bims-supasi 2024-06-30 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2024‒06‒30
sixteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Purification and Structural Analyses of Sulfated Polysaccharides from Low-Value Sea Cucumber Stichopus naso and Anticoagulant Activities of Its Oligosaccharides.
The Androgen Dehydroepiandrosterone Sulfate Shows a Greater Relationship with Impulsivity than Testosterone in a Healthy Male Sample.
Low molecular weight heparin promotes the PPAR pathway by protecting the glycocalyx of cells to delay the progression of diabetic nephropathy.
Effect of chondroitin sulfate modified polyethyleneimine on mediating oligodeoxynucleotide YW002 in the treatment of periodontitis.
Indoxyl Sulfate-Induced Macrophage Toxicity and Therapeutic Strategies in Uremic Atherosclerosis.
Monoclonal Antibody chP3R99 Reduces Subendothelial Retention of Atherogenic Lipoproteins in Insulin-Resistant Rats: Acute Treatment Versus Long-Term Protection as an Idiotypic Vaccine for Atherosclerosis.
Syndecans in hematopoietic cells and their niches.
Tyrosine Sulfation Modulates the Binding Affinity of Chemokine-Targeting Nanobodies.
Structural and mechanistic insights into a lysosomal membrane enzyme HGSNAT involved in Sanfilippo syndrome.
Hyaluronic Acid/Chondroitin Sulfate-Based Dynamic Thiol-Aldehyde Addition Hydrogel: An Injectable, Self-Healing, On-Demand Dissolution Wound Dressing.
Automated Synthesis of Algal Fucoidan Oligosaccharides.
Liquid Chromatography-Mass Spectrometry Analytical Methods for the Quantitation of p-Cresol Sulfate and Indoxyl Sulfate in Human Matrices: Biological Applications and Diagnostic Potentials.
The use of a pill containing ethinylestradiol-norgestimate improves female sexuality despite the decrease in circulating androgens: a pilot study.
A Novel Fluorescence-Based Microplate Assay for High-Throughput Screening of hSULT1As Inhibitors.
Beyond symptomatology: A comparative analysis of unilateral and bilateral macronodular mild autonomous cortisol secretion.
HEMA-Lysine-Based Cryogels for Highly Selective Heparin Neutralization.

Mar Drugs. 2024 Jun 08. pii: 265. [Epub ahead of print]22(6):

Purification and Structural Analyses of Sulfated Polysaccharides from Low-Value Sea Cucumber Stichopus naso and Anticoagulant Activities of Its Oligosaccharides.

Lige Cui, Huifang Sun, Xiaolei Shang, Jing Wen, Pengfei Li, Shengtao Yang, Linxia Chen, Xiangyang Huang, Haoyang Li, Ronghua Yin, Jinhua Zhao.

  Three polysaccharides (SnNG, SnFS and SnFG) were purified from the body wall of Stichopus naso. The physicochemical properties, including monosaccharide composition, molecular weight, sulfate content, and optical rotation, were analyzed, confirming that SnFS and SnFG are sulfated polysaccharides commonly found in sea cucumbers. The highly regular structure {3)-L-Fuc2S-(α1,}n of SnFS was determined via a detailed NMR analysis of its oxidative degradation product. By employing β-elimination depolymerization of SnFG, tri-, penta-, octa-, hendeca-, tetradeca-, and heptadeca-saccharides were obtained from the low-molecular-weight product. Their well-defined structures confirmed that SnFG possessed the backbone of {D-GalNAc4S6S-β(1,4)-D-GlcA}, and each GlcA residue was branched with Fuc2S4S. SnFS and SnFG are both structurally the simplest version of natural fucan sulfate and fucosylated glycosaminoglycan, facilitating the application of low-value sea cucumbers S. naso. Bioactivity assays showed that SnFG and its derived oligosaccharides exhibited potent anticoagulation and intrinsic factor Xase (iXase) inhibition. Moreover, a comparative analysis with the series of oligosaccharides solely branched with Fuc3S4S showed that in oligosaccharides with lower degrees of polymerization, such as octasaccharides, Fuc2S4S led to a greater increase in APTT prolongation and iXase inhibition. As the degree of polymerization increases, the influence from the sulfation pattern diminishes, until it is overshadowed by the effects of molecular weight.

Keywords:  Stichopus naso; anticoagulation; chemical depolymerization; polysaccharides; well-defined oligosaccharides

DOI:  https://doi.org/10.3390/md22060265
Brain Sci. 2024 Jun 03. pii: 569. [Epub ahead of print]14(6):

The Androgen Dehydroepiandrosterone Sulfate Shows a Greater Relationship with Impulsivity than Testosterone in a Healthy Male Sample.

Anton Aluja, Ferran Balada, Óscar García, Neus Aymamí, Luis F García.

  This study was designed to examine the relationships among the impulsivity construct as a personality trait, the dehydroepiandrosterone sulfate (DHEA-S), and testosterone in a sample of 120 healthy middle-aged males (Mage = 44.39; SD = 12.88). The sum of the three BIS-11 scales, the SR, and the five UPPS-P scales correlated with DHEA-S 0.23 (p < 0.006) and testosterone 0.19 (p < 0.04), controlling for age. Partial correlations showed that DHEA-S was significantly related to motor impulsivity (0.24; p < 0.008), Sensitivity to Reward (0.29; p < 0.002), Lack of Premeditation (0.26; p < 0.05), and, to a lesser extent, Sensation Seeking (0.19; p < 0.04) and Positive Urgency (0.19; p < 0.04). Testosterone correlated with attention impulsivity (0.18; p < 0.04), Sensation Seeking (0.18; p < 0.04), and Positive Urgency (0.22; p < 0.01). Sensitivity to Reward, Negative Urgency, and Positive Urgency were significant predictors of DHEA-S (R2 = 0.28), and Positive Urgency for testosterone (R2 = 0.09). Non-parametric LOESS graphical analyses for local regression allowed us to visualize the non-linear relationships between the impulsivity scales with the two androgens, including non-significant trends. We discuss the implications of these results for impulsive biological personality traits, the limitations of our analyses, and the possible development of future research.

Keywords:  BIS-11; UPPS-P; dehydroepiandrosterone sulfate (DHEA-S); impulsivity personality trait; testosterone

DOI:  https://doi.org/10.3390/brainsci14060569
J Biol Chem. 2024 Jun 24. pii: S0021-9258(24)01994-X. [Epub ahead of print] 107493

Low molecular weight heparin promotes the PPAR pathway by protecting the glycocalyx of cells to delay the progression of diabetic nephropathy.

Bin Zhang, Changkai Bu, Qingchi Wang, Qingqing Chen, Deling Shi, Hongyan Qiu, Zhangjie Wang, Jian Liu, Zhe Wang, Qunye Zhang, Lianli Chi.

  Diabetic nephropathy (DN) is one of the most important comorbidities for diabetic patients, which is the main factor leading to end-stage renal disease. Heparin analogues can delay the progression of DN, but the mechanism is not fully understood. In this study, we found that low molecular weight heparin (LMWH) therapy significantly upregulated some downstream proteins of the peroxisome proliferator-activated receptor (PPAR) signaling pathway by label-free quantification of the mouse kidney proteome. Through cell model verification, LMWH can protect the heparan sulfate (HS) of renal tubular epithelial cells from being degraded by heparanase that is highly expressed in a high-glucose environment, enhance the endocytic recruitment of fatty acid-binding protein 1 (FABP1), a coactivator of the PPAR pathway, and then regulate the activation level of intracellular PPAR. In addition, we have elucidated for the first time the molecular mechanism of HS and FABP1 interaction. These findings provide new insights into understanding the role of heparin in the pathogenesis of DN and developing corresponding treatments.

Keywords:  Diabetic nephropathy; Endocytosis; FABP1; Heparan sulfate; Low molecular weight heparin; PPAR pathway

DOI:  https://doi.org/10.1016/j.jbc.2024.107493
RSC Adv. 2024 Jun 18. 14(28): 20328-20338

Effect of chondroitin sulfate modified polyethyleneimine on mediating oligodeoxynucleotide YW002 in the treatment of periodontitis.

Xingyuan Qu, Qian Zhang, Chuang Zhang, Jichao Sun, Siyu Du, Chen Liang, Yabing Chen, Yi Zheng, Lei Wang.

PURPOSE: In a previous study, we found that oligodeoxynucleotide (ODN) YW002 could induce the activity of alkaline phosphatase of early osteogenesis in human periodontal membrane stem cells, and downregulate the synthesis of nitric oxide in RAW 264.7 cells in the late inflammatory stage, laying the experimental foundation for the subsequent application of ODN YW002 in periodontitis. However, free ODN does not easily adhere to cells and is easily hydrolyzed by nuclease, so the immune effect of ODN is greatly reduced. Therefore, the nano-drug delivery system provides a method for efficient delivery and uptake of ODN.METHODS: We synthesized a polyethyleneimine (PEI) modified chondroitin sulfate (CS) derivative (PEI-CS) via Michael addition to deliver ODN YW002. We aimed to evaluate whether PEI-CS could effectively deliver YW002 to RAW 264.7 cells and if it can regulate inflammation in vitro. PEI-CS/YW002 nanocomplexes were locally injected into a mouse periodontitis model, and the therapeutic effects were evaluated by microcomputed tomography (micro-CT) and hematoxylin-eosin (H&E) staining.
RESULTS: The results indicated that PEI-CS had good biocompatibility and could form a stable nanocomplex with YW002 at a mass ratio of 4 : 1. Moreover, PEI-CS could deliver YW002 into RAW 246.7 cells and markedly decreased the expression levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α. Histological evaluation and micro-CT scanning showed that PEI-CS/YW002 nanocomplexes effectively inhibited periodontitis and reduced alveolar bone resorption in mice.
CONCLUSION: Our study has underscored the potential of PEI-CS/YW002 nanocomplexes as promising agents for the prevention and treatment of periodontitis due to their potent anti-inflammatory effects.

DOI: https://doi.org/10.1039/d4ra00884g
Toxins (Basel). 2024 May 31. pii: 254. [Epub ahead of print]16(6):

Indoxyl Sulfate-Induced Macrophage Toxicity and Therapeutic Strategies in Uremic Atherosclerosis.

Takuya Wakamatsu, Suguru Yamamoto, Shiori Yoshida, Ichiei Narita.

  Cardiovascular disease (CVD) frequently occurs in patients with chronic kidney disease (CKD), particularly those undergoing dialysis. The mechanisms behind this may be related to traditional risk factors and CKD-specific factors that accelerate atherosclerosis and vascular calcification in CKD patients. The accumulation of uremic toxins is a significant factor in CKD-related systemic disorders. Basic research suggests that indoxyl sulfate (IS), a small protein-bound uremic toxin, is associated with macrophage dysfunctions, including increased oxidative stress, exacerbation of chronic inflammation, and abnormalities in lipid metabolism. Strategies to mitigate the toxicity of IS include optimizing gut microbiota, intervening against the abnormality of intracellular signal transduction, and using blood purification therapy with higher efficiency. Further research is needed to examine whether lowering protein-bound uremic toxins through intervention leads to a reduction in CVD in patients with CKD.

Keywords:  adsorption; atherosclerosis; chronic kidney disease; indoxyl sulfate; macrophage; uremia; uremic toxins

DOI:  https://doi.org/10.3390/toxins16060254
J Am Heart Assoc. 2024 Jun 27. e032419

Monoclonal Antibody chP3R99 Reduces Subendothelial Retention of Atherogenic Lipoproteins in Insulin-Resistant Rats: Acute Treatment Versus Long-Term Protection as an Idiotypic Vaccine for Atherosclerosis.

Yosdel Soto, Arletty Hernández, Roger Sarduy, Victor Brito, Sylvie Marleau, Donna F Vine, Ana M Vázquez, Spencer D Proctor.

  BACKGROUND: Atherosclerosis is triggered by the retention of apolipoprotein B-containing lipoproteins by proteoglycans. In addition to low-density lipoprotein, remnant lipoproteins have emerged as pivotal contributors to this pathology, particularly in the context of insulin resistance and diabetes. We have previously reported antiatherogenic properties of a monoclonal antibody (chP3R99) that recognizes sulfated glycosaminoglycans on arterial proteoglycans.METHODS AND RESULTS: Solid-phase assays demonstrated that chP3R99 effectively blocked >50% lipoprotein binding to chondroitin sulfate and vascular extracellular matrix in vitro. The preperfusion of chP3R99 (competitive effect) resulted in specific antibody-arterial accumulation and reduced fluorescent lipoprotein retention by ~60% in insulin resistant JCR:LA-cp rats. This competitive reduction was dose dependent (25-250 μg/mL), effectively decreasing deposition of cholesterol associated with lipoproteins. In a 5-week vaccination study in insulin resistant rats with (200 μg subcutaneously, once a week), chP3R99 reduced arterial lipoprotein retention, and was associated with the production of antichondroitin sulfate antibodies (Ab3) able to accumulate in the arteries (dot-blot). Neither the intravenous inoculation of chP3R99 (4.5 mg/kg), nor the immunization with this antibody displayed adverse effects on lipid or glucose metabolism, insulin resistance, liver function, blood cell indices, or inflammation pathways in JCR:LA-cp rats.
CONCLUSIONS: Both acute (passive) and long-term administration (idiotypic cascade) of chP3R99 antibody reduced low-density lipoprotein and remnant lipoprotein interaction with proteoglycans in an insulin-resistant setting. These findings support the innovative approach of targeting proatherogenic lipoprotein retention by chP3R99 as a passive therapy or as an idiotypic vaccine for atherosclerosis.

Keywords:  atherosclerosis; chondroitin sulfate; idiotypic antibodies; insulin resistance; remnant cholesterol

DOI:  https://doi.org/10.1161/JAHA.123.032419
Am J Physiol Cell Physiol. 2024 Jun 24.

Syndecans in hematopoietic cells and their niches.

Matthew W Hagen, Nicollette J Setiawan, Kelsey A Woodruff, Christina M Termini.

  Heparan sulfate proteoglycans are a family of glycoproteins that modulate cell signaling by binding growth factors and changing their bioavailability. Syndecans are a specific family of transmembrane heparan sulfate proteoglycans that regulate cell adhesion, migration, and signaling. In this review, we will summarize emerging evidence for the functions of Syndecans in the normal and malignant blood systems and their microenvironments. More specifically, we detail the known functions of Syndecans within normal hematopoietic stem cells. Further, we discuss the functions of Syndeans in hematological malignancies, including myeloid malignancies, lymphomas, and bleeding disorders. As normal and malignant hematopoietic cells require cues from their microenvironments to function, we also summarize the roles of Syndecans in cells of the stroma, endothelia, and osteolineage compartments. Syndecan biology is a rapidly evolving field; a comprehensive understanding of these molecules and their place in the hematopoietic system promises to improve our grasp on disease processes and better predict the efficacies of growth factor-targeting therapies.

Keywords:  Bone marrow niche; Hematopoiesis; Leukemia; Proteoglycan; Syndecan

DOI:  https://doi.org/10.1152/ajpcell.00326.2024
ACS Chem Biol. 2024 Jun 28.

Tyrosine Sulfation Modulates the Binding Affinity of Chemokine-Targeting Nanobodies.

Joshua J Dilly, Alexandra L Morgan, Max J Bedding, Jason K K Low, Joel P Mackay, Anne C Conibear, Ram Prasad Bhusal, Martin J Stone, Charlotte Franck, Richard J Payne.

Chemokines are an important family of small proteins integral to leukocyte recruitment during inflammation. Dysregulation of the chemokine-chemokine receptor axis is implicated in many diseases, and both chemokines and their cognate receptors have been the targets of therapeutic development. Analysis of the antigen-binding regions of chemokine-binding nanobodies revealed a sequence motif suggestive of tyrosine sulfation. Given the well-established importance of post-translational tyrosine sulfation of receptors for chemokine affinity, it was hypothesized that the sulfation of these nanobodies may contribute to chemokine binding and selectivity. Four nanobodies (16C1, 9F1, 11B1, and 11F2) were expressed using amber codon suppression to incorporate tyrosine sulfation. The sulfated variant of 16C1 demonstrated significantly improved chemokine binding compared to the non-sulfated counterpart, while the other nanobodies displayed equipotent or reduced affinity upon sulfation. The ability of tyrosine sulfation to modulate chemokine binding, both positively and negatively, could be leveraged for chemokine-targeted sulfo-nanobody therapeutics in the future.

DOI: https://doi.org/10.1021/acschembio.4c00230
Nat Commun. 2024 Jun 25. 15(1): 5388

Structural and mechanistic insights into a lysosomal membrane enzyme HGSNAT involved in Sanfilippo syndrome.

Boyang Zhao, Zhongzheng Cao, Yi Zheng, Phuong Nguyen, Alisa Bowen, Robert H Edwards, Robert M Stroud, Yi Zhou, Menno Van Lookeren Campagne, Fei Li.

Heparan sulfate (HS) is degraded in lysosome by a series of glycosidases. Before the glycosidases can act, the terminal glucosamine of HS must be acetylated by the integral lysosomal membrane enzyme heparan-α-glucosaminide N-acetyltransferase (HGSNAT). Mutations of HGSNAT cause HS accumulation and consequently mucopolysaccharidosis IIIC, a devastating lysosomal storage disease characterized by progressive neurological deterioration and early death where no treatment is available. HGSNAT catalyzes a unique transmembrane acetylation reaction where the acetyl group of cytosolic acetyl-CoA is transported across the lysosomal membrane and attached to HS in one reaction. However, the reaction mechanism remains elusive. Here we report six cryo-EM structures of HGSNAT along the reaction pathway. These structures reveal a dimer arrangement and a unique structural fold, which enables the elucidation of the reaction mechanism. We find that a central pore within each monomer traverses the membrane and controls access of cytosolic acetyl-CoA to the active site at its luminal mouth where glucosamine binds. A histidine-aspartic acid catalytic dyad catalyzes the transfer reaction via a ternary complex mechanism. Furthermore, the structures allow the mapping of disease-causing variants and reveal their potential impact on the function, thus creating a framework to guide structure-based drug discovery efforts.

DOI: https://doi.org/10.1038/s41467-024-49614-1
Materials (Basel). 2024 Jun 19. pii: 3003. [Epub ahead of print]17(12):

Hyaluronic Acid/Chondroitin Sulfate-Based Dynamic Thiol-Aldehyde Addition Hydrogel: An Injectable, Self-Healing, On-Demand Dissolution Wound Dressing.

Melissa Johnson, Rijian Song, Yinghao Li, Cameron Milne, Jing Lyu, Irene Lara-Sáez, Sigen A, Wenxin Wang.

  Frequent removal and reapplication of wound dressings can cause mechanical disruption to the healing process and significant physical discomfort for patients. In response to this challenge, a dynamic covalent hydrogel has been developed to advance wound care strategies. This system comprises aldehyde functionalized chondroitin sulfate (CS-CHO) and thiolated hyaluronic acid (HA-SH), with the distinct ability to form in situ via thiol-aldehyde addition and dissolve on-demand via the thiol-hemithioacetal exchange reaction. Although rarely reported, the dynamic covalent reaction of thiol-aldehyde addition holds great promise for the preparation of dynamic hydrogels due to its rapid reaction kinetics and easy reversible dissociation. The thiol-aldehyde addition chemistry provides the hydrogel system with highly desirable characteristics of rapid gelation (within seconds), self-healing, and on-demand dissolution (within 30 min). The mechanical and dissolution properties of the hydrogel can be easily tuned by utilizing CS-CHO materials of different aldehyde functional group contents. The chemical structure, rheology, self-healing, swelling profile, degradation rate, and cell biocompatibility of the hydrogels are characterized. The hydrogel possesses excellent biocompatibility and proves to be significant in promoting cell proliferation in vitro when compared to a commercial hydrogel (HyStem® Cell Culture Scaffold Kit). This study introduces the simple fabrication of a new dynamic hydrogel system that can serve as an ideal platform for biomedical applications, particularly in wound care treatments as an on-demand dissolvable wound dressing.

Keywords:  dynamic covalent chemistry; on-demand dissolution; self-healing; thiol–aldehyde addition; wound healing

DOI:  https://doi.org/10.3390/ma17123003
J Am Chem Soc. 2024 Jun 25.

Automated Synthesis of Algal Fucoidan Oligosaccharides.

Conor J Crawford, Mikkel Schultz-Johansen, Phuong Luong, Silvia Vidal-Melgosa, Jan-Hendrik Hehemann, Peter H Seeberger.

Fucoidan, a sulfated polysaccharide found in algae, plays a central role in marine carbon sequestration and exhibits a wide array of bioactivities. However, the molecular diversity and structural complexity of fucoidan hinder precise structure-function studies. To address this, we present an automated method for generating well-defined linear and branched α-fucan oligosaccharides. Our syntheses include oligosaccharides with up to 20 cis-glycosidic linkages, diverse branching patterns, and 11 sulfate monoesters. In this study, we demonstrate the utility of these oligosaccharides by (i) characterizing two endo-acting fucoidan glycoside hydrolases (GH107), (ii) utilizing them as standards for NMR studies to confirm suggested structures of algal fucoidans, and (iii) developing a fucoidan microarray. This microarray enabled the screening of the molecular specificity of four monoclonal antibodies (mAb) targeting fucoidan. It was found that mAb BAM4 has cross-reactivity to β-glucans, while mAb BAM2 has reactivity to fucoidans with 4-O-sulfate esters. Knowledge of the mAb BAM2 epitope specificity provided evidence that a globally abundant marine diatom, Thalassiosira weissflogii, synthesizes a fucoidan with structural homology to those found in brown algae. Automated glycan assembly provides access to fucoidan oligosaccharides. These oligosaccharides provide the basis for molecular level investigations into fucoidan's roles in medicine and carbon sequestration.

DOI: https://doi.org/10.1021/jacs.4c02348
Pharmaceutics. 2024 May 30. pii: 743. [Epub ahead of print]16(6):

Liquid Chromatography-Mass Spectrometry Analytical Methods for the Quantitation of p-Cresol Sulfate and Indoxyl Sulfate in Human Matrices: Biological Applications and Diagnostic Potentials.

Ala'a R Al-Dajani, Qi Kun Hou, Tony K L Kiang.

  Indoxyl sulfate (IxS) and p-cresyl sulfate (pCS) are toxic uremic compounds with documented pathological outcomes. This review critically and comprehensively analyzes the available liquid chromatography-mass spectrometry methods quantifying IxS and pCS in human matrices and the biological applications of these validated assays. Embase, Medline, PubMed, Scopus, and Web of Science were searched until December 2023 to identify assays with complete analytical and validation data (N = 23). Subsequently, citation analysis with PubMed and Scopus was utilized to identify the biological applications for these assays (N = 45). The extraction methods, mobile phase compositions, chromatography, and ionization methods were evaluated with respect to overall assay performance (e.g., sensitivity, separation, interference). Most of the assays focused on human serum/plasma, utilizing acetonitrile or methanol (with ammonium acetate/formate or formic/acetic acid), liquid-liquid extraction, reverse phase (e.g., C18) chromatography, and gradient elution for analyte separation. Mass spectrometry conditions were also consistent in the identified papers, with negative electrospray ionization, select multiple reaction monitoring transitions and deuterated internal standards being the most common approaches. The validated biological applications indicated IxS and/or pCS were correlated with renal disease progression and cardiovascular outcomes, with limited data on central nervous system disorders. Methods for reducing IxS and/or pCS concentrations were also identified (e.g., drugs, natural products, diet, dialysis, transplantation) where inconsistent findings have been reported. The clinical monitoring of IxS and pCS is gaining significant interest, and this review will serve as a useful compendium for scientists and clinicians.

Keywords:  indoxyl sulfate; kidney disease; liquid chromatography-mass spectrometry; p-Cresyl sulfate; protein-bound uremic toxins

DOI:  https://doi.org/10.3390/pharmaceutics16060743
Eur J Contracept Reprod Health Care. 2024 Jun 28. 1-3

The use of a pill containing ethinylestradiol-norgestimate improves female sexuality despite the decrease in circulating androgens: a pilot study.

Maurizio Guida, Luciano Quercitelli, Pasquale De Franciscis, Mariano Fiorenza, Alice Sgandurra, Antonio La Marca, Giovanni Grandi.

  PURPOSE: To evaluate the initial impact of a combined oral contraceptive (COC) containing norgestimate (NGM) on female sexuality and on circulating androgen levels in users.MATERIALS AND METHODS: Six months modification in the McCoy Female Sexuality Questionnaire (MFSQ) and testosterone (T) and dehydroepiandrosterone sulphate (DHEAS) serum levels in women starting a monophasic pill containing ethinyl-estradiol (EE) 35 µg and NGM 0.250 mg.
RESULTS: The study was completed by 36 subjects. There was a significant increase in MFSQ during treatment (p < 0.0001) (and its domains with the exclusion of vaginal lubrication domain) with concomitant decreases in T (-4.45%, p < 0.0001) and DHEAS (-19.41%, p < 0.0001) serum levels.
CONCLUSIONS: Contraception with EE/NGM was associated with a short term non-deteriorating effect on sexuality despite the evident decrease in androgen levels. Female sexuality during COC use is a complex topic and is not only linked with changes in serum androgen levels.

Keywords:  DHEAS; Norgestimate; androgen; contraception; libido; sex; sexuality; testosterone

DOI:  https://doi.org/10.1080/13625187.2024.2369833
Biosensors (Basel). 2024 May 27. pii: 275. [Epub ahead of print]14(6):

A Novel Fluorescence-Based Microplate Assay for High-Throughput Screening of hSULT1As Inhibitors.

Xiaoting Niu, Yufan Fan, Liwei Zou, Guangbo Ge.

  Human sulfotransferase 1As (hSULT1As) play a crucial role in the metabolic clearance and detoxification of a diverse range of endogenous and exogenous substances, as well as in the bioactivation of some procarcinogens and promutagens. Pharmacological inhibiting hSULT1As activities may enhance the in vivo effects of most hSULT1As drug substrates and offer protective strategies against the hSULT1As-mediated bioactivation of procarcinogens. To date, a fluorescence-based high-throughput assay for the efficient screening of hSULT1As inhibitors has not yet been reported. In this work, a fluorogenic substrate (HN-241) for hSULT1As was developed through scaffold-seeking and structure-guided molecular optimization. Under physiological conditions, HN-241 could be readily sulfated by hSULT1As to form HN-241 sulfate, which emitted brightly fluorescent signals around 450 nm. HN-241 was then used for establishing a novel fluorescence-based microplate assay, which strongly facilitated the high-throughput screening of hSULT1As inhibitors. Following the screening of an in-house natural product library, several polyphenolic compounds were identified with anti-hSULT1As activity, while pectolinarigenin and hinokiflavone were identified as potent inhibitors against three hSULT1A isozymes. Collectively, a novel fluorescence-based microplate assay was developed for the high-throughput screening and characterization of hSULT1As inhibitors, which offered an efficient and facile approach for identifying potent hSULT1As inhibitors from compound libraries.

Keywords:  fluorogenic substrate; hSULT1As inhibitors; high-throughput screening (HTS); human sulfotransferase 1As (hSULT1As); microplate-based assay

DOI:  https://doi.org/10.3390/bios14060275
Clin Endocrinol (Oxf). 2024 Jun 27.

Beyond symptomatology: A comparative analysis of unilateral and bilateral macronodular mild autonomous cortisol secretion.

Tugba Barlas, Isil Imge Gultekin, Sabri Engin Altintop, Emetullah Cindil, Mehmet Muhittin Yalcin, Ethem Turgay Cerit, Tevfik Sinan Sozen, Aylar Poyraz, Alev Eroglu Altinova, Fusun Balos Toruner, Mehmet Ayhan Karakoc, Mujde Akturk.

  OBJECTIVE: To investigate the clinical, laboratory findings and signal intensity index (SII) on magnetic resonance imaging (MRI) of patients with bilateral and unilateral macronodular mild autonomous cortisol secretion (MACS).PATIENTS AND MEASUREMENTS: Clinical and laboratory findings of 81 patients with MACS were examined from retrospective records. SII of adenomas and internodular areas were evaluated by MRI. The unilateral group included patients with an adrenal macronodule (≥1 cm) in a single adrenal gland, while the bilateral group included patients with at least one macronodule in both adrenal glands.
RESULTS: In total, 46 patients were in the unilateral (57%), while 35 (43%) patients were in the bilateral groups. The dehydroepiandrosterone sulphate (DHEA-S) level was lower in the unilateral than in the bilateral group (p < .001). The presence of type 2 diabetes mellitus (T2DM), glycosylated haemoglobin (HbA1c) and low-density lipoprotein (LDL) concentrations were higher in the bilateral group (p < .05). However, no significant difference was detected in terms of adrenocorticotropic hormone (ACTH) and overnight 1 mg dexamethasone suppression test (DST) between the two groups (p > .05). There was no difference in SII between adenomas within the same patient, as well as between the unilateral and bilateral groups (p > .05). Logistic regression analysis based on the differentiation between unilateral and bilateral macronodular MACS demonstrated that DHEA-S, HbA1c and LDL concentrations were associated factors.
CONCLUSION: DHEA-S levels may not be as suppressed in patients with bilateral macronodular MACS as compared to those with unilateral adenoma. T2DM and hypercholesterolaemia have a higher frequency in bilateral patients. However, ACTH, overnight 1 mg DST and SII may not provide additional information for differentiation of bilaterality and unilaterality.

Keywords:  Cushing's syndrome; adrenocorticotropic hormone; dehydroepiandrosterone sulphate; dexamethasone suppression test; signal intensity index

DOI:  https://doi.org/10.1111/cen.15109
Int J Mol Sci. 2024 Jun 13. pii: 6503. [Epub ahead of print]25(12):

HEMA-Lysine-Based Cryogels for Highly Selective Heparin Neutralization.

Tommaso Mecca, Fabiola Spitaleri, Rita La Spina, Sabrina Gioria, Valentina Giglio, Francesca Cunsolo.

  Unfractionated heparin (UFH) and its low-molecular-weight fragments (LMWH) are widely used as anticoagulants for surgical procedures and extracorporeal blood purification therapies such as cardiovascular surgery and dialysis. The anticoagulant effect of heparin is essential for the optimal execution of extracorporeal blood circulation. However, at the end of these procedures, to avoid the risk of bleeding, it is necessary to neutralize it. Currently, the only antidote for heparin neutralization is protamine sulphate, a highly basic protein which constitutes a further source of serious side events and is ineffective in neutralizing LMWH. Furthermore, dialysis patients, due to the routine administration of heparin, often experience serious adverse effects, among which HIT (heparin-induced thrombocytopenia) is one of the most severe. For this reason, the finding of new heparin antagonists or alternative methods for heparin removal from blood is of great interest. Here, we describe the synthesis and characterization of a set of biocompatible macroporous cryogels based on poly(2-hydroxyethyl methacrylate) (pHEMA) and L-lysine with strong filtering capability and remarkable neutralization performance with regard to UFH and LMWH. These properties could enable the design and creation of a filtering device to rapidly reverse heparin, protecting patients from the harmful consequences of the anticoagulant.

Keywords:  HEMA; anticoagulation; cryogels; dialysis; filtration; heparin neutralization; medical device

DOI:  https://doi.org/10.3390/ijms25126503