Feature Papers in Section Molecular Medicine

A topical collection in Biomolecules (ISSN 2218-273X). This collection belongs to the section "Molecular Medicine".

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Guest Editor
Department of Biochemical Sciences “A. Rossi-Fanelli”, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Roma, Italy
Interests: proteostasis; oxidative stress; neurodegeneration; proteomics; Alzheimer’s disease
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Department of Biochemical Sciences “A. Rossi-Fanelli”, Sapienza University of Rome, 00185 Rome, Italy
Interests: Alzheimer disease; Down syndrome; oxidative stress; unfolded protein response (UPR); autophagy
Special Issues, Collections and Topics in MDPI journals

Topical Collection Information

Dear Colleagues,

This Special Issue entitled “Feature Papers in the Molecular Medicine Section” aims to collect high-quality research articles, review articles, and communications concerning all described different molecular mechanisms leading to the development of a pathological condition. This Special Issue is dedicated to recent advances in the area of molecular pathology and encourages the submission of papers discussing novel and highly profiled therapeutic strategies. It will include papers focused on pathological mechanisms in the central nervous system and peripheral organs, their mutual molecular alterations during disease, and the identification of brain and periphery molecular markers, as well as studies employing and/or discussing genomics, transcriptomics, and proteomics approaches. It will present a selection of exclusive papers from the Editorial Board Members (EBMs) of the Section of Biomolecules, as well as invited papers from relevant experts. We also welcome senior experts in the field to make contributions to this Special Issue. Kindly note that all invited papers will be published online free of charge once accepted. We aim to represent our section as an attractive open access publishing platform for molecular medicine research.

Dr. Fabio Di Domenico
Dr. Chiara Lanzillotta
Guest Editors

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Keywords

  • neurodegenerative diseases
  • metabolic disorders
  • oxidative stress
  • protein homeostasis
  • brain therapies

Published Papers (88 papers)

2024

Jump to: 2023, 2022, 2021, 2020

13 pages, 3808 KiB  
Article
Enhanced Metabolic Effects of Fish Oil When Combined with Vitamin D in Diet-Induced Obese Male Mice
by Latha Ramalingam, Brennan Mabry, Kalhara R. Menikdiwela, Hanna Moussa and Naima Moustaid-Moussa
Biomolecules 2024, 14(4), 474; https://doi.org/10.3390/biom14040474 - 12 Apr 2024
Viewed by 351
Abstract
Vitamin D (vit D) and fish oil (FO) both offer unique health benefits, however, their combined effects have not been evaluated in obesity and nonalcoholic fatty liver disease (NAFLD). Hence, we hypothesized that vit D and FO supplementation would have additive effects in [...] Read more.
Vitamin D (vit D) and fish oil (FO) both offer unique health benefits, however, their combined effects have not been evaluated in obesity and nonalcoholic fatty liver disease (NAFLD). Hence, we hypothesized that vit D and FO supplementation would have additive effects in reducing obesity-associated inflammation and NAFLD. Male C57BL6 mice were split into four groups and fed a high fat (HF) diet supplemented with a low (HF; +200 IU vit D) or high dose of vitamin D (HF + D; +1000 IU vit D); combination of vit D and FO (HF-FO; +1000 IU vit D); or only FO (HF-FO; +200 IU vit D) for 12 weeks. We measured body weight, food intake, glucose tolerance, and harvested epididymal fat pad and liver for gene expression analyses. Adiposity was reduced in groups supplemented with both FO and vit D. Glucose clearance was higher in FO-supplemented groups compared to mice fed HF. In adipose tissue, markers of fatty acid synthesis and oxidation were comparable in groups that received vit D and FO individually in comparison to HF. However, the vit D and FO group had significantly lower fatty acid synthesis and higher oxidation compared to the other groups. Vit D and FO also significantly improved fatty acid oxidation, despite similar fatty acid synthesis among the four groups in liver. Even though we did not find additive effects of vit D and FO, our data provide evidence that FO reduces markers of obesity in the presence of adequate levels of vit D. Full article
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24 pages, 908 KiB  
Review
Krill Oil and Its Bioactive Components as a Potential Therapy for Inflammatory Bowel Disease: Insights from In Vivo and In Vitro Studies
by Yingying Liu, Ainsley M. Robinson, Xiao Qun Su and Kulmira Nurgali
Biomolecules 2024, 14(4), 447; https://doi.org/10.3390/biom14040447 - 06 Apr 2024
Viewed by 515
Abstract
Krill oil is extracted from krill, a small crustacean in the Antarctic Ocean. It has received growing attention because of krill oil’s unique properties and diverse health benefits. Recent experimental and clinical studies suggest that it has potential therapeutic benefits in preventing the [...] Read more.
Krill oil is extracted from krill, a small crustacean in the Antarctic Ocean. It has received growing attention because of krill oil’s unique properties and diverse health benefits. Recent experimental and clinical studies suggest that it has potential therapeutic benefits in preventing the development of a range of chronic conditions, including inflammatory bowel disease (IBD). Krill oil is enriched with long-chain n-3 polyunsaturated fatty acids, especially eicosapentaenoic and docosahexaenoic acids, and the potent antioxidant astaxanthin, contributing to its therapeutic properties. The possible underlying mechanisms of krill oil’s health benefits include anti-inflammatory and antioxidant actions, maintaining intestinal barrier functions, and modulating gut microbiota. This review aims to provide an overview of the beneficial effects of krill oil and its bioactive components on intestinal inflammation and to discuss the findings on the molecular mechanisms associated with the role of krill oil in IBD prevention and treatment. Full article
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19 pages, 3153 KiB  
Article
The Antioxidant Drug Edaravone Binds to the Aryl Hydrocarbon Receptor (AHR) and Promotes the Downstream Signaling Pathway Activation
by Caterina Veroni, Stefania Olla, Maria Stefania Brignone, Chiara Siguri, Alessia Formato, Manuela Marra, Rosa Manzoli, Maria Carla Macario, Elena Ambrosini, Enrico Moro and Cristina Agresti
Biomolecules 2024, 14(4), 443; https://doi.org/10.3390/biom14040443 - 04 Apr 2024
Viewed by 486
Abstract
A considerable effort has been spent in the past decades to develop targeted therapies for the treatment of demyelinating diseases, such as multiple sclerosis (MS). Among drugs with free radical scavenging activity and oligodendrocyte protecting effects, Edaravone (Radicava) has recently received increasing attention [...] Read more.
A considerable effort has been spent in the past decades to develop targeted therapies for the treatment of demyelinating diseases, such as multiple sclerosis (MS). Among drugs with free radical scavenging activity and oligodendrocyte protecting effects, Edaravone (Radicava) has recently received increasing attention because of being able to enhance remyelination in experimental in vitro and in vivo disease models. While its beneficial effects are greatly supported by experimental evidence, there is a current paucity of information regarding its mechanism of action and main molecular targets. By using high-throughput RNA-seq and biochemical experiments in murine oligodendrocyte progenitors and SH-SY5Y neuroblastoma cells combined with molecular docking and molecular dynamics simulation, we here provide evidence that Edaravone triggers the activation of aryl hydrocarbon receptor (AHR) signaling by eliciting AHR nuclear translocation and the transcriptional-mediated induction of key cytoprotective gene expression. We also show that an Edaravone-dependent AHR signaling transduction occurs in the zebrafish experimental model, associated with a downstream upregulation of the NRF2 signaling pathway. We finally demonstrate that its rapid cytoprotective and antioxidant actions boost increased expression of the promyelinating Olig2 protein as well as of an Olig2:GFP transgene in vivo. We therefore shed light on a still undescribed potential mechanism of action for this drug, providing further support to its therapeutic potential in the context of debilitating demyelinating conditions. Full article
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18 pages, 5206 KiB  
Article
Corinthian Currants Promote the Expression of Paraoxonase-1 and Enhance the Antioxidant Status in Serum and Brain of 5xFAD Mouse Model of Alzheimer’s Disease
by Dimitris Lymperopoulos, Anastasia-Georgia Dedemadi, Maria-Lydia Voulgari, Eirini Georgiou, Ioannis Dafnis, Christina Mountaki, Eirini A. Panagopoulou, Michalis Karvelas, Antonia Chiou, Vaios T. Karathanos and Angeliki Chroni
Biomolecules 2024, 14(4), 426; https://doi.org/10.3390/biom14040426 - 01 Apr 2024
Viewed by 1338
Abstract
Paraoxonase-1 (PON1), a serum antioxidant enzyme, has been implicated in Alzheimer’s disease (AD) pathogenesis that involves early oxidative damage. Corinthian currants and their components have been shown to display antioxidant and other neuroprotective effects in AD. We evaluated the effect of a Corinthian [...] Read more.
Paraoxonase-1 (PON1), a serum antioxidant enzyme, has been implicated in Alzheimer’s disease (AD) pathogenesis that involves early oxidative damage. Corinthian currants and their components have been shown to display antioxidant and other neuroprotective effects in AD. We evaluated the effect of a Corinthian currant paste-supplemented diet (CurD), provided to 1-month-old 5xFAD mice for 1, 3, and 6 months, on PON1 activity and levels of oxidation markers in serum and the brain of mice as compared to a control diet (ConD) or glucose/fructose-matched diet (GFD). Administration of CurD for 1 month increased PON1 activity and decreased oxidized lipid levels in serum compared to ConD and GFD. Longer-term administration of CurD did not, however, affect serum PON1 activity and oxidized lipid levels. Furthermore, CurD administered for 1 and 3 months, but not for 6 months, increased PON1 activity and decreased free radical levels in the cortex of mice compared to ConD and GFD. To probe the mechanism for the increased PON1 activity in mice, we studied the effect of Corinthian currant polar phenolic extract on PON1 activity secreted by Huh-7 hepatocytes or HEK293 cells transfected with a PON1-expressing plasmid. Incubation of cells with the extract led to a dose-dependent increase of secreted PON1 activity, which was attributed to increased cellular PON1 expression. Collectively, our findings suggest that phenolics in Corinthian currants can increase the hepatic expression and activity of antioxidant enzyme PON1 and that a Corinthian currant-supplemented diet during the early stages of AD in mice reduces brain oxidative stress. Full article
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11 pages, 1113 KiB  
Review
Heterogeneity and Differentiation of the Human Arterial Tree: Focus on microRNA Expression in Vascular Disease
by Carmen Ciavarella, Ilenia Motta, Miriam Capri, Mauro Gargiulo and Gianandrea Pasquinelli
Biomolecules 2024, 14(3), 343; https://doi.org/10.3390/biom14030343 - 12 Mar 2024
Viewed by 754
Abstract
Human arteries show structural and functional peculiarities according to the nutrient and oxygen needs of a specific vascular district. This architectural heterogeneity is reflected in the pathological setting of cardiovascular diseases (CVDs). Indeed, the responsiveness to cardiovascular risk factors, and the morphological and [...] Read more.
Human arteries show structural and functional peculiarities according to the nutrient and oxygen needs of a specific vascular district. This architectural heterogeneity is reflected in the pathological setting of cardiovascular diseases (CVDs). Indeed, the responsiveness to cardiovascular risk factors, and the morphological and molecular patterns are discriminating factors among CVDs affecting different vascular beds. MicroRNAs (miRNAs) are endogenous regulators of gene expression and fine-tuners of vascular cell differentiation; thus, these non-coding RNAs can modulate arterial heterogeneity. The identification of an artery-specific miRNA signature would be promising in the therapy of CVDs, especially in patients who are frail and elderly. In the present review, we will provide a concise description of the arterial tree heterogeneity on a structural and cellular basis, mainly in the pathological context. Secondly, we will address the miRNA potential as crucial mediators of arterial heterogeneity, focusing on the abdominal aorta and femoral artery, with the final goal of strengthening the search for more targeted therapies in CVDs and stratification approaches in patients who are frail and elderly. Full article
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17 pages, 705 KiB  
Review
The Role of MUC1 in Renal Cell Carcinoma
by Martina Milella, Monica Rutigliano, Francesco Lasorsa, Matteo Ferro, Roberto Bianchi, Giuseppe Fallara, Felice Crocetto, Savio Domenico Pandolfo, Biagio Barone, Antonio d’Amati, Marco Spilotros, Michele Battaglia, Pasquale Ditonno and Giuseppe Lucarelli
Biomolecules 2024, 14(3), 315; https://doi.org/10.3390/biom14030315 - 07 Mar 2024
Viewed by 893
Abstract
Mucins are a family of high-molecular-weight glycoproteins. MUC1 is widely studied for its role in distinct types of cancers. In many human epithelial malignancies, MUC1 is frequently overexpressed, and its intracellular activities are crucial for cell biology. MUC1 overexpression can enhance cancer cell [...] Read more.
Mucins are a family of high-molecular-weight glycoproteins. MUC1 is widely studied for its role in distinct types of cancers. In many human epithelial malignancies, MUC1 is frequently overexpressed, and its intracellular activities are crucial for cell biology. MUC1 overexpression can enhance cancer cell proliferation by modulating cell metabolism. When epithelial cells lose their tight connections, due to the loss of polarity, the mucins become dispersed on both sides of the epithelial membrane, leading to an abnormal mucin interactome with the membrane. Tumor-related MUC1 exhibits certain features, such as loss of apical localization and aberrant glycosylation that might cause the formation of tumor-related antigen epitopes. Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and it is the most common kidney cancer. The exact role of MUC1 in this tumor is unknown. Evidence suggests that it may play a role in several oncogenic pathways, including proliferation, metabolic reprogramming, chemoresistance, and angiogenesis. The purpose of this review is to explore the role of MUC1 and the meaning of its overexpression in epithelial tumors and in particular in RCC. Full article
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18 pages, 2267 KiB  
Article
Alterations of the Adipo–Myokine Irisin in Sepsis and Septic Shock: Diagnostic and Prognostic Implications
by Irene Karampela, Natalia G. Vallianou, Dimitrios Tsilingiris, Gerasimos Socrates Christodoulatos, Sotiria Psallida, Dimitris Kounatidis, Theodora Stratigou, Ioanna Marinou, Evaggelos Vogiatzakis and Maria Dalamaga
Biomolecules 2024, 14(3), 291; https://doi.org/10.3390/biom14030291 - 29 Feb 2024
Viewed by 807
Abstract
Irisin, a novel adipo-myokine with metabolic regulatory functions, exerts anti-inflammatory, antioxidant, and anti-apoptotic actions that may confer protection against sepsis-induced organ injury in experimental studies. Until now, only one human study has explored circulating irisin at sepsis onset. We aimed to examine serum [...] Read more.
Irisin, a novel adipo-myokine with metabolic regulatory functions, exerts anti-inflammatory, antioxidant, and anti-apoptotic actions that may confer protection against sepsis-induced organ injury in experimental studies. Until now, only one human study has explored circulating irisin at sepsis onset. We aimed to examine serum irisin and its kinetics in critically ill patients with sepsis and septic shock with regard to sepsis severity and outcome. We enrolled 102 critically ill patients with sepsis or septic shock within 48 h of diagnosis and 102 age- and gender-matched healthy controls. Irisin was determined in serum upon enrollment in all participants and one week later in patients using an immunoenzymatic method. The outcome of sepsis was recorded 28 days after enrollment. At enrollment, circulating irisin was significantly lower in patients than controls (22.3 ± 6.8 μg/L vs. 28.1 ± 6.7 μg/L, p < 0.001), and increased significantly one week later (22.3 ± 6.8 μg/L vs. 26.6 ± 9.5 μg/L, p < 0.001). Irisin was significantly lower in patients who presented with septic shock than those with sepsis, and in non-survivors than survivors both at enrollment and one week later. However, kinetics of irisin did not differ between the groups (p > 0.05). Patients with higher circulating irisin during the first week of sepsis had a better outcome (p < 0.001). Lower irisin was independently associated with 28-day mortality (sepsis onset: HR 0.44, 95% C.I. 0.26–0.77, p = 0.004 and one week after: HR 0.37, 95% C.I. 0.23–0.58, p < 0.001). Irisin was negatively correlated with severity scores, metabolic, and inflammatory biomarkers. Circulating irisin decreases early in sepsis and is an independent predictor of 28-day mortality. Irisin may be a promising diagnostic and prognostic sepsis biomarker; nevertheless, larger studies are needed to explore its role in sepsis. Full article
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24 pages, 9656 KiB  
Review
The Expression of the Claudin Family of Proteins in Colorectal Cancer
by Kristin E. Cox, Shanglei Liu, Robert M. Hoffman, Surinder K. Batra, Punita Dhawan and Michael Bouvet
Biomolecules 2024, 14(3), 272; https://doi.org/10.3390/biom14030272 - 24 Feb 2024
Viewed by 951
Abstract
Claudins (CLDN1–CLDN24) are a family of tight junction proteins whose dysregulation has been implicated in tumorigeneses of many cancer types. In colorectal cancer (CRC), CLDN1, CLDN2, CLDN4, and CLDN18 have been shown to either be upregulated or aberrantly expressed. In the normal colon, [...] Read more.
Claudins (CLDN1–CLDN24) are a family of tight junction proteins whose dysregulation has been implicated in tumorigeneses of many cancer types. In colorectal cancer (CRC), CLDN1, CLDN2, CLDN4, and CLDN18 have been shown to either be upregulated or aberrantly expressed. In the normal colon, CLDN1 and CLDN3–7 are expressed. Although a few claudins, such as CLDN6 and CLDN7, are expressed in CRC their levels are reduced compared to the normal colon. The present review outlines the expression profiles of claudin proteins in CRC and those that are potential biomarkers for prognostication. Full article
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14 pages, 1792 KiB  
Review
Contribution of the Paraoxonase-2 Enzyme to Cancer Cell Metabolism and Phenotypes
by Roberto Campagna, Emma Nicol Serritelli, Eleonora Salvolini, Valentina Schiavoni, Monia Cecati, Davide Sartini, Valentina Pozzi and Monica Emanuelli
Biomolecules 2024, 14(2), 208; https://doi.org/10.3390/biom14020208 - 09 Feb 2024
Viewed by 832
Abstract
Paraoxonase-2 (PON2) is a ubiquitously expressed intracellular protein that is localized in the perinuclear region, the endoplasmic reticulum (ER), and mitochondria, and is also associated with the plasma membrane. PON2 functions as an antioxidant enzyme by reducing the levels of reactive oxygen species [...] Read more.
Paraoxonase-2 (PON2) is a ubiquitously expressed intracellular protein that is localized in the perinuclear region, the endoplasmic reticulum (ER), and mitochondria, and is also associated with the plasma membrane. PON2 functions as an antioxidant enzyme by reducing the levels of reactive oxygen species (ROS) in the mitochondria and ER through different mechanisms, thus having an anti-apoptotic effect and preventing the formation of atherosclerotic lesions. While the antiatherogenic role played by this enzyme has been extensively explored within endothelial cells in association with vascular disorders, in the last decade, great efforts have been made to clarify its potential involvement in both blood and solid tumors, where PON2 was reported to be overexpressed. This review aims to deeply and carefully examine the contribution of this enzyme to different aspects of tumor cells by promoting the initiation, progression, and spread of neoplasms. Full article
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15 pages, 776 KiB  
Review
Exploratory Review of the Takotsubo Syndrome and the Possible Role of the Psychosocial Stress Response and Inflammaging
by Niklas Frank, Martin J. Herrmann, Martin Lauer and Carola Y. Förster
Biomolecules 2024, 14(2), 167; https://doi.org/10.3390/biom14020167 - 31 Jan 2024
Viewed by 900
Abstract
Takotsubo syndrome (TTS) is a cardiomyopathy that clinically presents as a transient and reversible left ventricular wall motion abnormality (LVWMA). Recovery can occur spontaneously within hours or weeks. Studies have shown that it mainly affects older people. In particular, there is a higher [...] Read more.
Takotsubo syndrome (TTS) is a cardiomyopathy that clinically presents as a transient and reversible left ventricular wall motion abnormality (LVWMA). Recovery can occur spontaneously within hours or weeks. Studies have shown that it mainly affects older people. In particular, there is a higher prevalence in postmenopausal women. Physical and emotional stress factors are widely discussed and generally recognized triggers. In addition, the hypothalamic-pituitary-adrenal (HPA) axis and the associated glucocorticoid-dependent negative feedback play an important role in the resulting immune response. This review aims to highlight the unstudied aspects of the trigger factors of TTS. The focus is on emotional stress/chronic unpredictable mild stress (CUMS), which is influenced by estrogen concentration and noradrenaline, for example, and can lead to changes in the behavioral, hormonal, and autonomic systems. Age- and gender-specific aspects, as well as psychological effects, must also be considered. We hypothesize that this leads to a stronger corticosteroid response and altered feedback of the HPA axis. This may trigger proinflammatory markers and thus immunosuppression, inflammaging, and sympathetic overactivation, which contributes significantly to the development of TTS. The aim is to highlight the importance of CUMS and psychological triggers as risk factors and to make an exploratory proposal based on the new knowledge. Based on the imbalance between the sympathetic and parasympathetic nervous systems, transcutaneous vagus nerve stimulation (tVNS) is presented as a possible new therapeutic approach. Full article
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17 pages, 3311 KiB  
Article
Role of Mitochondrial ROS for Calcium Alternans in Atrial Myocytes
by Yuriana Oropeza-Almazán and Lothar A. Blatter
Biomolecules 2024, 14(2), 144; https://doi.org/10.3390/biom14020144 - 24 Jan 2024
Viewed by 1139
Abstract
Atrial calcium transient (CaT) alternans is defined as beat-to-beat alternations in CaT amplitude and is causally linked to atrial fibrillation (AF). Mitochondria play a significant role in cardiac excitation–contraction coupling and Ca signaling through redox environment regulation. In isolated rabbit atrial myocytes, ROS [...] Read more.
Atrial calcium transient (CaT) alternans is defined as beat-to-beat alternations in CaT amplitude and is causally linked to atrial fibrillation (AF). Mitochondria play a significant role in cardiac excitation–contraction coupling and Ca signaling through redox environment regulation. In isolated rabbit atrial myocytes, ROS production is enhanced during CaT alternans, measured by fluorescence microscopy. Exogenous ROS (tert-butyl hydroperoxide) enhanced CaT alternans, whereas ROS scavengers (dithiothreitol, MnTBAP, quercetin, tempol) alleviated CaT alternans. While the inhibition of cellular NADPH oxidases had no effect on CaT alternans, interference with mitochondrial ROS (ROSm) production had profound effects: (1) the superoxide dismutase mimetic MitoTempo diminished CaT alternans and shifted the pacing threshold to higher frequencies; (2) the inhibition of cyt c peroxidase by SS-31, and inhibitors of ROSm production by complexes of the electron transport chain S1QEL1.1 and S3QEL2, decreased the severity of CaT alternans; however (3) the impairment of mitochondrial antioxidant defense by the inhibition of nicotinamide nucleotide transhydrogenase with NBD-Cl and thioredoxin reductase-2 with auranofin enhanced CaT alternans. Our results suggest that intact mitochondrial antioxidant defense provides crucial protection against pro-arrhythmic CaT alternans. Thus, modulating the mitochondrial redox state represents a potential therapeutic approach for alternans-associated arrhythmias, including AF. Full article
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13 pages, 1547 KiB  
Article
Serum Brevican as a Biomarker of Cerebrovascular Disease in an Elderly Cognitively Impaired Cohort
by Rachel S. L. Chia, Karolina Minta, Liu-Yun Wu, Kaung H. T. Salai, Yuek Ling Chai, Saima Hilal, Narayanaswamy Venketasubramanian, Christopher P. Chen, Joyce R. Chong and Mitchell K. P. Lai
Biomolecules 2024, 14(1), 75; https://doi.org/10.3390/biom14010075 - 07 Jan 2024
Cited by 1 | Viewed by 1142
Abstract
In the brain, the extracellular matrix (ECM) composition shapes the neuronal microenvironment and can undergo substantial changes with cerebral pathology. Brevican is integral to the formation of the ECM’s neuroprotective perineuronal nets (PNNs). Decreased brevican levels were reported in vascular dementia (VaD) but [...] Read more.
In the brain, the extracellular matrix (ECM) composition shapes the neuronal microenvironment and can undergo substantial changes with cerebral pathology. Brevican is integral to the formation of the ECM’s neuroprotective perineuronal nets (PNNs). Decreased brevican levels were reported in vascular dementia (VaD) but not in Alzheimer’s disease (AD). However, the status of brevican in clinical cohorts with high concomitance of AD pathological burden and cerebrovascular disease (CeVD) is unclear. In this study, 32 non-cognitively impaired (NCI), 97 cognitively impaired no dementia (CIND), 46 AD, and 23 VaD participants recruited from memory clinics based in Singapore underwent neuropsychological and neuroimaging assessments, together with measurements of serum brevican. Association analyses were performed between serum brevican and neuroimaging measures of CeVDs, including white matter hyperintensities (WMHs), lacunes, cortical infarcts, and cerebral microbleeds. Using an aggregated score for CeVD burden, only CIND participants showed lower brevican levels with higher CeVD compared to those with lower CeVD burden (p = 0.006). Among the CeVD subtypes assessed, only elevated WMH burden was associated with lower brevican levels (OR = 2.7; 95% CI = 1.3–5.5). Our findings suggest that brevican deficits may play a role in early cerebrovascular damage in participants at risk of developing dementia. Full article
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2023

Jump to: 2024, 2022, 2021, 2020

18 pages, 4572 KiB  
Article
Increased Risk for Atrial Alternans in Rabbit Heart Failure: The Role of Ca2+/Calmodulin-Dependent Kinase II and Inositol-1,4,5-trisphosphate Signaling
by Giedrius Kanaporis and Lothar A. Blatter
Biomolecules 2024, 14(1), 53; https://doi.org/10.3390/biom14010053 - 30 Dec 2023
Viewed by 1248
Abstract
Heart failure (HF) increases the probability of cardiac arrhythmias, including atrial fibrillation (AF), but the mechanisms linking HF to AF are poorly understood. We investigated disturbances in Ca2+ signaling and electrophysiology in rabbit atrial myocytes from normal and failing hearts and identified [...] Read more.
Heart failure (HF) increases the probability of cardiac arrhythmias, including atrial fibrillation (AF), but the mechanisms linking HF to AF are poorly understood. We investigated disturbances in Ca2+ signaling and electrophysiology in rabbit atrial myocytes from normal and failing hearts and identified mechanisms that contribute to the higher risk of atrial arrhythmias in HF. Ca2+ transient (CaT) alternans—beat-to-beat alternations in CaT amplitude—served as indicator of increased arrhythmogenicity. We demonstrate that HF atrial myocytes were more prone to alternans despite no change in action potentials duration and only moderate decrease of L-type Ca2+ current. Ca2+/calmodulin-dependent kinase II (CaMKII) inhibition suppressed CaT alternans. Activation of IP3 signaling by endothelin-1 (ET-1) and angiotensin II (Ang II) resulted in acute, but transient reduction of CaT amplitude and sarcoplasmic reticulum (SR) Ca2+ load, and lowered the alternans risk. However, prolonged exposure to ET-1 and Ang II enhanced SR Ca2+ release and increased the degree of alternans. Inhibition of IP3 receptors prevented the transient ET-1 and Ang II effects and by itself increased the degree of CaT alternans. Our data suggest that activation of CaMKII and IP3 signaling contribute to atrial arrhythmogenesis in HF. Full article
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29 pages, 7540 KiB  
Article
Piezo1 Regulation Involves Lipid Domains and the Cytoskeleton and Is Favored by the Stomatocyte–Discocyte–Echinocyte Transformation
by Amaury Stommen, Marine Ghodsi, Anne-Sophie Cloos, Louise Conrard, Andra C. Dumitru, Patrick Henriet, Christophe E. Pierreux, David Alsteens and Donatienne Tyteca
Biomolecules 2024, 14(1), 51; https://doi.org/10.3390/biom14010051 - 30 Dec 2023
Viewed by 1299
Abstract
Piezo1 is a mechanosensitive ion channel required for various biological processes, but its regulation remains poorly understood. Here, we used erythrocytes to address this question since they display Piezo1 clusters, a strong and dynamic cytoskeleton and three types of submicrometric lipid domains, respectively [...] Read more.
Piezo1 is a mechanosensitive ion channel required for various biological processes, but its regulation remains poorly understood. Here, we used erythrocytes to address this question since they display Piezo1 clusters, a strong and dynamic cytoskeleton and three types of submicrometric lipid domains, respectively enriched in cholesterol, GM1 ganglioside/cholesterol and sphingomyelin/cholesterol. We revealed that Piezo1 clusters were present in both the rim and the dimple erythrocyte regions. Upon Piezo1 chemical activation by Yoda1, the Piezo1 cluster proportion mainly increased in the dimple area. This increase was accompanied by Ca2+ influx and a rise in echinocytes, in GM1/cholesterol-enriched domains in the dimple and in cholesterol-enriched domains in the rim. Conversely, the effects of Piezo1 activation were abrogated upon membrane cholesterol depletion. Furthermore, upon Piezo1-independent Ca2+ influx, the above changes were not observed. In healthy donors with a high echinocyte proportion, Ca2+ influx, lipid domains and Piezo1 fluorescence were high even at resting state, whereas the cytoskeleton membrane occupancy was lower. Accordingly, upon decreases in cytoskeleton membrane occupancy and stiffness in erythrocytes from patients with hereditary spherocytosis, Piezo1 fluorescence was increased. Altogether, we showed that Piezo1 was differentially controlled by lipid domains and the cytoskeleton and was favored by the stomatocyte–discocyte–echinocyte transformation. Full article
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17 pages, 8669 KiB  
Article
Beta-Amyloid Enhances Vessel Formation in Organotypic Brain Slices Connected to Microcontact Prints
by Katharina Steiner and Christian Humpel
Biomolecules 2024, 14(1), 3; https://doi.org/10.3390/biom14010003 - 19 Dec 2023
Viewed by 778
Abstract
In Alzheimer’s disease, the blood–brain barrier breakdown, blood vessel damage and re-organization are early events. Deposits of the small toxic peptide beta-amyloid (Aβ) cause the formation of extracellular plaques and accumulate in vessels disrupting the blood flow but may also play a role [...] Read more.
In Alzheimer’s disease, the blood–brain barrier breakdown, blood vessel damage and re-organization are early events. Deposits of the small toxic peptide beta-amyloid (Aβ) cause the formation of extracellular plaques and accumulate in vessels disrupting the blood flow but may also play a role in blood clotting. In the present study, we aim to explore the impact of Aβ on the migration of endothelial cells and subsequent vessel formation. We use organotypic brain slices of postnatal day 10 wildtype mice (C57BL/6) and connect them to small microcontact prints (µCPs) of collagen. Our data show that laminin-positive endothelial cells migrate onto collagen µCPs, but without any vessel formation after 4 weeks. When the µCPs are loaded with human Aβ40, (aggregated) human Aβ42 and mouse Aβ42 peptides, the number and migration distance of endothelial cells are significantly reduced, but with a more pronounced subsequent vessel formation. The vessel formation is verified by zonula occludens (ZO)-1 and -2 stainings and confocal microscopy. In addition, the vessel formation is accompanied by a stronger GFAP-positive astroglial formation. Finally, we show that vessels can grow towards convergence when two opposed slices are connected via microcontact-printed lanes. In conclusion, our data show that Aβ promotes vessel formation, and organotypic brain slices connected to collagen µCPs provide a potent tool to study vessel formation. Full article
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27 pages, 2964 KiB  
Article
Resilience and Vulnerability to Stress-Induced Anhedonia: Unveiling Brain Gene Expression and Mitochondrial Dynamics in a Mouse Chronic Stress Depression Model
by Tatyana Strekalova, Evgeniy Svirin, Anna Gorlova, Elizaveta Sheveleva, Alisa Burova, Adel Khairetdinova, Kseniia Sitdikova, Elena Zakharova, Alexander M. Dudchenko, Aleksey Lyundup and Sergey Morozov
Biomolecules 2023, 13(12), 1782; https://doi.org/10.3390/biom13121782 - 12 Dec 2023
Viewed by 1494
Abstract
The role of altered brain mitochondrial regulation in psychiatric pathologies, including Major Depressive Disorder (MDD), has attracted increasing attention. Aberrant mitochondrial functions were suggested to underlie distinct inter-individual vulnerability to stress-related MDD syndrome. In this context, insulin receptor sensitizers (IRSs) that regulate brain [...] Read more.
The role of altered brain mitochondrial regulation in psychiatric pathologies, including Major Depressive Disorder (MDD), has attracted increasing attention. Aberrant mitochondrial functions were suggested to underlie distinct inter-individual vulnerability to stress-related MDD syndrome. In this context, insulin receptor sensitizers (IRSs) that regulate brain metabolism have become a focus of recent research, as their use in pre-clinical studies can help to elucidate the role of mitochondrial dynamics in this disorder and contribute to the development of new antidepressant treatment. Here, following 2-week chronic mild stress (CMS) using predation, social defeat, and restraint, MDD-related behaviour and brain molecular markers have been investigated along with the hippocampus-dependent performance and emotionality in mice that received the IRS dicholine succinate (DS). In a sucrose test, mice were studied for the key feature of MDD, a decreased sensitivity to reward, called anhedonia. Based on this test, animals were assigned to anhedonic and resilient-to-stress-induced-anhedonia groups, using a previously established criterion of a decrease in sucrose preference below 65%. Such assignment was based on the fact that none of control, non-stressed animals displayed sucrose preference that would be smaller than this value. DS-treated stressed mice displayed ameliorated behaviours in a battery of assays: sucrose preference, coat state, the Y-maze, the marble test, tail suspension, and nest building. CMS-vulnerable mice exhibited overexpression of the inflammatory markers Il-1β, tnf, and Cox-1, as well as 5-htt and 5-ht2a-R, in various brain regions. The alterations in hippocampal gene expression were the closest to clinical findings and were studied further. DS-treated, stressed mice showed normalised hippocampal expression of the plasticity markers Camk4, Camk2, Pka, Adcy1, Creb-ar, Nmda-2r-ar, and Nmda-2r-s. DS-treated and non-treated stressed mice who were resilient or vulnerable to anhedonia were compared for hippocampal mitochondrial pathway regulation using Illumina profiling. Resilient mice revealed overexpression of the mitochondrial complexes NADH dehydrogenase, succinate dehydrogenase, cytochrome bc1, cytochrome c oxidase, F-type and V-type ATPases, and inorganic pyrophosphatase, which were decreased in anhedonic mice. DS partially normalised the expression of both ATPases. We conclude that hippocampal reduction in ATP synthesis is associated with anhedonia and pro-inflammatory brain changes that are ameliorated by DS. Full article
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18 pages, 11051 KiB  
Article
Effects of 1,25-Vitamin D3 and 24,25-Vitamin D3 on Corneal Nerve Regeneration in Diabetic Mice
by Xiaowen Lu, Zhong Chen, Jerry Lu and Mitchell A. Watsky
Biomolecules 2023, 13(12), 1754; https://doi.org/10.3390/biom13121754 - 06 Dec 2023
Cited by 1 | Viewed by 1282
Abstract
Corneal nerve homeostasis is essential for the functional integrity of the ocular surface. Vitamin D deficiency (VDD) and vitamin D receptor knockout (VDR KO) have been found to reduce corneal nerve density in diabetic mice. This is the first study to comprehensively examine [...] Read more.
Corneal nerve homeostasis is essential for the functional integrity of the ocular surface. Vitamin D deficiency (VDD) and vitamin D receptor knockout (VDR KO) have been found to reduce corneal nerve density in diabetic mice. This is the first study to comprehensively examine the influence of vitamin D on nerve regeneration following corneal epithelial injury in diabetic mice. Corneal nerve regeneration was significantly retarded by diabetes, VDR KO, and VDD, and it was accelerated following topical 1,25 Vit D and 24,25 Vit D administration. Furthermore, topical 1,25 Vit D and 24,25 Vit D increased nerve growth factor, glial cell line-derived neurotropic factor, and neurotropin-3 protein expression, and it increased secretion of GDNF protein from human corneal epithelial cells. CD45+ cells and macrophage numbers were significantly decreased, and vitamin D increased CD45+ cell and macrophage recruitment in these wounded diabetic mouse corneas. The accelerated nerve regeneration observed in these corneas following topical 1,25 Vit D and 24,25 Vit D administration may be related to the vitamin D-stimulated expression, secretion of neurotrophic factors, and recruitment of immune cells. Full article
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14 pages, 3070 KiB  
Article
Integrin α6β4 Confers Doxorubicin Resistance in Cancer Cells by Suppressing Caspase-3–Mediated Apoptosis: Involvement of N-Glycans on β4 Integrin Subunit
by Yoshinobu Kariya, Jianguo Gu and Yukiko Kariya
Biomolecules 2023, 13(12), 1752; https://doi.org/10.3390/biom13121752 - 06 Dec 2023
Cited by 1 | Viewed by 936
Abstract
Drug resistance is a major obstacle to successful cancer treatment. Therefore, it is essential to understand the molecular mechanisms underlying drug resistance to develop successful therapeutic strategies. α6β4 integrin confers resistance to apoptosis and regulates the survival of cancer cells; however, it remains [...] Read more.
Drug resistance is a major obstacle to successful cancer treatment. Therefore, it is essential to understand the molecular mechanisms underlying drug resistance to develop successful therapeutic strategies. α6β4 integrin confers resistance to apoptosis and regulates the survival of cancer cells; however, it remains unclear whether α6β4 integrin is directly involved in chemoresistance. Here, we show that α6β4 integrin promotes doxorubicin resistance by decreasing caspase-3–mediated apoptosis. We found that the overexpression of α6β4 integrin by the β4 integrin gene rendered MDA-MB435S and Panc-1 cells more resistant to doxorubicin than control cells. The acquired resistance to doxorubicin by α6β4 integrin expression was abolished by the deletion of the cytoplasmic signal domain in β4 integrin. Similar results were found in MDA-MB435S and Panc-1 cells when N-glycan-defective β4 integrin mutants were overexpressed or bisecting GlcNAc residues were increased on β4 integrin by the co-expression of N-acetylglucosaminyltransferase III with β4 integrin. The abrogation of α6β4 integrin-mediated resistance to doxorubicin was accompanied by reduced cell viability and an increased caspase-3 activation. Taken together, our results clearly suggest that α6β4 integrin signaling plays a key role in the doxorubicin resistance of cancer cells, and N-glycans on β4 integrin are involved in the regulation of cancer cells. Full article
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23 pages, 4929 KiB  
Article
Response of Fibroblasts from Menkes’ and Wilson’s Copper Metabolism-Related Disorders to Ionizing Radiation: Influence of the Nucleo-Shuttling of the ATM Protein Kinase
by Laura El Nachef, Joëlle Al-Choboq, Michel Bourguignon and Nicolas Foray
Biomolecules 2023, 13(12), 1746; https://doi.org/10.3390/biom13121746 - 05 Dec 2023
Viewed by 1044
Abstract
Menkes’ disease (MD) and Wilson’s disease (WD) are two major copper (Cu) metabolism-related disorders caused by mutations of the ATP7A and ATP7B ATPase gene, respectively. While Cu is involved in DNA strand breaks signaling and repair, the response of cells from both diseases [...] Read more.
Menkes’ disease (MD) and Wilson’s disease (WD) are two major copper (Cu) metabolism-related disorders caused by mutations of the ATP7A and ATP7B ATPase gene, respectively. While Cu is involved in DNA strand breaks signaling and repair, the response of cells from both diseases to ionizing radiation, a common DNA strand breaks inducer, has not been investigated yet. To this aim, three MD and two WD skin fibroblasts lines were irradiated at two Gy X-rays and clonogenic cell survival, micronuclei, anti-γH2AX, -pATM, and -MRE11 immunofluorescence assays were applied to evaluate the DNA double-strand breaks (DSB) recognition and repair. MD and WD cells appeared moderately radiosensitive with a delay in the radiation-induced ATM nucleo-shuttling (RIANS) associated with impairments in the DSB recognition. Such delayed RIANS was notably caused in both MD and WD cells by a highly expressed ATP7B protein that forms complexes with ATM monomers in cytoplasm. Interestingly, a Cu pre-treatment of cells may influence the activity of the MRE11 nuclease and modulate the radiobiological phenotype. Lastly, some high-passage MD cells cultured in routine may transform spontaneously becoming immortalized. Altogether, our findings suggest that exposure to ionizing radiation may impact on clinical features of MD and WD, which requires cautiousness when affected patients are submitted to radiodiagnosis and, eventually, radiotherapy. Full article
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31 pages, 3380 KiB  
Review
Adipokines and Bacterial Metabolites: A Pivotal Molecular Bridge Linking Obesity and Gut Microbiota Dysbiosis to Target
by Teva Turpin, Katy Thouvenot and Marie-Paule Gonthier
Biomolecules 2023, 13(12), 1692; https://doi.org/10.3390/biom13121692 - 23 Nov 2023
Cited by 1 | Viewed by 1310
Abstract
Adipokines are essential mediators produced by adipose tissue and exert multiple biological functions. In particular, adiponectin, leptin, resistin, IL-6, MCP-1 and PAI-1 play specific roles in the crosstalk between adipose tissue and other organs involved in metabolic, immune and vascular health. During obesity, [...] Read more.
Adipokines are essential mediators produced by adipose tissue and exert multiple biological functions. In particular, adiponectin, leptin, resistin, IL-6, MCP-1 and PAI-1 play specific roles in the crosstalk between adipose tissue and other organs involved in metabolic, immune and vascular health. During obesity, adipokine imbalance occurs and leads to a low-grade pro-inflammatory status, promoting insulin resistance-related diabetes and its vascular complications. A causal link between obesity and gut microbiota dysbiosis has been demonstrated. The deregulation of gut bacteria communities characterizing this dysbiosis influences the synthesis of bacterial substances including lipopolysaccharides and specific metabolites, generated via the degradation of dietary components, such as short-chain fatty acids, trimethylamine metabolized into trimethylamine-oxide in the liver and indole derivatives. Emerging evidence suggests that these bacterial metabolites modulate signaling pathways involved in adipokine production and action. This review summarizes the current knowledge about the molecular links between gut bacteria-derived metabolites and adipokine imbalance in obesity, and emphasizes their roles in key pathological mechanisms related to oxidative stress, inflammation, insulin resistance and vascular disorder. Given this interaction between adipokines and bacterial metabolites, the review highlights their relevance (i) as complementary clinical biomarkers to better explore the metabolic, inflammatory and vascular complications during obesity and gut microbiota dysbiosis, and (ii) as targets for new antioxidant, anti-inflammatory and prebiotic triple action strategies. Full article
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19 pages, 5569 KiB  
Article
Influence of the Charge Ratio of Guanine-Quadruplex Structure-Based CpG Oligodeoxynucleotides and Cationic DOTAP Liposomes on Cytokine Induction Profiles
by Nguyen Bui Thao Le, Anh Thi Tram Tu, Dandan Zhao, Chiaki Yoshikawa, Kohsaku Kawakami, Yoshihisa Kaizuka and Tomohiko Yamazaki
Biomolecules 2023, 13(11), 1639; https://doi.org/10.3390/biom13111639 - 11 Nov 2023
Viewed by 970
Abstract
Cationic liposomes, specifically 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) liposomes, serve as successful carriers for guanine-quadruplex (G4) structure-based cytosine-guanine oligodeoxynucleotides (CpG ODNs). The combined benefits of CpG ODNs forming a G4 structure and a non-viral vector carrier endow the ensuing complex with promising adjuvant properties. Although G4-CpG [...] Read more.
Cationic liposomes, specifically 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) liposomes, serve as successful carriers for guanine-quadruplex (G4) structure-based cytosine-guanine oligodeoxynucleotides (CpG ODNs). The combined benefits of CpG ODNs forming a G4 structure and a non-viral vector carrier endow the ensuing complex with promising adjuvant properties. Although G4-CpG ODN-DOTAP complexes show a higher immunostimulatory effect than naked G4-CpG ODNs, the effects of the complex composition, especially charge ratios, on the production of the pro-inflammatory cytokines interleukin (IL)-6 and interferon (IFN)-α remain unclear. Here, we examined whether charge ratios drive the bifurcation of cytokine inductions in human peripheral blood mononuclear cells. Linear CpG ODN-DOTAP liposome complexes formed micrometer-sized positively charged agglomerates; G4-CpG ODN-DOTAP liposome complexes with low charge ratios (0.5 and 1.5) formed ~250 nm-sized negatively charged complexes. Notably, low-charge-ratio (0.5 and 1.5) complexes induced significantly higher IL-6 and IFN-α levels simultaneously than high-charge-ratio (2 and 2.5) complexes. Moreover, confocal microscopy indicated a positive correlation between the cellular uptake of the complex and amount of cytokine induced. The observed effects of charge ratios on complex size, surface charge, and affinity for factors that modify cellular-uptake, intracellular-activity, and cytokine-production efficiency highlight the importance of a rational complex design for delivering and controlling G4-CpG ODN activity. Full article
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25 pages, 1576 KiB  
Review
Immunomodulatory Potential of Fungal Extracellular Vesicles: Insights for Therapeutic Applications
by Stefano Nenciarini and Duccio Cavalieri
Biomolecules 2023, 13(10), 1487; https://doi.org/10.3390/biom13101487 - 06 Oct 2023
Cited by 1 | Viewed by 2280
Abstract
Extracellular vesicles (EVs) are membranous vesicular organelles that perform a variety of biological functions including cell communication across different biological kingdoms. EVs of mammals and, to a lesser extent, bacteria have been deeply studied over the years, whereas investigations of fungal EVs are [...] Read more.
Extracellular vesicles (EVs) are membranous vesicular organelles that perform a variety of biological functions including cell communication across different biological kingdoms. EVs of mammals and, to a lesser extent, bacteria have been deeply studied over the years, whereas investigations of fungal EVs are still in their infancy. Fungi, encompassing both yeast and filamentous forms, are increasingly recognized for their production of extracellular vesicles (EVs) containing a wealth of proteins, lipids, and nucleic acids. These EVs play pivotal roles in orchestrating fungal communities, bolstering pathogenicity, and mediating interactions with the environment. Fungal EVs have emerged as promising candidates for innovative applications, not only in the management of mycoses but also as carriers for therapeutic molecules. Yet, numerous questions persist regarding fungal EVs, including their mechanisms of generation, release, cargo regulation, and discharge. This comprehensive review delves into the present state of knowledge regarding fungal EVs and provides fresh insights into the most recent hypotheses on the mechanisms driving their immunomodulatory properties. Furthermore, we explore the considerable potential of fungal EVs in the realms of medicine and biotechnology. In the foreseeable future, engineered fungal cells may serve as vehicles for tailoring cargo- and antigen-specific EVs, positioning them as invaluable biotechnological tools for diverse medical applications, such as vaccines and drug delivery. Full article
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8 pages, 310 KiB  
Opinion
Glucocorticoid Receptor Signaling in NSCLC: Mechanistic Aspects and Therapeutic Perspectives
by Kostas A. Papavassiliou, Nektarios Anagnostopoulos and Athanasios G. Papavassiliou
Biomolecules 2023, 13(9), 1286; https://doi.org/10.3390/biom13091286 - 23 Aug 2023
Viewed by 1052
Abstract
Recent advances in non-small cell lung cancer (NSCLC) biology and the discovery of novel therapeutic targets have led to the development of new pharmacological agents that may improve the clinical outcome of patients with NSCLC. The glucocorticoid receptor (GR) is an evolutionarily conserved [...] Read more.
Recent advances in non-small cell lung cancer (NSCLC) biology and the discovery of novel therapeutic targets have led to the development of new pharmacological agents that may improve the clinical outcome of patients with NSCLC. The glucocorticoid receptor (GR) is an evolutionarily conserved protein belonging to the nuclear receptor superfamily of transcription factors and mediates the diverse actions of glucocorticoids in cells. Data suggest that the GR may play a relevant role in the molecular mechanisms of NSCLC tumorigenesis and malignant progression. Additionally, evidence indicates that glucocorticoids may affect the efficacy of standard treatment, including chemotherapy, immune checkpoint inhibitors, and targeted therapy. Furthermore, several findings show that GR expression may probably be associated with NSCLC patient survival. Finally, glucocorticoids may be used as therapeutic agents for the clinical management of NSCLC patients. Here, we briefly review the latest advances on the biological role of GR signaling in NSCLC and discuss the potential use of the GR as a prognostic and predictive biomarker. Importantly, we explore the therapeutic potential of glucocorticoids and the effect of adding such drugs to standard therapies for NSCLC. Full article
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20 pages, 5474 KiB  
Article
Pro-Calcifying Role of Enzymatically Modified LDL (eLDL) in Aortic Valve Sclerosis via Induction of IL-6 and IL-33
by Annemarie Witz, Denise Effertz, Nora Goebel, Matthias Schwab, Ulrich F. W. Franke and Michael Torzewski
Biomolecules 2023, 13(7), 1091; https://doi.org/10.3390/biom13071091 - 07 Jul 2023
Viewed by 1112
Abstract
One of the contributors to atherogenesis is enzymatically modified LDL (eLDL). eLDL was detected in all stages of aortic valve sclerosis and was demonstrated to trigger the activation of p38 mitogen-activated protein kinase (p38 MAPK), which has been identified as a pro-inflammatory protein [...] Read more.
One of the contributors to atherogenesis is enzymatically modified LDL (eLDL). eLDL was detected in all stages of aortic valve sclerosis and was demonstrated to trigger the activation of p38 mitogen-activated protein kinase (p38 MAPK), which has been identified as a pro-inflammatory protein in atherosclerosis. In this study, we investigated the influence of eLDL on IL-6 and IL-33 induction, and also the impact of eLDL on calcification in aortic valve stenosis (AS). eLDL upregulated phosphate-induced calcification in valvular interstitial cells (VICs)/myofibroblasts isolated from diseased aortic valves, as demonstrated by alizarin red staining. Functional studies demonstrated activation of p38 MAPK as well as an altered gene expression of osteogenic genes known to be involved in vascular calcification. In parallel with the activation of p38 MAPK, eLDL also induced upregulation of the cytokines IL-6 and IL-33. The results suggest a pro-calcifying role of eLDL in AS via induction of IL-6 and IL-33. Full article
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16 pages, 4047 KiB  
Article
Brain Monoamine Dysfunction in Response to Predator Scent Stress Accompanies Stress-Susceptibility in Female Rats
by Courtney S. Wilkinson, Harrison L. Blount, Marek Schwendt and Lori A. Knackstedt
Biomolecules 2023, 13(7), 1055; https://doi.org/10.3390/biom13071055 - 29 Jun 2023
Viewed by 1325
Abstract
Post-traumatic stress disorder (PTSD) is prevalent in women; however, preclinical research on PTSD has predominantly been conducted in male animals. Using a predator scent stress (PSS) rodent model of PTSD, we sought to determine if stress-susceptible female rats show altered monoamine concentrations in [...] Read more.
Post-traumatic stress disorder (PTSD) is prevalent in women; however, preclinical research on PTSD has predominantly been conducted in male animals. Using a predator scent stress (PSS) rodent model of PTSD, we sought to determine if stress-susceptible female rats show altered monoamine concentrations in brain regions associated with PTSD: the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and dorsal (dHIPP) and ventral (vHIPP) hippocampus. Female Sprague–Dawley rats were exposed to a single, 10-min PSS exposure and tested for persistent anhedonia, fear, and anxiety-like behavior over four weeks. Rats were phenotyped as stress-Susceptible based on sucrose consumption in the sucrose preference task and time spent in the open arms of the elevated plus maze. Brain tissue was collected, and norepinephrine, dopamine, serotonin, and their metabolites were quantified using high-performance liquid chromatography. Stress-susceptibility in female rats was associated with increased dopamine and serotonin turnover in the mPFC. Susceptibility was also associated with elevated dopamine turnover in the NAc and increased norepinephrine in the vHIPP. Our findings suggest that stress-susceptibility after a single stress exposure is associated with long-term effects on monoamine function in female rats. These data suggest interventions that decrease monoamine turnover, such as MAOIs, may be effective in the treatment of PTSD in women. Full article
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16 pages, 3444 KiB  
Article
Oligomerization and Adjuvant Activity of Peptides Derived from the VirB4-like ATPase of Clostridioides difficile
by Julya Sorokina, Irina Sokolova, Mariya Majorina, Anastasia Ungur, Vasiliy Troitskiy, Amir Tukhvatulin, Bogdan Melnik and Yury Belyi
Biomolecules 2023, 13(6), 1012; https://doi.org/10.3390/biom13061012 - 18 Jun 2023
Viewed by 1134
Abstract
In a previous study, we demonstrated that the Clostridioides difficile VirB4-like ATPase forms oligomers in vitro. In the current investigation, to study the observed phenomenon in more detail, we prepared a library of VirB4-derived peptides (delVirB4s) fused to a carrier maltose-binding protein (MBP). [...] Read more.
In a previous study, we demonstrated that the Clostridioides difficile VirB4-like ATPase forms oligomers in vitro. In the current investigation, to study the observed phenomenon in more detail, we prepared a library of VirB4-derived peptides (delVirB4s) fused to a carrier maltose-binding protein (MBP). Using gel chromatography and polyacrylamide gel electrophoresis, we found a set of overlapping fragments that contribute most significantly to protein aggregation, which were represented as water-soluble oligomers with molecular masses ranging from ~300 kD to several megadaltons. Membrane filtration experiments, sucrose gradient ultracentrifugation, and dynamic light scattering measurements indicated the size of the soluble complex to be 15–100 nm. It was sufficiently stable to withstand treatment with 1 M urea; however, it dissociated in a 6 M urea solution. As shown by the changes in GFP fluorescence and the circular dichroism spectra, the attachment of the delVirB4 peptide significantly altered the structure of the partner MBP. The immunization of mice with the hybrid consisting of the selected VirB4-derived peptide and MBP, GST, or GFP resulted in increased production of specific antibodies compared to the peptide-free carrier proteins, suggesting significant adjuvant activity of the VirB4 fragment. This feature could be useful for the development of new vaccines, especially in the case of “weak” antigens that are unable to elicit a strong immune response by themselves. Full article
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20 pages, 1038 KiB  
Article
Platelet Serotonin (5-HT) Concentration, Platelet Monoamine Oxidase B (MAO-B) Activity and HTR2A, HTR2C, and MAOB Gene Polymorphisms in Asthma
by Marcela Konjevod, Katherina B. Sreter, Sanja Popovic-Grle, Marina Lampalo, Lucija Tudor, Irena Jukic, Gordana Nedic Erjavec, Jasna Bingulac-Popovic, Hana Safic Stanic, Matea Nikolac Perkovic, Jasenka Markeljevic, Miroslav Samarzija, Nela Pivac and Dubravka Svob Strac
Biomolecules 2023, 13(5), 800; https://doi.org/10.3390/biom13050800 - 08 May 2023
Cited by 3 | Viewed by 1690
Abstract
The complex role of the serotonin system in respiratory function and inflammatory diseases such as asthma is unclear. Our study investigated platelet serotonin (5-HT) levels and platelet monoamine oxidase B (MAO-B) activity, as well as associations with HTR2A (rs6314; rs6313), HTR2C (rs3813929; [...] Read more.
The complex role of the serotonin system in respiratory function and inflammatory diseases such as asthma is unclear. Our study investigated platelet serotonin (5-HT) levels and platelet monoamine oxidase B (MAO-B) activity, as well as associations with HTR2A (rs6314; rs6313), HTR2C (rs3813929; rs518147), and MAOB (rs1799836; rs6651806) gene polymorphisms in 120 healthy individuals and 120 asthma patients of different severity and phenotypes. Platelet 5-HT concentration was significantly lower, while platelet MAO-B activity was considerably higher in asthma patients; however, they did not differ between patients with different asthma severity or phenotypes. Only the healthy subjects, but not the asthma patients, carrying the MAOB rs1799836 TT genotype had significantly lower platelet MAO-B activity than the C allele carriers. No significant differences in the frequency of the genotypes, alleles, or haplotypes for any of the investigated HTR2A, HTR2C and MAOB gene polymorphisms have been observed between asthma patients and healthy subjects or between patients with various asthma phenotypes. However, the carriers of the HTR2C rs518147 CC genotype or C allele were significantly less frequent in severe asthma patients than in the G allele carriers. Further studies are necessary to elucidate the involvement of the serotonergic system in asthma pathophysiology. Full article
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25 pages, 2280 KiB  
Review
β Cell and Autophagy: What Do We Know?
by Hamid-Reza Mohammadi-Motlagh, Mona Sadeghalvad, Niloofar Yavari, Rosita Primavera, Setareh Soltani, Shashank Chetty, Abantika Ganguly, Shobha Regmi, Tina Fløyel, Simranjeet Kaur, Aashiq H. Mirza, Avnesh S. Thakor, Flemming Pociot and Reza Yarani
Biomolecules 2023, 13(4), 649; https://doi.org/10.3390/biom13040649 - 04 Apr 2023
Cited by 5 | Viewed by 2751
Abstract
Pancreatic β cells are central to glycemic regulation through insulin production. Studies show autophagy as an essential process in β cell function and fate. Autophagy is a catabolic cellular process that regulates cell homeostasis by recycling surplus or damaged cell components. Impaired autophagy [...] Read more.
Pancreatic β cells are central to glycemic regulation through insulin production. Studies show autophagy as an essential process in β cell function and fate. Autophagy is a catabolic cellular process that regulates cell homeostasis by recycling surplus or damaged cell components. Impaired autophagy results in β cell loss of function and apoptosis and, as a result, diabetes initiation and progress. It has been shown that in response to endoplasmic reticulum stress, inflammation, and high metabolic demands, autophagy affects β cell function, insulin synthesis, and secretion. This review highlights recent evidence regarding how autophagy can affect β cells’ fate in the pathogenesis of diabetes. Furthermore, we discuss the role of important intrinsic and extrinsic autophagy modulators, which can lead to β cell failure. Full article
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13 pages, 1680 KiB  
Article
Nanobodies Selectively Binding to the Idiotype of a Dengue Virus Neutralizing Antibody Do Not Necessarily Mimic the Viral Epitope
by Monica Poggianella, Robert Bernedo, Sandra Oloketuyi and Ario de Marco
Biomolecules 2023, 13(3), 551; https://doi.org/10.3390/biom13030551 - 17 Mar 2023
Cited by 2 | Viewed by 1558
Abstract
Vaccination against dengue virus is challenged by the fact that a generic immune response can induce antibody-dependent-enhancement (ADE) in secondary infections. Only some antibodies targeting a quaternary epitope formed by the dimerization of the virus protein E possess sufficient neutralizing capacity. Therefore, the [...] Read more.
Vaccination against dengue virus is challenged by the fact that a generic immune response can induce antibody-dependent-enhancement (ADE) in secondary infections. Only some antibodies targeting a quaternary epitope formed by the dimerization of the virus protein E possess sufficient neutralizing capacity. Therefore, the immunization with anti-idiotypic antibodies of neutralizing antibodies might represent a safe vaccination strategy. Starting from a large pre-immune library, we succeeded in isolating a wide set of anti-idiotypic nanobodies characterized by selective and strong binding to the paratope of the neutralizing antibody 1C10. However, the mice immunized with such constructs did not produce effective antibodies, despite at least some of them eliciting an immune response selective for the nanobody variable regions. The results suggest that complex conformational epitopes might be difficult to be recreated by anti-idiotypic structures. The selection process of the anti-idiotypic candidates might be optimized by applying epitope mapping and modeling approaches aimed at identifying the key residues that is necessary to bind to trigger selective immune response. Full article
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13 pages, 819 KiB  
Systematic Review
Alterations in the Plasma Protein Expression Pattern in Congenital Analbuminemia—A Systematic Review
by Bailey M. Foster, Afsoun Abdollahi and Gregory C. Henderson
Biomolecules 2023, 13(3), 407; https://doi.org/10.3390/biom13030407 - 22 Feb 2023
Cited by 3 | Viewed by 2015
Abstract
Albumin is a highly abundant plasma protein with multiple functions, including the balance of fluid between body compartments and fatty acid trafficking. Humans with congenital analbuminemia (CAA) do not express albumin due to homozygosity for albumin gene mutation. Lessons about physiological control could [...] Read more.
Albumin is a highly abundant plasma protein with multiple functions, including the balance of fluid between body compartments and fatty acid trafficking. Humans with congenital analbuminemia (CAA) do not express albumin due to homozygosity for albumin gene mutation. Lessons about physiological control could be learned from CAA. Remarkably, these patients exhibit an apparently normal lifespan, without substantial impairments in physical functionality. There was speculation that tolerance to albumin deficiency would be characterized by significant upregulation of other plasma proteins to compensate for analbuminemia. It is unknown but possible that changes in plasma protein expression observed in CAA are required for the well-documented survival and general wellness. A systematic review of published case reports was performed to assess plasma protein pattern remodeling in CAA patients who were free of other illnesses that would confound interpretation. From a literature search in Pubmed, Scopus, and Purdue Libraries (updated October 2022), concentration of individual plasma proteins and protein classes were assessed. Total plasma protein concentration was below the reference range in the vast majority of CAA patients in the analysis, as upregulation of other proteins was not sufficient to prevent the decline of total plasma protein when albumin was absent. Nonetheless, an impressive level of evidence in the literature indicated upregulated plasma levels of multiple globulin classes and various specific proteins which may have metabolic functions in common with albumin. The potential role of this altered plasma protein expression pattern in CAA is discussed, and the findings may have implications for other populations with hypoalbuminemia. Full article
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12 pages, 2622 KiB  
Article
Therapeutic Potential of Phytocannabinoid Cannabigerol for Multiple Sclerosis: Modulation of Microglial Activation In Vitro and In Vivo
by Sigal Fleisher-Berkovich, Yvonne Ventura, Maya Amoyal, Arik Dahan, Valeria Feinshtein, Leenor Alfahel, Adrian Israelson, Nirit Bernstein, Jonathan Gorelick and Shimon Ben-Shabat
Biomolecules 2023, 13(2), 376; https://doi.org/10.3390/biom13020376 - 16 Feb 2023
Cited by 3 | Viewed by 1990
Abstract
Multiple sclerosis (MS) is a widespread chronic neuroinflammatory and neurodegenerative disease. Microglia play a crucial role in the pathogenesis of MS via the release of cytokines and reactive oxygen species, e.g., nitric oxide. Research involving the role of phytocannabinoids in neuroinflammation is currently [...] Read more.
Multiple sclerosis (MS) is a widespread chronic neuroinflammatory and neurodegenerative disease. Microglia play a crucial role in the pathogenesis of MS via the release of cytokines and reactive oxygen species, e.g., nitric oxide. Research involving the role of phytocannabinoids in neuroinflammation is currently receiving much attention. Cannabigerol is a main phytocannabinoid, which has attracted significant pharmacological interest due to its non-psychotropic nature. In this research, we studied the effects of cannabigerol on microglial inflammation in vitro, followed by an in vivo study. Cannabigerol attenuated the microglial production of nitric oxide in BV2 microglia and primary glial cells; concomitant treatment of the cells with cannabigerol and telmisartan (a neuroprotective angiotensin receptor blocker) decreased nitric oxide production additively. Inducible nitric oxide synthase (iNOS) expression was also reduced by cannabigerol. Moreover, tumor necrosis factor-α (TNF-α), a major cytokine involved in MS, was significantly reduced by cannabigerol in both cell cultures. Next, we studied the effects of cannabigerol in vivo using a mice model of MS, experimental autoimmune encephalomyelitis (EAE). The clinical scores of EAE mice were attenuated upon cannabigerol treatment; additionally, lumbar sections of EAE mice showed enhanced neuronal loss (relative to control mice), which was restored by cannabigerol treatment. Altogether, the set of experiments presented in this work indicates that cannabigerol possesses an appealing therapeutic potential for the treatment of MS. Full article
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9 pages, 522 KiB  
Perspective
The Cd/Zn Axis: Emerging Concepts in Cellular Fate and Cytotoxicity
by Colleen Elsa Johns, Mrudula Gattu, Samuel Camilli, Apoorva Desaraju, Narasaiah Kolliputi and Lakshmi Galam
Biomolecules 2023, 13(2), 316; https://doi.org/10.3390/biom13020316 - 07 Feb 2023
Cited by 4 | Viewed by 1530
Abstract
Cadmium (Cd) is a toxic and carcinogenic substance that is present in the natural environment. The underlying biomolecular mechanisms of Cd toxicity are not completely understood, and it continues to be a significant research target due to its impact on public health. The [...] Read more.
Cadmium (Cd) is a toxic and carcinogenic substance that is present in the natural environment. The underlying biomolecular mechanisms of Cd toxicity are not completely understood, and it continues to be a significant research target due to its impact on public health. The primary routes of exposure are through ingestion of contaminated food and water and inhalation. Cd’s long biological half-life of 10–30 years allows it to accumulate in the body, leading to organ dysfunction notably in the kidney, liver, bone, and lungs. Cd has similar biochemical characteristics to Zinc (Zn). It shares the import transporters, ZIP8 and ZIP14, to enter the cells. This competitive behavior can be observed in multiple instances throughout the progression of Cd toxicity. Future studies on the biochemical interactions of Cd and Zn will elucidate the potential protective effects of Zn supplementation in reducing the effects of Cd toxicity. In addition, research can be focused on discovering key proteins and effective pathways for Cd elimination that confer fewer adverse effects than current antioxidant therapies. Full article
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17 pages, 339 KiB  
Article
The Associations of Neutrophil–Lymphocyte, Platelet–Lymphocyte, Monocyte–Lymphocyte Ratios and Immune-Inflammation Index with Negative Symptoms in Patients with Schizophrenia
by Marina Šagud, Zoran Madžarac, Gordana Nedic Erjavec, Ivona Šimunović Filipčić, Filip Luka Mikulić, Dunja Rogić, Zoran Bradaš, Maja Bajs Janović and Nela Pivac
Biomolecules 2023, 13(2), 297; https://doi.org/10.3390/biom13020297 - 04 Feb 2023
Cited by 10 | Viewed by 1837
Abstract
Neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), monocyte–lymphocyte ratio (MLR) and systemic immune-inflammation index (SII index) are increasingly used as indicators of inflammation in different conditions, including schizophrenia. However, their relationship with negative symptoms, including anhedonia, is largely unknown. Included were 200 patients with [...] Read more.
Neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), monocyte–lymphocyte ratio (MLR) and systemic immune-inflammation index (SII index) are increasingly used as indicators of inflammation in different conditions, including schizophrenia. However, their relationship with negative symptoms, including anhedonia, is largely unknown. Included were 200 patients with schizophrenia and 134 healthy controls (HC), assessed for physical anhedonia (PA), using the Revised Physical Anhedonia Scale (RPAS), and social anhedonia (SA) by the Revised Social Anhedonia Scale (RSAS). Patients were rated by the Positive and Negative Syndrome Scale (PANSS), the Clinical Assessment Interview for Negative Symptoms (CAINS) and the Brief Negative Symptom Scale (BNSS). Most of the negative symptoms were in a weak to moderate positive correlations with blood cell inflammatory ratios, namely, between NLR and MLR with PANSS negative scale, CAINS, and BNSS, and in male patients, between PLR and PANSS negative scale and CAINS. Fewer correlations were detected in females, but also in a positive direction. An exception was SA, given the negative correlation between its severity and the SII index in females, and its presence and higher PLR in males. While different negative symptoms were associated with subclinical inflammation, the relationship between SA and lower inflammatory markers deserves further exploration. Full article
44 pages, 5252 KiB  
Review
Cellular and Molecular Mechanisms of Pathogenesis Underlying Inherited Retinal Dystrophies
by Andrew Manley, Bahar I. Meshkat, Monica M. Jablonski and T.J. Hollingsworth
Biomolecules 2023, 13(2), 271; https://doi.org/10.3390/biom13020271 - 01 Feb 2023
Cited by 5 | Viewed by 3671
Abstract
Inherited retinal dystrophies (IRDs) are congenital retinal degenerative diseases that have various inheritance patterns, including dominant, recessive, X-linked, and mitochondrial. These diseases are most often the result of defects in rod and/or cone photoreceptor and retinal pigment epithelium function, development, or both. The [...] Read more.
Inherited retinal dystrophies (IRDs) are congenital retinal degenerative diseases that have various inheritance patterns, including dominant, recessive, X-linked, and mitochondrial. These diseases are most often the result of defects in rod and/or cone photoreceptor and retinal pigment epithelium function, development, or both. The genes associated with these diseases, when mutated, produce altered protein products that have downstream effects in pathways critical to vision, including phototransduction, the visual cycle, photoreceptor development, cellular respiration, and retinal homeostasis. The aim of this manuscript is to provide a comprehensive review of the underlying molecular mechanisms of pathogenesis of IRDs by delving into many of the genes associated with IRD development, their protein products, and the pathways interrupted by genetic mutation. Full article
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13 pages, 1037 KiB  
Review
Parietal Epithelial Cell Behavior and Its Modulation by microRNA-193a
by Joyita Bharati, Praveen N. Chander and Pravin C. Singhal
Biomolecules 2023, 13(2), 266; https://doi.org/10.3390/biom13020266 - 31 Jan 2023
Cited by 2 | Viewed by 2304
Abstract
Glomerular parietal epithelial cells (PECs) have been increasingly recognized to have crucial functions. Lineage tracking in animal models showed the expression of a podocyte phenotype by PECs during normal glomerular growth and after acute podocyte injury, suggesting a reparative role of PECs. Conversely, [...] Read more.
Glomerular parietal epithelial cells (PECs) have been increasingly recognized to have crucial functions. Lineage tracking in animal models showed the expression of a podocyte phenotype by PECs during normal glomerular growth and after acute podocyte injury, suggesting a reparative role of PECs. Conversely, activated PECs are speculated to be pathogenic and comprise extracapillary proliferation in focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CrescGN). The reparative and pathogenic roles of PECs seem to represent two sides of PEC behavior directed by the local milieu and mediators. Recent studies suggest microRNA-193a (miR193a) is involved in the pathogenesis of FSGS and CrescGN. In a mouse model of primary FSGS, the induction of miR193a caused the downregulation of Wilms’ tumor protein, leading to the dedifferentiation of podocytes. On the other hand, the inhibition of miR193a resulted in reduced crescent lesions in a mouse model of CrescGN. Interestingly, in vitro studies report that the downregulation of miR193a induces trans-differentiation of PECs into a podocyte phenotype. This narrative review highlights the critical role of PEC behavior in health and during disease and its modulation by miR193a. Full article
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2022

Jump to: 2024, 2023, 2021, 2020

18 pages, 2228 KiB  
Review
Cucurbitacins as Potent Chemo-Preventive Agents: Mechanistic Insight and Recent Trends
by Hardeep Singh Tuli, Prangya Rath, Abhishek Chauhan, Anuj Ranjan, Seema Ramniwas, Katrin Sak, Diwakar Aggarwal, Manoj Kumar, Kuldeep Dhama, E Hui Clarissa Lee, Kenneth Chun-Yong Yap, Sharah Mae Capinpin and Alan Prem Kumar
Biomolecules 2023, 13(1), 57; https://doi.org/10.3390/biom13010057 - 27 Dec 2022
Cited by 3 | Viewed by 2178
Abstract
Cucurbitacins constitute a group of cucumber-derived dietary lipids, highly oxidized tetracyclic triterpenoids, with potential medical uses. These compounds are known to interact with a variety of recognized cellular targets to impede the growth of cancer cells. Accumulating evidence has suggested that inhibition of [...] Read more.
Cucurbitacins constitute a group of cucumber-derived dietary lipids, highly oxidized tetracyclic triterpenoids, with potential medical uses. These compounds are known to interact with a variety of recognized cellular targets to impede the growth of cancer cells. Accumulating evidence has suggested that inhibition of tumor cell growth via induction of apoptosis, cell-cycle arrest, anti-metastasis and anti-angiogenesis are major promising chemo-preventive actions of cucurbitacins. Cucurbitacins may be a potential choice for investigations of synergism with other drugs to reverse cancer cells’ treatment resistance. The detailed molecular mechanisms underlying these effects include interactions between cucurbitacins and numerous cellular targets (Bcl-2/Bax, caspases, STAT3, cyclins, NF-κB, COX-2, MMP-9, VEGF/R, etc.) as well as control of a variety of intracellular signal transduction pathways. The current study is focused on the efforts undertaken to find possible molecular targets for cucurbitacins in suppressing diverse malignant processes. The review is distinctive since it presents all potential molecular targets of cucurbitacins in cancer on one common podium. Full article
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9 pages, 1952 KiB  
Concept Paper
Lipidomic Profile Analysis of Lung Tissues Revealed Lipointoxication in Pulmonary Veno-Occlusive Disease
by Spiro Khoury, Antoine Beauvais, Jenny Colas, Anaïs Saint-Martin Willer, Frédéric Perros, Marc Humbert, Clarisse Vandebrouck, David Montani, Thierry Ferreira and Fabrice Antigny
Biomolecules 2022, 12(12), 1878; https://doi.org/10.3390/biom12121878 - 14 Dec 2022
Cited by 2 | Viewed by 1571
Abstract
Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary arterial hypertension (PAH) occurring in a heritable form (hPVOD) due to biallelic inactivating mutations of EIF2AK4 (encoding GCN2, general control nonderepressible 2) or in a sporadic form in older age (sPVOD), following exposure [...] Read more.
Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary arterial hypertension (PAH) occurring in a heritable form (hPVOD) due to biallelic inactivating mutations of EIF2AK4 (encoding GCN2, general control nonderepressible 2) or in a sporadic form in older age (sPVOD), following exposure to chemotherapy or organic solvents. In contrast to PAH, PVOD is characterized by a particular remodeling of the pulmonary venous system and the obliteration of small pulmonary veins by fibrous intimal thickening and patchy capillary proliferation. The pathobiological knowledge of PVOD is poor, explaining the absence of medical therapy for PVOD. Lung transplantation remains the only therapy for eligible PVOD patients. As we recently demonstrated, respiratory diseases, chronic obstructive pulmonary disease, or cystic fibrosis exhibit lipointoxication signatures characterized by excessive levels of saturated phospholipids contributing to the pathological features of these diseases, including endoplasmic reticulum stress, pro-inflammatory cytokines production, and bronchoconstriction. In this study, we investigated and compared the clinical data and lung lipid signature of control (10 patients), idiopathic PAH (7 patients), heritable PAH (9 BMPR2 mutations carriers), hPVOD (10 EIF2AK4 mutation carriers), and sPVOD (6 non-carriers) subjects. Mass spectrometry analyses demonstrated lung lipointoxication only in hPVOD patients, characterized by an increased abundance of saturated phosphatidylcholine (PC) at the expense of the polyunsaturated species in the lungs of hPVOD patients. The present data suggest that lipointoxication could be a potential player in the etiology of PVOD. Full article
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20 pages, 4761 KiB  
Article
Functional Resilience of Mutually Repressing Motifs Embedded in Larger Networks
by Pradyumna Harlapur, Atchuta Srinivas Duddu, Kishore Hari, Prakash Kulkarni and Mohit Kumar Jolly
Biomolecules 2022, 12(12), 1842; https://doi.org/10.3390/biom12121842 - 09 Dec 2022
Cited by 2 | Viewed by 1296
Abstract
Elucidating the design principles of regulatory networks driving cellular decision-making has important implications for understanding cell differentiation and guiding the design of synthetic circuits. Mutually repressing feedback loops between ‘master regulators’ of cell fates can exhibit multistable dynamics enabling “single-positive” phenotypes: (high A, [...] Read more.
Elucidating the design principles of regulatory networks driving cellular decision-making has important implications for understanding cell differentiation and guiding the design of synthetic circuits. Mutually repressing feedback loops between ‘master regulators’ of cell fates can exhibit multistable dynamics enabling “single-positive” phenotypes: (high A, low B) and (low A, high B) for a toggle switch, and (high A, low B, low C), (low A, high B, low C) and (low A, low B, high C) for a toggle triad. However, the dynamics of these two motifs have been interrogated in isolation in silico, but in vitro and in vivo, they often operate while embedded in larger regulatory networks. Here, we embed these motifs in complex larger networks of varying sizes and connectivity to identify hallmarks under which these motifs maintain their canonical dynamical behavior. We show that an increased number of incoming edges onto a motif leads to a decay in their canonical stand-alone behaviors. We also show that this decay can be exacerbated by adding self-inhibition but not self-activation loops on the ‘master regulators’. These observations offer insights into the design principles of biological networks containing these motifs and can help devise optimal strategies for the integration of these motifs into larger synthetic networks. Full article
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13 pages, 2497 KiB  
Article
Macrophage-Conditioned Media Promotes Adipocyte Cancer Association, Which in Turn Stimulates Breast Cancer Proliferation and Migration
by Karin A. Vallega, Dale B. Bosco, Yi Ren and Qing-Xiang Amy Sang
Biomolecules 2022, 12(12), 1757; https://doi.org/10.3390/biom12121757 - 26 Nov 2022
Cited by 4 | Viewed by 1981
Abstract
Background: Breast cancer is the most common cancer in women and the leading cause of female cancer deaths worldwide. Obesity causes chronic inflammation and is a risk factor for post-menopausal breast cancer and poor prognosis. Obesity triggers increased infiltration of macrophages into adipose [...] Read more.
Background: Breast cancer is the most common cancer in women and the leading cause of female cancer deaths worldwide. Obesity causes chronic inflammation and is a risk factor for post-menopausal breast cancer and poor prognosis. Obesity triggers increased infiltration of macrophages into adipose tissue, yet little research has focused on the effects of macrophages in early stages of breast tumor development in obese patients. In this study, the effects of pro-inflammatory macrophages on breast cancer–adipocyte crosstalk were investigated. Methods: An innovative human cell co-culture system was built and used to model the paracrine interactions among adipocytes, macrophages, and breast cancer cells and how they facilitate tumor progression. The effects on cancer cells were examined using cell counts and migration assays. Quantitative reverse-transcription polymerase chain reaction was used to measure the expression levels of several cytokines and proteases to analyze adipocyte cancer association. Results: Macrophage-conditioned media intensified the effects of breast cancer–adipocyte crosstalk. Adipocytes became delipidated and increased production of pro-inflammatory cytokines, even in the absence of cancer cells, although the expression levels were highest with all three cell components. As a result, co-cultured breast cancer cells became more aggressive, with increased proliferation and migration compared to adipocyte–breast cancer co-cultures treated with unconditioned media. Conclusions: A novel co-culture model was built to evaluate the crosstalk among human macrophages, adipocytes, and breast cancer cells. We found that macrophages may contribute to adipocyte inflammation and cancer association and thus promote breast cancer progression. Full article
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12 pages, 2622 KiB  
Article
SRF Rearrangements in Soft Tissue Tumors with Muscle Differentiation
by Alice Costa, Livia Gozzellino, Milena Urbini, Valentina Indio, Margherita Nannini, Maria Abbondanza Pantaleo, Silvia Stacchiotti, Annalisa Astolfi and Gianandrea Pasquinelli
Biomolecules 2022, 12(11), 1678; https://doi.org/10.3390/biom12111678 - 12 Nov 2022
Cited by 1 | Viewed by 1637
Abstract
The Serum Response Factor (SRF) is a transcription factor that regulates the expression of a wide set of genes involved in cell proliferation, migration, cytoskeletal organization and myogenesis. Accumulating evidence suggests that SRF may play a role in carcinogenesis and tumor progression in [...] Read more.
The Serum Response Factor (SRF) is a transcription factor that regulates the expression of a wide set of genes involved in cell proliferation, migration, cytoskeletal organization and myogenesis. Accumulating evidence suggests that SRF may play a role in carcinogenesis and tumor progression in various neoplasms, where it is often involved in different fusion events. Here we investigated SRF rearrangements in soft tissue tumors, along with a gene expression profile analysis to gain insight into the oncogenic mechanism driven by SRF fusion. Whole transcriptome analysis of cell lines transiently overexpressing the SRF::E2F1 chimeric transcript uncovered the specific gene expression profile driven by the aberrant gene fusion, including overexpression of SRF-dependent target genes and of signatures related to myogenic commitment, inflammation and immune activation. This result was confirmed by the analysis of two cases of myoepitheliomas harboring SRF::E2F1 fusion with respect to EWSR1-fusion positive tumors. The recognition of the specific gene signature driven by SRF rearrangement in soft tissue tumors could aid the molecular classification of this rare tumor entity and support therapeutic decisions. Full article
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24 pages, 1095 KiB  
Review
Molecular Pathways of the Therapeutic Effects of Ayahuasca, a Botanical Psychedelic and Potential Rapid-Acting Antidepressant
by Giordano Novak Rossi, Lorena T. L. Guerra, Glen B. Baker, Serdar M. Dursun, José Carlos Bouso Saiz, Jaime E. C. Hallak and Rafael G. dos Santos
Biomolecules 2022, 12(11), 1618; https://doi.org/10.3390/biom12111618 - 02 Nov 2022
Cited by 4 | Viewed by 6110
Abstract
Ayahuasca is a psychoactive brew traditionally used in indigenous and religious rituals and ceremonies in South America for its therapeutic, psychedelic, and entheogenic effects. It is usually prepared by lengthy boiling of the leaves of the bush Psychotria viridis and the mashed stalks [...] Read more.
Ayahuasca is a psychoactive brew traditionally used in indigenous and religious rituals and ceremonies in South America for its therapeutic, psychedelic, and entheogenic effects. It is usually prepared by lengthy boiling of the leaves of the bush Psychotria viridis and the mashed stalks of the vine Banisteriopsis caapi in water. The former contains the classical psychedelic N,N-dimethyltryptamine (DMT), which is thought to be the main psychoactive alkaloid present in the brew. The latter serves as a source for β-carbolines, known for their monoamine oxidase-inhibiting (MAOI) properties. Recent preliminary research has provided encouraging results investigating ayahuasca’s therapeutic potential, especially regarding its antidepressant effects. On a molecular level, pre-clinical and clinical evidence points to a complex pharmacological profile conveyed by the brew, including modulation of serotoninergic, glutamatergic, dopaminergic, and endocannabinoid systems. Its substances also interact with the vesicular monoamine transporter (VMAT), trace amine-associated receptor 1 (TAAR1), and sigma-1 receptors. Furthermore, ayahuasca’s components also seem to modulate levels of inflammatory and neurotrophic factors beneficially. On a biological level, this translates into neuroprotective and neuroplastic effects. Here we review the current knowledge regarding these molecular interactions and how they relate to the possible antidepressant effects ayahuasca seems to produce. Full article
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21 pages, 2253 KiB  
Article
Nusinersen Induces Disease-Severity-Specific Neurometabolic Effects in Spinal Muscular Atrophy
by Francesco Errico, Carmen Marino, Manuela Grimaldi, Tommaso Nuzzo, Valentina Bassareo, Valeria Valsecchi, Chiara Panicucci, Elia Di Schiavi, Tommaso Mazza, Claudio Bruno, Adele D’Amico, Manolo Carta, Anna Maria D’Ursi, Enrico Bertini, Livio Pellizzoni and Alessandro Usiello
Biomolecules 2022, 12(10), 1431; https://doi.org/10.3390/biom12101431 - 06 Oct 2022
Cited by 7 | Viewed by 2892
Abstract
Intrathecal delivery of Nusinersen–an antisense oligonucleotide that promotes survival motor neuron (SMN) protein induction–is an approved therapy for spinal muscular atrophy (SMA). Here, we employed nuclear magnetic resonance (NMR) spectroscopy to longitudinally characterize the unknown metabolic effects of Nusinersen in the cerebrospinal fluid [...] Read more.
Intrathecal delivery of Nusinersen–an antisense oligonucleotide that promotes survival motor neuron (SMN) protein induction–is an approved therapy for spinal muscular atrophy (SMA). Here, we employed nuclear magnetic resonance (NMR) spectroscopy to longitudinally characterize the unknown metabolic effects of Nusinersen in the cerebrospinal fluid (CSF) of SMA patients across disease severity. Modulation of amino acid metabolism is a common denominator of biochemical changes induced by Nusinersen, with distinct downstream metabolic effects according to disease severity. In severe SMA1 patients, Nusinersen stimulates energy-related glucose metabolism. In intermediate SMA2 patients, Nusinersen effects are also related to energy homeostasis but involve ketone body and fatty acid biosynthesis. In milder SMA3 patients, Nusinersen mainly modulates amino acid metabolism. Moreover, Nusinersen modifies the CSF metabolome of a more severe clinical group towards the profile of untreated SMA patients with milder disease. These findings reveal disease severity-specific neurometabolic signatures of Nusinersen treatment, suggesting a selective modulation of peripheral organ metabolism by this CNS-directed therapy in severe SMA patients. Full article
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15 pages, 2650 KiB  
Article
Inhibition of Malate Dehydrogenase-2 Protects Renal Tubular Epithelial Cells from Anoxia-Reoxygenation-Induced Death or Senescence
by Theodoros Eleftheriadis, Georgios Pissas, Spyridon Golfinopoulos, Maria Efthymiadi, Vassilios Liakopoulos and Ioannis Stefanidis
Biomolecules 2022, 12(10), 1415; https://doi.org/10.3390/biom12101415 - 03 Oct 2022
Cited by 5 | Viewed by 2052
Abstract
Ischemia-reperfusion injury is the leading cause of acute kidney injury. Reactive oxygen species (ROS) production causes cell death or senescence. In cultures of primary human renal tubular epithelial cells (RPTECs) subjected to anoxia-reoxygenation, inhibition of the Krebs cycle at the level of malate [...] Read more.
Ischemia-reperfusion injury is the leading cause of acute kidney injury. Reactive oxygen species (ROS) production causes cell death or senescence. In cultures of primary human renal tubular epithelial cells (RPTECs) subjected to anoxia-reoxygenation, inhibition of the Krebs cycle at the level of malate dehydrogenase-2 (MDH-2) decreases hypoxia-inducible factor-1α and oxidative stress and protects from apoptotic or ferroptotic cell death. Inhibition of MDH-2 decreased reoxygenation-induced upregulation of p53 and p21, restored the levels of the proliferation marker Ki-67, and prevented the upregulation of the senescence marker beta-galactosidase and interleukin-1β production. MDH-2 inhibition reduced the reoxygenation-induced upregulation of ATP, but the alterations of critical cell metabolism enzymes allowed enough ATP production to prevent cell energy collapse. Thus, inhibition of the Krebs cycle at the level of MDH-2 protects RPTECs from anoxia-reoxygenation-induced death or senescence. MDH-2 may be a promising pharmaceutical target against ischemia-reperfusion injury. Full article
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28 pages, 2509 KiB  
Review
Iron in Alzheimer’s Disease: From Physiology to Disease Disabilities
by Amit Pal, Giselle Cerchiaro, Isha Rani, Mariacarla Ventriglia, Mauro Rongioletti, Antonio Longobardi and Rosanna Squitti
Biomolecules 2022, 12(9), 1248; https://doi.org/10.3390/biom12091248 - 06 Sep 2022
Cited by 17 | Viewed by 2916
Abstract
Reactive oxygen species (ROS) play a key role in the neurodegeneration processes. Increased oxidative stress damages lipids, proteins, and nucleic acids in brain tissue, and it is tied to the loss of biometal homeostasis. For this reason, attention has been focused on transition [...] Read more.
Reactive oxygen species (ROS) play a key role in the neurodegeneration processes. Increased oxidative stress damages lipids, proteins, and nucleic acids in brain tissue, and it is tied to the loss of biometal homeostasis. For this reason, attention has been focused on transition metals involved in several biochemical reactions producing ROS. Even though a bulk of evidence has uncovered the role of metals in the generation of the toxic pathways at the base of Alzheimer’s disease (AD), this matter has been sidelined by the advent of the Amyloid Cascade Hypothesis. However, the link between metals and AD has been investigated in the last two decades, focusing on their local accumulation in brain areas known to be critical for AD. Recent evidence revealed a relation between iron and AD, particularly in relation to its capacity to increase the risk of the disease through ferroptosis. In this review, we briefly summarize the major points characterizing the function of iron in our body and highlight why, even though it is essential for our life, we have to monitor its dysfunction, particularly if we want to control our risk of AD. Full article
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10 pages, 2180 KiB  
Article
2-Hydroxypropyl-beta-cyclodextrin Treatment Does Not Induce Atherosclerotic Lesion Regression in Western-Type Diet-Fed Apolipoprotein E Knockout Mice
by Olga S.C. Snip, Menno Hoekstra, Yiheng Zhang, Janine J. Geerling and Miranda Van Eck
Biomolecules 2022, 12(9), 1205; https://doi.org/10.3390/biom12091205 - 31 Aug 2022
Cited by 2 | Viewed by 2216
Abstract
2-Hydroxypropyl-beta-cyclodextrin (2HPβCD) is able to bind and solubilize unesterified cholesterol and may therefore be able to reverse the deposition of cholesterol in macrophages within the aortic vessel wall, a hallmark of atherosclerotic cardiovascular disease. However, conflicting results regarding the potential of 2HPβCD to [...] Read more.
2-Hydroxypropyl-beta-cyclodextrin (2HPβCD) is able to bind and solubilize unesterified cholesterol and may therefore be able to reverse the deposition of cholesterol in macrophages within the aortic vessel wall, a hallmark of atherosclerotic cardiovascular disease. However, conflicting results regarding the potential of 2HPβCD to induce regression of established atherosclerotic lesions have been described. In the current study, we therefore also investigated the ability of 2HPβCD to stimulate cholesterol removal from macrophage foam cells in vitro and induce the regression of established atherosclerotic lesions in apolipoprotein E knockout (APOE KO) mice. In vitro studies using murine thioglycollate-elicited peritoneal macrophages verified that 2HPβCD is able to induce cholesterol efflux from macrophages in an ATP-binding cassette transporter-independent manner. Switching Western-type-diet-fed APOE KO mice with established atherosclerotic lesions back to a chow diet was associated with a reduction in the hypercholesterolemia extent and an increase in the absolute lesion size and plaque collagen-to-macrophage ratio. Importantly, parallel subcutaneous administration of 2HPβCD was not able to prevent the diet-switch-associated lesion growth or induce atherosclerosis regression. Although in our hands, 2HPβCD does effectively stimulate cellular cholesterol efflux from macrophages, we do not consider it worthwhile to further pursue 2HPβCD as therapeutic moiety in the atherosclerosis regression context. Full article
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4 pages, 185 KiB  
Perspective
Can PPAR γ Keep Cadmium in Check?
by Caila Robinson, Richard F. Lockey and Narasaiah Kolliputi
Biomolecules 2022, 12(8), 1094; https://doi.org/10.3390/biom12081094 - 09 Aug 2022
Viewed by 1517
Abstract
Cd, a naturally occurring endocrine toxin found in tobacco leaves, originates in the environment and enters the body through inhalation, targeting the lungs and kidneys. A study published by Larsen-Carey et al. revealed that cadmium mediates the persistence of classically activated lung macrophages [...] Read more.
Cd, a naturally occurring endocrine toxin found in tobacco leaves, originates in the environment and enters the body through inhalation, targeting the lungs and kidneys. A study published by Larsen-Carey et al. revealed that cadmium mediates the persistence of classically activated lung macrophages to exacerbate lung injury. The research discovered a novel role for PPAR γ as an effective regulator for the alternative activation of macrophages in response to Cd and Cd-induced lung injury. Full article
20 pages, 3015 KiB  
Article
Isolation, Characterization, and Autophagy Function of BECN1-Splicing Isoforms in Cancer Cells
by Chinmay Maheshwari, Chiara Vidoni, Rossella Titone, Andrea Castiglioni, Claudia Lora, Carlo Follo and Ciro Isidoro
Biomolecules 2022, 12(8), 1069; https://doi.org/10.3390/biom12081069 - 02 Aug 2022
Cited by 2 | Viewed by 2293
Abstract
Alternative splicing allows the synthesis of different protein variants starting from a single gene. Human Beclin 1 (BECN1) is a key autophagy regulator that acts as haploinsufficient tumor suppressor since its decreased expression correlates with tumorigenesis and poor prognosis in cancer [...] Read more.
Alternative splicing allows the synthesis of different protein variants starting from a single gene. Human Beclin 1 (BECN1) is a key autophagy regulator that acts as haploinsufficient tumor suppressor since its decreased expression correlates with tumorigenesis and poor prognosis in cancer patients. Recent studies show that BECN1 mRNA undergoes alternative splicing. Here, we report on the isolation and molecular and functional characterization of three BECN1 transcript variants (named BECN1-α, -β and -γ) in human cancer cells. In ovarian cancer NIHOVCAR3, these splicing variants were found along with the canonical wild-type. BECN1-α lacks 143 nucleotides at its C-terminus and corresponds to a variant previously described. BECN1-β and -γ lack the BCL2 homology 3 domain and other regions at their C-termini. Following overexpression in breast cancer cells MDA-MB231, we found that BECN1-α stimulates autophagy. Specifically, BECN1-α binds to Parkin and stimulates mitophagy. On the contrary, BECN1-β reduces autophagy with a dominant negative effect over the endogenous wild-type isoform. BECN1-γ maintains its ability to interact with the vacuolar protein sorting 34 and only has a slight effect on autophagy. It is possible that cancer cells utilize the alternative splicing of BECN1 for modulating autophagy and mitophagy in response to environmental stresses. Full article
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15 pages, 1570 KiB  
Article
Myristic Acid Supplementation Aggravates High Fat Diet-Induced Adipose Inflammation and Systemic Insulin Resistance in Mice
by Viswanathan Saraswathi, Narendra Kumar, Weilun Ai, Thiyagarajan Gopal, Saumya Bhatt, Edward N. Harris, Geoffrey A. Talmon and Cyrus V. Desouza
Biomolecules 2022, 12(6), 739; https://doi.org/10.3390/biom12060739 - 24 May 2022
Cited by 10 | Viewed by 3246
Abstract
Saturated fatty acids (SFAs) are considered to be detrimental to human health. One of the SFAs, myristic acid (MA), is known to exert a hypercholesterolemic effect in mice as well as humans. However, its effects on altering adipose tissue (AT) inflammation and systemic [...] Read more.
Saturated fatty acids (SFAs) are considered to be detrimental to human health. One of the SFAs, myristic acid (MA), is known to exert a hypercholesterolemic effect in mice as well as humans. However, its effects on altering adipose tissue (AT) inflammation and systemic insulin resistance (IR) in obesity are still unclear. Here, we sought to determine the effects of a high fat (HF) diet supplemented with MA on obesity-associated metabolic disorders in mice. Wild-type C57BL/6 mice were fed a HF diet in the presence or absence of 3% MA for 12 weeks. Plasma lipids, plasma adipokines, AT inflammation, systemic IR, glucose homeostasis, and hepatic steatosis were assessed. The body weight and visceral adipose tissue (VAT) mass were significantly higher in mice receiving the HF+MA diet compared to HF diet-fed controls. Plasma total cholesterol levels were marginally increased in HF+MA-fed mice compared to controls. Fasting blood glucose was comparable between HF and HF+MA-fed mice. Interestingly, the plasma insulin and HOMA-IR index, a measure of insulin resistance, were significantly higher in HF+MA-fed mice compared to HF controls. Macrophage and inflammatory markers were significantly elevated in the AT and AT-derived stromal vascular cells upon MA feeding. Moreover, the level of circulating resistin, an adipokine promoting insulin resistance, was significantly higher in HF+MA-fed mice compared with HF controls. The insulin tolerance test revealed that the IR was higher in mice receiving the MA supplementation compared to HF controls. Moreover, the glucose tolerance test showed impairment in systemic glucose homeostasis in MA-fed mice. Analyses of liver samples showed a trend towards an increase in liver TG upon MA feeding. However, markers of oxidative stress and inflammation were reduced in the liver of mice fed an MA diet compared to controls. Taken together, our data suggest that chronic administration of MA in diet exacerbates obesity-associated insulin resistance and this effect is mediated in part, via increased AT inflammation and increased secretion of resistin. Full article
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17 pages, 2074 KiB  
Article
Reduced Platelet MAO-B Activity Is Associated with Psychotic, Positive, and Depressive Symptoms in PTSD
by Senka Repovecki, Gordana Nedic Erjavec, Suzana Uzun, Lucija Tudor, Matea Nikolac Perkovic, Marcela Konjevod, Oliver Kozumplik, Dubravka Svob Strac, Zrnka Kovacic Petrovic, Ninoslav Mimica and Nela Pivac
Biomolecules 2022, 12(5), 736; https://doi.org/10.3390/biom12050736 - 23 May 2022
Viewed by 2674
Abstract
Post-traumatic stress disorder (PTSD) is a trauma-related disorder. Platelet monoamine oxidase (MAO-B) is a peripheral biomarker associated with various symptoms in different psychopathologies, but its role in PTSD or different symptoms in PTSD is not clear. This study elucidated the association between platelet [...] Read more.
Post-traumatic stress disorder (PTSD) is a trauma-related disorder. Platelet monoamine oxidase (MAO-B) is a peripheral biomarker associated with various symptoms in different psychopathologies, but its role in PTSD or different symptoms in PTSD is not clear. This study elucidated the association between platelet MAO-B activity and clinical symptoms occurring in PTSD. Platelet MAO-B activity was determined in 1053 male Caucasian subjects: 559 war veterans with PTSD (DSM-5 criteria), 62 combat exposed veterans who did not develop PTSD, and 432 non-combat exposed healthy controls. Clinical symptoms in PTSD were determined using CAPS and PANSS. Platelet MAO-B activity, controlled for the effect of smoking, was significantly increased in PTSD with severe versus mild and moderate traumatic symptoms, and was significantly decreased in PTSD subjects with severe versus mild positive, psychotic, and depressive symptoms. This finding was further confirmed with reduced platelet MAO-B activity in PTSD veterans with severe versus mild individual items of the PANSS-depressed, PANSS-psychotic, and PANSS-positive subscales. Altered platelet MAO-B activity, controlled for the possible confounders, was associated with the development and severity of different symptoms occurring in PTSD. These findings confirmed the role of platelet MAO-B activity as a peripheral marker of various psychopathological symptoms. Full article
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17 pages, 691 KiB  
Review
Long COVID-19 in Children: From the Pathogenesis to the Biologically Plausible Roots of the Syndrome
by Michele Piazza, Maria Di Cicco, Luca Pecoraro, Michele Ghezzi, Diego Peroni and Pasquale Comberiati
Biomolecules 2022, 12(4), 556; https://doi.org/10.3390/biom12040556 - 08 Apr 2022
Cited by 15 | Viewed by 5823
Abstract
Long Coronavirus disease-19 (COVID-19) refers to the persistence of symptoms related to the infection with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). This condition is described as persistent and can manifest in various combinations of signs and symptoms, such as fatigue, headache, dyspnea, depression, cognitive [...] Read more.
Long Coronavirus disease-19 (COVID-19) refers to the persistence of symptoms related to the infection with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). This condition is described as persistent and can manifest in various combinations of signs and symptoms, such as fatigue, headache, dyspnea, depression, cognitive impairment, and altered perception of smells and tastes. Long COVID-19 may be due to long-term damage to different organs—such as lung, brain, kidney, and heart—caused by persisting viral-induced inflammation, immune dysregulation, autoimmunity, diffuse endothelial damage, and micro thrombosis. In this review, we discuss the potential and biologically plausible role of some vitamins, essential elements, and functional foods based on the hypothesis that an individual’s dietary status may play an important adjunctive role in protective immunity against COVID-19 and possibly against its long-term consequences. Full article
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12 pages, 1759 KiB  
Article
Identification of Regions Involved in the Physical Interaction between Melanocortin Receptor Accessory Protein 2 and Prokineticin Receptor 2
by Maria Rosaria Fullone, Daniela Maftei, Martina Vincenzi, Roberta Lattanzi and Rossella Miele
Biomolecules 2022, 12(3), 474; https://doi.org/10.3390/biom12030474 - 20 Mar 2022
Cited by 9 | Viewed by 1949
Abstract
Melanocortin Receptor Accessory Protein 2 (MRAP2) modulates the trafficking and signal transduction of several G-protein-coupled receptors (GPCRs) involved in the control of energy homeostasis, such as Prokineticin receptors (PKRs). They bind the endogenous ligand prokineticin 2 (PK2), a novel adipokine that has an [...] Read more.
Melanocortin Receptor Accessory Protein 2 (MRAP2) modulates the trafficking and signal transduction of several G-protein-coupled receptors (GPCRs) involved in the control of energy homeostasis, such as Prokineticin receptors (PKRs). They bind the endogenous ligand prokineticin 2 (PK2), a novel adipokine that has an anorexic effect and modulates thermoregulation and energy homeostasis. In the present work, we used biochemical techniques to analyze the mechanism of interaction of MRAP2 with PKR2 and we identified the specific amino acid regions involved in the complex formation. Our results indicate that MRAP2 likely binds to the N-terminal region of PKR2, preventing glycosylation and consequently the correct receptor localization. We also identified a C-terminal region of MRAP2 that is critical for the interaction with PKR2. Consequently, we analyzed the role of the prokineticin transduction system in the regulation of MRAP2 expression in tissues involved in the control of food intake: at the central level, in hypothalamic explants, and at the peripheral level, in adipocytes. We demonstrated the modulation of MRAP2 expression by the prokineticin transduction system. Full article
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25 pages, 2122 KiB  
Review
Alcohol and Prostate Cancer: Time to Draw Conclusions
by Amanda J. Macke and Armen Petrosyan
Biomolecules 2022, 12(3), 375; https://doi.org/10.3390/biom12030375 - 28 Feb 2022
Cited by 11 | Viewed by 8465
Abstract
It has been a long-standing debate in the research and medical societies whether alcohol consumption is linked to the risk of prostate cancer (PCa). Many comprehensive studies from different geographical areas and nationalities have shown that moderate and heavy drinking is positively correlated [...] Read more.
It has been a long-standing debate in the research and medical societies whether alcohol consumption is linked to the risk of prostate cancer (PCa). Many comprehensive studies from different geographical areas and nationalities have shown that moderate and heavy drinking is positively correlated with the development of PCa. Nevertheless, some observations could not confirm that such a correlation exists; some even suggest that wine consumption could prevent or slow prostate tumor growth. Here, we have rigorously analyzed the evidence both for and against the role of alcohol in PCa development. We found that many of the epidemiological studies did not consider other, potentially critical, factors, including diet (especially, low intake of fish, vegetables and linoleic acid, and excessive use of red meat), smoking, family history of PCa, low physical activity, history of high sexual activities especially with early age of first intercourse, and sexually transmitted infections. In addition, discrepancies between observations come from selectivity criteria for control groups, questionnaires about the type and dosage of alcohol, and misreported alcohol consumption. The lifetime history of alcohol consumption is critical given that a prostate tumor is typically slow-growing; however, many epidemiological observations that show no association monitored only current or relatively recent drinking status. Nevertheless, the overall conclusion is that high alcohol intake, especially binge drinking, is associated with increased risk for PCa, and this effect is not limited to any type of beverage. Alcohol consumption is also directly linked to PCa lethality as it may accelerate the growth of prostate tumors and significantly shorten the time for the progression to metastatic PCa. Thus, we recommend immediately quitting alcohol for patients diagnosed with PCa. We discuss the features of alcohol metabolism in the prostate tissue and the damaging effect of ethanol metabolites on intracellular organization and trafficking. In addition, we review the impact of alcohol consumption on prostate-specific antigen level and the risk for benign prostatic hyperplasia. Lastly, we highlight the known mechanisms of alcohol interference in prostate carcinogenesis and the possible side effects of alcohol during androgen deprivation therapy. Full article
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18 pages, 1988 KiB  
Article
Butyrate Ameliorates Mitochondrial Respiratory Capacity of The Motor-Neuron-like Cell Line NSC34-G93A, a Cellular Model for ALS
by Xuejun Li, Li Dong, Ang Li, Jianxun Yi, Marco Brotto and Jingsong Zhou
Biomolecules 2022, 12(2), 333; https://doi.org/10.3390/biom12020333 - 19 Feb 2022
Cited by 9 | Viewed by 2921
Abstract
Mitochondrial defects in motor neurons are pathological hallmarks of ALS, a neuromuscular disease with no effective treatment. Studies have shown that butyrate, a natural gut-bacteria product, alleviates the disease progression of ALS mice overexpressing a human ALS-associated mutation, hSOD1G93A. In the [...] Read more.
Mitochondrial defects in motor neurons are pathological hallmarks of ALS, a neuromuscular disease with no effective treatment. Studies have shown that butyrate, a natural gut-bacteria product, alleviates the disease progression of ALS mice overexpressing a human ALS-associated mutation, hSOD1G93A. In the current study, we examined the potential molecular mechanisms underlying the effect of butyrate on mitochondrial function in cultured motor-neuron-like NSC34 with overexpression of hSOD1G93A (NSC34-G93A). The live cell confocal imaging study demonstrated that 1mM butyrate in the culture medium improved the mitochondrial network with reduced fragmentation in NSC34-G93A cells. Seahorse analysis revealed that NSC34-G93A cells treated with butyrate showed an increase of ~5-fold in mitochondrial Spare Respiratory Capacity with elevated Maximal Respiration. The time-dependent changes in the mRNA level of PGC1α, a master regulator of mitochondrial biogenesis, revealed a burst induction with an early increase (~5-fold) at 4 h, a peak at 24 h (~19-fold), and maintenance at 48 h (8-fold) post-treatment. In line with the transcriptional induction of PGC1α, both the mRNA and protein levels of the key molecules (MTCO1, MTCO2, and COX4) related to the mitochondrial electron transport chain were increased following the butyrate treatment. Our data indicate that activation of the PGC1α signaling axis could be one of the molecular mechanisms underlying the beneficial effects of butyrate treatment in improving mitochondrial bioenergetics in NSC34-G93A cells. Full article
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12 pages, 1448 KiB  
Article
Abnormal RasGRP1 Expression in the Post-Mortem Brain and Blood Serum of Schizophrenia Patients
by Arianna De Rosa, Anna Di Maio, Silvia Torretta, Martina Garofalo, Valentina Giorgelli, Rita Masellis, Tommaso Nuzzo, Francesco Errico, Alessandro Bertolino, Srinivasa Subramaniam, Antonio Rampino and Alessandro Usiello
Biomolecules 2022, 12(2), 328; https://doi.org/10.3390/biom12020328 - 18 Feb 2022
Cited by 2 | Viewed by 2153
Abstract
Schizophrenia (SCZ) is a polygenic severe mental illness. Genome-wide association studies (GWAS) have detected genomic variants associated with this psychiatric disorder and pathway analyses have indicated immune system and dopamine signaling as core components of risk in dorsolateral-prefrontal cortex (DLPFC) and hippocampus, but [...] Read more.
Schizophrenia (SCZ) is a polygenic severe mental illness. Genome-wide association studies (GWAS) have detected genomic variants associated with this psychiatric disorder and pathway analyses have indicated immune system and dopamine signaling as core components of risk in dorsolateral-prefrontal cortex (DLPFC) and hippocampus, but the mechanistic links remain unknown. The RasGRP1 gene, encoding for a guanine nucleotide exchange factor, is implicated in dopamine signaling and immune response. RasGRP1 has been identified as a candidate risk gene for SCZ and autoimmune disease, therefore representing a possible point of convergence between mechanisms involving the nervous and the immune system. Here, we investigated RasGRP1 mRNA and protein expression in post-mortem DLPFC and hippocampus of SCZ patients and healthy controls, along with RasGRP1 protein content in the serum of an independent cohort of SCZ patients and control subjects. Differences in RasGRP1 expression between SCZ patients and controls were detected both in DLPFC and peripheral blood of samples analyzed. Our results indicate RasGRP1 may mediate risk for SCZ by involving DLPFC and peripheral blood, thus encouraging further studies to explore its possible role as a biomarker of the disease and/or a target for new medication. Full article
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11 pages, 2585 KiB  
Article
Matrix Metalloproteinase 7 Expression and Apical Epithelial Defects in Atp8b1 Mutant Mouse Model of Pulmonary Fibrosis
by Emma Westermann-Clark, Ramani Soundararajan, Jutaro Fukumoto, Sahebgowda Sidramagowda Patil, Timothy M. Stearns, Smita Saji, Alexander Czachor, Helena Hernandez-Cuervo, Mason Breitzig, Sudarshan Krishnamurthy, Richard F. Lockey and Narasaiah Kolliputi
Biomolecules 2022, 12(2), 283; https://doi.org/10.3390/biom12020283 - 09 Feb 2022
Cited by 2 | Viewed by 2004
Abstract
Abnormalities in airway epithelia and lung parenchyma are found in Atp8b1 mutant mice, which develop pulmonary fibrosis after hyperoxic insult. Microarray and ingenuity pathway analysis (IPA) show numerous transcripts involved in ciliogenesis are downregulated in 14-month (14 M) -old Atp8b1 mouse lung compared [...] Read more.
Abnormalities in airway epithelia and lung parenchyma are found in Atp8b1 mutant mice, which develop pulmonary fibrosis after hyperoxic insult. Microarray and ingenuity pathway analysis (IPA) show numerous transcripts involved in ciliogenesis are downregulated in 14-month (14 M) -old Atp8b1 mouse lung compared with wild-type C57BL/6. Lung epithelium of Atp8b1 mice demonstrate apical abnormalities of ciliated and club cells in the bronchial epithelium on transmission electron microscopy (TEM). Matrix metalloproteinase 7 (MMP7) regulates of ciliogenesis and is a biomarker for idiopathic pulmonary fibrosis (IPF) in humans. Mmp7 transcript and protein expression are significantly upregulated in 14 M Atp8b1 mutant mouse lung. MMP7 expression is also increased in bronchoalveolar lavage fluid (BAL). Immunohistochemistry is localized MMP7 to bronchial epithelial cells in the Atp8b1 mutant. In conclusion, MMP7 is upregulated in the aged Atp8b1 mouse model, which displays abnormal ciliated cell and club cell morphology. This mouse model can facilitate the exploration of the role of MMP7 in epithelial integrity and ciliogenesis in IPF. The Atp8b1 mutant mouse is proposed as a model for IPF. Full article
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15 pages, 44475 KiB  
Article
CCN2 Binds to Tubular Epithelial Cells in the Kidney
by Sandra Rayego-Mateos, José Luis Morgado-Pascual, Carolina Lavoz, Raúl R. Rodrigues-Díez, Laura Márquez-Expósito, Antonio Tejera-Muñoz, Lucía Tejedor-Santamaría, Irene Rubio-Soto, Vanessa Marchant and Marta Ruiz-Ortega
Biomolecules 2022, 12(2), 252; https://doi.org/10.3390/biom12020252 - 03 Feb 2022
Cited by 6 | Viewed by 2478
Abstract
Cellular communication network-2 (CCN2), also called connective tissue growth factor (CTGF), is considered a fibrotic biomarker and has been suggested as a potential therapeutic target for kidney pathologies. CCN2 is a matricellular protein with four distinct structural modules that can exert a dual [...] Read more.
Cellular communication network-2 (CCN2), also called connective tissue growth factor (CTGF), is considered a fibrotic biomarker and has been suggested as a potential therapeutic target for kidney pathologies. CCN2 is a matricellular protein with four distinct structural modules that can exert a dual function as a matricellular protein and as a growth factor. Previous experiments using surface plasmon resonance and cultured renal cells have demonstrated that the C-terminal module of CCN2 (CCN2(IV)) interacts with the epidermal growth factor receptor (EGFR). Moreover, CCN2(IV) activates proinflammatory and profibrotic responses in the mouse kidney. The aim of this paper was to locate the in vivo cellular CCN2/EGFR binding sites in the kidney. To this aim, the C-terminal module CCN2(IV) was labeled with a fluorophore (Cy5), and two different administration routes were employed. Both intraperitoneal and direct intra-renal injection of Cy5-CCN2(IV) in mice demonstrated that CCN2(IV) preferentially binds to the tubular epithelial cells, while no signal was detected in glomeruli. Moreover, co-localization of Cy5-CCN2(IV) binding and activated EGFR was found in tubules. In cultured tubular epithelial cells, live-cell confocal microscopy experiments showed that EGFR gene silencing blocked Cy5-CCN2(IV) binding to tubuloepithelial cells. These data clearly show the existence of CCN2/EGFR binding sites in the kidney, mainly in tubular epithelial cells. In conclusion, these studies show that circulating CCN2(IV) can directly bind and activate tubular cells, supporting the role of CCN2 as a growth factor involved in kidney damage progression. Full article
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12 pages, 802 KiB  
Review
On the Effects of Disordered Tails, Supertertiary Structure and Quinary Interactions on the Folding and Function of Protein Domains
by Francesca Malagrinò, Valeria Pennacchietti, Daniele Santorelli, Livia Pagano, Caterina Nardella, Awa Diop, Angelo Toto and Stefano Gianni
Biomolecules 2022, 12(2), 209; https://doi.org/10.3390/biom12020209 - 26 Jan 2022
Cited by 6 | Viewed by 3024
Abstract
The vast majority of our current knowledge about the biochemical and biophysical properties of proteins derives from in vitro studies conducted on isolated globular domains. However, a very large fraction of the proteins expressed in the eukaryotic cell are structurally more complex. In [...] Read more.
The vast majority of our current knowledge about the biochemical and biophysical properties of proteins derives from in vitro studies conducted on isolated globular domains. However, a very large fraction of the proteins expressed in the eukaryotic cell are structurally more complex. In particular, the discovery that up to 40% of the eukaryotic proteins are intrinsically disordered, or possess intrinsically disordered regions, and are highly dynamic entities lacking a well-defined three-dimensional structure, revolutionized the structure–function paradigm and our understanding of proteins. Moreover, proteins are mostly characterized by the presence of multiple domains, influencing each other by intramolecular interactions. Furthermore, proteins exert their function in a crowded intracellular milieu, transiently interacting with a myriad of other macromolecules. In this review we summarize the literature tackling these themes from both the theoretical and experimental perspectives, highlighting the effects on protein folding and function that are played by (i) flanking disordered tails; (ii) contiguous protein domains; (iii) interactions with the cellular environment, defined as quinary structures. We show that, in many cases, both the folding and function of protein domains is remarkably perturbed by the presence of these interactions, pinpointing the importance to increase the level of complexity of the experimental work and to extend the efforts to characterize protein domains in more complex contexts. Full article
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27 pages, 6061 KiB  
Article
The Role of Rosmarinic Acid on the Bioproduction of Gold Nanoparticles as Part of a Photothermal Approach for Breast Cancer Treatment
by Tânia Ferreira-Gonçalves, Maria Manuela Gaspar, João M. P. Coelho, Vanda Marques, Ana S. Viana, Lia Ascensão, Lina Carvalho, Cecília M. P. Rodrigues, Hugo Alexandre Ferreira, David Ferreira and Catarina Pinto Reis
Biomolecules 2022, 12(1), 71; https://doi.org/10.3390/biom12010071 - 04 Jan 2022
Cited by 13 | Viewed by 2806
Abstract
Breast cancer is a high-burden malignancy for society, whose impact boosts a continuous search for novel diagnostic and therapeutic tools. Among the recent therapeutic approaches, photothermal therapy (PTT), which causes tumor cell death by hyperthermia after being irradiated with a light source, represents [...] Read more.
Breast cancer is a high-burden malignancy for society, whose impact boosts a continuous search for novel diagnostic and therapeutic tools. Among the recent therapeutic approaches, photothermal therapy (PTT), which causes tumor cell death by hyperthermia after being irradiated with a light source, represents a high-potential strategy. Furthermore, the effectiveness of PTT can be improved by combining near infrared (NIR) irradiation with gold nanoparticles (AuNPs) as photothermal enhancers. Herein, an alternative synthetic method using rosmarinic acid (RA) for synthesizing AuNPs is reported. The RA concentration was varied and its impact on the AuNPs physicochemical and optical features was assessed. Results showed that RA concentration plays an active role on AuNPs features, allowing the optimization of mean size and maximum absorbance peak. Moreover, the synthetic method explored here allowed us to obtain negatively charged AuNPs with sizes favoring the local particle accumulation at tumor site and maximum absorbance peaks within the NIR region. In addition, AuNPs were safe both in vitro and in vivo. In conclusion, the synthesized AuNPs present favorable properties to be applied as part of a PTT system combining AuNPs with a NIR laser for the treatment of breast cancer. Full article
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2021

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16 pages, 2819 KiB  
Article
Point Mutations at a Key Site Alter the Cytochrome P450 OleP Structural Dynamics
by Linda Celeste Montemiglio, Elena Gugole, Ida Freda, Cécile Exertier, Lucia D’Auria, Cheng Giuseppe Chen, Alessandro Nicola Nardi, Gabriele Cerutti, Giacomo Parisi, Marco D’Abramo, Carmelinda Savino and Beatrice Vallone
Biomolecules 2022, 12(1), 55; https://doi.org/10.3390/biom12010055 - 31 Dec 2021
Cited by 5 | Viewed by 2076
Abstract
Substrate binding to the cytochrome P450 OleP is coupled to a large open-to-closed transition that remodels the active site, minimizing its exposure to the external solvent. When the aglycone substrate binds, a small empty cavity is formed between the I and G helices, [...] Read more.
Substrate binding to the cytochrome P450 OleP is coupled to a large open-to-closed transition that remodels the active site, minimizing its exposure to the external solvent. When the aglycone substrate binds, a small empty cavity is formed between the I and G helices, the BC loop, and the substrate itself, where solvent molecules accumulate mediating substrate-enzyme interactions. Herein, we analyzed the role of this cavity in substrate binding to OleP by producing three mutants (E89Y, G92W, and S240Y) to decrease its volume. The crystal structures of the OleP mutants in the closed state bound to the aglycone 6DEB showed that G92W and S240Y occupied the cavity, providing additional contact points with the substrate. Conversely, mutation E89Y induces a flipped-out conformation of this amino acid side chain, that points towards the bulk, increasing the empty volume. Equilibrium titrations and molecular dynamic simulations indicate that the presence of a bulky residue within the cavity impacts the binding properties of the enzyme, perturbing the conformational space explored by the complexes. Our data highlight the relevance of this region in OleP substrate binding and suggest that it represents a key substrate-protein contact site to consider in the perspective of redirecting its activity towards alternative compounds. Full article
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22 pages, 3458 KiB  
Article
The Effects of Angiotensin II or Angiotensin 1-7 on Rat Pial Microcirculation during Hypoperfusion and Reperfusion Injury: Role of Redox Stress
by Dominga Lapi, Maurizio Cammalleri, Massimo Dal Monte, Martina Di Maro, Mariarosaria Santillo, Anna Belfiore, Gilda Nasti, Simona Damiano, Rossella Trio, Martina Chiurazzi, Barbara De Conno, Nicola Serao, Paolo Mondola, Antonio Colantuoni and Bruna Guida
Biomolecules 2021, 11(12), 1861; https://doi.org/10.3390/biom11121861 - 10 Dec 2021
Viewed by 2078
Abstract
Renin–angiotensin systems produce angiotensin II (Ang II) and angiotensin 1-7 (Ang 1-7), which are able to induce opposite effects on circulation. This study in vivo assessed the effects induced by Ang II or Ang 1-7 on rat pial microcirculation during hypoperfusion–reperfusion, clarifying the [...] Read more.
Renin–angiotensin systems produce angiotensin II (Ang II) and angiotensin 1-7 (Ang 1-7), which are able to induce opposite effects on circulation. This study in vivo assessed the effects induced by Ang II or Ang 1-7 on rat pial microcirculation during hypoperfusion–reperfusion, clarifying the mechanisms causing the imbalance between Ang II and Ang 1-7. The fluorescence microscopy was used to quantify the microvascular parameters. Hypoperfusion and reperfusion caused vasoconstriction, disruption of blood–brain barrier, reduction of capillary perfusion and an increase in reactive oxygen species production. Rats treated with Ang II showed exacerbated microvascular damage with stronger vasoconstriction compared to hypoperfused rats, a further increase in leakage, higher decrease in capillary perfusion and marker oxidative stress. Candesartan cilexetil (specific Ang II type 1 receptor (AT1R) antagonist) administration prior to Ang II prevented the effects induced by Ang II, blunting the hypoperfusion–reperfusion injury. Ang 1-7 or ACE2 activator administration, preserved the pial microcirculation from hypoperfusion–reperfusion damage. These effects of Ang 1-7 were blunted by a Mas (Mas oncogene-encoded protein) receptor antagonist, while Ang II type 2 receptor antagonists did not affect Ang 1-7-induced changes. In conclusion, Ang II and Ang 1-7 triggered different mechanisms through AT1R or MAS receptors able to affect cerebral microvascular injury. Full article
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35 pages, 1443 KiB  
Review
The Pathophysiology and Treatment of Essential Tremor: The Role of Adenosine and Dopamine Receptors in Animal Models
by Barbara Kosmowska and Jadwiga Wardas
Biomolecules 2021, 11(12), 1813; https://doi.org/10.3390/biom11121813 - 02 Dec 2021
Cited by 6 | Viewed by 4616
Abstract
Essential tremor (ET) is one of the most common neurological disorders that often affects people in the prime of their lives, leading to a significant reduction in their quality of life, gradually making them unable to independently perform the simplest activities. Here we [...] Read more.
Essential tremor (ET) is one of the most common neurological disorders that often affects people in the prime of their lives, leading to a significant reduction in their quality of life, gradually making them unable to independently perform the simplest activities. Here we show that current ET pharmacotherapy often does not sufficiently alleviate disease symptoms and is completely ineffective in more than 30% of patients. At present, deep brain stimulation of the motor thalamus is the most effective ET treatment. However, like any brain surgery, it can cause many undesirable side effects; thus, it is only performed in patients with an advanced disease who are not responsive to drugs. Therefore, it seems extremely important to look for new strategies for treating ET. The purpose of this review is to summarize the current knowledge on the pathomechanism of ET based on studies in animal models of the disease, as well as to present and discuss the results of research available to date on various substances affecting dopamine (mainly D3) or adenosine A1 receptors, which, due to their ability to modulate harmaline-induced tremor, may provide the basis for the development of new potential therapies for ET in the future. Full article
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17 pages, 2463 KiB  
Article
The Nuts and Bolts of SARS-CoV-2 Spike Receptor-Binding Domain Heterologous Expression
by Mariano Maffei, Linda Celeste Montemiglio, Grazia Vitagliano, Luigi Fedele, Shaila Sellathurai, Federica Bucci, Mirco Compagnone, Valerio Chiarini, Cécile Exertier, Alessia Muzi, Giuseppe Roscilli, Beatrice Vallone and Emanuele Marra
Biomolecules 2021, 11(12), 1812; https://doi.org/10.3390/biom11121812 - 02 Dec 2021
Cited by 19 | Viewed by 3588
Abstract
COVID-19 is a highly infectious disease caused by a newly emerged coronavirus (SARS-CoV-2) that has rapidly progressed into a pandemic. This unprecedent emergency has stressed the significance of developing effective therapeutics to fight the current and future outbreaks. The receptor-binding domain (RBD) of [...] Read more.
COVID-19 is a highly infectious disease caused by a newly emerged coronavirus (SARS-CoV-2) that has rapidly progressed into a pandemic. This unprecedent emergency has stressed the significance of developing effective therapeutics to fight the current and future outbreaks. The receptor-binding domain (RBD) of the SARS-CoV-2 surface Spike protein is the main target for vaccines and represents a helpful “tool” to produce neutralizing antibodies or diagnostic kits. In this work, we provide a detailed characterization of the native RBD produced in three major model systems: Escherichia coli, insect and HEK-293 cells. Circular dichroism, gel filtration chromatography and thermal denaturation experiments indicated that recombinant SARS-CoV-2 RBD proteins are stable and correctly folded. In addition, their functionality and receptor-binding ability were further evaluated through ELISA, flow cytometry assays and bio-layer interferometry. Full article
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11 pages, 1701 KiB  
Article
SNCA 3′ UTR Genetic Variants in Patients with Parkinson’s Disease
by Antonela Blažeković, Kristina Gotovac Jerčić and Fran Borovečki
Biomolecules 2021, 11(12), 1799; https://doi.org/10.3390/biom11121799 - 30 Nov 2021
Cited by 3 | Viewed by 2157
Abstract
The SNCA (Synuclein Alpha) gene represents a major risk gene for Parkinson’s disease (PD) and SNCA polymorphisms have been associated with the common sporadic form of PD. Numerous Genome-Wide Association Studies showed strong signals located in the SNCA 3′ UTR (untranslated region) region [...] Read more.
The SNCA (Synuclein Alpha) gene represents a major risk gene for Parkinson’s disease (PD) and SNCA polymorphisms have been associated with the common sporadic form of PD. Numerous Genome-Wide Association Studies showed strong signals located in the SNCA 3′ UTR (untranslated region) region indicating that variants in 3′ UTRs of PD-associated genes could contribute to neurodegeneration and may regulate the risk for PD. Genetic variants in 3′ UTR can affect miRNA activity and consequently change the translation process. The aim of this study was to access the differences in 3′ UTR variants of SNCA genes in a cohort of PD patients and control subjects from Croatia. The cohort consisted of 52 PD patients and 23 healthy control subjects. Differences between 3′ UTR allele and genotype frequencies were accessed through next generation sequencing approach from whole blood samples. In our study, we identified four previously reported single nucleotide polymorphisms (SNPs) and one insertion in the 3′ UTR region of SNCA gene, namely rs1045722, rs3857053, rs577490090, rs356165, and rs777296100, and five variants not reported in the literature, namely rs35270750, rs529553259, rs377356638, rs571454522, and rs750347645. Our results indicate a significantly higher occurrence of the rs571454522 variant in the PD population. To the best of our knowledge, this variant has not been reported until now in the literature. We analyzed our results in the context of previous research, creating a brief overview of the importance of 3′ UTR variants of the SNCA gene. Further studies will be needed to gain a more profound insight regarding their role in PD development, which will help to assess the role and impact of post-transcriptional regulation on disease pathology. Full article
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14 pages, 1863 KiB  
Review
Non-Antibody-Based Binders for the Enrichment of Proteins for Analysis by Mass Spectrometry
by Oladapo Olaleye, Natalia Govorukhina, Nico C. van de Merbel and Rainer Bischoff
Biomolecules 2021, 11(12), 1791; https://doi.org/10.3390/biom11121791 - 30 Nov 2021
Cited by 7 | Viewed by 3114
Abstract
There is often a need to isolate proteins from body fluids, such as plasma or serum, prior to further analysis with (targeted) mass spectrometry. Although immunoglobulin or antibody-based binders have been successful in this regard, they possess certain disadvantages, which stimulated the development [...] Read more.
There is often a need to isolate proteins from body fluids, such as plasma or serum, prior to further analysis with (targeted) mass spectrometry. Although immunoglobulin or antibody-based binders have been successful in this regard, they possess certain disadvantages, which stimulated the development and validation of alternative, non-antibody-based binders. These binders are based on different protein scaffolds and are often selected and optimized using phage or other display technologies. This review focuses on several non-antibody-based binders in the context of enriching proteins for subsequent liquid chromatography-mass spectrometry (LC-MS) analysis and compares them to antibodies. In addition, we give a brief introduction to approaches for the immobilization of binders. The combination of non-antibody-based binders and targeted mass spectrometry is promising in areas, like regulated bioanalysis of therapeutic proteins or the quantification of biomarkers. However, the rather limited commercial availability of these binders presents a bottleneck that needs to be addressed. Full article
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28 pages, 20509 KiB  
Article
The σ1 Receptor and the HINT1 Protein Control α2δ1 Binding to Glutamate NMDA Receptors: Implications in Neuropathic Pain
by María Rodríguez-Muñoz, Elsa Cortés-Montero, Yara Onetti, Pilar Sánchez-Blázquez and Javier Garzón-Niño
Biomolecules 2021, 11(11), 1681; https://doi.org/10.3390/biom11111681 - 12 Nov 2021
Cited by 7 | Viewed by 2049
Abstract
Nerve injury produces neuropathic pain through the binding of α2δ1 proteins to glutamate N-methyl-D-aspartate receptors (NMDARs). Notably, mice with a targeted deletion of the sigma 1 receptor (σ1R) gene do not develop neuropathy, whereas mice lacking the histidine triad nucleotide-binding protein [...] Read more.
Nerve injury produces neuropathic pain through the binding of α2δ1 proteins to glutamate N-methyl-D-aspartate receptors (NMDARs). Notably, mice with a targeted deletion of the sigma 1 receptor (σ1R) gene do not develop neuropathy, whereas mice lacking the histidine triad nucleotide-binding protein 1 (Hint1) gene exhibit exacerbated allodynia. σ1R antagonists more effectively diminish neuropathic pain of spinal origin when administered by intracerebroventricular injection than systemically. Thus, in mice subjected to unilateral sciatic nerve chronic constriction injury (CCI), we studied the participation of σ1Rs and HINT1 proteins in the formation of α2δ1-NMDAR complexes within the supraspinal periaqueductal gray (PAG). We found that δ1 peptides required σ1Rs in order to interact with the NMDAR NR1 variant that contains the cytosolic C1 segment. σ1R antagonists or low calcium levels provoke the dissociation of σ1R-NR1 C1 dimers, while they barely affect the integrity of δ1-σ1R-NR1 C1 trimers. However, HINT1 does remove δ1 peptides from the trimer, thereby facilitating the subsequent dissociation of σ1Rs from NMDARs. In σ1R−/− mice, CCI does not promote the formation of NMDAR-α2δ1 complexes and allodynia does not develop. The levels of α2δ1-σ1R-NMDAR complexes increase in HINT1−/− mice and after inducing CCI, degradation of α2δ1 proteins is observed. Notably, σ1R antagonists but not gabapentinoids alleviate neuropathic pain in these mice. During severe neuropathy, the metabolism of α2δ1 proteins may account for the failure of many patients to respond to gabapentinoids. Therefore, σ1Rs promote and HINT1 proteins hinder the formation α2δ1-NMDAR complexes in the PAG, and hence, the appearance of mechanical allodynia depends on the interplay between these proteins. Full article
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23 pages, 2095 KiB  
Review
Microglia and Astrocytes in Alzheimer’s Disease in the Context of the Aberrant Copper Homeostasis Hypothesis
by Amit Pal, Isha Rani, Anil Pawar, Mario Picozza, Mauro Rongioletti and Rosanna Squitti
Biomolecules 2021, 11(11), 1598; https://doi.org/10.3390/biom11111598 - 28 Oct 2021
Cited by 12 | Viewed by 3363
Abstract
Evidence of copper’s (Cu) involvement in Alzheimer’s disease (AD) is available, but information on Cu involvement in microglia and astrocytes during the course of AD has yet to be structurally discussed. This review deals with this matter in an attempt to provide an [...] Read more.
Evidence of copper’s (Cu) involvement in Alzheimer’s disease (AD) is available, but information on Cu involvement in microglia and astrocytes during the course of AD has yet to be structurally discussed. This review deals with this matter in an attempt to provide an updated discussion on the role of reactive glia challenged by excess labile Cu in a wide picture that embraces all the major processes identified as playing a role in toxicity induced by an imbalance of Cu in AD. Full article
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11 pages, 6714 KiB  
Article
Biocatalytic Production of Aldehydes: Exploring the Potential of Lathyrus cicera Amine Oxidase
by Elisa Di Fabio, Alessio Incocciati, Alberto Boffi, Alessandra Bonamore and Alberto Macone
Biomolecules 2021, 11(10), 1540; https://doi.org/10.3390/biom11101540 - 18 Oct 2021
Cited by 3 | Viewed by 1902
Abstract
Aldehydes are a class of carbonyl compounds widely used as intermediates in the pharmaceutical, cosmetic and food industries. To date, there are few fully enzymatic methods for synthesizing these highly reactive chemicals. In the present work, we explore the biocatalytic potential of an [...] Read more.
Aldehydes are a class of carbonyl compounds widely used as intermediates in the pharmaceutical, cosmetic and food industries. To date, there are few fully enzymatic methods for synthesizing these highly reactive chemicals. In the present work, we explore the biocatalytic potential of an amino oxidase extracted from the etiolated shoots of Lathyrus cicera for the synthesis of value-added aldehydes, starting from the corresponding primary amines. In this frame, we have developed a completely chromatography-free purification protocol based on crossflow ultrafiltration, which makes the production of this enzyme easily scalable. Furthermore, we determined the kinetic parameters of the amine oxidase toward 20 differently substituted aliphatic and aromatic primary amines, and we developed a biocatalytic process for their conversion into the corresponding aldehydes. The reaction occurs in aqueous media at neutral pH in the presence of catalase, which removes the hydrogen peroxide produced during the reaction itself, contributing to the recycling of oxygen. A high conversion (>95%) was achieved within 3 h for all the tested compounds. Full article
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17 pages, 5523 KiB  
Article
Alcohol-Induced Lysosomal Damage and Suppression of Lysosome Biogenesis Contribute to Hepatotoxicity in HIV-Exposed Liver Cells
by Moses New-Aaron, Paul G. Thomes, Murali Ganesan, Raghubendra Singh Dagur, Terrence M. Donohue, Jr., Kharbanda K. Kusum, Larisa Y. Poluektova and Natalia A. Osna
Biomolecules 2021, 11(10), 1497; https://doi.org/10.3390/biom11101497 - 11 Oct 2021
Cited by 10 | Viewed by 2418
Abstract
Although the causes of hepatotoxicity among alcohol-abusing HIV patients are multifactorial, alcohol remains the least explored “second hit” for HIV-related hepatotoxicity. Here, we investigated whether metabolically derived acetaldehyde impairs lysosomes to enhance HIV-induced hepatotoxicity. We exposed Cytochrome P450 2E1 (CYP2E1)-expressing Huh 7.5 (also [...] Read more.
Although the causes of hepatotoxicity among alcohol-abusing HIV patients are multifactorial, alcohol remains the least explored “second hit” for HIV-related hepatotoxicity. Here, we investigated whether metabolically derived acetaldehyde impairs lysosomes to enhance HIV-induced hepatotoxicity. We exposed Cytochrome P450 2E1 (CYP2E1)-expressing Huh 7.5 (also known as RLW) cells to an acetaldehyde-generating system (AGS) for 24 h. We then infected (or not) the cells with HIV-1ADA then exposed them again to AGS for another 48 h. Lysosome damage was assessed by galectin 3/LAMP1 co-localization and cathepsin leakage. Expression of lysosome biogenesis–transcription factor, TFEB, was measured by its protein levels and by in situ immunofluorescence. Exposure of cells to both AGS + HIV caused the greatest amount of lysosome leakage and its impaired lysosomal biogenesis, leading to intrinsic apoptosis. Furthermore, the movement of TFEB from cytosol to the nucleus via microtubules was impaired by AGS exposure. The latter impairment appeared to occur by acetylation of α-tubulin. Moreover, ZKSCAN3, a repressor of lysosome gene activation by TFEB, was amplified by AGS. Both these changes contributed to AGS-elicited disruption of lysosome biogenesis. Our findings indicate that metabolically generated acetaldehyde damages lysosomes and likely prevents their repair and restoration, thereby exacerbating HIV-induced hepatotoxicity. Full article
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9 pages, 2055 KiB  
Article
Shortening Epitopes to Survive: The Case of SARS-CoV-2 Lambda Variant
by Stefano Pascarella, Massimo Ciccozzi, Martina Bianchi, Domenico Benvenuto, Marta Giovanetti, Roberto Cauda and Antonio Cassone
Biomolecules 2021, 11(10), 1494; https://doi.org/10.3390/biom11101494 - 10 Oct 2021
Cited by 4 | Viewed by 2030
Abstract
Among the more recently identified SARS-CoV-2 Variants of Interest (VOI) is the Lambda variant, which emerged in Peru and has rapidly spread to South American regions and the US. This variant remains poorly investigated, particularly regarding the effects of mutations on the thermodynamic [...] Read more.
Among the more recently identified SARS-CoV-2 Variants of Interest (VOI) is the Lambda variant, which emerged in Peru and has rapidly spread to South American regions and the US. This variant remains poorly investigated, particularly regarding the effects of mutations on the thermodynamic parameters affecting the stability of the Spike protein and its Receptor Binding Domain. We report here an in silico study on the potential impact of the Spike protein mutations on the immuno-escape ability of the Lambda variant. Bioinformatics analysis suggests that a combination of shortening the immunogenic epitope loops and the generation of potential N-glycosylation sites may be a viable adaptation strategy, potentially allowing this emerging viral variant to escape from host immunity. Full article
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21 pages, 3805 KiB  
Article
DNA Double-Strand Breaks Induced in Human Cells by Twelve Metallic Species: Quantitative Inter-Comparisons and Influence of the ATM Protein
by Muriel Viau, Laurène Sonzogni, Mélanie L. Ferlazzo, Elise Berthel, Sandrine Pereira, Larry Bodgi, Adeline Granzotto, Clément Devic, Béatrice Fervers, Laurent Charlet and Nicolas Foray
Biomolecules 2021, 11(10), 1462; https://doi.org/10.3390/biom11101462 - 05 Oct 2021
Cited by 7 | Viewed by 1799
Abstract
Despite a considerable amount of data, the molecular and cellular bases of the toxicity due to metal exposure remain unknown. Recent mechanistic models from radiobiology have emerged, pointing out that the radiation-induced nucleo-shuttling of the ATM protein (RIANS) initiates the recognition and the [...] Read more.
Despite a considerable amount of data, the molecular and cellular bases of the toxicity due to metal exposure remain unknown. Recent mechanistic models from radiobiology have emerged, pointing out that the radiation-induced nucleo-shuttling of the ATM protein (RIANS) initiates the recognition and the repair of DNA double-strand breaks (DSB) and the final response to genotoxic stress. In order to document the role of ATM-dependent DSB repair and signalling after metal exposure, we applied twelve different metal species representing nine elements (Al, Cu, Zn Ni, Pd, Cd, Pb, Cr, and Fe) to human skin, mammary, and brain cells. Our findings suggest that metals may directly or indirectly induce DSB at a rate that depends on the metal properties and concentration, and tissue type. At specific metal concentration ranges, the nucleo-shuttling of ATM can be delayed which impairs DSB recognition and repair and contributes to toxicity and carcinogenicity. Interestingly, as observed after low doses of ionizing radiation, some phenomena equivalent to the biological response observed at high metal concentrations may occur at lower concentrations. A general mechanistic model of the biological response to metal exposure based on the nucleo-shuttling of ATM is proposed to describe the metal-induced stress response and to define quantitative endpoints for toxicity and carcinogenicity. Full article
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32 pages, 27417 KiB  
Review
Immunoaffinity Capillary Electrophoresis in the Era of Proteoforms, Liquid Biopsy and Preventive Medicine: A Potential Impact in the Diagnosis and Monitoring of Disease Progression
by Norberto A. Guzman and Daniel E. Guzman
Biomolecules 2021, 11(10), 1443; https://doi.org/10.3390/biom11101443 - 01 Oct 2021
Cited by 11 | Viewed by 3715
Abstract
Over the years, multiple biomarkers have been used to aid in disease screening, diagnosis, prognosis, and response to therapy. As of late, protein biomarkers are gaining strength in their role for early disease diagnosis and prognosis in part due to the advancements in [...] Read more.
Over the years, multiple biomarkers have been used to aid in disease screening, diagnosis, prognosis, and response to therapy. As of late, protein biomarkers are gaining strength in their role for early disease diagnosis and prognosis in part due to the advancements in identification and characterization of a distinct functional pool of proteins known as proteoforms. Proteoforms are defined as all of the different molecular forms of a protein derived from a single gene caused by genetic variations, alternative spliced RNA transcripts and post-translational modifications. Monitoring the structural changes of each proteoform of a particular protein is essential to elucidate the complex molecular mechanisms that guide the course of disease. Clinical proteomics therefore holds the potential to offer further insight into disease pathology, progression, and prevention. Nevertheless, more technologically advanced diagnostic methods are needed to improve the reliability and clinical applicability of proteomics in preventive medicine. In this manuscript, we review the use of immunoaffinity capillary electrophoresis (IACE) as an emerging powerful diagnostic tool to isolate, separate, detect and characterize proteoform biomarkers obtained from liquid biopsy. IACE is an affinity capture-separation technology capable of isolating, concentrating and analyzing a wide range of biomarkers present in biological fluids. Isolation and concentration of target analytes is accomplished through binding to one or more biorecognition affinity ligands immobilized to a solid support, while separation and analysis are achieved by high-resolution capillary electrophoresis (CE) coupled to one or more detectors. IACE has the potential to generate rapid results with significant accuracy, leading to reliability and reproducibility in diagnosing and monitoring disease. Additionally, IACE has the capability of monitoring the efficacy of therapeutic agents by quantifying companion and complementary protein biomarkers. With advancements in telemedicine and artificial intelligence, the implementation of proteoform biomarker detection and analysis may significantly improve our capacity to identify medical conditions early and intervene in ways that improve health outcomes for individuals and populations. Full article
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17 pages, 30100 KiB  
Article
Molecular Determinants of Filament Capping Proteins Required for the Formation of Functional Flagella in Gram-Negative Bacteria
by Marko Nedeljković, Sandra Postel, Brian G. Pierce and Eric J. Sundberg
Biomolecules 2021, 11(10), 1397; https://doi.org/10.3390/biom11101397 - 22 Sep 2021
Cited by 4 | Viewed by 2182
Abstract
Bacterial flagella are cell surface protein appendages that are critical for motility and pathogenesis. Flagellar filaments are tubular structures constructed from thousands of copies of the protein flagellin, or FliC, arranged in helical fashion. Individual unfolded FliC subunits traverse the filament pore and [...] Read more.
Bacterial flagella are cell surface protein appendages that are critical for motility and pathogenesis. Flagellar filaments are tubular structures constructed from thousands of copies of the protein flagellin, or FliC, arranged in helical fashion. Individual unfolded FliC subunits traverse the filament pore and are folded and sorted into place with the assistance of the flagellar capping protein complex, an oligomer of the FliD protein. The FliD filament cap is a stool-like structure, with its D2 and D3 domains forming a flat head region, and its D1 domain leg-like structures extending perpendicularly from the head towards the inner core of the filament. Here, using an approach combining bacterial genetics, motility assays, electron microscopy and molecular modeling, we define, in numerous Gram-negative bacteria, which regions of FliD are critical for interaction with FliC subunits and result in the formation of functional flagella. Our data indicate that the D1 domain of FliD is its sole functionally important domain, and that its flexible coiled coil region comprised of helices at its extreme N- and C-termini controls compatibility with the FliC filament. FliD sequences from different bacterial species in the head region are well tolerated. Additionally, head domains can be replaced by small peptides and larger head domains from different species and still produce functional flagella. Full article
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13 pages, 703 KiB  
Article
Association of Lipid Peroxidation Product 4-Hydroxynonenal with Post-Traumatic Stress Disorder
by Matea Nikolac Perković, Lidija Milković, Suzana Uzun, Ninoslav Mimica, Nela Pivac, Georg Waeg and Neven Žarković
Biomolecules 2021, 11(9), 1365; https://doi.org/10.3390/biom11091365 - 15 Sep 2021
Cited by 12 | Viewed by 3283
Abstract
Repeated activation of the hypothalamic-pituitary-adrenal axis system, sleep disturbances, and other symptoms related to posttraumatic stress disorder (PTSD) elevate reactive oxygen species, increase inflammation, and accelerate cellular aging, leading to neuroprogression and cognitive decline. However, there is no information about possible involvement of [...] Read more.
Repeated activation of the hypothalamic-pituitary-adrenal axis system, sleep disturbances, and other symptoms related to posttraumatic stress disorder (PTSD) elevate reactive oxygen species, increase inflammation, and accelerate cellular aging, leading to neuroprogression and cognitive decline. However, there is no information about possible involvement of 4-hydroxynonenal (4-HNE), the product of lipid peroxidation associated with stress-associated diseases, in the complex etiology of PTSD. Therefore, the aim of this study was to compare the plasma levels of 4-HNE between war veterans with PTSD (n = 62) and age-, sex- and ethnicity- matched healthy control subjects (n = 58) in order to evaluate the potential of HNE-modified proteins as blood-based biomarker of PTSD. The genuine 4-HNE-Enzyme-Linked Immunosorbent Assay (HNE-ELISA), based on monoclonal antibody specific for HNE-histidine (HNE-His) adducts, was used to determine plasma HNE-protein conjugates. Our results revealed significantly elevated levels of 4-HNE in patients with PTSD. Moreover, the accumulation of plasma 4-HNE seems to increase with aging but in a negative correlation with BMI, showing specific pattern of change for individuals diagnosed with PTSD. These findings suggest that oxidative stress and altered lipid metabolism reflected by increase of 4-HNE might be associated with PTSD. If confirmed with further studies, elevated 4-HNE plasma levels might serve as a potential biomarker of PTSD. Full article
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9 pages, 1004 KiB  
Article
The Activity of Chosen Antioxidant Enzymes in Ostrich Meat in Relation to the Type of Packaging and Storage Time in Refrigeration
by Olaf K. Horbańczuk, Artur Jóźwik, Jarosław Wyrwisz, Joanna Marchewka, Atanas G. Atanasov and Agnieszka Wierzbicka
Biomolecules 2021, 11(9), 1338; https://doi.org/10.3390/biom11091338 - 10 Sep 2021
Cited by 3 | Viewed by 1789
Abstract
The aim of the study was to investigate the changes in the activity of antioxidant enzymes, i.e., superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity in ostrich meat, as influenced by various packaging systems [...] Read more.
The aim of the study was to investigate the changes in the activity of antioxidant enzymes, i.e., superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity in ostrich meat, as influenced by various packaging systems and storage time under refrigeration. Three packaging methods were used: vacuum packaging (VP) and modified atmosphere packaging (MAP) in two combinations of gases, MAP1 (40% O2/40% CO2/20% N2) and MAP2 (60% O2/30% CO2/10% N2). Meat samples were taken from the M. ilifibularis (IF) muscles of eight ostriches in each treatment group. The meat samples were stored in a refrigerator in 2 °C and analyzed at days 0, 4, 8, 12 and 16. The lowest level of SOD activity during storage was observed in ostrich muscles packed in vacuum, as compared to MAP1 and MAP2. In turn, the highest increase in GPx activity was recorded in VP, especially up to day 8 of storage, when this parameter reached maximum value (54.37). GR increased up to the eighth day of storage in MAP1 and VP. Between the 12th and 16th days of storage, stabilization of the GR activity level was observed only in VP, while under MAP1, it further decreased. DPPH remained relatively stable until the eighth day of storage and after this period, a decrease in this parameter was recorded, reaching the lowest value on day 12 for all types of packaging systems. Full article
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15 pages, 2155 KiB  
Article
Vitamin C Enhances Antiviral Functions of Lung Epithelial Cells
by Trevor Teafatiller, Sudhanshu Agrawal, Gabriela De Robles, Farah Rahmatpanah, Veedamali S. Subramanian and Anshu Agrawal
Biomolecules 2021, 11(8), 1148; https://doi.org/10.3390/biom11081148 - 03 Aug 2021
Cited by 15 | Viewed by 4110
Abstract
Vitamin C is well documented to have antiviral functions; however, there is limited information about its effect on airway epithelial cells—the first cells to encounter infections. Here, we examined the effect of vitamin C on human bronchial epithelium transformed with Ad12-SV40 2B (BEAS-2B) [...] Read more.
Vitamin C is well documented to have antiviral functions; however, there is limited information about its effect on airway epithelial cells—the first cells to encounter infections. Here, we examined the effect of vitamin C on human bronchial epithelium transformed with Ad12-SV40 2B (BEAS-2B) cells, and observed that sodium-dependent vitamin C transporter 2 (SVCT2) was the primary vitamin C transporter. Transcriptomic analysis revealed that treating BEAS-2B cells with vitamin C led to a significant upregulation of several metabolic pathways and interferon-stimulated genes (ISGs) along with a downregulation of pathways involved in lung injury and inflammation. Remarkably, vitamin C also enhanced the expression of the viral-sensing receptors retinoic acid-inducible gene 1 (RIG-1) and melanoma differentiation-associated protein 5 (MDA-5), which was confirmed at the protein and functional levels. In addition, the lungs of l-gulono-γ-lactone oxidase knockout (GULO-KO) mice also displayed a marked decrease in these genes compared to wild-type controls. Collectively, our findings indicate that vitamin C acts at multiple levels to exert its antiviral and protective functions in the lungs. Full article
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10 pages, 1552 KiB  
Article
Pathological Mechanism of a Constitutively Active Form of Stromal Interaction Molecule 1 in Skeletal Muscle
by Ji Hee Park, Seung Yeon Jeong, Jun Hee Choi and Eun Hui Lee
Biomolecules 2021, 11(8), 1064; https://doi.org/10.3390/biom11081064 - 21 Jul 2021
Cited by 2 | Viewed by 2056
Abstract
Stromal interaction molecule 1 (STIM1) is the main protein that, along with Orai1, mediates store-operated Ca2+ entry (SOCE) in skeletal muscle. Abnormal SOCE due to mutations in STIM1 is one of the causes of human skeletal muscle diseases. STIM1-R304Q (a constitutively active [...] Read more.
Stromal interaction molecule 1 (STIM1) is the main protein that, along with Orai1, mediates store-operated Ca2+ entry (SOCE) in skeletal muscle. Abnormal SOCE due to mutations in STIM1 is one of the causes of human skeletal muscle diseases. STIM1-R304Q (a constitutively active form of STIM1) has been found in human patients with skeletal muscle phenotypes such as muscle weakness, myalgia, muscle stiffness, and contracture. However, the pathological mechanism(s) of STIM1-R304Q in skeletal muscle have not been well studied. To examine the pathological mechanism(s) of STIM1-R304Q in skeletal muscle, STIM1-R304Q was expressed in mouse primary skeletal myotubes, and the properties of the skeletal myotubes were examined using single-myotube Ca2+ imaging, transmission electron microscopy (TEM), and biochemical approaches. STIM1-R304Q did not interfere with the terminal differentiation of skeletal myoblasts to myotubes and retained the ability of STIM1 to attenuate dihydropyridine receptor (DHPR) activity. STIM1-R304Q induced hyper-SOCE (that exceeded the SOCE by wild-type STIM1) by affecting both the amplitude and the onset rate of SOCE. Unlike that by wild-type STIM1, hyper-SOCE by STIM1-R304Q contributed to a disturbance in Ca2+ distribution between the cytosol and the sarcoplasmic reticulum (SR) (high Ca2+ in the cytosol and low Ca2+ in the SR). Moreover, the hyper-SOCE and the high cytosolic Ca2+ level induced by STIM1-R304Q involve changes in mitochondrial shape. Therefore, a series of these cellular defects induced by STIM1-R304Q could induce deleterious skeletal muscle phenotypes in human patients carrying STIM1-R304Q. Full article
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38 pages, 4838 KiB  
Review
Mitostasis, Calcium and Free Radicals in Health, Aging and Neurodegeneration
by Juan A. Godoy, Juvenal A. Rios, Pol Picón-Pagès, Víctor Herrera-Fernández, Bronte Swaby, Giulia Crepin, Rubén Vicente, Jose M. Fernández-Fernández and Francisco J. Muñoz
Biomolecules 2021, 11(7), 1012; https://doi.org/10.3390/biom11071012 - 10 Jul 2021
Cited by 34 | Viewed by 5305
Abstract
Mitochondria play key roles in ATP supply, calcium homeostasis, redox balance control and apoptosis, which in neurons are fundamental for neurotransmission and to allow synaptic plasticity. Their functional integrity is maintained by mitostasis, a process that involves mitochondrial transport, anchoring, fusion and fission [...] Read more.
Mitochondria play key roles in ATP supply, calcium homeostasis, redox balance control and apoptosis, which in neurons are fundamental for neurotransmission and to allow synaptic plasticity. Their functional integrity is maintained by mitostasis, a process that involves mitochondrial transport, anchoring, fusion and fission processes regulated by different signaling pathways but mainly by the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). PGC-1α also favors Ca2+ homeostasis, reduces oxidative stress, modulates inflammatory processes and mobilizes mitochondria to where they are needed. To achieve their functions, mitochondria are tightly connected to the endoplasmic reticulum (ER) through specialized structures of the ER termed mitochondria-associated membranes (MAMs), which facilitate the communication between these two organelles mainly to aim Ca2+ buffering. Alterations in mitochondrial activity enhance reactive oxygen species (ROS) production, disturbing the physiological metabolism and causing cell damage. Furthermore, cytosolic Ca2+ overload results in an increase in mitochondrial Ca2+, resulting in mitochondrial dysfunction and the induction of mitochondrial permeability transition pore (mPTP) opening, leading to mitochondrial swelling and cell death through apoptosis as demonstrated in several neuropathologies. In summary, mitochondrial homeostasis is critical to maintain neuronal function; in fact, their regulation aims to improve neuronal viability and to protect against aging and neurodegenerative diseases. Full article
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23 pages, 3912 KiB  
Article
Copper Imbalance in Alzheimer’s Disease: Meta-Analysis of Serum, Plasma, and Brain Specimens, and Replication Study Evaluating ATP7B Gene Variants
by Rosanna Squitti, Mariacarla Ventriglia, Ilaria Simonelli, Cristian Bonvicini, Alfredo Costa, Giulia Perini, Giuliano Binetti, Luisa Benussi, Roberta Ghidoni, Giacomo Koch, Barbara Borroni, Alberto Albanese, Stefano L. Sensi and Mauro Rongioletti
Biomolecules 2021, 11(7), 960; https://doi.org/10.3390/biom11070960 - 29 Jun 2021
Cited by 32 | Viewed by 3491
Abstract
Evidence indicates that patients with Alzheimer’s dementia (AD) show signs of copper (Cu) dyshomeostasis. This study aimed at evaluating the potential of Cu dysregulation as an AD susceptibility factor. We performed a meta-analysis of 56 studies investigating Cu biomarkers in brain specimens (pooled [...] Read more.
Evidence indicates that patients with Alzheimer’s dementia (AD) show signs of copper (Cu) dyshomeostasis. This study aimed at evaluating the potential of Cu dysregulation as an AD susceptibility factor. We performed a meta-analysis of 56 studies investigating Cu biomarkers in brain specimens (pooled total of 182 AD and 166 healthy controls, HC) and in serum/plasma (pooled total of 2929 AD and 3547 HC). We also completed a replication study of serum Cu biomarkers in 97 AD patients and 70 HC screened for rs732774 and rs1061472 ATP7B, the gene encoding for the Cu transporter ATPase7B. Our meta-analysis showed decreased Cu in AD brain specimens, increased Cu and nonbound ceruloplasmin (Non-Cp) Cu in serum/plasma samples, and unchanged ceruloplasmin. Serum/plasma Cu excess was associated with a three to fourfold increase in the risk of having AD. Our replication study confirmed meta-analysis results and showed that carriers of the ATP7B AG haplotype were significantly more frequent in the AD group. Overall, our study shows that AD patients fail to maintain a Cu metabolic balance and reveals the presence of a percentage of AD patients carrying ATP7B AG haplotype and presenting Non-Cp Cu excess, which suggest that a subset of AD subjects is prone to Cu imbalance. This AD subtype can be the target of precision medicine-based strategies tackling Cu dysregulation. Full article
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23 pages, 3286 KiB  
Review
Hyperactivated RAGE in Comorbidities as a Risk Factor for Severe COVID-19—The Role of RAGE-RAS Crosstalk
by Sara Chiappalupi, Laura Salvadori, Rosario Donato, Francesca Riuzzi and Guglielmo Sorci
Biomolecules 2021, 11(6), 876; https://doi.org/10.3390/biom11060876 - 12 Jun 2021
Cited by 21 | Viewed by 3720
Abstract
The receptor for advanced glycation-end products (RAGE) is a multiligand receptor with a role in inflammatory and pulmonary pathologies. Hyperactivation of RAGE by its ligands has been reported to sustain inflammation and oxidative stress in common comorbidities of severe COVID-19. RAGE is essential [...] Read more.
The receptor for advanced glycation-end products (RAGE) is a multiligand receptor with a role in inflammatory and pulmonary pathologies. Hyperactivation of RAGE by its ligands has been reported to sustain inflammation and oxidative stress in common comorbidities of severe COVID-19. RAGE is essential to the deleterious effects of the renin–angiotensin system (RAS), which participates in infection and multiorgan injury in COVID-19 patients. Thus, RAGE might be a major player in severe COVID-19, and appears to be a useful therapeutic molecular target in infections by SARS-CoV-2. The role of RAGE gene polymorphisms in predisposing patients to severe COVID-19 is discussed.  Full article
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12 pages, 3280 KiB  
Article
An Antagonistic Peptide of Gpr1 Ameliorates LPS-Induced Depression through the Hypothalamic-Pituitary-Ovarian Axis
by Rongrong Li, Chiyuan Ma, Yue Xiong, Huashan Zhao, Yali Yang, Li Xue, Baobei Wang, Tianxia Xiao, Jie Chen, Xiaohua Lei, Baohua Ma and Jian Zhang
Biomolecules 2021, 11(6), 857; https://doi.org/10.3390/biom11060857 - 09 Jun 2021
Cited by 7 | Viewed by 2975
Abstract
Depression affects the reproductive axis at the hypothalamus and pituitary levels, which has a significant impact on female fertility. It has been reported that G protein-coupled receptor 1 (Gpr1) mRNA is expressed in both the hypothalamus and ovaries. However, it is unclear whether [...] Read more.
Depression affects the reproductive axis at the hypothalamus and pituitary levels, which has a significant impact on female fertility. It has been reported that G protein-coupled receptor 1 (Gpr1) mRNA is expressed in both the hypothalamus and ovaries. However, it is unclear whether there is a relationship between Gpr1 and depression, and its role in ovarian function is unknown. Here, the expression of Gpr1 was recorded in the hypothalamus of normal female mice, and co-localized with gonadotrophin-releasing hormone (GnRH) and corticotropin-releasing factor (CRF). We established a depression mouse model to evaluate the antidepressant effect of G5, an antagonistic peptide of Gpr1. The results show that an intraperitoneal injection of G5 improves depressant–like behaviors remarkably, including increased sucrose intake in the sucrose preference test and decreased immobility time in the forced swimming tests. Moreover, G5 treatment increased the release of reproductive hormone and the expression of ovarian gene caused by depression. Together, our findings reveal a link between depression and reproductive diseases through Gpr1 signaling, and suggest antagonistic peptide of Gpr1 as a potential therapeutic application for hormone-modulated depression in women. Full article
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58 pages, 11951 KiB  
Review
Understanding Emotions: Origins and Roles of the Amygdala
by Goran Šimić, Mladenka Tkalčić, Vana Vukić, Damir Mulc, Ena Španić, Marina Šagud, Francisco E. Olucha-Bordonau, Mario Vukšić and Patrick R. Hof
Biomolecules 2021, 11(6), 823; https://doi.org/10.3390/biom11060823 - 31 May 2021
Cited by 94 | Viewed by 29900
Abstract
Emotions arise from activations of specialized neuronal populations in several parts of the cerebral cortex, notably the anterior cingulate, insula, ventromedial prefrontal, and subcortical structures, such as the amygdala, ventral striatum, putamen, caudate nucleus, and ventral tegmental area. Feelings are conscious, emotional experiences [...] Read more.
Emotions arise from activations of specialized neuronal populations in several parts of the cerebral cortex, notably the anterior cingulate, insula, ventromedial prefrontal, and subcortical structures, such as the amygdala, ventral striatum, putamen, caudate nucleus, and ventral tegmental area. Feelings are conscious, emotional experiences of these activations that contribute to neuronal networks mediating thoughts, language, and behavior, thus enhancing the ability to predict, learn, and reappraise stimuli and situations in the environment based on previous experiences. Contemporary theories of emotion converge around the key role of the amygdala as the central subcortical emotional brain structure that constantly evaluates and integrates a variety of sensory information from the surroundings and assigns them appropriate values of emotional dimensions, such as valence, intensity, and approachability. The amygdala participates in the regulation of autonomic and endocrine functions, decision-making and adaptations of instinctive and motivational behaviors to changes in the environment through implicit associative learning, changes in short- and long-term synaptic plasticity, and activation of the fight-or-flight response via efferent projections from its central nucleus to cortical and subcortical structures. Full article
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17 pages, 1260 KiB  
Article
Activation of Anopheles stephensi Pantothenate Kinase and Coenzyme A Biosynthesis Reduces Infection with Diverse Plasmodium Species in the Mosquito Host
by Raquel M. Simão-Gurge, Neha Thakre, Jessica Strickland, Jun Isoe, Lillian R. Delacruz, Brandi K. Torrevillas, Anna M. Rodriguez, Michael A. Riehle and Shirley Luckhart
Biomolecules 2021, 11(6), 807; https://doi.org/10.3390/biom11060807 - 29 May 2021
Cited by 4 | Viewed by 3185
Abstract
Malaria parasites require pantothenate from both human and mosquito hosts to synthesize coenzyme A (CoA). Specifically, mosquito-stage parasites cannot synthesize pantothenate de novo or take up preformed CoA from the mosquito host, making it essential for the parasite to obtain pantothenate from mosquito [...] Read more.
Malaria parasites require pantothenate from both human and mosquito hosts to synthesize coenzyme A (CoA). Specifically, mosquito-stage parasites cannot synthesize pantothenate de novo or take up preformed CoA from the mosquito host, making it essential for the parasite to obtain pantothenate from mosquito stores. This makes pantothenate utilization an attractive target for controlling sexual stage malaria parasites in the mosquito. CoA is synthesized from pantothenate in a multi-step pathway initiated by the enzyme pantothenate kinase (PanK). In this work, we manipulated A. stephensi PanK activity and assessed the impact of mosquito PanK activity on the development of two malaria parasite species with distinct genetics and life cycles: the human parasite Plasmodium falciparum and the mouse parasite Plasmodium yoelii yoelii 17XNL. We identified two putative A. stephensi PanK isoforms encoded by a single gene and expressed in the mosquito midgut. Using both RNAi and small molecules with reported activity against human PanK, we confirmed that A. stephensi PanK manipulation was associated with corresponding changes in midgut CoA levels. Based on these findings, we used two small molecule modulators of human PanK activity (PZ-2891, compound 7) at reported and ten-fold EC50 doses to examine the effects of manipulating A. stephensi PanK on malaria parasite infection success. Our data showed that oral provisioning of 1.3 nM and 13 nM PZ-2891 increased midgut CoA levels and significantly decreased infection success for both Plasmodium species. In contrast, oral provisioning of 62 nM and 620 nM compound 7 decreased CoA levels and significantly increased infection success for both Plasmodium species. This work establishes the A. stephensi CoA biosynthesis pathway as a potential target for broadly blocking malaria parasite development in anopheline hosts. We envision this strategy, with small molecule PanK modulators delivered to mosquitoes via attractive bait stations, working in concert with deployment of parasite-directed novel pantothenamide drugs to block parasite infection in the human host. In mosquitoes, depletion of pantothenate through manipulation to increase CoA biosynthesis is expected to negatively impact Plasmodium survival by starving the parasite of this essential nutrient. This has the potential to kill both wild type parasites and pantothenamide-resistant parasites that could develop under pantothenamide drug pressure if these compounds are used as future therapeutics for human malaria. Full article
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20 pages, 1487 KiB  
Article
Moderating Effects of BDNF Genetic Variants and Smoking on Cognition in PTSD Veterans
by Gordana Nedic Erjavec, Matea Nikolac Perkovic, Lucija Tudor, Suzana Uzun, Zrnka Kovacic Petrovic, Marcela Konjevod, Marina Sagud, Oliver Kozumplik, Dubravka Svob Strac, Tina Peraica, Ninoslav Mimica, Ana Havelka Mestrovic, Denis Zilic and Nela Pivac
Biomolecules 2021, 11(5), 641; https://doi.org/10.3390/biom11050641 - 26 Apr 2021
Cited by 8 | Viewed by 2812
Abstract
Posttraumatic stress disorder (PTSD) is frequently associated with cognitive disturbances and high prevalence of smoking. This study evaluated cognition in war veterans with PTSD and control subjects, controlled for the effect of smoking and brain derived neurotrophic factor (BDNF) rs6265 and rs56164415 genotypes/alleles. [...] Read more.
Posttraumatic stress disorder (PTSD) is frequently associated with cognitive disturbances and high prevalence of smoking. This study evaluated cognition in war veterans with PTSD and control subjects, controlled for the effect of smoking and brain derived neurotrophic factor (BDNF) rs6265 and rs56164415 genotypes/alleles. Study included 643 male war veterans with combat related PTSD and 120 healthy controls. Genotyping was done by real time PCR. Cognitive disturbances were evaluated using the Positive and Negative Syndrome Scale (PANSS) cognition subscale and the Rey-Osterrieth Complex Figure (ROCF) test scores. Diagnosis (p < 0.001), BDNF rs56164415 (p = 0.011) and smoking (p = 0.028) were significant predictors of the cognitive decline in subjects with PTSD. BDNF rs56164415 T alleles were more frequently found in subjects with PTSD, smokers and non-smokers, with impaired cognition, i.e., with the higher PANSS cognition subscale scores and with the lower ROCF immediate recall test scores. Presence of one or two BDNF rs56164415 T alleles was related to cognitive decline in PTSD. The T allele carriers with PTSD had advanced cognitive deterioration in smokers and nonsmokers with PTSD, and worse short-term visual memory function. Our findings emphasize the role of the BDNF rs56164415 T allele and smoking in cognitive dysfunction in war veterans with PTSD. Full article
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15 pages, 1082 KiB  
Review
Phytochemicals as Regulators of Genes Involved in Synucleinopathies
by Andrei Surguchov, Libby Bernal and Alexei A. Surguchev
Biomolecules 2021, 11(5), 624; https://doi.org/10.3390/biom11050624 - 22 Apr 2021
Cited by 37 | Viewed by 3129
Abstract
Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein aggregates in neurons, nerve fibers or glial cells. Three main types of diseases belong to the synucleinopathies: Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. All of them [...] Read more.
Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein aggregates in neurons, nerve fibers or glial cells. Three main types of diseases belong to the synucleinopathies: Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. All of them develop as a result of an interplay of genetic and environmental factors. Emerging evidence suggests that epigenetic mechanisms play an essential role in the development of synucleinopathies. Since there is no disease-modifying treatment for these disorders at this time, interest is growing in plant-derived chemicals as a potential treatment option. Phytochemicals are substances of plant origin that possess biological activity, which might have effects on human health. Phytochemicals with neuroprotective activity target different elements in pathogenic pathways due to their antioxidants, anti-inflammatory, and antiapoptotic properties, and ability to reduce cellular stress. Multiple recent studies demonstrate that the beneficial effects of phytochemicals may be explained by their ability to modulate the expression of genes implicated in synucleinopathies and other diseases. These substances may regulate transcription directly via transcription factors (TFs) or play the role of epigenetic regulators through their effect on histone modification, DNA methylation, and RNA-based mechanisms. Here, we summarize new data about the impact of phytochemicals on the pathogenesis of synucleinopathies through regulation of gene expression. Full article
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21 pages, 35747 KiB  
Article
Expression and Functional Analysis of the Argonaute Protein of Thermus thermophilus (TtAgo) in E. coli BL21(DE3)
by Jiani Xing, Lixia Ma, Xinzhen Cheng, Jinrong Ma, Ruyu Wang, Kun Xu, Joe S. Mymryk and Zhiying Zhang
Biomolecules 2021, 11(4), 524; https://doi.org/10.3390/biom11040524 - 31 Mar 2021
Cited by 4 | Viewed by 3650
Abstract
The prokaryotic Argonaute proteins (pAgos) have been reported to cleave or interfere with DNA targets in a guide-dependent or independent manner. It is often difficult to characterize pAgos in vivo due to the extreme environments favored by their hosts. In the present study, [...] Read more.
The prokaryotic Argonaute proteins (pAgos) have been reported to cleave or interfere with DNA targets in a guide-dependent or independent manner. It is often difficult to characterize pAgos in vivo due to the extreme environments favored by their hosts. In the present study, we expressed functional Thermus thermophilus pAgo (TtAgo) in E. coli BL21 (DE3) cells at 37 °C. Initial attempts to express TtAgo in BL21(DE3) cells at 37 °C failed. This was not because of TtAgo mediated general toxicity to the host cells, but instead because of TtAgo-induced loss of its expression plasmid. We employed this discovery to establish a screening system for isolating loss-of-function mutants of TtAgo. The E. colifabI gene was used to help select for full-length TtAgo loss of function mutants, as overexpression of fabI renders the cell to be resistant to the triclosan. We isolated and characterized eight mutations in TtAgo that abrogated function. The ability of TtAgo to induce loss of its expression vector in vivo at 37 °C is an unreported function that is mechanistically different from its reported in vitro activity. These results shed light on the mechanisms by which TtAgo functions as a defense against foreign DNA invasion. Full article
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34 pages, 3326 KiB  
Review
Stress Responses in Down Syndrome Neurodegeneration: State of the Art and Therapeutic Molecules
by Chiara Lanzillotta and Fabio Di Domenico
Biomolecules 2021, 11(2), 266; https://doi.org/10.3390/biom11020266 - 11 Feb 2021
Cited by 17 | Viewed by 3556
Abstract
Down syndrome (DS) is the most common genomic disorder characterized by the increased incidence of developing early Alzheimer’s disease (AD). In DS, the triplication of genes on chromosome 21 is intimately associated with the increase of AD pathological hallmarks and with the development [...] Read more.
Down syndrome (DS) is the most common genomic disorder characterized by the increased incidence of developing early Alzheimer’s disease (AD). In DS, the triplication of genes on chromosome 21 is intimately associated with the increase of AD pathological hallmarks and with the development of brain redox imbalance and aberrant proteostasis. Increasing evidence has recently shown that oxidative stress (OS), associated with mitochondrial dysfunction and with the failure of antioxidant responses (e.g., SOD1 and Nrf2), is an early signature of DS, promoting protein oxidation and the formation of toxic protein aggregates. In turn, systems involved in the surveillance of protein synthesis/folding/degradation mechanisms, such as the integrated stress response (ISR), the unfolded stress response (UPR), and autophagy, are impaired in DS, thus exacerbating brain damage. A number of pre-clinical and clinical studies have been applied to the context of DS with the aim of rescuing redox balance and proteostasis by boosting the antioxidant response and/or inducing the mechanisms of protein re-folding and clearance, and at final of reducing cognitive decline. So far, such therapeutic approaches demonstrated their efficacy in reverting several aspects of DS phenotype in murine models, however, additional studies aimed to translate these approaches in clinical practice are still needed. Full article
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40 pages, 6609 KiB  
Review
“Cell Membrane Theory of Senescence” and the Role of Bioactive Lipids in Aging, and Aging Associated Diseases and Their Therapeutic Implications
by Undurti N. Das
Biomolecules 2021, 11(2), 241; https://doi.org/10.3390/biom11020241 - 08 Feb 2021
Cited by 58 | Viewed by 9659
Abstract
Lipids are an essential constituent of the cell membrane of which polyunsaturated fatty acids (PUFAs) are the most important component. Activation of phospholipase A2 (PLA2) induces the release of PUFAs from the cell membrane that form precursors to both pro- and ant-inflammatory bioactive [...] Read more.
Lipids are an essential constituent of the cell membrane of which polyunsaturated fatty acids (PUFAs) are the most important component. Activation of phospholipase A2 (PLA2) induces the release of PUFAs from the cell membrane that form precursors to both pro- and ant-inflammatory bioactive lipids that participate in several cellular processes. PUFAs GLA (gamma-linolenic acid), DGLA (dihomo-GLA), AA (arachidonic acid), EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) are derived from dietary linoleic acid (LA) and alpha-linolenic acid (ALA) by the action of desaturases whose activity declines with age. Consequently, aged cells are deficient in GLA, DGLA, AA, AA, EPA and DHA and their metabolites. LA, ALA, AA, EPA and DHA can also be obtained direct from diet and their deficiency (fatty acids) may indicate malnutrition and deficiency of several minerals, trace elements and vitamins some of which are also much needed co-factors for the normal activity of desaturases. In many instances (patients) the plasma and tissue levels of GLA, DGLA, AA, EPA and DHA are low (as seen in patients with hypertension, type 2 diabetes mellitus) but they do not have deficiency of other nutrients. Hence, it is reasonable to consider that the deficiency of GLA, DGLA, AA, EPA and DHA noted in these conditions are due to the decreased activity of desaturases and elongases. PUFAs stimulate SIRT1 through protein kinase A-dependent activation of SIRT1-PGC1α complex and thus, increase rates of fatty acid oxidation and prevent lipid dysregulation associated with aging. SIRT1 activation prevents aging. Of all the SIRTs, SIRT6 is critical for intermediary metabolism and genomic stability. SIRT6-deficient mice show shortened lifespan, defects in DNA repair and have a high incidence of cancer due to oncogene activation. SIRT6 overexpression lowers LDL and triglyceride level, improves glucose tolerance, and increases lifespan of mice in addition to its anti-inflammatory effects at the transcriptional level. PUFAs and their anti-inflammatory metabolites influence the activity of SIRT6 and other SIRTs and thus, bring about their actions on metabolism, inflammation, and genome maintenance. GLA, DGLA, AA, EPA and DHA and prostaglandin E2 (PGE2), lipoxin A4 (LXA4) (pro- and anti-inflammatory metabolites of AA respectively) activate/suppress various SIRTs (SIRt1 SIRT2, SIRT3, SIRT4, SIRT5, SIRT6), PPAR-γ, PARP, p53, SREBP1, intracellular cAMP content, PKA activity and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1-α). This implies that changes in the metabolism of bioactive lipids as a result of altered activities of desaturases, COX-2 and 5-, 12-, 15-LOX (cyclo-oxygenase and lipoxygenases respectively) may have a critical role in determining cell age and development of several aging associated diseases and genomic stability and gene and oncogene activation. Thus, methods designed to maintain homeostasis of bioactive lipids (GLA, DGLA, AA, EPA, DHA, PGE2, LXA4) may arrest aging process and associated metabolic abnormalities. Full article
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2020

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39 pages, 5758 KiB  
Review
Molecules, Mechanisms, and Disorders of Self-Domestication: Keys for Understanding Emotional and Social Communication from an Evolutionary Perspective
by Goran Šimić, Vana Vukić, Janja Kopić, Željka Krsnik and Patrick R. Hof
Biomolecules 2021, 11(1), 2; https://doi.org/10.3390/biom11010002 - 22 Dec 2020
Cited by 13 | Viewed by 7272
Abstract
The neural crest hypothesis states that the phenotypic features of the domestication syndrome are due to a reduced number or disruption of neural crest cells (NCCs) migration, as these cells differentiate at their final destinations and proliferate into different tissues whose activity is [...] Read more.
The neural crest hypothesis states that the phenotypic features of the domestication syndrome are due to a reduced number or disruption of neural crest cells (NCCs) migration, as these cells differentiate at their final destinations and proliferate into different tissues whose activity is reduced by domestication. Comparing the phenotypic characteristics of modern and prehistoric man, it is clear that during their recent evolutionary past, humans also went through a process of self-domestication with a simultaneous prolongation of the period of socialization. This has led to the development of social abilities and skills, especially language, as well as neoteny. Disorders of neural crest cell development and migration lead to many different conditions such as Waardenburg syndrome, Hirschsprung disease, fetal alcohol syndrome, DiGeorge and Treacher-Collins syndrome, for which the mechanisms are already relatively well-known. However, for others, such as Williams-Beuren syndrome and schizophrenia that have the characteristics of hyperdomestication, and autism spectrum disorders, and 7dupASD syndrome that have the characteristics of hypodomestication, much less is known. Thus, deciphering the biological determinants of disordered self-domestication has great potential for elucidating the normal and disturbed ontogenesis of humans, as well as for the understanding of evolution of mammals in general. Full article
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