Search Results (12,726)

Sprouty-related proteins with enabled/vasodilator-stimulated phosphoprotein homology 1 (EVH1) domain (SPREDs) are negative regulators of the Ras/MAPK signaling pathway and are known to modulate developmental and endocrine processes. While the roles of SPRED1 and SPRED2 are increasingly understood, the physiological relevance of SPRED3 remains elusive. To elucidate its function, we generated SPRED3 knockout (KO) mice and performed phenotypic, molecular, and hormonal analyses. SPRED3-deficient mice exhibited growth retardation and a non-Mendelian genotype distribution. X-Gal staining revealed Spred3 promoter activity in the thyroid, adrenal gland, pituitary, cerebral cortex, and kidney. Hormonal profiling identified elevated thyroid-stimulating hormone (TSH) and reduced thyroxine (T₄) levels, indicating primary hypothyroidism. Thyroidal extracellular signal-regulated kinase (ERK) signaling was mildly reduced in SPRED3 KO mice, and immunoblotting revealed altered expression of autophagy regulators, including reduced sequestosome 1 (p62), increased autophagy-related gene 5 (ATG5), as well as an elevated microtubule-associated protein 1 light chain 3 (LC3) II/I ratio and a decreased pBeclin/Beclin ratio in SPRED3 KO mice. Our findings indicate that SPRED3 is involved in thyroidal homeostasis and plays a regulatory role in autophagy processes within the thyroid gland. Full article

Fibromyalgia has unclear etiopathogenesis, no curative treatment, and a severe impact on the quality of life. Gratitude practices have been shown to enhance the quality of life in chronic diseases. This systematic review, performed by searching five electronic databases, following the PRISMA guidelines, is the first aiming to evaluate the impact of gratitude in fibromyalgia. Data from eligible studies was extracted and a narrative synthesis was performed. Six articles (four observational studies and two randomized clinical trials) were included. Higher levels of gratitude are associated with reduced symptom severity, an enhanced quality of life, improved well-being, and the improvement of pain-related outcomes in fibromyalgia patients. Gratitude is related to reduced stress, anxiety, and depression; better sleep patterns; and less functional impairment in FM patients. Higher levels of gratitude contribute to a better quality of life, general well-being, and higher functioning capacity in fibromyalgia patients. Based on the results gathered in this systematic review, we propose that gratitude should be investigated as a therapeutic adjuvant in the management of fibromyalgia. Full article

Background: This systematic review evaluates the efficacy of rehabilitation-focused exercise interventions for lumbar degenerative disc disease (DDD), a leading cause of chronic low back pain. Methods: Following PRISMA guidelines, a comprehensive search was conducted across international and regional databases (PubMed, Scopus, Web of Science, Magiran, SID, and Noormags) covering the period from January 2010 to January 2025. The review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD420251088811. Using keywords such as “lumbar DDD,” “exercise therapy,” and “rehabilitation,” a total of 2495 records were identified. After screening, 20 studies—including clinical trials, quasi-experimental, and experimental designs—met the inclusion criteria and were assessed using the McMaster Critical Review Form for Quantitative Studies. Results: Interventions such as hydrotherapy, core stability training, Pilates, and suspension exercises were found to significantly reduce pain and improve functional outcomes. While multimodal approaches (e.g., aquatic exercise combined with acupuncture) showed positive effects, the comparative studies revealed no significant differences between modalities. Suspension training demonstrated superior efficacy in pain reduction compared to isolated core stability exercises. The methodological quality of included studies ranged from good to excellent, with the majority rated as very good or excellent (McMaster scores: 8 “excellent,” 7 “very good,” and 5 “good”). Common limitations among the studies included methodological heterogeneity, small sample sizes (n = 14–30), and insufficient long-term follow-up. Conclusions: Exercise-based rehabilitation is an effective strategy for managing lumbar DDD. Evidence particularly supports the use of suspension training and aquatic therapy for superior improvements in pain and functional outcomes. Future research should aim to adopt standardized protocols, recruit larger sample sizes, and include extended follow-up periods to produce more robust and generalizable findings. Full article

(1) Background and aim: The benefit of surgical treatment compared to conservative management is unclear in degenerative cuff tears, and there is limited evidence regarding midterm functional outcomes. This study sought to compare the midterm functional outcomes of surgical versus conservative treatment for rotator cuff tears. (2) Methods: All patients on the waiting list for arthroscopy of cuff tears in a single center between 2013 and 2015 were analyzed. They were divided into two groups: those who underwent surgery (arthroscopy group) and those who declined the procedure (orthopedic group). The primary endpoint was shoulder functionality, evaluated with the CMS, SST, and SPADI-SP questionnaires. Inverse probability of treatment weighting (IPTW) was used to account for differences between the groups. (3) Results: Of 57 patients (67 (62–71) years old, 47% women), 32 were in the arthroscopy group and 25 in the orthopedic group. Functionality was assessed at a median of 7 (7–8) years after diagnosis. The patients in the arthroscopy group were younger (p = 0.023) and more frequently women (p = 0.074). No significant differences were observed in the type of tear (p = 0.205) or laterality (p = 0.164). Functional outcome analysis showed more favorable scores in the surgical group: constant (74.5 ± 16.6 vs. 58.4 ± 23, p = 0.016), SST (7.3 ± 3.1 vs. 4.9 ± 4.2, p = 0.016), and SPADI-SP (35.7 ± 26.6 vs. 56.1 ± 30.4, p = 0.006). (4) Conclusions: In this cohort of patients with cuff tears, arthroscopic repair was associated with better clinical and functional midterm results compared to conservative treatment, although the benefit was less evident in older patients and those with complete tears. Full article

Botrytis cinerea is a highly versatile pathogenic fungus, causing significant damage across a wide range of plant species. A central focus of this review is the recent advances made through proteomics, an advanced molecular tool, in understanding the mechanisms of B. cinerea infection. Recent advances in mass spectrometry-based proteomics—including LC-MS/MS, iTRAQ, MALDI-TOF, and surface shaving—have enabled the in-depth characterization of B. cinerea subproteomes such as the secretome, surfactome, phosphoproteome, and extracellular vesicles, revealing condition-specific pathogenic mechanisms. Notably, in under a decade, the proportion of predicted proteins experimentally identified has increased from 10% to 52%, reflecting the rapid progress in proteomic capabilities. We explore how proteomic studies have significantly enhanced our knowledge of the fungus secretome and the role of extracellular vesicles (EVs), which play key roles in pathogenesis, by identifying secreted proteins—such as pH-responsive elements—that may serve as biomarkers and therapeutic targets. These technologies have also uncovered fine regulatory mechanisms across multiple levels of the fungal proteome, including post-translational modifications (PTMs), the phosphomembranome, and the surfactome, providing a more integrated view of its infection strategy. Moreover, proteomic approaches have contributed to a better understanding of host–pathogen interactions, including aspects of the plant’s defensive responses. Furthermore, this review discusses how proteomic data have helped to identify metabolic pathways affected by novel, more environmentally friendly antifungal compounds. A further update on the advances achieved in the field of proteomics discovery for the organism under consideration is provided in this paper, along with a perspective on emerging tools and future developments expected to accelerate research and improve targeted intervention strategies. Full article

Objective: Visceral leishmaniasis (VL), a Neglected Tropical Disease caused by Leishmania donovani, remains insufficiently addressed by current therapies due to high toxicity, poor efficacy, and immunosuppressive complications. This study aimed to identify and characterize repurposed drugs that simultaneously target parasite-encoded and host-associated mechanisms essential for VL pathogenesis. Methods: Two complementary in silico drug repurposing strategies were employed. The first method utilized electron–ion interaction potential (EIIP) screening followed by molecular docking and molecular dynamics (MD) simulations targeting two L. donovani proteins: Rab5a and pteridine reductase 1 (PTR1). The second approach employed network-based drug repurposing using the Drugst.One platform, prioritizing candidates via STAT3-associated gene networks. Predicted drug–target complexes were validated by 100 ns MD simulations, and pharmacokinetic parameters were assessed via ADMET profiling using QikProp v7.0 and SwissADME web server. Results: Entecavir and valganciclovir showed strong binding to Rab5a and PTR1, respectively, with Glide Scores of −9.36 and −9.10 kcal/mol, and corresponding MM-GBSA ΔG_bind values of −14.00 and −13.25 kcal/mol, confirming their stable interactions and repurposing potential. Network-based analysis identified nifuroxazide as the top candidate targeting the host JAK2/TYK2–STAT3 axis, with high stability confirmed in MD simulations. Nifuroxazide also displayed the most favorable ADMET profile, including oral bioavailability, membrane permeability, and absence of PAINS alerts. Conclusions: This study highlights the potential of guanine analogs such as entecavir and valganciclovir, and the nitrofuran derivative nifuroxazide, as promising multi-target drug repurposing candidates for VL. Their mechanisms support a dual strategy targeting both parasite biology and host immunoregulation, warranting further preclinical investigation. Full article

Skin aging is closely related to mitochondrial dysfunction and cell cycle abnormalities, and developing intervention strategies targeting mitochondrial quality control is an important direction for anti-aging research. In this study, we investigated the anti-aging mechanism of Camellia japonica flower (CJF) extract and its active ingredient hyperoside based on a doxorubicin (DOX)-induced endogenous senescence model in human skin fibroblasts (HSFs). LC-MS proteomics analysis revealed that CJF extract and hyperoside specifically activated the FUNDC1-mediated mitochondrial autophagy pathway, significantly ameliorated the DOX-induced decrease in mitochondrial membrane potential and the accumulation of reactive oxygen species (ROS), and alleviated the cellular S-phase blockade and reversed the high expression of senescence-associated β-galactosidase (SA-β-gal). Further studies showed that the two cleared damaged mitochondria by enhancing mitochondrial autophagy and restoring cellular energy metabolism homeostasis while promoting type III collagen and elastin synthesis and repairing the expression of Claudin 1 related to skin barrier function. For the first time, the present study reveals the molecular mechanism of CJF extract in delaying skin aging by regulating the FUNDC1-dependent mitochondrial autophagy pathway, which provides a theoretical basis and a candidate strategy for developing novel anti-aging agents targeting mitochondrial quality control. Full article

Background: Dietary advice for Paralympic athletes (PAs) with a spinal cord injury (PAs-SCI) requires particular attention and has been widely studied. However, currently, no particular attention has been addressed to nutritional guidelines for athletes with an amputation (PAs-AMP). This study aimed at filling up this gap, at least partially, and compared veteran PAs-SCI with PAs-AMP. Methods: A sample of 25 male PAs (12 with SCI and 13 with AMP), recruited during two training camps, was submitted to the following questionnaires: allergy questionnaire for athletes (AQUA), Nordic Musculoskeletal Questionnaire (NMQ), Starvation Symptom Inventory (SSI), neurogenic bowel dysfunction (NBD), orthorexia (ORTO-15/ORTO-7), alcohol use disorders identification test (AUDIT), and Mediterranean diet adherence (MDS). The PAs were also submitted to the following measurements: dietary Oxygen Radical Absorbance Capacity (ORAC) and intakes, body composition, handgrip strength (HGS), basal energy expenditure (BEE), peak oxygen uptake (VO_2peak), peak power, peak heart rate (HR), post-exercise ketosis, and antioxidant response after a cardiopulmonary exercise test (CPET) to voluntary fatigue. Results: Compared to PAs-AMP, PAs-SCI had higher NBD and lower VO_2peak (p < 0.05), peak power, peak HR, peak lactate, phase angle (PhA) of the dominant leg (p < 0.05), and ORTO15 (p < 0.05). The latter was related to NBD (r = −0.453), MDS (r = −0.638), and ORAC (r = −0.529), whereas ORTO7 correlated with PhA of the dominant leg (r = 0.485). Significant differences between PAs-AMP and PAs-SCI were not found in the antioxidant response, glucose, and ketone levels after CPET, nor in dietary intake, AUDIT, AQUA, NMQ, SSI, BEE, HGS, and FM%. Conclusions: The present study showed that PAs-SCI and PAs-AMP display similar characteristics in relation to lifestyle, energy intake, basal energy expenditure, and metabolic response to CPET. Based on both the similarities with PAs-SCI and the consequences of the limb deficiency impairment, PAs-AMP and PAs-SCI require personalized nutritional advice. Full article

Background/Objectives: Accurate diagnosis of thyroid cancer is critical but challenging due to overlapping ultrasound (US) features of benign and malignant nodules. This study aimed to evaluate the diagnostic performance of non-invasive and minimally invasive US techniques, including B-mode US, shear wave elastography (SWE), color Doppler, superb microvascular imaging (SMI), and TI-RADS, in patients with suspected thyroid lesions and to assess their reliability and cost effectiveness compared with fine needle aspiration (FNA) biopsy. Methods: A prospective, single-center study (October 2023–February 2025) enrolled 300 patients with suspected thyroid cancer at a Spanish tertiary hospital. Of these, 296 patients with confirmed diagnoses underwent B-mode US, SWE, Doppler, SMI, and TI-RADS scoring, followed by US-guided FNA and Bethesda System cytopathology. Lasso-penalized logistic regression and a bootstrap analysis (1000 replicates) were used to develop diagnostic models. A utility function was used to balance diagnostic reliability and cost. Results: Thyroid cancer was diagnosed in 25 patients (8.3%). Elastography combined with SMI achieved the highest diagnostic performance (Youden index: 0.69; NPV: 97.4%; PPV: 69.1%), outperforming Doppler-only models. Intranodular vascularization was a significant risk factor, while peripheral vascularization was protective. The utility function showed that, when prioritizing cost, elastography plus SMI was cost effective (α < 0.716) compared with FNA. Conclusions: Elastography plus SMI offers a reliable, cost-effective diagnostic rule for thyroid cancer. The utility function aids clinicians in balancing reliability and cost. SMI and generalizability need to be validated in higher prevalence settings. Full article

The development of layer-by-layer polyelectrolyte microcapsules (PMCs) with defined buffer capacity (BC) is a key task for creating stable systems in biomedicine and materials science. Manganese carbonate (MnCO₃), which shares properties with CaCO₃ and the ability to form hollow structures, represents a promising alternative. However, its interaction with polyelectrolytes and its influence on BC remain insufficiently studied. This research focuses on determining the BC of PMCs templated on MnCO₃ cores under varying ionic strength (0.22–3 M NaCl) and temperature (60–90 °C), as well as comparing the results with PMCs templated on CaCO₃ and PS cores. It was found that MnCO₃-based PMCs (PMC_Mn) exhibit hybrid behavior between CaCO₃- and PS-based PMCs: the BC dynamics of PMC_Mn and CaCO₃-based PMCs (PMC_Ca) in water are identical. At different ionic strength at pH < 5, the BC of PMCMn and PS-based PMCs (PMC_PS) remains unchanged, while at pH > 8.5, the BC of PMC_Mn increases only at 3 M NaCl. The BC of PMC_Mn remains stable under heating, whereas the BC of PMC_Ca and PMC_PS decreases. These results confirm that the choice of core material dictates PMC functionality, paving the way for adaptive systems in biosensing and controlled drug delivery. Full article

Background: Persistent Postural-Perceptual Dizziness (PPPD) is a chronic vestibular disorder characterized by dizziness, instability, and visual hypersensitivity. Vestibular Physical Therapy (VPT) is commonly used, but its efficacy remains uncertain due to limited and heterogeneous evidence. Objective: This systematic review and meta-analysis aimed to evaluate the effectiveness of VPT in reducing dizziness and improving balance in individuals with PPPD. Methods: A systematic search of MEDLINE and PEDro was conducted in January 2025. Studies were selected following PRISMA guidelines and included if they assessed VPT interventions in patients diagnosed with PPPD. Risk of bias was assessed using the PEDro scale and the modified Newcastle–Ottawa Scale. The meta-analysis focused on pre- and post-intervention changes in Dizziness Handicap Inventory (DHI) scores using a random-effects model. Results: Six studies met the inclusion criteria. VPT significantly reduced DHI scores (pooled Hedges’ g = 1.60; 95% CI: 0.75–2.45), indicating a moderate to large improvement. Additional outcomes included improvements in postural control (e.g., mini-BESTest and posturography) and psychological well-being (anxiety and depression questionnaires). However, high heterogeneity (I² = 92%) was present across studies. Conclusions: VPT may improve dizziness and balance in PPPD, though evidence is limited. Further high-quality trials with standardized protocols are needed. Full article

Background: The long-term success of total knee arthroplasty (TKA) is often compromised by stress shielding, which can lead to bone resorption and even implant loosening. This study employs finite element analysis (FEA) to compare the stress-shielding effects of a knee prosthesis made from polyether ether ketone (PEEK) with a traditional titanium Ti6Al4V implant on an osteoporotic tibial bone model. Methods: Stress distribution and the stress-shielding factor (SSF) were evaluated at seven critical points in the proximal tibia under physiological loading conditions. Results: Results indicate that the PEEK prosthesis yields a more uniform stress transmission, with von Mises stress levels within the optimal 2–3 MPa range for bone maintenance and consistently negative or near-zero SSF values, implying minimal stress shielding. Conversely, titanium implants exhibited significant stress shielding with high positive SSF values across all points. Additionally, stress concentrations on the polyethylene liner were lower and more evenly distributed in the PEEK model, suggesting reduced wear potential. Conclusions: These findings highlight the biomechanical advantages of PEEK in reducing stress shielding and preserving bone integrity, supporting its potential use to improve implant longevity in TKA. Further experimental and clinical validation are warranted. Full article

Aging is a complex physiological process that profoundly affects the functionality of the musculoskeletal system, contributing to an increase in the incidence of diseases such as osteoporosis, osteoarthritis, and sarcopenia. Cellular senescence plays a crucial role in these degenerative processes, promoting chronic inflammation and tissue dysfunction through the senescence-associated secretory phenotype (SASP). Recently, senotherapeutics have shown promising results in improving musculoskeletal health. Natural compounds such as resveratrol, rapamycin, quercetin, curcumin, vitamin E, genistein, fisetin, and epicatechin act on key signaling pathways, offering protective effects against musculoskeletal decline. On the other hand, molecules such as dasatinib, navitoclax, UBX0101, panobinostat, and metformin have been shown to be effective in eliminating or modulating senescent cells. However, understanding the mechanisms of action, long-term safety, and bioavailability remain areas for further investigation. In this context, physical exercise emerges as an effective non-pharmacological countermeasure, capable of directly modulating cellular senescence and promoting tissue regeneration, representing an integrated strategy to combat age-related diseases. Therefore, we have provided an overview of the main anti-aging compounds and examined the potential of physical exercise as a strategy in the management of age-related musculoskeletal disorders. Further studies should focus on identifying synergistic combinations of pharmacological and non-pharmacological interventions to optimize the effectiveness of anti-aging strategies and promoting healthier musculoskeletal aging. Full article

Background/Objectives: Non-coding microRNA-34a (miR-34a) regulates the expression of key factors involved in several cellular processes, such as differentiation, apoptosis, proliferation, cell cycle, and senescence. Deregulation of the expression of these factors is implicated in the onset and progression of several human diseases, including cancer, neurodegenerative disorders, and pathologies associated with viral infections and inflammation. Despite numerous studies, the molecular mechanisms regulated by miR-34a remain to be fully understood. The present study aimed to generate miR-34a knockout cell lines to identify novel genes potentially regulated by its expression. Methods: We employed the CRISPR-Cas9 gene editing system to knock out the hsa-miR-34a gene in HeLa and 293T cell lines, two widely used models for studying molecular and cellular mechanisms. We compared proliferation rates and gene expression profiles via RNA-seq and qPCR analyses between the wild-type and miR-34a KO cell lines. Results: Knockout of miR-34a resulted in a decreased proliferation rate in both cell lines. Noteworthy, the ablation of miR-34a resulted in increased expression of the long non-coding RNA MALAT1. Additionally, miR-34a-5p silencing in the A375 melanoma cell line led to MALAT1 overexpression. Conclusions: Our findings support the role of the miR-34a/MALAT1 axis in regulating proliferation processes. Full article

Among brain regions, the cerebellum (CBL) has traditionally been associated with motor control. However, increasing evidence from connectomics and functional imaging has expanded this view, revealing its involvement in a wide range of cognitive and integrative processes. Despite this emerging relevance, the CBL has received comparatively less attention in aging research, which has focused mainly on other central nervous system (CNS) regions such as the neocortex and hippocampus. This review synthesizes the current evidence on glial cell aging across the CNS, emphasizing how cerebellar circuits follow distinct trajectories in terms of cellular remodeling, transcriptional reprogramming, and structural vulnerability. Recent findings highlight that cerebellar astrocytes and microglia exhibit specific signatures related to aging compared to their cortical counterpart, including moderate reactivity, selective immune response, and spatial reorganization. Cerebellar white matter (WM) undergoes structural alteration, suggesting that oligodendroglial cells may undergo region-specific alterations, particularly within WM tracts, although these aspects remain underexplored. Despite the presence of glial remodeling, the CBL maintains a notable degree of structural and functional integrity during aging. This resilience may be the result of the CBL’s ability to maintain synaptic adaptability and homeostatic balance, supported by its highly organized and compartmentalized architecture. A better understanding of the dynamics of cerebellar glial cells in aging may provide new insight into the mechanisms of brain maintenance and identify potential biomarkers for healthy brain aging. Full article