Saved Queries

by Marzia Savi, Fuhong Su, Elda Diletta Sterchele, Elisa Gouvêa Bogossian, Zoé Demailly, Marta Baggiani, Giuseppe Stefano Casu and Fabio Silvio Taccone

Cells 2024, 13(18), 1553; https://doi.org/10.3390/cells13181553 (registering DOI) - 14 Sep 2024

Viewed by 360

Abstract

Acute brain injury (ABI) remains one of the leading causes of death and disability world-wide. Its treatment is challenging due to the heterogeneity of the mechanisms involved and the variability among individuals. This systematic review aims at evaluating the impact of anti-histone treatments on outcomes in ABI patients and experimental animals and defining the trend of nucleosome levels in biological samples post injury. We performed a search in Pubmed/Medline and Embase databases for randomized controlled trials and cohort studies involving humans or experimental settings with various causes of ABI. We formulated the search using the PICO method, considering ABI patients or animal models as population (P), comparing pharmacological and non-pharmacological therapy targeting the nucleosome as Intervention (I) to standard of care or no treatment as Control (C). The outcome (O) was mortality or functional outcome in experimental animals and patients affected by ABI undergoing anti-NET treatments. We identified 28 studies from 1246 articles, of which 7 were experimental studies and 21 were human clinical studies. Among these studies, only four assessed the effect of anti-NET therapy on circulating markers. Three of them were preclinical and reported better outcome in the interventional arm compared to the control arm. All the studies observed a significant reduction in circulating NET-derived products. NETosis could be a target for new treatments. Monitoring NET markers in blood and cerebrospinal fluid might predict mortality and long-term outcomes. However, longitudinal studies and randomized controlled trials are warranted to fully evaluate their potential, as current evidence is limited. Full article

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PRISMA flowchart of the review. Full article ">Figure 2
Summary of preclinical and clinical findings and future directions for the clinical application of research on NETosis (illustration created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>). Acronyms: NET: neutrophil extracellular trap; ABI: acute brain injury; TBI: traumatic brain injury; SAH: subarachnoid aneurysmal haemorrhage; MPO-DNA: myeloperoxidase-deoxy-ribonuclease acid; CSF: cerebral spinal fluid. Full article ">Figure 3
The main pathways of NET formation involved in neuroinflammation (illustration created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>). Full article ">

12 pages, 931 KiB

Open AccessArticle

Establishment of an Antimicrobial Stewardship Program to Spare the Use of Oral Fluoroquinolones for Acute Uncomplicated Cystitis in Outpatients

by Tomoyuki Kato, Masayuki Nagasawa, Ippei Tanaka, Yuka Seyama, Reiko Sekikawa, Shiori Yamada, Eriko Ishikawa and Kento Kitajima

Antibiotics 2024, 13(9), 886; https://doi.org/10.3390/antibiotics13090886 (registering DOI) - 14 Sep 2024

Viewed by 162

Abstract

The increase in fluoroquinolone (FQ)-resistant Escherichia coli (EC) is a serious global problem. In addition, much of acute uncomplicated cystitis (AUC) cases are caused by EC. FQs have been selected for the treatment of cystitis in outpatients, and there is concern about treatment failure. It is therefore necessary to select appropriate antimicrobials to spare FQs. However, there are few reported effective antimicrobial stewardship programs (ASPs) for outpatients. We aimed to establish the effective ASP for outpatients diagnosed with AUC caused by EC, to spare the use of FQs, and to explore optimal oral antimicrobials for AUC. The study subjects were outpatients treated for AUC caused by extended-spectrum β-lactamase-non-producing EC (non-ESBL-EC). Based on the antibiogram results, we recommended cefaclor (CCL) as the initial treatment for AUC, and educated clinical pharmacists who also worked together to advocate for CCL or cephalexin (CEX) prescriptions. FQ usages decreased, and cephalosporin (Ceph) prescriptions increased in all medical departments. The Ceph group (n = 114; CCL = 60, CEX = 54) in the non-FQ group had fewer treatment failures than the FQ group (n = 86) (12.3% vs. 31.4%). Cephs, including CCL and CEX, were effective treatments for AUC caused by non-ESBL-EC. Antimicrobial selection based on antibiogram results and the practice of an ASP in collaboration with clinical pharmacists were useful for optimizing antimicrobial therapy in outpatients. Full article

(This article belongs to the Special Issue Antimicrobial Stewardship Intervention: Importance for Clinical Practice and Health Policy)

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Flow chart of patient enrollment in this study. Abbreviations: ESBL, extended-spectrum β-lactamase; EC, Escherichia coli. Full article ">Figure 2
Trends in the number of antimicrobial prescriptions for acute uncomplicated cystitis. The predictiveness evaluation of time series analysis is as follows. Mean absolute error (MAE): 0.286, root mean squared error (RMSE): 0.419. Regarding the number of prescriptions in 2023, the comparison between the actual value group and the predicted value group was evaluated using Mann–Whitney U test (respective p-values are as follows: 0.103 for FQ prescriptions, <0.05 for non-FQ prescriptions). Abbreviations: FQ, fluoroquinolones. Full article ">

21 pages, 5941 KiB

Open AccessArticle

Bioactivated Glucoraphanin Modulates Genes Involved in Necroptosis on Motor-Neuron-like Nsc-34: A Transcriptomic Study

by Aurelio Minuti, Alessandra Trainito, Agnese Gugliandolo, Ivan Anchesi, Luigi Chiricosta, Renato Iori, Emanuela Mazzon and Marco Calabrò

Antioxidants 2024, 13(9), 1111; https://doi.org/10.3390/antiox13091111 (registering DOI) - 14 Sep 2024

Viewed by 245

Abstract

Research on bioactive compounds has grown recently due to their health benefits and limited adverse effects, particularly in reducing the risk of chronic diseases, including neurodegenerative conditions. According to these observations, this study investigates the activity of sulforaphane (RS-GRA) on an in vitro model of differentiated NSC-34 cells. We performed a transcriptomic analysis at various time points (24 h, 48 h, and 72 h) and RS-GRA concentrations (1 µM, 5 µM, and 10 µM) to identify molecular pathways influenced by this compound and the effects of dosage and prolonged exposure. We found 39 differentially expressed genes consistently up- or downregulated across all conditions. Notably, Nfe2l2, Slc1a5, Slc7a11, Slc6a9, Slc6a5, Sod1, and Sod2 genes were consistently upregulated, while Ripk1, Glul, Ripk3, and Mlkl genes were downregulated. Pathway perturbation analysis showed that the overall dysregulation of these genes results in a significant increase in redox pathway activity (adjusted p-value 1.11 × 10⁻³) and a significant inhibition of the necroptosis pathway (adjusted p-value 4.64 × 10⁻³). These findings suggest RS-GRA’s potential as an adjuvant in neurodegenerative disease treatment, as both increased redox activity and necroptosis inhibition may be beneficial in this context. Furthermore, our data suggest two possible administration strategies, namely an acute approach with higher dosages and a chronic approach with lower dosages. Full article

(This article belongs to the Special Issue Role of Natural Antioxidants on Neuroprotection)

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15 pages, 4324 KiB

Open AccessArticle

Plasminogen Activation Inhibitor-1 Promotes Resilience to Acute Oxidative Stress in Cerebral Arteries from Females

by Safa and Charles E. Norton

Pharmaceuticals 2024, 17(9), 1210; https://doi.org/10.3390/ph17091210 (registering DOI) - 14 Sep 2024

Viewed by 196

Abstract

Plasminogen activation inhibitor-1 (PAI-1) plays a central role in thrombus formation leading to stroke; however, the contributions of PAI-1 to cellular damage in response to reactive oxygen species which are elevated during reperfusion are unknown. Given that PAI-1 can limit apoptosis, we hypothesized that PAI increases the resilience of cerebral arteries to H₂O₂ (200 µM). Cell death, mitochondrial membrane potential, and mitochondrial ROS production were evaluated in pressurized mouse posterior cerebral arteries from males and females. The effects of pharmacological and genetic inhibition of PAI-1 signaling were evaluated with the inhibitor PAI-039 (10 µM) and PAI-1 knockout mice, respectively. During exposure to H₂O₂, PCAs from male mice lacking PAI-1 had reduced mitochondrial depolarization and smooth muscle cell death, and PAI-039 increased EC death. In contrast, mitochondrial depolarization and cell death were augmented in female PCAs. With no effect of PAI-1 inhibition on resting mitochondrial ROS production, vessels from female PAI-1 knockout mice had increased mitochondrial ROS generation during H₂O₂ exposure. During acute exposure to oxidative stress, protein ablation of PAI-1 enhances cell death in posterior cerebral arteries from females while limiting cell death in males. These findings provide important considerations for blood flow restoration during stroke treatment. Full article

(This article belongs to the Special Issue Smooth Muscle and Endothelial Cells as Pharmacological Targets for Acute Oxidative Stress)

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Figure 1
Effects of pharmacological inhibition and genetic ablation of PAI-1 on H2O2-induced cell death in PCAs from males and females. Representative images of Hoechst 33342 dye staining all the nuclei (left), propidium iodide (PI) staining the nuclei of dead cells (middle), and merged image (right) following 50 min exposure to H2O2 in isolated pressurized PCAs from male (A) and female (B) mice. In the upper right panel, the white arrow denotes a SMC nuclei, the yellow arrow denotes an EC nuclei, and the green arrow denotes an adventitial cell nuclei (not counted). Full article ">Figure 2
H2O2-induced cell death is greater in SMCs of females in the absence of PAI-1 protein expression. Male and female SMC (A,B) and EC (C,D) death following exposure to H2O2 for 50 min in the control/wildtype PCAs ± the inhibitor of PAI-1 (PAI-039 10 µM) or PAI-KO mice. Individual values with means ± SEM for n = 4–6/group. # p < 0.05, female vs. male, * p < 0.05, PAI-039 vs. control, † p < 0.05, PAI-KO vs. control. § p < 0.05, PAI-KO vs. PAI-039. Full article ">Figure 3
PAI-1 expression is greater in brain, but not vessels of males. (A) Representative images of PAI-1 (red) and SMC actin (green) from male and female wildtype and PAI-KO mice. Quantification of mean PAI-1 fluorescence in (B) whole brain slices and (C) regions containing blood vessels identified by SMC actin. Individual values with means ± SEM for n = 4–6/group. # p <0.05, female vs. male. Full article ">Figure 4
PAI-1 attenuates the sustained [Ca2+]i response induced by H2O2 in females. [Ca2+]i responses (changes in Fura-2 fluorescence) in PCAs obtained from males (A) and females (B) from wildtype/control mice in the absence and presence of PAI-039, and PAI-KO mice during 50 min exposure to H2O2, followed by a 30 min wash period. Note in females (B), PAI-039 data overlays control data. (C) The peak changes of [Ca2+]i for both the male and female mice during the exposure to H2O2. Individual values and means ± SEM for n = 4–6/group. # p <0.05, female vs. male, † p < 0.05, PAI-KO vs. control. § p < 0.05, PAI-KO vs. PAI-039. Full article ">Figure 5
PAI-1 does not alter resting ΔΨm. (A) Red (left) and green (center) JC-1 (5 µM) fluorescence as an index of the resting ΔΨm in an intact pressurized PCA from a male wildtype mouse by evaluating the red/green fluorescence ratio (right). The switch from green to red fluorescence results when the dye is dimerized at a high concentration within the mitochondria. The resting ΔΨm in the (B) male and (C) female PCAs from the control/wildtype and PAI-KO mice. Individual values with means ± SEM for n = 6/group. No significant differences were detected. Full article ">Figure 6
Genetic deletion of PAI-1 enhances depolarization of ΔΨm to a greater extent in females than males. (A) Changes in ΔΨm (TMRM fluorescence; 10 nM; F/F0) during H2O2 (200 µM) exposure in PCAs from control male and PAI-KO male mice. (B) Changes in ΔΨm during H2O2 exposure in PCAs from control female and PAI-KO female mice. (C) Peak changes in ΔΨm during H2O2 exposure in PCAs from males and females (control, PAI-039, PAI-KO). Individual values and means ± SEM for n = 5–7/group. # p < 0.05, female vs. male, † p < 0.05, PAI-KO vs. control. § p < 0.05, PAI-KO vs. PAI-039. Full article ">Figure 7
PAI-1 Inhibition does not alter mitochondrial ROS production under baseline conditions. MitoSOX fluorescence accumulation under baseline conditions in male (A) and female (B) control/wildtype, PAI-039-treated, and PAI-KO PCAs. (C) MitoSOX fluorescence rate for PCAs from males and females for each treatment. Individual values and means ± SEM for n = 5–6/group. No significant differences were detected. Full article ">Figure 8
Genetic deletion of PAI-1 enhances mitochondrial ROS production in females during acute oxidative stress. MitoSOX fluorescence accumulation under baseline conditions in male (A) and female (B) control/wildtype, PAI-039-treated, and PAI-KO PCAs. (C) MitoSOX fluorescence rate for PCAs from males and females for each treatment. Individual values and means ± SEM for n = 4–6/group. # p < 0.05, female vs. male, † p < 0.05, PAI-KO vs. Control. Full article ">

24 pages, 1733 KiB

Open AccessReview

Functional Role of Extracellular Vesicles in Skeletal Muscle Physiology and Sarcopenia: The Importance of Physical Exercise and Nutrition

by Mauro Lombardo, Gilda Aiello, Deborah Fratantonio, Sercan Karav and Sara Baldelli

Nutrients 2024, 16(18), 3097; https://doi.org/10.3390/nu16183097 (registering DOI) - 13 Sep 2024

Viewed by 312

Abstract

Background/Objectives: Extracellular vesicles (EVs) play a key role in intercellular communication by transferring miRNAs and other macromolecules between cells. Understanding how diet and exercise modulate the release and content of skeletal muscle (SM)-derived EVs could lead to novel therapeutic strategies to prevent age-related muscle decline and other chronic diseases, such as sarcopenia. This review aims to provide an overview of the role of EVs in muscle function and to explore how nutritional and physical interventions can optimise their release and function. Methods: A literature review of studies examining the impact of exercise and nutritional interventions on MS-derived EVs was conducted. Major scientific databases, including PubMed, Scopus and Web of Science, were searched using keywords such as ‘extracellular vesicles’, ‘muscle’, ‘exercise’, ‘nutrition’ and ‘sarcopenia’. The selected studies included randomised controlled trials (RCTs), clinical trials and cohort studies. Data from these studies were synthesised to identify key findings related to the release of EVs, their composition and their potential role as therapeutic targets. Results: Dietary patterns, specific foods and supplements were found to significantly modulate EV release and composition, affecting muscle health and metabolism. Exercise-induced changes in EV content were observed after both acute and chronic interventions, with a marked impact on miRNAs and proteins related to muscle growth and inflammation. Nutritional interventions, such as the Mediterranean diet and omega-3 fatty acids, have also shown the ability to alter EV profiles, suggesting their potential to improve cardiovascular health and reduce inflammation. Conclusions: EVs are emerging as critical mediators of the beneficial effects of diet and exercise on muscle health. Both exercise and nutritional interventions can modulate the release and content of MS-derived EVs, offering promising avenues for the development of novel therapeutic strategies targeting sarcopenia and other muscle diseases. Future research should focus on large-scale RCT studies with standardised methodologies to better understand the role of EVs as biomarkers and therapeutic targets. Full article

(This article belongs to the Special Issue Nutritional Support, Dietary Strategies and Exercise on Bone and Muscle)

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Formation and release of various types of extracellular vesicles (EVs) from a cell. Full article ">Figure 2
Different roles of some miRNAs implicated in the process of muscle sarcopenia. Full article ">Figure 3
Flowchart of Study Selection Process. Full article ">Figure 4
Summary of the impact of nutritional interventions (diets and supplements) on extracellular vesicles (EVs) and their potential role in improving human health. Specific foods, nutrient-rich diets, and supplements influence the content and function of EVs, leading to improved muscle function, reduced inflammation, and improved metabolic health. The question marks (?) indicate areas where further research is needed to fully understand the mechanisms by which nutritional supplements impact EVs function, including how they enhance the delivery of bioactive molecules and improve EVs stability. Full article ">

12 pages, 1109 KiB

Open AccessArticle

Contrasting Effects of Oxytocin on MK801-Induced Social and Non-Social Behavior Impairment and Hyperactivity in a Genetic Rat Model of Schizophrenia-Linked Features

by Daniel Sampedro-Viana, Toni Cañete, Paula Ancil-Gascón, Sonia Cisci, Adolf Tobeña and Alberto Fernández-Teruel

Brain Sci. 2024, 14(9), 920; https://doi.org/10.3390/brainsci14090920 - 13 Sep 2024

Viewed by 199

Abstract

Social withdrawal in rodents is a measure of asociality, an important negative symptom of schizophrenia. The Roman high- (RHA) and low-avoidance (RLA) rat strains have been reported to exhibit differential profiles in schizophrenia-relevant behavioral phenotypes. This investigation was focused on the study of social and non-social behavior of these two rat strains following acute administration of dizocilpine (MK801, an NMDA receptor antagonist), a pharmacological model of schizophrenia-like features used to produce asociality and hyperactivity. Also, since oxytocin (OXT) has been proposed as a natural antipsychotic and a potential adjunctive therapy for social deficits in schizophrenia, we have evaluated the effects of OXT administration and its ability to reverse the MK801-impairing effects on social and non-social behavior and MK801-induced hyperactivity. MK801 administration produced hyperlocomotion and a decrease in social and non-social behavior in both rat strains, but these drug effects were clearly more marked in RHA rats. OXT (0.04 mg/kg and 0.2 mg/kg) attenuated MK801-induced hyperlocomotion in both rat strains, although this effect was more marked in RHA rats. The MK801-decreasing effect on exploration of the “social hole” was moderately but significantly attenuated only in RLA rats. This study is the first to demonstrate the differential effects of OXT on MK801-induced impairments in the two Roman rat strains, providing some support for the potential therapeutic effects of OXT against schizophrenia-like symptoms, including both a positive-like symptom (i.e., MK801-induced hyperlocomotion) and a negative-like symptom (i.e., MK801 decrease in social behavior), while highlighting the importance of the genetic background (i.e., the rat strain) in influencing the effects of both MK801 and oxytocin. Full article

(This article belongs to the Special Issue Exploring Negative Symptoms of Schizophrenia: Where Do We Stand?)

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Means (± SEM) of oxytocin (OXT) vs. MK801 results in the Roman rat strains tested for social interaction. (a) Social time of RHA and RLA rats is presented as the natural logarithm (Ln) of the social time. (b) Non-social time of RHA and RLA rats is presented as the natural logarithm (Ln) of the non-social time. Group symbols: VEH: vehicle. OXT: oxytocin. MK: MK801. VEH-VEH: injected with the two vehicles. VEH-MK: injected with (OXT) vehicle and MK801. OXT0.04-VEH: injected with OXT 0.04 mg/kg and the MK801 vehicle. OXT0.04-MK: injected with OXT 0.04 mg/kg and MK801 0.15 mg/kg. OXT0.2-VEH: injected with OXT 0.2 mg/kg and the MK801 vehicle. OXT0.2-MK: injected with OXT 0.2 mg/kg and MK801 0.15 mg/kg. RHA groups: VEH-VEH n = 14; VEH-MK n = 14; OXT0.04-VEH n = 12; OXT0.04-MK n = 14; OXT0.2-VEH n = 12; OXT0.2-MK n = 12. RLA groups: VEH-VEH n = 14; VEH-MK n = 14; OXT0.04-VEH n = 12; OXT0.04-MK n = 12; OXT0.2-VEH n = 12; OXT0.2-MK n = 11. “Strain”, “MK801”, Strain × MK801” and “Oxytocin × MK801” effects from factorial ANOVAs. (a) a = p < 0.05; b = p < 0.01; c = p < 0.001, between the groups with the same letter (Duncan’s multiple range test). (b) a = p < 0.05; b = p < 0.05; c = p < 0.05, between the groups with the same letter (Duncan’s multiple range test). * p < 0.05, ** p < 0.01, *** p < 0.001 (Duncan’s post hoc test for multiple comparisons). Full article ">Figure 2
Means (± SEM) of oxytocin (OXT) vs. MK801 results of (a) “Locomotor activity” (“Crossings”) during the SI test in the Roman rat strains. (b) “Total hole exploration” (Total activity in holes) is presented as the natural logarithm (Ln) of the sum of the social and non-social time. Group symbols and “n” per group as in <a href="#brainsci-14-00920-f001" class="html-fig">Figure 1</a>. “Strain”, “Oxytocin”, “MK801”, Strain × MK801” and “Oxytocin × MK801” effects from factorial ANOVAs. (a) a = p < 0.001; b = p < 0.05; c = p < 0.01, between the groups with the same letter (Duncan’s multiple range test). (b) a = p < 0.01; b = p < 0.001; c = p < 0.01, between the groups with the same letter (Duncan’s multiple range test). * p < 0.05, ** p < 0.01, *** p < 0.001 (Duncan’s post hoc test for multiple comparisons). Full article ">Scheme 1
Schematic drawing of the experimental SI setup. The “social” holes are those that face the other box, and the “non-social” holes are the distal ones. This schematic was modified from the drawing in references [<a href="#B19-brainsci-14-00920" class="html-bibr">19</a>,<a href="#B48-brainsci-14-00920" class="html-bibr">48</a>]. Full article ">

8 pages, 853 KiB

Open AccessCommunication

Clinical Utility of Synthesized 18-Lead Electrocardiography

by Tetsushi Yamamoto, Hiroyuki Awano, Shuichiro Ogawa and Masafumi Matsuo

Sensors 2024, 24(18), 5947; https://doi.org/10.3390/s24185947 - 13 Sep 2024

Viewed by 171

Abstract

Eighteen-lead electrocardiography (18-ECG) includes, in addition to those in standard 12-lead ECG (12-ECG), six additional chest leads: V7–V9 and V3RV5R. Leads V7–V9 require the patient to be in a lateral decubitus position for the electrodes to be attached to the back. Synthesized 18-ECG (syn18-ECG) is a method that only records 12-ECG and uses computational logic to record the posterior wall (V7–V9) and right-sided (V3R–V5R) leads. We review the clinical utility of syn18-ECG in conditions including acute coronary syndromes, arrhythmias, acute pulmonary embolism, and Duchenne muscular dystrophy. The syn18-ECG waveform correlates well with the actual 18-ECG waveform, indicating that syn18-ECG is an excellent substitute for 18-ECG, excluding negative T waves. ST elevation in leads V7–V9 has the effect of reducing missed acute coronary syndromes in the posterior wall. In cases of arrhythmia, syn18-ECG can accurately estimate the target site of radiofrequency catheter ablation using a simple algorithm. The use of additional leads in Duchenne muscular dystrophy is expected to provide new insights. To facilitate gaining more knowledge regarding diseases that have not yet been investigated, it is imperative that the cost of syn18-ECG is reduced in the future. Full article

(This article belongs to the Special Issue ECG Signal Processing and Analysis, Computational Technology and Applications: 2nd Edition)

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Positioning of chest electrodes and heart in 18-ECG chest electrode in horizontal cross-section. White: Electrodes of a standard 12-ECG; Red and blue: Electrodes added in 18-ECG; LV: left ventricular; LA: left atrium; RV: right ventricular; RA: right atrium. Full article ">Figure 2
Additional chest electrode attachment sites: (a) precordial lead site; (b) electrode position on the left rear section. Full article ">

14 pages, 19586 KiB

Open AccessArticle

Advanced Electrospun Composites Based on Polycaprolactone Fibers Loaded with Micronized Tungsten Powders for Radiation Shielding

by Chiara Giuliani, Ilaria De Stefano, Mariateresa Mancuso, Noemi Fiaschini, Luis Alexander Hein, Daniele Mirabile Gattia, Elisa Scatena, Eleonora Zenobi, Costantino Del Gaudio, Federica Galante, Giuseppe Felici and Antonio Rinaldi

Polymers 2024, 16(18), 2590; https://doi.org/10.3390/polym16182590 - 13 Sep 2024

Viewed by 221

Abstract

Exposure to high levels of radiation can cause acute, long-term health effects, such as acute radiation syndrome, cancer, and cardiovascular disease. This is an important occupational hazard in different fields, such as the aerospace and healthcare industry, as well as a crucial burden to overcome to boost space applications and exploration. Protective bulky equipment made of heavy metals is not suitable for many advanced purporses, such as mobile devices, wearable shields, and manned spacecrafts. In the latter case, the in-space manufacturing of protective shields is highly desirable and remains an unmet need. Composites made of polymers and high atomic number fillers are potential means for radiation protection due to their low weight, good flexibility, and good processability. In the present work, we developed electrospun composites based on polycaprolactone (polymer matrix) and tungsten powder for application as shielding materials. Electrospinning is a versatile technology that is easily scalable at an industrial level and allows obtaining very lightweight, flexible sheet materials for wearables. By controlling tungsten powder size, we engineered homogeneous, stable and processable suspensions to fabricate radiation composite shielding sheets. The shielding capability was assessed by an in vivo model on prototype composite sheets containing 80 w% of W filler in a polycaprolactone (PCL) fibrous matrix by means of irradiation tests (X-rays) on mice. The obtained results are promising; as expected, the shielding effectivity of the developed composite material increases with the thickness/number of stacked layers. It is worth noting that a thin barrier consisting of 24 layers of the innovative shielding material reduces the extent of apoptosis by 1.5 times compared to the non-shielded mice. Full article

(This article belongs to the Special Issue Advances in Functional Polymers and Composites)

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Figure 1
Schematic representation of the experimental setup (a), custom-built 3D printed PLA protective device for in vivo test mounted on a 3 mm thick solid lead sheet (b); PLA device wrapped up in 12 shielding sheets of PCL/W (c); PLA device wrapped up in 24 shielding sheets of PCL/W (d); schematic representation of a section of a cerebellum at 2 days of age (e); antero-dorsal cardinal lobe of the cerebellum (f). The dashed black line externally outlines the EGL. Figure in (a,e) was obtained by Biorender. Full article ">Figure 2
The SEM image of the commercial W powder is as follows: before (a,b), after 16 h (c,d) and 26 h (e,f) of ball milling. Full article ">Figure 3
Unstable suspension prepared using PCL and the commercial W powder (a), and stable suspension based on PCL and the optimized W powder (b). Full article ">Figure 4
Micro-fibrous PCL sheets characterized by different W content (w% with respect to the PCL polymer). Full article ">Figure 5
Microfibrous PCL/W sheets characterized as 10 w% (a), 40 w% (b), and 60 w% (c) of W with respect to the PCL polymer. Full article ">Figure 6
EDS analysis of the PCL/W electrospun sheets. Full article ">Figure 7
The apoptotic rate in EGL of irradiated mice under different experimental conditions. (a–d) Representative images of the EGL in the antero-dorsal cardinal lobe region of the cerebellum at postnatal day 2 (P2); Hematoxylin & Eosin staining; 40× magnification. The inset in (a) shows pyknotic nuclei at higher magnification (100×) indicative of apoptosis in WB irradiated mice; (e) a graphical representation of the percentage of apoptotic cells in the different experimental groups. *** p < 0.0001. Full article ">Figure 8
(a) Cerebellum at P2 labeled with activated caspase 3; the EGL, where the cells undergoing apoptosis reside, is colored red (2× magnification). (b) Detail of the EGL at higher magnification (40×). (c) Graphical representation of the quantification of the signal related to the antero-dorsal cardinal lobe region. * p < 0.05. Full article ">

15 pages, 2976 KiB

Open AccessArticle

The NF-κB1/p50 Subunit Influences the Notch/IL-6-Driven Expansion of Myeloid-Derived Suppressor Cells in Murine T-Cell Acute Lymphoblastic Leukemia

by Behnaz Abdollahzadeh, Noemi Martina Cantale Aeo, Nike Giordano, Andrea Orlando, Maria Basciani, Giovanna Peruzzi, Paola Grazioli, Isabella Screpanti, Maria Pia Felli and Antonio Francesco Campese

Int. J. Mol. Sci. 2024, 25(18), 9882; https://doi.org/10.3390/ijms25189882 - 13 Sep 2024

Viewed by 254

Abstract

T-cell acute lymphoblastic leukemia is an aggressive neoplasia due to hyper-proliferation of lymphoid progenitors and lacking a definitive cure to date. Notch-activating mutations are the most common in driving disease onset and progression, often in combination with sustained activity of NF-κB. Myeloid-derived suppressor cells represent a mixed population of immature progenitors exerting suppression of anti-cancer immune responses in the tumor microenvironment of many malignancies. We recently reported that in a transgenic murine model of Notch3-dependent T-cell acute lymphoblastic leukemia there is an accumulation of myeloid-derived suppressor cells, dependent on both Notch signaling deregulation and IL-6 production inside tumor T-cells. However, possible interaction between NF-κB and Notch in this context remains unexplored. Interestingly, we also reported that Notch3 transgenic and NF-κB1/p50 deleted double mutant mice display massive myeloproliferation. Here, we demonstrated that the absence of the p50 subunit in these mice dramatically enhances the induction and suppressive function of myeloid-derived suppressor cells. This runs in parallel with an impressive increase in IL-6 concentration in the peripheral blood serum, depending on IL-6 hyper-production by tumor T-cells from double mutant mice. Mechanistically, IL-6 increase relies on loss of the negative control exerted by the p50 subunit on the IL-6 promoter. Our results reveal the Notch/NF-κB cross-talk in regulating myeloid-derived suppressor cell biology in T-cell leukemia, highlighting the need to consider carefully the pleiotropic effects of NF-κB-based therapy on the tumor microenvironment. Full article

(This article belongs to the Special Issue The Role of Notch Signaling Activation and Its Cross-Talk with Other Pathways in Hematological Malignancies)

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Figure 1
CD11b+GR-1+ cells accumulate in the spleen of N3tg/p50−/− young mice. (A) Representative dot plots showing CD11b versus Gr-1 distributions in the spleen of wt, p50−/−, N3tg, and N3tg/p50−/− mice at 5–6 weeks of age, as measured by FACS analysis. The numbers inside each cytogram represent percentages of CD11b+Gr-1+ cells. (B) CD11b+Gr-1+ numbers in the spleen from wt, p50−/−, N3tg, and N3tg/p50−/− mice at 5–6 weeks of age (left part), as well as from N3tg and N3tg/p50−/− mice at 11–12 weeks of age (right part), as assessed by FACS analysis, as in (A). Data represent mean ± SD of four independent experiments (n = 4 mice for each genotype and for each age). ** p ≤ 0.01 and *** p ≤ 0.001 represent significant differences between the indicated groups. ns = not significant, p > 0.05. Full article ">Figure 2
CD11b+GR-1+ cells from N3tg/p50−/− mice are functional MDSCs. Representative FACS analysis at 72 h of an in vitro suppression assay with activated, CFSE-labeled wt T splenocytes, CD4−CD8+ gated, used as ‘responders’. In (A), wt T ‘responder’ cells were cultured alone, as a negative control (((upper panel), at a 0:1 suppressor/responder ratio), or in combination, with CD11b+GR-1+ cells from the spleen of wt or p50−/− mice, at 5–6 weeks of age ((lower panels), at a 1:2 suppressor/responder ratio), as a control. In (B), ‘responders’ were co-cultured with CD11b+GR-1+ cells from the spleens of N3tg or N3tg/p50−/− mice at 5–6 weeks of age ((left panels), at a 1:4 suppressor/responder ratio; (right panels), at a 1:2 suppressor/responder ratio). The numbers inside the cytograms represent the percentages of M1 non-proliferating, suppressed wt CD4−CD8+ T ‘responders’. The ratios of CD11b+GR-1+ ‘suppressors’: wt CD4−CD8+ T ‘target’ cells are also indicated above the panels (0:1, 1:4, or 1:2). (C) RT-qPCR assay of relative arginase-1 (Arg-1) mRNA expression in CD11b+GR-1+ cells purified from the spleens of N3tg, N3tg/p50−/−, and wt mice at 5–6 weeks of age. The expression level of Arg-1 mRNA in wt CD11b+GR-1+ controls was set to 1. Data represent the mean ± SD of three independent experiments (n = 3 mice for each genotype), each in triplicate. In (A,B), ns = not significant, p > 0.05, and * p ≤ 0.05 represents significant differences with respect to the negative control with wt T-cells cultured alone (the upper panel in (A)). ++ p ≤ 0.01 represents significant differences with respect to the N3tg counterparts (comparing the lower versus upper panels in (B)). In (C), * p ≤ 0.05 and ** p ≤ 0.01 represent significant differences between the indicated groups. Full article ">Figure 3
N3tg/p50−/− mice display enhanced production of the IL-6 cytokine. IL-6 protein concentrations (pg/mL) assessed by ELISA (A) in peripheral blood serum from N3tg/p50−/− and N3tg mice, at 5–6 weeks of age, compared to those of their wt or p50−/− controls and (B) in the supernatant medium of CD4+CD8+ DP T splenocytes derived from N3tg/p50−/− and N3tg mice, at 5–6 weeks of age, cultured alone for 48 h, compared to DP T thymocytes from their wt littermates. Data represent the mean values ± SDs of three independent experiments (n = 3 mice for each genotype), each in triplicate. nd, not determined; * p ≤ 0.05, ** p ≤ 0.01, and *** p ≤ 0.001 represent significant differences between the indicated samples. Full article ">Figure 4
The NF-κB1/p50 subunit represses the transcription of the IL-6 promoter in CD4+CD8+ DP T-cells. (A) The binding of the NF-κB1/p50 or RELA/p65 subunit to the κB-consensus Site1 and Site3 of the murine IL-6 promoter [<a href="#B44-ijms-25-09882" class="html-bibr">44</a>], analyzed by ChIP-qPCR in cross-linked protein–DNA complexes of CD4+CD8+ DP T thymocytes from wt mice, at 5–6 weeks of age. Fold enrichment of target region in p50-IP, p65-IP, or control IgG-IP is shown, and data are normalized to binding at the β-actin promoter (negative control). The values of IgG-IP controls were set to 1. (B) The binding of the RELA/p65 subunit to Site1 and Site3 of the murine IL-6 promoter, as in (A), analyzed by ChIP-qPCR in cross-linked protein–DNA complexes of CD4+CD8+ DP T splenocytes from N3tg or N3tg/p50−/− mice, compared to wt DP T thymocyte controls, at 5–6 weeks of age. Fold enrichment of target region in p65-IP versus control IgG-IP is shown, and data are normalized to binding at the β-actin promoter (negative control). The values in wt DP T thymocyte controls were set to 1. In (A,B), data represent the mean values ± SDs of three independent experiments (n = 3 mice for each genotype), each in triplicate. ns = not significant, p > 0.05. * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001, and **** p ≤ 0.0001 represent significant differences between the indicated samples. (C) Working hypothesis on how the NF-κB1/p50 subunit can regulate IL-6 transcription and then MDSC differentiation in mice of different genotypes (see the text for an exhaustive explanation). In the left parts, x = no transcription, ++ = enhanced transcription and ++++ = very high transcription of the IL-6 promoter; vertical black arrows of different thickness indicate differences in the strength of p65 binding to the IL-6 promoter; blunt arrows of different thickness indicate differences in the inhibition of IL-6 transcription, that lacks in the panel 3 due to the absence of p50/p50 homodimers, as indicated by the red X over them. In the right parts, the triple red arrow indicates very high levels of IL-6 production by DP T cells; blunt arrows of different thickness indicate differences in the inhibition of CD8+ cells exerted by MDSCs, that lacks in the panel 1 due to the absence of IL-6 and MDSCs, as indicated by the red X over them. Created with BioRender.com. Full article ">

17 pages, 8328 KiB

Open AccessArticle

Chitosan-Modified AgNPs Efficiently Inhibit Swine Coronavirus-Induced Host Cell Infections via Targeting the Spike Protein

by Dongliang Wang, Caiyun Yin, Yihan Bai, Mingxia Zhou, Naidong Wang, Chunyi Tong, Yi Yang and Bin Liu

Biomolecules 2024, 14(9), 1152; https://doi.org/10.3390/biom14091152 - 13 Sep 2024

Viewed by 337

Abstract

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has filled a gap in our knowledge regarding the prevention of CoVs. Swine coronavirus (CoV) is a significant pathogen that causes huge economic losses to the global swine industry. Until now, anti-CoV prevention and control have been challenging due to the rapidly generated variants. Silver nanoparticles (AgNPs) with excellent antimicrobial activity have attracted great interest for biosafety prevention and control applications. In this study, we synthesized chitosan-modified AgNPs (Chi-AgNPs) with good biocompatibility to investigate their antiviral effects on swine CoVs. In vitro assays showed that Chi-AgNPs could significantly impaired viral entry. The direct interaction between Chi-AgNPs and CoVs can destroy the viral surface spike (S) protein secondary structure associated with viral membrane fusion, which is caused by the cleavage of disulfide bonds in the S protein. Moreover, the mechanism showed that Chi-AgNPs reduced the virus-induced apoptosis of Vero cells via the ROS/p53 signaling activation pathway. Our data suggest that Chi-AgNPs can serve as a preventive strategy for CoVs infection and provide a molecular basis for the viricidal effect of Chi-AgNPs on CoVs. Full article

(This article belongs to the Topic Antimicrobial Agents and Nanomaterials)

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15 pages, 2034 KiB

Open AccessArticle

Effects of Maltodextrin–Fructose Supplementation on Inflammatory Biomarkers and Lipidomic Profile Following Endurance Running: A Randomized Placebo-Controlled Cross-Over Trial

by Stefano Righetti, Alessandro Medoro, Francesca Graziano, Luca Mondazzi, Serena Martegani, Francesco Chiappero, Elena Casiraghi, Paolo Petroni, Graziamaria Corbi, Riccardo Pina, Giovanni Scapagnini, Sergio Davinelli and Camillo Ricordi

Nutrients 2024, 16(18), 3078; https://doi.org/10.3390/nu16183078 - 12 Sep 2024

Viewed by 378

Abstract

Background: Managing metabolism for optimal training, performance, and recovery in medium-to-high-level endurance runners involves enhancing energy systems through strategic nutrient intake. Optimal carbohydrate intake before, during, and after endurance running can enhance glycogen stores and maintain optimal blood glucose levels, influencing various physiological responses and adaptations, including transitory post-endurance inflammation. This randomized trial investigates the impact of a high-dose 2:1 maltodextrin–fructose supplementation to medium-to-high-level endurance runners immediately before, during, and after a 15 km run at 90% VO_2max intensity on post-exercise inflammatory stress. Methods: We evaluated inflammatory biomarkers and lipidomic profiles before the endurance tests and up to 24 h after. We focused on the effects of high-dose 2:1 maltodextrin–fructose supplementation on white blood cell count, neutrophil number, IL-6, cortisol, and CRP levels, as well as polyunsaturated fatty acids, ω-3 index, and AA/EPA ratio. Results: This supplementation significantly reduced inflammatory markers and metabolic stress. Additionally, it may enhance the post-activity increase in blood ω-3 fatty acid levels and reduce the increase in ω-6 levels, resulting in a lower trend of AA/EPA ratio at 24 h in the treated arm. Conclusions: Adequate carbohydrate supplementation may acutely mitigate inflammation during a one-hour endurance activity of moderate-to-high intensity. These effects could be beneficial for athletes engaging in frequent, high-intensity activities. Full article

(This article belongs to the Section Sports Nutrition)

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Figure 1
Schematic diagram of cross-over study design (A) and experimental protocol during the 2nd and 3rd visits (B). AA = arachidonic acid; CK = creatine phosphokinase; CRP = C-reactive protein; DHA = docosahexaenoic acid; MS = muscle soreness; EPA = eicosapentaenoic acid; GI = gastrointestinal; IL-6 = interleukin-6; WBC = white blood cells. Full article ">Figure 2
Effects of treatment and placebo over time (at baseline, post-running, after 3 and 24 h post-running) on blood glucose levels. Data are reported as mean ± standard error of the mean. * significant difference between treatments. Full article ">Figure 3
Inflammatory indices pre- and post-activity and at 3 and 24 h post-activity: WBC (A), neutrophil (B), IL-6 (C), and cortisol (D). Data are reported as mean ± standard error of the mean. * significant difference between the two arms. Full article ">Figure 4
The proportion of CRP values not identifiable (≤0.16 mg/dL vs. >0.16 mg/dL) in placebo and treatment arms over time (at baseline, post-running, and 3 and 24 h post-running). Full article ">Figure 5
ω-3 index (A) and AA/EPA ratio (B) at baseline, post-activity, after 1.5, 3, and 24 h post-running. Data are reported as mean ± standard error of the mean. Full article ">Figure 6
Effects plot of the linear regression models used to predict CK values given a baseline AA/EPA ratio. The models were also adjusted for the treatment arm. * significant difference. Full article ">

23 pages, 2059 KiB

Open AccessArticle

Cost-Effectiveness Analysis of Routine Childhood Immunization with 20-Valent versus 15-Valent Pneumococcal Conjugate Vaccines in Germany

by Min Huang, Jessica P. Weaver, Elamin Elbasha, Thomas Weiss, Natalie Banniettis, Kristen Feemster, Meghan White and Matthew S. Kelly

Vaccines 2024, 12(9), 1045; https://doi.org/10.3390/vaccines12091045 (registering DOI) - 12 Sep 2024

Viewed by 463

Abstract

This study aimed to evaluate the cost-effectiveness of routine childhood immunization with the 20-valent pneumococcal conjugate vaccine (PCV20) in a four-dose regimen (3 + 1 schedule) versus the 15-valent PCV (PCV15/V114) in a three-dose regimen (2 + 1) in Germany. The study utilized a decision-analytic Markov model to estimate lifetime costs and effectiveness outcomes for a single birth cohort in Germany. The model tracked the incidence of acute pneumococcal infections and long-term pneumococcal meningitis sequelae for both vaccination strategies. The vaccine effectiveness data were derived from published clinical trials and observational studies of PCV7 and PCV13. Indirect effects, such as herd protection and serotype replacement, were included in the model. The model adopted a societal perspective, including direct medical, direct non-medical, and indirect costs. Scenario and sensitivity analyses were performed. In the base case, PCV20 prevented more pneumococcal disease cases and deaths, with an expected gain of 96 quality-adjusted life years (QALYs) compared to V114. However, PCV20 was associated with a total incremental cost of EUR 48,358,424, resulting in an incremental cost-effectiveness ratio (ICER) of EUR 503,620/QALY. Most of the scenario and sensitivity analyses estimated that the ICER for PCV20 exceeded EUR 150,000/QALY. Routine childhood immunization with PCV20 instead of V114 may not be an economically efficient use of healthcare resources in Germany. Full article

(This article belongs to the Section Vaccines against Infectious Diseases)

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Figure 1
Decision-analytical Markov model structure. Abbreviations: NBPP = non-bacteremic pneumococcal pneumonia; AOM = acute otitis media. Notes: This figure illustrates the potential health states and acute diseases that a birth cohort might experience in their lifetime. The model assumed that a single birth cohort in Germany entered the model without pneumococcal disease and might develop invasive pneumococcal disease (IPD), NBPP, and pneumococcal AOM, or transition to other health states, i.e., post-meningitis sequelae (PMS), including neurological deficits, hearing loss, and death. Individuals who developed PMS remained in this health state until death and were at risk of developing non-meningitis IPD, NBPP, and pneumococcal AOM in subsequent model cycles. In addition, the model assumed that individuals with IPD and inpatient NBPP experienced excess mortality, while individuals who developed other pneumococcal diseases (outpatient NBPP and AOM) were considered to have the same age-specific mortality as the general population. The curved arrows indicate that individuals might remain in the same health state in the next model cycle. Full article ">Figure 2
Results of one-way sensitivity analyses. Abbreviations: ICER = incremental cost-effectiveness ratio; PCV20 = 20-valent pneumococcal conjugate vaccine; V114 = 15-valent pneumococcal conjugate vaccine; QALY = quality-adjusted life year; VE = vaccine effectiveness; IPD = invasive pneumococcal disease; AOM = acute otitis media; ST = serotype. Notes: Tornado diagram depicting the results of one-way sensitivity analyses. The pink and light-blue bars show changes in the ICER for PCV20 (i.e., incremental costs per QALY gained) compared to V114 from the base-case analysis (black line) when the lower or upper values of an input were used, with all other model inputs being held constant. Full article ">Figure 3
Scattered plot of probabilistic sensitivity analysis comparing PCV20 (3 + 1 schedule) to V114 (2 + 1). Abbreviations: QALY = quality-adjusted life year; PCV20 = 20-valent pneumococcal conjugate vaccine; V114 = 15-valent pneumococcal conjugate vaccine; PSA = probabilistic sensitivity analysis. Notes: The PSA tested the robustness of the model with respect to uncertainty in all input parameters with the exception of the vaccine prices, wherein a theoretical probability distribution was assigned to each parameter and a Monte Carlo simulation with 1000 iterations was performed by varying all parameters simultaneously. Each “x” represents the results from one iteration. The orange diamond depicts the mean PSA results from the 1000 iterations. Full article ">Figure 4
Cost-effectiveness acceptability curve of probabilistic sensitivity analysis comparing PCV20 versus V114. Abbreviations: PCV20 = 20-valent pneumococcal conjugate vaccine; V114 = 15-valent pneumococcal conjugate vaccine. Notes: The PSA tested the robustness of the model with respect to uncertainty in all input parameters with the exception of the vaccine prices, wherein a theoretical probability distribution was assigned to each parameter and a Monte Carlo simulation with 1000 iterations was performed by varying all parameters simultaneously. The curve depicts the probability of PCV20 (3 + 1) being cost-effective compared to V114 (2 + 1) based on the willingness-to-pay thresholds shown on the x-axis. Specifically, the probability was estimated based on the proportion of incremental cost-effectiveness ratios generated from the Monte Carlo simulation that were less than or equal to each willingness-to-pay threshold. Full article ">

31 pages, 2531 KiB

Open AccessReview

Treatment of Acute and Long-COVID, Diabetes, Myocardial Infarction, and Alzheimer’s Disease: The Potential Role of a Novel Nano-Compound—The Transdermal Glutathione–Cyclodextrin Complex

by Ray Yutani, Vishwanath Venketaraman and Nisar Sheren

Antioxidants 2024, 13(9), 1106; https://doi.org/10.3390/antiox13091106 - 12 Sep 2024

Viewed by 488

Abstract

Oxidative stress (OS) occurs from excessive reactive oxygen species or a deficiency of antioxidants—primarily endogenous glutathione (GSH). There are many illnesses, from acute and post-COVID-19, diabetes, myocardial infarction to Alzheimer’s disease, that are associated with OS. These dissimilar illnesses are, in order, viral infections, metabolic disorders, ischemic events, and neurodegenerative disorders. Evidence is presented that in many illnesses, (1) OS is an early initiator and significant promotor of their progressive pathophysiologic processes, (2) early reduction of OS may prevent later serious and irreversible complications, (3) GSH deficiency is associated with OS, (4) GSH can likely reduce OS and restore adaptive physiology, (5) effective administration of GSH can be accomplished with a novel nano-product, the GSH/cyclodextrin (GC) complex. OS is an overlooked pathological process of many illnesses. Significantly, with the GSH/cyclodextrin (GC) complex, therapeutic administration of GSH is now available to reduce OS. Finally, rigorous prospective studies are needed to confirm the efficacy of this therapeutic approach. Full article

(This article belongs to the Topic Natural Bioactive Compounds as a Promising Approach to Mitigating Oxidative Stress)

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This illustrates the beneficial role of reactive oxygen species (ROS) when it is in physiologic balance with antioxidants. These include activating innate immunity and augmenting adaptive immunity. It should be noted that peroxynitrite and nitric oxide are co-existing reactive nitrogen species (RNS). Full article ">Figure 2
This illustrates the state of oxidative stress (OS) that occurs from an imbalance of ROS relative to antioxidants. It can result from excess ROS, a deficiency of antioxidants, or a combination of both. Acute insults occur when the stimulation of ROS overwhelms available antioxidants. Chronic insults occur when antioxidants are either deficient or exhausted. Presumptively, the development of numerous seemingly disparate acute and chronic diseases may be the result of OS. (Created with BioRender). Full article ">Figure 3
Illustrated are examples of acute and chronic diseases associated with OS. An acute disease resulting from OS is COVID-19. OS leads to a dysregulation of the cytokine response, which leads to the cytokine storm (CS). The CS causes multi-organ failure (MOF), including COVID-associated acute respiratory distress syndrome (ARDS). Chronically, OS causes beta-cell dysfunction and insulin resistance, leading to diabetes and its many neuro-vascular complications that result from the formation of advanced glycation end-products (AGEs). The onset of neurogenerative disorders appears to be initiated and enhanced by OS. (Created with BioRender). Full article ">Figure 4
This illustrates the concept that the prevention or early inhibition of OS is a more effective approach to managing diseases. This should be achieved by targeting diseases early when the pathophysiologic process is more easily controlled and prior to the development of irreversible tissue injury. (Created with BioRender). Full article ">

9 pages, 222 KiB

Open AccessArticle

Antibiotic Prescribing Habits in Endodontics among Dentists in the Federation of Bosnia and Herzegovina—A Questionnaire-Based Study

by Matea Galić, Ivana Miletić, Tina Poklepović Peričić, Valentina Rajić, Nikolina Nika Većek Jurčević, Ajka Pribisalić and Ivana Medvedec Mikić

Antibiotics 2024, 13(9), 876; https://doi.org/10.3390/antibiotics13090876 - 12 Sep 2024

Viewed by 295

Abstract

Backgrounds: Antibiotics are used in endodontic treatment to control acute odontogenic infection and for prophylactic purposes. This study aimed to investigate the knowledge of dentists from the Federation of Bosnia and Herzegovina about the choice and the routes of antibiotic administration in endodontics. Methods: This cross-sectional study involved dentists in Federation of Bosnia and Herzegovina health institutions. The Dental Chamber sent a twelve-question survey to members’ email addresses. They were asked about the type, dosage, indications, and side effects of antibiotics used in endodontics. The obtained data were screened and analyzed. Results: A total of 180 questionnaires were filled out. The most commonly prescribed antibiotic was amoxicillin with clavulanic acid. Pulp necrosis with symptomatic apical periodontitis, swelling, and moderately severe symptoms were the main indications for the therapeutic use of antibiotics. Amoxicillin, administered orally at 2 g 1 h before endodontic surgery for patients with bacterial endocarditis, was mostly indicated for the prophylactic use of antibiotics. Conclusions: Based on the results of this study, we can conclude that dentists from the Federation of Bosnia and Herzegovina have limited knowledge regarding antibiotic use in endodontics. Educational activities and campaigns are necessary to raise awareness about antibiotics in dental medicine in the Federation of Bosnia and Herzegovina. Full article

(This article belongs to the Special Issue Antibiotic Prescribing in Primary Dental Care)

25 pages, 4324 KiB

Open AccessReview

Polyunsaturated Fatty Acids as Potential Treatments for COVID-19-Induced Anosmia

by Yu-Han Wang, Chung-Wei Lin and Chiung-Wei Huang

Biomedicines 2024, 12(9), 2085; https://doi.org/10.3390/biomedicines12092085 - 12 Sep 2024

Viewed by 357

Abstract

Some individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) experience anosmia, or loss of smell. Although the prevalence of anosmia has decreased with the emergence of the Omicron variant, it remains a significant concern. This review examines the potential role of polyunsaturated fatty acids (PUFAs), particularly omega-3 PUFAs, in treating COVID-19-induced anosmia by focusing on the underlying mechanisms of the condition. Omega-3 PUFAs are known for their anti-inflammatory, neuroprotective, and neurotransmission-enhancing properties, which could potentially aid in olfactory recovery. However, study findings are inconsistent. For instance, a placebo-controlled randomized clinical trial found no significant effect of omega-3 PUFA supplementation on olfactory recovery in patients with COVID-19-induced anosmia. These mixed results highlight the limitations of existing research, including small sample sizes, lack of placebo controls, short follow-up periods, and combined treatments. Therefore, more rigorous, large-scale studies are urgently needed to definitively assess the therapeutic potential of omega-3 PUFAs for olfactory dysfunction. Further research is also crucial to explore the broader role of PUFAs in managing viral infections and promoting sensory recovery. Full article

(This article belongs to the Section Drug Discovery, Development and Delivery)

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Figure 1
The human olfactory system. The diagram shows the intricate anatomy of the human olfactory system. Olfactory stimuli are detected, transmitted, and processed by key anatomical structures and neurobiological pathways. In the nasal cavity, the olfactory epithelium contains olfactory receptor neurons (ORNs), which detect volatile odorant molecules inhaled through the nasal passages. When an odorant binds to its receptor, it activates the receptor and initiates a series of intracellular events that generate an electric signal in the ORN. The axons of these ORNs converge to form the olfactory nerve, which transmits olfactory information from the epithelium to the olfactory bulb. The olfactory bulb consists of glomeruli formed by synapsing olfactory nerve fibers with mitral and tufted cells. Olfactory signals are processed and refined in the olfactory bulb located on the ventral surface of the brain. Subsequently, the processed signals are transmitted from the olfactory bulb to the olfactory cortex through the olfactory tract. The olfactory cortex includes several regions (shaded blue). The olfactory tubercle integrates olfactory information with motivational and emotional contexts. The amygdala emotionally responds to olfactory stimuli. The periamygdaloid cortex associates olfactory signals with perception and memory. The piriform cortex distinguishes smells. The entorhinal cortex plays a critical role in memory formation, spatial navigation, and the integration of olfactory information with other sensory inputs. Through these complex and highly coordinated pathways, the brain is able to detect, identify, and respond to a wide variety of odors, linking them to past experiences and emotions. Full article ">Figure 2
The role of transient receptor potential vanilloid (TRPV) channels in the pathogenesis of coronavirus disease 2019 (COVID-19)-induced anosmia. TRPV channels are integral to sensory perception, immune responses, and inflammation. These channels, which are found in various tissues, detect physical and chemical stimuli. TRPV channel activation leads to calcium influx, which triggers the release of inflammatory mediators. This process contributes to a cytokine storm and subsequent tissue damage. In the context of COVID-19, TRPV channels play a pivotal role in the disease pathogenesis, including the development of anosmia (loss of smell). TRPV1 activation causes neurogenic inflammation in sensory neurons. Neuropeptides released within the olfactory epithelium and bulb, such as calcitonin gene-related peptide and substance P, may damage olfactory receptor neurons, resulting in olfactory dysfunction. In addition, TRPV4 is involved in the regulation of vascular permeability and inflammatory responses. The overactivation of TRPV4 can increase inflammation and exacerbate damage to olfactory neurons and supporting cells, further contributing to anosmia. Considering their role in inflammation and immune responses, modulating the activity of TRPV channels, particularly TRPV1 and TRPV4, offers potential therapeutic strategies to mitigate anosmia and improve olfactory function in affected individuals. Full article ">Figure 3
Current treatments of coronavirus disease 2019 (COVID-19)-induced anosmia. A variety of approaches are employed to treat COVID-19-induced anosmia, including olfactory training, corticosteroids, acupuncture, vitamins, omega-3 polyunsaturated fatty acid (PUFA) supplements, ST266, insulin, platelet-rich plasma (PRP), palmitoylethanolamide–luteolin (PEA–LUT), cerebrolysin, and 13-cis-retinoic acid. Olfactory training, which involves repeated exposure to different odors, helps stimulate olfactory function by re-engaging and retraining the olfactory system to recognize and distinguish various smells, thereby enhancing sensitivity and functionality. Corticosteroids reduce inflammation and nasal congestion, therefore improving olfactory function by minimizing the inflammatory response that impairs olfactory receptors. Acupuncture has shown potential in the treatment of anosmia by activating the central nervous system and influencing anti-inflammatory and immunomodulatory mechanisms. Vitamins and 13-cis-retinoic acid possess anti-inflammatory properties and influence cellular processes involved in receptor regeneration and neural plasticity, further promoting olfactory system recovery. Omega-3 PUFA supplements, known for their anti-inflammatory properties, help alleviate sensory disorders by reducing inflammation and supporting olfactory system regeneration. ST266 has shown the effective reversal of COVID-19-induced anosmia, although its mechanism of action remains unclear. Intranasal insulin may improve olfactory function by increasing the growth factor levels in the olfactory epithelium, supporting the regeneration and maintenance of olfactory neurons. PRP has shown potential in peripheral nerve regeneration by promoting vascular and axonal growth through growth factors and modulating inflammatory responses in the microenvironment. Cerebrolysin and PEA–LUT provide neuroprotection and modulate neuroinflammation, thus preserving and restoring olfactory function. Overall, these treatments exhibit anti-inflammatory, regenerative, and neuroprotective activities against COVID-19-induced anosmia. Full article ">Figure 4
Biosynthetic pathways and interactions of omega-3 and omega-6 fatty acids and their derivatives. Omega-3 and omega-6 fatty acids interact competitively and follow intricate biosynthetic pathways. In terms of omega-3 fatty acids, alpha-linolenic acid undergoes desaturation and elongation to be converted into eicosapentaenoic acid (EPA). As a precursor for series-3 thromboxanes (TXs), series-3 prostaglandins (PGs), series-5 leukotrienes (LTs), and resolvins, EPA is vital to anti-inflammatory and pro-resolving activities. EPA can be further converted into docosahexaenoic acid, another substance that acts as a precursor for resolvins and maresins and plays a crucial role in resolving inflammation and maintaining cellular homeostasis. Contrarily, linoleic acid, an essential omega-6 fatty acid, is metabolized into γ-linolenate and finally, arachidonic acid (AA). AA plays an important role in the production of series-2 PG, series-2 TX, and series-4 LT, which contribute to proinflammatory responses and immune responses. As omega-3 and omega-6 fatty acids compete for the same desaturase enzymes, this highlights the importance of maintaining a balanced diet. These fatty acids are essential in modulating inflammation processes and promoting overall health. Excessive intake of omega-6 fatty acids relative to omega-3 fatty acids can exacerbate inflammation and associated health disorders. Therefore, understanding the interaction of these metabolic pathways is pivotal for maintaining a healthy and anti-inflammatory state. Full article ">Figure 5
Omega-3 polyunsaturated fatty acids (PUFAs) exert anti-inflammatory effects by regulating a variety of immune cells. Omega-3 PUFAs are essential nutrients that serve as precursors to lipid mediators, including resolvins, protectins, and maresins, collectively known as “specialized pro-resolving mediators (SPMs).” These mediators play a pivotal role in resolving inflammation through multiple mechanisms. In neutrophils, SPMs inhibit adhesion, chemotaxis, and recruitment while enhancing the removal of apoptotic cells, thereby preventing further tissue damage. In macrophages, SPMs decrease the production of the proinflammatory cytokine TNF-α, increase phagocytosis, and promote migration and adhesion, thereby facilitating neutrophil clearance. As for natural killer (NK) cells, SPMs increase the NK cell-mediated apoptosis of eosinophils and neutrophils, a noninflammatory mechanism for cell removal from tissues, consequently promoting the resolution of an inflammatory response. In addition, SPMs regulate innate lymphoid cell type 2 (ILC2) by decreasing the secretion of proinflammatory cytokines, such as IL-5, IL-13, and IL-33. Through several intricate mechanisms, they prevent further recruitment of immune cells to the site of inflammation, effectively curbing the influx of leukocytes that can exacerbate tissue damage. Moreover, SPMs promote the sequestration of proinflammatory cytokines, interrupting the signaling pathways that perpetuate the inflammation response. In addition to these anti-inflammatory actions, SPMs enhance the clearance of apoptotic cells and cellular debris. This process is crucial for preventing secondary necrosis, which can lead to chronic inflammation and further tissue injury. Together, these actions help restore tissue homeostasis during the resolution of inflammation and facilitate the restoration of normal tissue architecture and function. Full article ">Figure 6
Biomolecular mechanisms of polyunsaturated fatty acid (PUFA) treatment for coronavirus disease 2019 (COVID-19)-induced anosmia. PUFAs are essential for maintaining optimal neurotransmission and facilitating rapid, precise information transfer across the nervous system. They achieve this by regulating the availability of synaptic vesicles at presynaptic terminals. Meanwhile, the dysregulation of the transient receptor potential vanilloid (TRPV) channels may lead to anosmia. Within the olfactory epithelium, PUFAs modulate the function and responsiveness of TRPV1 and TRPV4 channels in olfactory receptor cells and basal cells, respectively. This modulation is crucial, as TRPV channels play a pivotal role in sensory perception and neuronal excitability within the olfactory system. Furthermore, PUFAs exhibit significant anti-inflammatory properties that provide neuroprotective benefits by alleviating neuroinflammation and preventing neural injury, which are vital in combating anosmia, particularly in conditions such as COVID-19. The dual role of PUFAs in regulating inflammation and neuronal excitability in the olfactory epithelium helps maintain both the structural integrity and functional capabilities of the olfactory system. This regulation supports the potential recovery and restoration of olfactory function, highlighting PUFAs as promising treatments for olfactory disorders. Full article ">

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