring neurological sequelae. The present investigation endeavors to elucidate the involvement of C-X-C Motif Chemokine Receptor 2 (CXCR2) in the pathogenesis [...] Read more.
Septic encephalopathy (SE) represents a severe inflammatory syndrome linked to elevated septic mortality rates, lacking specific therapeutic interventions, and often resulting in enduring neurological sequelae. The present investigation endeavors to elucidate the involvement of C-X-C Motif Chemokine Receptor 2 (CXCR2) in the pathogenesis of SE and to explore the potential of CXCR2 modulation as a therapeutic avenue for SE. Employing a murine SE model induced by lipopolysaccharide (LPS) administration, CXCR2 knockout mice and the CXCR2 inhibitor SB225002 were utilized to assess neutrophil recruitment, endothelial integrity, and transendothelial migration. Our findings substantiate that either CXCR2 deficiency or its inhibition curtails neutrophil recruitment without impacting their adhesion to cerebral endothelial cells. This phenomenon is contingent upon endothelial CXCR2 expression rather than CXCR2’s presence on neutrophils. Furthermore, the CXCR2 blockade preserves the integrity of tight junction protein ZO-1 and mitigates F-actin stress fiber formation in cerebral endothelial cells following septic challenge. Mechanistically, CXCL1-mediated CXCR2 activation triggers cerebral endothelial actin contraction via Rho signaling, thereby facilitating neutrophil transmigration in SE. These observations advocate for the potential therapeutic efficacy of CXCR2 inhibition in managing SE. Full article
(This article belongs to the Special Issue Sepsis and Septic Shock: From Molecular Mechanism to Novel Therapies)
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16 pages, 3009 KiB  
Article
Large Language Models and Genomics for Summarizing the Role of microRNA in Regulating mRNA Expression
by Balu Bhasuran, Sharanya Manoharan, Oviya Ramalakshmi Iyyappan, Gurusamy Murugesan, Archana Prabahar and Kalpana Raja
Biomedicines 2024, 12(7), 1535; https://doi.org/10.3390/biomedicines12071535 - 10 Jul 2024
Viewed by 310
Abstract
microRNA (miRNA)–messenger RNA (mRNA or gene) interactions are pivotal in various biological processes, including the regulation of gene expression, cellular differentiation, proliferation, apoptosis, and development, as well as the maintenance of cellular homeostasis and pathogenesis of numerous diseases, such as cancer, cardiovascular diseases, [...] Read more.
microRNA (miRNA)–messenger RNA (mRNA or gene) interactions are pivotal in various biological processes, including the regulation of gene expression, cellular differentiation, proliferation, apoptosis, and development, as well as the maintenance of cellular homeostasis and pathogenesis of numerous diseases, such as cancer, cardiovascular diseases, neurological disorders, and metabolic conditions. Understanding the mechanisms of miRNA–mRNA interactions can provide insights into disease mechanisms and potential therapeutic targets. However, extracting these interactions efficiently from a huge collection of published articles in PubMed is challenging. In the current study, we annotated a miRNA–mRNA Interaction Corpus (MMIC) and used it for evaluating the performance of a variety of machine learning (ML) models, deep learning-based transformer (DLT) models, and large language models (LLMs) in extracting the miRNA–mRNA interactions mentioned in PubMed. We used the genomics approaches for validating the extracted miRNA–mRNA interactions. Among the ML, DLT, and LLM models, PubMedBERT showed the highest precision, recall, and F-score, with all equal to 0.783. Among the LLM models, the performance of Llama-2 is better when compared to others. Llama 2 achieved 0.56 precision, 0.86 recall, and 0.68 F-score in a zero-shot experiment and 0.56 precision, 0.87 recall, and 0.68 F-score in a three-shot experiment. Our study shows that Llama 2 achieves better recall than ML and DLT models and leaves space for further improvement in terms of precision and F-score. Full article
(This article belongs to the Section Molecular Genetics and Genetic Diseases)
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14 pages, 441 KiB  
Review
Energy Metabolism and Metformin: Effects on Ischemia-Reperfusion Injury in Kidney Transplantation
by Denise V. Nemeth, Leonardo Iannelli, Elena Gangitano, Vito D’Andrea and Maria Irene Bellini
Biomedicines 2024, 12(7), 1534; https://doi.org/10.3390/biomedicines12071534 - 10 Jul 2024
Viewed by 242
Abstract
Metformin (MTF) is the only biguanide included in the World Health Organization’s list of essential medicines; representing a widespread drug in the management of diabetes mellitus. With its accessibility and affordability being one of its biggest assets, it has become the target of [...] Read more.
Metformin (MTF) is the only biguanide included in the World Health Organization’s list of essential medicines; representing a widespread drug in the management of diabetes mellitus. With its accessibility and affordability being one of its biggest assets, it has become the target of interest for many trying to find alternative treatments for varied pathologies. Over time, an increasing body of evidence has shown additional roles of MTF, with unexpected interactions of benefit in other diseases. Metformin (MTF) holds significant promise in mitigating ischemia-reperfusion injury (IRI), particularly in the realm of organ transplantation. As acceptance criteria for organ transplants expand, IRI during the preservation phase remain a major concern within the transplant community, prompting a keen interest in MTF’s effects. Emerging evidence suggests that administering MTF during reperfusion may activate the reperfusion injury salvage kinase (RISK) pathway. This pathway is pivotal in alleviating IRI in transplant recipients, potentially leading to improved outcomes such as reduced rates of organ rejection. This review aims to contextualize MTF historically, explore its current uses, pharmacokinetics, and pharmacodynamics, and link these aspects to the pathophysiology of IRI to illuminate its potential future role in transplantation. A comprehensive survey of the current literature highlights MTF’s potential to recondition and protect against IRI by attenuating free radical damage, activating AMP-activated protein kinase to preserve cellular energy and promote repair, as well as directly reducing inflammation and enhancing microcirculation. Full article
(This article belongs to the Special Issue Molecular Mechanism of Ischemia and Reperfusion Injury)
3 pages, 163 KiB  
Editorial
Editorial to the Special Issue “Theranostic Drug Delivery: Prospects and Problems”
by M. R. Mozafari
Biomedicines 2024, 12(7), 1533; https://doi.org/10.3390/biomedicines12071533 - 10 Jul 2024
Viewed by 282
Abstract
The technical phrase theragnostic (also known as theranostic) was first introduced to the scientific community in the year 1998 by John Funkhouser, to describe a methodology or procedure employed to achieve disease diagnosis and treatment simultaneously [...] Full article
(This article belongs to the Special Issue Theranostic Drug Delivery: Prospects and Problems)
11 pages, 930 KiB  
Article
Predictive Value and Diagnostic Potential of IL-10, IL-17A, IL1-β, IL-6, CXCL, and MCP for Severe COVID-19 and COVID-19 Mortality
by Roxana-Elena Cîrjaliu, Ioan-Tiberiu Tofolean, Doina-Ecaterina Tofolean, Anca Chisoi, Cristian Oancea, Emanuela Vastag, Monica Marc, Felix Bratosin, Ovidiu Rosca and Ariadna-Petronela Fildan
Biomedicines 2024, 12(7), 1532; https://doi.org/10.3390/biomedicines12071532 - 10 Jul 2024
Viewed by 292
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates advanced prognostic tools to anticipate disease progression and optimize patient outcomes. This study evaluates the predictive value and diagnostic potential of interleukins interleukin (IL) IL-10, IL-17A, IL1-β, IL-6, chemokine ligand (CXCL), and Monocyte Chemotactic [...] Read more.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates advanced prognostic tools to anticipate disease progression and optimize patient outcomes. This study evaluates the predictive value and diagnostic potential of interleukins interleukin (IL) IL-10, IL-17A, IL1-β, IL-6, chemokine ligand (CXCL), and Monocyte Chemotactic Protein (MCP) for severe coronavirus disease 2019 (COVID-19) and COVID-19 mortality, aiming to correlate cytokine levels with disease severity. Conducted from January 2023 to January 2024, this prospective cohort study involved patients hospitalized with moderate and severe COVID-19 from Romania. This study analyzed statistically significant predictors of severe COVID-19 outcomes. IL-6 and MCP emerged as significant, with hazard ratios (HRs) of 2.35 (95% confidence interval (CI): 1.54–3.59, p = 0.014) and 2.05 (95% CI: 1.22–3.45, p = 0.007), respectively. Compound scores integrating multiple inflammatory markers also demonstrated predictive value; Compound Score 2 had an HR of 2.23 (95% CI: 1.35–3.68, p = 0.002), surpassing most single markers in association with severe disease. Notably, interleukins IL-10 and IL-1β did not show significant associations with disease severity. This study underscores the importance of IL-6 and MCP as robust predictors of severe COVID-19, substantiating their role in clinical assessments to foresee patient deterioration. The utility of compound scores in enhancing predictive accuracy suggests a composite approach may be more effective in clinical settings. Full article
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26 pages, 2162 KiB  
Review
Insight into IL-5 as a Potential Target for the Treatment of Allergic Diseases
by Katarzyna Antosz, Joanna Batko, Marta Błażejewska, Antoni Gawor, Jakub Sleziak and Krzysztof Gomułka
Biomedicines 2024, 12(7), 1531; https://doi.org/10.3390/biomedicines12071531 - 10 Jul 2024
Viewed by 303
Abstract
Interleukin-5 functions as a B-cell differentiation factor, but more importantly, in the context of this review, it plays a variety of roles in eosinophil biology, including eosinophil differentiation and maturation in the bone marrow, and facilitates eosinophil migration to tissue sites, usually in [...] Read more.
Interleukin-5 functions as a B-cell differentiation factor, but more importantly, in the context of this review, it plays a variety of roles in eosinophil biology, including eosinophil differentiation and maturation in the bone marrow, and facilitates eosinophil migration to tissue sites, usually in the context of an allergic reaction. Given the availability of selective anti-IL-5 drugs such as mepolizumab and reslizumab, as well as the IL-5 receptor antagonist benralizumab, it is worth investigating whether they could be used in some cases of allergic disease. Asthma has a well-documented involvement of IL-5 in its pathophysiology and has clear benefits in the case of anti-IL-5 therapy; therefore, current knowledge is presented to provide a reference point for the study of less-described diseases such as atopic dermatitis, chronic rhinosinusitis, chronic spontaneous urticaria, and its association with both IL-5 and anti-IL-5 treatment options. We then review the current literature on these diseases, explain where appropriate potential reasons why anti-IL-5 treatments are ineffective, and then point out possible future directions for further research. Full article
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