bims-supasi 2026-08-30 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2026–08–30
fifteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Role of EXT Family Enzymes in Heparan Sulfate Biosynthesis.
Chondroitin Sulfate Supplementation Is Associated with Body Weight Control in Ovariectomized Rats: A Multi-Omics Study of Gut Microbiota and Metabolite Profiles.
Low-molecular-weight chondroitin sulfate attenuates hyperalgesia via immunomodulation of macrophage polarization.
Insulin-like growth factor-binding protein 7 is a soluble cell adhesion molecule.
Immunohistochemical Characterization of Keratan Sulfate Preferentially Expressed in Papillary Thyroid Carcinoma Using a Novel Monoclonal Antibody 299-1C1.
Regulated HSPG Signaling Directs Epicardial Behavior to Support Cardiac Formation.
Indoxyl Sulfate Promotes Vascular Calcification in Association with Oxidative Stress and Activation of ERK and Wnt/β-Catenin Signaling Pathways.
Inhibition of chondroitin sulfate proteoglycans enhances cell migration following enteric neural stem cell transplantation.
Liquid biopsy-based detection of circulating and exfoliated cholangiocarcinoma tumor cells from blood and bile using heparan sulfate octasaccharides on integrated microfluidic systems.
Age-related differences in circulating heparanase-1 activity in sepsis and correlation with systemic vascular endotheliopathy.
Indoxyl Sulfate-Mediated Blood-Brain Barrier Damage in Chronic Kidney Disease.
A dietary sulfated polysaccharide from edible green alga Caulerpa chemnitzia modulates immune responses associated with host metabolism and gut microbiota in cyclophosphamide-induced immunosuppressed mice.
Indoxyl Sulfate Contributes to Progression of Renal Injury in the Postpartum Period Following Pregnancy-Related Acute Kidney Injury.
Coexisting mild autonomous cortisol secretion and isolated adrenocorticotropic hormone deficiency in a patient with an adrenal incidentaloma.
Cross-Linked Chondroitin Sulfate Adhesion Barrier System in Open Rectal Resection: A Randomized Clinical Trial.

J Histochem Cytochem. 2026 Aug 25. 221554261479792

Role of EXT Family Enzymes in Heparan Sulfate Biosynthesis.

Digantkumar Chapla, Kelley W Moremen.

  Heparan sulfate (HS) proteoglycans are essential regulators of cell signaling, development, and extracellular matrix organization. Central to the HS biosynthesis pathway is the exostosin family of enzymes that control commitment to HS assembly and catalyze formation of the polymer backbone in the Golgi apparatus. Recent structural studies have substantially revised our understanding by demonstrating that the HS co-polymerase is a tightly organized EXT1-EXT2 heterodimer, wherein the GT-B domain of EXT1 and the GT-A domain of EXT2 provide the β1,4-GlcA and α1,4-GlcNAc transferase activities, respectively. Parallel work on EXTL3 clarified how selective recognition of the linker-region glycopeptide commits to HS extension, outcompeting the default chondroitin sulfate pathway. In contrast, EXTL2 is best viewed as a regulatory GlcNAc transferase that can cap or divert linker intermediates rather than as a polymerase, whereas EXTL1 remains the least defined family member despite evidence for GlcNAc transferase activity. Genetic studies continue to reveal their importance in human disease, including hereditary multiple exostoses and EXTL3-associated immunodeficiency. Despite this progress, major questions remain regarding chain length control, enzyme coordination, and therapeutic targeting. This short review integrates recent structural, biochemical, and genetic advances to provide an updated narrative of how mammalian EXT proteins govern HS biosynthesis.

Keywords:  EXTs; HS biosynthesis; enzyme specificity; heparan sulfate; proteoglycans

DOI:  https://doi.org/10.1369/00221554261479792
Biomolecules. 2026 Jul 27. pii: 1095. [Epub ahead of print]16(8):

Chondroitin Sulfate Supplementation Is Associated with Body Weight Control in Ovariectomized Rats: A Multi-Omics Study of Gut Microbiota and Metabolite Profiles.

Qingshan Shen, Yanli Ma, Chunhui Zhang, Yujie Guo, Xiaojie Qin.

  The prevalence of obesity among elderly women is increasing, particularly in postmenopausal populations. This exploratory study investigated the associations between chondroitin sulfate (CS) supplementation and body weight control in ovariectomized (OVX) rats, a preclinical model for postmenopausal physiology. CS supplementation was associated with significantly reduced body weight gain and preserved adipocyte morphology. CS-treated OVX rats exhibited decreased gut microbiota diversity, with reduced abundance of Photobacterium and Rhodococcus and increased abundance of Turicibacter. Metabolomic analysis revealed elevated levels of carbohydrates, fatty acids, and their conjugates, some of which correlated with body weight parameters. Bioinformatic analysis identified enriched KEGG pathways including tyrosine metabolism, glucosinolate biosynthesis and thiamine metabolism. Collectively, these findings provide preliminary correlational evidence in an OVX rat model supporting the potential of CS as a food supplement for body weight control, although causal relationships and clinical applicability warrant further investigation in postmenopausal populations.

Keywords:  body weight control; chondroitin sulfate; gut microbiota; ovariectomized rat

DOI:  https://doi.org/10.3390/biom16081095
J Pharmacol Sci. 2026 Oct;pii: S1347-8613(26)00041-1. [Epub ahead of print]162(2): 109-116

Low-molecular-weight chondroitin sulfate attenuates hyperalgesia via immunomodulation of macrophage polarization.

Ribou Shiga, Kotaro Yamada, Tasuku Kawano, Osamu Nakagawasai, Yukari Seo, Chiaki Ogura, Ozora Kubo, Yusuke Miki, Uyu Tamada, Michihiro Satoh, Tomoko Takahashi, Koichi Tan-No, Wataru Nemoto.

  Osteoarthritis is the most common form of arthritis, for which effective and safer treatments are needed. While chondroitin sulfate (CS) has been reported to exert analgesic effects, its cellular targets and immunomodulatory mechanisms remain unclear. This study aimed to clarify the effects of low-molecular-weight CS-rich extract (LMW-CSE) derived from shark cartilage on the hyperalgesia observed in adjuvant-induced arthritis (AIA) mice and to investigate the role of peripheral macrophage (MΦ) subsets in its analgesic action. LMW-CSE was orally administered to mice at doses up to 300 mg/kg twice daily, starting 14 days before AIA with an injection of complete Freund's adjuvant (CFA), and continuing until the completion of behavioral testing. LMW-CSE significantly attenuated hyperalgesia in AIA mice. In addition, the increase in the number of activated excitatory neurons in the spinal superficial dorsal horn of AIA mice was attenuated by LMW-CSE treatment. Flow cytometric analysis revealed that LMW-CSE suppressed the accumulation of proinflammatory M1 MΦs and increased the proportion of immunoregulatory M2 MΦs at inflammatory sites, accompanied by reduced expression of proinflammatory cytokines. These findings suggest that LMW-CSE exerts anti-hyperalgesic effects, at least in part through modulation of peripheral macrophage subsets, supporting its potential as a therapeutic strategy for inflammatory pain.

Keywords:  Adjuvant-induced arthritis; Hyperalgesia; Low-molecular-weight chondroitin sulfate; Macrophage

DOI:  https://doi.org/10.1016/j.jphs.2026.07.003
Sci Adv. 2026 Aug 28. 12(35): eaeg1148

Insulin-like growth factor-binding protein 7 is a soluble cell adhesion molecule.

Kai Cai, Xuewu Zhang, Xiao-Chen Bai.

Insulin-like growth factor-binding protein 7 (IGFBP7) is a secreted protein with diverse roles in angiogenesis, cell differentiation, tissue remodeling, and regulating cell signaling and is linked to numerous human diseases. The molecular basis of the multifunctionality of IGFBP7 remains unclear. Using cryo-electron microscopy, we show that IGFBP7 assembles into a barrel-shaped dodecamer in the presence of heparin. The carboxyl-terminal IgC2 domain forms the central core of the barrel, which is capped by the amino-terminal heparin-binding IB domain at both ends. This homo-oligomer can simultaneously engage heparan sulfate proteoglycans on adjacent cells, functioning as a soluble "cell glue" to drive cell-cell adhesion. Furthermore, IGFBP7 enhances and prolongs signaling of receptor tyrosine kinases, including insulin receptor and c-MET, through its adhesion activity. These findings reveal a structural mechanism for IGFBP7's pleiotropy and establish it as a universal adhesion factor.

DOI: https://doi.org/10.1126/sciadv.aeg1148
J Histochem Cytochem. 2026 Aug 28. 221554261479793

Immunohistochemical Characterization of Keratan Sulfate Preferentially Expressed in Papillary Thyroid Carcinoma Using a Novel Monoclonal Antibody 299-1C1.

Eiichi Kato, Tomoya O Akama, Natsumi Yonemoto, Akifumi Muramoto, Shigeharu Fujieda, Motohiro Kobayashi.

  Keratan sulfate (KS) is a glycosaminoglycan consisting of repeating N-acetyllactosamine disaccharides, in which both galactose and N-acetylglucosamine are often 6-O-sulfated. It has been reported that KS recognized by the monoclonal antibodies 5D4 and 373E1 is preferentially expressed in papillary thyroid carcinoma (PTC) and only minimally in other thyroid tumors/lesions or normal thyroid tissue. However, the precise epitopes recognized by these antibodies remain incompletely characterized, and the expression and extent of low-sulfated KS in PTC have not been systematically evaluated. To better understand the nature of KS expressed in PTC, we generated a novel anti-KS monoclonal antibody, 299-1C1, and performed immunohistochemical analyses using 299-1C1 together with two existing anti-KS monoclonal antibodies, 5D4 and R-10G, in combination with keratanase II and endo-β-galactosidase. The results showed that both highly sulfated and low-sulfated KS are preferentially expressed in PTC, including lymph node metastases, accompanied by upregulation of genes encoding key KS biosynthetic enzymes (B3GNT7, B4GALT4, CHST2, and CHST6) in integrated TCGA/GTEx transcriptomic datasets. Expression of B3GNT7, B4GALT4, and CHST2, but not CHST6, was further increased in BRAF-mutant PTCs. These findings indicate that anti-KS monoclonal antibodies are useful for the pathological diagnosis of PTC, particularly for distinguishing lymph node metastases from intranodal thyroid inclusions.

Keywords:  BRAF V600E; VE1; diagnostic marker

DOI:  https://doi.org/10.1369/00221554261479793
Circ Res. 2026 Aug 25.

Regulated HSPG Signaling Directs Epicardial Behavior to Support Cardiac Formation.

Andia N Redpath, Irina-Elena Lupu, Louis Haffreingue, Quang M Dang, Ian R McCracken, Tamara Carsana, Toin H van Kuppevelt, Joaquim Miguel Vieira, Nicola Smart.

   BACKGROUND: Pathways controlling cardiac cell behavior share a common dependency on heparan sulfate proteoglycans (HSPGs), which tightly regulate signaling at extracellular locations. This signaling is essential for cardiac development, yet how HSPGs are regulated in the forming heart is unknown. The epicardium is a rich source of HSPG-dependent signaling and cellular progenitors. We hypothesized that extracellular heparan sulfate modifiers, 6-O-endosulfatases, orchestrate progenitor cell behavior to support cardiogenesis.
METHODS: We used single-cell RNA sequencing, microscopy, and flow cytometry-based single-molecule RNA ISH to systematically profile 6-O-endosulfatases and target HSPGs in the embryonic mouse heart. Subsequently, we utilized knockout and knockdown models that identified gene associations and a role for the main epicardial 6-O-endosulfatase isoform, Sulf1. Transcriptional regulation of Sulf1 was assessed using ATAC and CUT&RUN sequencing, luciferase assays, and siRNA, and the impact on epicardial cell behavior was confirmed in vivo and using in vitro functional assays.
RESULTS: Despite identical function, we find that Sulf1 is expressed in the embryonic epicardium, while Sulf2 is expressed broadly throughout the myocardium. We show that epicardial SULF1 dynamically regulates HSPG sulfation to fine-tune the magnitude and duration of signaling to impact cell fate and cardiac morphogenesis. Single-cell genomics and lineage tracing studies reveal Sulf1 to be strongly coexpressed with key transcriptional regulator Wt1 (Wilms tumor 1) in the epicardium, with reduction of both coinciding with epithelial-to-mesenchymal transition and quiescence. CUT&RUN-seq revealed transcriptional control of Sulf1 by WT1, which directly impacts essential HSPG-dependent downstream signaling. Ligand-receptor interaction predictions and functional assays indicated that FGF (fibroblast growth factor)-2 and TGF-β (transforming growth factor β)-driven processes were governed by this regulatory interaction.
CONCLUSIONS: Our study highlights, for the first time, essential fine-tuning of HSPG-dependent signaling to modulate key processes in heart formation, offering potential insights for therapeutically targeting congenital heart disease and enhancing epicardial proregenerative behaviors.

Keywords:  epithelial-mesenchymal transition; heparan sulfate proteoglycans; morphogenesis; pericardium; transforming growth factors

DOI:  https://doi.org/10.1161/CIRCRESAHA.125.327330
Int J Mol Sci. 2026 Aug 16. pii: 7314. [Epub ahead of print]27(16):

Indoxyl Sulfate Promotes Vascular Calcification in Association with Oxidative Stress and Activation of ERK and Wnt/β-Catenin Signaling Pathways.

Yi-Cheng Wang, I-Min Su, Chung-Jen Lee, Tsung-Jui Wu, Bang-Gee Hsu.

  Vascular calcification (VC) is a major complication of chronic kidney disease (CKD) that is strongly associated with cardiovascular mortality. While indoxyl sulfate (IS), a protein-bound uremic toxin, has been implicated in the progression of VC, the underlying molecular mechanisms remain unclear. We investigated the procalcific effects of IS using a two-step nephrectomy-induced CKD mouse model and cultured vascular smooth muscle cells. In vivo, progressive renal impairment was associated with elevated circulating IS levels and enhanced VC. In vitro, IS dose- and time-dependently induced calcium deposition, increased reactive oxygen species (ROS) production, and upregulated osteogenic markers, including runt-related transcription factor 2 (RUNX2), bone morphogenetic protein 2 (BMP2), and osteocalcin (OCN), whereas N-acetyl-L-cysteine (NAC) partially attenuated IS-induced ROS accumulation and cell injury. Mechanistically, IS exposure activated extracellular signal-regulated kinase (ERK) and Wnt/β-catenin signaling while suppressing nuclear factor erythroid 2-related factor 2 (Nrf2)-related antioxidant responses, as reflected by reductions in the phosphorylated Nrf2 (pNrf2) to total Nrf2 and heme oxygenase-1 (HO-1) expression. Pharmacological inhibition of ERK and Wnt/β-catenin signaling attenuated IS-induced osteogenic responses. These findings indicate that IS promotes VC in association with increased oxidative stress, activation of ERK and Wnt/β-catenin signaling, and impaired Nrf2-related antioxidant defense. These integrated findings provide mechanistic insight into IS-associated VC and highlight oxidative stress-related signaling networks as potential therapeutic targets in CKD.

Keywords:  chronic kidney disease; indoxyl sulfate; reactive oxygen species; vascular calcification; vascular smooth muscle cells

DOI:  https://doi.org/10.3390/ijms27167314
Development. 2026 Aug 15. pii: dev205625. [Epub ahead of print]153(16):

Inhibition of chondroitin sulfate proteoglycans enhances cell migration following enteric neural stem cell transplantation.

Emőke Szőcs, Jessica L Mueller, Csenge Jurenka, Réka Borbála Tóth, Viktória Halasy, Ryo Hotta, Ádám Soós, Allan M Goldstein, Nándor Nagy.

  Enteric nervous system development relies on migration, proliferation and differentiation of enteric neural crest-derived cells (ENCDCs), processes that are regulated by mesenchymal morphogens and the extracellular matrix (ECM). Hirschsprung disease (HD) is a congenital neurocristopathy in which abnormal gut motility results from loss of ENCDC-derived enteric ganglia in the colorectum. While enteric neural stem cell transplantation is a proposed therapy, current efforts are limited by poor cell migration in HD models. To address this, we investigated ECM-derived inhibitory cues on enteric neural stem cell transplantation efficiency. Immunohistochemistry of embryonic chick hindgut reveals dynamic chondroitin sulfate proteoglycan (CSPG) expression during development. In vitro assays show that CSPGs inhibit ENCDC migration, an effect reversed by chondroitinase ABC. Transplantation of enteric neurospheres into chick and mouse colon results in limited engraftment, but chondroitinase ABC significantly enhances migration of transplanted cells. Single-cell RNA sequencing of postnatal mouse neurospheres reveals high expression of CD44, a transmembrane glycoprotein that can act as a functional CSPG on the cell surface. Blocking CD44 function promotes neurosphere-derived ENCDC migration. Modulating inhibitory ECM components may enhance the success of regenerative therapies for HD.

Keywords:  CD44; CSPG; Chick; Enteric nervous system; Hirschsprung disease; Mouse; Neural crest; Neurosphere

DOI:  https://doi.org/10.1242/dev.205625
Methods. 2026 Aug 23. pii: S1046-2023(26)00186-6. [Epub ahead of print]255 62-72

Liquid biopsy-based detection of circulating and exfoliated cholangiocarcinoma tumor cells from blood and bile using heparan sulfate octasaccharides on integrated microfluidic systems.

Wei-Chun Tsai, Anandaraju Bandaru, Cheng-Hsiu Chang, Priya Gopinathan, Chih-Hung Wang, Yi-Cheng Tsai, Chien-Jui Huang, Nai-Jung Chiang, Yu-Jie Huang, Yan-Shen Shan, Shang-Cheng Hung, Gwo-Bin Lee.

  Early diagnosis of cholangiocarcinoma (CCA) remains challenging because existing diagnostic approaches often lack sufficient sensitivity for reliable detection of early-stage disease. Circulating tumor cells (CTCs) in blood and exfoliated tumor cells (ETCs) in bile represent valuable targets for liquid biopsy-based detection; however, their low abundance and the complexity of clinical sample analysis pose substantial technical challenges for reliable enrichment and identification. Herein, we present a reproducible workflow for isolating and identifying CCA tumor cells from blood for CTCs and bile for ETCs using synthetic cell-surface heparan sulfate (HS) octasaccharide-functionalized magnetic beads (MBs) on integrated microfluidic systems. The method combined sample pre-processing, magnetic bead-based enrichment, controlled low-shear mixing and immunofluorescence-based identification into a unified workflow compatible with distinct clinical sample types. Key operational parameters, including MB concentration, mixing frequency, and pressure settings, were detailed to facilitate consistent performance. Using this workflow, tumor cell capture rates of approximately 70% in bile (for ETCs) and blood (for CTCs) were achieved, with a total processing time of 60-90 min per sample under clinically relevant low-abundance conditions. The platform enables reliable detection of as few as 1 tumor cell per mL of blood or bile. This method provides a practical and adaptable strategy for glycosaminoglycan-mediated liquid biopsy applications and may be extended to other tumor-cell enrichment workflows involving heterogeneous cell-surface interactions.

Keywords:  Cholangiocarcinoma; Circulating tumor cells; Exfoliated tumor cells; Heparan sulfate octasaccharide; Integrated microfluidic system; Liquid biopsy

DOI:  https://doi.org/10.1016/j.ymeth.2026.08.008
Front Med (Lausanne). 2026 ;13 1893157

Age-related differences in circulating heparanase-1 activity in sepsis and correlation with systemic vascular endotheliopathy.

Colin J Sallee, Aaron S Noa, Mouli Bhowmik, Amber C Nobles, Zhangjie Wang, Jian Liu, Jillian R Richter, J Edwin Blalock, Rakesh P Patel, Amit Gaggar, Robert P Richter.

   Background: Heparanase-1 (HPSE)-mediated degradation of endothelial glycocalyx heparan sulfate (HS) contributes to vascular endotheliopathy in sepsis, yet age-dependent differences in HPSE biology remain undefined. Thus, we sought to determine age-related differences in circulating HPSE activity during sepsis and its association with markers of endotheliopathy and organ dysfunction.
Methods: Heparanase-1 enzymatic activity and HS disaccharide levels were measured in plasma from children (10 sepsis, 10 controls) and adults (16 sepsis, 15 controls) from prospective observational cohorts using liquid chromatography-tandem mass spectrometry. Associations with plasma angiopoietin-2 levels and change in serum albumin (markers of endotheliopathy) in addition to organ failure scores were assessed using Spearman correlations.
Results: Heparanase-1 activity and circulating HS were elevated in both sepsis cohorts compared to controls, with moderate-to-strong correlations between HPSE activity and HS levels. However, adults with sepsis demonstrated approximately 10-fold higher plasma HPSE activity than children (median 1,256 vs. 116, p < 0.001), despite children exhibiting greater endotheliopathy and higher organ failure scores. In both age groups, HPSE activity correlated with angiopoietin-2, serum albumin decline, and organ failure scores. Adult non-survivors had higher HPSE activity than survivors; no pediatric deaths occurred. Predominant neutrophilic/monocytic activation in adults versus greater platelet consumption in children may suggest developmental differences in cellular sources of circulating HPSE.
Conclusion: Heparanase-1-mediated glycocalyx degradation is a conserved feature of sepsis across the age spectrum, but the magnitude, cellular source, and clinical implications of circulating HPSE activity differ markedly by age, underscoring the need for age-stratified therapeutic approaches.

Keywords:  adults; children; endothelial glycocalyx; heparan sulfate; heparanase activity; sepsis; vascular endotheliopathy

DOI:  https://doi.org/10.3389/fmed.2026.1893157
Toxins (Basel). 2026 Aug 01. pii: 334. [Epub ahead of print]18(8):

Indoxyl Sulfate-Mediated Blood-Brain Barrier Damage in Chronic Kidney Disease.

MOMENTUM Consortium

  Chronic kidney disease is associated with neurovascular complications including cognitive impairment, potentially involving blood-brain barrier (BBB) impairment. The protein-bound uremic toxin indoxyl sulfate (IS) promotes endothelial injury, but its effects on human brain microvascular endothelial cells remain incompletely understood. Human cerebral microvascular endothelial cells (hCMEC/D3) were exposed to IS 200 and 900 μM. BBB integrity was assessed by the FITC-dextran (4 kDa) transwell permeability assay and claudin-5 immunofluorescence. Transcriptional responses were quantified by qPCR for aryl hydrocarbon (AhR) target genes, oxidative stress-associated and inflammatory markers, senescence, and junction-associated genes. Senescence-associated phenotypic changes were evaluated by SA-β-galactosidase staining and cytokine array profiling. IS increased endothelial permeability at 24 and 48 h (~1.5-fold relative to control) without evidence of cytotoxicity and reduced claudin-5 staining intensity. IS strongly upregulated AhR target genes, including CYP1A1, CYP1B1, and CYP1A2. NFE2L2 and IDO1 increased, while NFKB1 remained unchanged. SA-β-gal positivity increased, accompanied by elevated GM-CSF and G-CSF secretion, while CDKN1A decreased at IS 900 µM and CDKN2A remained unchanged. CDH5 was downregulated, TJP1 increased at 900 µM, and CLDN5 remained unchanged. These findings indicate that IS exposure is associated with impaired BBB integrity, AhR-related transcriptional responses, oxidative stress-associated transcriptional changes, junctional remodeling, and senescence-like endothelial features. However, causal attribution to individual pathways requires inhibition or knockdown studies.

Keywords:  blood-brain barrier; chronic kidney disease; indoxyl sulfate; uremic toxin

DOI:  https://doi.org/10.3390/toxins18080334
Food Res Int. 2026 Oct 31. pii: S0963-9969(26)01577-2. [Epub ahead of print]242(Pt 2): 119893

A dietary sulfated polysaccharide from edible green alga Caulerpa chemnitzia modulates immune responses associated with host metabolism and gut microbiota in cyclophosphamide-induced immunosuppressed mice.

Xuewei Xia, Jun Liu, Simon Wing-Fai Mok, Io Nam Wong, Qin Liu, Saiyi Zhong, Riming Huang.

  Sulfated polysaccharides from edible marine algae have attracted increasing interest as dietary components with immune-supporting potential. Caulerpa chemnitzia, an edible green alga widely distributed in Indo-Pacific regions, has long been consumed fresh as a vegetable and is rich in sulfated polysaccharides. In our previous study, a sulfated polysaccharide fraction (CRVP) isolated from the edible green alga Caulerpa chemnitzia was structurally characterized and shown to regulate macrophage immune responses in vitro. However, its in vivo immunomodulatory effects and functional relevance as a food-derived polysaccharide remain unclear. In the present study, the immune-supporting potential of CRVP was evaluated in a cyclophosphamide-induced immunosuppressed mouse model. CRVP supplementation improved peripheral blood immune cell profiles, enhanced plasma cytokine levels, and restored bone marrow cell numbers and macrophage differentiation capacity, indicating that CRVP may mitigate CTX-induced immune-related changes. These effects may be associated with increased succinate levels and the potential involvement of HIF-1α/IL-1β-related inflammatory signaling, as suggested by LW6 intervention. In addition, 16S rDNA sequencing revealed that CRVP modulated gut microbiota composition, with potential involvement of Alistipes, Lachnoclostridium, and members of Erysipelatoclostridiaceae. Furthermore, fecal metabolomic analysis indicated concurrent alterations in metabolic profiles, particularly in tryptophan metabolism. Overall, this study provides in vivo evidence that CRVP, a dietary sulfated polysaccharide from an edible green alga, exerts immune-supporting effects through metabolic and microbiota-associated pathways, thereby providing a basis for its potential application as an immune-supporting functional food ingredient.

Keywords:  Caulerpa chemnitzia; Edible green alga; Functional food ingredient; Gut-immune axis; Immune regulation; Sulfated polysaccharide

DOI:  https://doi.org/10.1016/j.foodres.2026.119893
Toxins (Basel). 2026 Aug 17. pii: 350. [Epub ahead of print]18(8):

Indoxyl Sulfate Contributes to Progression of Renal Injury in the Postpartum Period Following Pregnancy-Related Acute Kidney Injury.

Ashley Griffin, Brittany Berry, Lidia Melaku, Delijah Johnson, Perla Guevarra, Leslie A Shack, Shauna-Kay Spencer, Bindu Nanduri, Kedra Wallace.

  Pregnancy-related acute kidney injury (PR-AKI) increases the risk of chronic kidney disease (CKD) in the postpartum period, yet mechanisms driving this transition remain unclear. Uremic toxins, including indoxyl sulfate (IS), are implicated in AKI-to-CKD progression. Using a rat model of PR-AKI induced by ischemia-reperfusion on gestational day (GD) 18, we assessed IS contributions to renal injury in the postpartum. A subset of rats received the oral adsorbent AST-120 in the postpartum period to reduce IS. Additional groups received IS during pregnancy with or without AST-120 treatment in the postpartum period. Renal function, blood pressure, circulating and urinary IS concentrations, and renal histopathology were evaluated. PR-AKI resulted in sustained postpartum elevations in circulating (p = 0.03) and urinary (p < 0.03) IS, reduced urine output (p = 0.03), increased proteinuria (p < 0.0001), increased serum albumin, and increased renal fibrosis (p = 0.008) compared to normal pregnant control rats. Absorption of indole, a precursor for IS, significantly reduced urinary IS (p = 0.03), reduced serum creatinine (p = 0.006), and attenuated renal fibrosis (p = 0.002) in treated PR-AKI rats. While not significant, indole absorption improved urine output (p = 0.06) and reduced proteinuria (p = 0.07) in treated PR-AKI rats. IS administration during pregnancy recapitulated key features of postpartum CKD. Elevated IS contributes to persistent renal injury following PR-AKI. Postpartum reduction in IS with AST-120 dampens the progression of renal injury. These findings highlight uremic toxins as mechanistic drivers and potential therapeutic targets in post partum CKD following PR-AKI.

Keywords:  AKI; CKD; indoxyl sulfate; postpartum; pregnancy; renal injury; uremic toxin

DOI:  https://doi.org/10.3390/toxins18080350
JCEM Case Rep. 2026 Sep;4(9): luag229

Coexisting mild autonomous cortisol secretion and isolated adrenocorticotropic hormone deficiency in a patient with an adrenal incidentaloma.

Koki Ikeda, Shotaro Nakamura, Naoki Sekine, Satoshi Kadowaki, Daisuke Sugimoto, Hiroaki Satoh.

  Low adrenocorticotropic hormone (ACTH) in a patient with an adrenal incidentaloma is usually attributed to ACTH-independent cortisol secretion. A 71-year-old woman with a 20-mm left adrenal mass had no cushingoid features. After a 1-mg dexamethasone suppression test, serum cortisol was 5.59 μg/dL (SI: 154 nmol/L) (cutoff, <1.8 μg/dL [SI: <50 nmol/L]), and ACTH was below 1.5 pg/mL (SI: below 0.33 pmol/L) (reference range, 7-63 pg/mL [SI: 1.5-13.9 pmol/L]). Late-night serum cortisol was 7.29 μg/dL (SI: 201 nmol/L) (cutoff, <5.0 μg/dL [SI: <138 nmol/L]), supporting mild autonomous cortisol secretion. Combined pituitary stimulation testing showed a blunted, delayed ACTH increase from 4.2 (SI: 0.92 pmol/L) to 11.8 pg/mL (SI: 60 pmol/L) without a cortisol response, whereas other anterior pituitary axes were preserved. A short Synacthen test showed an inadequate peak cortisol of 10.8 μg/dL (SI: 298 nmol/L) (adequacy cutoff, ≥18 μg/dL [SI: approximately 500 nmol/L]), and dehydroepiandrosterone sulfate was 37 ng/mL (SI: 0.10 μmol/L) (reference range, 70-495 ng/mL [SI: 0.19-1.34 μmol/L]). Possible isolated ACTH deficiency was diagnosed. Annual testing remained unchanged over 4 years.

Keywords:  adrenal incidentaloma; adrenal insufficiency; corticotropin-releasing hormone test; isolated ACTH deficiency; mild autonomous cortisol secretion

DOI:  https://doi.org/10.1210/jcemcr/luag229
JAMA Surg. 2026 Aug 26.

Cross-Linked Chondroitin Sulfate Adhesion Barrier System in Open Rectal Resection: A Randomized Clinical Trial.

Yukihide Kanemitsu, Eiji Hashizume, Takeshi Suto, Kazunori Yawata, Kenichi Inaoka, Kazuhiro Hiramatsu, Koji Komori, Masataka Ikeda, Nobuhiro Ishido, Masahiko Watanabe.

Importance: Adhesions commonly occur after abdominal and pelvic surgery, causing infertility, intestinal obstruction, and pelvic pain. Existing anti-adhesion materials are often difficult to use on uneven organ surfaces, highlighting the need for novel solutions; SI-449, a cross-linked, powder-formed chondroitin sulfate (CS), may address these limitations.
Objective: To evaluate the anti-adhesion effect of the SI-449 adhesion barrier system (cs barrier) in patients undergoing open rectal resection for rectal cancer.
Design, Setting, and Participants: This multicenter, prospective, randomized, open, and blinded-end point (PROBE) method pivotal clinical trial was conducted at 53 hospitals in Japan from September 2020 to June 2023. The study participants and efficacy assessors on the central review board were blinded. Patients aged 20 years or older with clinical stage I through IV rectal cancer who underwent open rectal resection and were scheduled for follow-up ileostomy closure were eligible for inclusion. Data were analyzed from July 2023 through September 2023.
Intervention: The control group received no additional procedure before abdominal closure, while the experimental group received 2 to 3 g of SI-449 applied to the abdominal or pelvic cavity immediately before closure.
Main Outcomes and Measures: The primary end point was the incidence of adhesions under the incision. Secondary end points included adhesion number, severity, and extent; number and type of adhered organs; and number of adhesions per organ. Safety and operability were also evaluated.
Results: Among 155 screened patients, 131 met the inclusion criteria and were randomized. Of these, 128 underwent the intervention (safety analysis population; control group: n = 64; experimental group: n = 64), and 118 completed a second surgery (modified intention-to-treat population; control group: n = 60; experimental group: n = 58). Overall mean (SD) patient age was 68.2 (10.3) years, and 34 patients of 118 (29%) were female. Adhesion incidence was significantly lower in the experimental group (26 of 58 [45%]) compared to the control group (56 of 60 [93%]) (P < .001). The experimental group also showed significantly reduced adhesion severity and extent. No safety concerns were identified, and operability was good.
Conclusions and Relevance: In this randomized clinical trial, SI-449 in the powdered form reduced the incidence of adhesions, and the adhesion barrier system had good operability and no safety concerns. Thus, this system may provide a new anti-adhesion option for use in open surgery.
Trial Registration: jrct.mhlw.go.jp Identifier: jRCT1080225247.

DOI: https://doi.org/10.1001/jamasurg.2026.3416