bims-supasi 2026-08-23 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2026–08–23
twelve papers selected by
Jonathan Wolf Mueller, University of Birmingham

Quantitative Mapping of Glycosaminoglycan Secondary Structure Driven by Sulfation and Iduronic Acid.
Understanding Fibroblast Growth Factor-Heparan Sulfate Recognition by Molecular Dynamics Approaches.
Solution Structures of Glycosaminoglycan-bound CXCL8 Complexes Determined by Small-Angle X-Ray Scattering (SAXS).
Sulfated fuco-oligosaccharides from Acaudina leucoprocta: Structural characterization and anticoagulant activity.
Indoxyl Sulfate Promotes Uremic Arterial and Venous Thrombosis by Stabilizing IDO1 via the E3 Ligase SHFM3.
Wing Shape and Color Pattern Modifications in Giant Silk Moths Using Sulfated Polysaccharides: Understanding Morphogenic Signals in Pupal Wings of Lepidoptera.
Indoxyl Sulfate and Soluble Prorenin Receptor Axis Contributes to Sarcopenia in Maintenance Hemodialysis Patients by Inducing Mitochondrial Damage: An Integrated Clinical and Experimental Study.
Neuroinflammation and upregulation of chondroitin sulfate proteoglycans in both brain and spinal cord after chronic ischemic stroke.
Emissive nanoaggregate-based dual sensing of heparin and protamine sulphate.
Heparin Modulates SARS-CoV-2 Spike-Platelet Factor 4 Interactions through Concentration-Dependent Interface Remodeling.
Signaling by a tyrosine-sulfated peptide balances growth and osmotic stress response in rice.
Stress-related salivary biomarkers - cortisol, dehydroepiandrosterone, alpha amylase, and suicidal ideation among young women living in Kampala's informal settlements.

Glycobiology. 2026 Aug 18. pii: cwag064. [Epub ahead of print]

Quantitative Mapping of Glycosaminoglycan Secondary Structure Driven by Sulfation and Iduronic Acid.

Miguel Riopedre-Fernandez, Denys Biriukov, Hector Martinez-Seara.

  Glycosaminoglycans (GAGs) are extracellular matrix polysaccharides whose sequence variability and chemical modifications, particularly sulfation, generate substantial structural diversity. However, how sulfation patterns and monosaccharide composition encode secondary structure in GAGs is not systematically resolved, and quantitative metrics for classifying these structures are largely lacking. Here, we employ large-scale all-atom molecular dynamics simulations to investigate the molecular origin of secondary structure in sulfated GAGs. We systematically vary sulfation patterns and monosaccharide composition to isolate the factors that promote changes in three-dimensional structure. We show that GAG helical conformations arise from recurrent local compact motifs caused primarily by stabilization of l-iduronic acid in the 1C4 puckering conformation, promoted by 2-O-sulfation or by densely sulfated regions. We also introduce a two-parameter structural metric that objectively classifies GAG secondary structures and distinguishes heparin helices from related conformations. Together, our results establish a quantitative link between monosaccharide identity, sulfation pattern, and three-dimensional organization of polysaccharide chains, providing a framework for future studies of sequence-structure relationships in GAGs.

Keywords:  Glycosaminoglycans; Iduronic Acid; Molecular Dynamics; Secondary Structure; Sulfation Pattern

DOI:  https://doi.org/10.1093/glycob/cwag064
Glycobiology. 2026 Aug 22. pii: cwag067. [Epub ahead of print]

Understanding Fibroblast Growth Factor-Heparan Sulfate Recognition by Molecular Dynamics Approaches.

Sergey A Samsonov, Adam Sieradzan, Avner Yayon.

  Glycosaminoglycans, linear periodic anionic polysaccharides composed of repeating disaccharide units, are highly heterogeneous with respect to their chemical composition, sulfation patterns, conformational, dynamic and functional properties. The "sulfation code," which links specific sulfation patterns of these molecules to their biological function, is a key concept for understanding their structure-function relationships. However, both experimental and computational approaches face significant challenges in deciphering this code. In this computational study, we focus on fibroblast growth factor-glycosaminoglycan interactions, which play crucial roles in numerous biologically relevant processes. First, we evaluate the sensitivity and predictive power of currently available computational protocols for studying these systems. We then rigorously investigate the effects of heparin 6-O-desulfation on its interactions with several fibroblast growth factors. We conclude that, depending on the 6-O-sulfation pattern and the length of the oligosaccharide, either predominantly electrostatic interactions or a more complex interplay between electrostatic and hydrophobic interactions determines the specificity of the resulting protein-glycosaminoglycan complex. Finally, we demonstrate that a previously developed coarse-grained model successfully reproduces both the structural and thermodynamic properties of the analysed molecular systems. The results obtained in this study may contribute to the understanding of the fundamental mechanisms underlying protein-glycosaminoglycan interactions and represent a further step toward deciphering the glycosaminoglycan "sulfation code."

Keywords:  6-O sulfation; fibroblast growth factor; heparan sulfate; molecular dynamics; sulfation code

DOI:  https://doi.org/10.1093/glycob/cwag067
Biochem J. 2026 Aug 19. pii: BCJ20260348. [Epub ahead of print]

Solution Structures of Glycosaminoglycan-bound CXCL8 Complexes Determined by Small-Angle X-Ray Scattering (SAXS).

Mark A White, Bryon P Mahler, Prem Raj B Joseph, Balaji Nagarajan, Xu Wang, Umesh R Desai, Krishna Rajarathnam.

  Glycosaminoglycans (GAGs) play diverse and fundamental roles in physiology by regulating the function of large classes of proteins. Despite their importance, knowledge of how GAGs are organized in protein-bound complexes remains limited. This can be attributed to the linear structure, conformational flexibility, and high negative charge of GAGs, all of which disfavor structure determination by crystallography or NMR spectroscopy. A hybrid approach based on GAG-binding-induced changes in NMR protein chemical shifts, computational docking, and molecular dynamics simulations has proven to be valuable in providing structural models. However, these approaches can identify multiple plausible GAG geometries, making it difficult to determine whether the observed geometries reflect intrinsic plasticity or limitations of the NMR data and docking methods. In the case of chemokine CXCL8, two GAG-binding modes have been proposed, one within a monomer and the other across the dimer interface. Here, we determined low-resolution solution structures of heparin and chondroitin sulfate octasaccharides bound to the CXCL8 dimer using small-angle X-ray scattering (SAXS). SAXS analyses show that both heparin and chondroitin sulfate bind to a surface within a monomer and are incompatible with binding across the dimer. NMR paramagnetic relaxation enhancement measurements for heparin-bound CXCL8 dimer and monomer complexes show that heparin engages a similar surface within the monomer in both complexes, consistent with the SAXS models. Together, these studies establish how GAGs are organized in the CXCL8-bound complex and highlight the value of complementary low-resolution structural methods for characterizing GAG-protein complexes.

Keywords:  NMR spectroscopy; chemokines; glycosaminoglycans; heparin; small-angle scattering

DOI:  https://doi.org/10.1042/BCJ20260348
Bioorg Chem. 2026 Aug 13. pii: S0045-2068(26)00843-6. [Epub ahead of print]181 110307

Sulfated fuco-oligosaccharides from Acaudina leucoprocta: Structural characterization and anticoagulant activity.

Zhengwei Ying, Haroon Khan, Li Peipei, Huicheng Yang, Lingyan Wang, Manman Chen, Chunyu Niu, Syed Shams Ul Hassan, Yan Chen, Leifang Zhang, Yin Chen, Yanlei Yu.

  Sulfated fucans from sea cucumbers are potent anticoagulants, but their structural complexity has hindered understanding of their structure-activity relationship at the oligosaccharide level. Herein, we report the preparation, structural characterization, and anticoagulant evaluation of structurally defined sulfated fuco-oligosaccharides from the sea cucumber, Acaudina leucoprocta. Crude polysaccharides were fractionated by anion-exchange chromatography to obtain a fucan sulfate fraction (WS-0). Mild acid hydrolysis of WS-0 generated an oligosaccharide mixture, which was purified by sequential Bio-Gel P-2 and anion-exchange chromatography, yielding a series of oligosaccharide fractions with degrees of polymerization (DP) ranging from 1 to 9. Their structures were elucidated using ESI-MS, MS/MS, and 800 MHz NMR spectroscopy. Two structurally defined fuco-disaccharides were obtained: α-L-Fucp2S4S-(1 → 3)-α/β-L-Fucp (dWS0-4-0.14) and a mixture of α-L-Fucp2S-(1 → 3)-α/β-L-Fucp and α-L-Fucp4S-(1 → 3)-α/β-L-Fucp (dWS0-4-0.05). Among the oligosaccharide fractions, dWS0-3-1 (DP 3-6) exhibited the strongest anticoagulant activity, prolonging APTT to 47.4 ± 4.7 s and TT to 43.2 ± 1.0 s at 400 μg/mL, while showing minimal effect on PT. Comparative analysis revealed that both chain length and sulfation pattern co-determine anticoagulant potency, with 2,4-di-O-sulfation enabling shorter chains to inhibit thrombin. This study provided the first structural map of anticoagulant fuco-oligosaccharides from A. leucoprocta, identifying minimal structural motifs for activity and offering promising leads for developing novel antithrombotic agents.

Keywords:  Anticoagulant activity; Fucosylated oligosaccharides; Structural elucidation; Structure-activity relationship; Sulfated fucan

DOI:  https://doi.org/10.1016/j.bioorg.2026.110307
J Am Soc Nephrol. 2026 Aug 21.

Indoxyl Sulfate Promotes Uremic Arterial and Venous Thrombosis by Stabilizing IDO1 via the E3 Ligase SHFM3.

Ricardo Almiron, Abbas Brahim Malloum, Saran Lotfollahzadeh, Kashvi Sethuraman, Arjun Sharma, Isaac Selinger, Anna Natrakul, Arjun Patel, David Jasen Wu Wong, Farihah Chowdhury, Asha Jose, Maria Del Carmen Piqueras, Mohammad Shafiq, Nader Rahimi, You-Yang Zhao, Katya Ravid, Vipul C Chitalia.

BACKGROUND: The uremic milieu of chronic kidney disease (CKD) is characterized by the accumulation of protein-bound uremic toxins, which contribute to thrombosis. Indoxyl sulfate, a bona fide uremic toxin, upregulates indoleamine 2,3-dioxygenase 1 (IDO1), thereby augmenting kynurenine biogenesis. Both toxins activate tissue factor and thrombosis. Despite this pathogenic synergy, the mechanisms of indoxyl sulfate-mediated IDO1 stabilization remain undefined.
METHODS: We employed targeted metabolomics, super-resolution microscopy, and gain-and loss-of-function experiments using nanoparticle-mediated gene delivery in mice to modulate SHFM3 expression. This was followed by carotid artery or inferior vena cava thrombosis assays in indoxyl sulfate-fed and adenine-induced CKD models.
RESULTS: Among several F-box-containing E3 ligases, split-hand/foot malformation 3 (SHFM3) downregulates IDO1 in endothelial cells. SHFM3 constitutively interacts with IDO1, which is partially disrupted by indoxyl sulfate-induced nuclear sequestration of SHFM3 at concentrations corresponding to early to advanced CKD. SHFM3 interacts with the N-terminus of IDO1, ubiquitinates and destabilizes it. Indoxyl sulfate upregulates IDO1 activity, thereby increasing kynurenine biogenesis in N-terminus- and SHFM3-dependent manners. In an indoxyl sulfate-fed mouse model, endothelial cell-specific SHFM3 knockdown increased IDO1 and tissue factor and accelerated arterial thrombosis, and these effects were reversed by endothelial cell-specific SHFM3 overexpression. CKD mice exhibited 55% higher venous thrombogenicity than controls. Endothelial cell-specific SHFM3 overexpression significantly reversed these effects in control mice and to a lesser extent in CKD mice. Serum indoxyl sulfate levels significantly correlated with the global IDO1 activity and venous clot weights.
CONCLUSIONS: SHFM3 functions as an indoxyl sulfate-sensitive potent E3 ligase of IDO1, targeting it for degradation, even with partial interaction with IDO1 in the uremic milieu. This work also described CKD-induced venous thrombosis model and supports the selective rewiring of uremic toxins in post-translational proteostasis, amplifying indoxyl sulfate-mediated arterial and venous thrombosis.

DOI: https://doi.org/10.1681/ASN.0000001203
Evol Dev. 2026 Sep;28(3): e70058

Wing Shape and Color Pattern Modifications in Giant Silk Moths Using Sulfated Polysaccharides: Understanding Morphogenic Signals in Pupal Wings of Lepidoptera.

Andrei Sourakov.

  The tails and conspicuous eyespots of many saturniid moths are outstanding examples of anti-predator adaptations. These features vary intra- and interspecifically, and while there are hypotheses regarding the selective pressures that maintain these variations, there is little empirical information regarding the genetic and developmental mechanisms that control them. Exogenous chemical substances, like sulfated polysaccharides, can affect the expression of various genetic pathways, including those determining wing patterns. This study leveraged the effects of heparin and dextran sulfate, acting as agonist and antagonist of extracellular Wnt/wingless signaling, respectively, to consistently create aberrant wing shapes and patterns in Luna and Polyphemus Moths. Hindwing tails and eyespots were expanded and contracted by heparin and dextran sulfate, respectively, creating a framework for subsequent investigations into the genetic origins of hindwing tail shape and eyespots. This hidden variation could aid in fast adaptive evolution; revealing it provides a framework for investigating homologies and evolutionary development. Experimentally inducing changes to wing shape in a Lepidoptera species also opens the realm of morphological control: the creation of Luna Moth individuals with significantly wider or narrower hindwing tails may help in quantitative linking of wing shape and flight in future research.

Keywords:  Wnt; evo‐devo; genotype; phenotype; wingless

DOI:  https://doi.org/10.1111/ede.70058
J Ren Nutr. 2026 Aug 21. pii: S1051-2276(26)00162-7. [Epub ahead of print]

Indoxyl Sulfate and Soluble Prorenin Receptor Axis Contributes to Sarcopenia in Maintenance Hemodialysis Patients by Inducing Mitochondrial Damage: An Integrated Clinical and Experimental Study.

Liu Yun, Wen Luona, Zheng Yuanyuan, Zuo Sujun, Hu Jianguang, Liu Yan, Tan Rongshao, Zhong Xiaoshi.

   PURPOSE: This study aims to elucidate the role of indoxyl sulfate (IS) and soluble (pro)renin receptor [s(P)RR] in sarcopenia among maintenance hemodialysis (MHD) patients, integrating clinical observations with in vitro mechanistic investigations.
METHODS: A single-center cross-sectional study enrolled 141 MHD patients to analyze correlations between serum IS, s(P)RR, and sarcopenia parameters. Multivariate logistic regression was conducted to determine independent predictors of sarcopenia in MHD patients. Mechanistic insights were derived from C2C12 myotube experiments, including myostatin (MSTN) knockdown and renin-angiotensin system (RAS) inhibition, to evaluate IS- and s(P)RR-induced mitochondrial dysfunction, oxidative stress, and atrophy.
RESULTS: Sarcopenic patients exhibited elevated IS and s(P)RR levels and impaired physical performance. s(P)RR independently predicted sarcopenia. In vitro, IS upregulated s(P)RR, suppressed peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) and nuclear respiratory factor-1 (Nrf-1), and induced mitochondrial dysfunction, oxidative stress, and myotube atrophy, which were rescued by s(P)RR inhibition. Recombinant s(P)RR suppressed PGC1α and Nrf-1 expression, exacerbating mitochondrial damage and atrophy in C2C12 myotubes, which were reversed by PGC1α overexpression. MSTN knockdown attenuated IS-induced myotube atrophy, oxidative stress, and PGC1α downregulation, effects reversed by s(P)RR. Similarly, RAS blockade ameliorated IS-induced myotube atrophy and s(P)RR upregulation, and restored PGC1α expression.
CONCLUSION: Clinical data reveal significant associations between IS, s(P)RR, and sarcopenia in MHD patients. In vitro experiments further indicate that the IS-s(P)RR-PGC1α/Nrf-1 axis, with MSTN and the RAS as key mediators, contributes to muscle atrophy via mitochondrial dysfunction and oxidative stress. s(P)RR emerges as a novel diagnostic biomarker and a modifiable target, providing a foundation for further translational studies.

Keywords:  indoxyl sulfate; maintenance hemodialysis; sarcopenic; soluble (pro)renin receptor [s(P)RR]

DOI:  https://doi.org/10.1053/j.jrn.2026.08.007
Brain Res Bull. 2026 Aug 19. pii: S0361-9230(26)00378-3. [Epub ahead of print] 112091

Neuroinflammation and upregulation of chondroitin sulfate proteoglycans in both brain and spinal cord after chronic ischemic stroke.

Ching-Yi Lin, Hugh Hiunam Chan, Jason Lin, David Trent, Kenneth B Baker, Yu-Shang Lee.

  Ischemic stroke is caused by obstruction of a blood vessel reducing blood supply to a specific brain region and is one of the leading causes of disability worldwide. The pathophysiology of ischemic brain damage involves the formation of glial scars that can further limit functional recovery. Inhibitory chondroitin sulfate proteoglycans (CSPGs) are the major components of glial scars, but there is little information regarding their expression and distribution in either the damaged brain or, secondarily, in the more distant cervical spinal cord region after the chronic ischemic stroke. Here, we used a preclinical photothrombotic model to induce ischemic stroke and immunohistochemistry to characterize the expression of various CSPGs and neuroinflammatory cells that may produce CSPGs in (1) the peri-infarct area, a potentially salvageable area surrounding the ischemic core, and (2) the white (corticospinal tract) and gray matter regions of the cervical spinal cord. Our results demonstrate upregulation of neuroinflammatory cells and CSPG molecules in the damaged brain and cervical spinal cord at two months post-stroke. Reductions in aggrecan+ perineuronal nets (PNNs) and increases in wisteria floribunda agglutinin (WFA)+ PNNs were identified in the lesional cortex. In the spinal cord, aggrecan levels were similar, but there was increased WFA+ intensity. In addition, reactive astrocytes and microglia were increased and colocalized with CSPGs, which are responsible for the generation of CSPGs to persistent chronic neuroinflammation post-ischemia stroke.

Keywords:  aggrecan; chondroitin sulfate proteoglycans (CSPGs); chronic ischemic stroke; neuroinflammation; perineuronal nets (PNNs)

DOI:  https://doi.org/10.1016/j.brainresbull.2026.112091
Anal Methods. 2026 Aug 18.

Emissive nanoaggregate-based dual sensing of heparin and protamine sulphate.

Verbi P Bhagabati, Sampurna Routray, Malay Kumar Baroi, Sourav Das, Priyam Das, Debapratim Das.

Heparin (Hep), a widely used blood thinner, requires continuous monitoring upon administration, as both under- and overdosing can lead to complications such as thrombosis or haemorrhage. At the same time, protamine sulfate (PS) serves as the clinical antidote for Hep via electrostatic interactions. Inspired by the need to continuously monitor this clinically relevant Hep-PS pair, we have designed a simple tetraphenylethylene (TPE)-based tetracationic sensor to detect these analytes via a fluorescence switch-on/off mechanism. Hep binding induces strong electrostatic interactions between highly negative functional groups and the positively charged probe, leading to fluorescence enhancement due to the aggregation-induced emission (AIE) effect, whereas subsequent addition of PS competitively extracts Hep, restoring the quenched state. The probe exhibits good sensitivity and selectivity towards both Hep and PS with comparatively low LOD and LOQ, enabling detection in clinically optimum concentration. Practical applicability was further evaluated in complex biological matrices. In addition, fluorescence results with clinical Hep and the probe showed good agreement with the conventional apTT assay. This simple, reversible platform enables rapid dual detection of the Hep-PS pair and has potential for anticoagulation monitoring.

DOI: https://doi.org/10.1039/d6ay01478j
ACS Appl Bio Mater. 2026 Aug 17.

Heparin Modulates SARS-CoV-2 Spike-Platelet Factor 4 Interactions through Concentration-Dependent Interface Remodeling.

Dayamai Sai Satram, Li-Yu Chen, Thi H Ho, Doris Heinrich, Thuat T Trinh, Thi-Huong Nguyen.

  Heparin, a highly sulfated glycosaminoglycan, interacts with numerous proteins through electrostatic and multivalent binding mechanisms. In the context of SARS-CoV-2 infection, platelet factor 4 (PF4) has been proposed to form complexes with the viral spike protein (S protein), potentially contributing to immune-mediated thrombotic complications. However, the molecular mechanisms by which heparin modulates PF4-S protein interactions remain poorly understood. Here, we investigate how unfractionated heparin (UFH) influences the formation and stability of PF4-S protein complexes using a combination of ensemble binding assays, single-molecule force spectroscopy, and molecular dynamics simulations. ELISA measurements reveal concentration-dependent and partner-specific effects of UFH on S protein interactions. While low concentrations of UFH enhance ACE2-S protein binding, higher concentrations produce a modest reduction, indicating biphasic modulation of receptor engagement. In contrast, UFH inhibits PF4-S protein binding at low to intermediate concentrations, with partial restoration at higher levels. Single-molecule force spectroscopy confirms that UFH decreases the mechanical stability of the PF4-S protein complex, as reflected by reduced unbinding forces that reach saturation at concentrations ≥5 IU mL-1. Molecular dynamics simulations using the dp5 heparin fragment demonstrate energetically favorable binding to both PF4 and the S1 subunit of the S protein. In ternary S1-PF4-dp5 assemblies, heparin alters interfacial contacts and reshapes the energetic landscape of the protein-protein interaction, suggesting modulation through electrostatic reorganization and interfacial remodeling. These findings provide mechanistic insight into glycosaminoglycan-mediated regulation of PF4-S protein complexes and highlight how heparin can modulate biomacromolecular interactions at viral-host protein interfaces.

Keywords:  SARS-CoV-2 spike protein; heparin; molecular dynamics simulation; platelet factor 4; protein-protein interactions; single-molecule force spectroscopy

DOI:  https://doi.org/10.1021/acsabm.6c00502
bioRxiv. 2026 Aug 05. pii: 2026.08.04.742889. [Epub ahead of print]

Signaling by a tyrosine-sulfated peptide balances growth and osmotic stress response in rice.

Yejin Shim, Ellen Y Rim, Jin C-Y Liao, Myeong-Je Cho, George Austin, Patrick W Carlos, Sameer S Kulkarni, Richard J Payne, Maria Florencia Ercoli, Pamela C Ronald.

Peptide hormone signaling coordinates plant growth and osmotic stress responses, yet how the transition between these responses is regulated remains poorly understood. Here, we investigated the function of the rice PLANT PEPTIDES CONTAINING SULFATED TYROSINE 8 (OsPSY8) peptide in osmotic stress responses. OsPSY8 was predominantly expressed in root tissues under non-stress conditions, with preferential expression in lateral roots where it promoted root growth. Osmotic stress rapidly reduced OsPSY8 expression in roots through the OsWRKY24 transcription factor. Loss-of-function ospsy8 mutants exhibited enhanced osmotic stress tolerance, whereas OsPSY8 overexpression increased osmotic stress susceptibility. Transcriptomic analyses revealed that disruption of OsPSY8 activated stress-responsive pathways, including those associated with lignin biosynthesis, compatible solute production, cell wall remodeling, and reactive oxygen species (ROS) scavenging, and was accompanied by increased lignin accumulation in roots. In contrast, overexpression of OsPSY8 resulted in maintenance of growth-associated transcriptional programs while suppressing stress-responsive pathways under osmotic stress. Together, these findings identify OsPSY8 as an important regulator of the transition from growth to stress adaptation in rice and suggest that stress-induced repression of PSY signaling is required to disengage growth programs and activate adaptive responses during osmotic stress.
Significance Statement: Crop survival during drought depends on the ability to transition from growth to stress adaptation. Plant peptide hormones have emerged as important regulators of this critical transition, highlighting the importance of investigating their roles and potential for improving crop resilience. We show that a rice peptide hormone regulates this transition. Under non-stress conditions, this peptide hormone, predominantly expressed in rice roots, promotes root growth while suppressing stress responses. During osmotic stress, expression of the peptide hormone decreases, resulting in activation of stress-responsive pathways, such as lignin biosynthesis and reactive oxygen species scavenging. These findings demonstrate that a peptide hormone coordinates the balance between growth and stress adaptation in rice, with broader implications for understanding and improving crop resilience.

DOI: https://doi.org/10.64898/2026.08.04.742889
Soc Psychiatry Psychiatr Epidemiol. 2026 Aug 19.

Stress-related salivary biomarkers - cortisol, dehydroepiandrosterone, alpha amylase, and suicidal ideation among young women living in Kampala's informal settlements.

Godfrey S Bbosa, Rachel Culbreth, Charles Natuhamya, Jane Palmier, Gideon Matovu, Tanja Jovanovic, Rogers Kasirye, Monica H Swahn.

   BACKGROUND: Young women living in informal urban settlements experience intersecting structural disadvantages that may contribute to stress-related physiological changes and suicidal ideation. Evidence on salivary stress biomarkers in this population remains limited.
OBJECTIVE: To examine associations between salivary cortisol, dehydroepiandrosterone (DHEA), α-amylase, the cortisol-to-DHEA ratio, and suicidal ideation among young women in Kampala's informal settlements.
METHODS: This cross-sectional analysis included 300 women aged 18-24 years recruited from three informal settlements in Kampala, Uganda. Suicidal ideation was assessed using four items from the Columbia-Suicide Severity Rating Scale. Morning and afternoon salivary biomarkers were measured using COBAS E411 and C-111 analyzers. Independent-samples t-tests compared biomarker levels by suicidal ideation status, and modified Poisson regression examined adjusted associations. The final model was used to estimate the prevalence ratio (PR) and its 95% confidence interval (CI).
RESULTS: Overall, 46.0% reported suicidal ideation and 57.7% met the threshold for probable depression. Approximately 39% had DHEA values below published reference ranges at both collection times. Participants reporting suicidal ideation had lower square root-transformed morning DHEA levels than those without ideation (3.96 vs. 4.65; p = 0.048) and higher square root-transformed morning cortisol-to-DHEA ratios (1.19 vs. 1.00; p = 0.027). In the adjusted model, each one-unit increase in the square root-transformed morning cortisol-to-DHEA ratio was associated with a 12% higher prevalence of suicidal ideation (PR = 1.12; 95% CI: 1.04-1.21).
CONCLUSION: Suicidal ideation was common, and square root-transformed morning cortisol-to-DHEA ratios were independently associated with suicidal ideation. These findings highlight the importance of understanding suicidality through integrated biological, psychological, and social perspectives and reinforce the need for accessible, gender-responsive suicide prevention and mental health services in low-resource urban settings.

Keywords:  Cortisol; DHEA; Diurnal salivary stress biomarkers; Suicidal ideation; Women; α-amylase

DOI:  https://doi.org/10.1007/s00127-026-03192-3