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Search Results (7,003)

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18 pages, 1049 KiB  
Review
Hypertension: A Continuing Public Healthcare Issue
by Samaneh Goorani, Somaye Zangene and John D. Imig
Int. J. Mol. Sci. 2025, 26(1), 123; https://doi.org/10.3390/ijms26010123 (registering DOI) - 26 Dec 2024
Abstract
Hypertension is a cardiovascular disease defined by an elevated systemic blood pressure. This devastating disease afflicts 30–40% of the adult population worldwide. The disease burden for hypertension is great, and it greatly increases the risk of cardiovascular morbidity and mortality. Unfortunately, there are [...] Read more.
Hypertension is a cardiovascular disease defined by an elevated systemic blood pressure. This devastating disease afflicts 30–40% of the adult population worldwide. The disease burden for hypertension is great, and it greatly increases the risk of cardiovascular morbidity and mortality. Unfortunately, there are a myriad of factors that result in an elevated blood pressure. These include genetic factors, a sedentary lifestyle, obesity, salt intake, aging, and stress. Although lifestyle modifications have had limited success, anti-hypertensive drugs have been moderately effective in lowering blood pressure. New approaches to control and treat hypertension include digital health tools and compounds that activate the angiotensin receptor type 2 (AT2), which can promote cardiovascular health. Nonetheless, research on hypertension and its management is vital for lessening the significant health and economic burden of this condition. Full article
(This article belongs to the Special Issue Recent Research on Hypertension and Related Complications)
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Figure 1
<p>Hypertension considerations in different organs; high blood pressure affects all other organs of the body by affecting the cardiovascular and sympathetic nervous system. <b>Left Panel:</b> Major mechanisms controlling blood pressure are the renin–angiotensin–aldosterone system, kidney sodium retention, vasoconstriction and total peripheral resistance, and heart contractility and cardiac output. Hypertension can damage major organs, such as the kidney, brain, arteries, eyes, and heart. <b>Right Panel:</b> Environmental and genetic factors lead to increased sympathetic activity, which act on the kidneys, the adrenal gland, and the heart to increase blood pressure, resulting in hypertension. Created with BioRender.com.</p>
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<p>Classes of anti-hypertensive drugs affect blood pressure reduction through different pathways. There are six classes of anti-hypertensive drugs: calcium channel blockers (CCBs), beta-blockers, angiotensin receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACE), diuretics, and alpha blockers. Anti-hypertensive drugs act on the heart, small resistance arteries, and kidney to decrease total peripheral resistance (TPR) and cardiac output. Created with BioRender.com.</p>
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<p>The specific living conditions of individuals influence the occurrence and intensity of hypertension. Factors contributing to hypertension, including stress, high salt intake, and smoking, appear on the left side in red. Other factors contributing to hypertension are provided on the right side in blue, which includes chronic kidney disease, medications, pregnancy, and adrenal tumors. Created with BioRender.com.</p>
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13 pages, 695 KiB  
Review
Stroke in Athletes with Atrial Fibrillation: A Narrative Review
by Joana Certo Pereira, Maria Rita Lima, Francisco Moscoso Costa, Daniel A. Gomes, Sérgio Maltês, Gonçalo Cunha, Hélder Dores and Pedro Adragão
Diagnostics 2025, 15(1), 9; https://doi.org/10.3390/diagnostics15010009 - 25 Dec 2024
Abstract
Atrial fibrillation (AF) is the most common sustained arrhythmia, linked with a significantly heightened risk of stroke. While moderate exercise reduces AF risk, high-level endurance athletes paradoxically exhibit a higher incidence. However, their stroke risk remains uncertain due to their younger age, higher [...] Read more.
Atrial fibrillation (AF) is the most common sustained arrhythmia, linked with a significantly heightened risk of stroke. While moderate exercise reduces AF risk, high-level endurance athletes paradoxically exhibit a higher incidence. However, their stroke risk remains uncertain due to their younger age, higher cardiovascular fitness, and lower rate of comorbidities. Several key studies highlight that AF may increase the risk of stroke in endurance athletes, particularly those over 65. However, the overall risk within this population remains relatively low. Notably, older male athletes show a higher AF incidence but experience lower stroke risk than their non-athletic counterparts. Regular physical activity prior to a first stroke appears to reduce mortality, though recurrent stroke risk in athletes with AF mirrors that of non-athletes, despite an elevated AF incidence. Management of AF in athletes is complex, with limited evidence guiding anti-thrombotic strategies. In this setting, specific recommendations are sparse, particularly in sports where bleeding risk is heightened. Individualized management, emphasizing shared decision-making, is critical to balance stroke prevention with athletic performance. Rhythm control strategies, such as catheter ablation, may be a reasonable first-line treatment option for athletes, particularly in those desiring to avoid long-term medication. This review synthesizes the current literature on the incidence, predictors, and management of stroke in athletes with AF. Full article
(This article belongs to the Special Issue Diagnosis and Management of Arrhythmias)
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<p>Relationship between exercise, AF, and stroke.</p>
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14 pages, 2501 KiB  
Article
Urolithin A Modulates PER2 Degradation via SIRT1 and Enhances the Amplitude of Circadian Clocks in Human Senescent Cells
by Rassul Kuatov, Jiro Takano, Hideyuki Arie, Masaru Kominami, Norifumi Tateishi, Ken-ichi Wakabayashi, Daisuke Takemoto, Takayuki Izumo, Yoshihiro Nakao, Wataru Nakamura, Kazuyuki Shinohara and Yasukazu Nakahata
Nutrients 2025, 17(1), 20; https://doi.org/10.3390/nu17010020 - 25 Dec 2024
Abstract
Background/Objectives: Circadian clocks are endogenous systems that regulate numerous biological, physiological, and behavioral events in living organisms. Aging attenuates the precision and robustness of circadian clocks, leading to prolonged and dampened circadian gene oscillation rhythms and amplitudes. This study investigated the effects of [...] Read more.
Background/Objectives: Circadian clocks are endogenous systems that regulate numerous biological, physiological, and behavioral events in living organisms. Aging attenuates the precision and robustness of circadian clocks, leading to prolonged and dampened circadian gene oscillation rhythms and amplitudes. This study investigated the effects of food-derived polyphenols such as ellagic acid and its metabolites (urolithin A, B, and C) on the aging clock at the cellular level using senescent human fibroblast cells, TIG-3 cells. Methods: Lentivirus-infected TIG-3 cells expressing Bmal1-luciferase were used for real-time luciferase monitoring assays. Results: We revealed that urolithins boosted the amplitude of circadian gene oscillations at different potentials; urolithin A (UA) amplified the best. Furthermore, we discovered that UA unstabilizes PER2 protein while stabilizing SIRT1 protein, which provably enhances BMAL1 oscillation. Conclusions: The findings suggest that urolithins, particularly UA, have the potential to modulate the aging clock and may serve as therapeutic nutraceuticals for age-related disorders associated with circadian dysfunction. Full article
(This article belongs to the Section Nutrition and Public Health)
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<p>Effects of ellagic acid and urolithin A on the circadian clock of senescent cells. (<b>A</b>) Representative circadian oscillation patterns of DMSO-, ellagic acid (EA; 33.1 μM)-, or urolithin A (UA; 13.1 μM)-treated luciferase driven by <span class="html-italic">Bmal1</span> promoter were shown. (<b>B</b>,<b>C</b>) The period lengths and relative amplitudes were analyzed by the cosinor method using the data from (<b>A</b>). Each sample number was 6 or 7. The value of DMSO was set to 1 for the relative amplitude. ANOVA followed by Dunnett’s post-hoc test was analyzed. Statistical significance compared with the control “DMSO” is indicated as * <span class="html-italic">p</span> &lt; 0.05, or ** <span class="html-italic">p</span> &lt; 0.005.</p>
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<p>Effects of ellagic acid and urolithin A on the circadian clock of proliferative cells. (<b>A</b>) Representative circadian oscillation patterns of DMSO-, EA (33.1 μM)-, or UA (30 μM)-treated luciferase driven by <span class="html-italic">Bmal1</span> promoter were shown. (<b>B</b>,<b>C</b>) The period lengths and relative amplitudes were analyzed by the cosinor method using the data from (<b>A</b>). Each sample number was 5 or 6. The value of DMSO was set to 1 for the relative amplitude. ANOVA followed by Dunnett’s post-hoc test was analyzed. Statistical significance compared with the control “DMSO” is indicated as *** <span class="html-italic">p</span> &lt; 0.001.</p>
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<p>Effects of EA and its derivatives on the circadian clock of senescent cells. (<b>A</b>) Ellagic acid and its metabolites are shown. (<b>B</b>) Representative circadian oscillation patterns of EA-, UA-, UB, or UC-treated luciferase driven by <span class="html-italic">Bmal1</span> promoter were shown. (<b>C</b>) Amplitudes were analyzed with the cosinor method using the data from (<b>B</b>), and the amplitude of 0 mM for each metabolite was set to 1. Each sample number was 5 to 8. Values are presented as the mean ± SEM. ANOVA followed by Dunnett’s post-hoc test was analyzed. Statistical significance compared with the control “0” is indicated as * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, or *** <span class="html-italic">p</span> &lt; 0.001.</p>
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<p>Effects of UA on the circadian clock gene expressions in senescent cells. Circadian gene expression levels after the UA treatment were quantified by qPCR. Each sample was normalized by the amount of <span class="html-italic">18S rRNA</span>. Each gene expression level in DMSO was set to 1. Each sample number was 5 to 9. Values are presented as the mean ± SEM. The Student’s two-tailed <span class="html-italic">t</span>-tests were performed. Statistical significance compared with the control “DMSO” is indicated as * <span class="html-italic">p</span> &lt; 0.05.</p>
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<p>Effects of UA on Per2 protein stability in senescent cells. (<b>A</b>) The protein stability of luciferase-fused Per2 protein (Per2-luc) or luciferase alone (luc) was measured using the real-time monitoring system. (<b>B</b>) Effects of UA on protein stability were analyzed. Values indicate the percentages of t<sub>1/2</sub> of the UA-treated condition divided by t<sub>1/2</sub> of the DMSO-treated condition. Each sample number was 4. Values are presented as the mean ± SEM. The Student’s two-tailed <span class="html-italic">t</span>-tests were performed. Statistical significance compared with the control “luc” is indicated as ** <span class="html-italic">p</span> &lt; 0.01.</p>
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<p>Effects of UA on Sirt1 amount in senescent cells. (<b>A</b>) <span class="html-italic">SIRT1</span> expression levels after the UA treatment were quantified by qPCR. Samples were normalized by the amount of <span class="html-italic">18S rRNA</span>. <span class="html-italic">SIRT1</span> expression level in DMSO was set to 1. The sample numbers were 9. Values are presented as the mean ± SEM. The Student’s two-tailed <span class="html-italic">t</span>-tests were performed. Statistical significance compared with the control “DMSO” is indicated as ** <span class="html-italic">p</span> &lt; 0.01. (<b>B</b>) SIRT1 (upper panel) and a-TUBLIN (bottom panel) protein levels under indicated conditions were detected. The arrowhead indicates non-specific bands.</p>
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<p>Scheme of how UA amplifies circadian gene expression in senescent cells. UA treatment increases the SIRT1 protein amount, which may promote its deacetylation activity and subsequent degradation of PER2, thereby releasing CLOCK/BMAL1 repression by PER/CRY. This enhances oscillatory <span class="html-italic">REV-ERB</span> and thereby <span class="html-italic">BMAL1</span> gene expression.</p>
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39 pages, 3056 KiB  
Review
Green Silver Nanoparticles: An Antibacterial Mechanism
by Ekaterina O. Mikhailova
Antibiotics 2025, 14(1), 5; https://doi.org/10.3390/antibiotics14010005 - 25 Dec 2024
Abstract
Silver nanoparticles (AgNPs) are a promising tool in the fight against pathogenic microorganisms. “Green” nanoparticles are especially valuable due to their environmental friendliness and lower energy consumption during production, as well as their ability to minimize the number of toxic by-products. This review [...] Read more.
Silver nanoparticles (AgNPs) are a promising tool in the fight against pathogenic microorganisms. “Green” nanoparticles are especially valuable due to their environmental friendliness and lower energy consumption during production, as well as their ability to minimize the number of toxic by-products. This review focuses on the features of AgNP synthesis using living organisms (bacteria, fungi, plants) and the involvement of various biological compounds in this process. The mechanism of antibacterial activity is also discussed in detail with special attention given to anti-biofilm and anti-quorum sensing activities. The toxicity of silver nanoparticles is considered in light of their further biomedical applications. Full article
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<p>Biosynthesis of AgNPs. (<b>a</b>) reduction by different biological sources; (<b>b</b>) nanoparticle’s growth; (<b>c</b>) stabilization and capping by plant, fungal or bacterial compounds.</p>
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<p>The biosynthesis of AgNPs in bacteria with the participation of NADH-dependent reductase.</p>
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<p>Capping agents from different biological sources.</p>
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<p>The proposal mechanism of AgNP antibacterial activity.</p>
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<p>Antibacterial activity of AgNPs. The AgNPs source is indicated by a dot (•).</p>
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17 pages, 293 KiB  
Review
Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA): A Targeted Antioxidant Strategy to Counter Oxidative Stress in Retinopathy
by Marco Zeppieri, Caterina Gagliano, Fabiana D’Esposito, Mutali Musa, Irene Gattazzo, Maria Sole Zanella, Federico Bernardo Rossi, Alessandro Galan and Silvia Babighian
Antioxidants 2025, 14(1), 6; https://doi.org/10.3390/antiox14010006 - 24 Dec 2024
Abstract
Omega-3 fatty acids are critical components of cell membranes, including those in the retina. Specifically, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the primary omega-3 fatty acids that have been studied for their potential benefits in retinal health, preventing the progression of [...] Read more.
Omega-3 fatty acids are critical components of cell membranes, including those in the retina. Specifically, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the primary omega-3 fatty acids that have been studied for their potential benefits in retinal health, preventing the progression of retinopathy. Several studies have shown that a higher intake of omega-3 fatty acids is associated with a lower risk of developing diabetic retinopathy and age-related macular degeneration (AMD). Reviewing clinical trials and observational studies that support the protective role of omega-3s in retinal disorders is essential. This comprehensive review aims to evaluate the current literature on the role of omega-3 fatty acids, exploring their mechanisms of action and anti-inflammatory, anti-angiogenic, and neuroprotective roles in the retina. Omega-3s have been shown to inhibit abnormal blood vessel growth in the retina, which is a significant factor in proliferative diabetic retinopathy and neovascular AMD. Furthermore, omega-3 fatty acids are often studied with other nutrients, such as lutein, zeaxanthin, and vitamins, for their synergistic effects on retinal health. Reviewing these combinations can help understand how omega-3s can be part of a comprehensive approach to preventing or treating retinopathies, especially in diabetic patients. This review emphasizes the preventive function of EPA and DHA in alleviating oxidative stress-related damage in retinal diseases, concentrating on their antioxidative mechanisms. Full article
(This article belongs to the Special Issue Antioxidants and Retinal Diseases—2nd Edition)
26 pages, 2683 KiB  
Review
Imaging in Periprosthetic Joint Infection Diagnosis: A Comprehensive Review
by Armin Hoveidaei, Yasaman Tavakoli, Mohammad Reza Ramezanpour, Mahyaar Omouri-kharashtomi, Seyed Pouya Taghavi, Amir Human Hoveidaei and Janet D. Conway
Microorganisms 2025, 13(1), 10; https://doi.org/10.3390/microorganisms13010010 - 24 Dec 2024
Abstract
Various imaging methods assist in diagnosing periprosthetic joint infection (PJI). These include radiological techniques such as radiography, computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound (US); as well as advanced nuclear medicine techniques including bone scintigraphy (BS), anti-granulocyte antibody imaging (AGS), leukocyte [...] Read more.
Various imaging methods assist in diagnosing periprosthetic joint infection (PJI). These include radiological techniques such as radiography, computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound (US); as well as advanced nuclear medicine techniques including bone scintigraphy (BS), anti-granulocyte antibody imaging (AGS), leukocyte scintigraphy (LS), and fluorodeoxyglucose positron emission tomography (FDG-PET and FDG-PET/CT). Each imaging technique and radiopharmaceutical has been extensively studied, with unique diagnostic accuracy, limitations, and benefits for PJI diagnosis. This review aims to detail and describe the most commonly used imaging techniques and radiopharmaceuticals for evaluating PJI, focusing particularly on knee and hip arthroplasties. Full article
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<p>X-ray of PJI after hip arthroplasty; X-ray shows lytic lesions surrounding the femoral component (arrows) [<a href="#B50-microorganisms-13-00010" class="html-bibr">50</a>].</p>
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<p>US of PJI after hip arthroplasty; US shows thick fluid collections (C) surrounding the femoral component of the hip prosthesis (arrow) [<a href="#B50-microorganisms-13-00010" class="html-bibr">50</a>].</p>
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<p>CT scans demonstrate fluid collection and increased density around diseased bone with a prosthetic implant, as well as swelling and hyperdensity of soft tissues due to edema [<a href="#B68-microorganisms-13-00010" class="html-bibr">68</a>].</p>
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<p>MRI of PJI after hip arthroplasty; MRI imaging reveals layering (white arrow) and synovial hyperintensity, indicating an infection. Femoral bone marrow (a black, thin arrow) and muscle edema (black thick arrow) suggest periprosthetic stress reaction [<a href="#B80-microorganisms-13-00010" class="html-bibr">80</a>].</p>
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<p>(<b>A</b>) BS of PJI after hip arthroplasty. This BS shows irregularly increasing radiopharmaceutical buildup around the femoral component of a prosthesis. (<b>B</b>–<b>D</b>) On the flow and blood pool pictures, there is diffuse hyperperfusion and hyperemia around the prosthesis, as well as diffusely enhanced periprosthetic radiopharmaceutical on the delayed bone image. (<b>B</b>) Flow; (<b>C</b>) Blood pool; (<b>D</b>) Bone. [<a href="#B87-microorganisms-13-00010" class="html-bibr">87</a>].</p>
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<p>LS of PJI. Delayed images, (<b>A</b>) anterior and (<b>B</b>) posterior view, late images, (<b>C</b>) anterior and (<b>D</b>) posterior view. The increase in intensity and size between the delayed and late photos suggests a PJI [<a href="#B68-microorganisms-13-00010" class="html-bibr">68</a>].</p>
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<p>FDG-PET/CT of PJI after hip arthroplasty [<a href="#B68-microorganisms-13-00010" class="html-bibr">68</a>].</p>
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26 pages, 1014 KiB  
Article
Evaluation of Selected Pro- and Anti-Inflammatory Adipokines in Colostrum from Mothers with Gestational Diabetes Mellitus
by Jolanta Lis-Kuberka, Marta Berghausen-Mazur and Magdalena Orczyk-Pawiłowicz
Int. J. Mol. Sci. 2025, 26(1), 40; https://doi.org/10.3390/ijms26010040 - 24 Dec 2024
Abstract
Adipokines related to gestational diabetes mellitus (GDM) are an emerging area of interest. The aim of this study was to evaluate the associations between GDM and adipokine levels in human milk. This was an observational cohort study targeting mothers with gestational diabetes, which [...] Read more.
Adipokines related to gestational diabetes mellitus (GDM) are an emerging area of interest. The aim of this study was to evaluate the associations between GDM and adipokine levels in human milk. This was an observational cohort study targeting mothers with gestational diabetes, which evaluated the association of maternal hyperglycemia severity, classified as GDM-G1 (diet treatment) and GDM-G2 (insulin treatment), with colostral adipokines involved in pro- and anti-inflammatory processes. Colostrum was collected from hyperglycemic (N = 34) and normoglycemic (N = 26) mothers, and adipokine levels were determined by immunoenzymatic assay. Among anti-inflammatory adipokines, only for irisin and vaspin, but not for obestatin and adropin, were significantly different levels noted between the GDM-G1, GDM-G2 and non-GDM cohorts. Colostrum of the GDM-G2 subgroup contained more vaspin (4.77 ng/mL) than that of normoglycemic mothers (3.12 ng/mL) and more irisin (26.95 μg/mL) than in the GDM-G1 subgroup (17.59 μg/mL). The levels of pro-inflammatory adipokines, namely, dermcidin, chemerin and visfatin, were at similar levels irrespective of maternal glycemia. Moreover, irisin showed a negative correlation with dermcidin in GDM-G2 and non-GDM cohorts. Associations were observed between colostral irisin and maternal preconception BMI, dermcidin and gestational age, and vaspin and maternal age. This study provides evidence that the way of restoring glucose homeostasis in pregnant women has an impact on the anti-inflammatory adipokines irisin and vaspin, but not on obestatin and adropin. GDM, regardless of severity, did not influence the colostral pro-inflammatory adipokines visfatin, chemerin and dermcidin. Full article
(This article belongs to the Special Issue Molecular Advances in Gestational Diabetes Mellitus)
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<p>Comparison of irisin (<b>A</b>), adropin (<b>B</b>), obestatin (<b>C</b>), visfatin (<b>D</b>), vaspin (<b>E</b>), chemerin (<b>F</b>) and dermcidin (<b>G</b>) concentrations in colostrum between gestational diabetic (G1 and G2) and normoglycemic (non-GDM) mothers. Data are given as mean and median values and 25th and 75th quartiles. A <span class="html-italic">p</span>-value lower than 0.05 was regarded as significant.</p>
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<p>Correlations between the concentration of adipokine in milk collected from GDM and non-GDM mothers and day of lactation, age, preconceptional BMI, and week of gestation. The Spearman correlation coefficient is represented in the heat map following the color in the legend. BMI—preconceptional body mass index; HBD—week of gestation. Bold frames represent correlations with statistical significance (<span class="html-italic">p</span> &lt; 0.05).</p>
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29 pages, 6039 KiB  
Article
Innovative Solid Lipid Nanoparticle-Enriched Hydrogels for Enhanced Topical Delivery of L-Glutathione: A Novel Approach to Anti-Ageing
by Mengyang Liu, Manisha Sharma, Guoliang Lu, Zhiwen Zhang, Wenting Song and Jingyuan Wen
Pharmaceutics 2025, 17(1), 4; https://doi.org/10.3390/pharmaceutics17010004 - 24 Dec 2024
Abstract
Background: Skin ageing, driven predominantly by oxidative stress from reactive oxygen species (ROS) induced by environmental factors like ultraviolet A (UVA) radiation, accounts for approximately 80% of extrinsic skin damage. L-glutathione (GSH), a potent antioxidant, holds promise in combating UVA-induced oxidative stress. However, [...] Read more.
Background: Skin ageing, driven predominantly by oxidative stress from reactive oxygen species (ROS) induced by environmental factors like ultraviolet A (UVA) radiation, accounts for approximately 80% of extrinsic skin damage. L-glutathione (GSH), a potent antioxidant, holds promise in combating UVA-induced oxidative stress. However, its instability and limited penetration through the stratum corneum hinder its topical application. This study introduces a novel solid lipid nanoparticle (SLN)-enriched hydrogel designed to enhance GSH stability, skin penetration, and sustained release for anti-ageing applications. Methods: GSH-loaded SLNs were prepared via a double-emulsion technique and optimized using factorial design. These SLNs were incorporated into 1–3% (w/v) Carbopol hydrogels to produce a semi-solid formulation. The hydrogel’s characteristics, including morphology, mechanical and rheological properties, drug release, stability, antioxidant activity, cytotoxicity, and skin penetration, were evaluated. Results: SEM and FTIR confirmed the uniform dispersion of SLNs within the hydrogel. The formulation exhibited desirable properties, including gel strength (5.1 ± 0.5 g), spreadability (33.6 ± 1.9 g·s), pseudoplasticity, and elasticity. In vitro studies revealed a biphasic GSH release profile, with sustained release over 72 h and over 70% cumulative release. The hydrogel significantly improved antioxidant capacity, protecting human fibroblasts from UVA-induced oxidative stress and enhancing cell viability. Stability studies indicated that 4 °C was optimal for storage over three months. Notably, the hydrogel enhanced GSH penetration through the stratum corneum by 3.7-fold. Conclusions: This SLN-enriched hydrogel effectively improves GSH topical delivery and antioxidant efficacy, providing a promising platform for anti-ageing and other bioactive compounds with similar delivery challenges. Full article
(This article belongs to the Special Issue Advances in Delivery of Peptides and Proteins)
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<p>The SEM image of dry GSH-SLN-EH (where the black area is the mesh size of dry cross-linked hydrogels).</p>
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<p>FTIR spectra of GSH, GSH-SLN dry powder, gelling polymers (Carbopol 971), GSH -SLN-EH, and dry GSH-SLN-EH.</p>
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<p>Gel strength (positive peak), adhesion (negative area), and stickiness (negative peak) of (<b>a</b>) commercial control gel; (<b>b</b>) GSH-SLN-EH with 1% (<span class="html-italic">w</span>/<span class="html-italic">v</span>) Carbopol 971 inside; (<b>c</b>) GSH-SLN-EH with 3% (<span class="html-italic">w</span>/<span class="html-italic">v</span>) Carbopol 971 inside; and (<b>d</b>) GSH-SLN-EH with 5% (<span class="html-italic">w</span>/<span class="html-italic">v</span>) Carbopol 971 inside.</p>
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<p>Gel spreadability (positive peak area) of (<b>a</b>) commercial control gel; (<b>b</b>) GSH-SLN-EH with 1% (<span class="html-italic">w</span>/<span class="html-italic">v</span>) Carbopol 971 inside; (<b>c</b>) GSH-SLN-EH with 3% (<span class="html-italic">w</span>/<span class="html-italic">v</span>) Carbopol 971 inside; and (<b>d</b>) GSH-SLN-EH with 5% (<span class="html-italic">w</span>/<span class="html-italic">v</span>) Carbopol 971 inside.</p>
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<p>Rheograms of four tested gels. (<b>a</b>) Merino<sup>®</sup> 97% Pure Aloe Vera Gel (control); (<b>b</b>) GSH-SLN-EH with 1% (<span class="html-italic">w</span>/<span class="html-italic">v</span>) Carbopol 971; (<b>c</b>) GSH-SLN-EH with 3% (<span class="html-italic">w</span>/<span class="html-italic">v</span>) Carbopol 971; (<b>d</b>) GSH-SLN-EH with 5% (<span class="html-italic">w</span>/<span class="html-italic">v</span>) Carbopol 971.</p>
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<p>Viscograms of four tested gels. (<b>a</b>) Merino<sup>®</sup> 97% Pure Aloe Vera Gel (control); (<b>b</b>) GSH-SLN-EH with 1% (<span class="html-italic">w</span>/<span class="html-italic">v</span>) Carbopol 971 inside; (<b>c</b>) GSH-SLN-EH with 3% (<span class="html-italic">w</span>/<span class="html-italic">v</span>) Carbopol 971 inside; (<b>d</b>) GSH-SLN-EH with 5% (<span class="html-italic">w</span>/<span class="html-italic">v</span>) Carbopol 971 inside.</p>
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<p>Influence of oscillation rate on both storage and loss modulus in Merino<sup>®</sup> 97% Pure Aloe Vera Gel.</p>
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<p>Influence of oscillation rate on both storage and loss modulus in GSH-SLN-EH with 1% (<span class="html-italic">w</span>/<span class="html-italic">v</span>) Carbopol 971 inside.</p>
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<p>Influence of oscillation rate on both storage and loss modulus in GSH-SLN-EH with 3% (<span class="html-italic">w</span>/<span class="html-italic">v</span>) Carbopol 971 inside.</p>
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<p>Influence of oscillation rate on both storage and loss modulus in GSH-SLN-EH with 5% (<span class="html-italic">w</span>/<span class="html-italic">v</span>) Carbopol 971 inside.</p>
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<p>Release profiles of all samples of GSH, namely GSH solution, GSH-loaded hydrogels, GSH-SLN suspension, and GSH-SLN-EH with and without additional GSH in hydrogels (Mean ± S.D. n = 3).</p>
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<p>Release profiles of (<b>a</b>) GSH hydrogels; (<b>b</b>) GSH-SLN suspension; (<b>c</b>) GSH-SLN-EH without additional GSH in hydrogels; (<b>d</b>) GSH-SLN-EH with additional GSH in hydrogels compared with GSH solution (Mean ± S.D. n = 3).</p>
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<p>The microscopic images of Fbs cells after 72 h. (<b>a</b>) Fbs cells without any GSH formulations; (<b>b</b>) Fbs cells treated with GSH solution; (<b>c</b>) Fbs cells treated with GSH-SLN suspension; (<b>d</b>) Fbs cells treated with GSH-SLN-EH.</p>
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<p>Effect of three formulations of GSH on the Fbs cell viability. Cells were incubated for 24, 48, and 72 h; control is cell culture medium only without any treatment of GSH (<span class="html-italic">p</span> value ˂ 0.05) (Mean ± SD, n = 5).</p>
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<p>The micrographs of two control groups of Fbs cells, treated without (<b>a</b>) and with (<b>b</b>) UVA irradiation after culture for 72 h; the black circles in figure b represent dead Fbs cells.</p>
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<p>The micrographs of Fbs cells treated with a half hour of UVA irradiation after 72 h. (<b>a</b>) Fbs cells without any GSH formulations; (<b>b</b>) Fbs cells treated with GSH solution; (<b>c</b>) Fbs cells treated with GSH-SLN suspension; (<b>d</b>) Fbs cells treated with GSH-SLN-EH.</p>
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<p>Cytoprotective effects of GSH formulations at three time intervals (24, 48, and 72 h). The control group (2) was exposed to UVA irradiation without GSH treatment. Cell viability increased significantly for all GSH formulations (<span class="html-italic">p</span> value &lt; 0.05) (Mean ± SD, n = 5).</p>
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<p>Cumulative permeation data for GSH solution, GSH-SLN, GSH-hydrogel, and GSH-SLN-EH formulations over 48 h (Mean ± S.D., n = 3).</p>
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<p>Human skin deposition of GSH in SC and epi/dermis layers for five formulations after 48 h: GSH solution, GSH-SLNs, GSH-hydrogels, and GSH-SLN-EH with and without additional GSH in hydrogels, respectively (Mean ± S.D., n = 3).</p>
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34 pages, 7313 KiB  
Review
Sodium Thiosulfate: An Innovative Multi-Target Repurposed Treatment Strategy for Late-Onset Alzheimer’s Disease
by Melvin R. Hayden and Neetu Tyagi
Pharmaceuticals 2024, 17(12), 1741; https://doi.org/10.3390/ph17121741 - 23 Dec 2024
Abstract
Late-onset Alzheimer’s disease (LOAD) is a chronic, multifactorial, and progressive neurodegenerative disease that associates with aging and is highly prevalent in our older population (≥65 years of age). This hypothesis generating this narrative review will examine the important role for the use of [...] Read more.
Late-onset Alzheimer’s disease (LOAD) is a chronic, multifactorial, and progressive neurodegenerative disease that associates with aging and is highly prevalent in our older population (≥65 years of age). This hypothesis generating this narrative review will examine the important role for the use of sodium thiosulfate (STS) as a possible multi-targeting treatment option for LOAD. Sulfur is widely available in our environment and is responsible for forming organosulfur compounds that are known to be associated with a wide range of biological activities in the brain. STS is known to have (i) antioxidant and (ii) anti-inflammatory properties; (iii) chelation properties for calcium and the pro-oxidative cation metals such as iron and copper; (iv) donor properties for hydrogen sulfide production; (v) possible restorative properties for brain endothelial-cell-derived bioavailable nitric oxide. Thus, it becomes apparent that STS has the potential for neuroprotection and neuromodulation and may allow for an attenuation of the progressive nature of neurodegeneration and impaired cognition in LOAD. STS has been successfully used to prevent cisplatin oxidative-stress-induced ototoxicity in the treatment of head and neck and solid cancers, cyanide and arsenic poisoning, and fungal skin diseases. Most recently, intravenous STS has become part of the treatment plan for calciphylaxis globally due to vascular calcification and ischemia-induced skin necrosis and ulceration. Side effects have been minimal with reports of metabolic acidosis and increased anion gap; as with any drug treatment, there is also the possibility of allergic reactions, possible long-term osteoporosis from animal studies to date, and minor side-effects of nausea, headache, and rhinorrhea if infused too rapidly. While STS poorly penetrates the intact blood–brain barrier(s) (BBBs), it could readily penetrate BBBs that are dysfunctional and disrupted to deliver its neuroprotective and neuromodulating effects in addition to its ability to penetrate the blood–cerebrospinal fluid barrier of the choroid plexus. Novel strategies such as the future use of nano-technology may be helpful in allowing an increased entry of STS into the brain. Full article
(This article belongs to the Special Issue Novel Therapeutic Strategies for Alzheimer’s Disease Treatment)
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Figure 1

Figure 1
<p>Late-onset Alzheimer’s disease (LOAD) is a multifactorial neurodegenerative disease with multiple hypotheses and multiple targets (1–12 o’clock on the clock face). Sodium thiosulfate (STS) (red asterisks) is known to target at least five of these 10 targets and, therefore, represents a novel multi-target treatment approach. Note that the positive effects of STS on the vascular hypothesis inclusive of the vascular contributions to impaired cognition and dementia (VCID) and cerebral small vessel disease (SVD) may also improve cerebral blood flow (CBF) and the chronic cerebral hypoperfusion (CCH) and in turn may have a positive effect on mitochondrial function with a decrease in oxidative redox stress (OxRS) (red lines with arrows) with consequent less neuroinflammation. Also, the aging and genetic hypotheses are non-modifiable. Aβ and tau misfolded protein accumulation (green lines with arrows). Aβ, amyloid beta; APOEϵ4, apolipoprotein E epsilon 4; Asterisks, indicate emphasis; Ca++, calcium; CCH, chronic cerebral hypoperfusion; Cu++, copper; Fe++, iron; SNP, single nucleotide polymorphism.</p>
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<p>The scarlet letter A of Alzheimer’s disease in late-onset Alzheimer’s disease (LOAD). Note the dementia quartet mechanisms on the left-hand side of the figure and cerebral small vessel disease (SVD) are linked via LOAD and vascular contribution to cognitive impairment and dementia (VCID). Dementia quartet multifactorial mechanisms include (1) oxidative redox stress; (2) neuroinflammatory; (3) neurovascular; (4) neurodegenerative mechanisms in the development of LOAD. Image provided with permission by CC 4.0 [<a href="#B10-pharmaceuticals-17-01741" class="html-bibr">10</a>]. CMBs, cerebral microbleeds; EPVS, enlarged perivascular spaces; WMH, white matter hyperintensities; VCID, vascular contributions to impaired cognition and dementia; underlining, indicates emphasis.</p>
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<p>Sodium thiosulfate (STS) (Na<sub>2</sub>S<sub>2</sub>O<sub>3</sub>) acts as a chain-breaking antioxidant, and a chelator, and promotes vasodilation in late-onset Alzheimer’s disease (LOAD). Not only does STS act as a potent chain-breaking antioxidant due to its two unpaired electrons, but also STS is capable of generating the endogenous antioxidant, glutathione (GSH), and hydrogen sulfide (H<sub>2</sub>S). Further, STS is also capable of acting as a chelator of cations such as calcium (Ca++), copper (Cu++), and iron (Fe++). Modified image provided with permission by CC 4.0 [<a href="#B24-pharmaceuticals-17-01741" class="html-bibr">24</a>,<a href="#B30-pharmaceuticals-17-01741" class="html-bibr">30</a>]. eNOS, endothelial nitric oxide synthase; GSSG, oxidized GSH; H<sub>2</sub>O, water; H<sub>2</sub>S, hydrogen sulfide; NO, nitric oxide; NVU, neurovascular unit; VSMC, vascular smooth muscle cell.</p>
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<p>Sodium thiosulfate (STS/Na<sub>2</sub>S<sub>2</sub>O<sub>3</sub> may be considered a hydrogen sulfide (H<sub>2</sub>S) donor, which is in equilibrium with the sulfhydryl thiol groups and hydrogen with its proton and unpaired free electron along with STS ability to act as a reducing agent to re-pair the unpaired electrons of damaging free radicals of superoxide, hydrogen peroxide and hydroxyl groups, and peroxinitrite labeled (1–3) in addition to undergoing S-sulfhydration reactions with various proteins. EC, endothelial cell–brain endothelial cell; GSSG, glutathione disulfide or oxidized glutathione (GSH); H, hydrogen; NO, nitric oxide; OxRS, oxidation redox stress; R, amino acid peptide/protein side chain; S, sulfur; VEGFR2, vascular endothelial growth factor receptor 2.</p>
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<p>Impaired folate one-carbon metabolism (FOCM) in late-onset Alzheimer’s disease (LOAD) with hyperhomocystemia (HHCY) as a biomarker interferes with the normal function of the trans-sulfuration pathway in the production of hydrogen sulfide (H<sub>2</sub>S). This illustration demonstrates the normal methionine and folate cycles of normal FOCM and how the impaired FOCM (IFOCM) with HHCY that associates with LOAD impairs the trans-sulfuration pathway with decreased production of H<sub>2</sub>S (lower left panel outlined with red-dashed lines). The trans-sulfuration pathway yields H<sub>2</sub>S (antioxidant/anti-inflammatory, vasorelaxant angiogenic, and a neurotransmitter modulatory molecule, as well as producing the endogenous antioxidant glutathione (GSH). Importantly, HHCY would also impair the production of glutathione (GSH) in addition to depleting GSH due to increased oxidative redox stress. This modified image is provided with permission by CC4.0 [<a href="#B3-pharmaceuticals-17-01741" class="html-bibr">3</a>]. B6, pyridoxal 5′-phosphate; B12, cobalamin; CAT, cysteine aminotransferase; CBS, cystathionine-beta-synthase; CSE, cystathionine gamma lyase (CGL); GCS, glutamate cysteine ligase (gamma-glutamylcysteine synthetase); GS, glutathione synthase; GSH, glutathione; 3MST, 3-mercaptopyruvate sulfurtransferase; MTHFR, methylenetetrahydrofolate; MS, methionine synthase; SAM, S-adenosylmethionine; THF, tetrahydrofolate.</p>
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<p>Multifactorial effects of sodium thiosulfate (STS) and hydrogen sulfide (STS-H<sub>2</sub>S) in the neuroprotection and neuromodulation of late-onset Alzheimer’s disease (LOAD). BBB<b><span class="html-italic">dd</span></b>, blood–brain barrier dysfunction and disruption; BEC<span class="html-italic">act</span>/<span class="html-italic">dys</span>, brain endothelial cell activation and dysfunction; Ca++, calcium; <b><span class="html-italic">cns</span></b>CC, central nervous system cytokines/chemokines; Cu++, copper; eNOS, endothelial-derived nitric oxide synthase; Fe++, iron; Hb, hemoglobin; GSH, glutathione; NO, nitric oxide; NVU, neurovascular unit; OxRS, oxidative redox stress; <b><span class="html-italic">p</span></b>CC, peripherally derived cytokines/chemokines; RBCs, red blood cells; –SH, sulfhydryl thiols; SVD–CMBs, small vessel disease and cerebral microbleeds.</p>
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<p>Aberrant mitochondria (aMt) are a source for multiple damaging reactive oxygen, nitrogen, and sulfur species (RONSS) that comprise the reactive species interactome (RSI). The RSI is a complex network of interactions between reactive species and their biological targets. aMt can be identified due to their hyperlucency, with loss of Mt matrix electron density with fragmentation and loss of cristae. Also note the iron (red), sulfur (yellow)–cysteine (Cys) clusters (ISCs) that are liberated from the aMt in addition to the RONSS as a result of aMt remodeling with the formation of mitochondrial outer membrane (yellow lines) permeabilization (MOMP) (red-dashed line and open arrows) with the creation of leaky Mt that leak ROS, RONSS, and ISCs. Note the insert upper left, which demonstrates a normal healthy Mt with intact ISCs that are maintained within the healthy Mt. Note the mitochondrial outer membrane permeabilization (MOMP): labeled (1) through (3), which allow the contents of the aMt to leak damaging RONSS and ISCs into the cytosol of neurons, allowing oxidative redox stress to damage lipids, proteins, and nucleic acids. Impaired mitophagy allow these leaky aMT to exist and continue to be leaky with damaging reactive species that eventually result in synaptic dysfunction and loss as well as neurodegeneration and impaired cognition. Thus, aMts are an important early and significant finding in the development and progression of LOAD. Revised image provided with permission by CC 4.0 [<a href="#B57-pharmaceuticals-17-01741" class="html-bibr">57</a>]. This image is from the female obese diabetic <span class="html-italic">db</span>/<span class="html-italic">db</span> model at 20 weeks of age, and the insert is from a normal control model. Scale bars = 200 nm. Asterisk, indicates emphasis; ETC, electron transport chain.</p>
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<p>Upstream and downstream inflammatory effects on the development and progression of amyloid beta (Aβ) and tau in neurodegeneration. Upper panel (<b>A</b>) (upstream) depicts the effects of peripheral systemic injurious injuries such as homocysteine and lipopolysaccharides and peripheral cytokines and chemokines (<b><span class="html-italic">p</span></b>CC) and their effects on the neurovascular unit (NVU) that results in brain endothelial cell activation and dysfunction (BEC<span class="html-italic">act</span>/<span class="html-italic">dys</span>) in conjunction with blood–brain barrier dysfunction and disruption (BBB<b><span class="html-italic">dd</span></b>) providing Hit 1 of the 2-Hit vascular hypothesis. Lower panel (<b>B</b>) (below the horizontal dashed line is downstream) depicts the central importance of downstream Aβ and tau misfolded proteins that comprise Hit number 2 of the 2-Hit vascular hypothesis. Importantly, note the activation of microglia cell to reactive microglia cells (rMGCs) depicted on the far left and also the activation of astrocytes to reactive astrocyte (rACs) that are detached and retracted (drACs) from the NVU basement membrane on the far right of this image. Note that the rMGCs in the far-right image of the neurovascular unit appear to be invasive in addition to being attracted to the NVU that associate with detached and retracted drACs. Also, note that this image incorporates the vascular hypothesis in that it depicts hit-1 of Zlokovic’s 2-hit hypothesis in the upstream panel (<b>A</b>) [<a href="#B93-pharmaceuticals-17-01741" class="html-bibr">93</a>,<a href="#B94-pharmaceuticals-17-01741" class="html-bibr">94</a>]. aMT, aberrant mitochondria; BEC N, brain endothelial cell nucleus; CBF, cerebral blood flow; CCH, chronic cerebral hypoperfusion; cnsCC, central nervous system cytokines–chemokines; EC N, brain endothelial cell nucleus; MetS, metabolic syndrome; NFTs, neurofibrillary tangles; Pc N, pericyte nucleus; T2DM, type 2 diabetes mellitus.</p>
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<p>Glutamate excitotoxicity. Image 1 demonstrates a normal presynaptic neuron with multiple neurotransmitter vesicles. Image 2 depicts a blackened postsynaptic degenerative neuron due to glutamate excitotoxicity (open circles, accumulation of glutamate) promoting apoptotic neurodegeneration via excessive calcium and neurotoxicity. Image 3 depicts a transmission electron micrograph of an axon with three aberrant mitochondria (aMt) and myelin splitting. Image 4 depicts a compressed leaky aMt from previous <a href="#pharmaceuticals-17-01741-f007" class="html-fig">Figure 7</a> that is responsible for excessive mtROS and calcium excess. Also, note the 10 steps involved with glutamate excitotoxicity to result in synaptic dysfunction and neurodegeneration as listed in <a href="#pharmaceuticals-17-01741-box002" class="html-boxed-text">Box 2</a>. ATP, adenosine triphosphate; Ca++, calcium; GL, glutamate; Mt or mt, mitochondria; mtROS, mitochondrial reactive oxygen species.</p>
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<p>Late-onset Alzheimer’s disease (LOAD) and the brain injury: response to injury wound healing (BI:RTIWH) mechanism. While LOAD is considered to be a multifactorial disease, its initial injuries may be derived at the level of the brain endothelial cell of the neurovascular unit. However, the initial injury to neurons is thought to arise from the accumulation of misfolded proteins, which includes extracellular neurotoxic oligomers or plaques of amyloid beta (Aβ (1–42)) and intracellular tau neurofibrillary tangle(s) (NFTs) [<a href="#B11-pharmaceuticals-17-01741" class="html-bibr">11</a>,<a href="#B12-pharmaceuticals-17-01741" class="html-bibr">12</a>,<a href="#B13-pharmaceuticals-17-01741" class="html-bibr">13</a>]. There are five basic phases in this BI:RTIWH mechanism that include 1. hemostasis; 2. inflammation; 3. proliferation; 4. remodeling; 5. resolution. Note that only phases 1–4 are shown and that the resolution phase is not included in this illustration because injurious stimuli are not removed in the development and progression of LOAD. Also, note that glutamate excitotoxicity and its subsequent effects leading to neuronal apoptosis and neurodegeneration are in purple color. Modified image provided with permission by CC 4.0 [<a href="#B104-pharmaceuticals-17-01741" class="html-bibr">104</a>]. AC, astrocyte; <span class="html-italic">act</span>, activation; BECs, brain endothelial cells; CAA, cerebral amyloid angiopathy; Ca<sup>2+</sup>, calcium; CC, cytokines and chemokines; CMBs, cerebral microbleeds; CNS, central nervous system; <b><span class="html-italic">cns</span></b>CC, central nervous system cytokines, chemokines; <span class="html-italic">dys</span>, dysfunction; EPVS, enlarged perivascular spaces; lpsEVexos, lipopolysaccharide extracellular vesicle exosomes; MetS, metabolic syndrome; MΦ, macrophage; Mt, mitochondria; <b><span class="html-italic">p</span></b>CC, peripheral cytokines/chemokines; SVD, cerebral small vessel disease; T2DM, type 2 diabetes mellitus.</p>
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<p>Representative cross-section transition electron microscopy (TEM) images of microvessels from various animal models from layer III in the frontal cortex at various magnifications to illustrate (1) precapillary arterioles (far left), true capillaries (center), and postcapillary venules (far right). These images are in contrast to those macrovessels that have a diameter of ≥5 μm with greater than 2 layers of vascular smooth muscle cell(s) (VSMCs) within their media. Note the perivascular space/nano-glymphatic space [pseudo-colored green] far left; the true capillary without a perivascular space (center) and an enlarged perivascular space (yellow double arrows for right). Magnification 3 μm, 0.5 μm, and 5 μm (far left, middle, and far right respectively). Note the upper elongated illustration of the macro- and microvessel pia vessels (arteries and arterioles in red color and vein and venules in blue color) and capillaries that correspond to the lower TEM images (arrows). Modified image provided with permission by CC 4.0 [<a href="#B10-pharmaceuticals-17-01741" class="html-bibr">10</a>]. AC, astrocytes pseudo-colored gold in far-left and pseudo-colored blue far-right images. AQP-4, aquaporin 4; AC, perivascular astrocyte; AC1, AC2, astrocyte endfeet numbers 1 and 2 ACef, perivascular astrocyte endfeet; basement membrane (blue open arrows); CL, capillary lumen; EC, brain endothelial cell; gs, glymphatic space; lys, lysosome; Mt, mitochondria; N, nucleus; NVU, neurovascular unit; Pc, pericyte; PcN, pericyte nucleus; Pcp, pericyte endfeet processes; PVS, perivascular space; rMGC, interrogating or reactive microglia; rMΦ, reactive macrophage; TJ/AJ, tight junctions/adherens junctions.</p>
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<p>True capillary neurovascular unit (NVU) compared to the postcapillary venule perivascular unit (PVU). Protoplasmic perivascular astrocyte endfeet (pvACef) (pseudo-colored blue) within the true capillary (<b>A</b>) represent the creating and connecting ability of these cells, which allow remodeling of the normal PVU (<b>B</b>) and perivascular spaces (PVSs) to remodel into the pathologic enlarged perivascular space (EPV) that measures 1–3 mm on magnetic resonance imaging. (<b>A</b>) schematic illustrates the pseudo-colored blue true capillary neurovascular unit NVU (illustrating the transmission electron microscopic TEM true capillary image in <a href="#pharmaceuticals-17-01741-f011" class="html-fig">Figure 11</a>). Note that when the brain endothelial cells (BECs) become activated and NVU BBB disruption develops, due to BEC activation and dysfunction (BECact/dys) (due to multiple injurious species, which includes peripheral inflammation), there develops an increased permeability of fluids, peripheral cytokines and chemokines, and peripheral immune cells within the neutrophile (N) depicted herein penetrating the tight and adherens junction (TJ/AJ) paracellular spaces to enter the postcapillary venule along with monocytes (Ms) and lymphocytes (Ls) into the postcapillary venule PVS of the PVU B for step one of the two-step process of neuroinflammation. (<b>B</b>) depicts the postcapillary venule that contains the PVU. The PVU includes the normal PVS, which has the capability to remodel to the pathological EPVS. Notably, the proinflammatory leukocytes enter the PVS along with fluids, solutes, and cytokines/chemokines from an activated, disrupted, and leaky NVU in A. Further, note the pvACef (pseudo-colored blue) and its glia limitans (pseudo-colored cyan in the control NVU in (<b>A</b>) to the cyan color with exaggerated thickness for illustrative purposes in (<b>B</b>) that faces and adheres to the NVU BM extracellular matrix and faces the PVS PVU lumen that then becomes pseudo-colored red to denote the development of the EPVSs). Note that the pvACef have detached and separated, which allow for the creation of a perivascular space that transforms to an EPVS. The glia limitans becomes pseudo-colored red once the EPVSs have formed and then become breeched due to activation of matrix metalloproteinases and degradation of the proteins in the glia limitans. This remodeling allows neurotoxins and proinflammatory cells to leak into the interstitial spaces of the neuropil to mix with the ISF and result in neuroinflammation (step two) of the two-step process of neuroinflammation. Note that the dysfunctional pvACef AQP4 water channel is associated with the dysfunctional bidirectional signaling between the neuron (N) and the dysfunctional pvACef AQP4 water channel. Image provided by CC 4.0 [<a href="#B103-pharmaceuticals-17-01741" class="html-bibr">103</a>]. AQP4 = aquaporin 4; asterisk = tight and adherens junction; BBB = blood–brain barrier; BM = both inner (i) and outer (o) basement membrane; dACef and dpvACef = dysfunctional astrocyte endfeet; EC = brain endothelial cell; ecGCx = endothelial glycocalyx; EVPS = enlarged perivascular space; fAQP4 = functional aquaporin 4; GL = glia limitans; H<sub>2</sub>O = water; L = lymphocyte; M = monocyte; N = neutrophile and neuron; Pc = pericyte; PVS = perivascular space; PVU = perivascular unit; rPVMΦ = resident perivascular macrophage; TJ/AJ = tight and adherens junctions.</p>
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<p>Endothelial nitric oxide synthase (eNOS) enzyme uncoupling results in the endothelium becoming a net producer of superoxide. eNOS enzyme uncoupling is depicted in this cartoon of the brain endothelium. Reactive oxygen species (ROS) and their oxidative effects on the requisite cofactor tetrahydrobiopterin (BH<sub>4</sub>) result in eNOS uncoupling is depicted. The excessive oxidation of BH<sub>4</sub> results in the generation of BH<sub>2</sub> that will not run the eNOS reaction to completion due to its incomplete reduction to BH<sub>4</sub> to produce nitric oxide (NO). Instead, the reaction uncouples and shifts to the C terminal reductase domain, and oxygen reacts with the nicotine adenine dinucleotide phosphorus (NADPH)-reduced oxidase enzyme resulting in the generation of superoxide [O<sub>2</sub><sup>−</sup>]. The oxidative redox stress (OxRS)-induced uncoupling of the eNOS reaction is known to result in a proinflammatory, proconstrictive, and prothrombotic endothelium, which contributes to endothelial activation and dysfunction (BEC<span class="html-italic">act</span>/<span class="html-italic">dys</span>). This modified image is provided with permission by CC 4.0 [<a href="#B24-pharmaceuticals-17-01741" class="html-bibr">24</a>,<a href="#B30-pharmaceuticals-17-01741" class="html-bibr">30</a>]. Ca++, calcium; FAD, flavin adenine dinucleotide; Fe++, iron; FMN, flavin mononucleotide; NADPH ox, nicotinamide adenine dinucleotide phosphate-reduced oxidase; O<sub>2</sub>, oxygen.</p>
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<p>Medical uses, side effects, and possible future uses of sodium thiosulfate (STS) in clinical disease.</p>
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<p>Future directions in the treatment of late-onset Alzheimer’s disease (LOAD) utilizing sodium thiosulfate (STS). This schematic illustrates the central role for the treatment of hypertension that is readily available for individuals with hypertension, proper anticoagulation when indicated, and the utilization of higher image magnification intensity of 7 tesla (7T). Note the surrounding seven boxes that are important to the development and progression of LOAD and how sodium thiosulfate (STS) is suggested as a treatment modality in 6 of these 7 boxed in underlying targets for STS. Also, note that dual antiplatelet therapy should also include cilostazol and low-dose aspirin. BBB<b><span class="html-italic">dd</span></b>, blood–brain barrier dysfunction and disruption; BEC<span class="html-italic">act</span>/<span class="html-italic">dys</span>, brain endothelial cell activation and dysfunction; BH<sub>4</sub>, tetrahydrobiopterin (essential cofactor for the eNOS enzyme); Ca++, calcium cation; CMBs, cerebral microbleeds; <b><span class="html-italic">cns</span></b>CC, central nervous system cytokines/chemokines; e, electron; eNOS, endothelial nitric oxide synthase; Fe++, iron cation; GlutET, glutamate excitotoxicity; H<sub>2</sub>S, hydrogen sulfide; MMP, matrix metalloproteinases; MRI, magnetic resonance imaging; NO, brain endothelial-cell-derived nitric oxide; OxRS, oxidative redox stress; <b><span class="html-italic">p</span></b>CC, peripheral cytokines/chemokines; SVD, small vessel disease; −SH, sulfhydryl group; tPA, tissue-type plasminogen activator; VaD, vascular dementia.</p>
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16 pages, 10339 KiB  
Article
Exploring the Application Method of Bamboo Powder in Promoting the Development of Sustainable Outdoor Furniture
by Yafei Fan, Ziqian Zhu, Jiacheng Luan and Yi Liu
Sustainability 2024, 16(24), 11282; https://doi.org/10.3390/su162411282 - 23 Dec 2024
Abstract
With the depletion of fossil fuels, more and more green products are appearing in daily necessities. Bamboo is a common sustainable biomaterial with the characteristics of fast growth, easy bending, low cost, and easy processing, and it is widely used in furniture design. [...] Read more.
With the depletion of fossil fuels, more and more green products are appearing in daily necessities. Bamboo is a common sustainable biomaterial with the characteristics of fast growth, easy bending, low cost, and easy processing, and it is widely used in furniture design. However, the poor aging resistance and UV resistance of natural bamboo materials limit their application in outdoor furniture. In order to improve the service life of outdoor bamboo furniture, this study prepared bamboo boards from bamboo powder and utilized them in the design of outdoor furniture. The research was conducted in two stages. In the first stage, functional modification was carried out on the surface of bamboo fibers (BF). Epoxy resin and UV absorber ZnO were introduced into the bamboo powder matrix, and a three-dimensional network structure of bamboo powder-based polymer material was formed by adjusting the material ratio and reaction conditions. With the increase of ZnO content, the absorption of moisture by the bamboo powder-based polymer materials decreased. The compressive strength of 1.5%ZnO-Board reached 36.8 MPa, exceeding the compressive strength of C30 concrete. In the second stage, 1.5% ZnO-Board was selected for solidification and demolding, and used as the seat surface for outdoor chairs. Through the car crushing experiment, the chair panel did not undergo significant deformation during the car crushing process. The anti-aging experiment showed that the structure and morphology of the panel would not be damaged by long-term UV irradiation. The panel did not show any weight changes in the anti-water-absorption experiment. By using low-contrast color combinations, the seats can be organically integrated into the environmental background, effectively enhancing the coordination and unity of the overall aesthetic harmony of the space. Compared with the commonly used plastic outdoor seats, the outdoor seats prepared in this study showed a 144% increase in carbon reduction effect. This study highlights the potential of modified bamboo powder for the design of outdoor furniture, which is of great significance to reducing outdoor plastic products and promoting sustainable life. Full article
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Figure 1
<p>Preparation process ((<b>a</b>) Bamboo powder raw material; (<b>b</b>) Pretreatment of bamboo powder; (<b>c</b>) Blending treatment of zinc oxide, pretreated bamboo powder, and epoxy resin; (<b>d</b>) Curing and demolding process of bamboo powder-based polymers) of bamboo powder-based composite materials.</p>
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<p>The microstructure of ZnO-Board.</p>
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<p>(<b>a</b>) FTIR image of ZnO-Board, (<b>b</b>) UV Visible Absorption Spectroscopy of ZnO-Board, (<b>c</b>) Thermogravimetric curve of ZnO-Board, (<b>d</b>) Thermal degradation rate of ZnO-Board.</p>
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<p>Water contact angle (<b>a</b>) 0% ZnO-Board, (<b>b</b>) 0.5% ZnO-Board, (<b>c</b>) 1% ZnO-Board, (<b>d</b>) 1.5% ZnO-Board.</p>
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<p>Water absorption curve of ZnO-Board.</p>
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<p>Compressive strength testing of ZnO-Board.</p>
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<p>(<b>a</b>) ZnO-Board morphology after compression test. Surface condition after compression test of (<b>b</b>) 0% ZnO-Board, (<b>c</b>) 0.5% ZnO-Board, (<b>d</b>) 1% ZnO-Board, (<b>e</b>) 1.5% ZnO-Board.</p>
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<p>Outdoor chair finished product image.</p>
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<p>(<b>a</b>) Surface of chair after UV aging, (<b>b</b>) comparison of UV visible spectra before and after aging experiment.</p>
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10 pages, 468 KiB  
Article
Study on the Efficacy and Safety of Tedizolid in Japanese Patients
by Kazuhiro Ishikawa, Yasumasa Tsuda and Nobuyoshi Mori
Antibiotics 2024, 13(12), 1237; https://doi.org/10.3390/antibiotics13121237 - 23 Dec 2024
Abstract
Background/Objective: Tedizolid (TZD), an oxazolidinone, causes fewer adverse events than linezolid (LZD). However, studies on the long-term efficacy and safety of TZD, particularly in patients with hematological malignancies (HMs), remain limited. This study aimed to evaluate the safety of long-term TZD use [...] Read more.
Background/Objective: Tedizolid (TZD), an oxazolidinone, causes fewer adverse events than linezolid (LZD). However, studies on the long-term efficacy and safety of TZD, particularly in patients with hematological malignancies (HMs), remain limited. This study aimed to evaluate the safety of long-term TZD use in Japanese patients, including those with HM. Methods: We retrospectively reviewed the medical records of patients aged 15 years and older who received TZD treatment at St. Luke’s International Hospital between 2018 and 2023. Patient demographics, treatment duration, adverse events, and clinical outcomes were analyzed. Results: Data from 35 patients and 40 treatment episodes were analyzed, including 13 episodes in patients with HM, of whom 65.0% were male, with a median age of 69.0 years (IQR: 24.5 years). The median treatment duration was 13.5 days (IQR: 46.8), with a maximum of 203 days. TZD was switched from other anti-MRSA agents in 82.5% of cases, including 42.5% from LZD. One patient discontinued TZD due to liver dysfunction, attributed to concomitant medication use. Clinical cure rates were significantly higher in the non-HM group compared to the HM group (88.9% vs. 38.5%). The 90-day mortality rate differed notably between the HM and non-HM groups (69.2% and 3.7%). Despite 100% microbiological eradication, infection-related mortality rates were 3.7% in the non-HM and 38.5% in the HM group. No reported cases of optic neuritis, Clostridioides difficile colitis, or major bleeding; Conclusions: TZD appears to be safe for long-term use, regardless of HM status, with no major complications observed in this cohort. Full article
(This article belongs to the Section Antibiotic Therapy in Infectious Diseases)
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<p>The diagram of patient selection flow.</p>
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28 pages, 1398 KiB  
Review
Spotlight on the Mechanism of Action of Semaglutide
by Ilias Papakonstantinou, Konstantinos Tsioufis and Vasiliki Katsi
Curr. Issues Mol. Biol. 2024, 46(12), 14514-14541; https://doi.org/10.3390/cimb46120872 - 23 Dec 2024
Abstract
Initially intended to control blood glucose levels in patients with type 2 diabetes, semaglutide, a potent glucagon-like peptide 1 analogue, has been established as an effective weight loss treatment by controlling appetite. Integrating the latest clinical trials, semaglutide in patients with or without [...] Read more.
Initially intended to control blood glucose levels in patients with type 2 diabetes, semaglutide, a potent glucagon-like peptide 1 analogue, has been established as an effective weight loss treatment by controlling appetite. Integrating the latest clinical trials, semaglutide in patients with or without diabetes presents significant therapeutic efficacy in ameliorating cardiometabolic risk factors and physical functioning, independent of body weight reduction. Semaglutide may modulate adipose tissue browning, which enhances human metabolism and exhibits possible benefits in skeletal muscle degeneration, accelerated by obesity and ageing. This may be attributed to anti-inflammatory, mitochondrial biogenesis, antioxidant and autophagy-regulating effects. However, most of the supporting evidence on the mechanistic actions of semaglutide is preclinical, demonstrated in rodents and not actually confirmed in humans, therefore warranting caution in the interpretation. This article aims to explore potential innovative molecular mechanisms of semaglutide action in restoring the balance of several interlinking aspects of metabolism, pointing to distinct functions in inflammation and oxidative stress in insulin-sensitive musculoskeletal and adipose tissues. Moreover, possible applications in protection from infections and anti-aging properties are discussed. Semaglutide enhancement of the core molecular mechanisms involved in the progress of obesity and diabetes, although mostly preclinical, may provide a framework for future research applications in human diseases overall. Full article
(This article belongs to the Section Molecular Medicine)
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<p>Semaglutide and transcriptional regulation of WAT to BAT conversion and BAT activation. Because of primitive experimental research in humans, data were acquired from reviews and from experimental evidence in rodents. Semaglutide activates the AMPK/SIRT1 axis which presents a crucial role for promoting the differentiation process into BAT by increasing the expression levels of UCP1. AMPK/SIRT1 activates PGC1α and via the transcriptional regulator PRDM16, the enzyme CIDEA. CIDEA controls the development of brown adipocytes in BAT and interacts with PGC1α to differentiate BeAT. Semaglutide may activate FGF21 produced by BAT which enhances the browning of WAT by increasing the expression of UCP1 and CIDEA. FGF21 exerts further anti-inflammatory effects by stimulation of adiponectin secretion. Semaglutide may induce FNDC5 expression in pancreatic β-cells via CREB, promoting the conversion of WAT to BAT, but also insulin secretion and autophagy while reducing apoptosis. Semaglutide may mediate glucose transport through AMPK/SIRT1 activation and GLUT4 upregulation. Upward arrows symbolize increase or upregulation, while downward arrows indicate decrease or downregulation of the mentioned mechanisms. Abbreviations: BAT, brown adipose tissue; BeAT, beige adipose tissue; WAT, white adipose tissue; UCP1, uncoupling protein 1; PRDM16, PR domain-containing 16; PGC1a, peroxisome proliferator activated receptor gamma coactivator 1 alpha; FGF21, fibroblast growth factor 21; FNDC5, protein fibronectin type III domain-containing protein 5; CREB, cAMP-response element binding protein; CIDEA, cell death-inducing DNA fragmentation factor-α-like effector A; GLUT4, glucose transporter type 4; AMPK, adenosine monophosphate–activated protein kinase; SIRT1, sirtuin 1.</p>
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<p>Possible mechanisms of semaglutide on oxidative stress and inflammation. Semaglutide activates AMPK/SIRT1 to deacetylate the NF-kB and possibly interacts with AGE/RAGEs to mediate critical anti- inflammatory responses and ROS reduction. Also PGC1α activated by SIRT1 regulates factors like NRF2 to diminish oxidative stress, aberrant UPR and ROS. In addition, semaglutide may promote autophagy and mitophagy through AMPK/TFEB and AMPK/parkin activation respectively. Upward arrows symbolize increase or upregulation, while downward arrows indicate decrease or downregulation of the mentioned mechanisms. Abbreviations: AMPK, adenosine monophosphate–activated protein kinase; SIRT1, sirtuin 1; NF-kB, nuclear factor kB; TFEB, transcription factor EB; UPR, unfolded protein response; ROS, reactive oxygen species; NRF2, nuclear factor (erythroid-derived 2)-like 2; AGEs, advanced glycation end-products; RAGE, AGE receptors.</p>
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<p>Possible anti-aging mechanisms of semaglutide, hypothesis-generating from preclinical research. Semaglutide through AMPK/SIRT1 activation may blockade the NF-kB critical mediator of inflammation and FOXO transcription factors through SIRT1/PGC-1α. This activates autophagy and may regulate the UPS and autophagy-lysosomal system for removal of senescent cells and SASP. Semaglutide may upregulate transcriptional responses to oxidative stress and ROS production like NRF2 which decrease with ageing. In addition, possible PTBP1 depletion by semaglutide downmodulates the NF-kB pathway. Upward arrows symbolize increase or upregulation, while downward arrows indicate decrease or downregulation of the mentioned mechanisms. Abbreviations: UPS, ubiquitin–proteasome system; SASP, senescence-associated secretory phenotype; PTP1B, protein tyrosine phosphatase 1B or polypyrimidine tract binding protein 1; PGC1a, peroxisome proliferator activated receptor gamma coactivator 1 alpha; FOXO, forkhead box O proteins.</p>
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10 pages, 733 KiB  
Article
Development and Validation of a New Adherence Scale for Antiseizure Medications [ASASM]
by Sarah A. Alotaibi, Noura A. Alrukban, Layla N. Alanizy, Ahmad Saleh and Bshra A. Alsfouk
J. Clin. Med. 2024, 13(24), 7844; https://doi.org/10.3390/jcm13247844 - 23 Dec 2024
Abstract
Objective: The objective was to develop and validate a multidimensional scale that measures adherence levels to antiseizure medications and detects patients’ reasons for non-adherence. Methods: A new scale was developed, namely the “Adherence Scale for Anti-Seizure Medication(s)-10 items [ASASM-10]”. It consists of ten [...] Read more.
Objective: The objective was to develop and validate a multidimensional scale that measures adherence levels to antiseizure medications and detects patients’ reasons for non-adherence. Methods: A new scale was developed, namely the “Adherence Scale for Anti-Seizure Medication(s)-10 items [ASASM-10]”. It consists of ten statements that cover different causes of non-adherence to antiseizure medications. The domain selection was based on a comprehensive literature review. Guidelines for constructing an effective scale were followed to write the statements. Three independent expert judges assessed the content validity of the scale. The reliability of ASASM-10 was tested using three methods: internal consistency measurement (Cronbach’s alpha), Intraclass Correlation Coefficient [ICC] with a 95% Confidence Interval [95% CI], and test–retest reliability. Validity was tested using Principal Component Analysis [PCA] and a correlation coefficient. PCA was applied after measuring sampling adequacy via Kaiser–Meyer–Olkin [KMO] and Bartlett’s sphericity. The Medication Adherence Rating Scale [MARS] was selected as a pre-existing self-report method for validation of this new scale. Results: A total of 162 patients completed the study scales (mean ages ± SD: 34.07 ± 10.406 years). The scale demonstrated a good internal consistency with Cronbach’s alpha coefficient of 0.80 and exceeded the required value (i.e., 0.70) for the reliability of new scales. ASASM-10 showed a satisfactory ICC (95% CI) of 0.799 (0.718–0.857), p-value < 0.001. The test–retest reliability demonstrated a good correlation of ρ = 0.648, p-value < 0.001. The construct validity assessed by PCA retained four components as their eigenvalues exceeded one. The correlation coefficient demonstrated a positive moderate correlation between ASASM-10 and MARS (ρ = 0.283), p-value < 0.001. Conclusions: The present analyses provided evidence that ASASM-10 is a reliable and valid scale for evaluating patients’ adherence to antiseizure medications. It is the first available scale for assessing medication adherence in patients with epilepsy that can be utilized in clinical practice and research settings. Full article
(This article belongs to the Section Pharmacology)
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<p>Timeline of scales administration in the study. Abbreviations: ASASM-10, Adherence Scale for Anti-Seizure Medication(s)—10 items; MARS, Medication Adherence Rating Scale.</p>
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<p>Scree plot of Adherence Scale for Anti-Seizure Medication(s)-10 items [ASASM-10].</p>
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23 pages, 2201 KiB  
Article
Effects of Extremely Low-Frequency Electromagnetic Field Treatment on ASD Symptoms in Children: A Pilot Study
by Kierra Pietramala, Alessandro Greco, Alberto Garoli and Danielle Roblin
Brain Sci. 2024, 14(12), 1293; https://doi.org/10.3390/brainsci14121293 - 22 Dec 2024
Viewed by 415
Abstract
Background/Objectives: Autism Spectrum Disorder (ASD) are neurodevelopmental disorders marked by challenges in social interaction, communication, and repetitive behaviors. People with ASD may exhibit repetitive behaviors, unique ways of learning, and different ways of interacting with the world. The term “spectrum” reflects the wide [...] Read more.
Background/Objectives: Autism Spectrum Disorder (ASD) are neurodevelopmental disorders marked by challenges in social interaction, communication, and repetitive behaviors. People with ASD may exhibit repetitive behaviors, unique ways of learning, and different ways of interacting with the world. The term “spectrum” reflects the wide variability in how ASD manifests in individuals, including differences in abilities, symptoms, and support needs, and conditions characterized by difficulties in social interactions, communication, restricted interests, and repetitive behaviors. Inflammation plays a crucial role in the pathophysiology, with increased pro-inflammatory cytokines in cerebrospinal fluid. Previous studies with transcranial magnetic stimulation have shown promising results, suggesting nervous system susceptibility to electromagnetic fields, with evidence indicating that extremely low-frequency electromagnetic field (ELF-EMF) treatment may modulate inflammatory responses through multiple pathways, including the reduction of pro-inflammatory cytokines like IL-6 and TNF-α, and the enhancement of anti-inflammatory mediators. Methods: This pilot study included 20 children (ages 2–13) with a confirmed diagnosis of ASD. A 15-week protocol involved ELF-EMF treatments using the SEQEX device, with specific day and night programs. Assessment was conducted through standardized pre- and post-treatment tests: Achenbach Child Behavior Checklist, Peabody Picture Vocabulary Test-4, Expressive One Word Picture Vocabulary Test-4, and Conner’s 3GI. Results: Statistically significant improvements were observed in receptive language (PPVT-4: from 74.07 to 90.40, p = 0.002) and expressive language (EOWPVT-4: from 84.17 to 90.50, p = 0.041). Notable reductions, with statistical significance, were found in externalizing problems across both age groups (1.5–5 years: p = 0.028; 6–18 years: p = 0.027), with particular improvement in attention and behavioral problems. The results were observed over a short period of 15 weeks, therefore excluding the possibility of coincidental age-related gains, that would typically occur during a normal developmental timeframe. Parent evaluations showed significant reduction in ASD symptoms, particularly in the 1.5–5 years group (p = 0.046). Conclusions: ELF-EMF treatment demonstrated a high safety profile and efficacy in mitigating ASD-related symptoms. The observed improvements suggest both direct effects on central and autonomic nervous systems and indirect effects through inflammatory response modulation. Further studies are needed to confirm these promising results through broader demographics and randomized control designs. Full article
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<p>The Peabody Picture Vocabulary Test-4 shows significant difference between Pre- and Post-test t = −3.809, <span class="html-italic">p</span> = 0.002.</p>
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<p>The Expressive One Word Picture Vocabulary Test-4th Edition shows significant difference between Pre- and Post-Test t = −2.312, <span class="html-italic">p</span> = 0.041.</p>
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<p>Cumulative graph for areas with significant results in the Achenbach Teacher Data for participants from 1.5 to 5 years.</p>
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<p>Cumulative graph for areas with significant results in the Achenbach Teacher Data for participants aged 6–18.</p>
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<p>The DSM−5 Oriented Scales showed significant changes in the areas of anxiety disorders (<span class="html-italic">p</span> = 0.027) and attention disorders (<span class="html-italic">p</span> = 0.042).</p>
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<p>In the 1.5–5 age group, the Achenbach Parent Data DMS-5 Oriented Scale showed significant improvement in the ASD item.</p>
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<p>Achenbach Parent Data shows significant difference between Pre- and Post-Test in Thought Problems (t = −2.201, <span class="html-italic">p</span> = 0.028).</p>
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21 pages, 3763 KiB  
Communication
Fixation of Expression Divergences by Natural Selection in Arabidopsis Coding Genes
by Cheng Qi, Qiang Wei, Yuting Ye, Jing Liu, Guishuang Li, Jane W. Liang, Haiyan Huang and Guang Wu
Int. J. Mol. Sci. 2024, 25(24), 13710; https://doi.org/10.3390/ijms252413710 - 22 Dec 2024
Viewed by 191
Abstract
Functional divergences of coding genes can be caused by divergences in their coding sequences and expression. However, whether and how expression divergences and coding sequence divergences coevolve is not clear. Gene expression divergences in differentiated cells and tissues recapitulate developmental models within a [...] Read more.
Functional divergences of coding genes can be caused by divergences in their coding sequences and expression. However, whether and how expression divergences and coding sequence divergences coevolve is not clear. Gene expression divergences in differentiated cells and tissues recapitulate developmental models within a species, while gene expression divergences between analogous cells and tissues resemble traditional phylogenies in different species, suggesting that gene expression divergences are molecular traits that can be used for evolutionary studies. Using transcriptomes and evolutionary proxies to study gene expression divergences among differentiated cells and tissues in Arabidopsis, expression divergences of coding genes are shown to be strongly anti-correlated with phylostrata (gene ages), indicators of selective constraint Ka/Ks (nonsynonymous replacement rate/synonymous substitution rate) and indicators of positive selection (frequency of loci with Ka/Ks > 1), but only weakly or not correlated with indicators of neutral selection (Ks). Our results thus suggest that expression divergences largely coevolve with coding sequence divergences, suggesting that expression divergences of coding genes are selectively fixed by natural selection but not neutral selection, which provides a molecular framework for trait diversification, functional adaptation and speciation. Our findings therefore support that positive selection rather than negative or neutral selection is a major driver for the origin and evolution of Arabidopsis genes, supporting the Darwinian theory at molecular levels. Full article
(This article belongs to the Special Issue Power Up Plant Genetic Research with Genomic Data 2.0)
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<p>Gene expression abundance (GEA) was anti-correlated with phylostratum (PS). (<b>A</b>) ESTs/locus was strongly anti-correlated with PS. (<b>B</b>) cDNAs/locus was strongly anti-correlated with PS. (<b>C</b>) Log<sub>10</sub>(RPMs) from RNA-Seq of seedlings was strongly anti-correlated with PS. Each data point is an average of 100 loci grouped by expression amount. RPMs: reads per million. (<b>D</b>) Log<sub>10</sub>(microarray signals) from microarray data [<a href="#B36-ijms-25-13710" class="html-bibr">36</a>] was strongly anti-correlated with PS. Each data point was an average of 100 loci grouped by expression amount. (<b>E</b>) Genes expressed in one sample (black bars) had a higher PS than genes expressed in more than one sample (unfilled bars). *, **, and *** indicate significant differences at <span class="html-italic">p</span> &lt; 0.05, <span class="html-italic">p</span> &lt; 0.01, and <span class="html-italic">p</span> &lt; 0.001 (<span class="html-italic">t</span>-test), respectively. (<b>F</b>) Genes with smaller GEB (narrow expression) had a higher PS than genes with larger GEB (broad expression). Letters indicate significant differences at <span class="html-italic">p</span> &lt; 0.001 (One-way ANOVA). Grey lines indicate 95% confidence intervals and triangles represent data points (<b>A</b>–<b>D</b>). Error bars are standard deviation (<b>E</b>,<b>F</b>).</p>
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<p>Linkage disequilibrium near positive selection (ω &gt; 1) loci in <span class="html-italic">Arabidopsis</span>. Linkage disequilibrium near ω &gt; 1 loci derived from orthologous gene pairs between <span class="html-italic">A. thaliana</span> and <span class="html-italic">A. lyrata</span> (interspecies; (<b>A</b>)) and between <span class="html-italic">A. thaliana</span> and <span class="html-italic">C. rubella</span> (intergenus; (<b>B</b>)). The 0 represents ω &gt; 1 loci; 1–5 represents loci closest to locus 0 (5 on each side), while 6–10 and 11–15 represent positions of loci farther away from locus 0, with the distribution of ω for loci in each group (all loci, 1–5, 6–10 and 11–15, respectively). (<b>C</b>) Linkage disequilibrium near ω &gt; 1 loci from orthologous gene pairs within <span class="html-italic">Arabidopsis</span> species. The 0 represents ω &gt; 1 loci; 1–2 represents loci closest to locus 0 (2 on each side), while 3–4 and 5–6 represent positions of loci farther away from locus 0, distribution of ω for loci in each group (all loci, 1–2, 3–4 and 5–6, respectively). Letters indicate significant differences at <span class="html-italic">p</span> &lt; 0.05 (<span class="html-italic">t</span>-test). Error bars are standard deviation.</p>
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<p>Gene expression abundance (GEA) was strongly anti-correlated with selective constraint (ω) and the incidence of ω &gt; 1 loci (positive selection markers) derived from orthologous gene pairs between <span class="html-italic">A. thaliana</span> and <span class="html-italic">A. lyrata</span> (interspecies). GEA for ESTs, cDNAs, microarray and RNA-Seq data was treated as described in the main text and methods, as well as in <a href="#app1-ijms-25-13710" class="html-app">Tables S10–S13</a> (<b>A</b>,<b>C</b>,<b>E</b>,<b>G</b>), while GEA in (<b>B</b>,<b>D</b>,<b>F</b>,<b>H</b>) was divided into low, medium and high levels and then correlated with ω &gt; 1 loci. ESTs/locus was anti-correlated strongly with ω (<b>A</b>) and the incidence of positive selection (<b>B</b>) but weakly correlated with Ks (<b>A</b>). cDNAs/locus was anti-correlated only with ω (<b>C</b>) and the incidence of ω &gt; 1 loci (<b>D</b>) but not with Ks (<b>C</b>). Log<sub>10</sub>(RPMs) from RNA-Seq of seedlings was strongly anti-correlated with ω (<b>E</b>) and the incidence of ω &gt; 1 loci (<b>F</b>) but correlated weakly with Ks (<b>E</b>). RPMs: reads per million. Log<sub>10</sub>(microarray signals) from microarray data [<a href="#B36-ijms-25-13710" class="html-bibr">36</a>] was strongly anti-correlated with ω (<b>G</b>) and the incidence of ω &gt; 1 loci (<b>H</b>) but weakly correlated with Ks (<b>G</b>). Each data point was an average of 100 loci grouped by expression amount (<b>E</b>,<b>G</b>). For (<b>B</b>,<b>D</b>,<b>F</b>,<b>H</b>), the letters indicated the significant difference detected by χ<sup>2</sup> test (<span class="html-italic">p</span> &lt; 0.05).</p>
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<p>Gene expression breadth (GEB) was strongly anti-correlated with selective constraint (ω) and the incidence of ω &gt; 1 loci (positive selection markers) derived from orthologous gene pairs between <span class="html-italic">A. thaliana</span> and <span class="html-italic">A. lyrata</span> (interspecies). (<b>A</b>) GEB was strongly anti-correlated with ω. Letters indicate significant differences at <span class="html-italic">p</span> &lt; 0.001 (One-way ANOVA) for ω between any adjacent groups with differential GEB. Error bars are standard deviation. (<b>B</b>) GEB was only minimally anti-correlated with Ks (neutral selection markers). Letters indicate significant differences at <span class="html-italic">p</span> &lt; 0.01 (One-way ANOVA). There was no significant difference for Ks between any adjacent groups. Error bars are standard deviation. (<b>C</b>) GEB was strongly anti-correlated with the incidence of ω &gt; 1 loci (positive selection markers). Narrowly expressed genes had a significantly higher incidence of ω &gt; 1 loci than did broadly expressed genes. The parameter is the result of a chi-squared test between the levels of GEB and whether the gene is under positive selection (χ<sup>2</sup> = 843.1, <span class="html-italic">p</span> &lt; 0.0001). Error bars are standard deviation (<b>A</b>,<b>B</b>).</p>
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<p>Functional enrichment analysis of putative ω &gt;1 loci in <span class="html-italic">Arabidopsis</span>. (<b>A</b>) GO enrichment analysis of putative positively selected genes. (<b>B</b>) KEGG enrichment analysis of putative positively selected genes. Yellow strips represent the enrichment score [−log10(<span class="html-italic">p</span>-value)] of the pathway. Significantly enriched KEGG pathways (<span class="html-italic">p</span> &lt; 0.05) are presented.</p>
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