bims-supasi 2025-10-05 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2025–10–05
thirteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Chondroitin sulfate and hyaluronan in the vitreous of patients with rhegmatogenous retinal detachment.
Temporally increased 4-sulfated chondroitin sulfate promotes proper progression of bone morphogenetic protein 4-mediated chondrogenic differentiation.
Production and inhibition of human Heparan 6-O-Endosulfatase SULF1.
The equine placental extract ameliorates renal damage in mice with adenine-induced chronic kidney disease by inhibiting indoxyl sulfate production.
Evaluation of endogenous steroid sulfates and glucuronides in urine after oral and transdermal administration of testosterone. Part I: Male participants.
Structural and hormonal changes in the ovaries of women with polycystic ovary syndrome and healthy controls: a 13-year prospective study in an unselected population.
Transcriptomic and Metabolomic Mechanism of Ibuprofen, Chondroitin Sulfate, and Vitamins With Minerals Tablets (21) for Kashin-Beck Disease Treatment.
Sulfated polysaccharide from Apostichopus japonicus and its inhibition effects on Helicobacter pylori in vitro and in vivo.
3D-Printed Polysaccharide Scaffolds with NIR-Triggered Activity for Diabetic Wound Healing.
Innovative DCZCMC Platform: Dual Regulation of Cholesterol Dynamics and the cGAS/STING Pathway Activation to Combat Drug Resistance in Tumor Therapy.
Decellularised Cartilage-Based Hydrogels Functionalised With Chondroitin Sulphate and Quercetin: The Impact on Chondrogenesis.
Allosteric Mechanisms Triggering Substrate and Cofactor Binding in the SULT1A1 Dimer as Revealed by Molecular Dynamics Simulations.
Steroid anabolic and catabolic hormones in highly and recreationally trained female athletes across the menstrual cycle.

Exp Eye Res. 2025 Sep 27. pii: S0014-4835(25)00444-0. [Epub ahead of print] 110672

Chondroitin sulfate and hyaluronan in the vitreous of patients with rhegmatogenous retinal detachment.

Birgit Marlies Govers, Bjorn Bakker, Magdalena J de Bruijne, Arie Oosterhof, Elly Versteeg, Anneke I den Hollander, Sander Keijser, B Jeroen Klevering, Willeke F Daamen, T H van Kuppevelt.

   PURPOSE: To compare hyaluronan (HA) and chondroitin sulfate (CS) concentrations as well as the sulfation pattern of CS domains in the vitreous of rhegmatogenous retinal detachment (RRD) versus non-RRD patients.
METHODS: Vitreous samples from 56 patients with RRD and 41 patients with floaters, macular hole or epiretinal membranes were collected during pars plana vitrectomy. Disaccharide analysis was performed by high-pressure liquid chromatography (HPLC) to assess HA and CS concentrations in the vitreous and determine CS sulfation.
RESULTS: The vitreous of RRD patients showed significantly lower HA concentrations (Mann-Whitney U, p<0.001) and higher CS concentrations (Mann-Whitney U, p<0.001) compared to non-RRD patients. The higher total CS concentration in RRD patients was related to a significant increase in non-sulfated CS domains. The concentration of sulfated CS disaccharides with a 6S domain was significantly decreased in RRD patients compared to non-RRD patients: 4S6S (Mann-Whitney U; p=0.008), 2S6S (Mann-Whitney U; p=0.004), and 6S (Mann-Whitney U; p=0.013). The sulfated CS disaccharides 2S4S, 4S6S, 2S6S, 4S, 2S, and 6S, are significantly more abundant in non-RRD patients.
CONCLUSIONS: The significant degree of non-sulfated CS domains and decreased HA concentrations in the vitreous of RRD patients could weaken structural organization of the vitreous. Reduced vitreous stability can cause pathological vitreoretinal traction, ultimately leading to rhegmatogenous retinal detachment.

Keywords:  Chondroitin sulfate; Glycosaminoglycans; Hyaluronan; Retinal detachment; Vitreous

DOI:  https://doi.org/10.1016/j.exer.2025.110672
Biochem Biophys Res Commun. 2025 Sep 26. pii: S0006-291X(25)01429-9. [Epub ahead of print]786 152713

Temporally increased 4-sulfated chondroitin sulfate promotes proper progression of bone morphogenetic protein 4-mediated chondrogenic differentiation.

Tadahisa Mikami, Hiromi Takenaka, Tomoko Morita, Hiroshi Kitagawa.

  Chondroitin sulfate (CS) is a principal extracellular matrix component in cartilaginous tissues, well known for its role in cartilage elasticity owing to its physicochemical properties. However, its intrinsic role in chondrogenesis remains unelucidated. This study aimed to investigate the expression pattern and corresponding effects of 4-sulfated CS chains throughout the differentiation processes in chondrogenic ATDC5 cells. Herein, chondroitin 4-O-sulfotransferase-1 (C4ST-1) knockdown (KD) subclones, a potential late-limiting enzyme in 4-sulfated CS biosynthesis, were constructed. Notably, C4ST-1 KD did not affect the initial cellular condensation of ATDC5 cells, albeit it suppressed subsequent chondrogenic differentiation, markedly upregulating the production of cartilage matrix macromolecules, including proteoglycans bearing 4-sulfated CS chains. Additionally, bone morphogenetic protein (BMP)-4-mediated chondrogenic signaling events, including small mothers against decapentaplegic homolog 1/5/9 phosphorylation and N-cadherin cleavage, showed marked downregulation in C4ST-1 KD cells. Bath application of exogenous BMP-4 partially restored N-cadherin cleavage rate and upregulated the expression of chondrocyte markers in C4ST-1 KD cell cultures. Altogether, the findings of this study strongly suggest the function of 4-sulfated CS chains as an extracellular regulator, in addition to their role as a structural support for cartilage tissues, which effectively controls the progression of chondrocyte differentiation.

Keywords:  Bone morphogenetic protein; Chondrogenic differentiation; Chondroitin sulfate; N-cadherin; Sulfotransferase

DOI:  https://doi.org/10.1016/j.bbrc.2025.152713
Glycobiology. 2025 Sep 30. pii: cwaf059. [Epub ahead of print]

Production and inhibition of human Heparan 6-O-Endosulfatase SULF1.

Reem Aljuhani, Julius Benicky, Aswini Panigrahi, Pritha Mukherjee, Miloslav Sanda, Shiya Zhu, Zora Nováková, Vitor H Pomin, Jian Liu, Bruce Davidson, Cyril Bařinka, Radoslav Goldman.

  SULF1, a human extracellular heparan 6-O-endosulfatase isoform 1, plays a critical role in embryonic development and cancer progression by modulating the 6-O-sulfation of heparan sulfate proteoglycans. However, limited recombinant protein production has hindered structural and functional characterization. To address this issue, we optimized SULF1 expression in HEK293F and HEK293T cells. We achieved yields of 2.2 mg/L of culture media after Ni2+-affinity purification of greater than 80% purity, representing a substantial improvement compared to the reported expression systems. We demonstrated that co-expression of sulfatase-modifying factor 1 in this expression system is essential for enhancing SULF1 enzymatic activity, which depends on conversion of active site cysteine to Cα-formylglycine and the presence of a Ca2+ ion. We further showed that a marine fucosylated chondroitin sulfate polymer isolated from the sea cucumber Holothuria floridana inhibits SULF1 enzymatic activity with IC50 of 0.05 ± 0.006 μg/mL and 0.07 ± 0.008 μg/mL for the GlcNS6S-GlcA-GlcNS6S-IdoA2S-GlcNS6S-IdoA2S-GlcNS6S-GlcA and 4-methylumbelliferyl sulfate substrates, respectively. Kinetic analysis revealed a mixed-mode inhibition, characterized by alterations in Vmax at all inhibitor concentrations and Km at high inhibitor concentrations. Efficient SULF1 production also enabled us to develop specific monoclonal antibodies, which confirmed SULF1 expression in the stroma of head and neck squamous cell cancer tissues. Collectively, this study provides an efficient workflow for the production of active human SULF1, investigates SULF1 inhibitors, and characterizes anti-SULF1 monoclonal antibodies, which will support further studies of this enzyme in various pathophysiological conditions.

Keywords:   N-glycosylation; Heparan 6-O-endosulfatase SULF1; Sulfatase modifying factor SUMF1; calcium ion; enzymatic activity

DOI:  https://doi.org/10.1093/glycob/cwaf059
Open Vet J. 2025 ;15(7): 3334-3340

The equine placental extract ameliorates renal damage in mice with adenine-induced chronic kidney disease by inhibiting indoxyl sulfate production.

Koji Sugimoto, Junichi Nakamura, Dawei Deng, Eiichi Hirano.

   Background: Indoxyl sulfate (IS) is a dietary metabolite of tryptophan that is produced in the liver. It is a uremic toxin that facilitates the progression of chronic kidney disease (CKD). We previously observed that equine placental extract (ePE) inhibited IS synthesis in an in vitro inhibition assay using the liver S9 fraction.
Aim: This study was designed to investigate the effects of ePE on adenine-induced renal failure in mice at the histological and molecular levels to understand the mechanism of action of ePE.
Methods: We assessed this effect through biochemical and histological in vivo analyses using a mouse model of CKD and an adenine diet, which induces renal damage through IS production.
Results: ePE significantly suppressed serum, renal, and hepatic IS production in adenine diet-fed mice by inhibiting IS synthesis. Histological and semi-quantitative analyses using the tubulointerstitial injury index revealed that ePE effectively prevented the increase in adenine-induced mesangial-positive cell area. Additionally, ePE administration significantly suppressed adenine-induced renal fibrosis in mice. Moreover, immunohistochemical analysis demonstrated that ePE administration reduced the accumulation of F4/80-positive macrophages in the interstitial inflammatory infiltrates.
Conclusion: These results suggest that ePE ameliorates IS-associated renal injury in adenine diet-fed mice by reducing IS production in the interstitium of the kidneys.

Keywords:  Equine placental extract; Renal failure; Tubulointerstitial injury; Uremic toxin

DOI:  https://doi.org/10.5455/OVJ.2025.v15.i7.45
J Steroid Biochem Mol Biol. 2025 Sep 29. pii: S0960-0760(25)00198-0. [Epub ahead of print]255 106870

Evaluation of endogenous steroid sulfates and glucuronides in urine after oral and transdermal administration of testosterone. Part I: Male participants.

Sandra Pfeffer, Günter Gmeiner, Nenad Dikic, Marija Andjelkovic, Guro Forsdahl.

  The detection of the performance-enhancing drug testosterone (T) remains a significant challenge in doping control analysis. Longitudinal monitoring through the steroidal Athlete Biological Passport (ABP) is a valuable tool for T detection, but further research is needed to enhance its efficacy. Phase II metabolites of endogenous anabolic androgenic steroids (EAAS), including glucuronides and sulfates, have gained increasing interest as potential new biomarkers for the steroidal ABP. Notably, sulfate metabolites have demonstrated higher sensitivity to oral, transdermal, and intramuscular T administration, with extended detection windows compared to traditional biomarkers. However, before incorporating these promising biomarkers into urinary steroid profiling, it is essential to address the metabolic variations associated with different T administration methods, as well as differences related to ethnicity and sex. In this part of the study, we investigate the effects of oral and transdermal T administration on conventional biomarkers and phase II EAAS metabolites in male participants. Sulfate ratios indicated higher sensitivity to multiple administrations of testosterone undecanoate (TU) tablets and T gel, significantly prolonging detection times compared to conventional steroid profile biomarkers. Specifically, sulfate ratios such as androsterone sulfate (AS)/testosterone sulfate (TS) and epiandrosterone sulfate (EpiAS)/TS enabled detection for an average of 20 days following the last oral TU dose and at least 16 days after the last transdermal T application. These findings provide further evidence that incorporating sulfate EAAS metabolites into steroid profiling enhances detection capabilities. For advanced T doping detection, sulfate metabolites should be considered essential biomarkers in the steroid profile.

Keywords:  Combined ratio; Doping; Endogenous steroids; Glucuronides; Phase II metabolites; Sulfates

DOI:  https://doi.org/10.1016/j.jsbmb.2025.106870
Reprod Biol Endocrinol. 2025 Sep 30. 23(1): 126

Structural and hormonal changes in the ovaries of women with polycystic ovary syndrome and healthy controls: a 13-year prospective study in an unselected population.

Nevda Ceren Sonu, Seren Aksun, Gurkan Bozdag, Hakan Yarali, Bulent Okan Yildiz, Sezcan Mumusoglu.

   BACKGROUND: This study investigates whether ovarian structural and hormonal changes over a 13-year period differ between women diagnosed with polycystic ovary syndrome (PCOS) and healthy controls within an unselected population.
METHODS: This prospective nested cohort study followed up on a prevalence study conducted in 2009 in an unselected-population. A total of 41 women with PCOS (≥ 35 years-old, diagnosed using the Rotterdam criteria) and 43 age- and body-mass-index-(BMI)-matched healthy controls were included from this cohort. The relationship between ovarian structure and hormonal profiles was tracked over 13 years. Antral follicle count (AFC) and ovarian volume (OV) were assessed by transvaginal/pelvic ultrasonography. Anti-Mullerian hormone (AMH), total testosterone (TT), sex hormone-binding globulin (SHBG), free androgen index (FAI), and dehydroepiandrosterone sulfate (DHEAS) were measured. The cardiometabolic profile of these aging women in same cohort was reported in a recent study.
RESULTS: The mean age (44.1 ± 6.5 vs. 46.4 ± 4.2 years, p = 0.06), BMI (24.7; IQR:21.9-27.8 vs. 25.2; IQR:23.2-28.9, p = 0.16), and proportion of women in postmenopausal stage (75.6% vs. 62.8%, p = 0.24) were comparable between PCOS and control groups. Ovarian volume and AFC were significantly higher in the aging women with PCOS. At 13 years follow-up, PCOS group experienced a greater decline in AFC, AMH, and TT but retained higher levels of AMH, TT, FAI, and DHEAS than controls. An AMH cutoff of 1.17 ng/mL showed moderate diagnostic reliability for diagnosing PCOS in aging women, with an area under curve of 0.71 (95% CI:0.60-0.83).
CONCLUSIONS: Aging women with PCOS show greater declines in AFC, OV, AMH, and TT but maintain higher ovarian and hormonal levels than controls. Serum AMH provides moderate diagnostic utility for diagnosing PCOS in aging women.

Keywords:  Aging; Anti-Mullerian hormone; Antral follicle count; Ovarian volume; Polycystic ovary syndrome

DOI:  https://doi.org/10.1186/s12958-025-01462-4
Rapid Commun Mass Spectrom. 2025 Dec 30. 39(24): e10130

Transcriptomic and Metabolomic Mechanism of Ibuprofen, Chondroitin Sulfate, and Vitamins With Minerals Tablets (21) for Kashin-Beck Disease Treatment.

Jinfeng Wen, Xingxing Deng, Zhengjun Yang, Hui Niu, Qian Zhang, Yijun Zhao, Gaowa Naren, Huan Liu, Feng Zhang, Xiaodong Yang, Cuiyan Wu.

   BACKGROUND: Kashin-Beck disease (KBD) is an osteoarthropathy with no specific drug treatment. This study seeks to uncover the molecular mechanisms of ibuprofen, chondroitin sulfate, and vitamins with minerals tablets (21) in treating KBD.
METHODS: Integrated transcriptomic and metabolomic analyses were performed on peripheral blood samples collected from four KBD patients before and 1 month after treatment. Differential gene expression was assessed using the DESeq package, while differential metabolites were identified through univariate and multivariate statistical analyses.
RESULTS: After treatment, 5671 differential genes (|log2FC| ≥ 1, q < 0.05) were identified, with 4954 upregulated and 717 downregulated. Enriched pathways included PI3K-Akt, MAPK, ECM-receptor interaction, Rap1, and Ras signaling. Untargeted metabolomics analyses revealed five differentially expressed metabolites (VIP ≥ 1, |log2FC| > 0.58, p < 0.05): L-glutamine, 2-methylpropan-2-amine, epsilon-caprolactam, phosphocholine, and 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphocholine. Metabolite enrichment analysis suggested alterations in amino acid and fatty acid metabolism. Integrated analysis revealed key pathways such as alanine, aspartate, and glutamate metabolism and arginine biosynthesis.
CONCLUSIONS: The combination of ibuprofen, chondroitin sulfate, and vitamins with minerals tablets (21) may alleviate KBD through modulation of key genes (GDNF, BDNF, CCL2, VEGFA, and PPARG) and glutamine-related metabolic pathways.

Keywords:  Kashin–Beck disease (KBD); drugs treatment; metabolome; transcriptome

DOI:  https://doi.org/10.1002/rcm.10130
Int J Biol Macromol. 2025 Sep 30. pii: S0141-8130(25)08584-8. [Epub ahead of print]330(Pt 1): 148027

Sulfated polysaccharide from Apostichopus japonicus and its inhibition effects on Helicobacter pylori in vitro and in vivo.

Xinyue Gai, Hui Zhang, Yongjun Sun, Wen Zhao, Miansong Zhang, Tingting Cui, Hongfang Du, Xue Liu, Airong Jia.

  High-bioactivity sea cucumber polysaccharides (SCPs) exhibit significant potential for food industrial applications. However, research on SCPs with inhibitory effects against Helicobacter pylori (Hp) remains limited. Searching for SCPs with potent Hp inhibition is of great importance. In this study, a sulfated polysaccharide AJP was extracted from Apostichopus japonicus. Composition analysis indicated that AJP contained 45.99 ± 1.41 % total sugar, 4.89 ± 0.22 % protein, 24.22 ± 0.46 % sulfate ester, 4.65 ± 0.06 % amino sugar, and 3.44 ± 0.34 % uronic acid. In addition, AJP had a high fucose ratio of 58.29 % (mol%) and a molecular weight of 116-1069 kDa. Antibacterial assays demonstrated that AJP possessed inhibitory effects against Hp in vitro. Moreover, AJP significantly alleviated gastric inflammation in Hp-infected mice and effectively reduced the colonization levels of Hp in both the Prevention (P < 0.001) and Treatment groups (P < 0.001). Additionally, AJP mitigated intestinal flora dysbiosis induced by Hp, particularly in the Treatment group.

Keywords:  Antibacterial activity; Gut microbiota; Helicobacter pylori; Sea cucumber; Sulfated polysaccharide

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.148027
ACS Omega. 2025 Sep 23. 10(37): 43012-43023

3D-Printed Polysaccharide Scaffolds with NIR-Triggered Activity for Diabetic Wound Healing.

Brianda M Salazar Salas, Denis Scaini, Luis Fernando López Soto, Lucía Enríquez Rodríguez, Markel Lafuente-Merchan, Jorge Ordoyo-Pascual, Andya J Ramírez-Irigoyen, José Luis Pedraz, Teresa Del Castillo Castro.

Skin restoration in patients with diabetes constitutes a significant therapeutic challenge as sustained hyperglycemia interferes with fundamental processes such as angiogenesis, cell regeneration, and inflammation control. These alterations not only delay healing but also increase the risk of infections and complications. Emerging therapeutic strategies such as photothermal irradiation have gained attention for their potential to accelerate tissue repair. In this study, we developed novel three-dimensional (3D)-printed near-infrared (NIR)-responsive scaffolds based on chondroitin sulfate, hyaluronic acid, alginate, and nanofibrillated cellulose, with and without polydopamine photothermal nanoparticles, as a new approach to addressing complex tissue regeneration. The resulting 3D multicomponent scaffolds exhibited suitable morphology, swelling behavior, and biocompatibility for skin wound dressing. An in vitro scratch assay confirmed that the scaffold promotes keratinocyte migration and proliferation. In vivo studies demonstrated that treatment with an NIR-irradiated scaffold accelerated wound closure, leading to narrower scars and a denser dermis in diabetic rats. Notably, complete wound healing occurred 8 days earlier in animals treated with the nanocomposite scaffold under NIR irradiation compared to untreated controls. These findings highlight the therapeutic potential of multifunctional, NIR-responsive biomaterials and establish the proposed 3D-printed nanocomposite scaffold as a promising and innovative platform enhancing skin regeneration in challenging diabetic wound models.

DOI: https://doi.org/10.1021/acsomega.5c05898
Small. 2025 Sep 30. e09075

Innovative DCZCMC Platform: Dual Regulation of Cholesterol Dynamics and the cGAS/STING Pathway Activation to Combat Drug Resistance in Tumor Therapy.

Jing Wang, Xianchun Fu, Han Zhang, Zhi Liu.

  Chemoresistance remains a daunting challenge in bladder cancer therapy, primarily driven by cholesterol-enriched rigid membranes that impede drug penetration and an immunosuppressive tumor microenvironment (TME) that evades immune surveillance. Herein, a biomimetic nanoplatform (DOX@COD-ZCM@CS, DCZCMC) is reported engineered to orchestrate metabolic-immunological crosstalk for synergistic reversal of chemoresistance. This integrated system comprises a Zn-Co metal-organic framework (Zn-Co-MOF, ZCM) core loaded with cholesterol oxidase (COD) and doxorubicin (DOX), surface-functionalized with chondroitin sulfate (CS) for tumor-specific targeting. Mechanistically, DCZCMC achieves three-tiered synergism: 1) COD-mediated cholesterol depletion (71.5% reduction, 111.2 vs 389.8 µm in the saline group) disrupts membrane rigidity, augmenting intratumoral drug retention to 87% (vs 39% with free DOX); 2) ZCM converts COD-generated H2O2 into cytotoxic hydroxyl radicals (·OH), realizing pathological cholesterol-to- reactive oxygen species (ROS) reprogramming for selective tumor oxidation; 3) Zn2+ release triggers mitochondrial DNA (mtDNA) leakage, activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway to amplify interferon-β (IFN-β) and High Mobility Group Protein 1 (HMGB1) secretion, thereby driving dendritic cells (DCs) maturation and adaptive immune activation. In drug-resistant xenografts, DCZCMC exhibits exceptional antitumor efficacy (95.6% tumor suppression) without systemic toxicity. This self-amplifying "metabolic priming-immune activation" cascade represents a paradigm shift in overcoming chemoresistance, offering a transformative strategy for bladder cancer and other malignancies characterized by metabolic-immunological dysregulation.

Keywords:  STING pathway; bladder cancer; chemoresistance; cholesterol metabolism; reactive oxygen species

DOI:  https://doi.org/10.1002/smll.202509075
J Biomed Mater Res A. 2025 Oct;113(10): e37999

Decellularised Cartilage-Based Hydrogels Functionalised With Chondroitin Sulphate and Quercetin: The Impact on Chondrogenesis.

Nuno Da Silva Rosa, Nuno Neves, Michael Gelinsky, Susana Gomes Santos, Anne Bernhardt, Mário Adolfo Barbosa.

Tissue engineering and regenerative medicine approaches are being actively developed for degenerative disorders, including osteoarthritis (OA). Decellularized matrix (dECM) is a promising biomaterial; however, glycosaminoglycan (GAG) loss during decellularization limits its chondrogenic potential. In this study, we aimed to overcome this by developing a dECM hydrogel originating from cartilage, functionalized with the GAG chondroitin sulphate (CS), to replenish those originally depleted and incorporating quercetin to enhance hydrogel properties and chondrogenesis. An optimized decellularization protocol efficiently removed DNA, but with a significant loss of GAGs (73%). After dECM solubilization, functionalization with CS or aldehyde modified CS (mCS) was performed. CS-functionalized hydrogels maintained low stiffness compared to non-functionalized hydrogel, while 0.2 mg/mL mCS hydrogels exhibited significantly slower gelation kinetics. To aid the hydrogel's chondrogenic ability, a novel approach using quercetin was investigated. Incorporation of 0.3 mg/mL quercetin in 0.4 mg/mL mCS-functionalized hydrogels resulted in increased gel stiffness. The impact on cell viability and chondrogenic differentiation was evaluated. Results showed similar cell viability in dECM and CS-functionalized hydrogels at 1 and 3 days of culture, with no significant changes in gene expression of chondrogenic and hypertrophic genes. In quercetin-containing hydrogels, the viability of human dermal fibroblasts was not significantly different from non-functionalized hydrogels, while human chondrocytes showed a significant upregulation of collagen type II, with 6.6- and 2.2-fold increases for 0.15 and 0.3 mg/mL quercetin, respectively. These results provide an initial proof-of-concept for dECM functionalization strategies that restore lost CS while incorporating quercetin, creating a microenvironment favorable for cartilage repair.

DOI: https://doi.org/10.1002/jbm.a.37999
J Chem Inf Model. 2025 Sep 29.

Allosteric Mechanisms Triggering Substrate and Cofactor Binding in the SULT1A1 Dimer as Revealed by Molecular Dynamics Simulations.

Daniel Toth, Balint Dudas, Arnaud B Nicot, Maria A Miteva, Erika Balog.

Sulfotransferases (SULTs) are phase II drug-metabolizing enzymes metabolizing a wide range of endogenous compounds and xenobiotics including drugs. SULTs form dimers in vivo, and most isoforms share a conserved dimerization motif. Since it has been shown that the monomers of the SULT1A1 isoform maintain their activity in vitro, the biological significance of dimerization remains unclear. To elucidate the mechanism and the effects of dimerization on the SULT1A1 structure and function, we performed molecular dynamics (MD) simulations on both the monomer and dimer form of the enzyme and investigated the effect of cofactor and substrate binding into the dimer structure and dynamics. Our results show a clear dynamical effect on the dimerization of the apoenzyme, resulting in an increase of the ligand binding gate opening and greater fluctuation of the functional loops of one monomeric subunit. Furthermore, in the dimer, we uncovered intra- and intersubunit allosteric effects as a direct consequence of cofactor and the substrate binding, and we present the corresponding allosteric pathways. Our analyses suggest that the asymmetric behavior of the dimer in the presence of one PAPS molecule may reflect a half-site reactivity mechanism, previously suggested for SULT dimer function, which may be particularly important for large substrates. Thus, our study shed new light in our understanding of SULT1A1 structural dynamics and dimerization as related to enzyme function.

DOI: https://doi.org/10.1021/acs.jcim.5c00845
Physiol Rep. 2025 Oct;13(19): e70588

Steroid anabolic and catabolic hormones in highly and recreationally trained female athletes across the menstrual cycle.

Katia Collomp, Carole Castanier, Caroline Teulier, Agnès Olivier, Léane Blanchard, Juliette Bonnigal, Emmanuelle Duron, Eric Favory, Mathieu Zimmermann, Virgile Amiot, Valérie Carité, Marine Lefebvre, Cynthia Mongongu, Magnus Ericsson, Corinne Buisson.

  Sex hormone fluctuations across the normal menstrual cycle (NMC) may affect women's performance and health, but literature is sparse on the estradiol (E2) impact on anabolic and catabolic hormones and well-being in female athletes. We therefore measured in 21 NMC anaerobically trained female athletes: 12 highly (HT) and nine recreationally (RT) during late luteal/early follicular (Low E2) and late follicular/peri-ovulatory (High E2) phases: DHEAS, DHEA, androstenedione (A4), testosterone (T), sex hormone-binding globulin (SHBG), cortisol, free androgen index (FAI = T/SHBG), and their relative ratios. Body composition and well-being, assessed by positive and negative affects (PANAS), were determined in parallel. In High versus Low E2, subjects showed a significant percentage increase in T, A4 (p < 0.001) and FAI (p < 0.05), with high A4/T correlation (r = 0.78), without any change in the other parameters. While no group difference was detected in hormone concentrations, HT versus RT subjects presented higher muscle mass and positive affects and lower FAI (p < 0.05). In conclusion, T and A4 were modulated across NMC, probably resulting from a variable ovarian contribution, but without inducing any change in the anabolic/catabolic balance, regardless of the physical training level. However, high anaerobic training may enhance T sensitivity in view of the FAI, body composition and well-being outcomes.

Keywords:  PANAS; androstenedione; cortisol; estradiol; testosterone; training status

DOI:  https://doi.org/10.14814/phy2.70588