bims-supasi 2025-01-12 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2025–01–12
fourteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Oligosaccharide-assisted resolution of holothurian fucosylated chondroitin sulfate for fine structure and P-selectin inhibition.
New insights on health benefits, interactions with food components and potential application of marine-derived sulfated polysaccharides: A review.
Chondroitin Sulfate and Proteinoids in Neuron Models.
CHONDROITIN SULFATE AND GLUCOSAMINE SULFATE AS PROTECTIVE AND ANTI-INFLAMMATORY AGENTS IN THE ULCERATIVE COLITIS DSS MODEL IN RATS.
Enhanced expression of Cyp17a1 and production of DHEA-S in the liver of late-pregnant rats.
Characterization of heparin interactions with Clostridioides difficile toxins and its potential as anti-CDI therapeutics.
Indoxyl Sulfate and Its Potential Role in Mineralocorticoid Receptor Transactivation in Chronic Kidney Disease.
Maintaining the Cartilage Phenotype of Late-Passage Chondrocytes Using Salidroside, TGF-β, and Sulfated Alginate for Cartilage Tissue Engineering Applications.
Steroid sulfatase suppresses keratinization by inducing proteasomal degradation of E-cadherin via Hakai regulation.
Analysis of Levels of Vitamin D, Beta-Amyloid 42, Indoxyl Sulfate, and Serum Parathyroid Hormone in Hemodialysis Patients with Cognitive Impairment.
Anti-Dyslipidemic Potential of Sulfated Glycosaminoglycan from Rock Oyster Saccostrea cucullata: An in vivo study.
Effects of DHEA and DHEAS in Neonatal Hypoxic-Ischemic Brain Injury.
Sequential Targeting Chondroitin Sulfate-Bilirubin Nanomedicine Attenuates Osteoarthritis via Reprogramming Lipid Metabolism in M1 Macrophages.
Structure/function of ATP sulfurylase domain of human 3'-phosphoadenosine 5'-phosphosulfate synthase (hPAPSS).

Carbohydr Polym. 2025 Mar 01. pii: S0144-8617(24)01371-7. [Epub ahead of print]351 123145

Oligosaccharide-assisted resolution of holothurian fucosylated chondroitin sulfate for fine structure and P-selectin inhibition.

Ying Pan, Huifang Sun, Xi Gu, Sujuan Li, Shengtao Yang, Liang Zhang, Hui Mao, Pin Wang, Shasha Yang, Ronghua Yin, Zhili Zuo, Jinhua Zhao.

  Fucosylated chondroitin sulfate (FCS) from Holothuria mexicana (FCSHm) was selected for investigation because of its intriguing branch features. Selective β-eliminative depolymerization and the bottom-up assembly were performed to unravel that FCSHm consisted of a {D-GlcA-β1,3-D-GalNAc4S6S} backbone and branches of alternating FucS (55 %) and D-GalNAcS-α1,2-L-FucS (45 %), the highest proportion of disaccharide branch reported to date. In branches, sulfation could occur at every free -OH site except O-3 of GalNAc, being the most complex and various structure features of natural FCS. Detailed structure-activity relationship analyses showed that FCSHm and its depolymerized products (>8 kDa) effectively competed with SLeX and PSGL-1 to bind with P-sel at nano-molar level and the inhibition potency increased with Mw increasing. For the structural trisaccharide unit, di-O-sulfation of the FucS (Fuc2S4S and Fuc3S4S) was almost 10-fold more potent than mono-O-sulfation (Fuc4S). Unexpectedly, higher sulfation of the disaccharide-branched tetrasaccharide unit reduced inhibition. The reversal may attribute to fewer interactions with P-sel by molecular docking study. These results suggested that the specific configuration underpinned the potent inhibition, whereas the size and sulfate number of branches were not the key factors for the specific binding. dHmF4 (8.0 kDa) potently blocked the platelet-leukocyte aggregates formation, further verifying the potential value in use.

Keywords:  Chemical depolymerization; Fucosylated chondroitin sulfate; Holothuria mexicana; Oligosaccharide; P-selectin inhibition

DOI:  https://doi.org/10.1016/j.carbpol.2024.123145
Int J Biol Macromol. 2025 Jan 04. pii: S0141-8130(25)00065-0. [Epub ahead of print]294 139516

New insights on health benefits, interactions with food components and potential application of marine-derived sulfated polysaccharides: A review.

Xiquan Li, Ao Shen, Miaorong Xiao, Shuzhen Li, Weiwei Yang.

  Sulfated polysaccharides refer to polysaccharides containing sulfate groups on sugar units. In nature, sulfated polysaccharides are widely distributed in marine organisms, and the variation in sulfation sites, monosaccharide composition, and branched chain distribution among different species results in differences in the physicochemical properties and biological activities. From the latest perspective, this review summarized the types, structural characteristics, and potential health benefits of sulfated polysaccharides in marine foods. In recent years, marine-derived sulfated polysaccharides have been widely used as stabilizers and antimicrobial agents applied in nutraceutical delivery systems and food packaging, which depend on their interactions with food components. Hence, we outlined the non-covalent/covalent interactions of marine-derived sulfated polysaccharides with food components (e.g., proteins, polysaccharides, and polyphenols) as well as the application in food industry. Additionally, the prospects and potential development for sulfated polysaccharides are concluded, aiming to provide a deep understanding of marine-derived sulfated polysaccharides to promote the industrial application in food health.

Keywords:  Application; Bioactivity; Blue food; Marine sulfated polysaccharides

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.139516
ACS Appl Bio Mater. 2025 Jan 08.

Chondroitin Sulfate and Proteinoids in Neuron Models.

Panagiotis Mougkogiannis, Andrew Adamatzky.

  This study examines the relationship between chondroitin sulfate, proteinoids, and computational neuron models, with a specific emphasis on the Izhikevich neuron model. We investigate the effect of chondroitin sulfate-proteinoid complexes on the behavior and dynamics of simulated neurons. Through the use of computational simulations, we provide evidence that these biomolecular components have the power to regulate the responsiveness of neurons, the patterns of their firing, and the ability of their synapses to change within the Izhikevich architecture. The findings suggest that the interactions between chondroitin sulfate and proteinoid cause notable alterations in the dynamics of membrane potential and the timing of spikes. We detect adjustments in the features of neuronal responses, such as shifts in the thresholds for firing, alterations in spike frequency adaptation, and changes to bursting patterns. The findings indicate that chondroitin sulfate and proteinoids may have a role in precisely adjusting neuronal information processing and network behavior. This study offers valuable information about the complex connection between the many components of the extracellular matrix, protein-based structures, and the functioning of neurons. In addition, our analysis of the proteinoid-chondroitine system using game theory uncovers a significant Prisoner's Dilemma scenario. The system's inclination toward defection, due to the appeal of cheating and the significant penalty for cooperation, with a mean voltage of -9.19 mV, indicates that defective behaviors may prevail in the long term dynamics of these neuronal interactions.

Keywords:  Izhikevich neuron model; chondroitin sulfate; computational neuroscience; extracellular matrix; neuronal dynamics; proteinoids; synaptic plasticity; the Prisoner’s dilemma

DOI:  https://doi.org/10.1021/acsabm.4c01678
Arq Gastroenterol. 2024 ;pii: S0004-28032024000100611. [Epub ahead of print]61 e24079

CHONDROITIN SULFATE AND GLUCOSAMINE SULFATE AS PROTECTIVE AND ANTI-INFLAMMATORY AGENTS IN THE ULCERATIVE COLITIS DSS MODEL IN RATS.

Luiz Gustavo de Oliveira, Arthur Girardi Carpanez, João Victor Gerheim da Silva, Maria Christina Marques Nogueira Castañon, Julio Maria Fonseca Chebli, Jair Adriano Kopke de Aguiar.

Chondroitin sulfate (CS) and glucosamine (GlcN) are indicated for the treatment of some inflammatory diseases, such as osteoarthritis, mainly because of the anti-inflammatory effects in reducing metalloproteinases activities (MMP), and other inflammatory mediators. Herein, we reported the structure of the CS, the anti-inflammatory and protective effects of the CS, and GlcN administration in ulcerative colitis model induced by dextran sulfate sodium (DSS) in rats. Experimental data indicated that CS disaccharide composition is very similar to the C4S standard, with modal molecular weight at 30.4 kDa. Orally administration of the CS/GlcN improved the severity of acute colitis with reduction the histological score and goblet cells destruction. We also observed a decreasing in NO production, myeloperoxidase and MMP, especially MMP-9, activities. Moreover, CS/GlcN not cytotoxic in the intestinal epithelial cells. These results indicate that combination CS/GlcN showed improvements in intestinal inflammation and protection intestinal barrier, suggesting CS/GlcN might have beneficial effects in treatment of IBD.

DOI: https://doi.org/10.1590/S0004-2803.24612024-079
Gen Comp Endocrinol. 2025 Jan 04. pii: S0016-6480(25)00001-2. [Epub ahead of print]362 114661

Enhanced expression of Cyp17a1 and production of DHEA-S in the liver of late-pregnant rats.

Yuya Ohtsuki, Jumpei Fujiki, Naoyuki Maeda, Hidetomo Iwano.

  Cytochrome P450 17A1 (CYP17A1) catalyzes two enzymatic reactions in the biosynthesis of dehydroepiandrosterone (DHEA) from pregnenolone. In pregnant humans, the adrenal gland is responsible for DHEA biosynthesis, which is then sulfated by SULT2A1 and released into the bloodstream. This sulfated DHEA is subsequently taken up by the placenta and deconjugated to serve as a precursor for estrogen biosynthesis. The expression of Cyp17a1 is regulated by methylation, typically showing marked interspecies differences, including repression of Cyp17a1 expression in the adrenal gland of rodents. This study focused on the liver, an extragonadal steroidogenic organ showing active sulfate conjugation, as a site for DHEA-sulfate (DHEA-S) biosynthesis during pregnancy in rodents, rather than the adrenal glands. Cyp17a1 expression in rat liver was significantly lower than in the testis, with no differences between sexes. However, Cyp17a1 expression increased significantly before parturition (gestational days [GD] 19-21) compared to late pregnancy (GD 15-18). The Sult2a family were expressed in the livers of both pregnant and non-pregnant rats. We also observed increased DHEA and DHEA-S levels in the liver of pregnant rats before parturition compared to non-pregnant rats, with DHEA-S concentrations being significantly higher at GD 19-21 than at days 15-18. These findings suggest that increased expression of Cyp17a1 in the last trimester enhances DHEA synthesis in the liver, and that DHEA is quickly conjugated by Sult2a. In rodents, the liver may be involved in DHEA-S biosynthesis before parturition, compensating for the repression of Cyp17a1 in the adrenal glands.

Keywords:  Fetoplacental unit; Multi-drug resistance protein; Parturition; Reproduction; Steroid sulfatase; Steroidogenesis; Sulfate-sulfatase pathway

DOI:  https://doi.org/10.1016/j.ygcen.2025.114661
Carbohydr Polym. 2025 Mar 01. pii: S0144-8617(24)01369-9. [Epub ahead of print]351 123143

Characterization of heparin interactions with Clostridioides difficile toxins and its potential as anti-CDI therapeutics.

Fuming Zhang, Shaohui Wang, Jiyuan Yang, Keith Fraser, James M Gibson, Chunyu Wang, Jonathan S Dordick, Anastasia Tomatsidou, Robert J Linhardt, Lianchun Wang, Xingmin Sun.

  Clostridioides difficile (C. difficile) infection (CDI) is a life-threatening healthcare-associated infection occurring worldwide. C. difficile toxins (toxin A and toxin B) are the major virulence factors, causing CDI-related diarrhea and complications. Recent studies have shown that sulfated glycosaminoglcans (GAGs) are involved in mediating the cellular entry of these toxins. Although interactions between GAGs and toxins were reported, their binding kinetics and the structure features of glycans that facilitate toxin interaction have not been thoroughly studied. This research utilized surface plasmon resonance (SPR) to directly measure the kinetics of interactions between heparin and various toxins. Both toxin A and toxin B bind to heparin with high affinity (KD = 3.3 nM and 13.5 nM, respectively). SPR competition assay showed that both toxin A and B prefer binding to longer heparin chains and that all sulfation on the heparin chain is crucial for the heparin-toxin interaction. Finally, an in vitro assay showed that heparin and non-anticoagulant heparin inhibit the cell rounding caused by toxin A in HeLa cells.

Keywords:  Clostridioides difficile toxin; Glycosaminoglycan; Heparin; Surface plasmon resonance

DOI:  https://doi.org/10.1016/j.carbpol.2024.123143
Cureus. 2024 Dec;16(12): e75236

Indoxyl Sulfate and Its Potential Role in Mineralocorticoid Receptor Transactivation in Chronic Kidney Disease.

Akiko Kudo, Akihiro Fukuda, Koro Gotoh, Hirotaka Shibata.

   BACKGROUND: The uremic toxin indoxyl sulfate (IS) is an important factor in chronic kidney disease (CKD) progression. Inhibitors of the renin-angiotensin system and add-on therapy with mineralocorticoid receptor (MR) antagonists can help reduce proteinuria and suppress CKD progression. However, the association between IS and MR activation remains unknown.
MATERIALS AND METHODS: In vivo experiments utilized the 5/6 nephrectomy model to assess mineralocorticoid receptor (MR) activation in chronic kidney disease (CKD). The clinical parameters and immunohistochemical analysis of IS and MR proteins were investigated. In vitro experiments involved transfecting COS-7 cells with MR expression plasmids and MR response element-luciferase reporter plasmids. The cells were then treated with aldosterone (10⁻¹⁰ mol/L), indoxyl sulfate (IS, 500 μmol/L), and α-lipoic acid (10⁻³ mol/L). MR transcriptional activity was investigated by luciferase assays, and protein levels were measured by Western blotting.
RESULTS: In the 5/6 nephrectomy model, the serum IS concentration was significantly increased; however, the plasma aldosterone levels were decreased. Immunohistochemistry showed that the expression of IS protein increased in injured tubular cells in the 5/6 nephrectomy group compared with that in the sham group. Furthermore, evaluations of serial kidney sections revealed that the expression site of IS protein was colocalized with the distal nephron, where the expression of MR protein was observed. MR-mediated transcriptional activity in COS-7 cells was increased in an aldosterone concentration-dependent manner. IS increased MR-mediated transcriptional activity and protein levels with and without aldosterone, and α-lipoic acid attenuated this increase.
CONCLUSIONS: IS could enhance MR transactivation by increasing MR protein levels through oxidative stress in CKD rats, indicating that treatment with MR antagonists and antioxidants may play a permissive role in inhibiting IS-induced CKD progression.

Keywords:  aldosterone; chronic kidney disease (ckd); indoxyl sulfate; mineralocorticoid receptor; uremic toxins

DOI:  https://doi.org/10.7759/cureus.75236
Int J Mol Sci. 2024 Dec 19. pii: 13623. [Epub ahead of print]25(24):

Maintaining the Cartilage Phenotype of Late-Passage Chondrocytes Using Salidroside, TGF-β, and Sulfated Alginate for Cartilage Tissue Engineering Applications.

Rita G Diab, George Deeb, Rena Roda, Mia Karam, Marwa Faraj, Mohamad Harajli, Laila A Damiati, Rami Mhanna.

  The limited self-repair capacity of cartilage due to its avascular and aneural nature leads to minimal regenerative ability. Autologous chondrocyte transplantation (ACT) is a popular treatment for cartilage defects but faces challenges due to chondrocyte dedifferentiation in later passages, which results in undesirable fibroblastic phenotypes. A promising treatment for cartilage injuries and diseases involves tissue engineering using cells (e.g., chondrocytes), scaffolds (e.g., Alginate Sulfate (AlgSulf)), and biochemical signals (e.g., Salidroside and TGF-β). This study focuses on investigating the effects of AlgSulf scaffolds with varying degrees of sulfation, Salidroside, and TGF-β on the proliferation, viability, and phenotype maintenance of chondrocytes. The findings demonstrate that AlgSulf films with a degree of sulfation (DS) = 2, treated with a combination of Salidroside and TGF-β, significantly enhanced chondrocyte proliferation (p < 0.001 and p < 0.0001 in P2 and P4, respectively), preserved round cell morphology, and maintained cartilage-specific gene expression (Col2, Aggrecans, and SOX9) while downregulating fibroblastic markers (Col1, MMP13, IL-1β, and IL-6). Our findings suggest the potential of this combination for enhancing cartilage regeneration in tissue engineering applications.

Keywords:  Salidroside; TGF-β; alginate sulfate; cartilage; chondrocytes; tissue engineering

DOI:  https://doi.org/10.3390/ijms252413623
Biochim Biophys Acta Mol Cell Res. 2025 Jan 06. pii: S0167-4889(25)00003-5. [Epub ahead of print]1872(3): 119898

Steroid sulfatase suppresses keratinization by inducing proteasomal degradation of E-cadherin via Hakai regulation.

Tae-Uk Kwon, Yeo-Jung Kwon, Hyemin Park, Hyein Lee, Ji-Heung Kwak, Keon Wook Kang, Young-Jin Chun.

  X-linked ichthyosis (XLI) is a genetic disorder characterized by a steroid sulfatase (STS) deficiency inducing excessive cholesterol sulfate accumulation and keratinization. Our study utilizes STS knockout mice to reproduce the hyperkeratinization typical of XLI, providing a valuable model for investigating the underlying mechanisms. From the experiment of STS-deficient keratinocytes using the CRISPR/Cas9 system, we observed upregulation of E-cadherin, which is associated with keratinocyte differentiation and stratification. This was accompanied by elevated levels of keratinization markers, including involucrin and loricrin. We also found an increased expression of SULT2B1, which converts cholesterol to cholesterol sulfate, further accelerating cholesterol sulfate accumulation. As a result, STS deficiency and cholesterol sulfate accumulation lead to decreased expression of Hakai, the ubiquitin E3 ligase for E-cadherin. With reduced Hakai, endocytosis and ubiquitin-mediated degradation of E-cadherin are inhibited, resulting in its stabilization. This stabilization of E-cadherin is accompanied by increased expression of involucrin and loricrin, which is suppressed when the N-terminal extracellular domain of E-cadherin, responsible for cell-cell adhesion, is genetically modified. We propose that inhibition of E-cadherin, genetic modification of the N-terminal extracellular domain, and treatment with miR-6766 targeting E-cadherin significantly reduce the expression of keratinization markers, suggesting a potential therapeutic approach. We further suggest that the increased expression of E-cadherin observed in keratinocytes with STS deficiency is regulated by Hakai, underscoring the central role of E-cadherin in the pathogenesis of XLI.

Keywords:  E-cadherin; Hakai; Keratinization; Mir-6766; Steroid sulfatase

DOI:  https://doi.org/10.1016/j.bbamcr.2025.119898
Innov Clin Neurosci. 2024 Oct-Dec;21(10):21(10): 44-47

Analysis of Levels of Vitamin D, Beta-Amyloid 42, Indoxyl Sulfate, and Serum Parathyroid Hormone in Hemodialysis Patients with Cognitive Impairment.

Yuliarni Syafrita, Harnavi Harun, Restu Susanti, Syarif Indra.

Objective: Cognitive impairment is a recurrent complication in people with chronic kidney disease (CKD), which includes those undergoing hemodialysis (HD). Researchers aimed to analyze vitamin D levels, beta-amyloid 42, indoxyl sulfate, and serum parathyroid hormone (PTH) in patients with cognitive impairment who underwent HD.
Design: This comparative, cross-sectional study was conducted at the HD unit of Dr. M Djamil Padang Hospital. This study enrolled 60 patients with CKD who underwent routine HD and 20 normal subjects as controls. In both groups, serum levels of vitamin D, beta-amyloid 42, indoxyl sulfate, and PTH were measured using the enzyme-linked immunosorbent assay method, and cognitive function was assessed using the Indonesian version of the Montreal Cognitive Assessment neuropsychological test.
Results: The mean±standard deviation age of the study subjects was 51.48±11.44 years, with 53.4 percent being male. Vitamin D levels were higher in the control group, compared to the case group (p<0.05). The case group had higher levels of beta-amyloid, indoxyl sulfate, and PTH, compared to the control group (p<0.05). Significant differences were found in vitamin D and indoxyl sulfate levels between the groups with and without cognitive impairment (p<0.05).
Conclusion: Lower levels of vitamin D and higher levels of indoxyl sulfate were observed in the group with cognitive impairment when compared to the group without cognitive impairment.

Keywords: Beta-amyloid; cognitive impairment; hemodialysis; indoxyl sulfate; parathyroid hormone; vitamin D
Chem Biol Interact. 2025 Jan 06. pii: S0009-2797(25)00001-8. [Epub ahead of print] 111371

Anti-Dyslipidemic Potential of Sulfated Glycosaminoglycan from Rock Oyster Saccostrea cucullata: An in vivo study.

Ashwin Ashok Pai, Kajal Chakraborty, Shubhajit Dhara, Archana Raj, Bibu John Kariyil, Anoopraj R.

  The rock oyster, Saccostrea cucullata, native to the Indo-Pacific region, is renowned for its nutritional and therapeutic benefits. A sulfated glycosaminoglycan (SCP-2) with β-(1→3)-GlcNSp and α-(1→4)-GlcAp as recurring units isolated from S. cucullata. SCP-2 exhibited substantial 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) inhibition potential (IC50 0.65 mg/mL) in comparison with atorvastatin (IC50 0.72 mg/mL). An in vitro study of SCP-2 (0.1-160 μg/dL) revealed a 77-89% reduction in triglyceride levels in control Caco-2 cells after 4 days of incubation, similar to atorvastatin-treated cells (90%). The acute dyslipidemic efficacy of SCP-2 (at 90 mg/kg body weight) showed timely alleviation of triglyceride and cholesterol levels in tyloxapol-induced rats (∼43% and 81% inhibition at 5 h), which was analogous to the atorvastatin treatment group (∼66% and 71%). Furthermore, SCP-2 (at 90 mg/kg body weight) showed mitigation in triglyceride (> 50%) and cholesterol levels (> 25%) in high-fat high-cholesterol (HFHC) diet-induced rats, similar to the lovastatin treatment group (approximately 62% and 33% inhibition on the 45th day). Histopathological studies of SCP-2 also showed recovery in steatosis, inflammation, and ballooning degradation in liver tissues. Structure-activity relationship analysis suggested the sulfate groups in SCP-2 enhance its anti-dyslipidemic efficacy. The capability of SCP-2 to mitigate cholesterol, triglyceride, and HMGCR levels makes it a prospective functional food against dyslipidemia-related disorders.

Keywords:  Cholesterol; Saccostrea cucullata; Sulfated glycosaminoglycan; Triglyceride; in vivo study

DOI:  https://doi.org/10.1016/j.cbi.2025.111371
Antioxidants (Basel). 2024 Dec 16. pii: 1542. [Epub ahead of print]13(12):

Effects of DHEA and DHEAS in Neonatal Hypoxic-Ischemic Brain Injury.

Elena Mayer, Ira Winkler, Eva Huber, Martina Urbanek, Ursula Kiechl-Kohlendorfer, Elke Griesmaier, Anna Posod.

  Neonatal brain injury remains a significant issue with limited treatment options. This study investigates the potential of the endogenous neurosteroid dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) as neuroprotective agents, building on evidence of their mechanisms in adult brain injury models. The primary objective was to evaluate their neuroprotective and anti-oxidative properties in a mouse model of neonatal hypoxic-ischemic brain injury. Using the modified Rice-Vannucci model, brain injury was induced in 7-day-old mouse pups, followed by treatment with various concentrations of DHEA and DHEAS (0.1, 1, and 10 µg/g body weight) via intraperitoneal injection after a 2 h recovery period. Mice were sacrificed after 24 hours for analysis of somatometry, brain injury, apoptosis, microglial activation, and oxidative stress markers (NOX2, 4-HNE, 8-OHdG), along with the anti-oxidant marker SOD1. While no statistically significant effects of DHEA or DHEAS were observed at the tested doses and time points, the absence of toxic or adverse effects highlights their safety profile. These findings provide a foundation for further research into optimizing dosing strategies, timing, and delivery methods. Future studies should refine these variables to maximize neuroprotective efficacy, investigate DHEA(S)' exact mechanisms of action, and explore their potential for clinical application in neonatal care.

Keywords:  dehydroepiandrosterone; dehydroepiandrosterone sulfate; hypoxia–ischemia; mouse model; neonatal hypoxic–ischemic brain injury; neuroprotection

DOI:  https://doi.org/10.3390/antiox13121542
Adv Sci (Weinh). 2025 Jan 10. e2411911

Sequential Targeting Chondroitin Sulfate-Bilirubin Nanomedicine Attenuates Osteoarthritis via Reprogramming Lipid Metabolism in M1 Macrophages.

Caifeng Deng, Yongbing Xiao, Xuan Zhao, Hui Li, Yuxiao Chen, Kelong Ai, Ting Jiang, Jie Wei, Xiaoyuan Chen, Guanghua Lei, Chao Zeng.

  The infiltration and excessive polarization of M1 macrophages contribute to the induction and persistence of low-grade inflammation in joint-related degenerative diseases such as osteoarthritis (OA). The lipid metabolism dysregulation promotes M1 macrophage polarization by coordinating the compensatory pathways of the inflammatory and oxidative stress responses. Here, a self-assembling, licofelone-loaded nanoparticle (termed LCF-CSBN), comprising chondroitin sulfate and bilirubin joined by an ethylenediamine linker, is developed to selectively reprogram lipid metabolism in macrophage activation. LCF-CSBN is internalized by M1 macrophages via CD44-mediated endocytosis and targets the Golgi apparatus accompanied with the reactive oxygen species-responsive release of licofelone (LCF, dual inhibitor of arachidonic acid metabolism). LCF-CSBN effectively promotes M1 to M2 macrophage transition by reprogramming the Golgi apparatus-related sphingolipid metabolism and arachidonic acid metabolism. Intra-articularly injected LCF-CSBN retains in the joint for up to 28 days and accumulates into M1 macrophages. Moreover, LCF-CSBN can effectively attenuate joint inflammation, oxidative stress, and cartilage degeneration in OA model rats. These findings indicate the promising potential of lipid-metabolism-reprogramming LCF-CSBN in the targeted therapy of OA.

Keywords:  M1 macrophages repolarization; nanoparticles; osteoarthritis; reprogramming of lipid metabolism; targeted therapy

DOI:  https://doi.org/10.1002/advs.202411911
Biochem Biophys Rep. 2025 Mar;41 101892

Structure/function of ATP sulfurylase domain of human 3'-phosphoadenosine 5'-phosphosulfate synthase (hPAPSS).

K V Venkatachalam, Dhiraj Sinha, Chris Soha, Rudi H Ettrich.

3'-phosphoadenosine 5'-phosphosulfate (PAPS) is synthesized by PAPS synthase (PAPSS) in two steps. In the first step ATP sulfurylase (ATPS) transfers sulfate group onto adenylyl moiety of ATP to form adenosine 5'-phosphosulfate (APS) and PPi. APS-kinase (APSK) then transfers the gamma-phosphoryl from ATP onto 3'-OH of APS to form PAPS and ADP. Mutations of histidine's (H425/H428) of hPAPSS isoform1 knocked out ATPS and not APSK. In silico ATP binding and molecular dynamics experiments exhibited an unfavorable binding energy for mutant enzymes. Thus, requirements of H425NGH428 motif for ATPS is established. The N426 residue in various organisms is substituted with R. We mutated hPAPSS1 with basic residue K. The N426 to K426 (N-K) mutant exhibited slightly lower Km (3.7 mM) and higher Vmax (3X) for ATP compared to wildtype (WT, Km 4.3 mM). The Km for sulfate for N-K mutant was nearly same as WT but the Vmax was ∼4X higher for N-K. The catalytic efficiency (Vmax/Km) of N-K was ∼3 fold higher than WT. The full length hPAPSS1 evinced bimodal response against ATP, a paradigm that was deduced to be a trait of PAPSS that requires 2 mol of ATP/PAPS formed. This bimodal kinetics with ATP was lost when the N-terminal APSK was deleted from the C-terminal ATPS domain. The C-terminal domain contained ATPS activity, exhibited Km of 2.2 mM for ATP and Km of 0.53 mM for Sulfate and much higher catalytic efficiency compared to full length hPAPSS1. Thus, fused ATPS-APSK must be structurally and kinetically different than individual domains influenced by inter-domain residues.

DOI: https://doi.org/10.1016/j.bbrep.2024.101892