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Search Results (229)

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14 pages, 308 KiB  
Article
High Levels of Galectin-3 and Uric Acid Are Independent Predictors of Renal Impairment in Patients with Stable Coronary Artery Disease
by Nayleth Leal-Pérez, Luis M. Blanco-Colio, José Luis Martín-Ventura, Carlos Gutiérrez-Landaluce, Ignacio Mahíllo-Fernández, María Luisa González-Casaus, Óscar Lorenzo, Jesús Egido and José Tuñón
J. Clin. Med. 2025, 14(15), 5264; https://doi.org/10.3390/jcm14155264 - 25 Jul 2025
Viewed by 261
Abstract
Background: High plasma levels of Galectin-3 (Gal-3) and uric acid (UA) are associated with a decline in renal function in different populations. However, this association has not yet been studied in patients with coronary artery disease (CAD). Methods: We included 556 patients with [...] Read more.
Background: High plasma levels of Galectin-3 (Gal-3) and uric acid (UA) are associated with a decline in renal function in different populations. However, this association has not yet been studied in patients with coronary artery disease (CAD). Methods: We included 556 patients with stable CAD. Plasma levels of Gal-3, UA, N-Terminal probrain natriuretic peptide (NT-proBNP), calcidiol, fibroblast growth factor 23, phosphate, parathormone, and klotho were assessed at baseline. The primary outcome was the percentage decrease in eGFR; the secondary outcomes were the absolute decrease in eGFR and achieving a reduction of ≥20% in this parameter. Results: Age was 63.1 ± 12.2 years, and 73.9% of patients were male. The median eGFR was 86.77 (72.27, 97.85) mL/min/1.73 m2. After 3.47 (2.10–5.72) years of follow-up, eGFR declined by 3.62% [−2.07–13.82]. Baseline UA (0.012 [CI95% 0.003, 0.020]; p = 0.008), Gal-3 (0.0153 [CI95% 0.001, 0.029]; p = 0.037), and NT-proBNP (0.017 [CI95% 0.000–0.025]; p = 0.027) were independent positive predictors of the percentage decrease in eGFR, while calcidiol (−0.005 [CI95% −0.009, −0.002]; p = 0.005) was an inverse predictor of this outcome. Similarly, UA and Gal-3 were positive independent predictors of the absolute decline in eGFR (0.009 [0.003, 0.017]; p = 0.004 and 0.012 [0.001, 0.023]; p = 0.031, respectively), while calcidiol was inversely associated (−0.003 [−0.005]–[−0.001]; p = 0.020). Uric acid (1.237 [1.046–1.463]; p = 0.013) and NT-proBNP (1.000 [1.000–1.001]; p = 0.049) levels were positive independent predictors of a ≥20% decrease in eGFR. In patients with eGFR ≥ 60 mL/min/1.73 m2, UA was the only biomarker independently associated with renal function decline. Conclusions: In patients with CAD and normal or mildly reduced renal function, UA and Gal-3 plasma levels are independent positive predictors of a future decrease in eGFR. These findings could lead to a change in the approach to patients with CAD in the future. Full article
16 pages, 1068 KiB  
Article
Protective Effects of Regular Physical Activity: Differential Expression of FGF21, GDF15, and Their Receptors in Trained and Untrained Individuals
by Paulina Małkowska, Patrycja Tomasiak, Marta Tkacz, Katarzyna Zgutka, Maciej Tarnowski, Agnieszka Maciejewska-Skrendo, Rafał Buryta, Łukasz Rosiński and Marek Sawczuk
Int. J. Mol. Sci. 2025, 26(15), 7115; https://doi.org/10.3390/ijms26157115 - 23 Jul 2025
Viewed by 188
Abstract
According to the World Health Organization (WHO), a healthy lifestyle is defined as a way of living that lowers the risk of becoming seriously ill or dying prematurely. Physical activity, as a well-known contributor to overall health, plays a vital role in supporting [...] Read more.
According to the World Health Organization (WHO), a healthy lifestyle is defined as a way of living that lowers the risk of becoming seriously ill or dying prematurely. Physical activity, as a well-known contributor to overall health, plays a vital role in supporting such a lifestyle. Exercise induces complex molecular responses that mediate both acute metabolic stress and long-term physiological adaptations. FGF21 (fibroblast growth factor 21) and GDF15 (growth differentiation factor 15) are recognized as metabolic stress markers, while their receptors play critical roles in cellular signaling. However, the differential gene expression patterns of these molecules in trained and untrained individuals following exhaustive exercise remain poorly understood. This study aimed to examine the transcriptional and protein-level responses in trained and untrained individuals performed a treadmill maximal exercise test to voluntary exhaustion. Blood samples were collected at six time points (pre-exercise, immediately post-exercise, and 0.5 h, 6 h, 24 h, and 48 h post-exercise). Gene expression of FGF21, GDF15, FGFR1 (fibroblast growth factor receptors), FGFR3, FGFR4, KLB (β-klotho), and GFRAL (glial cell line-derived neurotrophic factor receptor alpha-like) was analyzed using RT-qPCR, while plasma protein levels of FGF21 and GDF15 were quantified via ELISA. The results obtained were statistically analyzed by using Shapiro–Wilk, Mann–Whitney U, and Wilcoxon tests in Statistica 13 software. Untrained individuals demonstrated significant post-exercise upregulation of FGFR3, FGFR4, KLB, and GFRAL. FGF21 and GDF15 protein levels were consistently lower in trained individuals (p < 0.01), with no significant correlations between gene and protein expression. Trained individuals showed more stable expression of genes, while untrained individuals exhibited transient upregulation of genes after exercise. Full article
(This article belongs to the Special Issue Cytokines in Inflammation and Health)
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21 pages, 353 KiB  
Review
Molecular and Environmental Modulators of Aging: Interplay Between Inflammation, Epigenetics, and RNA Stability
by Konstantina Dragoumani, Dimitris Kletsas, George P. Chrousos, Dimitrios Vlachakis and Nikolaos A. A. Balatsos
Genes 2025, 16(7), 796; https://doi.org/10.3390/genes16070796 - 1 Jul 2025
Viewed by 698
Abstract
Aging is a complex biological process characterized by the progressive accumulation of cellular and molecular damage, leading to functional decline and increased susceptibility to age-related diseases. Central to this process is cellular senescence, a state of irreversible cell cycle arrest that acts as [...] Read more.
Aging is a complex biological process characterized by the progressive accumulation of cellular and molecular damage, leading to functional decline and increased susceptibility to age-related diseases. Central to this process is cellular senescence, a state of irreversible cell cycle arrest that acts as both a protective mechanism against tumorigenesis and a contributor to tissue degeneration. Herein, we explore the genetic and molecular mechanisms underlying aging, with a focus on telomere dynamics, the Klotho gene, angiotensin-converting enzyme (ACE), and the NF-κB pathway. Telomeres, which serve as protective caps at chromosome ends, shorten with each cell division, leading to replicative senescence, while the enzyme telomerase plays a pivotal role in maintaining telomere length and cellular longevity. The Klotho gene encoding for an aging suppressor influences insulin/IGF-1 signaling and has antioxidant properties that protect against oxidative stress. ACE, through its dual role in regulating blood pressure and degrading amyloid-beta, impacts longevity and age-related pathologies. The NF-κB pathway drives chronic inflammation or “inflammaging,” contributing to the onset of age-related diseases. Understanding these pathways offers promising avenues for therapeutic interventions to extend health span and lifespan. Targeting mechanisms such as telomerase activation, Klotho supplementation, ACE inhibition, and NF-κB modulation hold potential for combating the detrimental effects of aging and promoting healthier aging in the population. Full article
(This article belongs to the Special Issue Genomic Approaches for Disease Diagnosis and Prognosis)
13 pages, 2708 KiB  
Article
Expression of FGF23 and α-KLOTHO in Normal Human Kidney Development and Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)
by Patricija Bajt, Anita Racetin, Nela Kelam, Nikola Pavlović, Petar Todorović, Marinela Jelinčić Korčulanin, Natalija Filipović, Ivana Kuzmić Prusac, Fila Raguž and Katarina Vukojević
Biomolecules 2025, 15(6), 811; https://doi.org/10.3390/biom15060811 - 4 Jun 2025
Viewed by 581
Abstract
Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric renal failure, but the molecular mechanisms driving these conditions are not yet fully understood. Fibroblast Growth Factor 23 (FGF23) and its co-receptor α-KLOTHO play crucial roles in regulating [...] Read more.
Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric renal failure, but the molecular mechanisms driving these conditions are not yet fully understood. Fibroblast Growth Factor 23 (FGF23) and its co-receptor α-KLOTHO play crucial roles in regulating calcium and phosphate homeostasis in adult kidneys, but their roles in kidney development and the pathogenesis of CAKUT remain unclear. Because of that, we analyzed the spatial and temporal expression of FGF23 and α-KLOTHO in normal fetal kidney development and CAKUT using an immunofluorescence technique. Our results demonstrate a dynamic pattern of FGF23 and α-KLOTHO expression in healthy kidney development, with FGF23 levels decreasing and α-KLOTHO levels increasing with gestational age. Also, we showed that FGF23 expression was significantly reduced in horseshoe (HKs) and duplex kidneys (DKs), while α-KLOTHO expression remained unchanged across all CAKUT conditions. Based on our results, we suggest that altered FGF23 expression in CAKUT contributes to disease pathogenesis and may represent a potential therapeutic target. Full article
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16 pages, 11480 KiB  
Article
Dasatinib and Quercetin Combination Increased Kidney Damage in Acute Folic Acid-Induced Experimental Nephropathy
by Antonio Battaglia-Vieni, Vanessa Marchant, Lucia Tejedor-Santamaria, Cristina García-Caballero, Elena Flores-Salguero, María Piedad Ruiz-Torres, Sandra Rayego-Mateos, Ana Belen Sanz, Alberto Ortiz and Marta Ruiz-Ortega
Pharmaceuticals 2025, 18(6), 822; https://doi.org/10.3390/ph18060822 - 30 May 2025
Viewed by 1623
Abstract
Background/Objectives: Acute kidney injury (AKI) remains an unsolved medical problem due to the lack of effective treatments, high mortality, and increased susceptibility to progression to chronic kidney disease (CKD), especially in the elderly. Cellular senescence has been described in AKI, CKD, and [...] Read more.
Background/Objectives: Acute kidney injury (AKI) remains an unsolved medical problem due to the lack of effective treatments, high mortality, and increased susceptibility to progression to chronic kidney disease (CKD), especially in the elderly. Cellular senescence has been described in AKI, CKD, and aging and has been proposed as a promising therapeutic target. The senolytic drug combination of dasatinib plus quercetin (D&Q) is beneficial in some pathological conditions, including experimental CKD, but there are no data for AKI. Methods: The effect of D&Q combination was tested in folic acid-induced nephrotoxicity (FAN-AKI), a murine AKI model. Results: D&Q pretreatment did not prevent renal dysfunction in the acute phase of FAN-AKI, as determined by serum creatinine and BUN levels at 48 h. Moreover, gene expression of the kidney damage biomarkers Lcn2 and Havcr1, the Cdkn1a gene, which encodes p21, and some genes encoding components of the senescent cell secretome were significantly increased in response to D&Q treatment. The number of senescent p21-positive cells in injured kidneys was similar in untreated or D&Q-treated FAN mice. In addition, D&Q did not prevent the downregulation of the antiaging factor Klotho in damaged kidneys. Conclusions: D&Q treatment was not protective in FAN-AKI, exacerbating some deleterious responses. These results suggest caution when exploring the clinical translation of D&Q senolytic activity. Full article
(This article belongs to the Section Biopharmaceuticals)
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40 pages, 2263 KiB  
Review
FGF-Mediated Axon Guidance: Role of Downstream Signaling Pathways in Cytoskeletal Control
by Jiyuan Li, Hanqi Gao and Fang Liu
Cells 2025, 14(11), 777; https://doi.org/10.3390/cells14110777 - 25 May 2025
Viewed by 869
Abstract
Axon guidance, a fundamental process in neural circuit formation, is intricately regulated by Fibroblast Growth Factors (FGFs) and their receptors (FGFRs) through dynamic cytoskeletal remodeling. FGF signaling, mediated by heparan sulfate proteoglycans or Klotho co-factors, activates key downstream pathways: PI3K-Akt, JAK-STAT, PLCγ, and [...] Read more.
Axon guidance, a fundamental process in neural circuit formation, is intricately regulated by Fibroblast Growth Factors (FGFs) and their receptors (FGFRs) through dynamic cytoskeletal remodeling. FGF signaling, mediated by heparan sulfate proteoglycans or Klotho co-factors, activates key downstream pathways: PI3K-Akt, JAK-STAT, PLCγ, and RAS-MAPK. These pathways orchestrate actin filament dynamics, microtubule stability, and the organization of intermediate filaments. These pathways converge on Rho GTPases, cofilin, profilin, and tau to balance the cytoskeletal assembly−disassembly cycles, enabling growth cone navigation. Unresolved questions, such as the mechanisms underlying FGF-mediated growth cone steering, highlight critical future research directions. This review integrates structural, molecular, and functional insights into how FGF-FGFR interactions regulate axon pathfinding, emphasizing the crosstalk between signaling cascades and cytoskeletal plasticity. Elucidating these mechanisms not only advances our understanding of neural development but also opens therapeutic avenues for neuro-developmental disorders, nerve injury, and neurodegenerative diseases by targeting FGF-driven cytoskeletal dynamics. Full article
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17 pages, 9155 KiB  
Article
Long-Term Alterations of Renal Microvasculature in Rats Following Maternal PM2.5 Exposure: Vitamin D Effects
by Eujin Park, Hyung-Eun Yim, Min-Hwa Son, Yoon-Jeong Nam, Yu-Seon Lee, Sang-Hoon Jeong and Ju-Han Lee
Biomedicines 2025, 13(5), 1166; https://doi.org/10.3390/biomedicines13051166 - 10 May 2025
Viewed by 463
Abstract
Background: This study aimed to investigate the long-term effects of maternal exposure to fine particulate matter (PM2.5) with or without vitamin D supplementation on the renal microvasculature in adult rat offspring. Methods: Pregnant Sprague–Dawley rats were exposed to normal [...] Read more.
Background: This study aimed to investigate the long-term effects of maternal exposure to fine particulate matter (PM2.5) with or without vitamin D supplementation on the renal microvasculature in adult rat offspring. Methods: Pregnant Sprague–Dawley rats were exposed to normal saline, PM2.5, and PM2.5 with vitamin D for one month during nephrogenesis. Male offspring kidneys were taken for analyses on postnatal day 56. Results: Adult offspring rats exposed to maternal PM2.5 exhibited lower body weights and greater glomerular and tubular injury scores compared to control rats. Semi-quantitative analysis revealed a significant reduction in glomerular and peritubular capillary endothelial cells, along with a decrease in the number of glomeruli in the PM2.5 group. Maternal vitamin D supplementation reduced these changes. In offspring rats exposed to maternal PM2.5, intrarenal expression of renin, angiotensin-converting enzyme (ACE), cytochrome P450 27B1, and vascular endothelial growth factor-A (VEGF-A) increased, while expression of the vitamin D receptor, Klotho, VEGF receptor 2, angiopoietin-1, and Tie-2 decreased. Maternal vitamin D supplementation restored VEGF receptor 2 and angiopoietin-1 activities and reduced ACE and VEGF-A protein expression in adult offspring kidneys. Conclusions: Early-life exposure to PM2.5 may lead to long-term alterations in renal microvasculature and nephron loss. Maternal vitamin D supplementation during renal development can ameliorate PM2.5-induced capillary rarefaction and nephron loss in the kidneys of adult offspring. Full article
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14 pages, 574 KiB  
Article
Associations Between Inflammatory and Bone Turnover Markers and Mortality in Hemodialysis Patients
by Alexandru Florin Sircuța, Iulia Dana Grosu, Adalbert Schiller, Ligia Petrica, Viviana Ivan, Oana Schiller, Felix-Mihai Maralescu, Marcel Palamar, Monica-Nicoleta Mircea, Daniel Nișulescu, Ionuț Goleț and Flaviu Bob
Biomedicines 2025, 13(5), 1163; https://doi.org/10.3390/biomedicines13051163 - 10 May 2025
Viewed by 481
Abstract
Background/Objectives: Chronic kidney disease–mineral and bone disorder (CKD-MBD) and systemic inflammation contribute to mortality in hemodialysis (HD) patients. The primary aim of this study was to determine whether specific CKD-MBD markers and inflammatory biomarkers are associated with increased mortality risk in HD patients. [...] Read more.
Background/Objectives: Chronic kidney disease–mineral and bone disorder (CKD-MBD) and systemic inflammation contribute to mortality in hemodialysis (HD) patients. The primary aim of this study was to determine whether specific CKD-MBD markers and inflammatory biomarkers are associated with increased mortality risk in HD patients. Methods: We conducted a retrospective cohort study on 63 stage 5D CKD patients undergoing maintenance HD. Serum intact parathyroid hormone (iPTH), soluble Klotho, calcium, phosphorus, 25(OH)D (25-hydroxyvitamin D), transforming growth factor-beta (TGF-β), vascular endothelial growth factor (VEGF), C-reactive protein (CRP), and interleukin-6 (IL-6) were analyzed. A Cox regression analysis assessed mortality predictors, and linear regression analysis evaluated CKD-MBD–inflammation correlations. Results: Lower iPTH (<329.3 pg/mL) levels were the only significant mortality predictor (p = 0.042). Other CKD-MBD markers (calcium, phosphorus, 25(OH)D, VEGF, TGF-β) did not impact survival. Soluble Klotho correlated positively with IL-6 (r = 0.57, p < 0.001), suggesting a compensatory inflammatory response. Conclusions: Our findings demonstrate that low iPTH levels and advanced age are independent predictors of mortality in hemodialysis patients. The positive association between soluble Klotho and IL-6 suggests a potential compensatory inflammatory response. These results highlight the need for further research to clarify underlying mechanisms and to explore novel therapeutic strategies. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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16 pages, 671 KiB  
Review
The Role of Klotho in Oral and Maxillofacial Diseases: Mechanisms and Research Progress
by Shiqi Lin, Bozhao Wang and Jian Li
Biomolecules 2025, 15(5), 624; https://doi.org/10.3390/biom15050624 - 27 Apr 2025
Viewed by 804
Abstract
Klotho, an anti-aging protein, has been extensively studied in systemic conditions such as chronic kidney disease and cardiovascular disorders. In recent years, its pivotal protective role and clinical significance in various oral and maxillofacial diseases have been increasingly demonstrated. It has been demonstrated [...] Read more.
Klotho, an anti-aging protein, has been extensively studied in systemic conditions such as chronic kidney disease and cardiovascular disorders. In recent years, its pivotal protective role and clinical significance in various oral and maxillofacial diseases have been increasingly demonstrated. It has been demonstrated that Klotho regulates oxidative stress, apoptosis, inflammation, and fibrosis via multiple molecular signaling pathways, including Nrf2, NF-κB, PI3K/Akt/FoxO1, insulin/IGF-1, FGF/FGFR, and Wnt/β-catenin. Consequently, these regulatory effects have been observed in conditions such as periodontitis, oral squamous cell carcinoma, malignant salivary gland tumors, oral submucous fibrosis, etc. Moreover, the decreased expression or dysfunctional activity of Klotho is frequently associated with the onset and progression of these diseases. This study provides a comprehensive review of the underlying mechanisms and recent advances in Klotho research within the realm of oral and maxillofacial diseases, offering novel perspectives for future basic and clinical investigations. Full article
(This article belongs to the Section Molecular Medicine)
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21 pages, 4619 KiB  
Article
Macrophage Depletion Alleviates Immunosenescence in Diabetic Kidney by Modulating GDF-15 and Klotho
by Asma S. Alonazi, Rana M. Aloraini, Lama M. Albulayhi, Layal M. Alshehri, Anfal F. Bin Dayel, Maha A. Alamin, Nouf T. Aldamri, Tahani K. Alshammari, Dalal A. Alkhelb, Wedad S. Sarawi, Hanan K. Alghibiwi, Nawal M. Alrasheed, Doaa M. Elnagar and Nouf M. Alrasheed
Int. J. Mol. Sci. 2025, 26(9), 3990; https://doi.org/10.3390/ijms26093990 - 23 Apr 2025
Viewed by 833
Abstract
Cellular senescence is a hallmark of aging and contributes to age-related diseases, including diabetic nephropathy (DN). Additionally, macrophage-mediated inflammation has been linked with DKD. Therefore, we investigated the effect of macrophage depletion on kidney cell senescence in DN, focusing on the relationship between [...] Read more.
Cellular senescence is a hallmark of aging and contributes to age-related diseases, including diabetic nephropathy (DN). Additionally, macrophage-mediated inflammation has been linked with DKD. Therefore, we investigated the effect of macrophage depletion on kidney cell senescence in DN, focusing on the relationship between the GDF-15 and Klotho signaling pathways. Wistar albino rats (n = 24) were divided into four groups: healthy control, liposomal clodronate (LC)-treated healthy, diabetic, and LC-treated diabetic groups. Rats in the LC-treated healthy, diabetic, and LC-treated diabetic groups were intravenously administered LC once a week for 4 weeks. Rat models of type 2 diabetes were successfully established via the administration of streptozotocin and a high-fat diet, as evidenced by increased blood glucose levels, kidney weight to body weight (KW/BW) ratio, serum albumin, creatinine, and urea levels, kidney damage, and oxidative stress. However, LC-mediated macrophage depletion reduced the KW/BW ratio, improved serum and oxidative parameters, decreased inflammatory markers (IL-6 and TNF-α), and ameliorated oxidative stress. Additionally, LC treatment promoted macrophage polarization towards the anti-inflammatory phenotype, downregulated GDF-15 expression, upregulated Klotho expression, and ameliorated kidney damage. In conclusion, macrophage depletion combats kidney senescence by modulating Klotho and GDF-15, indicating their potential as novel targets in DN treatment. Full article
(This article belongs to the Special Issue Novel Therapeutic Strategies in Diabetes)
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13 pages, 698 KiB  
Article
Independent and Combined Associations of Urinary Heavy Metal Exposures with Serum α-Klotho in Middle-Aged and Older Adults
by Xinliang Zheng, Wenxin Zhou, Zhuoying Jiang, Chan Ding, Minqian Feng, Yongxin Li, Fitri Kurniasari, Shuanghua Xie and Huadong Xu
Toxics 2025, 13(4), 237; https://doi.org/10.3390/toxics13040237 - 24 Mar 2025
Viewed by 734
Abstract
α-Klotho is an anti-aging protein linked to various age-related diseases. Environmental metal exposure has been associated with oxidative stress and aging, but its effect on α-Klotho levels remains unclear. This study investigated the relationship between urinary metal concentrations and serum α-Klotho levels using [...] Read more.
α-Klotho is an anti-aging protein linked to various age-related diseases. Environmental metal exposure has been associated with oxidative stress and aging, but its effect on α-Klotho levels remains unclear. This study investigated the relationship between urinary metal concentrations and serum α-Klotho levels using data from the National Health and Nutrition Examination Survey (NHANES) 2007–2016 cycles. A total of 4071 adults aged 40 to 79 years were included in the analysis. After adjusting for potential confounders, positive associations were found between serum α-Klotho levels and barium (Ba), cesium (Cs), and molybdenum (Mo), while tungsten (W) and uranium (U) were negatively correlated with α-Klotho levels. The combined effects of multiple metals were further analyzed using the qgcomp model, which demonstrated a negative correlation between increased metal mixtures and serum α-Klotho levels. Specifically, U, total arsenic (t-As), W, cadmium (Cd), antimony (Sb), and lead (Pb) contributed to the reduction of α-Klotho levels, while Ba, Cs, dimethylarsinic acid (DMA), Mo, thallium (Tl), and cobalt (Co) were positively associated with α-Klotho levels. These findings suggest that exposure to certain metals, particularly in combination, may reduce serum α-Klotho levels, potentially accelerating aging processes. Further studies should investigate the underlying mechanisms responsible for these associations. Full article
(This article belongs to the Special Issue Health Effects of Exposure to Environmental Pollutants)
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16 pages, 1669 KiB  
Systematic Review
FGF-23 as a Biomarker for Carotid Plaque Vulnerability: A Systematic Review
by Joana Oliveira-Sousa, Mariana Fragão-Marques, Luís Duarte-Gamas, Hugo Ribeiro and João Rocha-Neves
Med. Sci. 2025, 13(1), 27; https://doi.org/10.3390/medsci13010027 - 10 Mar 2025
Viewed by 1070
Abstract
Background/Objectives: Carotid artery disease is a condition affecting 3% of the general population which significantly contributes to the development of cerebrovascular events. Fibroblast Growth Factor-23 (FGF-23) is a hormone that has been linked to atherosclerosis and increased cardiovascular risk, including stroke and myocardial [...] Read more.
Background/Objectives: Carotid artery disease is a condition affecting 3% of the general population which significantly contributes to the development of cerebrovascular events. Fibroblast Growth Factor-23 (FGF-23) is a hormone that has been linked to atherosclerosis and increased cardiovascular risk, including stroke and myocardial infarction. This review explores the association of FGF-23 with carotid artery disease progression in an endarterectomy clinical context. Methods: Based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), a search was performed relying on MEDLINE, Scopus and Web of Science, identifying publications focused on the correlation between serum FGF-23 and carotid artery disease. Assessment of study quality was made using National Heart, Lung and Blood Institute Study Quality Assessment Tool (NHLBI). Results: Three observational studies, comprising 1039 participants, were included. There was considerable heterogeneity among the populations from the different studies. Elevated FGF-23 levels were consistently associated with unstable plaque features, including intraplaque neovascularization, as identified through Superb Microvascular Imaging (SMI). Plasma levels of inflammatory mediators, such as Interleukin-6 (Il-6), Monocyte Chemoattractant Protein-1 (MCP-1), and Osteoprotegerin (OPG), positively correlated with carotid artery disease, but their link to unstable plaques is conflicting. None of the studies investigated clinical complications following carotid endarterectomy. Conclusions: FGF-23 is a potential biomarker for plaque vulnerability in carotid disease. Despite promising findings, limitations such as small sample sizes and lack of longitudinal data suggest the need for larger and more diverse studies to improve risk stratification and inform personalized treatment strategies for carotid atherosclerosis. Full article
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19 pages, 4834 KiB  
Article
Dysregulation of Circadian Markers, HAT1 and Associated Epigenetic Proteins, and the Anti-Aging Protein KLOTHO in Placenta of Pregnant Women with Chronic Venous Disease
by Oscar Fraile-Martinez, Cielo García-Montero, Tatiana Pekarek, Julia Bujan, Silvestra Barrena-Blázquez, Eva Manuela Pena-Burgos, Laura López-González, Leonel Pekarek, Raul Díaz-Pedrero, Juan A. De León-Luis, Coral Bravo, Melchor Álvarez-Mon, Miguel A. Saez, Natalio García-Honduvilla and Miguel A. Ortega
J. Pers. Med. 2025, 15(3), 107; https://doi.org/10.3390/jpm15030107 - 9 Mar 2025
Cited by 1 | Viewed by 1203
Abstract
Background: Chronic venous disease (CVD) is a vascular disorder common among pregnant women, due to the impairment in the venous function associated with the mechanical, hemodynamical, and hormonal changes that occur during pregnancy. CVD is linked to venous hypertension, inflammation, oxidative stress, and [...] Read more.
Background: Chronic venous disease (CVD) is a vascular disorder common among pregnant women, due to the impairment in the venous function associated with the mechanical, hemodynamical, and hormonal changes that occur during pregnancy. CVD is linked to venous hypertension, inflammation, oxidative stress, and hypoxia, which alter placental structure and function, as demonstrated in previous works. The placenta fulfills several roles in fetal development and maternal well-being by mediating nutrient exchange; acting as a mechanical, chemical, and immunological shield; and producing essential hormones, making it crucial to investigate the effects of CVD in this organ. Patients and methods: This work specifically analyzes the gene expression of circadian markers (CLOCK, BMAL1, PER1, and PER2), epigenetic regulators (HAT1 and associated molecules like histones H3, H4, RBBP7, and ASF1), and the anti-aging protein KLOTHO in placental tissue of pregnant women with CVD (CVD-PW, N = 98) compared to healthy pregnant controls (HC-PW, N = 82), using RT-qPCR and immunohistochemistry (IHC) to determine protein expression. Results: Our study demonstrates that the placentas of CVD-PW exhibit the reduced gene and protein levels of circadian regulators (clock, bmal1, per1, and per2), increased expression of hat1 and related proteins (h3, h4, rbbp7, and asf1), and decreased klotho expression, indicative of accelerated aging. Conclusions: These findings highlight profound molecular disturbances in the placentas of women with CVD, offering insights into the disease’s pathophysiology and potential implications for maternofetal well-being. While this study deepens our understanding of the relationship between CVD and placental dysfunction, further research is required to fully elucidate these mechanisms and their long-term effects. Full article
(This article belongs to the Section Mechanisms of Diseases)
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17 pages, 1806 KiB  
Article
Non-Invasive Assessment of Vascular Damage Through Pulse Wave Velocity and Superb Microvascular Imaging in Pre-Dialysis Patients
by Julia Martín-Vírgala, Beatriz Martín-Carro, Sara Fernández-Villabrille, Belinda Fernández-Mariño, Elena Astudillo-Cortés, Minerva Rodríguez-García, Carmen Díaz-Corte, José Luis Fernández-Martín, Carlos Gómez-Alonso, Adriana S. Dusso, Cristina Alonso-Montes, Manuel Naves-Díaz, Sara Panizo and Natalia Carrillo-López
Biomedicines 2025, 13(3), 621; https://doi.org/10.3390/biomedicines13030621 - 4 Mar 2025
Viewed by 1030
Abstract
Background/Objectives: Cardiovascular disease is the main cause of morbidity and mortality in Chronic Kidney Disease (CKD), so it is of great importance to find simple and non-invasive tools to detect vascular damage in pre-dialysis CKD patients. This study aimed to assess the [...] Read more.
Background/Objectives: Cardiovascular disease is the main cause of morbidity and mortality in Chronic Kidney Disease (CKD), so it is of great importance to find simple and non-invasive tools to detect vascular damage in pre-dialysis CKD patients. This study aimed to assess the applicability of non-invasive techniques to evaluate vascular damage in stages CKD-2 to CKD-5 and its progression after an 18-month follow-up using (A) carotid–femoral pulse wave velocity (PWV) to assess aortic stiffness and (B) Superb Microvascular Imaging (SMI) ultrasound to assess adventitial neovascularization compared with other traditional techniques to evaluate vascular damage, such as carotid intima–media thickness and Kauppila index. Methods: The study involved 43 CKD patients in stages CKD-2 to CKD-5 and a group of 38 sex- and age-matched controls, studied at baseline and at an 18-month follow-up. Age, sex, body mass index, arterial pressure, pharmacological treatments, and blood and urinary parameters were collected. Aortic stiffness was determined by carotid–femoral PWV and abdominal aortic calcification was assessed in lateral lumbar X-rays and quantified by the Kauppila index. Carotid intima–media thickness (cIMT), the number of carotid plaques, and adventitial neovascularization were evaluated by SMI. Results: Vascular impairment was mostly detected in CKD-4 and CKD-5 stages, with increased aortic stiffness measured by PWV and increased carotid plaques and adventitial neovascularization measured by SMI ultrasound. Furthermore, CKD-5 patients showed greater abdominal aortic calcification. Interestingly, CKD patients displayed a negative correlation between serum soluble Klotho (sKlotho) and cIMT. Finally, CKD patients showed no progression of vascular impairment after the 18-month follow-up, with the exception of carotid plaques. Conclusions: Performing non-invasive PWV and SMI ultrasound might be useful to evaluate vascular damage in CKD before entering dialysis, possibly helping to prevent cardiovascular events, although future studies should clarify the use of these techniques in clinical practice. Full article
(This article belongs to the Special Issue Vascular Pathologies in the Omics Era)
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18 pages, 751 KiB  
Review
Influence of Klotho Protein Levels in Obesity and Sarcopenia: A Systematic Review
by Diana G. Ariadel-Cobo, Brisamar Estébanez, Elena González-Arnáiz, María Pilar García-Pérez, Marta Rivera-Viloria, Begoña Pintor de la Maza, David Emilio Barajas-Galindo, Diana García-Sastre, María D. Ballesteros-Pomar and María J. Cuevas
Int. J. Mol. Sci. 2025, 26(5), 1915; https://doi.org/10.3390/ijms26051915 - 23 Feb 2025
Cited by 2 | Viewed by 1616
Abstract
The Klotho gene is recognized for its anti-aging properties. Its downregulation leads to aging-like phenotypes, whereas overexpression can extend lifespan. Klotho protein exists in three forms: α-klotho, β-klotho and γ-klotho. The α-klotho has two isoforms: a membrane-bound form, primarily in the kidney and [...] Read more.
The Klotho gene is recognized for its anti-aging properties. Its downregulation leads to aging-like phenotypes, whereas overexpression can extend lifespan. Klotho protein exists in three forms: α-klotho, β-klotho and γ-klotho. The α-klotho has two isoforms: a membrane-bound form, primarily in the kidney and brain, and a secreted klotho protein present in blood, urine, and cerebrospinal fluid. Klotho functions as a co-receptor for fibroblast growth factor-23 (FGF23), regulating phosphate metabolism. The membrane-bound form controls various ion channels and receptors, while the secreted form regulates endocrine FGFs, including FGF19 and FGF21. The interaction between β-klotho and FGF21 in muscle is critical in the development of sarcopenic obesity. This systematic review, registered in PROSPERO and conducted following PRISMA guidelines, evaluates klotho levels in individuals with obesity or sarcopenic obesity. The study includes overweight, obese, and sarcopenic obese adults compared to those with a normal body mass index. After reviewing 713 articles, 20 studies were selected, including observational, cross-sectional, cohort studies, and clinical trials. Significant associations between klotho levels and obesity, metabolic syndrome (MS), and cardiovascular risk were observed. Exercise and dietary interventions positively influenced klotho levels, which were linked to improved muscle strength and slower decline. Klotho is a potential biomarker for obesity, MS, and sarcopenic obesity. Further research is needed to explore its mechanisms and therapeutic potential. Full article
(This article belongs to the Special Issue Latest Review Papers in Molecular and Cellular Biology 2024)
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