bims-supasi 2025-06-29 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2025–06–29
seventeen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Applications of Surface Plasmon Resonance in Heparan Sulfate Interactome Research.
Exploring the Inhibitory Effects of Fucosylated Chondroitin Sulfate (FCS) Oligosaccharide Isolated from Stichopus horrens and the Derivatives on P-Selectin.
Evolutionary dynamics of heparan sulfate utilization by SARS-CoV-2.
Synthesis of Chondroitin Sulfate Conjugated Nanofiber Shish Kebabs as a Biomimetic Bone Template.
Biomimetic double network hydrogels of chondroitin sulfate and synthetic polypeptides for cartilage tissue engineering.
Elucidating the multifaceted role and therapeutic potential of Sulf-2 in human tumor biology.
Chondroitin Sulfate as a Lysosomal Enhancer Attenuates Lipid-Driven Inflammation via Lipophagy and Mitophagy.
Coelenterazine sulfotransferase from the luminous squid Watasenia scintillans.
Pathogens that infect mammalian cells via sulfonated glycosaminoglycans.
Serum Indoxyl Sulfate as a Potential Biomarker of Peripheral Arterial Stiffness in Patients with Non-Dialysis Chronic Kidney Disease Stages 3 to 5.
Serum Testosterone and Dehydroepiandrosterone Sulfate Levels and Hearing Loss in Older Males: The Hitachi Health Study II.
The role of uremic toxin indoxyl sulfate in the pathophysiology of aortic valve stenosis.
Engineering Heparan Sulfate-Guided Peptide Self-Assembly to Restore Endothelial Angiogenesis under Hyperglycemia.
Arylsulfatase B Induces Melanoma Apoptosis by the Ubiquitin Ligase COP1.
Medium chain fatty acids are potent binding competitors to improve protein-bound uremic toxin clearance during hemodialysis.
Steroid Sulfatase Regulates Metabolic Reprogramming in Advanced Prostate Cancer.
Klotho Suppresses Indoxyl Sulfate-Mediated Apoptosis in Human Kidney Proximal Tubular (HK-2) Cells through Modulating the AKT/Nrf2 Mechanism.

Biomedicines. 2025 Jun 14. pii: 1471. [Epub ahead of print]13(6):

Applications of Surface Plasmon Resonance in Heparan Sulfate Interactome Research.

Payel Datta, Jonathan S Dordick, Fuming Zhang.

  Surface plasmon resonance (SPR) is a powerful tool for analyzing biomolecular interactions and is widely used in basic biomedical research and drug discovery. Heparan sulfate (HS) is a linear complex polysaccharide and a key component of the extracellular matrix and cell surfaces. HS plays a pivotal role in maintaining cellular functions and tissue homeostasis by interacting with numerous proteins, making it essential for normal physiological processes and disease states. Deciphering the interactome of HS unlocks the mechanisms underlying its biological functions and the potential for novel HS-related therapeutics. This review presents an overview of the recent advances in the application of SPR technology to HS interactome research. We discuss methodological developments, emerging trends, and key findings that illustrate how SPR is expanding our knowledge of HS-mediated molecular interactions. Additionally, we highlight the potential of SPR-based approaches in identifying novel therapeutic targets and developing HS-mimetic drugs, thereby opening new avenues for intervention in HS-related diseases.

Keywords:  heparan sulfate; heparin; interactome; surface plasmon resonance

DOI:  https://doi.org/10.3390/biomedicines13061471
Mar Drugs. 2025 May 30. pii: 236. [Epub ahead of print]23(6):

Exploring the Inhibitory Effects of Fucosylated Chondroitin Sulfate (FCS) Oligosaccharide Isolated from Stichopus horrens and the Derivatives on P-Selectin.

Caiyi Li, Huifang Sun, Xi Gu, Wen Long, Guangyu Zhu, Xiaolu Wu, Yu Wang, Pengfei Li, Le Sha, Jiali Zhang, Wenwu Sun, Na Gao, Zhili Zuo, Jinhua Zhao.

  Unique fucosylated chondroitin sulfate (FCS) extracted from the sea cucumber Stichopus horrens was subjected to deacetylation and deaminative depolymerization to generate oligosaccharide fragments containing anTal-diol, which were further purified to obtain the trisaccharide ShFCS-3. Subsequently, the coupling of ShFCS-3 and 4-azidoaniline was achieved by reductive amination. After purification, the main product ShFCS-A1 and by-product ShFCS-A2 were obtained, which were identified as (N-(L-Fuc2S4S-α1,3-D-GlcA-β1,3-D-anTalA4S6S-1-)-4-azidoaniline) and (4S)-[2-(3-L-Fuc2S4S-α1)-D-GlcA-β1]-2,4,5-trihydroxy-5-sulfated-pent-2-enoic-acid) by 1D/2D NMR spectroscopy, respectively. ELISA experiments revealed that ShFCS-A1 exhibited P-selectin inhibition rates of 19.73% ± 9.60% at 1 μM, 96.28% ± 2.37% at 10 μM, and near-complete inhibition (99.92% ± 0.84%) at 100 μM. ShFCS-A2 demonstrated inhibition rates of 8.29% ± 3.00% at 1 μM, 74.02% ± 8.80% at 10 μM, and maximal inhibition approaching 100% at 100 μM. Cellular-level experiments revealed that ShFCS-A1 and ShFCS-A2 inhibited P-selectin binding to HL-60 cells by 92.72% ± 0.85% and 96.97% ± 1.16% at 100 μM, respectively. Molecular docking analysis indicated binding energies of -5.954 kcal/mol for ShFCS-A1 and -6.140 kcal/mol for ShFCS-A2 with P-selectin, confirming their potent inhibitory effects. These findings highlight the therapeutic potential of FCS oligosaccharides as pharmacophores and provide an important foundation for developing novel small-molecule P-selectin inhibitors.

Keywords:  P-selectin; Stichopus horrens; fucosylated chondroitin sulfate; reductive amination

DOI:  https://doi.org/10.3390/md23060236
mBio. 2025 Jun 23. e0130325

Evolutionary dynamics of heparan sulfate utilization by SARS-CoV-2.

Shuhei Higuchi, Yafei Liu, Jun Shimizu, Chikako Ono, Yumi Itoh, Wataru Nakai, Hui Jin, Kazuki Kishida, Kazuo Takayama, Toru Okamoto, Yoshiko Murakami, Taroh Kinoshita, Yoshiharu Matsuura, Tatsuo Shioda, Hisashi Arase.

  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variants have acquired enhanced infectivity compared to earlier variants. To elucidate the underlying molecular mechanisms, we conducted CRISPR library screening to identify cell surface molecules that interact with the Omicron spike protein. Our findings revealed a significantly higher affinity between the Omicron spike and cell surface heparan sulfate compared to the wild-type spike. This increased binding affinity enables Omicron variants to infect cells expressing low levels of ACE2, which are minimally infected by the wild-type virus. Mutational analysis of heparan sulfate binding sites on the Omicron spike protein, coupled with electrostatic potential mapping, suggested that the accumulation of positively charged mutations has contributed to the enhanced heparan sulfate binding. Comparative analysis of heparan sulfate binding among Omicron subvariants-including BA.1, BA.2, BA.4, BA.5, XBB.1, and BA.2.86-revealed that most are likely to bind efficiently to heparan sulfate, but potential heparan sulfate binding sites of the spike protein have shifted from the early Omicron variants to more recent ones. Furthermore, we discovered that cell surface heparan sulfate proteoglycans are cleaved by TMPRSS2, a protease essential for wild-type SARS-CoV-2 infection. These findings suggest that SARS-CoV-2 is evolving to enhance its infectivity by optimizing its interaction with cell surface heparan sulfate.IMPORTANCEThe Omicron variant has evolved to become highly infectious by acquiring numerous mutations. Understanding the impact of these mutations can provide valuable insights into the drivers of viral evolution and aid in the development of improved viral surveillance and vaccines. Our study demonstrates that the Omicron variants contain mutations that enhance their ability to bind to heparan sulfate. Highly infectious human viruses often utilize heparan sulfate for infection, suggesting that heparan sulfate likely plays a crucial role in viral adaptation to human hosts. Furthermore, we found that cell surface heparan sulfate proteoglycans are sensitive to TMPRSS2, while most other cell surface proteins are resistant to TMPRSS2. Given that TMPRSS2 is known to enhance the infectivity of earlier severe acute respiratory syndrome coronavirus 2 variants but cleaves heparan sulfate proteoglycans, it is probable that the high heparan sulfate binding acquired by the Omicron variant contributes to its decreased infectivity against TMPRSS2-expressing cells compared to earlier variants.

Keywords:  Omicron; SARS-CoV-2; TMPRSS2; heparan sulfate

DOI:  https://doi.org/10.1128/mbio.01303-25
J Biomed Mater Res A. 2025 Jul;113(7): e37955

Synthesis of Chondroitin Sulfate Conjugated Nanofiber Shish Kebabs as a Biomimetic Bone Template.

Tony Yu, Paul DeSantis, Seyong Kim, Christopher Y Li, Michele Marcolongo.

  Synthetic polymeric bone grafts have emerged as a promising strategy for bone tissue engineering. Polycaprolactone (PCL) nanofiber shish kebab (NFSK) templates were fabricated as synthetic bone scaffolds via polymer crystallization of a block copolymer (BCP) of PCL-b-polyacrylic acid (PAA). The BCP-functionalized NSFKs provide a unique template that allows for the spatial and orientational control of the nanosized mineral crystals in the PAA anionic galleries, mimicking the molecular structure of bone. The objective of this study was to use this platform to design biomimetic bone templates by modifying the surface with biomimetic functional groups. As a result, chondroitin sulfate (CS) was conjugated onto the kebabs via 1-ethyl-3-(-3-dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide (EDC/NHS) crosslinking of the CS terminal amine group and the PAA carboxylic acid group. Fourier-transform infrared spectroscopy (FTIR) and mass balance showed the formation of an amide bond and an increase in mass after conjugation. MC3T3 E1 pre-osteoblast cells were cultured on the CS-NFSK templates and showed that the presence of CS promoted alkaline phosphatase (ALP) activity and cell proliferation. Osteogenic gene expression, including RUNX2, ALP, COL1, and BGLAP, were upregulated in the CS-NFSK templates. For the first time, CS-NFSK was molecularly engineered to mimic the bone structure and matrix, showing promise as a biomimetic bone template.

Keywords:  biomimetic; block copolymer; bone; chondroitin sulfate; crosslinking

DOI:  https://doi.org/10.1002/jbm.a.37955
Biomater Sci. 2025 Jun 23.

Biomimetic double network hydrogels of chondroitin sulfate and synthetic polypeptides for cartilage tissue engineering.

Juhi Singh, Jacob C Kadir, Jason D Orlando, Stefanie A Sydlik.

Articular cartilage defects are common, and the progressive deterioration of cartilage frequently results in the onset of osteoarthritis. However, the intrinsic regenerative capacity of articular cartilage is minimal. Synthetic therapeutic solutions for treating cartilage damage are being developed. However, current scaffolds and hydrogels employed in cartilage tissue engineering face limitations in promoting cellular activity and providing sufficient load-bearing strength. This is primarily due to suboptimal crosslinking methods for the synthetic scaffolds composed of natural proteins and glycosaminoglycans (GAGs). Synthetic polypeptides, owing to their customizable reactive functional groups, present an exciting opportunity to enhance crosslinking through both physical and chemical approaches. This study introduces a strategy for the development of injectable, shape-adaptive double network hydrogels that closely replicate the structural integrity and mechanical properties of native cartilage. These hydrogels are composed of photocrosslinkable GAGs, specifically methacrylated chondroitin sulfate A (CSMA), combined with a synthetic polypeptide, poly(L-lysine) (PLL). By varying the degree of polymerization (DP) of PLL and weight percentage of PLL in the composition, the hydrogels can be optimized for desired material properties. Varying DP of PLLs varies the molecular weight between crosslinks, thus leading to tunable rigidity (yield strength, ultimate compression strength, storage modulus) and toughness. We further this tunability through the integration of photoresponsive components, enabling controlled, non-invasive post-injection modifications. Initial testing indicates that these double network hydrogels exhibit significantly improved mechanical strength compared to hydrogels formed solely from CSMA, positioning them as strong candidates for minimally invasive cartilage defect repair. This innovative method offers the potential to accelerate recovery, restore joint function, and improve patients' overall quality of life.

DOI: https://doi.org/10.1039/d5bm00296f
Biomark Med. 2025 Jun 22. 1-10

Elucidating the multifaceted role and therapeutic potential of Sulf-2 in human tumor biology.

Huanyan Peng, Man Liu, Songkang Liu, Chun Ning, Dongye Yang.

  Sulf-2, a key member of the sulfatase family, regulated tumor progression, invasion, and metastasis through various mechanisms including genetic alterations, epigenetic modifications, transcriptional regulation, and microenvironmental influences. The dysregulation of Sulf-2 has been implicated as a pivotal driver in the development of numerous tumors. The lack of a comprehensive understanding of Sulf-2 enzymatic activities has limited the advancement of research progress, largely due to the intricate modulation of heparan sulfate (HS) biology by this enzyme. In this review, we will comprehensively discuss the structure, function, and regulatory mechanisms of Sulf-2, elucidated the mechanisms of Sulf-2 in different human-type tumors. Furthermore, we would summarize the potential applications and limitations of Sulf-2 as a target in combining therapies for human tumors, providing insights that could be instrumental in advancing targeted cancer treatments. Our comprehensive review will shed light on the multifaceted role and therapeutic potential of Sulf-2 in human tumor biology.

Keywords:  Sulf-2; enzymatic activities; heparan sulfate (HS); human tumor; multifaceted roles; therapeutic target

DOI:  https://doi.org/10.1080/17520363.2025.2521254
Mar Drugs. 2025 May 27. pii: 228. [Epub ahead of print]23(6):

Chondroitin Sulfate as a Lysosomal Enhancer Attenuates Lipid-Driven Inflammation via Lipophagy and Mitophagy.

Ting Sun, Huimin Lv, Huarong Shao, Xiuhua Zhang, Anqi Wang, Wei Zhang, Fei Liu, Peixue Ling.

  Non-alcoholic steatohepatitis (NASH), a progressive liver disease characterized by lipid accumulation and chronic inflammation, lacks effective therapies targeting its multifactorial pathogenesis. This study investigates marine-derived chondroitin sulfate (CS) as a multi-organelle modulator capable of regulating lipid metabolism, oxidative stress, and inflammation in NASH. By employing subcellular imaging and organelle-specific labeling techniques, we demonstrate that CS restores lysosomal acidification in a NASH model, enabling the reduction of lipid droplets via lysosomal-lipid droplet fusion. Concurrently, CS upregulates dynamin-related protein 1 (DRP1), driving mitochondrial terminal fission to spatially isolate reactive oxygen species (ROS) segments for mitophagy, thereby reducing ROS levels. Notably, pharmacological inhibition of lysosomal activity using chloroquine or bafilomycin A1 abolished the therapeutic effects of CS, confirming lysosomal acidification as an essential prerequisite. Collectively, these findings reveal the potential of CS as a therapeutic agent for NASH and provide critical insights into the subcellular mechanisms underlying its protective effects, thus offering a foundation for future research and therapeutic development.

Keywords:  chondroitin sulfate; lipid metabolism; lysosomal acidification; mitochondrial autophagy; non-alcoholic steatohepatitis; subcellular regulation

DOI:  https://doi.org/10.3390/md23060228
Biochem Biophys Res Commun. 2025 Jun 18. pii: S0006-291X(25)00930-1. [Epub ahead of print]777 152215

Coelenterazine sulfotransferase from the luminous squid Watasenia scintillans.

Nowshin Farjana, Yasuo Mitani, Souichiro Kato, Shusei Kanie.

  The squid Watasenia scintillans is a luminous marine organism that utilizes coelenterazine 2,6-disulfate (CTZ 2,6-SO3H) as its luminous substrate. CTZ 2,6-SO3H, a derivative of coelenterazine (CTZ), can be chemically synthesized by sulfating CTZ at its two phenolic hydroxyl groups. CTZ is produced by certain marine plankton and is widely distributed among marine organisms through the food web. However, CTZ 2,6-SO3H has been identified only in W. scintillans, and it remains unclear whether the squid biosynthesizes CTZ 2,6-SO3H from CTZ. In this study, we investigated the presence of a sulfotransferase (SULT) responsible for the sulfation of CTZ in W. scintillans. RNA-seq analysis of the squid's arm photophore revealed a putative SULT gene, which was successfully expressed in Escherichia coli. The recombinant protein exhibited sulfation activity toward CTZ in the presence of 3'-phosphoadenosine 5'-phosphosulfate (PAPS), as confirmed by ultra-performance liquid chromatography-photodiode array detection-mass spectrometry (UPLC-PDA-MS) analysis. The sulfated product was not CTZ 2,6-SO3H but rather CTZ 2-monosulfate (CTZ 2-SO3H). These findings suggest that W. scintillans possesses a biosynthetic pathway for CTZ 2,6-SO3H from CTZ, which may involve additional SULT(s).

Keywords:  Coelenterazine; Firefly squid; Luminous organism; Sulfation; Sulfotransferase

DOI:  https://doi.org/10.1016/j.bbrc.2025.152215
Front Cell Infect Microbiol. 2025 ;15 1613923

Pathogens that infect mammalian cells via sulfonated glycosaminoglycans.

Jessica S Morris, Paul A Dawson.

  Sulfonated glycosaminoglycans, such as heparan sulfate and dermatan sulfate, form major components of the cell surface and extracellular matrix, and display vital roles in mammalian physiology, including growth and development. The identification of specific binding to different glycosaminoglycans by a variety of pathogens has led to increased interest in this mechanism for understanding infection. Over the past four decades there have been more than 300 studies on various pathogens that utilize glycosaminoglycans in their infection process. Currently, no articles have collated all known pathogens that use this process. So it is timely that this article provides an overview of all known pathogens that use glycosaminoglycans to enhance their binding and/or infection in human cells. This was done by using the search terms "sulfate/sulphate" "pathogen", "virus", "bacteria", "parasite", "infection" and "glycosaminoglycans" to curate peer-reviewed and relevant original research articles from PubMed. This search found that glycosaminoglycans are used in the infection process for 59 viruses, 28 bacteria, and 8 other pathogens (i.e. parasitic protozoa, prions). These findings highlight the conserved and widespread use of glycosaminoglycans for enhancing pathogen infection. In addition, the curated list of pathogens in this study provides a resource for future studies to consider potential therapeutic approaches for targeted disruption of the interaction between pathogens and glycosaminoglycans.

Keywords:  bacteria; glycosaminoglycan; infection; parasite; proteoglycan; sulfate; virus

DOI:  https://doi.org/10.3389/fcimb.2025.1613923
Toxins (Basel). 2025 Jun 05. pii: 283. [Epub ahead of print]17(6):

Serum Indoxyl Sulfate as a Potential Biomarker of Peripheral Arterial Stiffness in Patients with Non-Dialysis Chronic Kidney Disease Stages 3 to 5.

Yahn-Bor Chern, Jen-Pi Tsai, Chin-Hung Liu, Yu-Li Lin, Chih-Hsien Wang, Bang-Gee Hsu.

  Indoxyl sulfate (IS), which is a protein-bound uremic toxin, is involved in vascular dysfunction and cardiovascular risk in subjects with chronic kidney disease (CKD). However, its role in peripheral arterial stiffness (PAS) remains unclear. This cross-sectional study evaluated the relationship between IS and PAS in patients diagnosed with CKD stages 3 through 5 who are not undergoing dialysis. Patients with CKD from a single center were enrolled. High-performance liquid chromatography analyzed the serum IS levels. PAS was evaluated using brachial-ankle pulse wave velocity (baPWV). IS was independently associated with PAS (odds ratio [OR]: 1.389 for 1 μg/mL increase in IS, 95% confidence interval [CI]: 1.086-1.775, p = 0.009) in a multivariable analysis after adjustment for age, hypertension, diabetes mellitus, blood pressure, lipid profiles, renal function, albumin, and proteinuria. Moreover, the mean baPWV (p = 0.010), left baPWV (p = 0.009), and right baPWV (p = 0.015) levels significantly correlated with the log-transformed IS (log-IS) levels. The area under the receiver operating characteristic curve for serum IS as a predictor of PAS was determined to be 0.667 (95% CI: 0.580-0.754; p = 0.0002). IS was associated with PAS in non-dialysis CKD stages 3-5, suggesting that IS may be a possible vascular risk marker. Future studies should address the nature of the relationship between IS and vascular dysfunction and assess therapeutic strategies to reduce IS.

Keywords:  brachial–ankle pulse wave velocity; cardiovascular risk; chronic kidney disease; indoxyl sulfate; peripheral arterial stiffness

DOI:  https://doi.org/10.3390/toxins17060283
Otol Neurotol. 2025 Jun 12.

Serum Testosterone and Dehydroepiandrosterone Sulfate Levels and Hearing Loss in Older Males: The Hitachi Health Study II.

Aoi Ito, Shohei Yamamoto, Yosuke Inoue, Ami Fukunaga, Maki Konishi, Katsuyuki Ohara, Shuichiro Yamamoto, Tohru Nakagawa, Tetsuya Mizoue.

   OBJECTIVE: This study aimed to examine the association of serum testosterone and dehydroepiandrosterone sulfate levels with hearing loss in older males.
STUDY DESIGN: Cross-sectional study.
SETTING: A health care center.
PATIENTS: This study included 1,421 males aged 60 to 69 yrs who participated in the baseline survey of the Hitachi Health Study II.
EXPOSURES: Serum testosterone and DHEAS levels were measured using chemiluminescence and chemiluminescent enzyme immunoassays, respectively.
MAIN OUTCOME MEASURES: Pure-tone audiometric testing was performed to identify hearing loss at 1 and 4 kHz.
RESULTS: Higher serum testosterone levels were associated with lower odds of hearing loss at 4 kHz. The OR (95% CI) of hearing loss was 0.71 (0.50, 0.999) for the highest compared with that for the lowest quartile of serum testosterone. A dose-response association was also found between serum testosterone levels and hearing loss at 4 kHz (P for linearity = 0.01). No association was found between serum testosterone levels and hearing loss at 1 kHz (OR for the highest vs lowest quartiles of serum testosterone = 1.06). Serum dehydroepiandrosterone sulfate levels were not associated with hearing loss: the ORs (95% CI) for the highest compared with that for the lowest quartile were 1.01 (0.64, 1.61) and 0.81 (0.58, 1.14) for 1 and 4 kHz, respectively.
CONCLUSION: Our findings suggest that older males with higher serum testosterone levels were less likely to have high-frequency hearing loss.

Keywords:  Dehydroepiandrosterone sulfate; Hearing loss; Older male; Testosterone

DOI:  https://doi.org/10.1097/MAO.0000000000004577
Cardiovasc Res. 2025 Jun 17. pii: cvaf106. [Epub ahead of print]

The role of uremic toxin indoxyl sulfate in the pathophysiology of aortic valve stenosis.

Philip Düsing, Isabel Göbel, Ansgar Ackerschott, Laurine Reese, Patrick Giavalisco, Frederik Dethloff, Sven Thomas Niepmann, Marta Stei, Thomas Beiert, Sebastian Zimmer, Christian Kurts, Georg Nickenig, Felix Jansen, Andreas Zietzer.

   AIMS: Chronic kidney disease (CKD) is closely associated with cardiovascular disease (CVD). This includes aortic valve stenosis (AS), one of the most common valve diseases among adults. CKD leads to the retention of uremic toxins such as indoxyl sulfate (IS), which is known to induce inflammatory and pro-calcific processes. We hypothesise that IS specifically induces AS formation.
METHODS AND RESULTS: Stimulation of human valvular interstitial cells (VICs) with IS in addition to phosphate led to increased calcification. RNA sequencing identified naked cuticle homolog 2 (NKD2) as an upregulated gene in VICs under uremic conditions. Knockdown of NKD2 reduced calcification of VICs and upregulation of IL-6. The organic anion transporting polypeptide 3A1 (OAT3A1) was identified to mediate IS uptake as well as upregulation of NKD2 and IL-6. We identified NF-κB signalling to be involved in IS-induced IL-6 upregulation. In vivo, we investigated combined models of adenine-induced kidney injury or oral IS supplementation with wire injury-induced AS in C57BL/6J mice. Echocardiography showed aggravated AS in uremic mice compared to control mice after wire injury. Explanted valves from uremic mice with AS exhibited a significant increase in macrophage infiltration, fibrotic areas and valvular NKD2 expression compared to controls. IS-treated mice showed aggravated AS compared to control mice. This was accompanied by more prominent valve fibrosis, macrophage infiltration, and NKD2 expression in explanted valves of IS-treated mice. In the blood and bone marrow, IS treatment led to the differentiation of monocytes into intermediate and non-classical monocytes. This was paralleled by IS-induced monocyte adhesion to valvular endothelial cells in vitro.
CONCLUSION: Uremic conditions aggravate AS development in mice by inducing valvular fibrosis and macrophage infiltration. Indoxyl sulfate is involved in this process and stimulates monocyte differentiation and adhesion to the valvular endothelium. On a cellular level, we hypothesize that IS-mediated NKD2 induction leads to a calcifying and inflammatory response in VICs.

Keywords:  Chronic kidney disease; aortic valve stenosis; cardiorenal syndrome; indoxyl sulfate; uremia; uremic toxins

DOI:  https://doi.org/10.1093/cvr/cvaf106
ACS Biomater Sci Eng. 2025 Jun 25.

Engineering Heparan Sulfate-Guided Peptide Self-Assembly to Restore Endothelial Angiogenesis under Hyperglycemia.

Longzhen Chen, Zhuofeng Li, Ziyi Su, Yuqi Luo, Xunwu Hu, Ye Zhang.

  Hyperglycemia-induced endothelial dysfunction impairs cytoskeletal plasticity, cell migration, and angiogenesis, contributing to the pathogenesis of diabetic vascular complications. To address this, we engineered a heparan sulfate (HS)-targeting peptide that couples a glycan-binding motif with a self-assembling domain, enabling localized formation of supramolecular nanostructures at the endothelial surface. These assemblies attenuate actomyosin contractility by remodeling cell-matrix interactions, thereby restoring contractile homeostasis, the dynamic equilibrium of intracellular tension and cytoskeletal adaptability, without compromising global cytoskeletal integrity. In vitro, the peptide reverses hyperglycemia-induced cytoskeletal stiffening, enhances endothelial motility, and rescues network formation in Matrigel tube formation assays, without inducing cytotoxicity. Through plasma membrane surface-selective self-assembly, this HS-guided platform offers a localized, biomimetic strategy for correcting mechanical dysfunction in diabetic endothelium and holds translational potential for vascular repair in metabolic diseases.

Keywords:  cytoskeletal contractility; endothelial angiogenesis; heparan sulfate; hyperglycemia; peptide self-assembly

DOI:  https://doi.org/10.1021/acsbiomaterials.5c00802
J Biol Chem. 2025 Jun 23. pii: S0021-9258(25)02252-5. [Epub ahead of print] 110402

Arylsulfatase B Induces Melanoma Apoptosis by the Ubiquitin Ligase COP1.

Sumit Bhattacharyya, Insug O-Sullivan, Herbert E Whiteley, Jiyuan Yang, Fuming Zhang, Joanne K Tobacman.

  Previous experiments in the syngeneic, murine, subcutaneous model of malignant melanoma and in human melanoma cells showed that treatment by recombinant human (rh) Arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) markedly reduced the volume of tumors, improved survival, and inhibited invasiveness. In this report, the impact of ARSB on the progression of metastatic, pulmonary B16F10 melanomas in C57BL/6J mice is addressed and the underlying, apoptotic mechanism by which ARSB inhibits melanoma growth is identified. Exogenous ARSB, which has mannose 6-phosphate attachments, acts through insulin-like growth factor 2 receptor (IGF2R), a cation-independent mannose-6-phosphate receptor, and increases expression of constitutive photomorphogenic protein (COP)1. Expression of COP1, an E3 ubiquitin ligase, is increased by decline in phospho(Ser473)-AKT1 and increase in nuclear FOXO3a. ARSB-induced declines in carbohydrate sulfotransferase (CHST)15 expression and in transmembrane receptor tyrosine kinase-like orphan receptor 1 (ROR1) activation mediate the decline in phospho(Ser473)-AKT1. Inverse effects of rhARSB and ARSB knockdown on phospho(Ser473)-AKT1 indicate that ARSB acts as a tumor suppressor and that decline in ARSB is pro-oncogenic. COP1, which inhibits ultraviolet-B stimulated growth in plants, suppresses nuclear ETS1 and ETS1-mediated expression of BCL2 in the murine melanomas and in human melanoma cells. These effects increase cytoplasmic cytochrome c, caspase-3/7 activation, and apoptosis. Since UVB exposure is recognized as a significant etiological factor in melanoma, identification of COP1 as an inhibitor of melanoma growth suggests the underlying presence of an ARSB-initiated growth inhibitory mechanism, analogous to that in plants, which contributes to regulation of melanoma progression.

Keywords:  Melanoma; N-acetylgalactosamine-4-sulfatase; chondroitin sulfate; sulfotransferase

DOI:  https://doi.org/10.1016/j.jbc.2025.110402
Kidney Int. 2025 Jun 25. pii: S0085-2538(25)00492-2. [Epub ahead of print]

Medium chain fatty acids are potent binding competitors to improve protein-bound uremic toxin clearance during hemodialysis.

Laure-Anne Raillon, Nans Florens, Florine Payelle, Marie Martin, Laurent Soulère, Dan Yi, Zoé Simon-Onfroy, Stéphane Chambert, Marie Legras, Laurence Chardon, Griet Glorieux, Fitsum Guebre-Egziabher, Christophe O Soulage.

   INTRODUCTION: Protein-bound uremic toxins (PBUTs) remain a concerning burden in patients with kidney failure since their removal during hemodialysis is limited due to their tight binding to albumin. Here, we test whether medium chain fatty acids (MCFAs), potent ligands of human serum albumin (HSA), could be used as binding competitors of PBUTs to increase their removal during a hemodialysis session.
METHODS: A simulated hemodialysis session was performed using bovine blood spiked with PBUTs in the presence of various MCFAs. Blood was sampled serially to measure the concentrations of PBUTs indoxyl sulfate (IS) and p-cresyl sulfate (p-CS).
RESULTS: The binding of MCFAs to HSA was investigated in silico and using fluorescent probe displacement. The free fraction of IS and p-CS were measured after ultrafiltration of HSA solutions and uremic plasma in the presence of MCFAs (0.25-3 mmol/L). Among the five MCFAs tested, octanoate and decanoate were the most prone to interact with HSA Sudlow site II, one of two main binding sites on HSA. The in vitro incubation of HSA solutions and uremic plasma with MCFAs increased the free fraction of IS and p-CS. The per-dialytic infusion of octanoate significantly improved the fractional removal of p-CS from 38% to 88% and IS from 36% to 91%.
CONCLUSIONS: MCFAs can effectively compete with PBUTs for binding to HSA. The per-dialytic administration of octanoate, which strikingly increased the removal of PBUTs, could constitute an efficient and cost-effective strategy to improve the possible clearance of these compounds and prevent their accumulation in patients with kidney failure.

Keywords:  hemodialysis; medium chain fatty acids; protein bound uremic toxins; uremic toxins

DOI:  https://doi.org/10.1016/j.kint.2025.06.004
Cancers (Basel). 2025 Jun 12. pii: 1959. [Epub ahead of print]17(12):

Steroid Sulfatase Regulates Metabolic Reprogramming in Advanced Prostate Cancer.

Masuda Sharifi, Cameron M Armstrong, Shu Ning, Amy R Leslie, Zachary A Schaaf, James P Maine, Wei Lou, Pui-Kai Li, Hongyu Xu, Chengfei Liu, Allen C Gao.

   BACKGROUND/OBJECTIVE: The expression of human steroid sulfatase (STS) is upregulated in castration-resistant prostate cancer (CRPC) and is associated with resistance to anti-androgen drugs, such as enzalutamide (Enza) and abiraterone (Abi). Despite the known link between STS overexpression and therapeutic unresponsiveness, the mechanism by which STS confers this phenotype remains incompletely understood. In this study, we sought to understand how STS induces treatment resistance in advanced prostate cancer (PCa) cells by exploring its role in altering mitochondrial activity.
METHODS: To examine the effects of increased STS expression on mitochondrial respiration and programming, we performed RNA sequencing (RNA-seq) analysis, the Seahorse XF Mito Stress Test, and a mitochondrial Complex I enzyme activity assay in STS-overexpressing cells (C4-2B STS) and in enzalutamide-resistant CPRC cells (C4-2B MDVR). We employed SI-2, the specific chemical inhibitor of STS, on C4-2B STS and C4-2B MDVR cells and evaluated STS activity inhibition on mitochondrial molecular pathways and mitochondrial respiration. Lastly, we examined the effects of dehydroepiandrosterone sulfate (DHEAS) supplementation on C4-2B STS organoids.
RESULTS: We present evidence from the transcriptomic profiling of C4-2B STS cells that there are enriched metabolic pathway signatures involved in oxidative phosphorylation, the electron transport chain, and mitochondrial organization. Moreover, upon STS inhibition, signaling in the electron transport chain and mitochondrial organization pathways is markedly attenuated. Findings from the Seahorse XF Mito Stress Test and mitochondrial Complex I enzyme activity assay demonstrate that STS overexpression increases mitochondrial respiration, whereas the inhibition of STS by SI-2 significantly reduces the oxygen consumption rate (OCR) and Complex I enzyme activity in C4-2B STS cells. Similarly, an increased OCR and electron transport chain Complex I enzymatic activity are observed in C4-2B MDVR cells and a decreased OCR upon SI-2 inhibition. Lastly, we show that STS overexpression promotes organoid growth upon DHEAS treatment.
CONCLUSIONS: Our study demonstrates STS as a key driver of metabolic reprogramming and flexibility in advanced prostate cancer. Disrupting enhanced mitochondrial respiration via STS presents a promising strategy in improving CRPC treatment.

Keywords:  metabolic reprogramming; prostate cancer; steroid sulfatase; therapeutic resistance

DOI:  https://doi.org/10.3390/cancers17121959
ACS Omega. 2025 Jun 17. 10(23): 24018-24029

Klotho Suppresses Indoxyl Sulfate-Mediated Apoptosis in Human Kidney Proximal Tubular (HK-2) Cells through Modulating the AKT/Nrf2 Mechanism.

Chien-Yao Sun, Yao-Tsung Lin, Yu-Ting Huang, Hui-Ching Cheng, Wan-Ching Chou, Yu-Tzu Chang, Tsai-Chieh Ling, Pei-Ling Hsieh, Kun-Ling Tsai.

Chronic kidney disease (CKD) is a progressive condition with substantial prevalence worldwide. The uremic toxin indoxyl sulfate (IS) is known to induce tubulotoxicity and adverse effects in various organs. It has been shown that the expression of the antiaging klotho protein is downregulated in the IS-stimulated proximal tubule cells and kidneys, but the detailed mechanism underlying the implication of reduced klotho in nephropathy remains largely unclear. In the present study, we demonstrated that the repressed klotho following IS stimulation contributed to the reduced cell viability and increased cytotoxicity of HK-2 cells (a proximal tubular cell line). We showed that recombinant klotho reversed the AKT/Nrf2 axis in the IS-treated HK-2 cells, leading to the restoration of the antioxidant HO-1, NQO1, and SOD as well as diminished ROS production. Most importantly, our results suggested that the IS-induced alteration of mitochondrial membrane potential, mitochondrial COX-III mRNA expression, and mitochondrial complex III activity was all mediated by the klotho/AKT/Nrf2 axis. By examining the expression of Bax, Bcl-2, and cytochrome c using Western blot and caspase-3-positive cells using flow cytometry, we demonstrated that klotho participated in the IS-induced apoptosis of HK-2 cells as well. Taken together, our data revealed that downregulation of klotho in the IS-stimulated HK-2 cells leads to decreased cell viability as a result of lower antioxidant capacity and ROS accumulation following mitochondrial respiratory chain dysfunction and subsequent apoptosis, possibly through inhibition of the AKT/Nrf2 axis.

DOI: https://doi.org/10.1021/acsomega.4c08038