bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2025–12–14
fourteen papers selected by
Jonathan Wolf Mueller, University of Birmingham
  1. Sulfonated, sulfated thioglycosides and multivalence in heparanase inhibition.
  2. N-Sulfated Heparan Sulfate Promotes Reelin Signaling as a Co-receptor.
  3. Optimized fluorescent probes for heparan sulfate sensing in live cells and human blood.
  4. Dysregulation of glycosaminoglycans during oocyte maturation in vitro: Implications for developmental potential.
  5. A Novel Chimeric Molecule of Heparanase and Ig-Fc Enables Histochemical and Cytochemical Detection of O-sulfated Heparan Sulfate.
  6. Indoxyl sulfate: clinical implications for anemia management in chronic kidney disease.
  7. Transport of CCL2 across an induced pluripotent stem cell-derived in vitro model of the human blood-brain barrier is heparan sulfate-dependent.
  8. Mass spectrometry (MS)-based proteomics and the sulfome: clinical potential.
  9. Unraveling the Potential of Small Molecule Heparin Glycomimetics in Neuroregenerative Therapeutics.
  10. Altered excitability and glutamatergic synaptic transmission in the medium spiny neurons of the nucleus accumbens in mice deficient in the heparan sulfate endosulfatase Sulf1.
  11. Biodegradable Polyglycerols Combining Antioxidant Activity and Sulfation-Induced Complement Inhibition.
  12. Glycocalyx kinetics and injury during liver procurement and transplantation as predictors of early graft dysfunction.
  13. Exploring Emerging Therapeutic Targets in Osteosarcoma by Revisiting the Immune and Cancer-Intrinsic Hallmarks of Cancer.
  14. Rare Conditions of Hyperandrogenism Through Lifespan: A Case Series.
  1. Org Biomol Chem. 2025 Dec 09.
    Sulfonated, sulfated thioglycosides and multivalence in heparanase inhibition.
    Dindet Steve-Evanes Koffi Teki, Bamoro Coulibaly, Jamal El-Abid, Abed Bil, Aurélie Vallin, José Kovensky, Vincent Chagnault.
      Heparan sulfate (HS) analogs are synthetic oligo- and polysaccharides designed to mimic or enhance several biological properties of native HS. Organic synthesized compounds are very useful tools for understanding the structure-activity relationships of many biological events. Unlike heterogeneous mixtures of tissue-isolated biomolecules, synthetic compounds offer a valuable platform to probe structure-activity relationships with reduced off-target effects in pharmacological applications. In our research group, we are particularly focused on the design and synthesis of thiodisaccharide analogs mimicking HS structural motifs. In recently published work, we reported the synthesis and biological evaluation of both new sulfated and non-sulfated O- and S-linked disaccharides, demonstrating their potential as heparanase inhibitors. In this article, we introduced a sulfonate moiety as a stable analog of the sulfate group. Comparative heparanase inhibition assays reveal that sulfated disaccharides exhibit significantly greater activity than their sulfonated counterparts. Furthermore, multivalent glycoclusters were prepared by coupling sulfated thiodisaccharides to maltotriose and cyclodextrin scaffolds, providing novel molecular architectures that show promising heparanase inhibition.
    DOI:  https://doi.org/10.1039/d5ob01623a
  2. J Am Chem Soc. 2025 Dec 08.
    N-Sulfated Heparan Sulfate Promotes Reelin Signaling as a Co-receptor.
    Lin Pan, Xuehong Song, Guowei Su, Lauren A Gandy, Biqin Fang, Mason Buttaci, James Gibson, Ke Xia, Fuming Zhang, Jian Liu, Lianchun Wang, Sally Temple, Chunyu Wang.
      Heparan sulfate (HS) plays a central role in signal transduction, while Reelin is an essential signaling protein in both the developing and adult brain. A Reelin COLBOS variant was recently discovered with enhanced HS binding and resilience against autosomal dominant Alzheimer's disease (ADAD), underscoring the importance of Reelin-HS interactions. However, the glycan determinants of Reelin-HS interactions have not been well-characterized, which we systematically investigated here. Surface plasmon resonance (SPR) showed that full length Reelin binds HS with high affinity (KD = 17 ± 5 nM), which is enhanced by the COLBOS variant (KD = 10 ± 2 nM). Competition SPR and glycan array studies further revealed that HS N-sulfation is critical for Reelin-HS binding, consistent with Haddock modeling. In cell surface binding assays, heparinase treatment, which degrades HS, or the knockout of a key HS N-sulfation enzyme (NDST1) significantly reduced Reelin attachment. Functionally, a cellular split-luciferase assay showed that heparinase treatment or adding heparin in culture medium reduces Reelin-induced ApoER2 dimerization, demonstrating that HS is a coreceptor for Reelin receptor activation. In contrast, N-desulfated heparin does not inhibit Reelin receptor dimerization. Our work establishes HS as a coreceptor for Reelin signaling and N-sulfation as a key glycan determinant of Reelin-HS recognition. Our work provides mechanistic insights into diverse neurodevelopmental and neurodegenerative diseases associated with Reelin signaling and suggests novel therapeutic strategies targeting HS sulfation.
    DOI:  https://doi.org/10.1021/jacs.5c15573
  3. Biosens Bioelectron. 2025 Dec 03. pii: S0956-5663(25)01169-8. [Epub ahead of print]295 118292
    Optimized fluorescent probes for heparan sulfate sensing in live cells and human blood.
    Hyun Jung Hwang, Sumita Subedi, Kishor Khadka, Jae-Seon Lee, Keun-Hyeung Lee.
      Heparan sulfate (HS) proteoglycans on the cell surface play pivotal roles in cell signaling, angiogenesis, endocytosis, infectious disease progression, and tumor invasion. Real-time detection and quantification of HS in live cells remain challenging due to its structural heterogeneity and probe internalization issues. Here, we report rationally designed fluorescent probes (1-3) incorporating a branched peptide receptor with fatty-acid and/or PEG conjugation for selective targeting of HS proteoglycans. Among them, the PEGylated probe 3 showed stable and selective ratiometric fluorescence responses to HS in RPMI medium, with exclusive cell-surface localization for 120 min. In contrast, the fatty-acid-conjugated probe 2 exhibited partial accumulation at the plasma membrane for approximately 20 min, but was subsequently internalized into the cytoplasm, limiting its cell-surface retention. Notably, probe 3 enabled quantitative monitoring of HS depletion in live cells following inhibition of HS sulfation by siRNA or chemical treatment, as well as after heparinase digestion, while simultaneously attenuating fibroblast growth factor signaling and suppressing cancer cell migration. Furthermore, PEG conjugation reduced nonspecific serum protein binding, thereby enhancing sensitivity and selectivity for HS detection in human blood. These findings demonstrate that PEG conjugation is an effective strategy to optimize fluorescent HS probes by enhancing cell-surface anchoring, prolonging retention, and improving ratiometric responses in both cellular and plasma environments.
    Keywords:  Cell-surface binding; Fluorescent probe; Heparan sulfate; Human blood; Ratiometric
    DOI:  https://doi.org/10.1016/j.bios.2025.118292
  4. Glycobiology. 2025 Dec 10. pii: cwaf085. [Epub ahead of print]
    Dysregulation of glycosaminoglycans during oocyte maturation in vitro: Implications for developmental potential.
    Darren J X Chow, Edward S X Moh, Laura N Watson, Tasman Daish, Robert B Gilchrist, Nicolle H Packer, Kylie R Dunning, Darryl L Russell.
      A complex extracellular matrix (ECM) assembles around the mammalian oocyte during maturation and ovulation, comprising hyaluronan as well as proteoglycans. These proteoglycans are hypothesised to carry heparan and chondroitin sulfate side chains. This matrix is essential for ovulation, mediates signalling, and regulates solute diffusion to control the oocyte environment. In vivo, ECM formation is initiated by epidermal growth factor-like peptides released within the follicle, acting together with oocyte-derived growth factors. Although proteoglycans are known components, the specific glycosaminoglycan (GAG) composition remains poorly understood. Here, we characterised GAG abundance in murine cumulus-oocyte-complexes and assessed differences between in vivo and in vitro maturation. The latter is an assisted reproductive technology that requires less drugs than IVF, but oocytes have reduced developmental potential. We found that sulfated GAG abundance increased significantly in vivo but not during in vitro oocyte maturation. We also employed high performance liquid-chromatography to measure the abundance of specific GAGs-hyaluronan, chondroitin sulfate, and heparan sulfate-in this matrix at different stages of maturation. These were enriched within the ECM during in vivo maturation but reduced or undetectable in vitro. Reduced GAG abundance following in vitro maturation was associated with poorer oocyte developmental potential. GAG deficiency following in vitro maturation likely arises from the failure of in vitro conditions to replicate the signalling milieu that occurs in vivo. Altered GAG abundance during in vitro maturation may impair functions of the ECM, including growth factor binding and activity or the regulated diffusion of solutes, potentially contributing to decreased oocyte developmental potential.
    Keywords:  chondroitin sulfate; cumulus extracellular matrix; heparan sulfate; hyaluronan; oocyte maturation
    DOI:  https://doi.org/10.1093/glycob/cwaf085
  5. Int J Mol Sci. 2025 Nov 22. pii: 11293. [Epub ahead of print]26(23):
    A Novel Chimeric Molecule of Heparanase and Ig-Fc Enables Histochemical and Cytochemical Detection of O-sulfated Heparan Sulfate.
    Jia Shi, Momoko Nakamura, Ryoya Baba, Sojiro Arakawa, Arisa Yamaguchi, Tomonori Hariya, Rin Suzuki, Yu Inazuki, Katsuhiko Takahashi, Makoto Tsuiji, Teruaki Oku, Mayumi Komine, Momo Shimekake, Kyohei Higashi, Masao Nakamura, Kazuki Sasaki, Motowo Nakajima, Tatsuro Irimura, Nobuaki Higashi.
      A chimeric protein of heparanase and Ig-Fc was designed as a novel tool to expand the detection of structurally heterogeneous heparan sulfate (HS) and related glycosaminoglycans. The whole mouse heparanase gene was combined with the gene segment encoding the mouse IgG1 hinge-Fc domain. A point mutation E335A was inserted to disable putative HS degradation activity. Chimeric proteins consisted of the latent form of the enzyme devoid of HS degradation activity. The chimeric proteins bound to heparin, N-desulfated heparin, and O-sulfated N-acetylheparosan. Their binding spectrum to glycosaminoglycans differed from that of anti-HS mAb 10E4. The chimeric proteins bound to Kato III and A549 cell lines. The binding was reduced by knocking down EXT1 gene expression. One of the chimeric proteins stained the epidermal cells in the hyperplastic spinous layer of inflamed atopic dermatitis skin and inflammatory cells in the dermis, which were not stained with mAb 10E4. The protein stained a polarized structure on the surface of monocytic U937 and THP1 cells. Similar polarized structures were observed with anti-syndecan-1 antibody staining. The chimeric protein and anti-syndecan-1 antibody precipitated similar sets of proteins that included syndecan-1 from the lysates of U937 cells. These novel chimeric proteins are useful to detect HS abundant in O-sulfation in histochemical, cytochemical, and biochemical studies.
    Keywords:  Fc-chimeric molecules; O-sulfation; atopic dermatitis skin; heparan sulfate; heparanase; heparin; inflammatory leukocytes; syndecan
    DOI:  https://doi.org/10.3390/ijms262311293
  6. Curr Opin Nephrol Hypertens. 2025 Dec 08.
    Indoxyl sulfate: clinical implications for anemia management in chronic kidney disease.
    Manoch Rattanasompattikul, Thatsaphan Srithongkul, Ekamol Tantisattamo, Kamyar Kalantar-Zadeh, Kajohnsak Noppakun.
       PURPOSE OF REVIEW: This review examines the role of indoxyl sulfate, a gut-derived uremic toxin, in the development of anemia in chronic kidney disease. It dissects the cellular and biochemical mechanisms through which indoxyl sulfate suppresses erythropoietin production, disrupts iron metabolism, and promotes oxidative stress and inflammation.
    RECENT FINDINGS: Indoxyl sulfate interferes directly with the hypoxia-inducible factor pathway, thereby reducing the transcriptional activation of erythropoietin. In parallel, indoxyl sulfate-induced oxidative stress damages red blood cells and accelerates premature cell death, while its stimulation of pro-inflammatory pathways further downregulates erythroid progenitor cell function. Therapeutic strategies such as dietary protein modulation, gut microbiota interventions, oral adsorbents, and enhanced dialysis modalities have shown promise in lowering indoxyl sulfate levels and, consequently, improving erythropoietin responsiveness and iron homeostasis in chronic kidney disease patients.
    SUMMARY: The review synthesizes evidence from clinical and experimental studies that position indoxyl sulfate as a central yet underappreciated mediator of anemia in chronic kidney disease. Indoxyl sulfate establishes a vicious cycle that exacerbates anemia and contributes to erytropoiesis-stimulating agent hyporesponsiveness. The article advocates for targeted interventions aimed at reducing indoxyl sulfate burden, which could transform anemia management in chronic kidney disease and pave the way for personalized treatment strategies.
    Keywords:  dialysis modalities; erythropoiesis; gut microbiota; iron metabolism; uremic toxins
    DOI:  https://doi.org/10.1097/MNH.0000000000001145
  7. PLoS One. 2025 ;20(12): e0338780
    Transport of CCL2 across an induced pluripotent stem cell-derived in vitro model of the human blood-brain barrier is heparan sulfate-dependent.
    Lindsey M Williams, Takashi Fujimoto, Mamatha Damodarasamy, Riley R Weaver, C Dirk Keene, William A Banks, May J Reed, Michelle A Erickson.
      Transport of immune-active substances across the blood-brain barrier (BBB) is an important mechanism of neuroimmune regulation. CCL2 is an exemplary chemokine that regulates neuroinflammation and can cross the intact BBB from blood to brain in mice. This study aimed to characterize the blood-to-brain transport mechanisms of human CCL2 using human induced pluripotent stem cell (iPSC)-derived brain endothelial-like cells (iBECs), an in vitro BBB model. Since heparan sulfate (HS) is an important component of the in vivo BBB that regulates CCL2 transport in mice, we first assessed HS deposition in iBECs and found that HS levels increased with extended culture time. We therefore evaluated transport of radiolabeled 125I-CCL2 and 131I-BSA after nine days in subculture, after HS had sufficient time to accumulate. To determine the predominant transport mechanism in vitro, we evaluated whether transport of 125I-CCL2 and 131I-BSA was altered in the presence of an inhibitor of the chemokine receptor CCR2, and following treatment with heparin, heparinase enzymes, or the heparan sulfate synthesis inhibitor GalNaz which all test HS-dependent mechanisms of transport. We also evaluated the expression of CCR2 and membrane-bound HS proteoglycans (HSPGs) in iBECs and in isolated human brain microvessels. We found that iBECs have a functional blood-to-brain transport system for CCL2. Similar to findings in mice, heparin inhibited CCL2 transport whereas the CCR2 inhibition did not. Both heparinase treatment and treatment with GalNaz inhibited CCL2 transport across the BBB, further supporting the involvement of HS in CCL2 transport. The iBECs expressed CCR2 at levels comparable to human brain microvessels, and had detectable expression of the syndecans 1-4 and glypicans 1-6, whereas human brain microvessels expressed syndecans 2-4 and glypicans 2-5 in all subjects tested. Our findings highlight that iBECs are a useful tool for studying the involvement of heparan sulfate/glycocalyx components in the transport of substances across the BBB.
    DOI:  https://doi.org/10.1371/journal.pone.0338780
  8. Expert Rev Proteomics. 2025 Dec 11.
    Mass spectrometry (MS)-based proteomics and the sulfome: clinical potential.
    Sally O Oswald, Leonard A Daly, Shahram Mesdaghi, Sarah Jones, Daniel J Rigden, Patrick A Eyers, Claire E Eyers.
       INTRODUCTION: Protein tyrosine sulfation is of growing scientific interest due to its biological and clinical significance, yet it remains an underexplored post-translational modification (PTM). Catalyzed by Golgi-localized TPST1 and TPST2, tyrosine sulfation modulates protein - protein interactions and receptor - ligand binding in inflammation, hemostasis, immunity, and viral entry. Despite functional relevance, this modification is underrepresented in databases such as UniProt (accessed July 2025), in large part due to a lack of robust analytical strategies. Advances in mass spectrometry (MS)-based analyses have recently improved sensitivity of detection, expanding the known tyrosine 'sulfome.' Systematic profiling of sulfated residues can now be undertaken, expanding knowledge of their regulatory roles in both health and disease, and for pioneering new sulfation-targeted therapeutics.
    AREAS COVERED: We review known biological roles of protein sulfation by TPSTs and approaches for characterization of sulfotyrosine and other residues such as cysteine. More broadly, we consider how these strategies might be useful in a clinical context.
    EXPERT OPINION: High throughput MS-based proteomics has proven invaluable for the discovery of PTMs, advancing understanding of their roles in human health and disease. With recent advances in strategies for the characterization of protein sulfation, the field is now ready for exploration in a clinical context.
    Keywords:  Mass spectrometry; PTM; Sulfation; Sulfocysteine; Sulfotyrosine; TPST
    DOI:  https://doi.org/10.1080/14789450.2025.2601523
  9. J Am Chem Soc. 2025 Dec 08.
    Unraveling the Potential of Small Molecule Heparin Glycomimetics in Neuroregenerative Therapeutics.
    Melis Özkan, Giada Cellot, Sujeet Pawar, Deepika Sardana, Ivana Barravecchia, Laura Ballerini, Debora Angeloni, Silvestro Micera, Francesco Stellacci.
      Heparin and heparan sulfate (HS) glycosaminoglycans (GAGs) are essential regulators of neurotrophic signaling. However, their therapeutic applications are hindered by structural heterogeneity, batch variability, and anticoagulant activity. Thus, there is a need for well-defined glycomimetics that replicate the function of native HS in regenerative medicine. Here, we synthesized HS glycomimetics through a modular strategy that enables the installation of sulfate groups at the designated positions along the sugar backbone. These glycomimetics selectively bind and stabilize neurotrophins, such as fibroblast growth factors (FGF-1, FGF-2) and nerve growth factor (NGF), in a sulfation-dependent manner with dissociation constants in the low micromolar range. They exhibit no anticoagulant activity, a crucial prerequisite for clinical translation. We show that our lead compound has neuritogenic ability because in two neuronal cell models, PC12 and SH-SY5Y, it enhances NGF-mediated neural maturation when immobilized on a surface. Furthermore, in primary rat hippocampal neurons, it promotes FGF-2-mediated neurite outgrowth and spontaneous synaptic activity. Our findings show that HS glycomimetics have the potential for regenerative therapies.
    DOI:  https://doi.org/10.1021/jacs.5c13142
  10. eNeuro. 2025 Dec 11. pii: ENEURO.0088-25.2025. [Epub ahead of print]
    Altered excitability and glutamatergic synaptic transmission in the medium spiny neurons of the nucleus accumbens in mice deficient in the heparan sulfate endosulfatase Sulf1.
    Ken Miya, Etsuko Suzuki, Kazuko Keino-Masu, Takuya Okada, Kenta Kobayashi, Toshihiko Momiyama, Masayuki Masu.
      Sulf1 is an extracellular sulfatase that regulates cell signaling by removing 6-O-sulfates from heparan sulfate. Although the roles of Sulf1 in neural development have been studied extensively, its functions in the adult brain remain largely unknown. Here, we report the effects of Sulf1 disruption on the neuronal properties of the medium spiny neurons (MSNs) in the nucleus accumbens (NAc) shell, one of the regions highly expressing Sulf1 We separately labeled MSNs expressing dopamine D1 receptors (D1-MSNs) or D2 receptors (D2-MSNs) by injecting adult male Drd1-Cre and Drd2-Cre mice with a Cre-dependent AAV vector expressing a red fluorescent protein, mCherry, and examined their electrophysiological properties by means of whole-cell patch-clamp recording. In the D2-MSNs, Sulf1 disruption led to drastic changes in neural firing responses to depolarizing current injections: in the Sulf1 knockout mice, the rheobase was smaller than in the wild-type mice, but the number of action potentials elicited by depolarization did not increase at larger current injections. In the D1-MSNs, Sulf1 disruption resulted in more depolarized resting membrane potentials and increase in the AMPA/NMDA ratio. These results suggest that Sulf1 is essential for regulation of neuronal excitability and glutamatergic transmission of NAc MSNs in adult mice and implicate the potential roles of Sulf1 in NAc circuit activity, reward-aversion behaviors, and psychiatric disorders such as schizophrenia and drug addiction.Significance Statement Heparan sulfate plays critical roles in neural differentiation, axon guidance, synaptogenesis, and neurotransmission. Sulf1 is an extracellular sulfatase that removes 6-O-sulfate from heparan sulfate, thereby regulating various cellular functions. Although its roles during development have been studied extensively, its functions in the adult brain remain largely unknown. Here, we examined the electrophysiological properties of medium spiny neurons in the nucleus accumbens shell of adult mice by means of whole-cell patch-clamp recording. We found that Sulf1 disruption led to changes in neuronal excitability and glutamatergic transmission in medium spiny neurons. This study demonstrates the roles of the Sulf1 gene in neuronal activities at the cellular level, providing an important clue toward understanding the functions of Sulf1 in the adult brain.
    DOI:  https://doi.org/10.1523/ENEURO.0088-25.2025
  11. Biomacromolecules. 2025 Dec 11.
    Biodegradable Polyglycerols Combining Antioxidant Activity and Sulfation-Induced Complement Inhibition.
    Hanna Koeppe, Daniel Horn, Jens Dernedde, Rainer Haag.
      Polyglycerol platforms are promising for polymer therapeutics due to their multifunctionality and biocompatibility. Our aim was to introduce biodegradability as well as antioxidant properties to the polyglycerol backbone using cyclic comonomers with thioether and ester functionalities. Anionic ring-opening copolymerization of glycidol and either 1,4-oxathiepan-7-one or thiodiglycolic anhydride yielded the hyperbranched structures: GOTO or GTA, respectively. Characterization confirmed molecular weights of 10 kDa and the successful incorporation of 10 mol % comonomer while maintaining water solubility. Sulfated derivatives, GOTO-S and GTA-S, were obtained with a high degree of sulfation. All copolymers showed good cytocompatibility as well as degradability under physiological conditions. Significant antioxidant activity attributed to the thioether groups of the copolymers was demonstrated via the ABTS radical scavenging assay. GTA emerged as the strongest radical scavenger among the polymers tested, likewise, GTA-S outperformed GOTO-S. Notably, the sulfated derivatives effectively inhibit complement activation with potencies comparable to dPGS and heparin, demonstrating their potential for applications in oxidative stress-related inflammation.
    DOI:  https://doi.org/10.1021/acs.biomac.5c01615
  12. Front Transplant. 2025 ;4 1662187
    Glycocalyx kinetics and injury during liver procurement and transplantation as predictors of early graft dysfunction.
    Nassiba Beghdadi, Alexis Texier, Marc Antoine Allard, Mylene Sebagh, Nour Bousaleh, Haitham Triki, Daniel Pietrasz, Nicolas Cabrit, Nicolas Golse, René Adam, Cyrille Feray, Peter J Lenting, Stéphanie Roullet, Daniel Azoulay.
       Introduction: Ischemia-reperfusion injury causes endothelial damage, partly through degradation of the glycocalyx. This study aimed to evaluate glycocalyx degradation from graft procurement to reperfusion and assess its potential as a biomarker of early graft function (early allograft dysfunction, EAD).
    Methods: This single-center observational prospective study was conducted at Paul Brousse Hospital from April 2022 to April 2023. All primary liver transplantation (LT) recipients were included. Glycocalyx degradation was assessed at procurement, at the end of cold ischemia, and during LT in liver graft caval effluent and correlated with liver histological injury. The primary endpoint was EAD, defined as a Model for Early Allograft Function score ≥9. We quantified glycocalyx components [Syndecan-1 (Synd-1), heparan sulfate, angiopoietin-1, and angiopoietin-2], inflammation (TNF-alpha), and cell death markers.
    Results: Thirty-one patients were included; 12 (39%) developed EAD. Synd-1 plasma levels at procurement (donor Synd-1 level = d-Synd-1) were significantly higher in patients with EAD [12,173 pg/mL (10,538-17,570) vs. 6,282 pg/mL (4,604-10,002), p = 0.004]. A plasma d-Synd-1 cutoff of 9,419.7 pg/mL predicted EAD [AUC = 0.81, 95% confidence interval (95% CI) (0.65-0.97); sensitivity 83%; specificity 74%, positive predictive value = 67%, negative predictive value = 88%, p < 0.05]. d-Synd-1 ≥9,419.7 pg/mL was associated with severe post-LT complications (p = 0.007).
    Conclusions: d-Synd-1 levels in graft effluent during procurement may serve as a predictor of early allograft dysfunction. Strategies aimed at protecting the endothelial during procurement could improve graft outcomes.
    Keywords:  angiopoietin (Ang); glycocalyx (MeSH: d019276); heparan sulfate (HS); ischemia–reperfusion (I/R) injury; liver transplantation complications; syndecan-1 (SDC1)
    DOI:  https://doi.org/10.3389/frtra.2025.1662187
  13. Cancers (Basel). 2025 Nov 30. pii: 3846. [Epub ahead of print]17(23):
    Exploring Emerging Therapeutic Targets in Osteosarcoma by Revisiting the Immune and Cancer-Intrinsic Hallmarks of Cancer.
    Lidia Tarone, Antonella Iacoviello, Antonino Di Lorenzo, Roberta Verta, Chiara Cossu, Laura Conti, Federica Cavallo, Federica Riccardo.
      Osteosarcoma (OSA) is an aggressive primary bone cancer mainly affecting the pediatric population. Despite intensive multimodal treatments, therapeutic progress has remained limited for decades, resulting in high recurrence rates, poor prognosis driven by metastatic progression, and severe chemotherapy-associated toxicities. To advance the development of more effective and safer therapeutic strategies, our recent studies identified Chondroitin Sulfate Proteoglycan (CSPG)4 as a relevant mediator of the malignant behavior of OSA cells. Targeting CSPG4 DNA-based vaccine demonstrated encouraging antitumor activity against OSA. Nevertheless, since single-agent immunotherapies are often constrained by tumor immune escape, the need for rational combinatorial strategies is of utmost importance. In this perspective, we broaden our analysis to include other potentially complementary targets beyond CSPG4, which may contribute to OSA pathogenesis. Among these, the cystine/glutamate antiporter xCT and Toll-like Receptor 2 (TLR2) emerge as particularly promising due to their established role in tumor progression, therapy resistance, and immune modulation. We discuss the contribution of all these molecules in major hallmarks of OSA-(1) proliferative and survival advantages, (2) metastasis and angiogenesis, and (3) immune evasion-and examine potential strategies for their combined targeting. By leveraging knowledge gained from other cancer models and integrating it with the distinct biological and clinical features of OSA, this perspective seeks to outline rational and innovative combinatorial strategies that may overcome current therapeutic limitations and ultimately improve patient outcomes.
    Keywords:  CSPG4; TLR2; cancer hallmarks; combinatorial strategies; immunotherapy; osteosarcoma; xCT
    DOI:  https://doi.org/10.3390/cancers17233846
  14. Case Rep Endocrinol. 2025 ;2025 8604843
    Rare Conditions of Hyperandrogenism Through Lifespan: A Case Series.
    Maria Apostolopoulou, Robert Taayedi, Cosmin Paul Sărac, Frank Demtröder.
      A wide spectrum of clinical entities can lead to pre and postmenopausal hyperandrogenism, which is characterized by slow or more rapid onset of virilizing symptoms (menstrual irregularities, hirsutism, androgenetic alopecia). Functional hyperandrogenism in the context of polycystic ovary syndrome (PCOS) remains the most prevalent cause for hyperandrogenism both in pre and postmenopausal females; however, other clinical entities such as ovarian hyperthecosis and benign or malignant neoplasms (e.g., adrenal androgen-secreting adenomas and ovarian tumors of androgen-secreting cells) are often challenging to diagnose. Laboratory testing should include measurement of testosterone, sex hormone binding globulin (SHBG), gonadotropins, estradiol, androstenedione, dehydroepiandrosterone sulfate (DHEA-S), and 17-OH-progesterone values, as well as markers of other endocrine disorders leading to secondary hyperandrogenism, especially Cushing's syndrome. Testosterone values of more than 150 ng/dL generally require further investigation, and increased DHEA-S (more than 700 μg/dL) is suggestive of adrenal androgen-secreting tumors. Androgen suppression during prolonged dexamethasone test can facilitate differential diagnosis between adrenal and ovarian androgen excess production and point to autonomous production in case of tumors. In case of smaller ovarian tumors (e.g., Leydig cell), imaging might not be diagnostic, so that in case of high clinical suspicion, selective ovarian catheterization can be a valuable tool, when available. In this paper, we highlight four rare conditions of hyperandrogenism beyond PCOS, each reflecting specific stages or challenges across the female lifespan. We suggest that detailed biochemical testing and high clinical suspicion should promptly lead to valuable invasive diagnostic tools (ovarian catheterization/laparoscopy) in case imaging is not diagnostic.
    DOI:  https://doi.org/10.1155/crie/8604843
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