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Keywords = heparan-sulfate proteoglycans

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31 pages, 23068 KiB  
Article
Heparan Sulfate Proteoglycans as Potential Markers for In Vitro Human Neural Lineage Specification
by Chieh Yu, Duy L. B. Nguyen, Martina Gyimesi, Ian W. Peall, Son H. Pham, Lyn R. Griffiths, Rachel K. Okolicsanyi and Larisa M. Haupt
Cells 2025, 14(15), 1158; https://doi.org/10.3390/cells14151158 - 26 Jul 2025
Viewed by 372
Abstract
Heparan sulfate proteoglycans (HSPGs) within the neuronal niche are expressed during brain development, contributing to multiple aspects of neurogenesis, yet their roles in glial lineage commitment remain elusive. This study utilised three human cell models expanded under basal culture conditions followed by media-induced [...] Read more.
Heparan sulfate proteoglycans (HSPGs) within the neuronal niche are expressed during brain development, contributing to multiple aspects of neurogenesis, yet their roles in glial lineage commitment remain elusive. This study utilised three human cell models expanded under basal culture conditions followed by media-induced lineage induction to identify a reproducible and robust model of gliogenesis. SH-SY5Y human neuroblastoma cells (neuronal control), ReNcell CX human neural progenitor cells (astrocyte inductive) and ReNcell VM human neural progenitor (mixed neural induction) models were examined. The cultures were characterised during basal and inductive states via Q-PCR, Western Blotting, immunocytochemistry (ICC) and calcium signalling activity analyses. While the ReNcell lines did not produce fully mature or homogeneous astrocyte cultures, the ReNcell CX cultures most closely resembled an astrocytic phenotype with ReNcell VM cells treated with platelet-derived growth factor (PDGF) biased toward an oligodendrocyte lineage. The glycated variant of surface-bound glypican-2 (GPC2) was found to be associated with lineage commitment, with GPC6 and 6-O HS sulfation upregulated in astrocyte lineage cultures. Syndecan-3 (SDC3) emerged as a lineage-sensitive proteoglycan, with its cytoplasmic domain enriched in progenitor-like states and lost upon differentiation, supporting a role in maintaining neural plasticity. Conversely, the persistence of transmembrane-bound SDC3 in astrocyte cultures suggest continued involvement in extracellular signalling and proteoglycan secretion, demonstrated by increased membrane-bound HS aggregates. This data supports HSPGs and HS GAGs as human neural lineage differentiation and specification markers that may enable better isolation of human neural lineage-specific cell populations and improve our understanding of human neurogenesis. Full article
(This article belongs to the Collection Feature Papers in 'Cells of the Nervous System' Section)
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19 pages, 1543 KiB  
Article
Peripheral Leukocyte Syndecan-3 Is Elevated in Alzheimer’s Disease: Evidence from a Human Study
by Anett Hudák, Annamária Letoha and Tamás Letoha
Int. J. Mol. Sci. 2025, 26(14), 6587; https://doi.org/10.3390/ijms26146587 - 9 Jul 2025
Viewed by 702
Abstract
Syndecan-3 (SDC3), a transmembrane heparan sulfate proteoglycan involved in cell signaling and endocytosis, has recently been implicated in the pathogenesis of neurodegenerative disorders. While preclinical studies have demonstrated its role in Alzheimer’s disease (AD), its diagnostic relevance in peripheral blood remains unexplored. In [...] Read more.
Syndecan-3 (SDC3), a transmembrane heparan sulfate proteoglycan involved in cell signaling and endocytosis, has recently been implicated in the pathogenesis of neurodegenerative disorders. While preclinical studies have demonstrated its role in Alzheimer’s disease (AD), its diagnostic relevance in peripheral blood remains unexplored. In this human cohort study, we measured SDC3 expression in peripheral blood mononuclear cells (PBMCs) from 22 clinically diagnosed AD patients and 20 cognitively unimpaired non-AD controls using a custom ELISA. The findings were compared with plasma p-tau217 levels and a panel of systemic laboratory markers. PBMC-expressed SDC3 was significantly elevated in AD patients and moderately correlated with AD status (r = 0.309, p = 0.0465) independent of age. Notably, SDC3 levels were inversely correlated with systemic inflammatory markers, including C-reactive protein (CRP; r = −0.421, p = 0.0055) and D-dimer (r = −0.343, p = 0.038), suggesting an AD-associated immune phenotype distinct from acute-phase or vascular inflammation. Conversely, plasma p-tau217 levels did not significantly differ between groups but correlated with markers of tissue injury and inflammation (LDH, GOT, and ferritin), potentially reflecting systemic influences in non-AD controls. A multivariable logistic regression model incorporating SDC3, p-tau217, and age demonstrated high diagnostic accuracy (AUC = 0.85). These findings identify PBMC-expressed SDC3 as a promising blood-based biomarker candidate for AD, warranting further validation in larger, biomarker-confirmed cohorts. Full article
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12 pages, 1044 KiB  
Article
Endplate Lesions of the Lumbar Spine: Biochemistry and Genetics
by Alessandra Colombini, Vincenzo Raffo, Angela Elvira Covone, Tito Bassani, Domenico Coviello, Sabina Cauci, Ludovica Pallotta and Marco Brayda-Bruno
Genes 2025, 16(7), 738; https://doi.org/10.3390/genes16070738 - 26 Jun 2025
Viewed by 406
Abstract
Background/Objectives: Endplate lesions of the lumbar spine are often asymptomatic and frequently observed incidentally by radiological assessment. Variants in the vitamin D receptor gene (VDR) and an increase in some biochemical markers related to the osteo-cartilaginous metabolism were found in patients [...] Read more.
Background/Objectives: Endplate lesions of the lumbar spine are often asymptomatic and frequently observed incidentally by radiological assessment. Variants in the vitamin D receptor gene (VDR) and an increase in some biochemical markers related to the osteo-cartilaginous metabolism were found in patients with endplate lesions. The aim of this study was to identify biochemical and genetic markers putatively associated with the presence of endplate lesions of the lumbar spine. Methods: Quantification of circulating bone remodeling proteins was obtained from 10 patients with endplate lesions and compared with age- and sex-matched controls. Whole exome sequencing (WES) was performed on patient genomic DNA using the Novaseq 6000 platform (Illumina, San Diego, CA, USA), obtaining a median read depth of 117×–200×, with ≥98% of regions covering at least 20×. The sequencing product was aligned to the reference genome (GRCh38.p13-hg38) and analyzed with Geneyx software. Results: We observed modifications in the levels of circulating proteins involved in bone remodeling and angiogenesis. We identified variants of interest in aggrecan (ACAN), bone morphogenetic protein 4 (BMP4), cytochrome P450 family 3 subfamily A member 4 (CYP3A4), GLI family zinc finger 2 (GLI2), heparan sulfate proteoglycan 2 (HSPG2), and mesoderm posterior bHLH transcription factor 2 (MESP2). VDR polymorphism (rs2228570) was present in nine patients, with the homozygotic ones having more severe endplate lesions and higher levels of the analyzed circulating markers in comparison with heterozygotic patients. Conclusions: These data represent interesting evidence of genetic variants, particularly in VDR, and altered levels of circulating markers of bone remodeling associated with endplate lesions, which should be confirmed in a larger population. The hypothesis suggested by our results is that the endplate lesions could be the consequence of an altered ossification mechanism at the vertebral level. Full article
(This article belongs to the Special Issue Genes and Gene Polymorphisms Associated with Complex Diseases)
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19 pages, 6864 KiB  
Article
Co-Aggregation of Syndecan-3 with β-Amyloid Aggravates Neuroinflammation and Cognitive Impairment in 5×FAD Mice
by Fan Ye, Mingfeng Li, Min Liu, Xinghan Wu, Fan Tian, Yanju Gong, Yan Cao, Jingtai Zhang, Xueling Zhang, Chuan Qin and Ling Zhang
Int. J. Mol. Sci. 2025, 26(12), 5502; https://doi.org/10.3390/ijms26125502 - 8 Jun 2025
Viewed by 3007
Abstract
Abnormal deposition of β-amyloid (Aβ) is a core pathological feature of Alzheimer’s disease (AD). Syndecan-3 (SDC3), a type I transmembrane heparan sulfate proteoglycan (HSPG), is abnormally overexpressed in the brains of AD patients and model animals, specifically accumulating in the peri-plaque region of [...] Read more.
Abnormal deposition of β-amyloid (Aβ) is a core pathological feature of Alzheimer’s disease (AD). Syndecan-3 (SDC3), a type I transmembrane heparan sulfate proteoglycan (HSPG), is abnormally overexpressed in the brains of AD patients and model animals, specifically accumulating in the peri-plaque region of amyloid plaques. However, its regulatory mechanism in the process of Aβ deposition remains unclear. This study aims to clearly define the role of SDC3 in Aβ aggregation and neuroinflammation, two critical processes in AD pathogenesis. Specifically, we investigate how SDC3 modulates Aβ aggregation and its interaction with neuroinflammatory pathways, which may contribute to the progression of AD. By elucidating the mechanisms underlying SDC3’s involvement in these processes, we seek to provide new insights into potential therapeutic targets for AD. In this study, a 5×FAD mouse model with downregulated SDC3 expression was constructed. Behavioral assessments and synaptic function tests were performed to explore the effects of SDC3 on cognition in 5×FAD mice. Immunofluorescence co-localization technology was utilized to analyze the pathological co-deposition of SDC3 and Aβ in the hippocampus, cortex, and meningeal blood vessels. Quantitative assessments of pro-inflammatory cytokines such as Tnf-α and Cxcl10 in the brain were performed through histopathological analysis combined with qPCR. Western blotting was used to examine the phosphorylation status of STAT1/STAT3 and the expression changes of IBA1/GFAP to systematically analyze the molecular mechanisms through which SDC3 regulates AD pathology. This study revealed that SDC3 expression was significantly upregulated in the brain regions of the 5×FAD model mice and co-localized pathologically with Aβ. Cell lineage tracing analysis showed that the elevated SDC3 expression primarily originated from glial cells. Behavioral and pathological results demonstrated that downregulation of SDC3 significantly improved cognitive dysfunction in the model mice and effectively reduced the Aβ burden in the brain. Molecular mechanism studies showed that downregulation of SDC3 reduced the phosphorylation of STAT1 and STAT3, thereby inhibiting the activation of the JAK-STAT and cGAS-STING signaling pathways, reducing the activation of microglia/astrocytes and suppressing the expression of pro-inflammatory cytokines such as Tnf-α and Cxcl10. This study reveals that SDC3 co-localizes with Aβ pathology and synergistically exacerbates neuroinflammation. Knockdown of SDC3 can simultaneously reduce both Aβ deposition and the release of inflammatory factors from glial cells. Mechanistic research indicates that SDC3 drives a “glial activation–cytokine release” vicious cycle through the JAK-STAT and cGAS-STING signaling pathways. These findings suggest that SDC3 may serve as a key hub coordinating amyloid pathology and neuroinflammation in AD, providing new insights for the development of combination therapies targeting the HSPG network. Full article
(This article belongs to the Section Molecular Neurobiology)
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24 pages, 6482 KiB  
Article
Transmembrane Protein-184A Interacts with Syndecan-4 and Rab GTPases and Is Required to Maintain VE-Cadherin Levels
by Leanna M. Altenburg, Stephanie H. Wang, Grace O. Ciabattoni, Amelia Kennedy, Rachel L. O’Toole, Sara L. N. Farwell, M. Kathryn Iovine and Linda J. Lowe-Krentz
Cells 2025, 14(11), 833; https://doi.org/10.3390/cells14110833 - 3 Jun 2025
Viewed by 781
Abstract
VE-cadherin (VE-cad) membrane stability and localization regulates adhesion formation and actin cytoskeleton dynamics in angiogenesis and vascular remodeling and requires the heparan sulfate proteoglycan (HSPG), Syndecan-4 (Sdc4). This study characterizes the interactions of the heparin receptor, Transmembrane protein-184A (TMEM184A), and Sdc4 in bovine [...] Read more.
VE-cadherin (VE-cad) membrane stability and localization regulates adhesion formation and actin cytoskeleton dynamics in angiogenesis and vascular remodeling and requires the heparan sulfate proteoglycan (HSPG), Syndecan-4 (Sdc4). This study characterizes the interactions of the heparin receptor, Transmembrane protein-184A (TMEM184A), and Sdc4 in bovine aortic endothelial cells (BAOECs) and the regenerating Zebrafish (ZF) caudal fin and measures the effect of siRNA TMEM184A KD (siTMEM) and TMEM184A overexpression (TMEM OE) on VE-cad levels and localization in confluent and sub-confluent cultured BAOECs. Additionally, we examined the effect of siTMEM on key Rab GTPase trafficking regulators and migrating BAOECs in scratch wound healing assays. We demonstrated that TMEM184A and Sdc4 colocalize in BAOECs and that Sdc4 OE increases colocalization in an HS chain dependent manner, while both Tmem184a and Sdc4 cooperate synergistically in ZF fin angiogenic and tissue repair. We also showed that siTMEM decreases VE-cad membrane and cytoplasmic levels, while increasing scratch wound migration rates. However, TMEM OE cells show increased vesicle formation and VE-cad trafficking and membrane recovery. These findings characterize TMEM184A-Sdc4 cooperation in angiogenesis and indicate a dual function of TMEM184A in signaling and trafficking in vascular cells that promotes VE-cad recovery and membrane localization. Full article
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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 887
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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21 pages, 5986 KiB  
Article
FAM20B Gain-of-Function Blocks the Synthesis of Glycosaminoglycan Chains of Proteoglycans and Inhibits Proliferation and Migration of Glioblastoma Cells
by Lydia Barré, Irfan Shaukat and Mohamed Ouzzine
Cells 2025, 14(10), 712; https://doi.org/10.3390/cells14100712 - 14 May 2025
Viewed by 546
Abstract
Heparan sulfate (HS) and chondroitin sulfate (CS) proteoglycans (PGs) are essential regulators of many biological processes including cell differentiation, signalization, and proliferation. PGs interact mainly via their glycosaminoglycan (GAG) chains, with a large number of ligands including growth factors, enzymes, and extracellular matrix [...] Read more.
Heparan sulfate (HS) and chondroitin sulfate (CS) proteoglycans (PGs) are essential regulators of many biological processes including cell differentiation, signalization, and proliferation. PGs interact mainly via their glycosaminoglycan (GAG) chains, with a large number of ligands including growth factors, enzymes, and extracellular matrix components, thereby modulating their biological activities. HSPGs and CSPGs share a common tetrasaccharide linker region, which undergoes modifications, particularly the phosphorylation of the xylose residue by the kinase FAM20B. Here, we demonstrated that FAM20B gain-of-function decreased, in a dose dependent manner, the synthesis of both CS- and HS-attached PGs. In addition, we showed that blockage of GAG chain synthesis by FAM20B was suppressed by the mutation of aspartic acid residues D289 and D309 of the catalytic domain. Interestingly, we bring evidence that, in contrast to FAM20B, expression of the 2-phosphoxylose phosphatase XYLP increases, in a dose dependent manner, GAG chain synthesis and rescues the blockage of GAG chains synthesis induced by FAM20B. In line with previous reports, we found that FAM20B loss-of-function reduced GAG chain synthesis. Finally, we found that FAM20B inhibited proliferation and migration of glioblastoma cells, thus revealing the critical role of GAG chains of PGs in glioblastoma cell tumorigenesis. This study revealed that both gain- and loss-of-function of FAM20B led to decreased GAG chain synthesis, therefore suggesting that a balance between phosphorylation and dephosphorylation of the xylose by FAM20B and XYLP, respectively, is probably an essential factor for the regulation of the rate of PG synthesis. Full article
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18 pages, 1121 KiB  
Review
Shed Syndecan-4 and Its Possible Roles in Osteoarthritis
by Kangping He, Haozhe Ren, Xiaohua Chen, Feng He, Yueying Zhang, Hongyun Zhang, Feifei Li and Shibin Yu
Biomedicines 2025, 13(5), 1037; https://doi.org/10.3390/biomedicines13051037 - 25 Apr 2025
Viewed by 639
Abstract
The specific pathogenesis of osteoarthritis (OA) remains not fully understood. As a transmembrane heparan sulfate proteoglycan, syndecan-4 (SDC4) has been proven to play an important role in the development of OA. Notably, the extracellular domain of SDC4 can be cleaved by proteolytic enzymes, [...] Read more.
The specific pathogenesis of osteoarthritis (OA) remains not fully understood. As a transmembrane heparan sulfate proteoglycan, syndecan-4 (SDC4) has been proven to play an important role in the development of OA. Notably, the extracellular domain of SDC4 can be cleaved by proteolytic enzymes, leading to the release of shed SDC4 (sSDC4), which subsequently regulates various biological processes in an autocrine or paracrine manner. This review analyzed 97 publications (1987–2025) from Pubmed and the Web of Science Core Collection using specific key words (syndecan-4, shed syndecan-4, and osteoarthritis), providing a comprehensive overview of the current research on sSDC4, including its shedding enzymes and specific cleavage sites, as well as the factors and mechanisms that influence SDC4 shedding. Furthermore, it summarizes the functions of both sSDC4 and its remaining membrane-bound domain. Finally, the roles of sSDC4 in OA are discussed to identify potential therapeutic targets and explore new strategies for the treatment of OA. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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24 pages, 1707 KiB  
Review
Endocytic Pathways Unveil the Role of Syndecans in the Seeding and Spreading of Pathological Protein Aggregates: Insights into Neurodegenerative Disorders
by Anett Hudák and Tamás Letoha
Int. J. Mol. Sci. 2025, 26(9), 4037; https://doi.org/10.3390/ijms26094037 - 24 Apr 2025
Cited by 1 | Viewed by 720
Abstract
Alzheimer’s disease and other neurodegenerative disorders are characterized by the accumulation of misfolded proteins, such as amyloid-beta, tau, and α-synuclein, which disrupt neuronal function and contribute to cognitive decline. Heparan sulfate proteoglycans, particularly syndecans, play a pivotal role in the seeding, aggregation, and [...] Read more.
Alzheimer’s disease and other neurodegenerative disorders are characterized by the accumulation of misfolded proteins, such as amyloid-beta, tau, and α-synuclein, which disrupt neuronal function and contribute to cognitive decline. Heparan sulfate proteoglycans, particularly syndecans, play a pivotal role in the seeding, aggregation, and spreading of toxic protein aggregates through endocytic pathways. Among these, syndecan-3 is particularly critical in regulating the internalization of misfolded proteins, facilitating their propagation in a prion-like manner. This review examines the mechanisms by which syndecans, especially SDC3, contribute to the seeding and spreading of pathological protein aggregates in neurodegenerative diseases. Understanding these endocytic pathways provides valuable insights into the potential of syndecans as biomarkers and therapeutic targets for early intervention in Alzheimer’s disease and other related neurodegenerative disorders. Full article
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17 pages, 13939 KiB  
Article
FAM20B-Catalyzed Glycosylation Regulates the Chondrogenic and Osteogenic Differentiation of the Embryonic Condyle by Controlling IHH Diffusion and Release
by Xiaoyan Chen, Han Liu, Yuhong Huang, Leilei Li, Xuxi Jiang, Bo Liu, Nan Li, Lei Zhu, Chao Liu and Jing Xiao
Int. J. Mol. Sci. 2025, 26(9), 4033; https://doi.org/10.3390/ijms26094033 - 24 Apr 2025
Viewed by 554
Abstract
Although the roles of proteoglycans (PGs) have been well documented in the development and homeostasis of the temporomandibular joint (TMJ), how the glycosaminoglycan (GAG) chains of PGs contribute to TMJ chondrogenesis and osteogenesis still requires explication. In this study, we found that FAM20B, [...] Read more.
Although the roles of proteoglycans (PGs) have been well documented in the development and homeostasis of the temporomandibular joint (TMJ), how the glycosaminoglycan (GAG) chains of PGs contribute to TMJ chondrogenesis and osteogenesis still requires explication. In this study, we found that FAM20B, a hexokinase essential for attaching GAG chains to the core proteins of PGs, was robustly activated in the condylar mesenchyme during TMJ development. The inactivation of Fam20b in craniofacial neural crest cells (CNCCs) dramatically reduced the synthesis and accumulation of GAG chains rather than core proteins in the condylar cartilage, which resulted in a hypoplastic condylar cartilage by severely promoting chondrocyte hypertrophy and perichondral ossification. In the condyles of Wnt1-Cre;Fam20bf/f mouse embryos, enlarged Ihh- and COL10-expressing domains indicated premature hypertrophy resulting from an attenuated IHH-PTHRP negative feedback in condylar chondrocytes, while increased osteogenic markers, canonical Wnt activity, and type-H angiogenesis verified the enhanced osteogenesis in the perichondrium. Further ex vivo investigations revealed that the loss of Fam20b decreased the domain area but increased the activity of HH signaling in the embryonic condylar mesenchyme. Moreover, the abrogation of GAG chains in heparan sulfate and chondroitin sulfate proteoglycans led to a rapid up- and then downregulation of HH signaling in condylar chondrocytes, implicating a “slow-release” manner of growth factors controlled by GAG chains. Overall, this study revealed a comprehensive role of the FAM20B-catalyzed GAG chain synthesis in the chondrogenic and osteogenic differentiation of the embryonic TMJ condyle. Full article
(This article belongs to the Special Issue Glycobiology in Human Health and Disease)
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16 pages, 2129 KiB  
Article
Trastuzumab Decreases the Expression of G1/S Regulators and Syndecan-4 Proteoglycan in Human Rhabdomyosarcoma
by Dora Julianna Szabo, Eniko Toth, Kitti Szabo, Zsofia Kata Hegedus, Noemi Bozsity-Farago, Istvan Zupko, Laszlo Rovo, Xue Xiao, Lin Xu and Aniko Keller-Pinter
Int. J. Mol. Sci. 2025, 26(5), 2137; https://doi.org/10.3390/ijms26052137 - 27 Feb 2025
Viewed by 962
Abstract
Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, arises from skeletal muscle cells that fail to differentiate terminally. Two subgroups of RMS, fusion-positive and fusion-negative RMS (FPRMS and FNRMS, respectively), are characterized by the presence or absence of the PAX3/7-FOXO1 fusion [...] Read more.
Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, arises from skeletal muscle cells that fail to differentiate terminally. Two subgroups of RMS, fusion-positive and fusion-negative RMS (FPRMS and FNRMS, respectively), are characterized by the presence or absence of the PAX3/7-FOXO1 fusion gene. RMSs frequently exhibit increased expression of human epidermal growth factor receptor-2 (HER2). Trastuzumab is a humanized monoclonal antibody targeting HER2, and its potential role in RMS treatment remains to be elucidated. Syndecan-4 (SDC4) is a heparan sulfate proteoglycan (HSPG) affecting myogenesis via Rac1-mediated actin remodeling. Previously, we demonstrated that the SDC4 gene is amplified in 28% of human FNRMS samples, associated with high mRNA expression, suggesting a tumor driver role. In this study, after analyzing the copy numbers and mRNA expressions of other HSPGs in human RMS samples, we found that in addition to SDC4, syndecan-1, syndecan-2, and glypican-1 were also amplified and highly expressed in FNRMS. In RD (human FNRMS) cells, elevated SDC4 expression was accompanied by low levels of phospho-Ser179 of SDC4, leading to high Rac1-GTP activity. Notably, this high SDC4 expression in RD cells decreased following trastuzumab treatment. Trastuzumab decreased the levels of G1/S checkpoint regulators cyclin E and cyclin D1 and reduced the cell number; however, it also downregulated the cyclin-dependent kinase inhibitor p21. The level of MyoD, a transcription factor essential for RMS cell survival, also decreased following trastuzumab administration. Our findings contribute to the understanding of the role of SDC4 in FNRMS. Since HER2 is expressed in about half of RMSs, the trastuzumab-mediated changes observed here may have therapeutic implications. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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13 pages, 2526 KiB  
Review
A Narrative Review: Syndecans in Aortic Aneurysm Pathogenesis and Course—Biomarkers and Targets?
by Calogera Pisano, Laura Asta, Adriana Sbrigata and Carmela Rita Balistreri
Int. J. Mol. Sci. 2025, 26(3), 1211; https://doi.org/10.3390/ijms26031211 - 30 Jan 2025
Cited by 4 | Viewed by 1198
Abstract
The maintenance of the integrity of the entire endothelium, glycocalyx included, and, therefore, of tissue aorta’s homeostasis, depends on the expressions of several molecular pathways and their interactions, such as syndecan molecules. Alterations in syndecans, i.e., quantitative alterations or linking to their shedding, [...] Read more.
The maintenance of the integrity of the entire endothelium, glycocalyx included, and, therefore, of tissue aorta’s homeostasis, depends on the expressions of several molecular pathways and their interactions, such as syndecan molecules. Alterations in syndecans, i.e., quantitative alterations or linking to their shedding, contributes to invoking endothelium dysfunction, which causes damage to the vessel wall due to the increased production of growth-stimulating and pro-inflammatory gene products. Inflammatory processes negatively affect the integrity of the endothelial glycocalyx, a dynamic layer of the luminal portion of endothelial cells composed of proteoglycans, glycoproteins, and glycosaminoglycans, i.e., syndecans. In turn, structural alterations in the endothelial glycocalyx influence the coagulative state, increasing pro-thrombotic processes. The family of syndecans constitutes a major component of glycocalyx or, more accurately, the major source of cell surface heparan sulfate. It encompasses four components: syndecan-1, syndecan-2, and syndecan-4 (with syndecan-3 only expressed in neural tissue), which have a fundamental role in regulating the events of acute and chronic aorta damage subsequently correlated with the formation of aneurysms. As such, the aim of our review is to highlight the current knowledge on the roles of syndecans and to analyze their relationship with the pathological processes of the aortic wall based on the most recent literature. Full article
(This article belongs to the Special Issue Molecular Diagnosis in Cardiovascular Diseases)
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21 pages, 2838 KiB  
Article
A Nanoparticle Comprising the Receptor-Binding Domains of Norovirus and Plasmodium as a Combination Vaccine Candidate
by Ming Xia, Pengwei Huang, Frank S. Vago, Wen Jiang, Xi Jiang and Ming Tan
Vaccines 2025, 13(1), 34; https://doi.org/10.3390/vaccines13010034 - 1 Jan 2025
Viewed by 1953
Abstract
Background: Noroviruses, which cause epidemic acute gastroenteritis, and Plasmodium parasites, which lead to malaria, are two infectious pathogens that pose threats to public health. The protruding (P) domain of norovirus VP1 and the αTSR domain of the circumsporozoite protein (CSP) of Plasmodium sporozoite [...] Read more.
Background: Noroviruses, which cause epidemic acute gastroenteritis, and Plasmodium parasites, which lead to malaria, are two infectious pathogens that pose threats to public health. The protruding (P) domain of norovirus VP1 and the αTSR domain of the circumsporozoite protein (CSP) of Plasmodium sporozoite are the glycan receptor-binding domains of the two pathogens for host cell attachment, making them excellent targets for vaccine development. Modified norovirus P domains self-assemble into a 24-meric octahedral P nanoparticle (P24 NP). Methods: We generated a unique P24-αTSR NP by inserting the αTSR domain into a surface loop of the P domain. The P-αTSR fusion proteins were produced in the Escherichia coli expression system and the fusion protein self-assembled into the P24-αTSR NP. Results: The formation of the P24-αTSR NP was demonstrated through gel filtration, electron microscopy, and dynamic light scattering. A 3D structural model of the P24-αTSR NP was constructed, using the known cryo-EM structure of the previously developed P24 NP and P24-VP8* NP as templates. Each P24-αTSR NP consists of a P24 NP core, with 24 surface-exposed αTSR domains that have retained their general conformations and binding function to heparan sulfate proteoglycans. The P24-αTSR NP is immunogenic, eliciting strong antibody responses in mice toward both the norovirus P domain and the αTSR domain of Plasmodium CSP. Notably, sera from mice immunized with the P24-αTSR NP bound strongly to Plasmodium sporozoites and blocked norovirus VLP attachment to their glycan receptors. Conclusion: These data suggest that the P24-αTSR NP may serve as a combination vaccine against both norovirus and Plasmodium parasites. Full article
(This article belongs to the Collection Advance in Nanoparticles as Vaccine Adjuvants)
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80 pages, 2449 KiB  
Review
Exploring the Chemical Features and Biomedical Relevance of Cell-Penetrating Peptides
by Liliana Marisol Moreno-Vargas and Diego Prada-Gracia
Int. J. Mol. Sci. 2025, 26(1), 59; https://doi.org/10.3390/ijms26010059 - 25 Dec 2024
Cited by 3 | Viewed by 3527
Abstract
Cell-penetrating peptides (CPPs) are a diverse group of peptides, typically composed of 4 to 40 amino acids, known for their unique ability to transport a wide range of substances—such as small molecules, plasmid DNA, small interfering RNA, proteins, viruses, and nanoparticles—across cellular membranes [...] Read more.
Cell-penetrating peptides (CPPs) are a diverse group of peptides, typically composed of 4 to 40 amino acids, known for their unique ability to transport a wide range of substances—such as small molecules, plasmid DNA, small interfering RNA, proteins, viruses, and nanoparticles—across cellular membranes while preserving the integrity of the cargo. CPPs exhibit passive and non-selective behavior, often requiring functionalization or chemical modification to enhance their specificity and efficacy. The precise mechanisms governing the cellular uptake of CPPs remain ambiguous; however, electrostatic interactions between positively charged amino acids and negatively charged glycosaminoglycans on the membrane, particularly heparan sulfate proteoglycans, are considered the initial crucial step for CPP uptake. Clinical trials have highlighted the potential of CPPs in diagnosing and treating various diseases, including cancer, central nervous system disorders, eye disorders, and diabetes. This review provides a comprehensive overview of CPP classifications, potential applications, transduction mechanisms, and the most relevant algorithms to improve the accuracy and reliability of predictions in CPP development. Full article
(This article belongs to the Section Biochemistry)
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13 pages, 847 KiB  
Article
Excess Weight Impairs Oocyte Quality, as Reflected by mtDNA and BMP-15
by Emiliya Sigal, Maya Shavit, Yuval Atzmon, Nardin Aslih, Asaf Bilgory, Daniella Estrada, Mediea Michaeli, Nechama Rotfarb, Yasmin Shibli Abu-Raya, Shilhav Meisel-Sharon and Einat Shalom-Paz
Cells 2024, 13(22), 1872; https://doi.org/10.3390/cells13221872 - 12 Nov 2024
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Abstract
This prospective, case-control study evaluated the impact of obesity on oocyte quality based on mtDNA expression in cumulus cells (CC), and on bone morphogenetic protein 15 (BMP-15) and heparan sulfate proteoglycan 2 (HSPG2) in follicular fluid (FF). It included women 18 to <40 [...] Read more.
This prospective, case-control study evaluated the impact of obesity on oocyte quality based on mtDNA expression in cumulus cells (CC), and on bone morphogenetic protein 15 (BMP-15) and heparan sulfate proteoglycan 2 (HSPG2) in follicular fluid (FF). It included women 18 to <40 years of age, divided according to BMI < 24.9 (Group 1, n = 28) and BMI > 25 (Group 2, n = 22). Demographics, treatment, and pregnancy outcomes were compared. The mtDNA in CC, BMP-15, HSPG2, the lipid profile, the hormonal profile, and C-reactive protein were evaluated in FF and in blood samples. The BMP-15 levels in FF and the mitochondrial DNA in CC were higher in Group 1 (38.8 ± 32.5 vs. 14.3 ± 10.8 ng/mL; p = 0.001 and 1.10 ± 0.3 vs. 0.87 ± 0.18-fold change; p = 0.016, respectively) than in Group 2. High-density lipoprotein levels in blood and FF were higher in Group 1 (62 ± 18 vs. 50 ± 12 mg/dL; p = 0.015 and 34 ± 26 vs. 20.9 ± 7.2 mg/dL; p = 0.05, respectively). Group 2 had higher blood C-reactive protein (7.1 ± 5.4 vs. 3.4 ± 4.3 mg/L; p = 0.015), FF (5.2 ± 3.8 vs. 1.5 ± 1.6 mg/L; p = 0.002) and low-density lipoprotein levels (91 ± 27 vs. 71 ± 22 mg/dL; p = 0.008) vs. Group 1. Group 1 demonstrated a trend toward a better clinical pregnancy rate (47.8% vs. 28.6%: p = 0.31) and frozen embryo transfer rate (69.2% vs. 53.8; p = 0.69). Higher BMI resulted in lower BMP-15 levels and reduced mtDNA expression, which reflect decreased oocyte quality in overweight women. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Reproductive System Diseases)
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