bims-supasi 2025-11-16 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2025–11–16
fourteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Dysfunctional Chondroitin 4-O-Sulfotransferase-1 Impairs Cellular Redox State and Promotes Tau Aggregation.
Heparin Provides Antiviral Activity Against Rhinovirus-16 via an Heparan Sulfate Proteoglycan-Independent Mechanism.
Structural Characterization and Antioxidant Activity of Chondroitin Sulfate Derived from Channa argus in Changbai Mountain.
Liposome-chondroitin sulfate/chitosan hybrid system for combinational drug delivery of curcumin and dexamethasone: In vitro anti-cancer activities.
Urinary Uremic Toxin Signatures and the Metabolic Index of Gut Dysfunction (MIGD) in Autism Spectrum Disorder: A Stool-Phenotype-Stratified Analysis.
The Link Between Serum Levels of Dehydroepiandrosterone and Alzheimer's Disease: A Pilot Study in the Serbian Population.
Effects of intravesical cocktail instillation on outcomes and serum pain factors of patients with bladder pain syndrome.
Spatial and Functional Roles of Syndecans in Skin Wound Healing.
Coral Hydrate improves renal fibrosis by inhibiting indoxyl sulfate-induced ROS-mediated NLRP3 inflammasome activation.
Lymphocyte Phenotypes and Protein-Bound Uremic Toxins as Determinants of Clinical Outcomes in Hemodialysis Patients.
Clinical Quantitative Method Development of serum indoxyl sulfate (IS) assay using LC-MS/MS.
Charge-Driven Self-Assembly of Cholesterol Surfactants into Biofunctional Nanodiscs with Antiviral Activity.
Reproductive hormones during minipuberty suggest subtle testicular impairments in boys with hypospadias.
Dopamine-functionalized bioinspired pre-chondrogenic hydrogel for cell-free cartilage regeneration.

Cells. 2025 Oct 28. pii: 1686. [Epub ahead of print]14(21):

Dysfunctional Chondroitin 4-O-Sulfotransferase-1 Impairs Cellular Redox State and Promotes Tau Aggregation.

Satomi Nadanaka, Yuto Imamoto, Toru Takarada, Masafumi Tanaka, Hiroshi Kitagawa.

  Chondroitin sulfate (CS) chains on the cell surface are sulfated in various patterns, and this structure is the basis of CS function. We aimed to investigate the role of chondroitin 4-O-sulfotransferase-1 (C4ST-1), the enzyme responsible for the 4-sulfation of CS, in redox homeostasis and protein aggregation in mouse neuroblastoma Neuro2a and neural progenitor C17.2 cells. Results showed that C4ST-1 deficiency significantly reduced 4-sulfated CS, which led to markedly decreased intracellular glutathione levels and increased reactive oxygen species production. Mechanistically, C4ST-1 loss reduced the CS modification of neurocan, decreased the stability of the cystine transporter xCT, and decreased intracellular glutathione levels. This redox imbalance promoted protein aggregation and caused lysosomal membrane damage, indicating a failure of protein quality control. Although C4ST-1 deficiency alone did not cause tau protein aggregation, it significantly accelerated the aggregation of a familial tauopathy mutant following the introduction of seeds. These findings suggest that C4ST-1-mediated CS sulfation regulates the intracellular redox state and tau pathology. Thus, C4ST-1 may serve as a therapeutic target for neurodegenerative diseases.

Keywords:  chondroitin sulfate; glutathione; oxidative stress; proteoglycan; tau aggregation

DOI:  https://doi.org/10.3390/cells14211686
Int J Mol Sci. 2025 Oct 25. pii: 10393. [Epub ahead of print]26(21):

Heparin Provides Antiviral Activity Against Rhinovirus-16 via an Heparan Sulfate Proteoglycan-Independent Mechanism.

Leanne C Helgers, Killian E Vlaming, Tanja M Kaptein, Julia Eder, Jan Willem Duitman, Teunis B H Geijtenbeek.

  Human rhinovirus 16 (HRV-16) is a major cause of common colds and can exacerbate asthma and COPD, yet no approved antiviral treatments exist. Heparin, a highly sulfated polysaccharide, is known to block viral infection of many viruses that require attachment to heparan sulfate proteoglycans (HSPGs). Here, we investigated whether heparin inhibits HRV-16 infection. HRV-16 uses ICAM-1 as its attachment receptor and lacks a confirmed HSPG-binding mechanism. Notably, heparin inhibited HRV-16 infection in vitro in a dose- and time-dependent manner. Pre-treatment of either cells or virus particles with unfractionated heparin significantly reduced HRV-16 RNA expression at 24 and 48 h post-infection. In contrast, low-molecular-weight heparins blocked infection of HRV-16 significantly less effectively compared to unfractionated heparins. Our findings suggest that the inhibitory effect of unfractionated heparin on HRV-16 infection is likely independent of specific HSPGs interactions and may be mediated by the size and highly negative charge of unfractionated heparin. Importantly, the ability of unfractionated heparin to block viruses that do not require HSPGs for attachment implies a broader antiviral potential as a prophylactic or therapeutic agent against a variety of respiratory viruses.

Keywords:  heparan sulfate proteoglycans (HSPGs); heparin; human rhinovirus (HRV)

DOI:  https://doi.org/10.3390/ijms262110393
Foods. 2025 Oct 22. pii: 3588. [Epub ahead of print]14(21):

Structural Characterization and Antioxidant Activity of Chondroitin Sulfate Derived from Channa argus in Changbai Mountain.

Siyu An, Xu Zhang, Xiaoqin Wan, Wei Bing, Linlin Zhang, Yue Xiang, Wei An, Changhui Zhao.

  Chondroitin sulfate (CS), commonly derived from animal cartilages, is a glycosaminoglycan with various bioactivities. This study employed an alkaline-enzyme method to prepare CS derived from Channa argus (referred to as CCS), using the heads and spines, which are food processing byproducts, as raw materials. Following this, we characterized its structure using HPLC, GPC, FTIR, and NMR and evaluated its antioxidant activity based on a TBHP-induced oxidative stress cell model. Structural analysis revealed that the CCS had a molecular weight of 5.09 kDa and was primarily composed of glucose and galactose units, featuring acetylated glucuronic acid-galactan chains with mixed α/β-glycosidic bonds. In vitro cellular antioxidant assays showed that CCS (80 μg/mL) significantly protected ARPE-19 cells against TBHP-induced oxidative damage by reducing ROS and MDA levels while enhancing the activity of typical antioxidant enzymes (CAT, SOD and GSH-Px). These findings indicate that CS derived from the byproduct of Channa argus processing has notable antioxidant properties and could serve as a promising food supplement for health applications.

Keywords:  Channa argus; antioxidant activity; chondroitin sulfate; structural characterization

DOI:  https://doi.org/10.3390/foods14213588
Int J Biol Macromol. 2025 Nov 09. pii: S0141-8130(25)09498-X. [Epub ahead of print] 148941

Liposome-chondroitin sulfate/chitosan hybrid system for combinational drug delivery of curcumin and dexamethasone: In vitro anti-cancer activities.

Shima Eldurini, Emad Tolba, Bothaina M Abd El-Hady, Ayman M Ibrahim, Medhat W Shafaa.

  This study explored a novel drug delivery system for colorectal cancer (CRC) treatment, focusing on cationic liposomes (L+ve) and chondroitin sulfate (CHS). The CHS-coated cationic liposome system (CHS@L+ve) was used to develop different formulations of dexamethasone (DEXA) and curcumin (CURC) using the thin-film hydration technique. The obtained formulations underwent detailed analyses to characterize their physicochemical properties and biological impacts. The formulation designated as CHS-coated DEXA-loaded CURC liposomes CHSD@LC, characterized by an average particle size of 80 ± 14 nm, exhibited high encapsulation efficiency (EE%) for both CURC and DEXA. In vitro drug release studies revealed a modified release profile, where DEXA exhibited a higher early release compared to CURC, supporting a staggered immunomodulatory-then-cytotoxic therapeutic strategy. This formulation notably induced 42.18 % S phase arrest and 51.07 % total apoptosis in HCT-116 cells, suggesting effective inhibition of cancer cell proliferation and survival. Mechanistically, this response is effectively linked to the pharmacological action of both agents, as well as extracellular matrix (ECM) modulation and chitosan's mucoadhesive and antibacterial properties. These findings highlight the promise of this dual-drug, polymer-stabilized nanocarrier for targeted CRC treatment, warranting further in vivo validation and clinical translation.

Keywords:  Cell cycle arrest; Chondroitin sulfate; Colorectal cancer; Curcumin; Liposome

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.148941
Int J Mol Sci. 2025 Oct 28. pii: 10475. [Epub ahead of print]26(21):

Urinary Uremic Toxin Signatures and the Metabolic Index of Gut Dysfunction (MIGD) in Autism Spectrum Disorder: A Stool-Phenotype-Stratified Analysis.

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

  Gut-derived uremic toxins may play a key role in neurodevelopmental conditions such as autism spectrum disorder (ASD) via host-microbe metabolic interactions. We evaluated five uremic toxins-p-cresyl sulfate (PCS), indoxyl sulfate (IS), trimethylamine N-oxide (TMAO), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA)-in urine samples of 97 children with ASD and 71 neurotypical controls, stratified by Bristol Stool Chart (BSC) consistency types. Four of these toxins (PCS, IS, TMAO, ADMA) were integrated into a novel composite biomarker called the Metabolic Index of Gut Dysfunction (MIGD), while SDMA was measured as a complementary renal function marker. While individual metabolite levels showed no statistically significant differences, group-wise analysis by stool phenotype revealed distinct trends. ASD children with hard stools (BSC 1-2) showed elevated PCS levels and the MIGD score (median 555.3), reflecting phenolic fermentation dominance with reduced indolic detoxification. In contrast, children with loose stools (BSC 6-7) had the lowest MIGD values (median 109.8), driven by higher IS and lower ADMA concentrations, suggestive of enhanced indole metabolism. These findings indicate that MIGD may serve as a novel biomarker to stratify metabolic phenotypes in ASD, linking urinary metabolite patterns to gut function. Further validation in larger and longitudinal cohorts is warranted to confirm its potential utility in precision microbiota-targeted interventions.

Keywords:  Bristol Stool Chart; autism spectrum disorder; gut metabolic dysfunction; indoxyl sulfate; microbiota–host interactions; p-cresyl sulfate; uremic toxins; urinary biomarkers

DOI:  https://doi.org/10.3390/ijms262110475
Cureus. 2025 Oct;17(10): e94489

The Link Between Serum Levels of Dehydroepiandrosterone and Alzheimer's Disease: A Pilot Study in the Serbian Population.

Nemanja Nenezic, Jelena Dragicevic Jeremic, Nemanja Rancic, Bratislav Dejanovic, Dejan Kostic, Dragana Nenezic, Teodora Safiye, Christos Alexopoulos, Smiljana Kostic.

  Background and aim Alzheimer's disease (AD) is the most prevalent type of dementia and a major health concern among the elderly population. Considering the role of neurosteroids in neurodegenerative processes, this pilot study aimed to investigate the association between serum dehydroepiandrosterone sulfate (DHEA-S) and cortisol concentrations, as well as their ratio, in patients with AD compared with cognitively intact individuals. Methods An observational case-control study was conducted involving 45 patients with clinically probable AD, diagnosed according to the 2011 National Institute on Aging-Alzheimer's Association criteria, and 40 healthy control participants matched for age and sex. Fasting morning serum concentrations of DHEA-S and cortisol were measured after a 12-hour overnight fast in all participants, and the cortisol/DHEA-S ratio was calculated. Cognitive status was assessed using the Montreal Cognitive Assessment and Clinical Dementia Rating scales. Results No statistically significant difference in serum DHEA-S concentrations was found between patients with AD and controls. However, patients with AD had significantly higher cortisol levels (398.85 vs. 337.40 nmol/L; p = 0.026) and a higher cortisol/DHEA-S ratio, showing a trend toward statistical significance (p = 0.078). Among participants aged 65-75 years, the cortisol/DHEA-S ratio was significantly higher in patients with AD than in controls (p = 0.031). In the control group, males had significantly higher DHEA-S levels than females (p = 0.020), whereas no sex difference was observed in the AD group. Conclusions The findings of this pilot study suggest that elevated cortisol levels and an imbalance in the cortisol/DHEA-S ratio may contribute to AD pathophysiology. DHEA-S alone did not show a significant association with disease presence, but the observed age- and sex-related differences indicate that this neurosteroid may play a differential role in the development and progression of AD.

Keywords:  alzheimer's disease (ad); dehydroepiandrosterone sulfate; hydrocortisone; mental cognition; neurosteroids

DOI:  https://doi.org/10.7759/cureus.94489
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2025 Nov 11.

Effects of intravesical cocktail instillation on outcomes and serum pain factors of patients with bladder pain syndrome.

Yunpeng Jia, Yuanning Zhang, Bo Wang, Junjia Shi.

   AIMS: We aimed to assess the effects of intravesical cocktail instillation on the outcomes and serum pain factors of patients with bladder pain syndrome (BPS).
METHODS: The clinical data of 86 female BPS patients hospitalized between March 2017 and March 2024 were collected for retrospective analysis. All patients were treated with oral medication (amitriptyline) + local intravesical instillation of drugs, and then assigned to a control group (sodium hyaluronate intravesical instillation) and a research group [intravesical instillation of dimethyl sulfoxide (DMSO) + chondroitin sulfate (CS) + low-molecular-weight heparin (LMWH) cocktail].
RESULTS: The research group (n=43) had lower urination frequency in 24 h, Pelvic Pain and Urgency/Frequency Patient Symptom Scale score, and O'Leary-Sant interstitial cystitis symptom index and interstitial cystitis problem index, as well as larger single urination volume than those of the control group (n=43) after 3 and 6 months of treatment (P<0.05). In the serum, the levels of substance P (SP), 5-hydroxytryptamine (5-HT), prostaglandin E2 (PGE2), neuropeptide Y (NPY), β-endorphin (β-EP), and dopamine (DA) declined in the two groups after 1 month of treatment in comparison to the pre-treatment levels. The levels of SP, 5-HT, PGE2, and NPY were lower, while the levels of β-EP and DA were higher in the research group than those in the control group (P<0.05).
CONCLUSION: The intravesical instillation of DMSO + CS + LMWH cocktail is superior in long-term outcomes. It is more conducive to improving the levels of serum pain factors, with a good safety profile and without increasing adverse reactions.

Keywords:  bladder pain syndrome; cocktail; intravesical instillation; outcome

DOI:  https://doi.org/10.5507/bp.2025.029
Int J Mol Sci. 2025 Oct 30. pii: 10571. [Epub ahead of print]26(21):

Spatial and Functional Roles of Syndecans in Skin Wound Healing.

Eunhye Park, Han-Gyeol Kim, Yowon Un, Eok-Soo Oh.

  Wound healing is a complex, multi-phase process involving hemostasis, inflammation, proliferation, and tissue remodeling. Syndecans (SDCs), a family of transmembrane heparan sulfate proteoglycans, serve as co-receptors for growth factors, cytokines, and ECM components, playing critical roles in cell adhesion, migration, proliferation, and angiogenesis. Among them, SDC-1 and SDC-4 are key regulators of skin wound healing. Due to their distinct spatial and temporal expression across various cell types-such as epithelial cells, fibroblasts, and immune cells-SDCs are well-positioned to coordinate regenerative responses. This review focuses on the spatial regulation of SDCs during skin wound healing, highlighting their roles in epidermal and dermal repair, modulation of intracellular signaling, and remodeling of the wound microenvironment. Overall, SDCs are emerging as central modulators of skin wound healing, with promising implications for regenerative medicine in the skin and beyond.

Keywords:  extracellular matrix; homeostasis; keratinocytes; syndecan; wound healing

DOI:  https://doi.org/10.3390/ijms262110571
Eur J Pharmacol. 2025 Nov 12. pii: S0014-2999(25)01121-5. [Epub ahead of print] 178367

Coral Hydrate improves renal fibrosis by inhibiting indoxyl sulfate-induced ROS-mediated NLRP3 inflammasome activation.

Tsai-Kun Wu, Yi-Hsien Hsieh, Tung-Wei Hung, Hui-Ling Chiou, Hsiang-Yao Shih, Yi-Hsuan Ting, Ying-Ru Pan, Chung-Jung Liu, Shao-Hsuan Kao.

  Chronic kidney disease (CKD) is a global kidney disease characterized by chronic inflammation, oxidative stress and fibrosis in the kidney. A hydrogenated coral material known as coral hydrate (CH) has potent antioxidant activity. However, the effect of CH on renal fibrosis is rarely explored. This study aims to determine the effects of CH on renal fibrosis and indoxyl sulfate (IS)-induced renal cell injury and to elucidate the mechanisms underlying such effects. In vivo unilateral ureteral obstruction (UUO) mouse model, our findings showed that UL-CH group (UUO mice administered with low-dose CH) or UH-CH group (UUO mice administered with high-dose CH) significantly ameliorated renal fibrosis, reduced the levels of collagen I, α-smooth muscle actin (α-SMA), vimentin, Snail and Slug in renal tissues in addition to decreasing the levels of NLRP3, cleaved (c)-caspase-1, and c-IL-1β. In NRK-52E cells, CH downregulated IS-induced NLRP3, c-caspase-1, and c-IL-1β. CH treatment resulted in decreased ROS, HO-1, and p-NRF2 induced by IS stimulation, and combination treatment with CH and the NLRP3 inhibitor MCC950 further reduced NLRP3 inflammasome to levels lower than those with CH treatment alone. Collectively, these results indicate that CH has the potential to ameliorate NLRP3 inflammasome-mediated renal fibrosis. Thus, CH has the potential to ameliorate NLRP3 inflammasome-mediated renal fibrosis.

Keywords:  Coral hydrate; Interleukin-1β; NLRP3 inflammasome; Reactive oxygen species; Renal fibrosis; Unilateral ureteral obstruction; cleaved-caspase-1

DOI:  https://doi.org/10.1016/j.ejphar.2025.178367
Int J Mol Sci. 2025 Oct 24. pii: 10376. [Epub ahead of print]26(21):

Lymphocyte Phenotypes and Protein-Bound Uremic Toxins as Determinants of Clinical Outcomes in Hemodialysis Patients.

Theodoros Tourountzis, Georgios Lioulios, Stamatia Stai, Steven Van Laecke, Eleni Moysidou, Michalis Christodoulou, Ariadni Fouza, Asimina Fylaktou, Konstantia Kantartzi, Griet Glorieux, Maria Stangou.

  The impact of protein bound uremic toxins (PBUTs) and lymphocyte alterations in morbidity and mortality in patients on hemodialysis (HD) is of great concern. The aim of this study was the assessment of association between PBUTs, immunosenescent lymphocytes' phenotype and clinical events [cardiovascular, severe infections (hospitalization due to infection, respiratory infection), all-cause mortality] during 2-year follow-up. In this prospective observational study, lymphocytes' phenotype of 54 patients on HD and 31 age-matched controls was analyzed by flow cytometry, and simultaneously, PBUT serum levels [hippuric acid (HA), indoxyl sulfate (IxS), p-cresyl sulfate (pCS), p-cresyl glycuronide (pCG), in-dole-3-acetic acid (IAA), and 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF)] were quantified by ultra-performance liquid chromatography. Patients with increased levels of free IxS and total and free HA had higher mortality within a 2-year follow-up period (p = 0.049, p = 0.01, p = 0.01, respectively). In patients who experienced cardiovascular events, higher concentrations of CMPF (p = 0.015) were observed. Higher total and free HA levels associate with increased all-cause mortality in patients on HD, independently of age, dialysis vintage, and decreased count of CD4+CD45RA+CD31+ and naïve B cells (CD19+IgD+CD27-). In patients on HD, increased levels of total and free HA associate with an increased risk of death.

Keywords:  hemodialysis; immunosenescence; morbidity; mortality; protein bound uremic toxins

DOI:  https://doi.org/10.3390/ijms262110376
Biochem Biophys Rep. 2025 Dec;44 102316

Clinical Quantitative Method Development of serum indoxyl sulfate (IS) assay using LC-MS/MS.

Sohei Kobayashi, Kazuyuki Matsushita, Kenji Kawasaki, Masanori Seimiya.

   Background: Indoxyl sulfate (IS) accumulates in the blood with decreases in the voided volume due to a decline in renal function and promotes the progression of renal failure. Assay reagents for IS are marketed by several companies, but they have not been standardized because of the absence of a standard assay method. In this study, the performance of the LC-MS/MS (liquid chromatography tandem mass spectrometry) was evaluated for the establishment of a standard assay method.
Methods: The same analytical procedure was performed by two examiners using the AB SCIEX QTRAP® 4500 LC-MS/MS System. A calibration curve was prepared according to the target analyte (IS)/internal standard: 3-Indoxyl sulfate-d4 potassium salt (IS-d4) peak area ratio, and the linearity, reproducibility, selectivity tests, interferent tests, limit of blank (LOB), limit of detection (LOD), lower limit of quantification (LLOQ), and correlations were evaluated.
Results: By dilution tests of IS standard solution, linearity (R2 = 0.9995) passing through the origin was observed up to 440 μmol/L. Repeatability was coefficient of variation 2.6-4.7 % at 8.3-124.6 μmol/L, and the intermediate precision was 7.9-9.2 % at 12.9-171.2 μmol/L. In the selectivity testing, the recovery rate was 101.0-104.3 %. Regarding the effects of interferents, the interference rate was about 5.0 % at the maximum. LOB was 0.004 μmol/L, LOD was 1.248 μmol/L, and LOQ was 3.23 μmol/L. The correlation between this method (y) and conventional enzymatic analysis (x) was R = 0.996, y = 1.13x - 2.89.
Discussion: The basic performance of this method was satisfactory. Also, because excellent precision was obtained in both examiners, the stability of the assay method was also suggested to be guaranteed. This method is considered useful as a reference method for IS assay.

Keywords:  Analytical validation; Chronic kidney disease (CKD); Clinical quantitative method development; Protein-bound uremic toxins (PBUT); Reference assay method

DOI:  https://doi.org/10.1016/j.bbrep.2025.102316
Angew Chem Int Ed Engl. 2025 Nov 13. e16207

Charge-Driven Self-Assembly of Cholesterol Surfactants into Biofunctional Nanodiscs with Antiviral Activity.

Yanping Long, Seyyed Mohammad Mousavifard, Xianfeng He, Roland R Netz, Hesam Makki, Mathias Dimde, Chuanxiong Nie, Abhishek K Singh, Rainer Haag.

  Self-assembly of lipid structures derived from amphiphilic molecules plays a crucial role in the development of biomimetic systems. Here we report a modular synthetic strategy for developing cholesteryl-oligo-glycerol-based surfactants with tunable head group functionalities ranging from nonionic to anionic. This approach enables the systematic incorporation of functional groups and thus precise control of surface charge and hydrophilicity. To investigate the influence of multivalent charges on supermolecular-assembly behavior, we compared three structurally cholesterol (CL) related surfactants: CL-4S, with four sulfate groups, CL-1S, with a single sulfate group, and CL-4OH, a nonionic analog with four hydroxyl groups. We then incorporated these surfactants into lipid bilayers of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and cholesterol (CL) to study their behavior in membrane-like environments. Experimental, simulation, and theoretical studies demonstrated that the CL-4S formulation was able to convert lipid vesicles into nanodiscs, unlike CL-1S and CL-4OH, demonstrating the importance of adequate charges in supramolecular transition. Furthermore, both 1S-Vesicles (CL-1S based sulfated vesicles) and 4S-Nanodiscs (CL-4S based sulfated nanodiscs) showed inhibitory activity against herpes simplex virus-1 (HSV-1), indicating the potential of this multivalent supramolecular platform for antiviral applications.

Keywords:  Antiviral; Cholesterol; Nanodiscs; Oligo‐glycerol Surfactants; Vesicles

DOI:  https://doi.org/10.1002/anie.202516207
J Clin Endocrinol Metab. 2025 Nov 13. pii: dgaf618. [Epub ahead of print]

Reproductive hormones during minipuberty suggest subtle testicular impairments in boys with hypospadias.

Tina L Leunbach, Andreas Ernst, Trine Holm Johannsen, Agnethe Berglund, Jakob Albrethsen, Hanne Frederiksen, Anders Juul, Yazan F Rawasdeh.

   CONTEXT: The ontogeny of hypospadias and its implications remain incompletely understood.
OBJECTIVE: To examine whether fetal outcomes and reproductive hormone concentrations in boys with hypospadias differ from reference standards during minipuberty.
DESIGN: Prospective cohort study (May 2021 - January 2023).
SETTING: Tertiary hypospadias centre.
PATIENTS: Infants presenting with hypospadias (n=139), of whom 113 were enrolled following parental consent (median postnatal age: 0.28 years).
INTERVENTIONS: Examination of hypospadias grade, external masculinization score (EMS), placental- and birth weight and blood sampling (reproductive hormones).
MAIN OUTCOME MEASURES: Fisher's exact test assessed gestational age (GA)-specific birth weight- and placental centiles by hypospadias severity. GA-specific reproductive hormone concentrations were converted to standard deviation scores (SDS) according to an established reference standard for healthy Danish boys. The one-sample Wilcoxon signed-rank test compared concentrations to zero SDS.
RESULTS: Eighty-nine boys (79%) had distal hypospadias with a median EMS of 11 whilst median EMS was 9 in boys with proximal hypospadias.Birth weight-and placental centiles were lower in boys with proximal hypospadias (p=0.014 and p=0.038).The median concentration of follicle-stimulating hormone (0.83 SDS), testosterone (0.71 SDS), and free testosterone (0.83 SDS) were higher in boys with hypospadias compared to zero SDS (p<0.001). The median concentrations of inhibin B (-0.38 SDS), anti-Müllerian hormone (AMH) (-0.23 SDS), insulin-like factor 3 (INSL3) (-0.31 SDS), androstenedione (-0.52 SDS) and dehydroepiandrosterone sulfate (-0.50 SDS) were significantly lower. Luteinizing hormone, sex hormone-binding globulin, 17-hydroxyprogesterone, and dihydrotestosterone were not statistically different. Hormone SDSs did not differ significantly by hypospadias severity.
CONCLUSION: Hypospadias severity was significantly associated with birth- and placental weight centiles. Testicular Sertoli cell markers (AMH and inhibin B) and the Leydig cell-derived INSL3 were reduced, suggesting subtle testicular dysfunction in boys with hypospadias during minipuberty. Further research to identify implications for future reproductive health is warranted.

Keywords:  Hypospadias; androgens; hypogonadism; hypothalamic-pituitary-gonadal axis; mini-puberty

DOI:  https://doi.org/10.1210/clinem/dgaf618
J Control Release. 2025 Nov 12. pii: S0168-3659(25)01021-1. [Epub ahead of print] 114407

Dopamine-functionalized bioinspired pre-chondrogenic hydrogel for cell-free cartilage regeneration.

Qi Zhu, Luwen Zhu, Jialu Lang, Jiawen Zhu, Di Chen, Yuanyan Huang, Jucong Zhang, Xiaochuan Wu, Jiahao Hu, Jiansong Ji, Qining Yang, Yongzhong Du.

  Articular cartilage has limited self-repair capacity due to the low metabolic activity and sparse distribution of chondrocytes. Although implantation of scaffolds that could induce the recruitment and chondrogenesis of endogenous bone marrow mesenchymal stem cells (BMSCs) provides a promising strategy for in-situ cartilage regeneration, establishing a culture environment suitable for the proliferation and oriented differentiation of BMSCs is challenging. Here, inspired by native cartilage architecture, we develop a biomimetic pre-chondrogenic hydrogel. Specifically, dopamine-functionalized chondroitin sulfate and hyaluronic acid are integrated into a self-assembled type I collagen network to mimic the cartilage-like extracellular matrix, while Kartogenin (KGN)-conjugated polydopamine nanoparticles are incorporated into the scaffold. In vitro and in vivo results demonstrated that the cartilage-mimicking microenvironment supports various cellular activities. The abundant dopamine in the hydrogel effectively attracts BMSCs and modulates oxidative stress. Meanwhile, the sustainable KGN release driven by the hydrolysis of covalent bonds promotes chondrogenic differentiation of recruited cells, thereby accelerating the repair of full-thickness cartilage defects. The synchronization effects of these two components achieved superior repair outcomes, providing support for the further application of cell-free advanced biomaterials scaffold in cartilage tissue engineering.

Keywords:  Articular cartilage injury; Cartilage-inspired structure; Chondrogenesis;; Dopamine-modified polymers; Mesenchymal stem cell recruitment

DOI:  https://doi.org/10.1016/j.jconrel.2025.114407