bims-supasi 2023-05-28 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2023–05–28
thirteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Increased 3-O-sulfated heparan sulfate in Alzheimer's disease brain is associated with genetic risk gene HS3ST1.
SPR Sensor-Based Analysis of the Inhibition of Marine Sulfated Glycans on Interactions between Monkeypox Virus Proteins and Glycosaminoglycans.
Loss of chondroitin sulfate proteoglycan sulfation allows delayed sympathetic reinnervation after cardiac ischemia-reperfusion.
Enzymatic preparation of chondroitin sulfate oligosaccharides and its alleviating effect on ovariectomy-induced osteoporosis in rats.
Low-Molecular-Weight Chondroitin Sulfates Alleviate Simulated Microgravity-Induced Oxidative Stress and Bone Loss in Mice.
Extracellular vesicles released by glioma cells are decorated by Annexin A2 allowing for cellular uptake via heparan sulfate.
Efficient Therapy of Inflammatory Bowel Disease (IBD) with Highly Specific and Durable Targeted Ta2 C Modified with Chondroitin Sulfate (TACS).
Predicting Regioselectivity of Cytosolic Sulfotransferase Metabolism for Drugs.
Cerium Oxide and Chondroitin Sulfate Doped Polyurethane Scaffold to Bridge Tendons.
Hurler Syndrome (Mucopolysaccharidosis Type 1): A Case Report.
A model combining testosterone, Androstenedione and free testosterone index improved the diagnostic efficiency of polycystic ovary syndrome.
Marine Sulfated Polysaccharide PMGS Synergizes with Paclitaxel in Inhibiting Cervical Cancer In Vitro.
The role of glycosaminoglycan modification in Hedgehog regulated tissue morphogenesis.

Sci Adv. 2023 May 26. 9(21): eadf6232

Increased 3-O-sulfated heparan sulfate in Alzheimer's disease brain is associated with genetic risk gene HS3ST1.

Zhangjie Wang, Vaishali N Patel, Xuehong Song, Yongmei Xu, Andrea M Kaminski, Vivien Uyen Doan, Guowei Su, Yien Liao, Dylan Mah, Fuming Zhang, Vijayakanth Pagadala, Chunyu Wang, Lars C Pedersen, Lianchun Wang, Matthew P Hoffman, Marla Gearing, Jian Liu.

HS3ST1 is a genetic risk gene associated with Alzheimer's disease (AD) and overexpressed in patients, but how it contributes to the disease progression is unknown. We report the analysis of brain heparan sulfate (HS) from AD and other tauopathies using a LC-MS/MS method. A specific 3-O-sulfated HS displayed sevenfold increase in the AD group (n = 14, P < 0.0005). Analysis of the HS modified by recombinant sulfotransferases and HS from genetic knockout mice revealed that the specific 3-O-sulfated HS is made by 3-O-sulfotransferase isoform 1 (3-OST-1), which is encoded by the HS3ST1 gene. A synthetic tetradecasaccharide (14-mer) carrying the specific 3-O-sulfated domain displayed stronger inhibition for tau internalization than a 14-mer without the domain, suggesting that the 3-O-sulfated HS is used in tau cellular uptake. Our findings suggest that the overexpression of HS3ST1 gene may enhance the spread of tau pathology, uncovering a previously unidentified therapeutic target for AD.

DOI: https://doi.org/10.1126/sciadv.adf6232
Mar Drugs. 2023 Apr 25. pii: 264. [Epub ahead of print]21(5):

SPR Sensor-Based Analysis of the Inhibition of Marine Sulfated Glycans on Interactions between Monkeypox Virus Proteins and Glycosaminoglycans.

Peng He, Deling Shi, Yunran Li, Ke Xia, Seon Beom Kim, Rohini Dwivedi, Marwa Farrag, Vitor H Pomin, Robert J Linhardt, Jonathan S Dordick, Fuming Zhang.

  Sulfated glycans from marine organisms are excellent sources of naturally occurring glycosaminoglycan (GAG) mimetics that demonstrate therapeutic activities, such as antiviral/microbial infection, anticoagulant, anticancer, and anti-inflammation activities. Many viruses use the heparan sulfate (HS) GAG on the surface of host cells as co-receptors for attachment and initiating cell entry. Therefore, virion-HS interactions have been targeted to develop broad-spectrum antiviral therapeutics. Here we report the potential anti-monkeypox virus (MPXV) activities of eight defined marine sulfated glycans, three fucosylated chondroitin sulfates, and three sulfated fucans extracted from the sea cucumber species Isostichopus badionotus, Holothuria floridana, and Pentacta pygmaea, and the sea urchin Lytechinus variegatus, as well as two chemically desulfated derivatives. The inhibitions of these marine sulfated glycans on MPXV A29 and A35 protein-heparin interactions were evaluated using surface plasmon resonance (SPR). These results demonstrated that the viral surface proteins of MPXV A29 and A35 bound to heparin, which is a highly sulfated HS, and sulfated glycans from sea cucumbers showed strong inhibition of MPXV A29 and A35 interactions. The study of molecular interactions between viral proteins and host cell GAGs is important in developing therapeutics for the prevention and treatment of MPXV.

Keywords:  heparin; marine sulfated glycans; monkeypox virus; protein A29; protein A35; sea cucumbers; surface plasmon resonance

DOI:  https://doi.org/10.3390/md21050264
Physiol Rep. 2023 05;11(10): e15702

Loss of chondroitin sulfate proteoglycan sulfation allows delayed sympathetic reinnervation after cardiac ischemia-reperfusion.

Matthew R Blake, Diana C Parrish, Melanie A Staffenson, Morgan A Johnson, William R Woodward, Beth A Habecker.

Sympathetic nerve loss in the heart predicts the risk of ventricular arrhythmias after myocardial infarction (MI) in patients. Sympathetic denervation after cardiac ischemia-reperfusion is sustained by matrix components chondroitin sulfate proteoglycans (CSPGs) in the cardiac scar. We showed that 4,6-sulfation of CSPGs was critical for preventing nerve growth into the scar. Promoting early reinnervation with therapeutics reduces arrhythmias during the first 2 weeks after MI, but the longer-term consequences of restoring innervation are unknown. Therefore, we asked if the beneficial effects of early reinnervation were sustained. We compared cardiac function and arrhythmia susceptibility 40 days after MI in mice treated on Days 3-10 with vehicle or with intracellular sigma peptide to restore innervation. Surprisingly, both groups had normal innervation density in the cardiac scar 40 days after MI, indicating delayed reinnervation of the infarct in vehicle-treated mice. That coincided with similar cardiac function and arrhythmia susceptibility in the two groups. We investigated the mechanism allowing delayed reinnervation of the cardiac scar. We found that CSPG 4,6-sulfation, which is elevated early after ischemia-reperfusion, was reduced to control levels allowing reinnervation of the infarct. Thus, remodeling of extracellular matrix weeks after injury leads to remodeling of sympathetic neurons in the heart.

DOI: https://doi.org/10.14814/phy2.15702
Biomed Pharmacother. 2023 May 18. pii: S0753-3322(23)00684-4. [Epub ahead of print]164 114894

Enzymatic preparation of chondroitin sulfate oligosaccharides and its alleviating effect on ovariectomy-induced osteoporosis in rats.

Wei Zhang, Jikang Han, Zhiwen Jiang, Yanfei Peng, Xiaorui Sun, Baoqin Han.

  Postmenopausal osteoporosis is the most common type of osteoporosis. Chondroitin sulfate (CS) has been successfully employed as food supplement against osteoarthritis, while the therapeutic potential on postmenopausal osteoporosis is little explored. In this study, CS oligosaccharides (CSOs) were enzymatically prepared through the lysis of CS by a chondroitinase from Microbacterium sp. Strain. The alleviating effects of CS, CSOs and Caltrate D (a clinically used supplement) on ovariectomy (OVX) - induced rat's osteoporosis were comparatively investigated. Our data showed that the prepared CSOs was basically unsaturated CS disaccharide mixture of ∆Di4S (53.1%), ∆Di6S (27.7%) and ∆Di0S (17.7%). 12 weeks' intragastric administration of Caltrate D (250 mg/kg/d), CS or CSOs (500 mg/kg/d, 250 mg/kg/d, 125 mg/kg/d) could obviously regulate the disorder of serum indices, recover the mechanical strength and mineral content of bone, improve the cortical bones' density and the number and length of trabecular bones in OVX rats. Both CS and CSOs in 500 mg/kg/d and 250 mg/kg/d could restore more efficiently the serum indices, bone fracture deflection and femur Ca than Caltrate D. As compared with CS at the same dosage, CSOs exhibited a more significant alleviating effect. These findings suggested that there was great potential of CSOs as daily interventions for delaying the progression of postmenopausal osteoporosis.

Keywords:  Chondroitin sulfate oligosaccharides; Chondroitinase; Postmenopausal osteoporosis

DOI:  https://doi.org/10.1016/j.biopha.2023.114894
Curr Issues Mol Biol. 2023 May 10. 45(5): 4214-4227

Low-Molecular-Weight Chondroitin Sulfates Alleviate Simulated Microgravity-Induced Oxidative Stress and Bone Loss in Mice.

Rong Lan, Ye Li, Xinying Zhao, Rong Shen, Ruili Wang, Ruixin Mao, Shuangsheng Guo.

  (1) Background: Many studies have shown that microgravity experienced by astronauts or long-term bedridden patients results in increased oxidative stress and bone loss. Low-molecular-weight chondroitin sulfates (LMWCSs) prepared from intact chondroitin sulfate (CS) have been demonstrated to possess good antioxidant and osteogenic activities in vitro. This study aimed to assess the antioxidant activity of the LMWCSs in vivo and evaluate their potential in preventing microgravity-induced bone loss. (2) Methods: we used hind limb suspension (HLS) mice to simulate microgravity in vivo. We investigated the effects of LMWCSs against oxidative stress damage and bone loss in HLS mice and compared the findings with those of CS and a non-treatment group. (3) Results: LMWCSs reduced the HLS-induced oxidative stress level, prevented HLS-induced alterations in bone microstructure and mechanical strength, and reversed changes in bone metabolism indicators in HLS mice. Additionally, LMWCSs downregulated the mRNA expression levels of antioxidant enzyme- and osteogenic-related genes in HLS mice. The results showed that overall effect of LMWCSs was better than that of CS. (4) Conclusions: LMWCSs protect against the bone loss caused by simulated microgravity, which may be related to their ability to reduce oxidative stress. LMWCSs can be envisaged as potential antioxidants and bone loss protective agents in microgravity.

Keywords:  anti-bone loss; anti-oxidative stress; hindlimb suspension; low-molecular-chondroitin sulfate; simulated microgravity

DOI:  https://doi.org/10.3390/cimb45050268
Cancer Gene Ther. 2023 May 25.

Extracellular vesicles released by glioma cells are decorated by Annexin A2 allowing for cellular uptake via heparan sulfate.

Yu-Xi Song, Xin Li, Sheng-Dan Nie, Zhong-Xu Hu, Di Zhou, Ding-Ya Sun, Gao-Ya Zhou, Ying Wang, Jia-Jia Liu, Tao Song, Shan Wang.

Extracellular vesicles (EVs) play a crucial role in regulating cell behavior by delivering their cargo to target cells. However, the mechanisms underlying EV-cell interactions are not well understood. Previous studies have shown that heparan sulfate (HS) on target cell surfaces can act as receptors for exosomes uptake, but the ligand for HS on EVs has not been identified. In this study, we isolated EVs from glioma cell lines and glioma patients and identified Annexin A2 (AnxA2) on EVs as a key HS-binding ligand and mediator of EV-cell interactions. Our findings suggest that HS plays a dual role in EV-cell interactions, where HS on EVs captures AnxA2, and on target cells, it acts as a receptor for AnxA2. Removal of HS from the EV surface inhibits EV-target cell interaction by releasing AnxA2. Furthermore, we found that AnxA2-mediated binding of EVs to vascular endothelial cells promotes angiogenesis, and that antibody against AnxA2 inhibited the ability of glioma-derived EVs to stimulate angiogenesis by reducing the uptake of EVs. Our study also suggests that the AnxA2-HS interaction may accelerate the glioma-derived EVs-mediated angiogenesis and that combining AnxA2 on glioma cells with HS on endothelial cells may effectively improve the prognosis evaluation of glioma patients.

DOI: https://doi.org/10.1038/s41417-023-00627-w
Adv Mater. 2023 May 24. e2301585

Efficient Therapy of Inflammatory Bowel Disease (IBD) with Highly Specific and Durable Targeted Ta2 C Modified with Chondroitin Sulfate (TACS).

Xiangping Song, Qiong Huang, Yuqi Yang, Liang Ma, Wenguang Liu, Chunlin Ou, Qiaohui Chen, Tianjiao Zhao, Zuoxiu Xiao, Mingyuan Wang, Yitian Jiang, Yunrong Yang, Jinping Zhang, Yang Xiao, Yayun Nan, Wei Wu, Kelong Ai.

  Non-invasive localization of lesions and specific targeted therapy are still the main challenges for inflammatory bowel disease (IBD). Ta, as a medical metal element, has been widely used in the treatment of different diseases because of its excellent physicochemical properties, but is still far from being explored in IBD. Here, Ta2 C modified with chondroitin sulfate (CS) (TACS) was evaluated as a highly targeted therapy nanomedicine for IBD. Specifically, TACS was modified with dual targeting CS functions due to IBD lesion-specific positive charges and high expression of CD44 receptor. Thanks to the acid stability, sensitive CT imaging function and strong ROS elimination ability, oral TACS can accurately locate and delineate IBD lesions through non-invasive CT imaging, and specifically targeted treat IBD effectively because high levels of ROS are a central factor in the progression of IBD. As expected, TACS has much better imaging and therapeutic effects than clinical CT contrast agent and first-line drug 5-aminosalicylic acid, respectively. The mechanism of TACS treatment mainly involves protection of mitochondria, elimination of oxidative stress, inhibiting macrophage M1 polarization, protection of intestinal barrier, and restoration of intestinal flora balance. Collectively, this work provides unprecedented opportunities for oral nanomedicines to targeted therapy of IBD. This article is protected by copyright. All rights reserved.

Keywords:  Anti-inflammatory; Inflammatory bowel disease; ROS scavenger; TACS; specific CT imaging

DOI:  https://doi.org/10.1002/adma.202301585
J Chem Inf Model. 2023 May 25.

Predicting Regioselectivity of Cytosolic Sulfotransferase Metabolism for Drugs.

Mario Öeren, Sylvia C Kaempf, David J Ponting, Peter A Hunt, Matthew D Segall.

Cytosolic sulfotransferases (SULTs) are a family of enzymes responsible for the sulfation of small endogenous and exogenous compounds. SULTs contribute to the conjugation phase of metabolism and share substrates with the uridine 5'-diphospho-glucuronosyltransferase (UGT) family of enzymes. UGTs are considered to be the most important enzymes in the conjugation phase, and SULTs are an auxiliary enzyme system to them. Understanding how the regioselectivity of SULTs differs from that of UGTs is essential from the perspective of developing novel drug candidates. We present a general ligand-based SULT model trained and tested using high-quality experimental regioselectivity data. The current study suggests that, unlike other metabolic enzymes in the modification and conjugation phases, the SULT regioselectivity is not strongly influenced by the activation energy of the rate-limiting step of the catalysis. Instead, the prominent role is played by the substrate binding site of SULT. Thus, the model is trained only on steric and orientation descriptors, which mimic the binding pocket of SULT. The resulting classification model, which predicts whether a site is metabolized, achieved a Cohen's kappa of 0.71.

DOI: https://doi.org/10.1021/acs.jcim.3c00275
ACS Appl Mater Interfaces. 2023 May 23.

Cerium Oxide and Chondroitin Sulfate Doped Polyurethane Scaffold to Bridge Tendons.

Eleonora Bianchi, Marco Ruggeri, Barbara Vigani, Elena Del Favero, Caterina Ricci, Cinzia Boselli, Antonia Icaro Cornaglia, César Viseras, Silvia Rossi, Giuseppina Sandri.

  Tendon disorders are common medical conditions, which can be greatly debilitating as they are often accompanied by great pain and inflammation. The techniques used nowadays for the treatment of chronic tendon injuries often involve surgery. However, one critical aspect of this procedure involves the scar tissue, characterized by mechanical properties that vary from healthy tissue, rendering the tendons inclined to reinjury or rupture. Synthetic polymers, such as thermoplastic polyurethane, are of special interest in the tissue engineering field as they allow the production of scaffolds with controlled elastic and mechanical properties, which could guarantee an effective support during the new tissue formation. The aim of this work was the design and the development of tubular nanofibrous scaffolds based on thermoplastic polyurethane and enriched with cerium oxide nanoparticles and chondroitin sulfate. The scaffolds were characterized by remarkable mechanical properties, especially when tubular aligned, reaching values comparable to the ones of the native tendons. A weight loss test was performed, suggesting a degradation in prolonged times. In particular, the scaffolds maintained their morphology and also remarkable mechanical properties after 12 weeks of degradation. The scaffolds promoted the cell adhesion and proliferation, in particular when in aligned conformation. Finally, the systems in vivo did not cause any inflammatory effect, representing interesting platforms for the regeneration of injured tendons.

Keywords:  cerium oxide; chondroitin sulfate; electrospinning; mechanical properties; tendon disorders; thermoplastic polyurethane

DOI:  https://doi.org/10.1021/acsami.3c06144
Cureus. 2023 Apr;15(4): e37785

Hurler Syndrome (Mucopolysaccharidosis Type 1): A Case Report.

Noman Khalid, Muhammad Abdullah, Abeer Bin Awais, Muhammad Hassan, Ameer Muhammad.

  Hurler syndrome is a rare autosomal recessive disorder of deficiency in the metabolism of glycosaminoglycans (GAGs), including heparan sulfate and dermatan sulfate, which consequently accumulate in the different organs of the body, resulting from deficiency of an enzyme named Alpha-L-iduronidase. Here, we present an interesting case of a young female patient who presented with a combination of skeletal, oro-facial, ophthalmologic, neurological, and radiological findings of this disease. A diagnosis of Hurler syndrome (Mucopolysaccharidosis Type I) was made late in the disease due to lack of facilities, and the patient was ultimately managed supportively.

Keywords:  alpha l iduronidase; glycosaminoglycans; hurler syndrome; lysosomal storage disorder; mucopolysaccharidosis type 1

DOI:  https://doi.org/10.7759/cureus.37785
Endocr Pract. 2023 May 22. pii: S1530-891X(23)00414-7. [Epub ahead of print]

A model combining testosterone, Androstenedione and free testosterone index improved the diagnostic efficiency of polycystic ovary syndrome.

Wanwan Yi, Mengyu Zhang, XueYu Yuan, Lishuai Shi, Xie Yuan, Ming Sun, Jin Liu, Haidong Cai, Zhongwei Lv.

   OBJECTIVE: Hyperandrogenism is frequently observed in patients with polycystic ovary (PCOS). The purpose of this study was to develop an easy-to-use tool for predicting polycystic ovary syndrome (PCOS) and to evaluate and compare the value of androstenedione (Andro) and other hormone indicators in the diagnosis of patients with hyperandrogenic PCOS.
METHODS: This study included 139 women diagnosed with hyperandrogenic PCOS according to the Rotterdam criteria and 74 healthy control women from Shanghai Tenth People's Hospital. The serum hormone levels of the patients and controls were measured using a chemiluminescence immunoassay (CLIA) and incorporated for further analysis.
RESULTS: Total testosterone (TT), Andro, Dehydroepiandrosterone sulfate (DHEAS), and Free androgen index (FAI) were significantly higher in the PCOS group than the control group. Further, Andro, FSH, LH, TT, FAI and LH/FSH in the hyper-androstenedione (HA) group were higher than the normal Andro (NA) group. The Youden index was the highest for Andro (0.65), with 81.82% sensitivity and 83.16% specificity. Correlation analysis showed that FSH, LH, TT, FAI, Insulin Sensitivity Index (ISI), and LH/FSH were positively correlated with Andro, while Fasting blood glucose (FPG) and two-hour postprandial blood glucose (2h PG) were negatively correlated with Andro.
CONCLUSIONS: The model using Andro, TT, FAI may help to identifying women with undiagnosed PCOS. Serum Andro is a meaningful biomarker for hyperandrogenism in PCOS patients and may further aid disease diagnosis.

Keywords:  PCOS; androstenedione; diagnostic; hyperandrogenism; steroid hormones

DOI:  https://doi.org/10.1016/j.eprac.2023.05.007
Mar Drugs. 2023 Apr 23. pii: 259. [Epub ahead of print]21(5):

Marine Sulfated Polysaccharide PMGS Synergizes with Paclitaxel in Inhibiting Cervical Cancer In Vitro.

Xuan Xia, Yanhong Wang, Yingchun Shao, Jiazhen Xu, Bing Liang, Wenjing Liu, Jun Zeng, Chunxia Li, Huashi Guan, Shixin Wang, Dongming Xing.

  The incidence and mortality of cervical cancer in female malignancies are second only to breast cancer, which brings a heavy health and economic toll worldwide. Paclitaxel (PTX)-based regimens are the first-class choice; however, severe side effects, poor therapeutic effects, and difficulty in effectively preventing tumor recurrence or metastasis are unavoidable. Therefore, it is necessary to explore effective therapeutic interventions for cervical cancer. Our previous studies have shown that PMGS, a marine sulfated polysaccharide, exhibits promising anti-human papillomavirus (anti-HPV) effects through multiple molecular mechanisms. In this article, a continuous study identified that PMGS, as a novel sensitizer, combined with PTX exerted synergistic anti-tumor effects on cervical cancer associated with HPV in vitro. Both PMGS and PTX inhibited the proliferation of cervical cancer cells, and the combination of PMGS with PTX displayed significant synergistic effects on Hela cells. Mechanistically, PMGS synergizes with PTX by enhancing cytotoxicity, inducing cell apoptosis and inhibiting cell migration in Hela cells. Collectively, the combination of PTX and PMGS potentially provides a novel therapeutic strategy for cervical cancer.

Keywords:  cervical cancer; marine sulfated polysaccharides; paclitaxel; synergistic effect

DOI:  https://doi.org/10.3390/md21050259
Biochem Soc Trans. 2023 May 24. pii: BST20220719. [Epub ahead of print]

The role of glycosaminoglycan modification in Hedgehog regulated tissue morphogenesis.

Fabian Gude, Jurij Froese, Georg Steffes, Kay Grobe.

  Patterns of gene expression, cell growth and cell-type specification during development are often regulated by morphogens. Morphogens are signalling molecules produced by groups of source cells located tens to hundreds of micrometers distant from the responding tissue and are thought to regulate the fate of receiving cells in a direct, concentration-dependent manner. The mechanisms that underlie scalable yet robust morphogen spread to form the activity gradient, however, are not well understood and are currently intensely debated. Here, based on two recent publications, we review two in vivo derived concepts of regulated gradient formation of the morphogen Hedgehog (Hh). In the first concept, Hh disperses on the apical side of developing epithelial surfaces using the same mechanistic adaptations of molecular transport that DNA-binding proteins in the nucleus use. In the second concept, Hh is actively conveyed to target cells via long filopodial extensions, called cytonemes. Both concepts require the expression of a family of sugar-modified proteins in the gradient field called heparan sulphate proteoglycans as a prerequisite for Hh dispersal, yet propose different - direct versus indirect - roles of these essential extracellular modulators.

Keywords:  Drosophila; Hedgehog; cytoneme; development; glypican; heparan sulphate

DOI:  https://doi.org/10.1042/BST20220719