bims-supasi 2025-01-19 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2025–01–19
eightteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Involvement of GTPases and vesicle adapter proteins in Heparan sulfate biosynthesis: role of Rab1A, Rab2A and GOLPH3.
Crucial role of low molecular weight chondroitin sulfate from hybrid sturgeon cartilage in osteoarthritis improvement: Focusing on apoptosis, systemic inflammation, and intestinal flora.
Specific recognition mechanism of an antibody to sulfated tyrosine and its potential use in biological research.
Inhibition of chondroitin sulphate-degrading enzyme Chondroitinase ABC by dextran sulphate.
Competitive displacement of lipoprotein lipase from heparan sulfate is orchestrated by a disordered acidic cluster in GPIHBP1.
Discovery of a heparan sulfate binding domain in monkeypox virus H3 as an anti-poxviral drug target combining AI and MD simulations.
HSPG-binding peptide Pep19-2.5 is a potent inhibitor of HPV16 infection.
Heparan sulfate 6-O-sulfotransferase 2 promotes gastric cancer progression by modulating the TGF-β/smad2/3 pathway.
Heparan Sulfate Proteoglycan Affinity of Adeno-Associated Virus Vectors: Implications for Retinal Gene Delivery.
Correlation of Hyaluronic Acid (HA), Syndecan-1 (SDC-1), Heparan Sulfate (HS) with early stage ad organ dysfunction in sepsis patients.
Heparan sulfate acts in synergy with tight junction through STAT3 signaling to maintain the endothelial barrier and prevent lung injury development.
Intravesical administration of highly concentrated hyaluronic acid and chondroitin sulfate as add-on therapy for chemical cystitis induced by Bacillus Calmette-Guérin (BCG) immunotherapy.
Woxuanzhongzhou formula improves DHEAS and high-fat diet-induced IR and anovulatory mice via AMPK/PGC1- α/Irisin pathway.
Impact of sex hormones on pheochromocytomas, paragangliomas, and gastroenteropancreatic neuroendocrine tumors.
Identification and Characterization of a New Thermophilic κ-Carrageenan Sulfatase.
Synthesis of Sulfonated Peptides Using a Trifluoromethyltoluene-Protected Amino Acid.
High interindividual variability of indoxyl sulfate production identified by an oral tryptophan challenge test.
Heparin-binding of the human chitinase-like protein YKL-40 is allosterically modified by chitin oligosaccharides.

FEBS J. 2025 Jan 13.

Involvement of GTPases and vesicle adapter proteins in Heparan sulfate biosynthesis: role of Rab1A, Rab2A and GOLPH3.

Maria C Z Meneghetti, Renan P Cavalheiro, Edwin A Yates, Helena B Nader, Marcelo A Lima.

  Vesicle trafficking is pivotal in heparan sulfate (HS) biosynthesis, influencing its spatial and temporal regulation within distinct Golgi compartments. This regulation modulates the sulfation pattern of HS, which is crucial for governing various biological processes. Here, we investigate the effects of silencing Rab1A and Rab2A expression on the localisation of 3-O-sulfotransferase-5 (3OST5) within Golgi compartments and subsequent alterations in HS structure and levels. Interestingly, silencing Rab1A led to a shift in 3OST5 localization towards the trans-Golgi, resulting in increased HS levels within 24 and 48 h, while silencing Rab2A caused 3OST5 accumulation in the cis-Golgi, with a delayed rise in HS content observed after 48 h. Furthermore, a compensatory mechanism was evident in Rab2A-silenced cells, where increased Rab1A protein expression was detected. This suggests a dynamic interplay between Rab1A and Rab2A in maintaining the fine balance of vesicle trafficking processes involved in HS biosynthesis. Additionally, we demonstrate that the trafficking of 3OST5 in COPI vesicles is facilitated by GOLPH3 protein. These findings identify novel vesicular transport mechanisms regulating HS biosynthesis and reveal a compensatory relationship between Rab1A and Rab2A in maintaining baseline HS production.

Keywords:  GOLPH3; Rab1A; Rab2A; biosynthesis; heparan sulfate

DOI:  https://doi.org/10.1111/febs.17398
Int J Biol Macromol. 2025 Jan 13. pii: S0141-8130(25)00399-X. [Epub ahead of print] 139850

Crucial role of low molecular weight chondroitin sulfate from hybrid sturgeon cartilage in osteoarthritis improvement: Focusing on apoptosis, systemic inflammation, and intestinal flora.

Yinghuan Jing, Kangyu Wang, Tianxiang Pi, Zefan Chen, Tianhong Liu, Xinyu Liu, Hangyu Ye, Xinxing Xu, Yuanhui Zhao.

  Low molecular weight chondroitin sulfate (CS) has gained considerable attention for its superior bioactivity compared to native CS. In this study, the mechanisms of low molecular weight chondroitin sulfate from hybrid sturgeon cartilage (LMSCS), prepared using the H2O2/Vc system, on the remission of osteoarthritis (OA) were investigated both in in vitro and in vivo. A Caco-2/SW1353 co-culture cell model and a monosodium iodoacetate (MIA)-induced OA mouse model were used to validate its inhibited apoptosis, anti-inflammatory effects, and intestinal flora modulation. LMSCS was found to effectively alleviate inflammation, decrease chondrocyte apoptosis, and reduce MMP-13 levels by inhibiting the activation of NF-κB and MAPK signaling pathways. Notably, in vivo experiments, LMSCS exhibited significant anti-inflammatory effects compared to SCS. This trend, however, was not observed in vitro, which could be largely attributed to LMSCS' ability to regulate intestinal flora. Compared to SCS, LMSCS enhanced the abundance of beneficial bacteria, particularly, the Prevotellaceae_NK3B31_group and Akkermansia, and increased the levels of short-chain fatty acids such as butyrate and propionate. The effectiveness of LMSCS in mitigating inflammatory responses in vivo is thus largely due to its intestinal flora modulation, providing for its development and application.

Keywords:  Apoptosis; Inflammation; Intestinal flora; Low molecular weight chondroitin sulfate; Osteoarthritis

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.139850
J Biol Chem. 2025 Jan 09. pii: S0021-9258(25)00023-7. [Epub ahead of print] 108176

Specific recognition mechanism of an antibody to sulfated tyrosine and its potential use in biological research.

Kan Ujiie, Makoto Nakakido, Seisho Kinoshita, Jose Caaveiro M M, Kevin Entzminger C, C J Okumura, Toshiaki Maruyama, Kosuke Miyauchi, Tetsuro Matano, Kouhei Tsumoto.

  Post-translational modification of proteins is a crucial biological reaction that regulates protein functions by altering molecular properties. The specific detection of such modifications in proteins has made significant contributions to molecular biology research and holds potential for future drug development applications. In HIV research, for example, tyrosine sulfation at the N-terminus of C-C chemokine receptor type 5 (CCR5) is considered to significantly enhance HIV infection efficiency. However, antibodies specific to sulfated CCR5 still need to be developed. In this study, we successfully generated an antibody that specifically recognized the sulfated N-terminal peptide of CCR5 through rabbit immunization and panning via phage display using a CCR5 N-terminal peptide containing sulfate modification. We used various physicochemical methods in combination with molecular dynamics simulation to screen for residues that could be involved in recognition of the sulfated peptide by this antibody. We also confirmed that this antibody recognized the sulfated full-length CCR5 on the cell surface, which suggested it should be useful as a research tool that could lead to the development of novel therapeutics. Although the antibody binding did not inhibit HIV infection, it could be also described as sulfation site-specific binding, beyond sulfation-specific binding.

Keywords:  Antibody; Crystal structure; HIV infection; Molecular dynamics simulation; Physicochemical analyses; Post-translational modification; Sulfated tyrosine

DOI:  https://doi.org/10.1016/j.jbc.2025.108176
Glycoconj J. 2025 Jan 16.

Inhibition of chondroitin sulphate-degrading enzyme Chondroitinase ABC by dextran sulphate.

Sagar Dalal, Rachana Pathak, Edward X S Moh, Nicolle H Packer.

  Chondroitin sulphate (CS) is a sulphated glycosaminoglycan (GAG) polysaccharide found on proteoglycans (CSPGs) in extracellular and pericellular matrices. Chondroitinase ABC (CSase ABC) derived from Proteus vulgaris is an enzyme that has gained attention for the capacity to cleave chondroitin sulphate (CS) glycosaminoglycans (GAG) from various proteoglycans such as Aggrecan, Neurocan, Decorin etc. The substrate specificity of CSase ABC is well-known for targeting various structural motifs of CS chains and has gained popularity in the field of neuro-regeneration by selective degradation of CS GAG chains. Within this context, our investigation into the biochemistry of CSase ABC led us to a previously unreported inhibition of CSase ABC activity by Dextran Sulphate (DexS). To understand the inhibitory effects of DexS, we compared its inhibition of CSase ABC to that of other polysaccharides such as Heparan Sulphate, Heparin, Colominic Acid, Fucoidan, and Dextran. This analysis identified key structural factors such as monosaccharide composition and linkage, sulphation degree and overall charge as influencing CSase ABC inhibition. Remarkably, DexS emerged as a unique inhibitor of CSase ABC, with distinctive inhibitory effects that correlate with its chain length. DexS has been used to reliably induce ulcerative colitis in mice, effectively mimicking inflammatory bowel diseases in humans, and has been previously shown to inhibit both RNA polymerase and reverse transcriptase. Our investigation emphasizes the interplay between the properties of DexS and CSase ABC, providing significant insights into the utilization of polysaccharide-based inhibitors for modulating enzyme activity.

Keywords:  Chondroitin sulphate; Chondroitinase ABC; Colorimetric assay; Dextran sulfate; WST-1

DOI:  https://doi.org/10.1007/s10719-024-10175-6
J Lipid Res. 2025 Jan 13. pii: S0022-2275(25)00005-7. [Epub ahead of print] 100745

Competitive displacement of lipoprotein lipase from heparan sulfate is orchestrated by a disordered acidic cluster in GPIHBP1.

Anamika Biswas, Samina Arshid, Kristian Kølby Kristensen, Thomas J D Jørgensen, Michael Ploug.

  Movement of lipoprotein lipase (LPL) from myocytes or adipocytes to the capillary lumen is essential for intravascular lipolysis and plasma triglyceride homeostasis-low LPL activity in the capillary lumen causes hypertriglyceridemia. The trans-endothelial transport of LPL depends on ionic interactions with GPIHBP1's intrinsically disordered N-terminal tail, which harbors two acidic clusters at positions 5-12 and 19-30. This polyanionic tail provides a molecular switch that controls LPL detachment from heparan sulfate proteoglycans (HSPGs) by competitive displacement. When the acidic tail was neutralized in gene-edited mice, LPL remained trapped in the sub-endothelial spaces triggering hypertriglyceridemia. Due to its disordered state, the crystal structure of LPL•GPIHBP1 provided no information on these electrostatic interactions between LPL and GPIHBP1s acidic tail. In the current study, we positioned the acidic tail on LPL using zero-length crosslinking. Acidic residues at positions 19-30 in GPIHBP1 mapped to Lys445, Lys441, Lys414 and Lys407 close to the interface between the C- and N-terminal domains in LPL. Modeling this interface revealed widespread polyelectrolyte interactions spanning both LPL domains, which explains why the acidic tail stabilizes LPL activity and protein conformation. In functional assays, we showed that the acidic cluster at 19-30 also had the greatest impact on preserving LPL activity, mitigating ANGPTL4-catalyzed LPL inactivation, preventing PSCK3-mediated LPL cleavage, and, importantly, displacing LPL from HSPGs. Our current study provides key insights into the biophysical mechanism(s) orchestrating intravascular compartmentalization of LPL activity-an intriguing pathway entailing competitive displacement of HSPG-bound LPL by a disordered acidic tail in GPIHBP1.

Keywords:  ANGPTL4; Competitive displacement; Intrinsically disordered regions; Lipase/Lipoprotein; Lipolysis and fatty acid metabolism; PSCK3 cleavage; Transport; Triglycerides; polyelectrolytes

DOI:  https://doi.org/10.1016/j.jlr.2025.100745
Elife. 2025 Jan 16. pii: RP100545. [Epub ahead of print]13

Discovery of a heparan sulfate binding domain in monkeypox virus H3 as an anti-poxviral drug target combining AI and MD simulations.

Bin Zheng, Meimei Duan, Yifen Huang, Shangchen Wang, Jun Qiu, Zhuojian Lu, Lichao Liu, Guojin Tang, Lin Cheng, Peng Zheng.

  Viral adhesion to host cells is a critical step in infection for many viruses, including monkeypox virus (MPXV). In MPXV, the H3 protein mediates viral adhesion through its interaction with heparan sulfate (HS), yet the structural details of this interaction have remained elusive. Using AI-based structural prediction tools and molecular dynamics (MD) simulations, we identified a novel, positively charged α-helical domain in H3 that is essential for HS binding. This conserved domain, found across orthopoxviruses, was experimentally validated and shown to be critical for viral adhesion, making it an ideal target for antiviral drug development. Targeting this domain, we designed a protein inhibitor, which disrupted the H3-HS interaction, inhibited viral infection in vitro and viral replication in vivo, offering a promising antiviral candidate. Our findings reveal a novel therapeutic target of MPXV, demonstrating the potential of combination of AI-driven methods and MD simulations to accelerate antiviral drug discovery.

Keywords:  CHO-K1 cell; E. coli; MD simulations; Vero E6 cell; computational biology; molecular biophysics; monkeypox virus; mouse; structural biology; systems biology; viral adhesion; viruses

DOI:  https://doi.org/10.7554/eLife.100545
Antimicrob Agents Chemother. 2025 Jan 14. e0157524

HSPG-binding peptide Pep19-2.5 is a potent inhibitor of HPV16 infection.

Snježana Mikuličić, Annika Massenberg, Tatjana Döring, Klaus Brandenburg, Thorsten Lang, Luise Florin.

  Peptide-based therapeutics are gaining attention for their potential to target various viral and host cell factors. One notable example is Pep19-2.5 (Aspidasept), a synthetic anti-lipopolysaccharide peptide that binds to heparan sulfate proteoglycans (HSPGs) and has demonstrated inhibitory effects against certain bacteria and enveloped viruses. This study explores, for the first time, the effectiveness of Pep19-2.5 against a non-enveloped virus, using pseudoviruses of the oncogenic human papillomavirus type 16 (HPV16) as a model. HPV16 infects epithelial cells of the skin and mucosa by using multiple cell surface receptors with initial attachment to HSPGs. Pharmacological inhibition with Pep19-2.5 in HeLa and HaCaT cells resulted in a concentration-dependent reduction of HPV16 PsV infection, with near-complete blockade observed at higher concentrations. The half-maximal inhibitory concentration (IC50) was determined to be 116 nM in HeLa cells and 183 nM in HaCaT cells, highlighting its potent antiviral activity. Our results demonstrate that Pep19-2.5 not only inhibits HPV16 PsV binding to the cell surface but also significantly reduces infection when administered post-binding. Imaging analyses revealed Pep19-2.5-dependent release of large cell-associated crowds of viral particles, suggesting interference with the transfer to secondary receptor molecules. This was corroborated by the effectiveness of Pep19-2.5 in an HSPG-negative cell line, indicating that the peptide disrupts virus binding to both primary and secondary interaction partners. Based on these findings, we propose that the antimicrobial effect of Pep19-2.5 is not limited to HSPG-dependent infections. Additionally, Pep19-2.5 may be a valuable tool for dissecting specific steps in the viral entry process.

Keywords:  Aspidasept; HPV16; Pep19-2.5; Peptide 19-2.5; SALP; heparan sulfate proteoglycans (HSPGs); human papillomavirus; synthetic anti-lipopolysaccharide peptide; virus entry

DOI:  https://doi.org/10.1128/aac.01575-24
Am J Transl Res. 2024 ;16(12): 7924-7936

Heparan sulfate 6-O-sulfotransferase 2 promotes gastric cancer progression by modulating the TGF-β/smad2/3 pathway.

Shuai Wu, Changqin Xu, Weijia Sun, Qianqian Xu, Feifei Zhou, Ruzhen Jia, Hongwei Xu.

   OBJECTIVE: To investigate the role of heparan sulfate 6-O-sulfotransferase 2 (HS6ST2) in gastric cancer (GC).
METHODS: HS6ST2 expression in GC and adjacent normal gastric mucosa was first detected via immunohistochemical (IHC) staining. The correlation between the expression level of HS6ST2 and clinicopathological parameters were observed. The protein expression of HS6ST2 in AGS, MKN45 and GES-1 cells was examined using Western blotting. The function of HS6ST2 in GC cells was explored via CCK-8, wound healing and Transwell assays. To elucidate the underlying molecular mechanisms, we detected whether HS6ST2 modulated the TGF-β/smad2/3 signaling pathway. Finally, we investigated the role of HS6ST2 in tumor growth in a nude mouse model.
RESULTS: The expression level of HS6ST2 in GC tissues was significantly higher than that in adjacent normal gastric mucosa and was positively correlated with tumor size. Compared with GES-1 cells, the expression level of HS6ST2 in AGS and MKN45 cells was significantly elevated. Silencing HS6ST2 impaired GC cell growth, mobility and epithelial-mesenchymal transition (EMT). On the other hand, HS6ST2 upregulation increased GC cell growth, migration and invasion, which was dramatically blocked by SB431542 treatment. Furthermore, mouse xenograft experiments demonstrated that HS6ST2 silencing inhibited tumor growth and EMT in vivo.
CONCLUSION: HS6ST2 promotes GC progression through the modulation of the TGF-β/smad2/3 pathway.

Keywords:  Epithelial-mesenchymal transition; TGF-β/smad2/3; gastric cancer; heparan sulfate 6-O-sulfotransferase 2; progression

DOI:  https://doi.org/10.62347/LWZR1836
Eur J Pharm Sci. 2025 Jan 11. pii: S0928-0987(25)00011-9. [Epub ahead of print] 107012

Heparan Sulfate Proteoglycan Affinity of Adeno-Associated Virus Vectors: Implications for Retinal Gene Delivery.

Dimitri Romanovsky, Hanna Scherk, Bastian Föhr, Sabrina Babutzka, Jacqueline Bogedein, Yi Lu, Alice Reschigna, Stylianos Michalakis.

  Adeno-associated virus (AAV)-based vectors have emerged as an effective and widely used technology for somatic gene therapy approaches, including those targeting the retina. A major advantage of the AAV technology is the availability of a large number of serotypes that have either been isolated from nature or produced in the laboratory. These serotypes have different properties in terms of sensitivity to neutralizing antibodies, cellular transduction profile and efficiency. The infectivity of AAV vectors depends on the affinity to certain molecules on the cell surface, in particular to cellular glycosaminoglycans (GAGs) such as heparan sulfate proteoglycans (HSPGs). Here, we tested how altering HSPG affinity in AAV vectors affects cellular tropism and transduction efficiency. The previously developed AAV2.GL variant was used as a starting variant to alter or disrupt HSPG affinity. The HSPG-independent AAV9 serotype was used to introduce different HSPG binding sites. As an indicator of HSPG affinity, we measured the binding strength of the vector variant on a heparin chromatography column. We show that modification of capsid-exposed residues has a strong impact on HSPG affinity, cellular tropism and transduction efficiency in HeLa cells and in vivo in mouse retina. Our study shows that key properties of AAV vectors can be tailored in different directions and used to improve tropism and efficiency.

Keywords:  Adeno-associated virus; capsid engineering; gene therapy; heparin affinity chromatography; virus-receptor interactions

DOI:  https://doi.org/10.1016/j.ejps.2025.107012
J Cardiovasc Pharmacol. 2024 Nov 25.

Correlation of Hyaluronic Acid (HA), Syndecan-1 (SDC-1), Heparan Sulfate (HS) with early stage ad organ dysfunction in sepsis patients.

Zhengchao Li, Xingpeng Jiang, Jinghui Li, Yuzhu Wang.

This study aimed to explore the relationship between the changes in early degradation products of polysaccharide coatings (such as hyaluronic acid (HA), syndecan-1 (SDC-1), and heparan sulfate (HS)) and the development of organ dysfunction in sepsis patients. We conducted a retrospective analysis on 140 sepsis patients admitted from January 2021 to June 2022, who formed the study group; 100 healthy individuals who underwent health checks during the same period were included as the control group. The study found that the expression levels of HA, SDC-1, and HS upon admission and within 24 hours of admission in sepsis patients, as well as the early change rates, were positively correlated with organ dysfunction (P < 0.05). Through receiver operating characteristic (ROC) curve analysis, we discovered that the early change rates of HA, SDC-1, and HS have high predictive value for organ dysfunction in sepsis patients, with the combined predictive value being the most significant. The study conclusion points out that the increased levels of HA, SDC-1, HS, and other degradation products of polysaccharide coatings in the early stage of sepsis are positively associated with the occurrence of organ dysfunction. Clinicians can utilize the early expression changes of these biomarkers to predict the risk of organ dysfunction in sepsis patients, enabling timely implementation of preventive measures that may improve patient outcomes.

DOI: https://doi.org/10.1097/FJC.0000000000001654
Int Immunopharmacol. 2025 Jan 09. pii: S1567-5769(24)02479-2. [Epub ahead of print]147 113957

Heparan sulfate acts in synergy with tight junction through STAT3 signaling to maintain the endothelial barrier and prevent lung injury development.

Dong Zhang, Boyang Qi, Zhenyi Peng, Xiao Huang, Yuanyuan Chen, Ting Sun, Fangyu Ning, Dong Hao, Xiaozhi Wang, Tao Wang.

  Damage to glycocalyx and tight junction are key determinants of endothelial permeability, which is the main pathological feature of acute respiratory distress syndrome (ARDS). However, the effect of glycocalyx heparan sulfate (HS) on tight junction proteins occludin and ZO-1 has not been revealed. In this study, the mice exposed to LPS results showed that FITC-albumin infiltration, HS shedding, and tight junction protein impairment were most severe at 6 h of LPS treatment compared with those in other treatment times. The in vitro and vivo experiments revealed that tight junction damage, FITC-albumin infiltration, and pathological injury induced by LPS were significantly alleviated via protection of glycocalyx HS shedding. mRNA sequencing analysis demonstrated that the STAT signaling pathways played a crucial role in the inhibition of LPS-induced HS shedding in mice. Supplementation of exogenous HS in human umbilical vein endothelial cells (HUVECs) and mice ameliorated LPS-induced the tight junction barrier defect by inhibiting STAT3 phosphorylation. Further analysis uncovered that intervention of STAT3 signaling significantly alleviated LPS-induced tight junction proteins damage and vascular permeability in HUVECs and mice. Mechanistically, HS modulated tight junction proteins by STAT3 signaling, which might directly bind to the promoter regions of occludin and ZO-1. In conclusion, glycocalyx HS played an important role in protecting endothelial barrier function and preventing injury development, in synergy with tight junction through STAT3 signaling, which further alleviated pulmonary edema.

Keywords:  Acute respiratory distress syndrome; Endothelial permeability; Glycocalyx; Heparan sulfate; Tight junction

DOI:  https://doi.org/10.1016/j.intimp.2024.113957
Int Urol Nephrol. 2025 Jan 16.

Intravesical administration of highly concentrated hyaluronic acid and chondroitin sulfate as add-on therapy for chemical cystitis induced by Bacillus Calmette-Guérin (BCG) immunotherapy.

M Gubbiotti, E Rubilotta, M Bacchiani, A Cocci, S Rosadi, S Serni, A Minervini, V Li Marzi.

   PURPOSE: Intravesical (i) immunotherapy with Bacillus Calmette-Guérin (BCG) is the recommended treatment for patients with intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC) after complete tumor resection. Discontinuation or suspension of this therapy is often due to local side effects. Aim of the study was to evaluate the efficacy and safety of sequential intravesical instillations of combined hyaluronic acid (HA) and chondroitin sulfate (CS) in reducing local BCG toxicity and urinary symptoms.
METHODS: This was a prospective, multicentric study. Patients underwent BCG intravesical administration after Transurethral Resection of Bladder Tumor (TURBT) for intermediate/high-risk NMIBC. Patients underwent to HA + CS instillations after every (i) BCG (Group A) were compared with a control group (Group B) that included patient underwent only to BCG instillations, during the maintenance period. 3-day voiding diary, the International Prostate Symptom Score (IPSS), IPSS quality-of-life index (IPSS-QoL), and VAS score (to evaluate bladder pain) were evaluated at baseline and at 1-, 3-, and 6-month follow- up.
RESULTS: One hundred-eighteen patients were included (Group A: 63 patients, Group B: 55 patients). Mean value of IPSS, IPSS-QoL, and VAS score has significantly increase in Group A at 1-, 3-, and 6-month follow-up (p < 0.00). Group A showed also a significant improvement about irritative lower urinary symptoms (LUTS), which was maintained in the 6-month follow-up, as opposed to Group B that demonstrated a worsening in urinary symptoms during all follow-up (p < 0.00). No local or major side effects were reported during or after treatment.
CONCLUSION: This study demonstrated that adding (i) HA + CS significantly reduces storage symptoms, pelvic pain, and day-time urinary frequency in patients with BCG-induced chemical cystitis. This therapy could therefore improve patient adherence, ensuring better adherence and lower drop-out rates.

Keywords:  Add-on therapy; Bacillus Calmette–Guérin; Chemical cystitis; Chondroitin sulfate; Hyaluronic acid; Intravesical therapy

DOI:  https://doi.org/10.1007/s11255-025-04375-8
J Ovarian Res. 2025 Jan 16. 18(1): 7

Woxuanzhongzhou formula improves DHEAS and high-fat diet-induced IR and anovulatory mice via AMPK/PGC1- α/Irisin pathway.

Haijuan Liu, Guohua Wang, Conglu Sui, Yanan Guo, Xiangyu He.

   BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder in women of reproductive age. Anovulation is one of the most important clinical features of PCOS, and insulin resistance (IR) is one of the critical pathogenic factors. Woxuanzhongzhou (WXZZ) is a traditional herbal formulation that has shown efficacy in treating PCOS combined with IR, but the underlying mechanism is not clear. The aim of this study was to investigate the molecular mechanism of WXZZ on dehydroepiandrosterone sulfate and high fat diet induced PCOS with IR mice.
METHODS: 40 female C57BL/6 mice were randomized to 4 groups: control group, model group, metformin group, and WXZZ group. Some mice is induced by dehydroepiandrosterone sulfate (DHEA) and high-fat diet (HFD) for 3 weeks. Following model induction, metformin and WXZZ were administered by gavage. Body weight, fasting blood glucose (FBG), fasting insulin (FINS) levels, the homeostatic model assessment of insulin resistance (HOMA-IR), and gonadal hormones were measured. Estrous cycles were monitored. The structure of the gastrocnemius muscle and subcutaneous fatty tissue were also evaluated. Additionally, serum irisin and non-esterified fatty acids (NEAF) levels and the protein and gene expression levels of AMPK, PGC1-α, FNDC5, irisin in the gastrocnemius muscle and CaMKK, AMPK, PGC1-α, UCP1 in fat were analyzed.
RESULTS: The DHEA + HFD + WXZZ group exhibited significant improvements in several key parameters compared to the DHEA + HFD group. WXZZ ameliorated endocrine and metabolic disorders, resumed estrous cycle in DHEAS and high-fat diet-induced IR and anovulatory mice. Significant reductions were observed in body weight, serum testosterone, luteinizing hormone, luteinizing hormone/ follicle-stimulating hormone ratio, FINS, and HOMA-IR. Additionally, WXZZ promoted irisin expression and secretion by up-regulating the protein and gene AMPK/PGC1-α/FNDC5 expression in gastrocnemius muscle and up-regulated the protein and gene CaMKK/AMPK/PGC1-α/UCP1 expression in fat. WXZZ inhibited the overproduction of serum NEFA, and reduced lipid accumulation. Structural analysis of the gastrocnemius muscle and adipose tissue revealed partial restoration.
CONCLUSION: WXZZ exhibits therapeutic effects in DHEAS and high-fat diet-induced IR and anovulatory mice. These effects may be mediated through the activation of AMPK/PGC1-α pathway in muscle to promote the secretion of irisin.

Keywords:  AMPK; FNDC5; Insulin resistance; Irisin; PGC1-α; Polycystic ovary syndrome

DOI:  https://doi.org/10.1186/s13048-025-01587-5
Eur J Endocrinol. 2025 Jan 06. 192(1): 46-60

Impact of sex hormones on pheochromocytomas, paragangliomas, and gastroenteropancreatic neuroendocrine tumors.

Katharina Wang, Alessa Fischer, Umberto Maccio, Kathrin Zitzmann, Mercedes Robledo, Michael Lauseker, Jana Bauer, Nicole Bechmann, Simon Gahr, Julian Maurer, Lea Peischer, Astrid Reul, Hanno Nieß, Petra Zimmermann, Matthias Ilmer, Katharina Schilbach, Thomas Knösel, Matthias Kroiss, Martin Fassnacht, Simon A Müller, Gregoire B Morand, Alexander Huber, Diana Vetter, Kuno Lehmann, Zsolt Kulcsar, Hermine Mohr, Natalia S Pellegata, Constanze Hantel, Martin Reincke, Felix Beuschlein, Karel Pacak, Ashley B Grossman, Christoph J Auernhammer, Svenja Nölting.

   OBJECTIVE: The effects of sex hormones remain largely unexplored in pheochromocytomas and paragangliomas (PPGLs) and gastroenteropancreatic neuroendocrine tumors (GEP-NETs).
METHODS: We evaluated the effects of estradiol, progesterone, Dehydroepiandrosterone sulfate (DHEAS), and testosterone on human patient-derived PPGL/GEP-NET primary culture cell viability (n = 38/n = 12), performed next-generation sequencing and immunohistochemical hormone receptor analysis in patient-derived PPGL tumor tissues (n = 36).
RESULTS: In PPGLs, estradiol and progesterone (1 µm) demonstrated overall significant antitumor effects with the strongest efficacy in PPGLs with NF1 (cluster 2) pathogenic variants. Estrogen receptor alpha (ERα) positivity was detected in 11/36 PPGLs, including 4/4 head-and-neck paragangliomas (HNPGLs). ERα-positive tumors responded with a significant cell viability decrease to estradiol. DHEAS and testosterone (1 µm) displayed no effects, but higher doses of testosterone (10 µm) demonstrated significant antitumor effects, including a pheochromocytoma lung metastasis with strong androgen receptor positivity (30%). Driven by the antitumor effects of estrogen, we evaluated G-protein-coupled estrogen receptor (GPER) agonist G-1 as a potential therapeutic option for PPGLs and found strong significant antitumor potential, with the strongest efficacy in tumors with NF1 pathogenic variants. Moreover, we detected sex-related differences-tumors from male patients showed significantly stronger responsivity to G-1 compared with tumors from female patients. In GEP-NETs, sex hormones showed overall no effects, especially no tumor growth-promoting effects.
CONCLUSION: We provide novel data on the effects of elevated sex hormone levels, potentially seen during pregnancy or hormone replacement therapy, on PPGL/GEP-NET tumor growth. G-1 might offer a novel therapeutic approach for some PPGLs depending on patient's sex and the individual tumor's genetic/molecular background. All HNPGLs showed ERα positivity.

Keywords:  estrogen; hormone receptor; neuroendocrine tumor; pheochromocytoma; progesterone

DOI:  https://doi.org/10.1093/ejendo/lvae163
J Agric Food Chem. 2025 Jan 11.

Identification and Characterization of a New Thermophilic κ-Carrageenan Sulfatase.

Nanna Rhein-Knudsen, Diego S Reyes-Weiss, Leesa J Klau, Alexandra Jeudy, Thomas Roret, Runar Stokke, Vincent G H Eijsink, Finn L Aachmann, Mirjam Czjzek, Svein Jarle Horn.

  Carrageenans are sulfated polysaccharides found in the cell wall of certain red seaweeds. They are widely used in the food industry for their gelling and stabilizing properties. In nature, carrageenans undergo enzymatic modification and degradation by marine organisms. Characterizing these enzymes is crucial for understanding carrageenan utilization and may eventually enable the development of targeted processes to modify carrageenans for industrial applications. In our study, we characterized a κ-carrageenan sulfatase, AMOR_S1_16A, belonging to the sulfatase S1_16 subfamily, which selectively desulfates the nonreducing end galactoses of κ-carrageenan oligomers in an exomode. Notably, AMOR_S1_16A represents the first κ-carrageenan sulfatase within the S1_16 subfamily and exhibits a novel enzymatic activity. This study provides further understanding of the substrate specificity and characteristics of the S1_16 subfamily. Moreover, this research highlights that many processes and enzymes remain to be discovered to fully understand carrageenan utilization pathways and to develop enzymatic processes for carrageenan modification and processing.

Keywords:  4-O-sulfatase; carbohydrate sulfatase; carrageenan modification; substrate specificity; sulfated carbohydrate

DOI:  https://doi.org/10.1021/acs.jafc.4c09751
J Org Chem. 2025 Jan 14.

Synthesis of Sulfonated Peptides Using a Trifluoromethyltoluene-Protected Amino Acid.

Ashley E DeYong, Kaicheng Li, Elliot L Chaikof.

A scalable, seven step synthesis is reported for a trifluoromethyl toluene protected sulfonated phenylalanine building block whose utility was demonstrated in the synthesis of four CXCR4-derived sulfonopeptides. When compared to a conventional trichloroethyl protected building block, overall yield was improved by up to 4-fold. We believe this building block will prove to be of significant value for the synthesis of a variety of peptide targets containing phenylalanine sulfonate, a bioisostere of tyrosine sulfate, enabling orthogonal protection strategies and improving synthetic efficiency and yield.

DOI: https://doi.org/10.1021/acs.joc.4c02529
NPJ Biofilms Microbiomes. 2025 Jan 13. 11(1): 15

High interindividual variability of indoxyl sulfate production identified by an oral tryptophan challenge test.

Ting-Yun Lin, Wei-Kai Wu, Szu-Chun Hung.

Indoxyl sulfate (IS) has been implicated in the pathogenesis of cardiovascular diseases. IS is converted from indole, a metabolite of dietary tryptophan through the action of gut microbial tryptophanase, by two hepatic enzymes: CYP2E1 and SULT1A1. We hypothesized that the effect of tryptophan intake on IS production might differ from person to person. We enrolled 72 healthy persons (33 ± 7 years; 54.2% women) to undergo an oral tryptophan challenge test (OTCT), in which 7 blood samples were collected at 0, 4, 8, 12, 24, 36, and 48 h following oral administration of L-tryptophan 2000 mg. We observed high interindividual variability of IS production in the response to an OTCT. Twenty-four subjects in the lowest tertile of the baseline-adjusted area under the curve of IS were defined as low-IS producers, whereas 24 subjects in the highest tertile were defined as high-IS producers. There was no significant difference in baseline characteristics or CYP2E1 and SULT1A1-SNP genotyping distributions between the two IS-producing phenotypes. However, distinct differences in gut microbial composition were identified. In addition, the abundance of tryptophanase was significantly higher in the high-IS producers than in the low-IS producers (P = 0.01). The OTCT may serve as personalized dietary guidance. High-IS producers are more likely to be at greater risk of cardiovascular diseases and may benefit from consuming foods low in tryptophan. Potential clinical applications of the OTCT in precision nutrition warrant further investigation.

DOI: https://doi.org/10.1038/s41522-025-00651-8
Biochem Biophys Rep. 2025 Mar;41 101908

Heparin-binding of the human chitinase-like protein YKL-40 is allosterically modified by chitin oligosaccharides.

Unnur Magnusdottir, Finnbogi R Thormodsson, Lilja Kjalarsdottir, Hordur Filippusson, Johannes Gislason, Kristinn Ragnar Oskarsson, Jens G Hjorleifsson, Jon M Einarsson.

  The chitinase-like protein YKL-40 (CHI3L1) has been implicated in the pathophysiology of inflammation and cancer. Recent studies highlight the growing interest in targeting and blocking the activity of YKL-40 to treat cancer. Some of those targeting-strategies have been developed to directly block the heparin-affinity of YKL-40 with promising results. This study explores how short chain chitooligosaccharides (ChOS) affect the heparin-binding affinity of YKL-40. Our findings reveal that ChOS act as allosteric effectors, decreasing the heparin-binding affinity of YKL-40 in a size- and dose-dependent manner. Our results provide insights into the heparin affinity of YKL-40 and how ChOS can be used to target the heparin activity of YKL-40 in diseases. Since ChOS has many beneficial properties, such as being non-toxic and biodegradable, these results provide intriguing opportunities for applying them as allosteric effectors of the heparin-binding affinity of YKL-40.

Keywords:  Allostery; Binding affinity; Chitin oligosaccharides; Conformational change; Heparin; YKL-40

DOI:  https://doi.org/10.1016/j.bbrep.2024.101908