bims-supasi 2025-07-20 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2025–07–20
nine papers selected by
Jonathan Wolf Mueller, University of Birmingham

Multilayered electrospun chondroitin sulfate nanofiber impregnated with aortic extracellular matrix hydrogel for dermal regeneration: In vitro and in vivo study.
Transporter-Mediated Interactions Between Uremic Toxins and Drugs: A Hidden Driver of Toxicity in Chronic Kidney Disease.
Heparanase-Inhibiting Polymeric Heparan Sulfate Mimetic Attenuates Myeloma Tumor Growth and Bone Metastasis.
Chondroitin Sulfate A-Selenium Nanoparticles Activate Autophagy Through the AMPK-mTOR Pathway to Alleviate Oxidative Stress and Mitochondrial Dysfunction to Repair Kashin-Beck Disease Chondrocytes.
Functional aptamer evolution-enabled elucidation of a melanoma migration-related bioactive epitope.
Modulation of the PTPRS proteoglycan switch by antibodies binding to the membrane-proximal fibronectin-type III domain.
Saliva-Activated Nanohybrid Aggregates Are Rapid-Acting Agglutination Agents with Potent Anticaries Activity and Limited Toxicity.
Loop diuretics in anuric hemodialysis patients for the clearance of protein-bound uremic toxins.
A specifically designed multi-biotic reduces uremic toxin generation and improves kidney function.

Int J Biol Macromol. 2025 Jul 10. pii: S0141-8130(25)06453-0. [Epub ahead of print] 145898

Multilayered electrospun chondroitin sulfate nanofiber impregnated with aortic extracellular matrix hydrogel for dermal regeneration: In vitro and in vivo study.

Fahimeh Sangsefidi, Maryam Tamimi, Khadijeh Baaji, Sara Rajabi, Tayyeb Ghadimi, Mojgan Zandi, Mohamad Pezeshki-Modaress.

  During the exploratory trial and error investigation, we developed a multilayered composite structure composed of nanofibers containing chondroitin sulfate (CS) impregnated with aortic extracellular matrix (ECM) hydrogel as a bioactive and innovative material. The high mechanical performance, three-dimensional nanofibrous structure, and high porosity in the prepared composite scaffolds demonstrate their potential applications for dermal regeneration. Multilayered nanofiber/hydrogel composite scaffolds were prepared based on different concentrations of ECM (0, 0.5, 1, and 2 % w/v), followed by freeze drying and a crosslinking process. The physical, mechanical, and cellular interaction features of prepared multilayered scaffolds were investigated using corresponding tests, and associated results reported. Additionally, an in vivo study was performed by subcutaneous implantation. Results revealed that the porosity of scaffolds was approximately 80 % with high swelling ratios. An in vivo study demonstrated the biocompatibility and degradability of the optimum scaffold (M3DE1), which was previously confirmed by in vitro studies and degradability studies. Overall, the promising aspect of M3DE1 as a dermal substitution, compensating challenges associated with autograft was revealed. However, some other approaches are also needed to get a full skin substitution.

Keywords:  Chondroitin sulfate; ECM; Electrospun nanofibers; Skin tissue engineering

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.145898
Int J Mol Sci. 2025 Jun 30. pii: 6328. [Epub ahead of print]26(13):

Transporter-Mediated Interactions Between Uremic Toxins and Drugs: A Hidden Driver of Toxicity in Chronic Kidney Disease.

Pierre Spicher, François Brazier, Solène M Laville, Sophie Liabeuf, Saïd Kamel, Maxime Culot, Sandra Bodeau.

  Chronic kidney disease (CKD) is associated with the systemic accumulation of uremic toxins (UTs) due to impaired renal elimination. Among these, indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are particularly challenging because of their high protein binding and limited removal by dialysis. In addition to renal excretion, the transport of IS and PCS, and their microbiota-derived precursors, indole and p-cresol, across key physiological barriers-the intestinal barrier, blood-brain barrier, and renal proximal tubule-critically influences their distribution and elimination. This review provides an overview of transporter-mediated mechanisms involved in the disposition of IS, PCS, and their microbial precursors, indole and p-cresol. It also examines how these UTs may interact with commonly prescribed drugs in CKD, particularly those that share transporter pathways as substrates or inhibitors. These drug-toxin interactions may influence the pharmacokinetics and toxicity of IS and PCS, but remain poorly characterized and largely overlooked in clinical settings. A better understanding of these processes may guide future efforts to optimize pharmacotherapy and support more informed management of CKD patients, particularly in the context of polypharmacy.

Keywords:  blood–brain barrier; chronic kidney disease; indole; indoxyl sulfate; intestinal barrier; organic anion transporter; p-cresol; para-cresyl sulfate; renal barrier; solute carrier transporter

DOI:  https://doi.org/10.3390/ijms26136328
ACS Appl Bio Mater. 2025 Jul 15.

Heparanase-Inhibiting Polymeric Heparan Sulfate Mimetic Attenuates Myeloma Tumor Growth and Bone Metastasis.

Kartikey Singh, April Sweet Tapayan, Eric T Sletten, Ravi S Loka, Uri Barash, Israel Vlodavsky, Hien M Nguyen.

  Multiple myeloma (MM) is the second most common hematologic malignancy, heavily relying on the bone marrow microenvironment for its growth, leading to severe clinical complications. A critical factor of MM progression is the aberrant expression of heparanase (HPSE), an enzyme responsible for degrading heparan sulfate (HS) chains in the extracellular matrix (ECM) and cell surface. This degradation fosters tumor cell proliferation, migration, and resistance to chemotherapy. Consequently, targeting HPSE has emerged as a promising therapeutic strategy for MM, though clinical application of HPSE inhibitors remains limited. Herein, we report a HS-mimicking glycopolymer as a highly effective HPSE inhibitor that demonstrates a significant reduction in the viability of myeloma cells. Furthermore, this HS mimetic downregulates HPSE expression and prevents ECM degradation. In vivo analyses reveal that this polymeric HS mimetic significantly inhibited the growth of MPC-11 myeloma tumors, achieving a tumor growth inhibition (TGI) index of 85.77%, surpassing the clinically tested SST0001, which had a TGI value of 67.78%. Additionally, the glycopolymer exhibited promising efficacy against metastatic CAG human myeloma, comparable to bortezomib, a widely used proteasome inhibitor for MM treatment. A combined treatment further reduced tumor burden. These results highlight the remarkable potential of HS-mimicking glycopolymer as a promising therapeutic option for MM.

Keywords:  cancer therapeutics; glycopolymer; heparan sulfate mimetics; heparanase; metastasis; myeloma

DOI:  https://doi.org/10.1021/acsabm.5c00771
Biol Trace Elem Res. 2025 Jul 15.

Chondroitin Sulfate A-Selenium Nanoparticles Activate Autophagy Through the AMPK-mTOR Pathway to Alleviate Oxidative Stress and Mitochondrial Dysfunction to Repair Kashin-Beck Disease Chondrocytes.

Huan Deng, Lichun Qiao, Yude Jiang, Abebe Feyissa Amhare, Jing Han.

  Kashin-Beck disease (KBD) is a chronic osteoarticular disease. Chondroitin sulfate A-selenium nanoparticles (CSA-SeNP), a polysaccharide-based nanoparticle, have shown promise in facilitating cartilage repair, but the mechanism remains unclear. Given our previous findings of downregulated AMPK-mTOR pathway and autophagy in KBD chondrocytes, this study explored the effects of CSA-SeNP on the AMPK-mTOR pathway and autophagy levels in KBD chondrocytes. KBD chondrocytes were treated with CSA-SeNP and AMPK inhibitors alone or in combination. We found that CSA-SeNP promoted autolysosome content and autophagic flux and upregulated the AMPK-mTOR pathway and autophagy markers, while reducing apoptosis in KBD chondrocytes. It effectively alleviated oxidative stress, as evidenced by decreased ROS level and MDA concentration, along with increased activities of antioxidant enzymes (SOD, CAT, and T-AOC). Concurrently, it also improved mitochondrial function, including elevated ATP content, enhanced SDH and ATPase activities, and restored mitochondrial membrane potential. However, co-treatment of KBD chondrocytes with CSA-SeNP and AMPK inhibitor resulted in levels of autolysosome content, autophagic flow, AMPK-mTOR pathway activity, autophagy markers, apoptosis, oxidative stress, and mitochondrial function that were intermediate between those observed with respective treatment with CSA-SeNP or AMPK inhibitor. In summary, CSA-SeNP could effectively activate AMPK-mTOR pathway to promote autophagy process, reduce oxidative stress and apoptosis, and improve mitochondrial function, thereby repairing KBD chondrocytes. This study may provide new insights into the potential of CSA-SeNP as a therapeutic agent for KBD.

Keywords:  AMPK-mTOR signaling; Autophagy; Chondrocytes; Kashin-Beck disease; Mitochondrial function; Oxidative stress; Selenium nanoparticles

DOI:  https://doi.org/10.1007/s12011-025-04732-9
Acta Pharm Sin B. 2025 Jun;15(6): 3196-3209

Functional aptamer evolution-enabled elucidation of a melanoma migration-related bioactive epitope.

Hong Xuan, Siqi Bian, Qinguo Liu, Jun Li, Shaojin Li, Sharpkate Shaker, Haiyan Cao, Tongxuan Wei, Panzhu Yao, Yifan Chen, Xiyang Liu, Ruidong Xue, Youbo Zhang, Liqin Zhang.

  Metastasis is the leading cause of death from cutaneous melanoma. Identifying metastasis-related targets and developing corresponding therapeutic strategies are major areas of focus. While functional genomics strategies provide powerful tools for target discovery, investigations at the protein level can directly decode the bioactive epitopes on functional proteins. Aptamers present a promising avenue as they can explore membrane proteomes and have the potential to interfere with cell function. Herein, we developed a target and epitope discovery platform, termed functional aptamer evolution-enabled target identification (FAETI), by integrating affinity aptamer acquisition with phenotype screening and target protein identification. Utilizing the aptamer XH3C, which was screened for its migration-inhibitory function, we identified the Chondroitin Sulfate Proteoglycan 4 (CSPG4), as a potential target involved in melanoma migration. Further evidence demonstrated that XH3C induces cytoskeletal rearrangement by blocking the interaction between the bioactive epitope of CSPG4 and integrin α4. Taken together, our study demonstrates the robustness of aptamer-based molecular tools for target and epitope discovery. Additionally, XH3C is an affinity and functional molecule that selectively binds to a unique epitope on CSPG4, enabling the development of innovative therapeutic strategies.

Keywords:  Aptamer; CSPG4; Chondroitin sulfate chain; Cytoskeletal rearrangement; FAETI; Melanoma migration; Phenotype screening; Target and epitope discovery

DOI:  https://doi.org/10.1016/j.apsb.2025.03.003
J Biol Chem. 2025 Jul 10. pii: S0021-9258(25)02320-8. [Epub ahead of print] 110470

Modulation of the PTPRS proteoglycan switch by antibodies binding to the membrane-proximal fibronectin-type III domain.

Thales Hein Da Rosa, Sterling H Ramsey, Judy J Lee, Natalia Y Kozlova, Zixuan Zhao, Jaeyeon Kim, Ava C Schneider, Sheng Li, Madhusudhanarao Katiki, Gary S Firestein, Ramachandran Murali, Eugenio Santelli, Stephanie M Stanford, Nunzio Bottini.

  Protein tyrosine phosphatases (PTPs) receptor type II A (R2A) are negatively regulated through oligomerization upon binding of their extracellular domains to glycosaminoglycans (GAGs) on heparan sulfate proteoglycans (HSPGs). Inactivation of receptor PTP sigma (PTPRS) by HSPGs promotes the aggressive behavior of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA). Blocking the binding of its N-terminal, membrane-distal immunoglobulin-like 1 and 2 (Ig1&2) domains to its GAG ligands on the HSPG syndecan-4 promotes PTPRS activity and reverses the pathogenic phenotype of FLS. The potential for therapeutically leveraging other PTPRS ectodomain regions is, however, unknown. We show targeting the membrane-proximal fibronectin type III-like 9 (Fn9) domain offers a novel avenue to activate PTPRS. We mapped PTPRS Fn9 as the binding site of three antibodies (Abs) (13G5, 22H8, 49F2) and characterized their effects on cells. Despite sharing similar epitopes, we found large differences in the ability of these Abs to regulate PTPRS activity. One of these, 13G5, reduced PTPRS-dependent cell migration, PTPRS co-localization with syndecan-4, and PTPRS oligomerization. Single-chain variable fragment Abs of 13G5 and 22H8 were similarly effective at activating cellular PTPRS as 13G5. Replacing the entire 13G5 constant region enhanced its binding and cellular activity, indicating the Ab's potency can be optimized via isotype engineering. Treatment of cells with recombinant Fn9 protein acted as a decoy, disrupting PTPRS colocalization with syndecan-4 and oligomerization and inhibiting FLS migration. Finally, significant disease mitigation in mice using 13G5-derived Abs suggests a viable strategy for the generation of novel drugs for RA therapy.

Keywords:  antibody; phosphatase; proteoglycan; receptor regulation

DOI:  https://doi.org/10.1016/j.jbc.2025.110470
ACS Pharmacol Transl Sci. 2025 Jul 11. 8(7): 2106-2116

Saliva-Activated Nanohybrid Aggregates Are Rapid-Acting Agglutination Agents with Potent Anticaries Activity and Limited Toxicity.

Kassapa Ellepola, Mohamad Khalid Alhadlaq, Angeliki Andrianopoulou, Bibash Sapkota, Heidi Yuan, Lin Chen, Richard A Gemeinhart, Robert F Klie, Matthew Lindeblad, Russell P Pesavento.

  Dental caries is a multifactorial process attributed to a diet high in fermentable carbohydrates, tooth-adherent plaque comprising acidogenic microbes (Streptococcus mutans), and a host of associated risk factors. We previously reported a nanohybrid aggregate formulation comprising nanoceria (CeO2-NP) and chondroitin sulfate A (CSA) that limited sucrose-dependent biofilm formation of S. mutans via the induction of nonadherent cell clusters. Herein, we report the chemical and bioactivity analysis of CeO2-NP-CSA and a related derivative (CeO2-NP-CSA-B) in a series of preclinical studies culminating in both in vivo efficacy and toxicity studies. Time-dependent sedimentation assays and dynamic light scattering studies in whole human saliva model systems demonstrate changes to aggregate size/zeta potential (activation) of both CeO2-NP-CSA and CeO2-NP-CSA-B that correlate with the rapid clearance of S. mutans. Further, CeO2-NP-CSA-B was found to significantly inhibit tooth-retained rodent plaque and dental caries, similar to an over-the-counter anticaries mouth rinse. Human cell toxicity and maximum tolerated dose studies provided no significant evidence of toxicity of CeO2-NP-CSA-B as quantified in a series of well-known clinical chemistry and hematological assays. This study summarizes the chemical and biological data supporting the potential of nanohybrid aggregate formulation(s) as future caries prevention agents.

Keywords:  Streptococcus mutans; agglutination; caries; chondroitin sulfate A; nanoceria; saliva

DOI:  https://doi.org/10.1021/acsptsci.5c00201
Clin Kidney J. 2025 Jul;18(7): sfaf195

Loop diuretics in anuric hemodialysis patients for the clearance of protein-bound uremic toxins.

Didier Sánchez-Ospina, Maria Romero-Cote, Lucia Criado-Bellido, Maria Isabel Saez-Calero, Badawi Hijazi-Prieto, Sandra Delgado-Cuesta, Francisco Herrera-Gómez, Maddalen Mujika-Marticorena, Emilio Gonzalez-Parra, Maria Jesus Izquierdo-Ortiz, Sebastián Mas-Fontao.

   Background: In chronic kidney disease, the accumulation of protein-bound uremic toxins (PBUTs), such as hippuric acid (HA), p-cresyl sulfate (PCS) and indoxyl sulfate (IS), contributes to systemic toxicity and organ dysfunction. These toxins bind to plasma proteins, primarily albumin, rendering them resistant to clearance by conventional dialysis. This study hypothesizes that loop diuretics, particularly torasemide and furosemide, can displace PBUTs from their albumin-binding sites, increasing their free fraction and enhancing their removal during hemodialysis.
Methods: This pilot multicenter crossover study included 17 anuric hemodialysis patients recruited from two hospitals. Participants underwent sequential treatment with furosemide and torasemide, each phase separated by a 1-week washout period. Plasma concentrations of HA, PCS and IS were measured pre- and post-dialysis during baseline (no diuretics) and diuretic treatment phases using high-performance liquid chromatography coupled with tandem mass spectrometry. Changes in pre- and post-dialysis toxin levels were evaluated across treatment phases. Repeated measures analysis of variance assessed the effect of each diuretic treatment on toxin levels and clearance rates.
Results: Both loop diuretics increased the free fraction and clearance of PBUTs compared with baseline. Torasemide demonstrated higher efficacy in enhancing the clearance of HA (76.8%) compared with furosemide (63.2%) and baseline (57.3%). For PCS, furosemide achieved greater reductions (66.3%) than torasemide (61.8%) and baseline (24%). Indoxyl sulfate clearance increased significantly with both diuretics (59.1% for furosemide and 58.8% for torasemide) compared with baseline (26.2%).
Conclusion: This study demonstrates that loop diuretics, especially torasemide, can enhance the clearance of PBUTs during hemodialysis. Their use mobilizes PBUTs from tissue stores and increases their dialyzability. These findings warrant further investigation in larger, long-term studies to validate the efficacy and clinical benefits of this approach.

Keywords:  dialysis; loop diuretics; protein-bound uremic toxins; torasemide; uremia

DOI:  https://doi.org/10.1093/ckj/sfaf195
Gut Microbes. 2025 Dec;17(1): 2531202

A specifically designed multi-biotic reduces uremic toxin generation and improves kidney function.

Alice Beau, Jane Natividad, Berengère Benoit, Philippe Delerive, Stéphane Duboux, Yuan Feng, Marie Jammes, Cecile Barnel, Giuseppina Sequino, Claudie Pinteur, Griet Glorieux, Denis Fouque, Hubert Vidal, Laetitia Koppe.

  Chronic kidney disease (CKD) is characterized by accumulation of uremic toxins (UTs), such as p-cresyl sulfate and indoxyl sulfate, generated through the transformation of tyrosine and tryptophan by the gut microbiota. Using an ex vivo Simulator of the Human Intestinal Microbial Ecosystem (SHIME) colonized with fecal samples from eight CKD patients or nine healthy volunteers, a higher bacterial generation of p-cresol and indoles post-amino acid enrichment, as well lower basal butyrate levels, in the feces of CKD patients were found. Through in silico data mining, we selected a probiotic strain lacking the capacity to produce UT, i.e. without genes for tryptophanase, tyrosinase and urease. In vitro, we confirmed the potential of cellobiose as a prebiotic supporting the growth of this strain. We further designed a novel specific multi-biotic for CKD (SynCKD) [containing a probiotic Lactobacillus johnsonii NCC533, a prebiotic (1% cellobiose), and a postbiotic (1% short and medium chain triglycerides C4-C8, a source of butyrate)]. SynCKD effectively curtailed UT precursor generation ex vivo. The in vivo efficacy of SynCKD (and the synergic effect) was established in two uremic rodent models, demonstrating lower plasma levels of UTs and enhancing kidney function after 6-8 weeks of treatment. These effects were linked to better gut microbial ecology. Metagenomic analysis revealed reduced microbial genes for tryptophan/tyrosine degradation. This study lays the foundation for SynCKD as a potential therapy to mitigate CKD progression.

Keywords:  Multi-biotic; chronic kidney disease; gut microbiota; uremic toxins

DOI:  https://doi.org/10.1080/19490976.2025.2531202