bims-supasi 2023-06-25 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2023–06–25
eleven papers selected by
Jonathan Wolf Mueller, University of Birmingham

Efficient platform for synthesizing comprehensive heparan sulfate oligosaccharide libraries for decoding glycosaminoglycan-protein interactions.
VSIG4 interaction with heparan sulfates inhibits VSIG4-complement binding.
New structural insights provide a different angle on steroid sulfatase action.
Cholesterol sulfate inhibits osteoclast differentiation and survival by regulating the AMPK-Sirt1-NF-κB pathway.
Conformations, interactions and functions of intrinsically disordered syndecans.
Indoxyl sulfate inhibits muscle cell differentiation via Myf6/MRF4 and MYH2 downregulation.
Fast profiling of primary, secondary, conjugated, and sulfated bile acids in human urine and murine feces samples.
Pharmacokinetics of oral tapentadol in cats.
Serum Levels of Indoxyl Sulfate and P-cresol in Type II Diabetic Patients With and Without Nephropathy.
Efficacy of resveratrol in women with polycystic ovary syndrome: a systematic review and meta-analysis of randomized clinical trials.
Self-Assembled Sulfated Hyaluronan Coating Modulates Transforming Growth Factor-Beta1 Penetration for Corneal Scarring Alleviation.

Nat Chem. 2023 Jun 22.

Efficient platform for synthesizing comprehensive heparan sulfate oligosaccharide libraries for decoding glycosaminoglycan-protein interactions.

Lei Wang, Alexander W Sorum, Bo-Shun Huang, Mallory K Kern, Guowei Su, Nitin Pawar, Xuefei Huang, Jian Liu, Nicola L B Pohl, Linda C Hsieh-Wilson.

Glycosaminoglycans (GAGs) are abundant, ubiquitous carbohydrates in biology, yet their structural complexity has limited an understanding of their biological roles and structure-function relationships. Synthetic access to large collections of well defined, structurally diverse GAG oligosaccharides would provide critical insights into this important class of biomolecules and represent a major advance in glycoscience. Here we report a new platform for synthesizing large heparan sulfate (HS) oligosaccharide libraries displaying comprehensive arrays of sulfation patterns. Library synthesis is made possible by improving the overall synthetic efficiency through universal building blocks derived from natural heparin and a traceless fluorous tagging method for rapid purification with minimal manual manipulation. Using this approach, we generated a complete library of 64 HS oligosaccharides displaying all possible 2-O-, 6-O- and N-sulfation sequences in the tetrasaccharide GlcN-IdoA-GlcN-IdoA. These diverse structures provide an unprecedented view into the sulfation code of GAGs and identify sequences for modulating the activities of important growth factors and chemokines.

DOI: https://doi.org/10.1038/s41557-023-01248-4
Glycobiology. 2023 Jun 21. pii: cwad050. [Epub ahead of print]

VSIG4 interaction with heparan sulfates inhibits VSIG4-complement binding.

S Y Ebstein, A Rafique, Y Zhou, A Krasco, W Montalvo-Ortiz, L Yu, L Custodio, R C Adam, N Bloch, K Lee, F Adewale, D Vergata, A Luz, S Coquery, B Daniel, E Ullman, M C Franklin, A Hermann, T Huang, W Olson, S Davis, A J Murphy, M A Sleeman, J Wei, D Skokos.

  V-set and immunoglobulin domain-containing 4 (VSIG4) is a complement receptor of the immunoglobulin superfamily that is specifically expressed on tissue resident macrophages, and its many reported functions and binding partners suggest a complex role in immune function. VSIG4 is reported to have a role in immune surveillance as well as in modulating diverse disease phenotypes such as infections, autoimmune conditions, and cancer. However, the mechanism(s) governing VSIG4's complex, context-dependent role in immune regulation remain elusive. Here, we identify cell surface and soluble glycosaminoglycans (GAGs), specifically heparan sulfates, as novel binding partners of VSIG4. We demonstrate that genetic deletion of heparan sulfate synthesis enzymes or cleavage of cell-surface heparan sulfates reduced VSIG4 binding to the cell surface. Furthermore, binding studies demonstrate that VSIG4 interacts directly with heparan sulfates, with a preference for highly sulfated moieties and longer GAG chains. To assess the impact on VSIG4 biology, we show that heparan sulfates compete with known VSIG4 binding partners C3b and iC3b. Further, mutagenesis studies indicate this competition occurs through overlapping binding epitopes for heparan sulfates and complement on VSIG4. Together these data suggest a novel role for heparan sulfates in VSIG4-dependent immune modulation.

Keywords:  Complement; Glycosaminoglycan; Heparan sulfate; Heparin-binding-protein; VSIG4

DOI:  https://doi.org/10.1093/glycob/cwad050
J Steroid Biochem Mol Biol. 2023 Jun 17. pii: S0960-0760(23)00108-5. [Epub ahead of print]232 106353

New structural insights provide a different angle on steroid sulfatase action.

P A Foster, J W Mueller.

  A central part of human sulfation pathways is the spatially and temporally controlled desulfation of biologically highly potent steroid hormones. The responsible enzyme - steroid sulfatase (STS) - is highly expressed in placenta and peripheral tissues, such as fat, colon, and the brain. The shape of this enzyme and its mechanism are probably unique in biochemistry. STS was believed to be a transmembrane protein, spanning the Golgi double-membrane by stem region formed by two extended internal alpha-helices. New crystallographic data however challenge this view. STS now is portraited as a trimeric membrane-associated complex. We discuss the impact of these results on STS function and sulfation pathways in general and we hypothesis that this new STS structural understanding suggests product inhibition to be a regulator of STS enzymatic activity.

Keywords:  Membrane-associated; Steroid sulfatase; Structural biology; Sulfation pathways; Trimer formation

DOI:  https://doi.org/10.1016/j.jsbmb.2023.106353
J Cell Physiol. 2023 Jun 19.

Cholesterol sulfate inhibits osteoclast differentiation and survival by regulating the AMPK-Sirt1-NF-κB pathway.

Jin Ha Park, Jiae Lee, Gong-Rak Lee, Minjeong Kwon, Hye In Lee, Narae Kim, Hee Jin Kim, Mi-Ock Lee, Woojin Jeong.

  Cholesterol sulfate (CS) is an activator of retinoic acid-related orphan receptor α (RORα). CS treatment or RORα overexpression attenuates osteoclastogenesis in a collagen-induced arthritis mouse model. However, the mechanism by which CS and RORα regulate osteoclast differentiation remains largely unknown. Thus, we aimed to investigate the role of CS and RORα in osteoclastogenesis and their underlying mechanism. CS inhibited osteoclast differentiation, but RORα deficiency did not affect osteoclast differentiation and CS-mediated inhibition of osteoclastogenesis. CS enhanced adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and sirtuin1 (Sirt1) activity, leading to nuclear factor-κB (NF-κB) inhibition by decreasing acetylation at Lys310 of p65. The NF-κB inhibition was restored by AMPK inhibitor, but the effects of CS on AMPK and NF-κB were not altered by RORα deficiency. CS also induced osteoclast apoptosis, which may be due to sustained AMPK activation and consequent NF-κB inhibition, and the effects of CS were significantly reversed by interleukin-1β treatment. Collectively, these results indicate that CS inhibits osteoclast differentiation and survival by suppressing NF-κB via the AMPK-Sirt1 axis in a RORα-independent manner. Furthermore, CS protects against bone destruction in lipopolysaccharide- and ovariectomy-mediated bone loss mouse models, suggesting that CS is a useful therapeutic candidate for treating inflammation-induced bone diseases and postmenopausal osteoporosis.

Keywords:  AMPK; NF-κB; Sirt1; cholesterol sulfate; osteoclast

DOI:  https://doi.org/10.1002/jcp.31064
Biochem Soc Trans. 2023 Jun 19. pii: BST20221085. [Epub ahead of print]

Conformations, interactions and functions of intrinsically disordered syndecans.

Sylvie Ricard-Blum, John R Couchman.

  Syndecans are transmembrane heparan sulfate proteoglycans present on most mammalian cell surfaces. They have a long evolutionary history, a single syndecan gene being expressed in bilaterian invertebrates. Syndecans have attracted interest because of their potential roles in development and disease, including vascular diseases, inflammation and various cancers. Recent structural data is providing important insights into their functions, which are complex, involving both intrinsic signaling through cytoplasmic binding partners and co-operative mechanisms where syndecans form a signaling nexus with other receptors such as integrins and tyrosine kinase growth factor receptors. While the cytoplasmic domain of syndecan-4 has a well-defined dimeric structure, the syndecan ectodomains are intrinsically disordered, which is linked to a capacity to interact with multiple partners. However, it remains to fully establish the impact of glycanation and partner proteins on syndecan core protein conformations. Genetic models indicate that a conserved property of syndecans links the cytoskeleton to calcium channels of the transient receptor potential class, compatible with roles as mechanosensors. In turn, syndecans influence actin cytoskeleton organization to impact motility, adhesion and the extracellular matrix environment. Syndecan clustering with other cell surface receptors into signaling microdomains has relevance to tissue differentiation in development, for example in stem cells, but also in disease where syndecan expression can be markedly up-regulated. Since syndecans have potential as diagnostic and prognostic markers as well as possible targets in some forms of cancer, it remains important to unravel structure/function relationships in the four mammalian syndecans.

Keywords:  co-receptors; interaction networks; intrinsically disordered proteins; proteoglycan; signaling

DOI:  https://doi.org/10.1042/BST20221085
Nephrol Dial Transplant. 2023 Jun 22. pii: gfad123. [Epub ahead of print]

Indoxyl sulfate inhibits muscle cell differentiation via Myf6/MRF4 and MYH2 downregulation.

Stanislas Bataille, Nathalie McKay, Laetitia Koppe, Alice Beau, Bérengère Benoit, Marc Bartoli, Nathalie Da Silva, Stéphane Poitevin, Julien Aniort, Rania Chermiti, Stéphane Burtey, Laetitia Dou.

   BACKGROUND: Chronic kidney disease is associated with a significant decrease in muscle strength and mass, possibly related to muscle cell damage by uremic toxins. Here, we studied in vitro and in vivo the effect of indoxyl sulfate (IS), an indolic uremic toxin, on myoblast proliferation, differentiation, expression of myogenic regulatory factors (MRF): myoblast determination protein 1 (MyoD1), myogenin (Myog), Myogenic Factor 5 (Myf5), and myogenic regulatory factor 4 (Myf6 /MRF4), and expression of myosin heavy chain, Myh2.
METHODS: C2C12 myoblasts were cultured in vitro and differentiated in myotubes for 7 days in presence of IS at a uremic concentration of 200 µM. Myocytes morphology and differentiation was analyzed after Hematoxylin-eosin staining. MRF genes expression was studied using RT-PCR in myocytes and 5/6th nephrectomized mice muscle. Myf6 /MRF4 protein expression was studied using ELISA; MYH2 protein expression was studied using western blotting. The role of Aryl Hydrocarbon Receptor (AHR) - the cell receptor of IS- was studied by adding an AHR inhibitor in cell culture milieu.
RESULTS: In presence of IS, myotubes obtained were narrower and had less nuclei than control myotubes. The presence of IS during differentiation did not modify the gene expression of the MRFs Myf5, MyoD1, and Myog, but induced a decrease in expression of Myf6/MRF4 and MYH2 at the mRNA and the protein level. AHR inhibition by CH223191 did not reverse the decrease in Myf6/MRF4 mRNA expression induced by IS, which rules out the implication of the ARH genomic pathway. In 5/6th nephrectomized mice, Myf6/MRF4 gene was down-regulated in striated muscles.
CONCLUSION: In conclusion, IS inhibits Myf6/MRF4 and MYH2 expression during differentiation of muscle cells, which could lead to a defect in myotube structure. Through these new mechanisms, IS could participate in muscle atrophy observed in chronic kidney disease.

Keywords:  chronic kidney disease; indoxyl sulfate; myogenesis; uremic toxin

DOI:  https://doi.org/10.1093/ndt/gfad123
Anal Bioanal Chem. 2023 Jun 20.

Fast profiling of primary, secondary, conjugated, and sulfated bile acids in human urine and murine feces samples.

Victoria Ramos-Garcia, Isabel Ten-Doménech, Máximo Vento, Clara Bullich-Vilarrubias, Marina Romaní-Pérez, Yolanda Sanz, Angelica Nobili, Marika Falcone, Marina Di Stefano, Guillermo Quintás, Julia Kuligowski.

  Bile acids (BAs) are a complex class of metabolites that have been described as specific biomarkers of gut microbiota activity. The development of analytical methods allowing the quantification of an ample spectrum of BAs in different biological matrices is needed to enable a wider implementation of BAs as complementary measures in studies investigating the functional role of the gut microbiota. This work presents results from the validation of a targeted ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for the determination of 28 BAs and six sulfated BAs, covering primary, secondary, and conjugated BAs. The analysis of 73 urine and 20 feces samples was used to test the applicability of the method. Concentrations of BAs in human urine and murine feces were reported, ranging from 0.5 to 50 nmol/g creatinine and from 0.012 to 332 nmol/g, respectively. Seventy-nine percent of BAs present in human urine samples corresponded to secondary conjugated BAs, while 69% of BAs present in murine feces corresponded to primary conjugated BAs. Glycocholic acid sulfate (GCA-S) was the most abundant BA in human urine samples, while taurolithocholic acid was the lowest concentrated compound detected. In murine feces, the most abundant BAs were α-murocholic, deoxycholic, dehydrocholic, and β-murocholic acids, while GCA-S was the lowest concentrated BA. The presented method is a non-invasive approach for the simultaneous assessment of BAs and sulfated BAs in urine and feces samples, and the results will serve as a knowledge base for future translational studies focusing on the role of the microbiota in health.

Keywords:  Bile acids; Human urine; Microbiota; Murine feces

DOI:  https://doi.org/10.1007/s00216-023-04802-8
J Vet Pharmacol Ther. 2023 Jun 23.

Pharmacokinetics of oral tapentadol in cats.

J Lakritz, T K Aarnes, B Alva, J Howard, G Magnin, P Lerche, B Kukanich.

  To evaluate pharmacokinetics of one dose of tapentadol hydrochloride orally administered to cats. Prospective experimental study. Five healthy adult mixed-breed cats. Each cat received 18.8 ± 1.0 mg/kg tapentadol orally. Venous blood samples were collected at time 0 (immediately prior to administration of tapentadol) 1, 2, 5, 10, 15, 30, 45, 60, 90 min, and 2, 4, 8, 12 to 24 h after drug administration. Plasma tapentadol concentrations and its metabolites were determined using ultra-performance liquid chromatography-tandem mass spectrometry. Geometric mean Tmax of tapentadol, desmethyltapentadol, tapentadol-O-glucuronide, and tapentadol-O-sulfate was 2.3, 7.0, 6.0, and 4.6 h, respectively. Mean Cmax of tapentadol, desmethyltapentadol, tapentadol-O-glucuronide, and tapentadol-O-sulfate was 637, 66, 1134, and 15,757 ng/mL, respectively, after administration. Mean half-life of tapentadol, desmethyltapentadol, tapentadol-O-glucuronide, and tapentadol-O-sulfate was 2.4, 4.7, 2.9, and 10.8 h. The relative exposure of tapentadol and its metabolites were tapentadol 2.65%, desmethyltapentadol 0.54%, tapentadol-O-glucuronide 6.22%, and tapentadol-O-sulfate 90.6%. Tapentadol-O-sulfate was the predominant metabolite following the administration of oral tapentadol in cats. Further studies are warranted to evaluate the association of analgesia with plasma concentrations of tapentadol.

Keywords:  cats; opioids; pharmacokinetics; tapentadol

DOI:  https://doi.org/10.1111/jvp.13399
Iran J Kidney Dis. 2023 May;17(3): 126-134

Serum Levels of Indoxyl Sulfate and P-cresol in Type II Diabetic Patients With and Without Nephropathy.

Roghayeh Oladi-Ghadikolaei, Akbar Aliasgharzadeh, Ali Shayanfar, Jafar Soleymani, Milad Moradi, Abolghasem Jouyban, Hamid Tayebi Khosroshahi.

INTRODUCTION: Indoxyl sulfate (IS) and para-cresol (p-cresol) are uremic toxins with high protein bonding index that accumulate in the body with decreasing kidney function. The main purpose of the current investigation was to compare the concentration of p-cresol and IS in serum of the type II diabetic individuals with and without nephropathy.
METHODS: Fifty-five patients with type II diabetes mellitus were divided into two groups: case and control. The case group consisted of 26 diabetic patients with nephropathy (proteinuria and serum creatinine below 1.5 mg/dL) without any other kidney diseases. The control group included 29 patients without diabetic nephropathy. Patients with advanced heart disease, cerebrovascular accident and other inflammatory or infectious diseases were excluded. Five mL of venous blood was taken from each patient in the morning fasting state. Then other laboratory tests including serum uric acid and creatinine levels, serum urea nitrogen, lipids and glucose were measured by standard methods. P-Cresol and IS levels were measured by the spectrofluorimetric method after extraction. We also filled out a checklist with information regarding the duration of their disease, medication history (oral or injectable), and other demographic information. There were no significant differences between the two groups regarding the investigated factors Results. There were no significant difference among the investigated factors between the two groups (P > .05) except for the serum creatinine, proteinuria and estimated glomerular filtration rate, where the mean values of cases were considerably higher than those of the controls. Serum IS and p-cresol levels were also significantly higher in the case group (P < .05).
CONCLUSION: According to the findings, it seems that IS, and p-cresol may play a role in the development of diabetic nephropathy and other complications of diabetes mellitus. DOI: 10.52547/ijkd.7266.
Pan Afr Med J. 2023 ;44 134

Efficacy of resveratrol in women with polycystic ovary syndrome: a systematic review and meta-analysis of randomized clinical trials.

Hammad Ali Fadlalmola, Amal Mohammed Elhusein, Khaled Mohammed Al-Sayaghi, Muayad Saud Albadrani, Duggahatti Veerabhadra Swamy, Daniel Mon Mamanao, Ehab Ibrahim El-Amin, Salma Elhadi Ibrahim, Siddiqa Mohammed Abbas.

  Polycystic ovarian syndrome (PCOS) is a metabolic and hormonal condition affecting women of a reproductive age. It causes an abnormal menstrual cycle, anovulation, infertility, acne, hirsutism, obesity, hyperlipidemia, and cardiovascular disorders. Because resveratrol decreases testosterone levels, it may be of value in treating PCOS. We aimed to evaluate the efficacy of resveratrol in treating women with PCOS. We searched for randomized clinical trials (RCTs) in PubMed, Cochrane CENTRAL, Scopus and Web of Science. With 95% confidence intervals, the data was retrieved and analyzed as a mean difference (MD) or a standardized mean difference (SMD). Four RCTs with 218 women were included in the analysis. Resveratrol significantly reduced testosterone (SMD = -0.40; 95% CI [-0.71, -0.10], P = 0.009), luteinizing hormone (LH) (SMD = -0.32; 95% CI [-0.62, 0.01], P = 0.04), and dehydroepiandrosterone sulfate (DHEAS) (MD = -0.85; 95% CI [-1.25, -0.45], P < 0.0001) compared with the placebo. Resveratrol is effective in treating women with PCOS due to reducing the levels of testosterone, LH, and DHEAS. In combination with other treatments, especially for hyperlipidemia, resveratrol is beneficial for women diagnosed with PCOS.

Keywords:  Meta-analysis; polycystic ovary syndrome; resveratrol; systematic review

DOI:  https://doi.org/10.11604/pamj.2023.44.134.32404
ACS Appl Mater Interfaces. 2023 Jun 21.

Self-Assembled Sulfated Hyaluronan Coating Modulates Transforming Growth Factor-Beta1 Penetration for Corneal Scarring Alleviation.

Yongrui Huang, Jia Liu, Xiaomin Sun, Yuehai Peng, Yingni Xu, Sa Liu, Wenjing Song, Li Ren.

  Corneal scarring caused by epithelial-stromal injury impairs corneal transparency and visual acuity. Excess secretion of transforming growth factor-beta 1 (TGF-β1), which promotes wound closure, penetrates the corneal stroma via defects in the epithelial basement membrane and induces the differentiation of corneal fibroblasts to myofibroblasts, leading to scar formation. Modulating TGF-β1 penetration might alleviate corneal scar formation and restore transparency. In this study, sulfated hyaluronan (sHA) coatings were self-assembled above wounded corneal stroma to modulate TGF-β1 penetration, and their ability to alleviate corneal scarring was investigated. The formation of sHA coatings was rapid (within 30 s), and the high-sulfated hyaluronan coating efficiently blocked penetration by TGF-β1 and reduced the concentration of TGF-β1 in the corneal stroma. Further investigation showed that the ability of TGF-β1 to induce differentiation of corneal fibroblasts into myofibroblasts was inhibited by sHA binding. Evaluation of corneal scarring with sHA coating in a rabbit model of lamellar resection indicated that a sHA (high sulfation) coating effectively reduced scar formation. Immunohistochemical staining of α-smooth muscle actin and optical coherence tomography of the anterior segment showed minimal scar tissue formation in the sHA group. This work presents a promising alternative to alleviate scarring in corneal epithelial-stromal injury.

Keywords:  TGF-β1; coating; corneal scarring; corneal stromal surface; sulfated hyaluronan

DOI:  https://doi.org/10.1021/acsami.3c02910