bims-supasi 2025-04-20 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2025–04–20
seven papers selected by
Jonathan Wolf Mueller, University of Birmingham

Hair Dehydroepiandrosterone Sulfate (DHEA(S)) and Cortisol/DHEA(S) Ratio as Long-Lasting Biomarkers of Clinical Syndromes Exhibited by Piglets Early in Life.
In vitro effects of structurally diverse low molecular weight chondroitin sulfates on gut microbiota and metabolome.
Heparan sulfate proteoglycans remodel SARS-CoV-2 spike conformation to allow integrin interaction and infection of endothelial cells.
Use of the Malaria Protein VAR2CSA for the Detection of Small Extracellular Vesicles to Diagnose Adenocarcinoma.
Indoxyl sulfate is associated with cognitive impairment in ESRD patients by activating the extrinsic apoptosis in the neuronal cells during differentiating process.
Impact of Gut Microbiome Modulation on Uremic Toxin Reduction in Chronic Kidney Disease: A Systematic Review and Network Meta-Analysis.
Preparation of gastrointestinal pH-responsive zein coated tea polyphenol-heparin hydrocolloids using for inflammatory bowel disease therapy.

Animals (Basel). 2025 Apr 03. pii: 1032. [Epub ahead of print]15(7):

Hair Dehydroepiandrosterone Sulfate (DHEA(S)) and Cortisol/DHEA(S) Ratio as Long-Lasting Biomarkers of Clinical Syndromes Exhibited by Piglets Early in Life.

Annalisa Scollo, Alessio Cotticelli, Tanja Peric, Alice Perrucci, Alberto Prandi, Paolo Ferrari.

  Poor health and increased susceptibility to infectious diseases are among the main sources of economic losses in the pig industry worldwide, and they also serve as indicators of compromised animal welfare. However, there is limited information on long-lasting biomarkers of poor health and common infections experienced by piglets early in life. Hair cortisol, dehydroepiandrosterone sulfate (DHEA(S)), and their ratio have been proposed as components of the mammalian stress response due to the activation of the hypothalamus-pituitary-adrenal axis and were investigated in this study using 30 batches of pigs from 16 farms. The research hypothesis was that batches of piglets experiencing clinical syndromes (as indicated by enteric, neurological, cutaneous, and locomotor scores) during suckling would exhibit a different pattern of resilience and allostatic load later in life compared to healthy ones. Hair from 25 gilts per batch were collected at either 3.5 or 9 months of age, and hormone extraction was subsequently performed. The farm of origin and the age of the animals significantly influenced hormone concentrations. Moreover, batches affected by enteric disease showed lower DHEA(S) levels (p < 0.0001; 15.89 vs. 23.51 pg/mg) and higher cortisol/DHEA(S) ratio (p < 0.0001; 82.83 vs. 55.02) than healthy batches. Similar results were observed in batches with a neurological syndrome (DHEA(S): p < 0.0001; 12.91 vs. 19.43; cortisol/DHEA(S) ratio: p < 0.0001; 97.15 vs. 70.26 pg/mg). These results suggest that pig hair biomarkers carry an intrinsic and temporally stable signal related to early life health status.

Keywords:  allostatic load; clinical syndromes; cortisol; dehydroepiandrosterone sulfate; hair; long-lasting biomarkers; pig

DOI:  https://doi.org/10.3390/ani15071032
Int J Biol Macromol. 2025 Apr 11. pii: S0141-8130(25)03603-7. [Epub ahead of print]310(Pt 1): 143051

In vitro effects of structurally diverse low molecular weight chondroitin sulfates on gut microbiota and metabolome.

Kangyu Wang, Yue Liu, Yujie Guo, Chunhui Zhang.

  In this study, low molecular weight chondroitin sulfates (LMCSs) with different structures, named LMCSO, LMCSD, and LMCSH, were prepared by oxidative degradation, deamidation cleavage, and hydrothermal depolymerization, respectively. In vitro fermentation modeling was used to study the effects of CS and LMCSs on gut microbiota and metabolite composition. The degree of carbohydrate metabolism was in the order of CS > LMCSH > LMCSO > LMCSD. Significantly, GlcA in chondroitin-6-sulfate (CSC) was more readily utilized by gut microbiota during fermentation, and this trend was more pronounced in LMCSs. The LMCSs group notably increased microbial richness and evenness, especially in the LMCSD group. Bacteroides fragilis was identified as a potential primary degrader of CS and LMCSs through species-level analysis. The abundance of Escherichia-Shigella was reduced by LMCSs, and short-chain fatty acids production was enhanced, particularly by LMCSO, while the production of beneficial metabolites such as N-acetyl-D-Glucosamine 6-Phosphate (GlcNAc-6P), lactate, and progesterone was stimulated. Among these, the metabolism of the key metabolite GlcNAc-6P was significantly and positively correlated with the abundance of Bacteroides, Clostridium_sensu_stricto_1, and Parabacteroides. Exploring the mechanisms by which gut microbiota metabolize LMCSs with different structures can provide theoretical support for the targeted preparation of LMCSs that modulate the gut microbiota.

Keywords:  Gut microbiota; Low molecular weight chondroitin sulfate; Metabolism; Structure

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.143051
Front Cell Infect Microbiol. 2025 ;15 1552116

Heparan sulfate proteoglycans remodel SARS-CoV-2 spike conformation to allow integrin interaction and infection of endothelial cells.

Antonella Bugatti, Alberto Zani, Marta Bardelli, Marta Giovanetti, Cosetta Ravelli, Massimo Ciccozzi, Arnaldo Caruso, Francesca Caccuri.

  SARS-CoV-2 infects ACE2-negative primary HL-mECs through the interaction of an RGD motif, included in all spike proteins, up to the Omicron BA.1 subvariant, with αvβ3 integrin. Following its entry, SARS-CoV-2 remodels ECs phenotype and promotes angiogenesis in the absence of productive viral replication. Moreover, lack of spike/αvβ3 interaction, occurring in Omicron BA.5 which contains the D405N mutation in the RGD motif, inhibits HL-mECs infection and dysfunction. It is worth noting that anti-spike antibodies do not impact SARS-CoV-2 entry into HL-mECs. This data highlights the fact that i) the RGD motif is not exposed in the entire spike protein and ii) the need of a cofactor favoring spike/αvβ3 interaction. HSPGs are used by different viruses as receptors and coreceptors for their entry into host cells. Here, we use different approaches to scrutinize the role exerted by HSPGs in favoring SARS-CoV-2 infection of ECs. We highlight HSPGs as key molecules responsible for RGD exposure allowing its binding to the αvβ3 integrin as the first step toward viral entry by endocytosis. Indeed, SPR analysis showed lack of spike/αvβ3 interaction in the absence of heparin. This data was further corroborated by immunofluorescence and infectivity assays. Interestingly, the use of Heparinase III or sodium chlorate counteracts the release of proangiogenic molecules and inhibits signaling pathways induced by SARS-CoV-2 infection. Thus, HSPGs may represent a target for preventing SARS-CoV-2 infection of ECs and EC dysfunction-related COVID-19 severity.

Keywords:  FAK-Src and Erk signaling pathway; SARS-CoV-2; angiogenesis; heparan sulphates; integrins; von Willebrand factor

DOI:  https://doi.org/10.3389/fcimb.2025.1552116
J Extracell Vesicles. 2025 Apr;14(4): e70067

Use of the Malaria Protein VAR2CSA for the Detection of Small Extracellular Vesicles to Diagnose Adenocarcinoma.

Yaru Zhao, Chenlei Wen, Qi Wang, Yue Qing, Serena Tondi, Chiara Reina, Berina Šabanović, Cherry Yin-Yi Chang, Chu-Hu Lai, Huimin Wang, Mette Ø Agerbaek, Thomas M Clausen, Tobias Gustavsson, Thor G Theander, Ali Salanti, Clara Csilla Meny, Baiyong Shen, Alexandra Aicher, Jiajia Tang, Christopher Heeschen.

  Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge for early diagnosis due to the lack of sensitive and specific biomarkers. This encouraged us to explore the diagnostic value of cancer-derived small extracellular vesicles (sEVs) as early detection biomarkers. We previously showed that the recombinant malaria protein VAR2CSA (rVAR2) selectively binds to oncofetal chondroitin sulfate (ofCS) on the surfaces of cancer cells, which might be useful for identifying cancer-derived sEVs. Indeed, flow cytometry revealed strong ofCS expression in PDAC cell-derived sEVs, as evidenced by the presence of mutant KRAS, a common genetic alteration in PDAC. Plasma from PDAC patients showed significantly higher ofCS+ sEV levels compared to healthy donors and patients with benign gastrointestinal diseases. ROC analysis for ofCS+ sEVs revealed an AUC of 0.9049 for the detection of all-stage and 0.9222 for early-stage PDAC. Notably, mutant KRAS was also detected in these patient-derived sEVs. Most intriguingly, combining ofCS+ sEVs and CA19-9 resulted in an AUC of 0.9707 for the detection of early PDAC. Our study demonstrates that rVAR2 is suitable for detecting ofCS+ cancer-derived sEVs in plasma, thereby providing high efficiency for identifying PDAC patients among a diverse population. These findings suggest that rVAR2-based sEV detection could serve as a powerful diagnostic tool to improve patient survival through early detection.

Keywords:  Early diagnosis; extracellular vesicles; oncofetal chondroitin sulfate; pancreatic ductal adenocarcinoma; recombinant malaria protein

DOI:  https://doi.org/10.1002/jev2.70067
Int J Med Sci. 2025 ;22(8): 1736-1749

Indoxyl sulfate is associated with cognitive impairment in ESRD patients by activating the extrinsic apoptosis in the neuronal cells during differentiating process.

Chih-Chuan Hsieh, Kuo-Cheng Lu, Chuen-Lin Huang, Jiun-Jie Wang, Ting-Yin Yeh, Shyh-Min Lin, Ya-Ling Chung, Yi-Chou Hou, Yuahn-Sieh Huang.

  Aim: This study investigates the correlation between indoxyl sulfate (IS) levels and cognitive impairment in end-stage renal disease (ESRD) patients from human study, in vivo and in vitro study. Materials and Methods: Comparison of demographic and biochemical data, including IS concentrations, was conducted between a control group(n=16) and the ESRD with cognitive impairment group (n=14) and without cognitive impairment (n=17). A CKD animal model induced renal impairment in adenine-fed C57BL/6 mice, assessing memory loss and behavioral changes. Immunohistochemistry evaluated choline acetyltransferase activity and GFAP expression. Differentiating SH-SY5Y cells were treated with IS, assessing cell viability and apoptosis via annexin V and propidium iodide staining and western blotting. Reactive oxidized species generation was measured using DCFCA fluorescence and NAC pretreatment. Results: In ESRD patients with cognitive impairment, IS levels were significantly higher compared to healthy controls, along with older age. CKD mice exhibited renal impairment and memory loss, accompanied by altered choline acetyltransferase activity and GFAP expression. IS treatment induced early apoptosis in SH-SY5Y cells, associated with increased cleaved caspase 3 levels and Fas/Fas-ligand activity, altered Bax/Bcl2 ratio, and reactive oxidized species generation. Conclusion: Elevated IS levels are associated with cognitive impairment and neuronal apoptosis, potentially mediated by oxidative stress. IS could be a therapeutic target for cognitive dysfunction in CKD, necessitating further research into its mechanisms and therapeutic interventions.

Keywords:  Cognitive impairment; End stage renal disease; Stem cell.; choline acetyltransferase; differentiating; differentiation; extrinsic apoptosis; indoxyl sulfate; memory loss

DOI:  https://doi.org/10.7150/ijms.109245
Nutrients. 2025 Apr 03. pii: 1247. [Epub ahead of print]17(7):

Impact of Gut Microbiome Modulation on Uremic Toxin Reduction in Chronic Kidney Disease: A Systematic Review and Network Meta-Analysis.

Renata Cedillo-Flores, Miguel Angel Cuevas-Budhart, Iván Cavero-Redondo, Maria Kappes, Marcela Ávila-Díaz, Ramón Paniagua.

  Background/Objectives: Chronic kidney disease is associated with increased intestinal barrier permeability, leading to heightened inflammation and oxidative stress. These changes contribute to complications such as cardiovascular disease, anemia, altered mineral metabolism, and CKD progression. Interventions using prebiotics, probiotics, and synbiotics may mitigate dysbiosis and improve intestinal barrier function, Under this premise, the objective of this network meta-analysis was to evaluate the effect of probiotics, prebiotics, and synbiotics in reducing uremic toxins produced by the gut microbiota in CKD patients. Methods: A systematic review and network meta-analysis of randomized clinical trials (RCTs) was performed in the following databases: Web of Science, Scopus, the Cochrane Register of Controlled Trials, and PubMed published between 2019 and 2023. The analysis focused on the use of prebiotics, probiotics, and synbiotics in CKD patients at stages 3 to 5, as per KDIGO guidelines, and their association with reductions in uremic toxins such as Indoxyl Sulfate, p-Cresyl Sulfate, urea, and creatinine. The risk of bias was assessed using the Cochrane risk of bias tool (RoB 2), with evaluations conducted independently by two reviewers, and a third consulted for disagreements. The study follows the PRISMA statement. Results: The studies included 331 patients, primarily male, across CKD stages 3a to 5. The interventions positively impacted the gut microbiota composition, leading to reductions in free and total p-Cresyl Sulfate (SUCRA: 72.6% and 66.2, respectively) and indoxyl sulfate (SUCRA: 88.5% and 83.1%). Conclusions: The findings suggest that modulating the gut microbiota through these interventions can effectively reduce specific uremic toxins. However, further trials are necessary to better understand microbiota modulation and its impact on intestinal bacterial composition (PROSPERO number: CRD42023438901).

Keywords:  chronic kidney disease; gut microbiota; prebiotics; probiotics; synbiotics; uremic toxins

DOI:  https://doi.org/10.3390/nu17071247
Int J Biol Macromol. 2025 Apr 13. pii: S0141-8130(25)03687-6. [Epub ahead of print]309(Pt 4): 143135

Preparation of gastrointestinal pH-responsive zein coated tea polyphenol-heparin hydrocolloids using for inflammatory bowel disease therapy.

Hui Li, Shuangshuang Chen, Yumei Li, Zelin Sang, Zhenhua Chen, Xifan Mei, Xiuli Ren.

  In the pathogenesis of inflammatory bowel disease (IBD), overstimulation of inflammatory factors can trigger a coagulation cascade, increase the risk of intestinal micro-thrombosis and lead to microcirculation disorders. However, prevention of microcirculation pathways has not received enough attention. Heparin is commonly used in anticoagulant therapy, but oral delivery does not have an excellent anticoagulant effect. To improve the stability of heparin (HEP) in the gastrointestinal tract, zein/tea polyphenol nanospheres with a core-shell structure (EGNs@Z) were developed for oral administration of heparin (HEGNs@Z). The Zein shell has pH-responsive properties and is effective in preventing premature dissolution of heparin. At the same time, EGCG nanospheres (EGNs) play an anti-inflammatory role, jointly improve the vicious cycle between inflammation and microthrombosis. The results of SEM, TEM and FTIR showed that EGNs successfully encapsulated heparin and formed zein shells on the surface of microspheres with a thickness of 50-100 nm. In vitro simulated digestion experiments showed that zein shells prevented the breakdown of microspheres and heparin in a simulated gastric environment, whereas EGNs and HEP were slowly degraded and released in a simulated intestinal environment. Coagulation analysis showed that HEGNs@Z was effective in delaying clotting time. A mouse model of acute colitis has also shown that HEGNs@Z robust promotes colonic epithelial regeneration, inhibits malignant microcirculation, and reduces bleeding risk. These findings reveal that this orally bioavailable multifunctional material may provide a novel, effective and convenient treatment for inflammatory bowel disease.

Keywords:  Core shell structure; Oral heparin; pH-responsive

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.143135