bims-supasi 2024-10-06 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2024–10–06
twenty papers selected by
Jonathan Wolf Mueller, University of Birmingham

Extracellular Matrix Components and Mechanosensing Pathways in Health and Disease.
Influence of Anticoagulants and Heparin Contaminants on the Suitability of MMP-9 as a Blood-Derived Biomarker.
Boosting Chondrocyte Bioactivity with Ultra-Sulfated Glycopeptide Supramolecular Polymers.
Diversity of human salivary heparan sulfate.
New Bacterial Aryl Sulfotransferases: Effective Tools for Sulfation of Polyphenols.
Site-specific sulfations regulate the physicochemical properties of papillomavirus-heparan sulfate interactions for entry.
Can longer lifespan be associated with gut microbiota involvement in lipid metabolism?
Local Sustained Dinutuximab Delivery and Release From Methacrylated Chondroitin Sulfate.
Chondroitin Sulfate for Cartilage Regeneration, Administered Topically Using a Nanostructured Formulation.
Synthesis and Biological Profiling of Seven Heparin and Heparan Sulphate Analogue Trisaccharides.
Interaction of myricetin, ampelopsin (dihydromyricetin), and their sulfate metabolites with serum albumin, cytochrome P450 (CYP2C9, 2C19, and 3A4) enzymes, and organic anion-transporting polypeptides (OATP1B1 and OATP2B1).
Enzymatically cross-linkable sulfated bacterial polyglucuronic acid as an affinity-based carrier of FGF-2 for therapeutic angiogenesis.
Dehydroepiandrosterone and Its Metabolite 5-Androstenediol: New Therapeutic Targets and Possibilities for Clinical Application.
Aspirin increases estrogen levels in the placenta to prevent preeclampsia by regulating placental metabolism and transport function.
Dietary protein intake and the tubular handling of indoxyl sulfate.
Polydopamine-coated chondroitin sulfate methacryloyl multifunctional microspheres for wound treatment.
SULF1 expression is increased and promotes fibrosis through the TGF-β1/SMAD pathway in idiopathic pulmonary fibrosis.
Sulfated fucans from algae Saccharina japonica promotes intestinal stem cell-mediated intestinal development in juvenile mouse by modulating the gut microbiota.
Indoxyl sulfate induces retinal microvascular injury via COX-2/PGE2 activation in diabetic retinopathy.
Diabetic Kidney Disease: Contribution of Phenyl Sulfate Derived from Dietary Tyrosine upon Gut Microbiota Catabolism.

Biomolecules. 2024 Sep 20. pii: 1186. [Epub ahead of print]14(9):

Extracellular Matrix Components and Mechanosensing Pathways in Health and Disease.

Aikaterini Berdiaki, Monica Neagu, Petros Tzanakakis, Ioanna Spyridaki, Serge Pérez, Dragana Nikitovic.

  Glycosaminoglycans (GAGs) and proteoglycans (PGs) are essential components of the extracellular matrix (ECM) with pivotal roles in cellular mechanosensing pathways. GAGs, such as heparan sulfate (HS) and chondroitin sulfate (CS), interact with various cell surface receptors, including integrins and receptor tyrosine kinases, to modulate cellular responses to mechanical stimuli. PGs, comprising a core protein with covalently attached GAG chains, serve as dynamic regulators of tissue mechanics and cell behavior, thereby playing a crucial role in maintaining tissue homeostasis. Dysregulation of GAG/PG-mediated mechanosensing pathways is implicated in numerous pathological conditions, including cancer and inflammation. Understanding the intricate mechanisms by which GAGs and PGs modulate cellular responses to mechanical forces holds promise for developing novel therapeutic strategies targeting mechanotransduction pathways in disease. This comprehensive overview underscores the importance of GAGs and PGs as key mediators of mechanosensing in maintaining tissue homeostasis and their potential as therapeutic targets for mitigating mechano-driven pathologies, focusing on cancer and inflammation.

Keywords:  cancer; glycosaminoglycans; glypican; inflammation; mechanosensing; mechanotransduction; proteoglycans; syndecans

DOI:  https://doi.org/10.3390/biom14091186
Int J Mol Sci. 2024 Sep 20. pii: 10106. [Epub ahead of print]25(18):

Influence of Anticoagulants and Heparin Contaminants on the Suitability of MMP-9 as a Blood-Derived Biomarker.

Daniela Küper, Josefin Klos, Friederike Kühl, Rozan Attili, Korbinian Brand, Karin Weissenborn, Ralf Lichtinghagen, René Huber.

  In contrast to other common anticoagulants such as citrate and low-molecular-weight heparin (LMWH), high-molecular-weight heparin (HMWH) induces the expression of matrix metalloproteinase (MMP)-9, which is also measured as a biomarker for stroke in blood samples. Mechanistically, HMWH-stimulated T cells produce cytokines that induce monocytic MMP-9 expression. Here, the influence of further anticoagulants (Fondaparinux, Hirudin, and Alteplase) and the heparin-contaminating glycosaminoglycans (GAG) hyaluronic acid (HA), dermatan sulfate (DS), chondroitin sulfate (CS), and over-sulfated CS (OSCS) on MMP-9 was analyzed to assess its suitability as a biomarker under various conditions. Therefore, starved Jurkat T cells were stimulated with anticoagulants/contaminants. Subsequently, starved monocytic THP-1 cells were incubated with the conditioned Jurkat supernatant, and MMP-9 mRNA levels were monitored (quantitative (q)PCR). Jurkat-derived mediators secreted in response to anticoagulants/contaminants were also assessed (proteome profiler array). The supernatants of HMWH-, Hirudin-, CS-, and OSCS-treated Jurkat cells comprised combinations of activating mediators and led to a significant (in the case of OSCS, dramatic) MMP-9 induction in THP-1. HA induced MMP-9 only in high concentrations, while LMWH, Fondaparinux, Alteplase, and DS had no effect. This indicates that depending on molecular weight and charge (but independent of anticoagulant activity), anticoagulants/contaminants provoke the expression of T-cell-derived cytokines/chemokines that induce monocytic MMP-9 expression, thus potentially impairing the diagnostic validity of MMP-9.

Keywords:  MMP-9; anticoagulants; blood sampling; contaminants; heparin; over-sulfated chondroitin sulfate

DOI:  https://doi.org/10.3390/ijms251810106
Acta Biomater. 2024 Oct 01. pii: S1742-7061(24)00574-9. [Epub ahead of print]

Boosting Chondrocyte Bioactivity with Ultra-Sulfated Glycopeptide Supramolecular Polymers.

Christopher H Sollenberger, Ruomeng Qiu, Hiroaki Sai, James K Carrow, Timmy Fyrner, Zijun Gao, Liam C Palmer, Samuel I Stupp.

  Although autologous chondrocyte transplantation can be effective in articular cartilage repair, negative side effects limit the utility of the treatment, such as long recovery times, poor engraftment or chondrogenic dedifferentiation, and cell leakage. Peptide-based supramolecular polymers have emerged as promising bioactive systems to promote tissue regeneration through cell signaling and dynamic behavior. We report here on the development of a series of glycopeptide amphiphile supramolecular nanofibers with chondrogenic bioactivity. These supramolecular polymers were found to have the ability to boost TGFβ-1 signaling by displaying galactosamine moieties with differing degrees of sulfation on their surfaces. We were also able to encapsulate chondrocytes with these nanostructures as single cells without affecting viability and proliferation. Among the monomers tested, assemblies of trisulfated glycopeptides led to elevated expression of chondrogenic markers relative to those with lower degrees of sulfation that mimic chondroitin sulfate repeating units. We hypothesize the enhanced bioactivity is rooted in specific interactions of the supramolecular assemblies with TGFβ-1 and its consequence on cell signaling, which may involve elevated levels of supramolecular motion as a result of high charge in trisulfated glycopeptide amphiphiles. Our findings suggest that supramolecular polymers formed by the ultra-sulfated glycopeptide amphiphiles could provide better outcomes in chondrocyte transplantation therapies for cartilage regeneration. STATEMENT OF SIGNIFICANCE: : This study prepares glycopeptide amphiphiles conjugated at their termini with chondroitin sulfate mimetic residues with varying degrees of sulfation that self-assemble into supramolecular nanofibers in aqueous solution. These supramolecular polymers encapsulate chondrocytes as single cells through intimate contact with cell surface structures, forming artificial matrix that can localize the growth factor TGFβ-1 in the intercellular environment. A high degree of sulfation on the glycopeptide amphiphile is found to be critical in elevating chondrogenic cellular responses that supersede the efficacy of natural chondroitin sulfate. This work demonstrates that supramolecular assembly of a unique molecular structure designed to mimic chondroitin sulfate successfully boosts chondrocyte bioactivity by single cell encapsulation, suggesting a new avenue implementing chondrocyte transplantation with supramolecular nanomaterials for cartilage regeneration.

Keywords:  Supramolecular polymerization; articular cartilage degeneration; chondrocyte transplantation; peptide amphiphile; single-cell encapsulation

DOI:  https://doi.org/10.1016/j.actbio.2024.09.047
Glycobiology. 2024 Oct 03. pii: cwae084. [Epub ahead of print]

Diversity of human salivary heparan sulfate.

Charlotte B Spliid, Sanjay Mehta, Mark M Fuster, Cameron Martino, Claire L Morris, Nharae Lee, Ivan Florentino, Khang Tong, Lin Liu, Gail Ackermann, Rob Knight, Jeffrey D Esko, Tatiana Hurtado De Mendoza.

  The human oral cavity and upper airway serves as an early barrier and reservoir in the transmission of SARS-CoV-2. Saliva in this microenvironment may serve as a key host factor that can modulate susceptibility to infection and eventual infection of the lower respiratory tract. We sought to analyze the content and composition of heparan sulfate, a glycosaminoglycan identified as an important co-receptor for viral entry, and whether there is any correlation with SARS-CoV-2 infection. We enlisted 98 participants stratified by age, gender, race, and COVID-19 history. Notably, the concentration of heparan sulfate in saliva increased with age, and its composition showed a wide range of variability within each age group independently of age. Heparan sulfate concentration and composition did not differ significantly with gender, ethnicity or race. Compared to patients with no COVID-19 history, patients with previous infection had a similar salivary heparan sulfate concentration, but significant increases in overall sulfation were noted. Moreover, in a subset of participants, for which data was available pre- and post- infection, significant elevation in N-sulfoglucosamine in heparan sulfate was observed post- COVID-19. Examination of salivary bacterial 16S rRNA, showed a significant reduction in species predicted to possess heparan sulfate-modifying capacity among participants >60 years old, which correlates with the increase in heparan sulfate content in older individuals. These findings demonstrate a surprisingly wide variation in heparan sulfate content and composition in saliva across the sampled population and confirm other findings showing variation in content and composition of glycosaminoglycans in blood and urine.

Keywords:  Covid-19; age; heparan sulfate; microbiome; saliva

DOI:  https://doi.org/10.1093/glycob/cwae084
J Agric Food Chem. 2024 Oct 01.

New Bacterial Aryl Sulfotransferases: Effective Tools for Sulfation of Polyphenols.

Katerina Brodsky, Barbora Petránková, Lucie Petrásková, Helena Pelantová, Vladimír Křen, Kateřina Valentová, Pavla Bojarová.

  The preparation of pure metabolites of bioactive compounds, particularly (poly)phenols, is essential for the accurate determination of their pharmacological profiles in vivo. Since the extraction of these metabolites from biological material is tedious and impractical, they can be synthesized enzymatically in vitro by bacterial PAPS-independent aryl sulfotransferases (ASTs). However, only a few ASTs have been studied and used for (poly)phenol sulfation. This study introduces new fully characterized recombinant ASTs selected according to their similarity to the previously characterized ASTs. These enzymes, produced in Escherichia coli, were purified, biochemically characterized, and screened for the sulfation of nine flavonoids and two phenolic acids using p-nitrophenyl sulfate. All tested compounds were proved to be substrates for the new ASTs, with kaempferol and luteolin being the best converted acceptors. ASTs from Desulfofalx alkaliphile (DalAST) and Campylobacter fetus (CfAST) showed the highest efficiency in the sulfation of tested polyphenols. To demonstrate the efficiency of the present sulfation approach, a series of new authentic metabolite standards, regioisomers of kaempferol sulfate, were enzymatically produced, isolated, and structurally characterized.

Keywords:  aryl sulfotransferase; enzymatic sulfation; kaempferol sulfate; metabolite; polyphenol

DOI:  https://doi.org/10.1021/acs.jafc.4c06771
Sci Adv. 2024 Oct 04. 10(40): eado8540

Site-specific sulfations regulate the physicochemical properties of papillomavirus-heparan sulfate interactions for entry.

Fouzia Bano, Laura Soria-Martinez, Dominik van Bodegraven, Konrad Throsteinsson, Anna M Brown, Ines Fels, Nicole L Snyder, Marta Bally, Mario Schelhaas.

Certain human papillomaviruses (HPVs) are etiological agents for several anogenital and oropharyngeal cancers. During initial infection, HPV16, the most prevalent cancer-causing type, specifically interacts with heparan sulfates (HSs), not only enabling initial cell attachment but also triggering a crucial conformational change in viral capsids termed structural activation. It is unknown, whether these HPV16-HS interactions depend on HS sulfation patterns. Thus, we probed potential roles of HS sulfations using cell-based functional and physicochemical assays, including single-molecule force spectroscopy. Our results demonstrate that N-sulfation of HS is crucial for virus binding and structural activation by providing high-affinity sites, and that additional 6O-sulfation is required to mechanically stabilize the interaction, whereas 2O-sulfation and 3O-sulfation are mostly dispensable. Together, our findings identify the contribution of HS sulfation patterns to HPV16 binding and structural activation and reveal how distinct sulfation groups of HS synergize to facilitate HPV16 entry, which, in turn, likely influences the tropism of HPVs.

DOI: https://doi.org/10.1126/sciadv.ado8540
FEMS Microbiol Ecol. 2024 Oct 01. pii: fiae135. [Epub ahead of print]

Can longer lifespan be associated with gut microbiota involvement in lipid metabolism?

Sára Šardzíková, Marta Gajewska, Norbert Gałka, Matúš Štefánek, Andrej Baláž, Martina Garaiová, Roman Holič, Wiesław Świderek, Katarína Šoltys.

  Biological aging is linked to altered body composition and reduced neuroactive steroid hormones like dehydroepiandrosterone sulfate (DHEAS), which can stimulate the GABA signaling pathway via gut microbiota. Our study examined the association of gut microbiota with lifespan in mice through comprehensive analysis of its composition and functional involvement in cholesterol sulfate, a precursor of DHEAS, metabolism. We used 16S rRNA and metagenomic sequencing, followed by metabolic pathway prediction and TLC and MALDI-TOF cholesterol sulfate identification. Significant increases in bacteria such as Bacteroides, typical for long-lived and Odoribacter and Colidextribacter, specific for short-lived mice were detected. Furthermore, for males (Rikenella, Alloprevotella) and females (Lactobacillus, Bacteroides), specific bacterial groups emerged as predictors (AUC=1), highlighting sex-specific patterns. Long-lived mice showed a strong correlation of Bacteroides (0.918) with lipid and steroid hormone metabolism, while a negative correlation of GABAergic synapse with body weight (-0.589). We found that several Bacteroides species harboring the sulfotransferase gene and gene cluster for sulfonate donor synthesis are involved in converting cholesterol to cholesterol sulfate, significantly higher in the feces of long-lived individuals. Overall, we suggest that increased involvement of gut bacteria, mainly Bacteroides spp., in cholesterol sulfate synthesis could ameliorate aging through lipid metabolism.

Keywords:  Bacteroides; body weight; cholesterol sulfate; gut microbiome; lifespan; longevity

DOI:  https://doi.org/10.1093/femsec/fiae135
J Biomed Mater Res A. 2024 Oct 02.

Local Sustained Dinutuximab Delivery and Release From Methacrylated Chondroitin Sulfate.

Katelyn S Mistretta, Jane Tiche, Bill Chiu, Jeannine M Coburn.

  Neuroblastoma (NB) is the most common pediatric extracranial solid tumor. High-risk NB is a subset of the disease that has poor prognosis and requires multimodal treatment regimens, with a 50% rate of recurrence despite intervention. There is a need for improved treatment strategies to reduce high-risk patient mortality. Dinutuximab is an anti-GD2 antibody ideal for targeting GD2 expressing NB cells, but binding of the antibody to peripheral nerve fibers leads to severe pain during systemic administration. Intratumoral delivery of the anti-GD2 antibody would allow for increased local antibody concentration, without increasing systemic toxicity. Chondroitin Sulfate (CS) is a biocompatible glycosaminoglycan that can be methacrylated to form CSMA, a photocrosslinkable hydrogel that can be loaded with therapeutic agents. The methacrylation reaction time can be varied to achieve different degrees of substitution, resulting in different release and degradation profiles. In this work, 4 and 24 h reacted CSMA was used to create hydrogels at 10% and 20% CSMA. Sustained in vitro release of dinutuximab from these formulations was observed over a 24-day period, and 4 h reacted 10% CSMA hydrogels had the highest overall dinutuximab release over time. An orthotropic mouse model was used to evaluate in vivo response to dinutuximab loaded 4 h methacrylated 10% CSMA hydrogels as compared to bolus tail vein injections. Tumor growth was monitored, and there was a statistically significant increase in the days to reach specific tumor size for tumors treated with intratumoral dinutuximab-loaded hydrogel compared to those treated with dinutuximab solution through tail vein injection. This supports the concept that locally delivering dinutuximab within the hydrogel formulation slowed tumor growth. The CSMA hydrogel-only treatment slowed tumor growth as well, an interesting effect that may indicate interactions between the CSMA and cell adhesion molecules in the tumor microenvironment. These findings demonstrate a potential avenue for local sustained delivery of dinutuximab for improved anti-tumoral response in high-risk NB.

Keywords:  biopolymers; chondroitin sulfate; dinutuximab; drug delivery; neuroblastoma; pediatric oncology; sustained release

DOI:  https://doi.org/10.1002/jbm.a.37803
Int J Mol Sci. 2024 Sep 18. pii: 10023. [Epub ahead of print]25(18):

Chondroitin Sulfate for Cartilage Regeneration, Administered Topically Using a Nanostructured Formulation.

Marta E Bustos Araya, Anna Nardi-Ricart, Ana C Calpena Capmany, Montserrat Miñarro Carmona.

  In the pharmaceutical sector, solid lipid nanoparticles (SLN) are vital for drug delivery incorporating a lipid core. Chondroitin sulfate (CHON) is crucial for cartilage health. It is often used in osteoarthritis (OA) treatment. Due to conflicting results from clinical trials on CHON's efficacy in OA treatment, there has been a shift toward exploring effective topical systems utilizing nanotechnology. This study aimed to optimize a solid lipid nanoparticle formulation aiming to enhance CHON permeation for OA therapy. A 3 × 3 × 2 Design of these experiments determined the ideal parameters: a CHON concentration of 0.4 mg/mL, operating at 20,000 rpm speed, and processing for 10 min for SLN production. Transmission electron microscopy analysis confirmed the nanoparticles' spherical morphology, ensuring crucial uniformity for efficient drug delivery. Cell viability assessments showed no significant cytotoxicity within the tested parameters, indicating a safe profile for potential clinical application. The cell internalization assay indicates successful internalization at 1.5 h and 24 h post-treatment. Biopharmaceutical studies supported SLNs, indicating them to be effective CHON carriers through the skin, showcasing improved skin permeation and CHON retention compared to conventional methods. In summary, this study successfully optimized SLN formulation for efficient CHON transport through pig ear skin with no cellular toxicity, highlighting SLNs' potential as promising carriers to enhance CHON delivery in OA treatment and advance nanotechnology-based therapeutic strategies in pharmaceutical formulations.

Keywords:  biopharmaceutical studies; cell viability; chondroitin sulfate; design of experiments; drug delivery; osteoarthritis; skin permeation; solid lipid nanoparticles

DOI:  https://doi.org/10.3390/ijms251810023
Biomolecules. 2024 Aug 25. pii: 1052. [Epub ahead of print]14(9):

Synthesis and Biological Profiling of Seven Heparin and Heparan Sulphate Analogue Trisaccharides.

Fruzsina Demeter, Zsófia Peleskei, Katalin Kútvölgyi, Ágnes Rusznyák, Ferenc Fenyvesi, Richárd Kajtár, Éva Sipos, István Lekli, Petra Molnár, Attila Gábor Szöllősi, Erika Lisztes, Balázs István Tóth, Anikó Borbás, Mihály Herczeg.

  Researchers are paying increasing attention to the strongly negatively charged heteropolysaccharides in cells, in the extracellular matrix or in the cell wall. Examples of such molecules are glycosaminoglycans (e.g., heparin, heparan sulphate). It is well known from the literature that heparin and its derivatives have anti-inflammatory, angiogenic, metastatic and growth factor inhibitory activity. Herein, we present the efficient synthesis of six non-glycosaminoglycan (Glc-GlcA-Glc-sequenced) and one heparin-related (GlcN-GlcA-Glc-sequenced) trisaccharides with various functional group patterns. The anti-inflammatory, antioxidant and cell growth-inhibitory/cytotoxic effects of the synthesized compounds were tested. Among the investigated molecules, we have found some derivatives with a promising anti-inflammatory and antioxidant effect.

Keywords:  anti-inflammatory; antioxidant; heparan sulphate; heparin; trisaccharides

DOI:  https://doi.org/10.3390/biom14091052
Pharmacol Res Perspect. 2024 Oct;12(5): e70021

Interaction of myricetin, ampelopsin (dihydromyricetin), and their sulfate metabolites with serum albumin, cytochrome P450 (CYP2C9, 2C19, and 3A4) enzymes, and organic anion-transporting polypeptides (OATP1B1 and OATP2B1).

Ágnes Dombi, Hana Kaci, Kateřina Valentová, Éva Bakos, Csilla Özvegy-Laczka, Miklós Poór.

  Myricetin (MYR) and ampelopsin (AMP, or dihydromyricetin) are flavonoid aglycones found in certain plants and dietary supplements. During the presystemic biotransformation of flavonoids, mainly sulfate and glucuronide derivatives are produced, which are the dominant metabolites in the circulation. In this study, we tested the interactions of MYR, myricetin-3'-O-sulfate (M3'S), AMP, and ampelopsin-4'-O-sulfate (A4'S) with human serum albumin (HSA), cytochrome P450 enzymes (CYPs), and organic anion-transporting polypeptides (OATPs) using in vitro models, including the recently developed method for measuring flavonoid levels in living cells. M3'S and MYR bound to albumin with high affinity, and they showed moderate displacing effects versus the Site I marker warfarin. MYR, M3'S, AMP, and A4'S exerted no or only minor inhibitory effects on CYP2C9, CYP2C19, and CYP3A4 enzymes. M3'S and MYR caused considerable inhibitory actions on OATP1B1 at low micromolar concentrations (IC50 = 1.7 and 6.4 μM, respectively), while even their nanomolar levels resulted in strong inhibitory effects on OATP2B1 (IC50 = 0.3 and 0.4 μM, respectively). In addition, M3'S proved to be a substrate of OATP1B1 and OATP2B1. These results suggest that MYR-containing dietary supplements may affect the OATP-mediated transport of certain drugs, and OATPs are involved in the tissue uptake of M3'S.

Keywords:  CYP enzymes; OATP transporters; ampelopsin; human serum albumin; myricetin

DOI:  https://doi.org/10.1002/prp2.70021
J Biosci Bioeng. 2024 Sep 28. pii: S1389-1723(24)00258-5. [Epub ahead of print]

Enzymatically cross-linkable sulfated bacterial polyglucuronic acid as an affinity-based carrier of FGF-2 for therapeutic angiogenesis.

Ryota Goto, Shinji Sakai, Cédric Delattre, Emmanuel Petit, Redouan El Boutachfaiti, Masaki Nakahata.

  The fibroblast growth factor-2 (FGF-2) is a critical protein for biological processes such as angiogenesis and tissue regeneration. Recently, hydrogels based on semi-synthetic sulfated polysaccharides have been developed for the controlled delivery of FGF-2. These affinity-based FGF-2 carriers utilizing hydrogels based on sulfated polysaccharides enable sustained delivery of FGF-2, yet choice of materials is limited. Here, we demonstrate a novel synthetic sulfated polysaccharide-based hydrogel based on bacterial polyglucuronic acid (PGU). We synthesized phenol-grafted sulfated PGU (PGUS-Ph), an enzymatically cross-linkable PGU derivative that exhibited an enhanced affinity for FGF-2. The aqueous solution of PGUS-Ph, when combined with FGF-2, could be injected into affected sites and form a hydrogel in a minimally invasive manner. The FGF-2 released from the PGUS-Ph hydrogel induced blood vessel formation, as proven by a chick embryo-based angiogenesis assay. Our results indicate that the PGUS-Ph has the potential as an enzymatically cross-linkable and minimally invasively injectable affinity-based FGF-2 delivery system.

Keywords:  Angiogenesis; Fibroblast growth factor-2; Horseradish peroxidase; Hydrogel; Polyglucuronic acid; Sulfation

DOI:  https://doi.org/10.1016/j.jbiosc.2024.08.011
Pharmaceuticals (Basel). 2024 Sep 09. pii: 1186. [Epub ahead of print]17(9):

Dehydroepiandrosterone and Its Metabolite 5-Androstenediol: New Therapeutic Targets and Possibilities for Clinical Application.

Tatiana A Fedotcheva, Maria E Uspenskaya, Darya N Ulchenko, Nikolay L Shimanovsky.

  Dehydroepiandrosterone and its sulfate are the most abundant steroids in humans. The metabolism of dehydroepiandrosterone can differ significantly depending on the organ or tissue and the subtype of steroid receptors expressed in it. For dehydroepiandrosterone, as a precursor of all steroid hormones, intracrine hormonal activity is inherent. This unique feature could be beneficial for the medicinal application, especially for the local treatment of various pathologies. At present, the clinical use of dehydroepiandrosterone is limited by its Intrarosa® (Quebec city, QC, Canada) prasterone) 6.5 mg vaginal suppositories for the treatment of vaginal atrophy and dyspareunia, while the dehydroepiandrosterone synthetic derivatives Triplex, BNN 27, and Fluasterone have the investigational status for the treatment of various diseases. Here, we discuss the molecular targets of dehydroepiandrosterone, which open future prospects to expand its indications for use. Dehydroepiandrosterone, as an oral drug, is surmised to have promise in the treatment of osteoporosis, cachexia, and sarcopenia, as does 10% unguent for skin and muscle regeneration. Also, 5-androstenediol, a metabolite of dehydroepiandrosterone, is a promising candidate for the treatment of acute radiation syndrome and as an immunostimulating agent during radiopharmaceutical therapy. The design and synthesis of new 5-androstenediol derivatives with increased bioavailability may lead to the appearance of highly effective cytoprotectors on the pharmaceutical market. The argumentations for new clinical applications of these steroids and novel insights into their mechanisms of action are discussed.

Keywords:  5-AED; DHEA; androstenes; constitutive androstane receptor CAR; immunostimulation; intracrine regulation; membrane receptors; nuclear receptors; osteoporosis; prasterone; regeneration

DOI:  https://doi.org/10.3390/ph17091186
Biochem Pharmacol. 2024 Sep 27. pii: S0006-2952(24)00561-6. [Epub ahead of print]230(Pt 1): 116561

Aspirin increases estrogen levels in the placenta to prevent preeclampsia by regulating placental metabolism and transport function.

Shengbo Huang, Yuan Xu, Yuanqing Guo, Yuanjin Zhang, Yu Tang, Chenmeizi Liang, Liangcai Gao, Bingyi Yao, Xin Wang.

  Preeclampsia is a unique multisystem progressive disease during pregnancy, which seriously endangers the health of pregnant women and fetuses. In clinical practice, aspirin is recommended for the prevention of preeclampsia, but the mechanism by which aspirin prevents preeclampsia has not yet been revealed. This report comprehensively evaluates the effects of aspirin on the expression and activity of placental metabolic enzymes and transporters. We found that after aspirin administration, only the expression of organic anion transporter 4 (OAT4) in the placenta showed a significant increase at both mRNA and protein levels, consistent with the results in JAR cells. Meanwhile, studies on the metabolic enzyme activity in the placenta showed a high upregulation of CYP19A1 activity. Subsequently, significant increases in endogenous substrates of OAT4 and CYP19A1 (dehydroepiandrosterone sulfate (DHEAS) and androstenedione) as well as estrone were detected in placental tissue. In summary, aspirin enhances the transport of DHEAS through OAT4 and promotes the metabolism of androstenedione through CYP19A1, thereby increasing estrogen levels in the placenta. This may be the mechanism by which aspirin prevents preeclampsia and maintains pregnancy by regulating the metabolism and transport function of the placenta.

Keywords:  Aspirin; Metabolic enzymes; Placenta; Preeclampsia; Transporters

DOI:  https://doi.org/10.1016/j.bcp.2024.116561
Nephrol Dial Transplant. 2024 Oct 01. pii: gfae220. [Epub ahead of print]

Dietary protein intake and the tubular handling of indoxyl sulfate.

Mara Lauriola, Ricard Farré, Sander Dejongh, Henriette de Loor, Pieter Evenepoel, Rosalinde Masereeuw, Ward Zadora, Björn Meijers.

   BACKGROUND AND HYPOTHESIS: Chronic kidney disease (CKD) patients are advised to limit their protein intake. A high protein diet is known to induce glomerular hyperfiltration, as well as hypertrophy of the remnant kidney, and glomerulosclerosis. Whether the diet causes changes in kidney tubule transport via gut microbiome metabolites is still unknown. We hypothesized that protein intake affects not only the intestinal generation and absorption, but also the kidney disposal of microbial amino acid metabolites.
METHODS: We combined data from animal models and human studies. 5/6th nephrectomy rats were administered a high (HP) or low-protein (LP) diet for 7 weeks. Plasma and urine concentration of the uremic toxins (UTs) indoxyl sulfate (IS), p-cresyl sulfate (PCS), and p-cresyl glucuronide (PCG) were measured. Their fractional excretion (FE) was calculated. The expression of kidney membrane transporters OAT1, OAT3, BCRP, OCT2 and MRP4 was analyzed. Differences in FE of UTs between individuals with higher and lower protein intake in two CKD cohorts were sought.
RESULTS: CKD rats on an HP diet showed increased plasma levels of PCS and PCG but not IS compared to rats on a LP diet. Conversely, urinary excretion and FE of IS were higher in the HP CKD group. BCRP, MRP4 and OCT2 were not influenced by the diet. OAT1 and OAT3 were upregulated in the HP CKD group. In two independent cohorts of CKD patients, individuals with a high dietary protein intake showed a significantly higher FE of IS.
CONCLUSIONS: A HP diet leads to a higher generation and/or absorption of aminoacid-derived UT precursors in CKD rodent models and humans, most likely via gut microbiome modulation. We demonstrate that dietary protein intake modulates transcription and expression of OAT1 and OAT3, corroborating the existence of the remote sensing and signaling hypothesis. Dietary protein intake influences kidney physiology beyond glomerular filtration.

Keywords:  chronic kidney disease; gut-kidney axis; indoxyl sulfate; kidney transporters; uremic toxins

DOI:  https://doi.org/10.1093/ndt/gfae220
Int J Biol Macromol. 2024 Sep 26. pii: S0141-8130(24)06896-X. [Epub ahead of print]280(Pt 4): 136087

Polydopamine-coated chondroitin sulfate methacryloyl multifunctional microspheres for wound treatment.

Huaqian Xue, Huanxuan Zeng, Shaoyu Zhou, Yunyuan Shao, Han Chen, Lanjie Lei, Xing Fan.

  The disappearance of the protective barrier after skin injury leads to the overproduction of reactive oxygen species (ROS) in response to various stimuli. Oxidative stress is one of the most important causes of delayed wound healing, leading to negative outcomes, such as excessive inflammatory response and impaired angiogenesis. In this study, we used microfluidic technology to integrate Prussian blue nanozymes and vascular endothelial growth factor and constructed multifunctional microspheres that improved local oxidative stress. In order to enhance the adhesion of the microspheres on the wound surface and prolong the release of the drug, we coated them with dopamine, ensuring uniform encapsulation on their surface. The microspheres adhered well to the wound surface and promoted wound healing by scavenging ROS, reducing the inflammatory response, and promoting angiogenesis. This strategy of integrating nanozymes and growth factors can have a synergistic effect, which is significant for wound healing.

Keywords:  Chondroitin sulfate; Microsphere; Prussian blue nanozyme

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.136087
J Transl Med. 2024 Oct 01. 22(1): 885

SULF1 expression is increased and promotes fibrosis through the TGF-β1/SMAD pathway in idiopathic pulmonary fibrosis.

Meng Tu, Chunya Lu, Hongxia Jia, Shanshan Chen, Yan Wang, Jing Li, Jiuling Cheng, Ming Yang, Guojun Zhang.

   BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease of unknown etiology. Despite the increasing global incidence and poor prognosis, the exact pathogenic mechanisms remain elusive. Currently, effective therapeutic targets and treatment methods for this disease are still lacking. This study tried to explore the pathogenic mechanisms of IPF. We found elevated expression of SULF1 in lung tissues of IPF patients compared to normal control lung tissues. SULF1 is an enzyme that modifies heparan sulfate chains of heparan sulfate proteoglycans, playing a critical role in biological regulation. However, the effect of SULF1 in pulmonary fibrosis remains incompletely understood. Our study aimed to investigate the impact and mechanisms of SULF1 in fibrosis.
METHODS: We collected lung specimens from IPF patients for transcriptome sequencing. Validation of SULF1 expression in IPF patients was performed using Western blotting and RT-qPCR on lung tissues. ELISA experiments were employed to detect SULF1 concentrations in IPF patient plasma and TGF-β1 levels in cell culture supernatants. We used lentiviral delivery of SULF1 shRNA to knock down SULF1 in HFL1 cells, evaluating its effects on fibroblast secretion, activation, proliferation, migration, and invasion capabilities. Furthermore, we employed Co-Immunoprecipitation (Co-IP) to investigate the regulatory mechanisms involved.
RESULTS: Through bioinformatic analysis of IPF transcriptomic sequencing data (HTIPF) and datasets GSE24206, and GSE53845, we identified SULF1 may potentially play a crucial role in IPF. Subsequently, we verified that SULF1 was upregulated in IPF and predominantly increased in fibroblasts. Furthermore, SULF1 expression was induced in HFL1 cells following exposure to TGF-β1. Knockdown of SULF1 suppressed fibroblast secretion, activation, proliferation, migration, and invasion under both TGF-β1-driven and non-TGF-β1-driven conditions. We found that SULF1 catalyzes the release of TGF-β1 bound to TGFβRIII, thereby activating the TGF-β1/SMAD pathway to promote fibrosis. Additionally, TGF-β1 induces SULF1 expression through the TGF-β1/SMAD pathway, suggesting a potential positive feedback loop between SULF1 and the TGF-β1/SMAD pathway.
CONCLUSIONS: Our findings reveal that SULF1 promotes fibrosis through the TGF-β1/SMAD pathway in pulmonary fibrosis. Targeting SULF1 may offer a promising therapeutic strategy against IPF.

Keywords:  Fibroblasts; Idiopathic pulmonary fibrosis; SULF1; TGF-β1; TGF-β1/SMAD pathway

DOI:  https://doi.org/10.1186/s12967-024-05698-3
Int J Biol Macromol. 2024 Oct 01. pii: S0141-8130(24)07016-8. [Epub ahead of print] 136207

Sulfated fucans from algae Saccharina japonica promotes intestinal stem cell-mediated intestinal development in juvenile mouse by modulating the gut microbiota.

Biqian Wei, Pengfei Ren, Wanting Qin, Dehua Wang, Yinfeng Wang, Yaoguang Chang, Yuming Wang, Changhu Xue, Qingjuan Tang.

  Intestinal development has a crucial role in the absorption of nutrients and the ability to resist infections in the early stages of life. This study utilized a 3-week-old C57BL/6 mice model to evaluate the beneficial impacts of sulfated fucans from Saccharina japonica (SJ-FUC) on the growth and development of the intestines. SJ-FUC enhanced the dimensions of the intestine, specifically the length, height of villi, and depth of the crypts. Additionally, it raised the mRNA expression of ZO-1 and Occludin, hence enhancing the structural integrity of the intestinal epithelium. SJ-FUC significantly increased mRNA expression of Lyz1, Muc2, and Math1, which resulted in the promotion of intestinal epithelial development. Furthermore, SJ-FUC augmented the mRNA levels of the ISC markers (Lgr5, Olfm4, and Ascl2). Our further research uncovered that SJ-FUC has a positive impact on the growth of beneficial bacteria, such as Akkermansia, Dubosiella, and Lactobacillus, which in turn promotes epithelial development of the intestine. In summary, our research indicates that SJ-FUC has a beneficial impact on the growth of the intestines in young mice. This is achieved by enhancing the stemness of intestinal stem cells (ISCs) and promoting the formation of the intestinal epithelium through the regulation of gut bacteria.

Keywords:  Gut microbiota; Intestinal development; Sulfated fucans

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.136207
J Transl Med. 2024 Sep 27. 22(1): 870

Indoxyl sulfate induces retinal microvascular injury via COX-2/PGE2 activation in diabetic retinopathy.

Lan Zhou, Hongyan Sun, Gongyi Chen, Cunzi Li, Dan Liu, Xurui Wang, Ting Meng, Zhenyou Jiang, Shu Yang, Ming-Ming Yang.

   BACKGROUND: Diabetic retinopathy (DR), the principal cause of acquired blindness among the working-age population, is the most frequent microvascular complication of diabetes. Although metabolic disorders are hypothesized to play a role in its pathogenesis, the underlying mechanism remains largely elusive.
METHODS: To elucidate the mechanism, we initially compared metabolite profiles of vitreous fluid between 23 patients with DR and 12 non-diabetic controls using liquid chromatography/tandem mass spectrometry, identifying the distinct metabolite indoxyl sulfate (IS). Subsequently, streptozotocin (STZ)-induced diabetic and IS-injected rat models were established to examine the effects of IS on retinal microvasculature. RNA sequencing was conducted to identify potential regulatory mechanisms in IS-treated human retinal endothelial cells (HREC). Finally, target gene knockdown in HREC and treatment of IS-injected rats with inhibitors (targeting IS production or downstream regulators) were employed to elucidate the detailed mechanisms and identify therapeutic targets for DR.
RESULTS: Metabolomics identified 172 significantly altered metabolites in the vitreous humor of diabetics, including the dysregulated tryptophan metabolite indoxyl sulfate (IS). IS was observed to breach the blood-retinal barrier and accumulate in the intraocular fluid of diabetic rats. Both in vivo and in vitro experiments indicated that elevated levels of IS induced endothelial apoptosis and disrupted cell junctions. RNA sequencing pinpointed prostaglandin E2 (PGE2) synthetase-cyclooxygenase 2 (COX-2) as a potential target of IS. Validation experiments demonstrated that IS enhanced COX-2 expression, which subsequently increased PGE2 secretion by promoting transcription factor EGR1 binding to COX-2 DNA following entry into cells via organic anion transporting polypeptides (OATP2B1). Furthermore, inhibition of COX-2 in vivo or silencing EGR1/OATP2B1 in HREC mitigated IS-induced microcapillary damage and the activation of COX-2/PGE2.
CONCLUSION: Our study demonstrated that indoxyl sulfate (IS), a uremic toxin originating from the gut microbiota product indole, increased significantly and contributed to retinal microvascular damage in diabetic retinopathy (DR). Mechanistically, IS impaired retinal microvascular integrity by inducing the expression of COX-2 and the production of PGE2. Consequently, targeting the gut microbiota or the PGE2 pathway may offer effective therapeutic strategies for the treatment of DR.

Keywords:  COX-2; Diabetic retinopathy; Indoxyl sulfate; Microcapillary damage; PGE2

DOI:  https://doi.org/10.1186/s12967-024-05654-1
Biomolecules. 2024 Sep 13. pii: 1153. [Epub ahead of print]14(9):

Diabetic Kidney Disease: Contribution of Phenyl Sulfate Derived from Dietary Tyrosine upon Gut Microbiota Catabolism.

Haoxin Liu, Tram N Diep, Ying Wang, Yucheng Wang, Liang-Jun Yan.

  Deranged gut microbiota can release increased levels of uremic toxins leading to exacerbated kidney injury. In diabetic kidney disease (DKD), phenyl sulfate (PS) derived from tyrosine catabolism by gut microbiota has been demonstrated to be both an early diagnostic marker and a therapeutic target. In this perspective article, we summarize PS generation pathways and recent findings on PS and kidney injury in DKD. Increasing evidence has shown that the underlying mechanisms of PS-induced kidney injury mainly involve oxidative stress, redox imbalance, and mitochondrial dysfunction, which all may be targeted to attenuate PS-induced kidney injury. For future research directions, we think that a deeper understanding of the pathogenic role of PS in kidney injury using a variety of diabetic animal models should be investigated. Moreover, we also suggest beneficial approaches that could be used to mitigate the deleterious effect of PS on the kidney. These approaches include caloric restriction, tyrosine restriction, and administration of ketogenic drugs, ketogenic diets or natural products; all of which should be conducted under obese and diabetic conditions.

Keywords:  diabetic kidney disease; gut microbiota; mitochondrial dysfunction; oxidative stress; phenyl sulfate; tyrosine

DOI:  https://doi.org/10.3390/biom14091153