bims-supasi 2023-06-04 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2023–06–04
nine papers selected by
Jonathan Wolf Mueller, University of Birmingham

Distinct serum steroid profiles between adrenal Cushing syndrome and Cushing disease.
Heparin, Heparan Sulphate and Sepsis: Potential New Options for Treatment.
Peptide-modified bioresponsive chondroitin sulfate micelles for targeted doxorubicin delivery in triple-negative breast cancer.
Hallmarks of the relationship between host and Trypanosoma cruzi sulfated glycoconjugates along the course of Chagas disease.
Enzyme replacement with transferrin receptor-targeted α-L-iduronidase rescues brain pathology in mucopolysaccharidosis I mice.
Sulfo-peptide CLEL6 inhibits anthocyanin biosynthesis in Arabidopsis thaliana.
Assessing stress using repeated saliva concentration of steroid hormones in dementia care dyads: results from a controlled pilot care music intervention.
Disease stage-dependent changes in brain levels and neuroprotective effects of neuroactive steroids in Parkinson's disease.
Risk estimation of gestational diabetes mellitus in the first trimester.

Front Endocrinol (Lausanne). 2023 ;14 1158573

Distinct serum steroid profiles between adrenal Cushing syndrome and Cushing disease.

Chang Gao, Li Ding, Xiaona Zhang, Menghua Yuan, Shaofang Tang, Wei Li, Yuanyuan Ye, Ming Liu, Qing He.

   Background: Differentiating between adrenal Cushing syndrome (adrenal CS) and Cushing disease (CD) can be challenging if there are equivocal or falsely elevated adrenocorticotropic hormone (ACTH) values. We aim to investigate the diagnostic value of serum steroid profiles in differentiating adrenal CS from CD.
Method: A total of 11 serum steroids in adrenal CS (n = 13) and CD (n = 15) were analyzed by liquid chromatography with tandem mass spectrometry (LC-MS/MS). Age- and gender-specific steroid ratios were generated by dividing the actual steroid concentration by the upper limit of the relevant reference range. A principal component analysis (PCA) and an orthogonal partial least squares discriminant analysis (OPLS-DA) were performed.
Results: The PCA and OPLS-DA analyses showed distinct serum steroid profiles between adrenal CS and CD. Dehydroepiandrosterone sulfate (DHEA-S), dehydroepiandrosterone (DHEA), and androstenedione ratios were identified as biomarkers for discrimination by variable importance in projection (VIP) in combination with t-tests. The sensitivity and specificity of DHEA-S ratios <0.40 were 92.31% (95% CI 64.0%-99.8%) and 93.33% (95% CI 68.1%-99.8%), respectively, in identifying adrenal CS. The sensitivity and specificity of DHEA ratios <0.18 were 100% (95% CI 75.3%-100.0%) and 100% (95% CI 78.2%-100.0%), respectively, in identifying adrenal CS.
Conclusion: Our data support the clinical use of the DHEA-S and DHEA ratios in the differential diagnosis of adrenal CS and CD, especially when falsely elevated ACTH is suspected.

Keywords:  Cushing syndrome; dehydroepiandrosterone sulfate (DHEA-S); mass spectrometry; orthogonal partial least squares discriminant analysis (OPLS-DA); serum steroids

DOI:  https://doi.org/10.3389/fendo.2023.1158573
Pharmaceuticals (Basel). 2023 Feb 10. pii: 271. [Epub ahead of print]16(2):

Heparin, Heparan Sulphate and Sepsis: Potential New Options for Treatment.

John Hogwood, Elaine Gray, Barbara Mulloy.

  Sepsis is a life-threatening hyperreaction to infection in which excessive inflammatory and immune responses cause damage to host tissues and organs. The glycosaminoglycan heparan sulphate (HS) is a major component of the cell surface glycocalyx. Cell surface HS modulates several of the mechanisms involved in sepsis such as pathogen interactions with the host cell and neutrophil recruitment and is a target for the pro-inflammatory enzyme heparanase. Heparin, a close structural relative of HS, is used in medicine as a powerful anticoagulant and antithrombotic. Many studies have shown that heparin can influence the course of sepsis-related processes as a result of its structural similarity to HS, including its strong negative charge. The anticoagulant activity of heparin, however, limits its potential in treatment of inflammatory conditions by introducing the risk of bleeding and other adverse side-effects. As the anticoagulant potency of heparin is largely determined by a single well-defined structural feature, it has been possible to develop heparin derivatives and mimetic compounds with reduced anticoagulant activity. Such heparin mimetics may have potential for use as therapeutic agents in the context of sepsis.

Keywords:  heparan sulphate; heparanase; heparin; heparin mimetics; neutrophils; sepsis

DOI:  https://doi.org/10.3390/ph16020271
Colloids Surf B Biointerfaces. 2023 May 26. pii: S0927-7765(23)00259-X. [Epub ahead of print]227 113381

Peptide-modified bioresponsive chondroitin sulfate micelles for targeted doxorubicin delivery in triple-negative breast cancer.

Jingmou Yu, Liangliang Wang, Yun Ling, Xin Xiao, Juntao Gong, Hongguang Jin, Jing Xu, Pu Chen, Xin Xie, Lei Zhang.

  Triple-negative breast cancer is an offensive tumor that is highly challenging to cure. In this study, we developed novel polymeric nanoparticles that target dual receptors and respond to reducing conditions for chemotherapeutic drug release in the treatment of triple-negative breast cancer. Then we synthesized and characterized a targeted peptide-grafted chondroitin sulfate A-ss-deoxycholic acid (TCSSD) copolymer and prepare doxorubicin (DOX)-loaded TCSSD (TCSSD-D) micelles high-loading content. The bioresponsive drug release of TCSSD-D nanoparticles was demonstrated in a glutathione-containing phosphate buffer solution. We found that TCSSD-D effectively targeted CD44 and P-selectin receptors both in vitro and in vivo. TCSSD-D micelles were higher cytotoxicity and cellular uptake than unmodified DOX-containing micelles in MDA-MB-231 cells. Furthermore, TCSSD-D micelles showed the strongest suppression of tumor growth among three DOX-based formulations in triple-negative MDA-MB-231-bearing nude mice. These results suggest that amphiphilic TCSSD nanoparticles can serve as a targeted and intelligent delivery vehicle for triple-negative breast cancer therapy.

Keywords:  Controlled release; Doxorubicin; Peptide, Micelles; Targeted delivery; Triple-negative breast cancer

DOI:  https://doi.org/10.1016/j.colsurfb.2023.113381
Front Cell Infect Microbiol. 2023 ;13 1028496

Hallmarks of the relationship between host and Trypanosoma cruzi sulfated glycoconjugates along the course of Chagas disease.

Luciana L Soprano, Maximiliano R Ferrero, Thomas Jacobs, Alicia S Couto, Vilma G Duschak.

  American Trypanosomiasis or Chagas disease (ChD), a major problem that is still endemic in large areas of Latin America, is caused by Trypanosoma cruzi. This agent holds a major antigen, cruzipain (Cz). Its C-terminal domain (C-T) is retained in the glycoprotein mature form and bears several post-translational modifications. Glycoproteins containing sulfated N-linked oligosaccharides have been mostly implicated in numerous specific procedures of molecular recognition. The presence of sulfated oligosaccharides was demonstrated in Cz, also in a minor abundant antigen with serine-carboxypeptidase (SCP) activity, as well as in parasite sulfatides. Sulfate-bearing glycoproteins in Trypanosomatids are targets of specific immune responses. T. cruzi chronically infected subjects mount specific humoral immune responses to sulfated Cz. Unexpectedly, in the absence of infection, mice immunized with C-T, but not with sulfate-depleted C-T, showed ultrastructural heart anomalous pathological effects. Moreover, the synthetic anionic sugar conjugate GlcNAc6SO3-BSA showed to mimic the N-glycan-linked sulfated epitope (sulfotope) humoral responses that natural Cz elicits. Furthermore, it has been reported that sulfotopes participate via the binding of sialic acid Ig-like-specific lectins (Siglecs) to sulfosialylated glycoproteins in the immunomodulation by host-parasite interaction as well as in the parasite infection process. Strikingly, recent evidence involved Cz-sulfotope-specific antibodies in the immunopathogenesis and infection processes during the experimental ChD. Remarkably, sera from chronically T. cruzi-infected individuals with mild disease displayed higher levels of IgG2 antibodies specific for sulfated glycoproteins and sulfatides than those with more severe forms of the disease, evidencing that T. cruzi sulfotopes are antigenic independently of the sulfated glycoconjugate type. Ongoing assays indicate that antibodies specific for sulfotopes might be considered biomarkers of human cardiac ChD progression, playing a role as predictors of stability from the early mild stages of chronic ChD.

Keywords:  Chagas disease; Trypanosoma cruzi; biomarkers; immunomodulation; immunopathogenesis; infection; sulfated glycoconjugates; sulfotopes

DOI:  https://doi.org/10.3389/fcimb.2023.1028496
Mol Ther Methods Clin Dev. 2023 Jun 08. 29 439-449

Enzyme replacement with transferrin receptor-targeted α-L-iduronidase rescues brain pathology in mucopolysaccharidosis I mice.

Sachiho Kida, Yuri Koshimura, Eiji Yoden, Aya Yoshioka, Hideto Morimoto, Atsushi Imakiire, Noboru Tanaka, Satowa Tanaka, Ayaka Mori, Jun Ito, Asuka Inoue, Ryuji Yamamoto, Kohtaro Minami, Tohru Hirato, Kenichi Takahashi, Hiroyuki Sonoda.

  Mucopolysaccharidosis I (MPS I), a lysosomal storage disease caused by dysfunction of α-L-iduronidase (IDUA), is characterized by the deposition of dermatan sulfate (DS) and heparan sulfate (HS) throughout the body, which causes several somatic and central nervous symptoms. Although enzyme-replacement therapy (ERT) is currently available to treat MPS I, it does not alleviate central nervous disorders, as it cannot penetrate the blood-brain barrier. Here we evaluate the brain delivery, efficacy, and safety of JR-171, a fusion protein comprising humanized anti-human transferrin receptor antibody Fab and IDUA, using monkeys and MPS I mice. Intravenously administered JR-171 was distributed in major organs, including the brain, and reduced DS and HS concentrations in the central nervous system and peripheral tissues. JR-171 exerted similar effects on peripheral disorders similar to conventional ERT and further reversed brain pathology in MPS I mice. We found that JR-171 improved spatial learning ability, which was seen to deteriorate in the vehicle-treated mice. Further, no safety concerns were noted in repeat-dose toxicity studies in monkeys. This study provides nonclinical evidence that JR-171 might potentially prevent and even improve disease conditions in patients with neuronopathic MPS I without serious safety concerns.

Keywords:  blood-brain barrier; enzyme-replacement therapy; heparan sulfate; lysosomal storage disease; mucopolysaccharidosis I

DOI:  https://doi.org/10.1016/j.omtm.2023.05.010
Plant Physiol. 2023 May 31. pii: kiad316. [Epub ahead of print]

Sulfo-peptide CLEL6 inhibits anthocyanin biosynthesis in Arabidopsis thaliana.

Eric Bühler, Elisa Fahrbach, Andreas Schaller, Nils Stührwohldt.

  Post-translationally modified peptides are now recognized as important regulators of plant stress responses. Here, we identified the small sulfated CLE-LIKE6 (CLEL6) peptide as a negative regulator of anthocyanin biosynthesis in etiolated and in light-stressed Arabidopsis (Arabidopsis thaliana) seedlings. CLEL6 function depends on proteolytic processing of the CLEL6 precursor by subtilisin-like serine proteinase 6.1 (SBT6.1) and on tyrosine sulfation by tyrosylprotein sulfotransferase (TPST). Loss-of-function mutants of either sbt6.1 or tpst showed significantly higher anthocyanin accumulation than the wild type upon light stress. The anthocyanin overaccumulation phenotype of sbt6.1 and tpst was suppressed by application of mature CLEL6. Overexpression and external application of CLEL6 inhibited the expression of anthocyanin biosynthesis genes in etiolated and light-stressed seedlings, confirming the role of CLEL6 as an inhibitor of anthocyanin biosynthesis. Small post-translationally modified peptides are perceived by leucine-rich-repeat receptor like kinases. Using a quintuple mutant of ROOT MERISTEM GROWTH FACTOR 1 INSENSITIVE (RGI) receptors, we showed the essential function of the RGI receptor family in CLEL6 signaling. Our data indicate that overexpression or application of CLEL6 inhibit anthocyanin biosynthesis through RGI receptors. We propose that CLEL6 inhibits anthocyanin biosynthesis in etiolated seedlings, and that anthocyanin biosynthesis is derepressed when CLEL6 expression is down-regulated upon light exposure. Hyperaccumulation of anthocyanins in light-stressed tpst and sbt6.1 mutant seedlings suggests that CLEL6, or related sulfopeptides, continue to act as negative regulators to limit pigment accumulation in the light.

Keywords:  CLEL6; TPST; anthocyanins; light stress; peptide signaling; tyrosine sulfation

DOI:  https://doi.org/10.1093/plphys/kiad316
Ups J Med Sci. 2023 ;128

Assessing stress using repeated saliva concentration of steroid hormones in dementia care dyads: results from a controlled pilot care music intervention.

Azita Emami, Töres Theorell, Hyejin Kim, Lars Berglund, Helena Hallinder, Gabriella Engström.

   Background: Stress-related biomarkers have the potential to provide objective measures of whether interventions directed at people with dementia (PWD) and their family caregivers (FCG) are successful. The use of such biomarkers has been limited by logistical barriers to sample collection.
Objective: Explore saliva concentration of steroid hormones in dementia care dyads during a music intervention.
Methods: Consecutive PWD attending a memory evaluation center and their FCG were allocated to either an intervention-with-music or a non-intervention control group. All were living at home. Stress biomarkers, salivary cortisol and dehydroepiandrosterone sulfate (DHEA-S) samples were collected by the PWD and their FCG, in the morning and evening, 5 days a week, for 8 consecutive weeks. Biomarker concentrations of the intervention and the control groups were compared at week 8, in an intention-to-treat approach with adjustment for baseline value.
Results: Twenty-four PWD in the intervention group and 10 in the control group, and their FCG were included in the analyses. The mean number of morning saliva collections was similar in the intervention and the control groups, ranging from 4.3 to 4.9 per participant weekly during the first 7 weeks, declining to 3.3 during week 8. Median log morning cortisol (pg/mL) among caregivers was lower in the intervention group than in the control group (8.09 vs. 8.57, P = 0.0133).
Conclusion: This study demonstrates that music intervention was associated with lower morning saliva cortisol concentrations for FCGs.

Keywords:  Caregivers; DHEA-S; cortisol; dementia; music; saliva; stress

DOI:  https://doi.org/10.48101/ujms.v128.9340
Neurobiol Dis. 2023 May 29. pii: S0969-9961(23)00184-5. [Epub ahead of print] 106169

Disease stage-dependent changes in brain levels and neuroprotective effects of neuroactive steroids in Parkinson's disease.

Sabina Luchetti, Philippe Liere, Antoine Pianos, Ronald W H Verwer, Arja Sluiter, Inge Huitinga, Michael Schumacher, Dick F Swaab, Matthew R J Mason.

  Neuroactive steroids are known neuroprotective agents and neurotransmitter regulators. We previously found that expression of the enzymes synthesizing 5α-dihydroprogesterone (5α-DHP), allopregnanolone (ALLO), and dehydroepiandrosterone sulfate (DHEAS) were reduced in the substantia nigra (SN) of Parkinson's Disease (PD) brain. Here, concentrations of a comprehensive panel of steroids were measured in human post-mortem brains of PD patients and controls. Gas chromatography-mass spectrometry (GC/MS) was used to measure steroid levels in SN (involved in early symptoms) and prefrontal cortex (PFC) (involved later in the disease) of five control (CTR) and nine PD donors, divided into two groups: PD4 (PD-Braak stages 1-4) and PD6 (PD-Braak stages 5-6). In SN, ALLO was increased in PD4 compared to CTR and 5α-DHP and ALLO levels were diminished in PD6 compared to PD4. The ALLO metabolite 3α5α20α-hexahydroprogesterone (3α5α20α-HHP) was higher in PD4 compared to CTR. In PFC, 3α5α20α-HHP was higher in PD4 compared to both CTR and PD6. The effects of 5α-DHP, ALLO and DHEAS were tested on human post-mortem brain slices of patients and controls in culture. RNA expression of genes involved in neuroprotection, neuroinflammation and neurotransmission was analysed after 5 days of incubation with each steroid. In PD6 slices, both 5α-DHP and ALLO induced an increase of the glutamate reuptake effector GLAST1, while 5α-DHP also increased gene expression of the neuroprotective TGFB. In CTR slices, ALLO caused reduced expression of IGF1 and GLS, while DHEAS reduced the expression of p75 and the anti-apoptotic molecule APAF1. Together these data suggest that a potentially protective upregulation of ALLO occurs at early stages of PD, followed by a downregulation of progesterone metabolites at later stages that may exacerbate the pathological changes, especially in SN. Neuroprotective effects of neurosteroids are thus dependent on the neuropathological stage of the disease.

Keywords:  5α-dihydroprogesterone; Allopregnanolone; GC/MS; Neurosteroids; Post-mortem; Slice culture

DOI:  https://doi.org/10.1016/j.nbd.2023.106169
J Clin Endocrinol Metab. 2023 May 29. pii: dgad301. [Epub ahead of print]

Risk estimation of gestational diabetes mellitus in the first trimester.

Dóra Gerszi, Gergő Orosz, Marianna Török, Balázs Szalay, Gellért Karvaly, László Orosz, Judit Hetthéssy, Barna Vásárhelyi, Olga Török, Eszter M Horváth, Szabolcs Várbíró.

   PURPOSE: There is no early - first trimester- risk estimation available to predict later (gestational week 24-28) gestational diabetes mellitus (GDM) - however it would be beneficial to start an early treatment to prevent the development of complications.We aimed to identify early, first trimester prediction markers for GDM.
METHODS: The present case-control study is based on the study cohort of a Hungarian biobank containing the biological samples and follow-up data from 2545 pregnant women. Oxidative-nitrative stress-related parameters, steroid hormone, and metabolite levels were measured in the serum/plasma samples collected at the end of the first trimester from 55-55 randomly selected control and later GDM women.
RESULTS: Pregnant women, who developed GDM later during the pregnancy were older and had higher body mass indexes (BMI). The following parameters showed higher concentration in their serum/plasma samples: fructosamine, total antioxidant capacity (TAC), testosterone, cortisone, 21-deoxycortisol; while soluble urokinase plasminogen activator receptor (SuPAR), dehydroepiandrosterone sulfate (DHEAS), dihydrotestosterone (DHT), cortisol and 11-deoxycorticosterone levels were lower. Analyzing these variables using a forward stepwise multivariate logistic regression model we established a GDM prediction model with a specificity of 96.6% and sensitivity of 97.5% (included variables: fructosamine, cortisol, cortisone, 11-deoxycorticosterone, SuPAR).
CONCLUSIONS: Based on these measurements we accurately predict the development of later onset GDM (24th-28th weeks of pregnancy). Early risk estimation provides the opportunity for targeted prevention and the timely treatment of GDM. Prevention and slowing the progression of GDM result in a lower lifelong metabolic risk for both mother and offspring.

Keywords:  GDM; early risk estimation; first trimester; oxidative-nitrative stress; steroid metabolites

DOI:  https://doi.org/10.1210/clinem/dgad301