bims-supasi 2022-09-11 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2022–09–11
ten papers selected by
Jonathan Wolf Mueller, University of Birmingham

Heparan sulfate proteoglycans (HSPGs) of the ocular lens.
Oxidized chondroitin sulfate eye drops ameliorate the prognosis of fungal keratitis with anti-inflammatory and antifungal effects.
Sulfation of 12-hydroxy-nevirapine by human SULTs and the effects of genetic polymorphisms of SULT1A1 and SULT2A1.
11-oxygenated C19 steroids are the predominant androgens responsible for hyperandrogenemia in Cushing's disease.
Heparan Sulfate and Sialic Acid in Viral Attachment: Two Sides of the Same Coin?
Sulfated Galactans from Gracilaria fisheri with Supplementation of Octanoyl Promote Wound Healing Activity In Vitro and In Vivo.
Effects of sulfated polysaccharides from Laminaria japonica on regularating the gut microbiotan and alleviating intestinal inflammation in obese mice.
Two novel predictive biomarkers for osteosarcoma and glycolysis pathways: A profiling study on HS2ST1 and SDC3.
Investigation of free and conjugated estrogen fate and emission coefficients in three duck farms.
Low Serum Total Testosterone Is Associated with Non-Alcoholic Fatty Liver Disease in Men but Not in Women with Type 2 Diabetes Mellitus.

Prog Retin Eye Res. 2022 Sep 03. pii: S1350-9462(22)00078-7. [Epub ahead of print] 101118

Heparan sulfate proteoglycans (HSPGs) of the ocular lens.

Tayler F L Wishart, Frank J Lovicu.

Heparan sulfate proteoglycans (HSPGs) reside in most cells; on their surface, in the pericellular milieu and/or extracellular matrix. In the eye, HSPGs can orchestrate the activity of key signalling molecules found in the ocular environment that promote its development and homeostasis. To date, our understanding of the specific roles played by individual HSPG family members, and the heterogeneity of their associated sulfated HS chains, is in its infancy. The crystalline lens is a relatively simple and well characterised ocular tissue that provides an ideal stage to showcase and model the expression and unique roles of individual HSPGs. Individual HSPG core proteins are differentially localised to eye tissues in a temporal and spatial developmental- and cell-type specific manner, and their loss or functional disruption results in unique phenotypic outcomes for the lens, and other ocular tissues. More recent work has found that different HS sulfation enzymes are also presented in a cell- and tissue-specific manner, and that disruption of these different sulfation patterns affects specific HS-protein interactions. Not surprisingly, these sulfated HS chains have also been reported to be required for lens and eye development, with dysregulation of HS chain structure and function leading to pathogenesis and eye-related phenotypes. In the lens, HSPGs undergo significant and specific changes in expression and function that can drive pathology, or in some cases, promote tissue repair. As master signalling regulators, HSPGs may one day serve as valuable biomarkers, and even as putative targets for the development of novel therapeutics, not only for the eye but for many other systemic pathologies.

DOI: https://doi.org/10.1016/j.preteyeres.2022.101118
J Mater Chem B. 2022 Sep 07.

Oxidized chondroitin sulfate eye drops ameliorate the prognosis of fungal keratitis with anti-inflammatory and antifungal effects.

Xue Tian, Xudong Peng, Xiaojing Long, Jing Lin, Yingxue Zhang, Lu Zhan, Guiqiu Zhao.

Fungal keratitis (FK) is a refractory ophthalmic disease that can result in vision impairment and even blindness due to the severe fungal invasiveness and excessive inflammatory response. Therefore, antifungal treatment combined with local immunosuppressive therapy is regarded as the most effective strategy to improve the clinical outcome of FK. Oxidized polysaccharides with aldehyde groups possess obvious inhibitory activity towards microorganisms. Herein, we use chondroitin sulfate (CS), a recognized anti-inflammatory biopolysaccharide, to prepare oxidized chondroitin sulfate (OCS) via sodium periodate (NaIO4) oxidation for the treatment of FK. The chemical structure of OCS was characterized by FTIR, 1H NMR, and XPS, revealing that the O-dihydroxy in the D-glucuronic acid unit of CS was selectively broken by NaIO4, forming active aldehyde groups. The introduction of aldehydes not only retains the anti-inflammatory activity but also confers OCS with antifungal property. In vitro antifungal experiments showed that OCS inhibits the growth, represses the biofilm formation and alters the membrane integrity of A. fumigatus. The toxicity of OCS was evaluated by cytotoxicity tests (CCK-8) and the Draize eye test in vitro and in vivo. qRT-PCR confirmed that OCS had similar anti-inflammatory activity as CS. In mice with A. fumigatus keratitis, OCS versus CS or PBS showed an excellent therapeutic effect, characterized by a lower corneal inflammation score, less fungal load, reduced neutrophil recruitment, and the downregulated expression of pro-inflammatory factors. Our findings demonstrate that OCS improves the prognosis of A. fumigatus keratitis in mice by inhibiting the growth of fungi, reducing the recruitment of neutrophils and inhibiting the inflammatory response. It provides innovative ideas for the development and application of OCS in medicine and biomaterials fields.

DOI: https://doi.org/10.1039/d2tb00114d
Biochem Pharmacol. 2022 Sep 06. pii: S0006-2952(22)00337-9. [Epub ahead of print] 115243

Sulfation of 12-hydroxy-nevirapine by human SULTs and the effects of genetic polymorphisms of SULT1A1 and SULT2A1.

Katsuhisa Kurogi, Yanshan Cao, Koshi Segawa, Yoichi Sakakibara, Masahito Suiko, Jack Uetrecht, Ming-Cheh Liu.

  Nevirapine (NVP) is an effective drug for the treatment of HIV infections, but its use is limited by a high incidence of severe skin rash and liver injury. 12-Hydroxynevirapine (12-OH-NVP) is the major metabolite of nevirapine. There is strong evidence that the sulfate of 12-OH-NVP is responsible for the skin rash. While several cytosolic sulfotransferases (SULTs) have been shown to be capable of sulfating 12-OH-NVP, the exact mechanism of sulfation in vivo is unclear. The current study aimed to clarify human SULT(s) and human organs that are capable of sulfating 12-OH-NVP and investigate the metabolic sulfation of 12-OH-NVP using cultured HepG2 human hepatoma cells. Enzymatic assays revealed that of the thirteen human SULTs, SULT1A1 and SULT2A1 displayed strong 12-OH-NVP-sulfating activity. 1-Phenyl-1-hexanol (PHHX), which applied topically prevents the skin rash in rats, inhibited 12-OH-NVP sulfation by SULT1A1 and SULT2A1, implying the involvement of these two enzymes in the sulfation of 12-OH-NVP in vivo. Among five human organ cytosols analyzed, liver cytosol displayed the strongest 12-OH-NVP-sulfating activity, while a low but significant activity was detected with skin cytosol. Cultured HepG2 cells were shown to be capable of sulfating 12-OH-NVP. The effects of genetic polymorphisms of SULT1A1 and SULT2A1 genes on the sulfation of 12-OH-NVP by SULT1A1 and SULT2A1 allozymes were investigated. Two SULT1A1 allozymes, Arg37Asp and Met223Val, showed no detectable 12-OH-NVP-sulfating activity, while a SULT2A1 allozyme, Met57Thr, displayed significantly higher 12-OH-NVP-sulfating activity compared with the wild-type enzyme. Collectively, these results contribute to a better understanding of the involvement of sulfation in NVP-induced skin rash and provide clues to the possible role of SULT genetic polymorphisms in the risk of this adverse reaction.

Keywords:  12-hydroxynevirapine; SULT; Sulfation; allozymes; cytosolic sulfotransferase; idiosyncratic drug reaction; reactive metabolite; single nucleotide polymorphism

DOI:  https://doi.org/10.1016/j.bcp.2022.115243
Eur J Endocrinol. 2022 Sep 01. pii: EJE-22-0320. [Epub ahead of print]

11-oxygenated C19 steroids are the predominant androgens responsible for hyperandrogenemia in Cushing's disease.

Hanna F Nowotny, Leah Braun, Frederick Vogel, Martin Bidlingmaier, Martin Reincke, Lea Tschaidse, Matthias K Auer, Christian Lottspeich, Stefan A Wudy, Michaela F Hartmann, James Hawley, Joanne E Adaway, Brian Keevil, Katharina Schilbach, Nicole Reisch.

BACKGROUND: Symptoms of hyperandrogenism are common in patients with Cushing's disease (CD), yet they are not sufficiently explained by androgen concentrations. In this study we analyzed the contribution of 11-oxygenated C19 steroids (11oxC19) to hyperandrogenemia in female patients with CD.
METHODS: We assessed saliva day profiles in females with CD pre (n = 23) and post (n = 13) successful transsphenoidal surgery, 26 female controls, 5 females with CD treated with metyrapone and 5 treated with osilodrostat for cortisol, cortisone, androstenedione (A4), 11-hydroxyandrostenedione (11OHA4), testosterone (T), 11-ketotestosterone (11KT) as well as metabolites of classic and 11oxygenated androgens in 24-hour urine. In addition, morning baseline levels of gonadotropins and estradiol, sex hormone-binding globulin, cortisol and dehydroepiandrosterone sulfate (DHEAS) in serum and adrenocorticotropic hormone in plasma in patients and controls were investigated.
RESULTS: Treatment naïve females with CD showed significantly elevated area under the curve (AUC) of 11OHA4 and 11KT in saliva throughout the day compared to controls (11OHA4 mean rank difference (mrd) 18.13, p = 0.0002; 11KT mrd 17.42; p = 0.0005) whereas A4, T and DHEAS were comparable to controls. Gonadotropin concentrations were normal in all patients with CD. After transphenoidal surgery 11oxC19 and their metabolites dropped significantly in saliva (11OHA4 p < 0.0001; 11KT p = 0.0010) and urine (11-O-An p = 0.0011; 11-OH-AN p < 0.0001), treatment with osilodrostat and metyrapone efficaciously blocked 11oxC19 synthesis. Conclusion Hyperandrogenemia in CD is predominantly caused by excess of 11oxC19 steroids.

DOI: https://doi.org/10.1530/EJE-22-0320
Int J Mol Sci. 2022 Aug 30. pii: 9842. [Epub ahead of print]23(17):

Heparan Sulfate and Sialic Acid in Viral Attachment: Two Sides of the Same Coin?

Ivan Emmanuel Ramos-Martínez, Edgar Ramos-Martínez, René Álvaro Segura-Velázquez, Manuel Saavedra-Montañez, Jacquelynne Brenda Cervantes-Torres, Marco Cerbón, Dulce Papy-Garcia, Edgar Zenteno, José Ivan Sánchez-Betancourt.

  Sialic acids and heparan sulfates make up the outermost part of the cell membrane and the extracellular matrix. Both structures are characterized by being negatively charged, serving as receptors for various pathogens, and are highly expressed in the respiratory and digestive tracts. Numerous viruses use heparan sulfates as receptors to infect cells; in this group are HSV, HPV, and SARS-CoV-2. Other viruses require the cell to express sialic acids, as is the case in influenza A viruses and adenoviruses. This review aims to present, in a general way, the participation of glycoconjugates in viral entry, and therapeutic strategies focused on inhibiting the interaction between the virus and the glycoconjugates. Interestingly, there are few studies that suggest the participation of both glycoconjugates in the viruses addressed here. Considering the biological redundancy that exists between heparan sulfates and sialic acids, we propose that it is important to jointly evaluate and design strategies that contemplate inhibiting the interactions of both glycoconjugates. This approach will allow identifying new receptors and lead to a deeper understanding of interspecies transmission.

Keywords:  Heparan sulfates; glycoconjugates; sialic acid; viral entry; virus receptors

DOI:  https://doi.org/10.3390/ijms23179842
Macromol Biosci. 2022 Sep 06. e2200172

Sulfated Galactans from Gracilaria fisheri with Supplementation of Octanoyl Promote Wound Healing Activity In Vitro and In Vivo.

Tawut Rudtanatip, Somsuda Somintara, Waraporn Sakaew, Jamal El-Abid, Maria Emilia Cano, Kamonwan Jongsomchai, Kanokpan Wongprasert, José Kovensky.

  Sulfated galactans (SG) isolated from Gracilaria fisheri was partially degraded (DSG), and subsequentially supplemented with octanoyl (DSGO) and sulfate (DSGS) groups. The molecular weights of DSG, DSGO, and DSGS were 7.87, 152.79, and 97.07 kDa, respectively. The modification was confirmed using FTIR and NMR, whilst in vitro wound healing activity was assessed using scratched wound fibroblasts. The results revealed that DSGO exhibited highest percentage of wound closure in scratched fibroblast L929 cells. Furthermore, DSGO was able to promote proliferation and accelerate migration of scratched fibroblasts, which corresponded to the regulation of proteins and mRNA (Ki67, p-FAK, vimentin and E-cadherin) determined by Western blotting and qPCR analysis. The superior wound healing activity of DSGO was also confirmed in excision wound of rats. The results demonstrated that DSGO significantly enhanced the percentage of wound closure, re-epithelialization, and collagen arrangement, increased α-SMA and vimentin expression, and decreased that of TNF-α at the wound site. The results suggest that degraded SG supplemented with medium-chain fatty acids of octanoyl group might pass through the membrane, subsequently activating the mediators associated with proliferation and migration of fibroblasts, which could potentially lead to the promotion of wound healing activity. This article is protected by copyright. All rights reserved.

Keywords:  excision rat; fibroblast culture; healing mechanism; octanoyl-sulfated galactans; wound healing

DOI:  https://doi.org/10.1002/mabi.202200172
Food Chem Toxicol. 2022 Sep 03. pii: S0278-6915(22)00599-3. [Epub ahead of print]168 113401

Effects of sulfated polysaccharides from Laminaria japonica on regularating the gut microbiotan and alleviating intestinal inflammation in obese mice.

Yanan Gao, Mingkun Guo, Peng Zheng, Ruoyi Liu, Dandan Wang, Daqing Zhao, Mingxing Wang.

  Due to their known health-enhancing properties, Laminaria japonica polysaccharides (LJP) may alleviate obesity via unknown mechanisms. This study aimed to investigate beneficial LJP effects and mechanism(s) of action using an animal obesity model (ICR mice fed a high-fat diet). First, LJP were confirmed to consist of sulfated polysaccharides via infrared spectroscopy. Next, LJP administration to mice was found to induce weight loss, reduce liver fat accumulation, and support healthy obesity-related blood serum indicator levels. Notably, LJP treatment significantly reduced TC and LDL levels and significantly increased HDL, LPL, UCP-2, and PPAR-α levels. Furthermore, examinations of tissues of LJP-treated mice revealed significantly reduced intestinal tissue inflammation as compared to corresponding results obtained for untreated obese controls. Additionally, LJP treatment relieved colonic shortening and reduced colonic levels of inflammatory factors TNF-α and IL-6. Further exploration of LJP treatment effects on mouse gut microbiota conducted via fecal 16S rRNA gene sequence-based gut microbiome profiling analysis revealed that LJP treatment increased the Bacteroidetes/Firmicutes ratio and increased gut abundances of probiotics Bacteroides acidifaciens, s_Lactobacillus intestinalis, and s_Lactobacillus murinus. In conclusion, these results collectively suggest that LJP use as a food supplement may alleviate obesity and related gut microbiota dysbiosis and intestinal inflammatory disorders.

Keywords:  Gut microbiota; Intestinal inflammation; Laminaria japonica; Obesity inhibition; Sulfated polysaccharides

DOI:  https://doi.org/10.1016/j.fct.2022.113401
Medicine (Baltimore). 2022 Sep 09. 101(36): e30192

Two novel predictive biomarkers for osteosarcoma and glycolysis pathways: A profiling study on HS2ST1 and SDC3.

Guozhi Yang, Jie Jiang, Ruifeng Yin, Zhian Li, Lei Li, Feng Gao, Chong Liu, Xinli Zhan.

INTRODUCTION: Prognostic biomarkers for osteosarcoma (OS) are still very few, and this study aims to examine 2 novel prognostic biomarkers for OS through combined bioinformatics and experimental approach.
MATERIALS AND METHODS: Expression profile data of OS and paraneoplastic tissues were downloaded from several online databases, and prognostic genes were screened by differential expression analysis, Univariate Cox analysis, least absolute shrinkage and selection operator regression analysis, and multivariate Cox regression analysis to construct prognostic models. The accuracy of the model was validated using principal component analysis, constructing calibration plots, and column line plots. We also analyzed the relationship between genes and drug sensitivity. Gene expression profiles were analyzed by immunocytotyping. Also, protein expressions of the constructed biomarkers in OS and paraneoplastic tissues were verified by immunohistochemistry.
RESULTS: Heparan sulfate 2-O-sulfotransferase 1 (HS2ST1) and Syndecan 3 (SDC3, met all our requirements after screening. The constructed prognostic model indicated that patients in the high-risk group had a much lower patient survival rate than in the low-risk group. Moreover, these genes were closely related to immune cells (P < .05). Drug sensitivity analysis showed that the 2 genes modeled were strongly correlated with multiple drugs. Immunohistochemical analysis showed significantly higher protein expression of both genes in OS than in paraneoplastic tissues.
CONCLUSIONS: HS2ST1 and SDC3 are significantly dysregulated in OS, and the prognostic models constructed based on these 2 genes have much lower survival rates in the high-risk group than in the low-risk group. HS2ST1 and SDC3 can be used as glycolytic and immune-related prognostic biomarkers in OS.

DOI: https://doi.org/10.1097/MD.0000000000030192
Environ Sci Pollut Res Int. 2022 Sep 05.

Investigation of free and conjugated estrogen fate and emission coefficients in three duck farms.

Hao-Shen Hung, Kuei-Jyum C Yeh, Ting-Chien Chen.

  Concentration animal feeding operation (CAFO) is an important source of environmental estrogen. However, to the best of our knowledge, the data on estrogen discharge during duck breeding and growth is insufficient. This study used liquid chromatography with tandem mass spectrometry (LC/MS/MS) to analyze the free and conjugated estrogen concentrations in the surface water, outlet water, groundwater, and duck manure/soil mixture at three duck farms in Taiwan. Natural estrogen species included estrone (E1), 17β-estradiol (E2), estriol (E3), estrone-3-sulfate (E1-3S), 17β-estradiol-3-sulfate (E2-3S), estrone-3-glucuronide (E1-3G), and 17β-estradiol-3-glucuronide (E2-3G), whereas synthetic estrogen included 17α-ethynylestradiol (EE2) and diethylstilbestrol (DES). This study showed that the total estrogen concentrations in the surface water and groundwater were 15.4 and 4.5 ng/L, respectively, which constituted 56% and 58%, respectively, conjugated estrogen. From the pond to the outlet water, the total estrogen concentration decreased by 3.9 ng/L (23% loss) in the duck farms. However, the estrogenic potency was slightly reduced from 0.91 to 0.88 E2 equivalent/L, showing a negligible decrease. From the pond to the outlet water, the field results showed that converting the conjugated estrogen into free estrogen in the duck farm-released water increased their environmental hazard. Primarily E1, with an average concentration of 0.9 ± 1.6 ng/g, was present in the duck manure. The estrogen excreted by the ducks in the pond (from surface water to outlet water) was estimated to be 0.18 kg/million head-year. Although the estrogen concentration in the duck farms was low, the environmental impact of CAFO should not be neglected.

Keywords:  Concentration animal feeding operation; Ducks; Estrogen; Fate

DOI:  https://doi.org/10.1007/s11356-022-22829-9
Int J Endocrinol. 2022 ;2022 8509204

Low Serum Total Testosterone Is Associated with Non-Alcoholic Fatty Liver Disease in Men but Not in Women with Type 2 Diabetes Mellitus.

Xinxin Zhang, Jinfeng Xiao, Qi Liu, Yuanyuan Ye, Weihong Guo, Jingqiu Cui, Qing He, Wenli Feng, Ming Liu.

Materials and Methods: There were 1155 patients with T2DM included in the analysis. Serum levels of total testosterone and the precursors of androgens, including androstenedione, DHEA, and DHEAS, were quantified using liquid chromatography-tandem mass spectrometry assays.
Results: The risk of NAFLD decreased as total testosterone concentration increased in men with T2DM. After adjusting for age, current smoking, current drinking, body mass index, duration of T2DM, diastolic blood pressure, total cholesterol, triglycerides, low-density lipoprotein/high-density lipoprotein cholesterol ratio, uric acid, C-reactive protein, and sex hormones in model 4, the adjusted odds ratio (OR) and 95% confidence interval (CI) of NAFLD for tertile3 vs tertile1 was 0.37 (0.17-0.77; P = 0.024 for trend). When taken as a continuous variable, this association was still robust in model 4 (OR, 0.58; 95% CI, 0.42-0.80; P < 0.05). No significant associations were found between increasing levels of the precursors of androgens and the odds of NAFLD in men with T2DM (all P > 0.05). Moreover, women showed no significant associations of total testosterone, androstenedione, DHEA, and DHEAS, with the odds of NAFLD (all P > 0.05).
Conclusions: Serum total testosterone was independently associated with the risk of NAFLD among men with T2DM. This study highlights the potential role of testosterone as a risk factor for NAFLD in patients with T2DM.

DOI: https://doi.org/10.1155/2022/8509204