bims-supasi 2025-08-17 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2025–08–17
nineteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Correlation of Indoxyl Sulfate to Hearing Impairment in Chronic Kidney Disease Patients.
Chondroitin sulfate protects against synaptic impairment caused by fluorosis through the Erk1/2-MMP-9 signaling pathway.
Molecular expression of glycosaminoglycans modifies the plasticity of biphasic mesothelioma in favor of tumor progression.
Advances in Chondroitin Sulfate-Based Nanoplatforms for Biomedical Applications.
Heparan sulfate N-deacetylase/N-sulfotransferase-1 regulates glioblastoma cell migration and invasion.
Heparan Sulfate Proteoglycans as Potential Markers for In Vitro Human Neural Lineage Specification.
Insights into the alkaline degradation of oxidized chondroitin sulfate: Implications in Schiff base formation for hydrogel fabrication.
Neuroligin-3 interaction with CSPG4 regulates normal and malignant glial precursors through PIEZO1.
Dehydroepiandrosterone sulfate (DHEA-S), cortisol, and adrenocorticotropic hormone (ACTH) levels in drug-naïve, first-episode patients with psychosis.
Preparation, structure, and biological activity of sulfated polysaccharides from green algae in the Cladophoraceae (Cladophorales, Ulvophyceae).
Sulfated Polysaccharides of Potamogeton lucens as a Promising Immunostimulatory Agent in Activation of RAW264.7 and NK Cells.
Translocation of penetratin-like peptides involving calcium-dependent interactions between glycosaminoglycans and phosphocholine headgroups of the membrane lipid bilayer.
Dehydroepiandrosterone (DHEA) in relation to breast cancer.
Selective inhibition of cathepsin S elastolytic activity by exopolysaccharides from deep-sea hydrothermal bacteria.
Double-network carboxymethyl chitosan/chondroitin sulfate hydrogel microspheres prepared by green-LED-triggered droplet photopolymerization for malachite green adsorption.
Changes of hormone levels for postmenopausal women after bilateral oophorectomy: A meta-analysis.
Peripheral Macular Endothelial Dystrophy: Clinical, Histopathologic, Genetic and Functional Characterization.
Cortisol, DHEAS, and the cortisol/DHEAS ratio as predictors of epigenetic age acceleration.
Systemic Uremic Toxin Burden in Autism Spectrum Disorder: A Stratified Urinary Metabolite Analysis.

Iran J Otorhinolaryngol. 2025 ;37(4): 197-204

Correlation of Indoxyl Sulfate to Hearing Impairment in Chronic Kidney Disease Patients.

Fadillah-Akbar Sanjani, Tengku-Siti-Hajar Haryuna, Farhat Farhat, Syafrizal Nasution, Juliandi Harahap, Yuliani M Lubis, Harry-Agustaf Asroel, Khalisanni Khalid.

   Introduction: Chronic Kidney Disease (CKD) is considered a public health issue because its frequency is increasing in adults. When a person experiences renal failure, one of the most researched solutes that builds up in plasma is indoxyl sulfate. This toxin can attach to proteins, and it is a byproduct of the tryptophan metabolism in the diet, which provides pro-oxidative and pro-inflammatory activity. In CKD, the redox imbalance associated with oxidative stress is associated with pathophysiological issues brought on by the buildup of uremic toxins. The cochlea is highly susceptible to oxidative stress, which consequently causes permanent cochlear degeneration. To better understand the connection between Indoxyl sulfate levels and hearing loss in CKD patients, we examined the results of pure tone audiometry and OAE examinations.
Materials and Methods: This research was conducted on 27 people with stage 5 CKD who had their blood plasma levels of indoxyl sulfate measured before having their hearing ability assessed by OAE and pure tone audiometry. Next, a correlation test was carried out between the results of Indoxyl sulfate levels and the results of hearing function tests in CKD patients.
Results: The indoxyl sulfate value and degree of auditory impairment had a strong positive correlation, according to the Spearman correlation test. (r = 0.881; p = 0.001) and an inverse relationship between the Indoxyl sulfate value and SNR (r = -0.761; p = 0.001).
Conclusion: CKD patients have impaired hearing, which is correlated with the amount of uremic toxin Indoxyl Sulfate that has accumulated.

Keywords:  Chronic kidney disease; Hearing loss; Indoxyl sulfate; OAE; Pure tone audiometry

DOI:  https://doi.org/10.22038/ijorl.2025.77733.3633
Sci Rep. 2025 Aug 13. 15(1): 29760

Chondroitin sulfate protects against synaptic impairment caused by fluorosis through the Erk1/2-MMP-9 signaling pathway.

Fujun Ai, Shengyuan Wang, Ling Ye, Wen Wan, Xiao Zhou, Minghai Liu, Kaiju Mo, Yongheng Lu, Na Wei, Zhizhong Guan, Yanjie Liu.

  Prolonged exposure to fluoride may induce neurotoxic effects. Chondroitin sulfate (CS) exhibits protective functions within the central nervous system (CNS); however, the mechanism by which CS protects synapses against fluoride remains incompletely understood. Our objective was to investigate the protective efficacy of CS on synapses and decipher its underlying mechanisms. We showed that fluoride exposure reduced the expression of synaptic protein synaptophysin (SYN) and impaired learning and memory functions, whereas CS counteracted these alterations, suggesting its protective effect against fluoride-induced cognitive deficits. Further studies revealed disruption of the Erk1/2/MMP-2/MMP-9 signaling pathway both in vivo and in vitro, manifested by increased total Erk1/2, Erk1/2 phosphorylation and MMP-9 expression, along with decreased MMP-2 levels. Importantly, treatment of SH-SY5Y cells with PD98059 or CS attenuated fluoride-induced effects, indicating a regulatory role of CS in the Erk1/2/MMP-9 signaling pathway. However, MMP-2 was not implicated in this process. These data demonstrate the neuroprotective effects of CS and highlight its potential for protecting against fluoride-induced neurotoxicity and synaptic impairment.

Keywords:  Chondroitin sulfate; Erk1/2; Fluoride; MMP-2; MMP-9; SYN

DOI:  https://doi.org/10.1038/s41598-025-14631-7
Glycoconj J. 2025 Aug 13.

Molecular expression of glycosaminoglycans modifies the plasticity of biphasic mesothelioma in favor of tumor progression.

Camila Machado Baldavira, Aline Nery Qualiotto, Tabatha Gutierrez Prieto, Sandra de Morais Fernezlian, Aline Assato, Marcelo Balancin, Teresa Takagaki, Alexandre Ab'Saber, Ana Paula Pereira Velosa, Walcy Rosolia Teodoro, Vera Luiza Capelozzi.

  The study aimed to verify whether the expression of glycosaminoglycans (GAGs) and proteoglycans (PGs) in the tumor matrix affects the plasticity of mesothelioma and its relationship with the phenotype, progression, and resistance to treatment of malignant mesothelioma (MM). As MM is highly aggressive, understanding the molecular mechanisms that regulate the abilities of tumor cells to alter their behaviors and shapes is essential to the development of new therapeutic strategies. To test this hypothesis, we studied 66 samples of human biphasic MM. The expression levels of the GAGs heparan sulfate (HS) and chondroitin sulfate (SC), as well as the PGs versican, biglycan, and perlecan were detected using immunohistochemistry, and their expression was quantified using semi-automated digital analysis. We found that the fusiform phenotype of MM cells was associated with higher expression levels of HS, versican, and biglycan (all P-values < 0.001) in the extracellular matrix. This suggests that the increase and eventual rapid turnover of cell membrane PGs resulted in a variation in shape from polygonal to fusiform phenotypes, whereas GAGs were associated with cell aggregation-thus indicating the distinct functions of different GAGs. Multivariate Cox regression analysis showed that non-surgical patients (hazard ratio [HR]: 4.03 (1.26-12.82); P = 0.02), whose tumors presented necrosis (P < 0.001), high HS expression (P = 0.02), and low biglycan expression (HR: 2.68 [1.16-6.18]; P = 0.02) had significantly worse overall survival rates. We concluded that the expression of GAGs and PGs in the ECM affects the plasticity of MM, modifies its phenotype, and facilitates both its progression and resistance to treatment.

Keywords:  Glycosaminoglycans; Mesothelioma; Proteoglycans; Resistance; Tumor progression

DOI:  https://doi.org/10.1007/s10719-025-10192-z
Int J Nanomedicine. 2025 ;20 9857-9881

Advances in Chondroitin Sulfate-Based Nanoplatforms for Biomedical Applications.

Cunming Peng, Anna Zheng, Liangliang Wang, Yingjie Shen, Changchun Peng, Jingmou Yu, Shengwen Shao.

  Chondroitin sulfate (CS) is a naturally sulfated glycosaminoglycan with diverse biofunctional properties, including anti-inflammatory effects, reactive oxygen species scavenging, cartilage regeneration and immune regulation. In recent years, CS has shown significant progress in biomedical applications, particularly in drug delivery, tissue engineering, and biosensing. This paper reviews the latest advancements of CS-based nanoplatforms in the biomedical field. CS can be integrated with functional molecules to construct a variety of nanostructures, further expanding its potential applications. CS exhibits distinctive characteristics, and CS-based nanoparticles could serve as promising drug delivery vehicles in tumor therapy. Beyond their roles in drug delivery, CS-based nanoplatforms exhibit transformative potential in tissue engineering, offering promising solutions for wound repair and tissue regeneration. Additionally, CS enhances early disease diagnostics through biomarker detection, leveraging its unique molecular structure and biocompatibility. This comprehensive review explored the properties of CS-based nanoplatforms and their diverse applications, aiming to provide a reference for related research and encourage further advancements in the biomedical fields.

Keywords:  biological sensing; chondroitin sulfate; nanoplatforms; tissue engineering; tumor therapy

DOI:  https://doi.org/10.2147/IJN.S533559
Matrix Biol. 2025 Aug 10. pii: S0945-053X(25)00069-1. [Epub ahead of print]

Heparan sulfate N-deacetylase/N-sulfotransferase-1 regulates glioblastoma cell migration and invasion.

Argyris Spyrou, Ananya Roy, Anqi Xiong, Soumi Kundu, Xi Lu, Ylva Jansson, Anna Falk, Christoph Riethmüller, Burkhard Greve, Martin Götte, Xinqi Chen, Lena Kjellén, Karin Forsberg-Nilsson.

  The glioblastoma (GBM) microenvironment undergoes adaptations to support tumor progression, including a dysregulated extracellular matrix, with altered heparan sulfate (HS) proteoglycans. We investigated N-deacetylase/N-sulfotransferase-1 (NDST1) because NDSTs are initial modifying enzymes of HS biosynthesis and have key roles in designing the HS sulfation pattern. This, in turn governs interactions with growth factors and other biomolecules. We report that NDST1 expression is lower in GBM than in the normal brain, and that patient-derived GBM cells, grown under neural stem cell culture conditions have lower levels of HS than normal astrocytes. Overexpression of NDST1 in GBM cells with low inherent NDST1 levels stimulates cell migration, reduce cell adhesion, induce EMT markers and increase invasion. Conversely, when NDST1 levels were reduced by shRNA in GBM cells, that had higher baseline expression, we find that invasion is reduced, and instead, self-renewal capacity increases alongside elevated stem cell marker expression. Moreover, overexpression of NDST1 changes chromatin accessibility of gene regulatory regions with the capacity to affect transcription factor expression, and pathways that favors cell motility and invasion. Furthermore, NDST1 overexpression results in increased activation of several receptor tyrosine kinases. This study shows that low NDST1 levels support GBM cell stemness, whereas high NDST1 levels endow tumor cells with a motile cell phenotype. We therefore propose that NDST1 is important for regulation of the balance between proliferation and invasive properties in GBM cells.

Keywords:  brain tumor; glioblastoma; heparan sulfate; proteoglycan; stemness; tumor invasion

DOI:  https://doi.org/10.1016/j.matbio.2025.08.003
Cells. 2025 Jul 26. pii: 1158. [Epub ahead of print]14(15):

Heparan Sulfate Proteoglycans as Potential Markers for In Vitro Human Neural Lineage Specification.

Chieh Yu, Duy L B Nguyen, Martina Gyimesi, Ian W Peall, Son H Pham, Lyn R Griffiths, Rachel K Okolicsanyi, Larisa M Haupt.

  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.

Keywords:  glypican; heparan sulfate proteoglycans; human neurogenesis; lineage differentiation; neural cell lines; syndecan

DOI:  https://doi.org/10.3390/cells14151158
Carbohydr Polym. 2025 Nov 01. pii: S0144-8617(25)00800-8. [Epub ahead of print]367 124016

Insights into the alkaline degradation of oxidized chondroitin sulfate: Implications in Schiff base formation for hydrogel fabrication.

Jose Antonio Duran-Mota, Harrison Moon, Margalida-Esmeralda Artigues Cladera, Salvador Borrós, Nuria Oliva.

  Chondroitin sulfate (CS) shows great promise for hydrogels and scaffolds in tissue engineering due to its biocompatibility and compressive strength. However, its chemical structure limits its use, necessitating modifications like oxidation to render CS with aldehyde groups (oxCS) and enabling hydrogel formation via Schiff base chemistry with amines. While an alkaline pH is essential for this crosslinking, high alkalinity affects the stability of oxCS. Despite extensive studies on CS, the extent of this in oxCS has not been thoroughly explored. This study examines oxCS degradation under alkaline conditions using spectrometric and spectroscopic techniques, suggesting possible pathways associated with decreased aldehyde functionality and reduced potential for Schiff base formation. At pH 10, aldehyde groups diminish by 50 % within 2 h, accompanied by enhanced chain scission compared to CS. These findings are applied as proof of concept in the development of two hydrogel families using 8-arm PEG-amines with varying pKa values, demonstrating the critical impact on oxCS stability and affecting the hydrogels' mechanical properties and performance. All in all, the present work provides essential insights into the design of glycosaminoglycan-based hydrogels and scaffolds. These findings advance the development of tailored biomaterials for tissue engineering, addressing the challenges posed by oxCS's stability under alkaline conditions.

Keywords:  Alkaline degradation; Chondroitin sulfate; Glycosaminoglycan modifications; Hydrogel crosslinking; Oxidized chondroitin sulfate; Schiff Base chemistry; Tissue engineering scaffolds

DOI:  https://doi.org/10.1016/j.carbpol.2025.124016
bioRxiv. 2025 Jul 17. pii: 2025.07.12.664340. [Epub ahead of print]

Neuroligin-3 interaction with CSPG4 regulates normal and malignant glial precursors through PIEZO1.

Shawn M Gillespie, Yoon Seok Kim, Anna C Geraghty, Belgin Yalçın, Rebecca Mancusi, Jared Hysinger, Alexis English Ivec, James Reed, Richard Drexler, Michael Quezada, Karen Malacon, Pamelyn Woo, Christopher Mount, Aerin Yang, Mable Lam, Yuan Pan, J Bradley Zuchero, Jacqueline Trotter, Michelle Monje.

Glioma pathophysiology is robustly regulated by interactions with neurons. Key to these interactions is the role of neuroligin-3 (NLGN3), a synaptic adhesion molecule shed in response to neuronal activity 1-5 that functions as a paracrine factor crucial for glioma growth. Here, we elucidate the mechanistic pathway whereby shed NLGN3 interacts with glioma and their normal glial counterpart. NLGN3 interacts with Chondroitin Sulfate Proteoglycan 4 (CSPG4) on both glioma and healthy oligodendrocyte precursor cells (OPCs) 6-9 , facilitating CSPG4 shedding by ADAM10. NLGN3-CSPG4 interactions and consequent shedding alter membrane tension, thereby activating PIEZO1 mechanosensitive channels and causing membrane depolarization. The NLGN3-CSPG4-PIEZO1 axis maintains OPCs in an undifferentiated, stem-like state and promotes glioma proliferation, underscoring important functional roles for the NLGN3-CSPG4-PIEZO1 axis in both healthy and malignant glial precursors.

DOI: https://doi.org/10.1101/2025.07.12.664340
Psychiatriki. 2025 Aug 05.

Dehydroepiandrosterone sulfate (DHEA-S), cortisol, and adrenocorticotropic hormone (ACTH) levels in drug-naïve, first-episode patients with psychosis.

Andreas Karampas, Maria Christou, Spirydon Brikos, Giorgos Georgiou, Marios Plakoutsis, Danai-Dimitra Koutsogianni, Stelios Tigas, Petros Petrikis.

  The hypothalamic-pituitary-adrenal (HPA) axis plays a crucial role in regulating dopamine activity in specific brain areas, particularly in the limbic system, as well as in the stress response. The assessment of the HPA axis is important for the research of biological mechanisms leading from stressful experiences to the onset of psychosis. The release of adrenocorticotropic hormone (ACTH) by the anterior pituitary stimulates the production of cortisol and Dehydroepiandrosterone (DHEA) by the adrenal cortex as a response to stress. The co-release of DHEA may act as a protective mechanism against the damaging effects of excessive cortisol activity. We aimed to measure and compare serum DHEA-S, as well as ACTH, cortisol levels, and cortisol/DHEA-S ratio in drug-naïve FEP patients and matched controls. Data were included for 110 subjects (70 men and 40 women), comprising 55 patients and 55 controls. The mean age was 31.3 years (SD 8.7) in patients and 31.4 years (SD 8.9) in controls. Serum DHEA-S was higher in patients compared to controls [0.69 (0.40) versus 0.50 (0.19), respectively]. Serum ACTH was similar between patients and controls [28.0 pg/ml (6.2-73.9) versus 22.4 pg/ml (7.0-70.5), respectively]. Serum cortisol levels and cortisol/DHEA-S ratio were lower in patients [12.6 μg/dl (4.5) and 4.4% (1.3-19.5), respectively] compared to controls [15.4μg/dl (3.7) and 7.0% (2.4-25.5), respectively]. Sub-analysis revealed that in men, serum DHEA-S was similar between male patients and controls [0.53 (0.23) versus 0.48 (0.17), respectively], whereas in women, serum DHEA-S was higher in patients compared to controls [0.97 (0.47) versus 0.55 (0.20), respectively]. ACTH levels were not different in the above subgroups. Serum cortisol in men was lower in patients compared to controls [12.8 μg/dl (4.4) versus 15.9 μg/dl (3.6)]. Additionally, the cortisol/DHEA-S ratio was lower in patients compared to controls in men [4.4% (1.3-19.5) versus 5.8% (2.4-15.4)], as well as in women [4.3% (1.8-15.2) versus 7.9% (4.0-25.5), respectively]. Correlation analysis was performed to examine the association between different psychopathological characteristics in patients and measured hormones. It was found that the PANSS cognitive subscale was positively correlated with DHEA-S in men and the PANSS positive subscale was negatively correlated with DHEA-S in women. In the linear regression analysis, DHEA-S was positively associated with the PANSS cognitive subscale in men.

Keywords:  Dehydroepiandrosterone sulfate (DHEA-S); adrenocorticotropic hormone (ACTH); cortisol; drug-naïve; first episode psychosis

DOI:  https://doi.org/10.22365/jpsych.2025.016
Antonie Van Leeuwenhoek. 2025 Aug 15. 118(9): 131

Preparation, structure, and biological activity of sulfated polysaccharides from green algae in the Cladophoraceae (Cladophorales, Ulvophyceae).

Xiaoya Yao, Xinyu Wan, Yongzhou Chi, Xiaobao Nie.

  Sulfated polysaccharides have received significant interest due to their broad range of biological properties, which include immunomodulation, anticoagulation, and antiviral activity. Green algae are an important source of structurally diverse sulfated polysaccharides, but efforts directed at research and development of these compounds have lagged far behind efforts directed at sulfated polysaccharides from brown and red algae. The family Cladophoraceae, represented by the genera Cladophora and Chaetomorpha, are widely distributed in resource-rich marine, brackish, and freshwater environments. These algal genera are rich in sulfated polysaccharides primarily composed of galactose and arabinose that exhibit unique structures not yet comprehensively investigated. The present review provides information on the extraction and purification of sulfated polysaccharides from the Cladophoraceae (SPC), an analysis of‌ their chemical composition and structural features‌, and an overview of their biological activity. Studies have shown that SPC exhibit anticoagulant, immunomodulatory, anti-obesity (and related complications), and antibacterial properties‌. However, the mechanisms underlying their bioactivity, particularly the molecular targets of their anticoagulant and immunomodulant activity, remain poorly characterized, and systematic structure-activity relationship studies are lacking. The objective of our review is to provide a theoretical foundation for further research and development of SPC and to promote their use in pharmaceuticals, nutraceuticals, and cosmetics.

Keywords:   Chaetomorpha ; Cladophora ; Biological activity; Cladophoraceae; Sulfated polysaccharides

DOI:  https://doi.org/10.1007/s10482-025-02146-0
Food Sci Nutr. 2025 Aug;13(8): e70692

Sulfated Polysaccharides of Potamogeton lucens as a Promising Immunostimulatory Agent in Activation of RAW264.7 and NK Cells.

Rongan Cao, Mehdi Tabarsa, SangGuan You, Fatemeh Noormand Chaloshtori, Jiamiao Zhang, Kou Fang, Seyedeh Zahra Bathaie.

  Sulfated polysaccharides are naturally occurring biomacromolecules with complex structures and promising therapeutic effects, the mechanism of which remains to be fully understood. This study isolated a novel sulfated polysaccharide from Potamogeton lucens, followed by fractionation by a DAEA Sepharose FF column to assess its immunostimulatory effects on NK-92 and RAW264.7 cells. The primary components within the crude polysaccharides and fractions (PLF1, PLF2 and PLF3) were predominantly neutral sugars, with comparatively lower proportions of sulfate and uronic acids. The isolated polysaccharides exhibited a range of weight average molecular weights (M w) from 488.7 to 918.9 × 103 g/mol. Polysaccharide composition included glucose, galactose, arabinose, rhamnose, mannose, and xylose units linked through various glycosidic linkages, including (1 → 4)-Galp, (1 → 6)-Galp, (1 → 3)-Galp, (1 → 3)-Arap, (1 → 2,4)-Rhap, (1 → 2)-Glcp and (1 → 4)-Glcp residues. The PLF2 polysaccharide showed remarkable efficacy by activating RAW264.7 macrophage cells to synthesize NO, TNF-α, IL-1β and IL-6, while also activating NK-92 cells to synthesize TNF-α, INF-γ, granzyme-B, perforin, NKG2D, and FasL via the NF-κB and MAPKs signaling pathways. Collective findings indicated that polysaccharides derived from P. lucens have the potential to serve as potent immunostimulatory compounds in functional foods, capable of eliciting responses in both RAW264.7 and NK cells.

Keywords:  freshwater plant; immunostimulatory; structure; sulfated polysaccharide

DOI:  https://doi.org/10.1002/fsn3.70692
RSC Chem Biol. 2025 Aug 02.

Translocation of penetratin-like peptides involving calcium-dependent interactions between glycosaminoglycans and phosphocholine headgroups of the membrane lipid bilayer.

Bingwei He, Sonia Khemaissa, Sébastien Cardon, Rodrigue Marquant, Françoise Illien, Delphine Ravault, Fabienne Burlina, Emmanuelle Sachon, Astrid Walrant, Sandrine Sagan.

Cell-penetrating peptides (CPPs) can internalize ubiquitously in cells. To explore the specific targeting issue of CPPs, we used glycosaminoglycan (GAG)-binding peptides previously identified in Otx2 and En2 homeoproteins (HPs). The Otx2 sequence preferentially recognizes highly sulfated chondroitin (CS) and the En2 one, heparan sulfates (HS) GAGs. The two HPs internalize in specific cells thanks to their GAG-targeting sequence. We studied the capacity of chimeric peptides containing a GAG-targeting and a penetratin-like sequences to enter into various cell lines known to express different levels and types of GAGs. Since GAGs are found at the vicinity the membrane lipid bilayer, we also analyzed the putative binary and ternary interactions between heparin (HI), (4S,6S)-CS (CS-E), zwitterionic phosphocholine (PC) model membranes and those chimeric peptides. Altogether, our results demonstrate the existence of Ca2+-dependent interactions between GAGs and PC lipid bilayers, the major phospholipid headgroup found in animal cell plasma membrane. In addition, the interaction of CS-E (but not HI), with PC favors the binding of the chimeric CS-E-recognition motif-penetratin-like peptide and its subsequent crossing of the lipid membrane to access directly to the cytosol of cells. Altogether, this study brings further understanding of translocation mechanism of CPPs, which requires specific GAGs at the cell-surface. It also shed light on the role of GAGs in the cell transfer specificity and paracrine activity of HPs.

DOI: https://doi.org/10.1039/d5cb00099h
Vitam Horm. 2025 ;pii: S0083-6729(24)00081-5. [Epub ahead of print]129 61-97

Dehydroepiandrosterone (DHEA) in relation to breast cancer.

Robert T Chatterton.

  Prediagnostic serum concentrations of dehydroepiandrosterone (DHEA) and its sulfated form (DS) are generally increased in breast cancer patients; serum cortisol concentrations are predictably increased as well. The association of increased adrenal steroids with breast cancer may indicate a causal role. However, administration of DHEA to rats and mice has shown a beneficial effect of DHEA in preventing or suppressing breast cancer in numerous studies. DHEA treatment inhibits the development of spontaneous virally induced mammary cancers and suppresses carcinogen-induced as well as radiation-induced mammary tumors. DHEA also antagonizes the effect of estrogen on growth of human breast cancer xenografts in nude mice. DHEA is effective in suppressing cancer development in other organ systems as well including lung, liver, colon, prostate, lymphatic, and skin cancers. We hypothesize that the increase of DHEA in breast fluid and serum is the result of stress-induced adrenal activation and that the glucocorticoid component is the detrimental component rather than DHEA or DS. The mechanisms by which DHEA suppresses tumor growth includes the non-competitive inhibition of glucose-6-phosphate dehydrogenase, inhibition of cholesterol biosynthesis, immune suppression of virally induced breast cancer, enhancement of natural killer cell cytotoxicity by both DHEA and DS, suppression of IL-6, and promotion of estrogen receptor beta expression. The evidence supports the use of DHEA or its derivatives for suppression of cancers regardless of the mechanism by which the cancer arises.

Keywords:  Breast; Breast cancer; Cortisol; Dehydroepiandrosterone; Dehydroepiandrosterone sulfate; Mechanisms; Prevention; Transport

DOI:  https://doi.org/10.1016/bs.vh.2024.11.002
Carbohydr Polym. 2025 Nov 01. pii: S0144-8617(25)00751-9. [Epub ahead of print]367 123968

Selective inhibition of cathepsin S elastolytic activity by exopolysaccharides from deep-sea hydrothermal bacteria.

Alexis David, Baptiste Rigoux, Martyna Maszota-Zieleniak, Corinne Sinquin, Catherine Neau, Agata Zykwinska, Ahlame Saidi, Gilles Lalmanach, Sergey A Samsonov, Sylvia Colliec-Jouault, Fabien Lecaille.

  Human cathepsin S (CatS) constitutes a key orchestrator of extracellular matrix (ECM) remodeling. Recent evidence suggest that CatS inhibition is a valuable therapeutic option for inflammatory diseases that are characterized by an excessive degradation of insoluble elastin, a process in which CatS contributes significantly when it is overexpressed. Here, we report novel findings that highlight the inhibition of CatS by two low-molecular weight highly sulphated exopolysaccharides (EPS), named diabolican (Dia9-Hsulf) and infernan (Inf19-Hsulf), derived from two marine bacterial strains Vibrio diabolicus and Alteromonas infernus, respectively. Dia9-Hsulf and to a lesser extent Inf19-Hsulf were selective and potent uncompetitive inhibitors of CatS (nanomolar range), which represents an unprecedented mechanism of CatS inhibition. In addition, both EPS selectively inhibited the elastolytic activity of CatS, without affecting the degradation of its other biological substrates (e.g. collagen, thyroglobulin). Combined experimental and in silico approaches provided new insights on how highly sulfated diabolican prevented the CatS elastolytic activity by hindering its elastin-binding exosite. These results evidenced EPS as promising molecules to preserve the elastin integrity during inflammatory events implying CatS.

Keywords:  Basement membrane; Chondroitin sulfate; Cysteine cathepsin; Elastase; Elastin; Elastolytic; Exosite; Extracellular matrix; Glycosaminoglycan; Inhibitor; Molecular dynamic; Polysaccharide; Protease; Proteolysis

DOI:  https://doi.org/10.1016/j.carbpol.2025.123968
Int J Biol Macromol. 2025 Aug 13. pii: S0141-8130(25)07455-0. [Epub ahead of print] 146898

Double-network carboxymethyl chitosan/chondroitin sulfate hydrogel microspheres prepared by green-LED-triggered droplet photopolymerization for malachite green adsorption.

Qingyun Liu, Boxuan Peng, Jiahui Li, Fangzheng Zhao, Enchang Liu, Huizhen Han, Tong Wu, Jinfeng Xing.

  To overcome the inherent mechanical limitations of polysaccharide hydrogels for dye adsorption, we developed dual-network hydrogel microspheres via efficient one-step droplet photopolymerization initiated by green LED. The primary network was photopolymerized from sodium acrylate monomers and ethylene glycol dimethacrylate cross-linker, while the secondary network formed through Schiff base conjugation between oxidized chondroitin sulfate and carboxymethyl chitosan. Systematic characterization (FTIR, TGA, SEM, XPS) confirmed the hydrogels' structural and thermal properties. Key operational parameters including contact time, temperature, initial MG concentration, pH, and ionic strength were optimized. At room temperature, adsorption equilibrium was achieved within 3 h, following pseudo-second-order kinetics. The adsorption capacity is 806.51 mg/g and fitted the Langmuir isotherm model. Electrostatic interactions dominated the adsorption mechanism, as verified by pH and ionic strength experiments. After five adsorption-desorption cycles, MG removal efficiency remained more than 80 %.

Keywords:  Adsorption; Droplet photopolymerization; Hydrogel beads; Malachite green

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.146898
Medicine (Baltimore). 2025 Aug 08. 104(32): e43726

Changes of hormone levels for postmenopausal women after bilateral oophorectomy: A meta-analysis.

Xiaoqin Wu, Yong Lin, Yan Long, Qinqin Yi.

   BACKGROUND: Bilateral oophorectomy has a significant effect on changes in hormone levels in postmenopausal women. This meta-analysis aimed to evaluate the effects of bilateral oophorectomy on estradiol, testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), sex hormone-binding globulin (SHBG), and estrone levels.
METHOD: We conducted a search for studies on focused ultrasound for cervical high-grade squamous intraepithelial lesions in PubMed, EMBASE, Web of Science, and Cochrane Library databases. This review included 7 studies related to bilateral ovariectomy or retention in postmenopausal women. Using Stata software version 12.0, we applied the random effect model, fixed effect model, and subgroup analysis to evaluate the change of different hormones.
RESULTS: After bilateral ovariectomy, estradiol levels decreased significantly (standardized mean difference [SMD] = -0.26, 95% confidence interval [CI] [-0.50, -0.02], P = .031). The overall analysis did not show significant differences (SMD = -0.10, 95% CI [-0.46, 0.26], P = .585), although significant differences were observed between subgroups (P = .025). Testosterone levels also decreased significantly after bilateral ovariectomy (SMD = -0.58, 95% CI [-0.86, -0.31], P < .001). The overall analysis indicated a significant difference between the 2 groups (SMD = -0.35, 95% CI [-0.63, -0.07], P = .014). DHEA levels decreased significantly after bilateral ovariectomy (SMD = -0.51, 95% CI [-0.93, -0.10], P = .015). In contrast, the hormone levels of androstenedione, DHEAS, SHBG, and estrone did not show significant differences between the 2 groups: androstenedione (SMD = -0.04, P = .682), DHEAS (SMD = -0.07, P = .489), SHBG (SMD = -0.02, P = .781), and estrone (SMD = -0.04, P = .587).
CONCLUSIONS: The present meta-analysis showed that bilateral ovariectomy had a significant effect on both estrogen and androgen levels in postmenopausal women, especially estradiol, testosterone, and DHEA. In contrast, the changes in androstenedione, DHEAS, SHBG, and estrone were not obvious. The findings of this study underscore the importance of monitoring hormone levels in postmenopausal women in clinical practice and considering the impact of oophorectomy on women's long-term health when developing individualized treatment options.

Keywords:  estradiol; hormone; meta-analysis; oophorectomy; postmenopausal; testosterone

DOI:  https://doi.org/10.1097/MD.0000000000043726
Am J Ophthalmol. 2025 Aug 11. pii: S0002-9394(25)00412-X. [Epub ahead of print]

Peripheral Macular Endothelial Dystrophy: Clinical, Histopathologic, Genetic and Functional Characterization.

Wenlin Zhang, Huong Duong, Passara Jongkhajornpong, Do Thi Thuy Hang, Huan Pham, Mai Nguyen, Charlene Choo, Dominic Williams, Xuan Nguyen, Tien Dat Nguyen, Brian Aguirre, Shaukat Khan, Madhuri Wadehra, Shunji Tomatsu, Anthony J Aldave.

   OBJECTIVE: To report a CHST6-associated corneal endothelial dystrophy.
DESIGN: Prospective observational case series.
PARTICIPANTS: Thirty-five individuals from seven families, including 13 affected individuals exhibiting corneal epithelial and stromal edema, peripheral posterior corneal macular opacities, and endothelial guttae, as well as 22 unaffected family members.
METHODS: Whole-exome sequencing was performed in three families and Sanger sequencing of CHST6 was performed in all individuals. Histological examination of Descemet membrane (DM) excised at the time of endothelial keratoplasty was performed for three probands. Serum keratan sulfate (KS) levels were measured in members of six families. Functional analysis of identified mutations was performed using CHST6 promoter containing CHST6 expression vector in human keratocytes (HK) and corneal endothelial cells (HCEnC).
MAIN OUTCOME MEASURES: Clinical phenotype; genetic analysis; functional analysis of identified CHST6 mutations; serum KS levels; histologic examinations of DM.
RESULTS: All affected individuals demonstrated peripheral macular opacities at the level of DM. Visually significant corneal edema in affected individuals was successfully managed by endothelial keratoplasty. Genetic analysis demonstrated a rare CHST6 promoter mutation (c.-690G>C) in the homozygous state in affected individuals from three families and in the compound heterozygous state with a CHST6 coding mutation (p.R211Q, p.Y268C or p.P280L) in affected individuals from the other four families. In silico analysis predicted c.-690G>C to be a regulatory variant, located at the RNA polymerase II binding site. Functional analysis in vitro demonstrated that c.-690G>C leads to increased KS sulfation the corneal endothelium and DM, with no change of KS sulfation in keratocytes. Histologic examination of DM from affected individuals revealed elevated levels of sulfated and non-sulfated KS in DM and endothelium, consistent with the functional analysis. Minimum changes in serum sulfated KS levels were observed in affected individuals.
CONCLUSIONS: We suggest the name Peripheral macular endothelial dystrophy (PMED) to describe this dystrophy that is characterized by peripheral posterior corneal macular opacities and endothelial dysfunction without stromal haze or opacities. Given that both PMED and macular corneal dystrophy are associated with promoter and coding region mutations in CHST6, we propose that they be categorized as CHST6-associated corneal dystrophies.

Keywords:  CHST6; Corneal endothelial dystrophy; keratan sulfate

DOI:  https://doi.org/10.1016/j.ajo.2025.08.006
Biogerontology. 2025 Aug 16. 26(5): 164

Cortisol, DHEAS, and the cortisol/DHEAS ratio as predictors of epigenetic age acceleration.

Rafaela S C Takeshita, Amber T Nguyen, Anthony P Auger, Wilson C J Chung.

  Cortisol has been widely used as biomarker of stress and aging, but confounding effects and disruption of the hypothalamic-pituitary-adrenal axis can lead to misinterpretation of results based on a single measurement. A possible alternative is the co-measurement of cortisol and the adrenal hormone dehydroepiandrosterone-sulfate (DHEAS), a glucocorticoid antagonist that modulates the stress response. Using data from 969 individuals from the Midlife in the United States study, this study aimed to investigate the influence of age, sex, and self-identified biosocial group (SIBG) on DHEAS, cortisol, and the cortisol/DHEAS ratio, to test whether these hormones add predictive power to epigenetic age estimates, and to compare the performance of these three hormonal measures in predicting epigenetic age acceleration (EAA) using sex epigenetic clocks: Horvath, Horvath's skin & blood (Horvath2), Hannum, PhenoAge, GrimAge, and DunedinPACE. Our findings revealed that age, sex and SIBG significantly influenced all three hormonal measures. Controlling for these biodemographic factors, we found that the cortisol/DHEAS was the best predictor of epigenetic clocks. There was a significant and positive correlation between cortisol and Hannum epigenetic age, and between cortisol/DHEAS ratio in three out of the six clocks (Hannum, Horvath2, PhenoAge), but no significant associations between DHEAS and epigenetic age. The cortisol/DHEAS ratio also had a significant and positive correlation with Hannum EAA. DHEAS and cortisol were not significantly associated with EAA for any epigenetic clock. Our results reinforce the importance of co-measuring cortisol and DHEAS in studies investigating the effect of stress in aging processes.

Keywords:  Adrenal hormones; Aging biomarkers; DNA methylation; Dehydroepiandrosterone-sulfate; Epigenetic clock; Stress response

DOI:  https://doi.org/10.1007/s10522-025-10307-x
Int J Mol Sci. 2025 Jul 23. pii: 7070. [Epub ahead of print]26(15):

Systemic Uremic Toxin Burden in Autism Spectrum Disorder: A Stratified Urinary Metabolite Analysis.

Joško Osredkar, Teja Fabjan, Uroš Godnov, Maja Jekovec-Vrhovšek, Joanna Giebułtowicz, Barbara Bobrowska-Korczak, Gorazd Avguštin, Kristina Kumer.

  Autism spectrum disorder (ASD) is increasingly associated with microbial and metabolic disturbances, including the altered production of gut-derived uremic toxins. We investigated urinary concentrations of five representative uremic toxins-indoxyl sulfate (IS), p-cresyl sulfate (PCS), trimethylamine N-oxide (TMAO), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA)-in 161 children with ASD and 71 healthy controls. Toxins were measured using LC-MS/MS and were normalized to creatinine. Subgroup analyses were performed by sex, age group (2-5.9 vs. 6-17 years), and autism severity based on the Childhood Autism Rating Scale (CARS). In addition to individual concentrations, we calculated the total toxin burden, proportional contributions, and functional ratios (IS/PCS, PCS/TMAO, and IS/ADMA). While individual toxin levels did not differ significantly between groups, stratified analyses revealed that PCS was higher in girls and in severe cases of ASD, whereas IS and TMAO were reduced in younger and more severely affected children. The functional ratios shifted consistently with severity-IS/PCS declined from 1.69 in controls to 0.99 in severe cases of ASD, while PCS/TMAO increased from 12.2 to 20.5. These patterns suggest a phenolic-dominant microbial signature and an altered host-microbial metabolic balance in ASD. Functional toxin profiling may offer a more sensitive approach to characterizing metabolic disturbances in ASD than concentration analysis alone.

Keywords:  ADMA; TMAO; autism spectrum disorder; gut microbiota; indoxyl sulfate; metabolomics; p-cresyl sulfate; uremic toxins; urinary biomarkers

DOI:  https://doi.org/10.3390/ijms26157070