bims-supasi 2024-09-29 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2024–09–29
nine papers selected by
Jonathan Wolf Mueller, University of Birmingham

In situ crosslinked injectable chondroitin sulfate hydrogel for preventing postoperative adhesion.
Chemoenzymatic Synthesis of Keratan Sulfate Oligosaccharides Using UDP-Galactose-6-aldehyde To Control Sulfation at Galactosides.
Differential regulation of heparan sulfate biosynthesis in fibroblasts cocultured with normal vs. cancerous prostate cells.
Chondroitin Sulfate from Halaelurus burgeri Skin Inhibits Hepatic Endoplasmic Reticulum Stress and Inflammation, and Regulates Gut Microbiota.
Direct mapping of tyrosine sulfation states in native peptides by nanopore.
CIRCULATING HEPARAN SULFATE PROFILES IN PEDIATRIC ACUTE RESPIRATORY DISTRESS SYNDROME.
Bioengineered heparin: Advances in production technology.
An Integrated Strategy to Identify Tyrosine Sulfation from the Therapeutic Proteins.
Evaluating the diagnostic accuracy of androgen measurement in polycystic ovary syndrome: a systematic review and diagnostic meta-analysis to inform evidence-based guidelines.

Biomed Pharmacother. 2024 Sep 25. pii: S0753-3322(24)01381-7. [Epub ahead of print]180 117495

In situ crosslinked injectable chondroitin sulfate hydrogel for preventing postoperative adhesion.

Shijun Wang, Yunhe Zheng, Yanyao Gao, Jiangchuan He, Feng Lv, Yizhuo Bu, Kailai Liu, Yuchen Zhang, Jinpeng Wen, Lei Wang, Ke Wang, Xiqian Zhang.

  Postoperative adhesion is a common clinical disease caused by surgical trauma, accompanying serious subsequent complications. Current non-surgical drug therapy and biomaterial barrier administration have limited therapeutic effects due to their inherent deficiencies. Therefore, developing a simple, effective, and feasible method to effectively prevent postoperative adhesions after surgical procedures remains a challenge. An injectable chondroitin sulfate complex hydrogel was prepared based on aldehyde-modified chondroitin sulfate (ChS-CHO) and hydrazine-modified chondroitin sulfate (ChS-ADH). The hydrogel showed enhanced strength and good self-healing ability. By using the Schiff base reaction principle that aldehyde group reacts with hydrazide to form hydrazone bond, C-A hydrogel physical barrier is formed at the wound site to reduce the occurrence of postoperative adhesion. There is no use of chemical crosslinkers in the whole reaction system to prepare C-A hydrogel, which has excellent biocompatibility and is safe and non-toxic. The results showed that C-A hydrogel showed excellent mechanical properties, good self-healing, and biocompatibility. The cecal-abdominal wall adhesion model and hepatic adhesion model of rats were constructed respectively to evaluate its preventive effect on postoperative adhesion. The results showed that C-A hydrogel had a more significant preventive effect on postoperative adhesion, and appears to be a promising candidate for postoperative adhesion.

Keywords:  Chondroitin sulfate; In situ crosslinking; Postoperative adhesion prevention

DOI:  https://doi.org/10.1016/j.biopha.2024.117495
Org Lett. 2024 Sep 23.

Chemoenzymatic Synthesis of Keratan Sulfate Oligosaccharides Using UDP-Galactose-6-aldehyde To Control Sulfation at Galactosides.

Yunfei Wu, Gerlof P Bosman, Gaël M Vos, Elif Uslu, Digantkumar Chapla, Chin Huang, Kelley W Moremen, Geert-Jan Boons.

Keratan sulfate (KS) is a highly complex proteoglycan that has a poly-LacNAc chain that can be modified by diverse patterns of sulfate esters at C-6 positions of galactoside (Gal) and N-acetylglucosamine (GlcNAc) residues. Here, a chemo-enzymatic methodology is described that can control the pattern of sulfation at Gal using UDP-Gal-aldehyde as a donor for poly-LacNAc assembly to temporarily block specific sites from sulfation by galactose 6-sulfotransferase (CHST1).

DOI: https://doi.org/10.1021/acs.orglett.4c02899
Front Immunol. 2024 ;15 1440623

Differential regulation of heparan sulfate biosynthesis in fibroblasts cocultured with normal vs. cancerous prostate cells.

Elvira V Grigorieva, Anastasia V Strokotova, Ingemar Ernberg, Vladimir I Kashuba.

  Heparan sulfate proteoglycans (HSPGs) regulate a wide range of biological activities in both physiological and pathological conditions. Altered expression or deregulated function of HSPGs and their heparan sulfate (HS) chains significantly contribute to carcinogenesis as well and crucially depends on the functioning of the complex system of HS biosynthetic/modifying enzymes termed as "GAGosome". Here, we aimed at investigating the expression profile of the system in a cell culture model of stroma-epithelial crosstalk and searching for transcription factors potentially related to the regulation of expression of the genes involved. Coculture of BjTERT-fibroblasts with normal PNT2 human prostate epithelial cells resulted in significant downregulation (2-4-fold) of transcriptional activity of HS metabolism-involved genes (EXT1/2, NDST1/2, GLCE, HS2ST1, HS3ST1/2, HS6ST1/2, SULF1/2, HPSE) in both cell types, whereas coculture with prostate cancer cells (LNCaP, PC3, DU145) demonstrated no significant interchanges. Human Transcription Factor RT2 Profiler PCR array and manual RT-PCR verification supposed FOS, MYC, E2F, SRF, NR3C1 as potential candidates for regulation and/or coordination of HS biosynthesis. Taken together, transcriptional activity of HS biosynthetic system in normal fibroblasts and prostate epithelial cells during their coculture might be controlled by their intercellular communication, reflecting of adaptation of these cells to each other. The regulation is attenuated or abrogated if normal fibroblasts interact with prostate cancer cells making the cancer cells independent of the limiting effects of fibroblasts, thus contributing to possibility of unlimited growth and progression. Overall, these data demonstrate an ability of cell-cell interactions to affect transcriptional activity of HS biosynthesis-involved genes.

Keywords:  fibroblast; gene expression; glycosylation; heparan sulfate biosynthesis; prostate cancer cells; transcription factor; transcriptional regulation

DOI:  https://doi.org/10.3389/fimmu.2024.1440623
Mol Nutr Food Res. 2024 Sep 27. e2400501

Chondroitin Sulfate from Halaelurus burgeri Skin Inhibits Hepatic Endoplasmic Reticulum Stress and Inflammation, and Regulates Gut Microbiota.

Zhaocai Ren, Shang Gao, Shiwei Hu, Sichun Chen, Wei Jiang, Yaming Ge.

   SCOPE: Previous study has demonstrated the chemical structure of chondroitin sulfate (CHS) from Halaelurus burgeri skin and its effects on insulin resistance. However, the precise impact of this phenomenon on endoplasmic reticulum (ER) stress and inflammation, which contribute to insulin resistance, remains unclear. This study is to investigate the impact of CHS on ER stress, inflammatory response and signaling, and gut microbiota in high-fat diet (HFD)-fed mice.
METHODS AND RESULTS: HFD-fed C57BL/6J mice receive dietary gavage intervention of CHS for 18 weeks. Blood, liver tissue, and feces are harvested for further investigation. Results show that CHS inhibits ER stress, accompanied by lowered blood glucose, nitric oxide (NO), reactive oxygen (ROS), and free fatty acids (FFA) levels, and increases hepatic glycogen accumulation. Moreover, hepatic inflammation is improved by CHS treatment via inactivation of Toll-like receptor 4 (TLR4) signaling and its downstream c-jun N-terminal kinase (JNK) and nuclear factor kappa B (NFκB) pathways. Additionally, CHS regulates gut microbiota, particularly the decline in the Firmicutes to Bacteroidetes ratio. CHS also lowers fecal lipopolysaccharide and elevates several fecal short chain fatty acids.
CONCLUSION: These findings suggest that CHS from H. burgeri skin may be an alternative functional food supplement for anti-ER stress, anti-inflammtion, and regulation of gut microbiota.

Keywords:  Halaelurus burgeri skin; chondroitin sulfate; endoplasmic reticulum stress; gut microbiota; inflammation

DOI:  https://doi.org/10.1002/mnfr.202400501
Nat Chem Biol. 2024 Sep 25.

Direct mapping of tyrosine sulfation states in native peptides by nanopore.

Hongyan Niu, Meng-Yin Li, Yan Gao, Jun-Ge Li, Jie Jiang, Yi-Lun Ying, Yi-Tao Long.

Sulfation is considered the most prevalent post-translational modification (PTM) on tyrosine; however, its importance is frequently undervalued due to difficulties in direct and unambiguous determination from phosphorylation. Here we present a sequence-independent strategy to directly map and quantify the tyrosine sulfation states in universal native peptides using an engineered protein nanopore. Molecular dynamics simulations and nanopore mutations reveal specific interactions between tyrosine sulfation and the engineered nanopore, dominating identification across diverse peptide sequences. We show a nanopore framework to discover tyrosine sulfation in unknown peptide fragments digested from a native protein and determine the sequence of the sulfated fragment based on current blockade enhancement induced by sulfation. Moreover, our method allows direct observation of peptide sulfation in ultra-low abundance, down to 1%, and distinguishes it from isobaric phosphorylation. This sequence-independent strategy suggests the potential of nanopore to explore specific PTMs in real-life samples and at the omics level.

DOI: https://doi.org/10.1038/s41589-024-01734-x
Shock. 2024 Oct 01. 62(4): 496-504

CIRCULATING HEPARAN SULFATE PROFILES IN PEDIATRIC ACUTE RESPIRATORY DISTRESS SYNDROME.

Colin J Sallee, Aline B Maddux, Joseph A Hippensteel, Daniela Markovic, Kaori Oshima, Andreas Schwingshackl, Peter M Mourani, Eric P Schmidt, Anil Sapru.

ABSTRACT: Introduction: Sepsis-induced degradation of endothelial glycocalyx heparan sulfate (HS) contributes to the pulmonary microvascular endothelial injury characteristic of acute respiratory distress syndrome (ARDS) pathogenesis. Our objectives were to (1) examine relationships between plasma indices of HS degradation and protein biomarkers of endothelial injury and (2) identify patient subgroups characterized by distinct profiles of HS degradation in children with ARDS. Methods: We analyzed prospectively collected plasma (2018-2020) from a cohort of invasively mechanically ventilated children (aged >1 month to <18 years) with ARDS. Mass spectrometry characterized and quantified patterns of HS disaccharide sulfation. Protein biomarkers reflective of endothelial injury (e.g., angiopoietin-2, vascular cell adhesion molecule-1, soluble thrombomodulin) were measured with a multiplex immunoassay. Pearson correlation coefficients were used to construct a biomarker correlation network. Centrality metrics detected influential biomarkers (i.e., network hubs). K-means clustering identified unique patient subgroups based on HS disaccharide profiles. Results: We evaluated 36 patients with pediatric ARDS. HS disaccharide sulfation patterns, 6S, NS, and NS2S, positively correlated with all biomarkers of endothelial injury (all P < 0.05) and were classified as network hubs. We identified three patient subgroups, with cluster 3 (n = 5) demonstrating elevated levels of 6S and N-sulfated HS disaccharides. In cluster 3, 60% of children were female and nonpulmonary sepsis accounted for 60% of cases. Relative to cluster 1 (n = 12), cluster 3 was associated with higher oxygen saturation index (P = 0.029) and fewer 28-day ventilator-free days (P = 0.016). Conclusions: Circulating highly sulfated HS fragments may represent emerging mechanistic biomarkers of endothelial injury and disease severity in pediatric ARDS.

DOI: https://doi.org/10.1097/SHK.0000000000002421
Biotechnol Adv. 2024 Sep 24. pii: S0734-9750(24)00150-2. [Epub ahead of print] 108456

Bioengineered heparin: Advances in production technology.

Razia Sultana, Masamichi Kamihira.

  Heparin, a highly sulfated glycosaminoglycan, is considered an indispensable anticoagulant with diverse therapeutic applications and has been a mainstay in medical practice for nearly a century. Its potential extends beyond anticoagulation, showing promise in treating inflammation, cancer, and infectious diseases such as COVID-19. However, its current sourcing from animal tissues poses challenges due to variable structures and adulterations, impacting treatment efficacy and safety. Recent advancements in metabolic engineering and synthetic biology offer alternatives through bioengineered heparin production, albeit with challenges such as controlling molecular weight and sulfonation patterns. This review offers comprehensive insight into recent advancements, encompassing: (i) the metabolic engineering strategies in prokaryotic systems for heparin production; (ii) strides made in the development of bioengineered heparin; and (iii) groundbreaking approaches driving production enhancements in eukaryotic systems. Additionally, it explores the potential of recombinant Chinese hamster ovary cells in heparin synthesis, discussing recent progress, challenges, and future prospects, thereby opening up new avenues in biomedical research.

Keywords:  Anticoagulant drug; Bioengineered heparin; Glycosaminoglycan; Metabolic engineering; Synthetic biology

DOI:  https://doi.org/10.1016/j.biotechadv.2024.108456
J Am Soc Mass Spectrom. 2024 Sep 26.

An Integrated Strategy to Identify Tyrosine Sulfation from the Therapeutic Proteins.

Eunju Jang, Fengfei Ma, Daniela Tomazela, Laurence Fayadat-Dilman, Mohammad Ahmed Al-Sayah.

  Posttranslational modifications (PTMs) are potential critical quality attributes in biotherapeutic development, as they can affect drug efficacy and safety. Tyrosine sulfation plays a critical role in protein-protein interactions and has been found on many surface receptors as well as antibody complementarity-determining regions (CDR). However, the presence and function of tyrosine sulfation in therapeutic proteins have not been broadly investigated due to difficulties in detecting the modification. Here, we establish an integrated strategy to identify tyrosine sulfation in biotherapeutic proteins. In silico prediction was used to estimate possible modification sites, followed by the elucidation with intact LCMS and native SCX-MS. The combination of these three steps takes less than 1 h, which provides quick and confident preliminary detection of potential CQAs. Taking NB1 as an example, three +80 Da mass shifts were observed from intact mass analysis and three acidic peaks were monitored by SCX, allowing confirmation of modification as either phosphorylation or sulfation. Peptide mapping, Fe3+-IMAC enrichment, and dephosphorylation were further conducted to provide improved signal intensity and differentiation of modification such as sulfation or phosphorylation. With this integrated strategy, we were able to identify for the first time both tyrosine sulfation and serine phosphorylation in one therapeutic protein.

Keywords:  enrichment; mass spectrometry; peptide mapping; phosphorylation; sulfation

DOI:  https://doi.org/10.1021/jasms.4c00303
Hum Reprod Update. 2024 Sep 20. pii: dmae028. [Epub ahead of print]

Evaluating the diagnostic accuracy of androgen measurement in polycystic ovary syndrome: a systematic review and diagnostic meta-analysis to inform evidence-based guidelines.

Asmamaw Demis Bizuneh, Anju E Joham, Helena Teede, Aya Mousa, Arul Earnest, James M Hawley, Laura Smith, Ricardo Azziz, Wiebke Arlt, Chau Thien Tay.

   BACKGROUND: Biochemical hyperandrogenism is a hallmark and diagnostic feature of polycystic ovary syndrome (PCOS). However, the most accurate androgen measurement for assessing biochemical hyperandrogenism in PCOS diagnosis remains uncertain.
OBJECTIVE AND RATIONALE: This systematic review aimed to assess different androgen measures [including total testosterone (TT), calculated free testosterone (cFT), free androgen index (FAI), androstenedione (A4), dehydroepiandrosterone sulfate (DHEAS), and dihydrotestosterone (DHT)] for accuracy in diagnosing biochemical hyperandrogenism in women with PCOS, to inform the 2023 International PCOS Evidence-based Guidelines.
SEARCH METHODS: To update evidence from the 2018 International PCOS Guidelines, a systematic search from 3 July 2017 to 23 June 2023 was conducted across Medline (Ovid), CINAHL, all EBM, EMBASE, and PsycInfo for articles evaluating androgens in the diagnosis of biochemical hyperandrogenism. The revised Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) was used to assess the risk of bias and applicability. A diagnostic test accuracy meta-analysis was performed using STATA 18 software. Summary sensitivity and specificity were calculated with 95% CIs using the bivariate model, while the hierarchical summary receiver operating characteristics (ROC) model was used to produce a summary ROC curve.
OUTCOMES: Of 23 studies reviewed, 18 were included in the meta-analysis, with data from 2857 participants (1650 with PCOS and 1207 controls). For diagnosing biochemical hyperandrogenism in PCOS, the pooled sensitivity, specificity, and AUC with 95% CI were for TT: 0.74 (0.63-0.82), 0.86 (0.77-0.91), and 0.87 (0.84-0.90); cFT: 0.89 (0.69-0.96), 0.83 (0.79-0.86), and 0.85 (0.81-0.88); FAI: 0.78 (0.70-0.83), 0.85 (0.76-0.90), and 0.87 (0.84-0.90); A4: 0.75 (0.60-0.86), 0.71 (0.51-0.85), and 0.80 (0.76-0.83); and DHEAS: 0.75 (0.61-0.85), 0.67 (0.48-0.81), and 0.77 (0.73-0.81), respectively. In subgroup analyses, liquid chromatography with tandem mass spectrometry (LC-MS/MS) had superior sensitivity for measuring cFT, FAI, A4, and DHEAS, and superior specificity for measuring TT, cFT, and FAI, compared to the direct immunoassay method.
WIDER IMPLICATIONS: Our results directly informed the 2023 International PCOS Guideline recommendations to use TT and FT as the first-line laboratory tests to assess biochemical hyperandrogenism in the diagnosis of PCOS. cFT should be assessed by equilibrium dialysis or ammonium sulfate precipitation, or calculated using FAI. If TT or cFT are not elevated, A4 and DHEAS could also be considered, noting their poorer specificity. Laboratories should utilize LC-MS/MS for androgen measurement given its high accuracy. Future studies should focus on establishing optimal normative cut-off values in large, unselected, and ethnically diverse cohorts of women.
REGISTRATION NUMBER: The review protocol was prepublished in the 2023 PCOS Guideline Technical Report (https://www.monash.edu/__data/assets/pdf_file/0010/3379591/TechnicalReport-2023.pdf).

Keywords:  PCOS; androgen; diagnostic accuracy; hyperandrogenemia; hyperandrogenism; sensitivity; specificity; testosterone

DOI:  https://doi.org/10.1093/humupd/dmae028