bims-supasi 2022-11-06 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2022–11–06
eight papers selected by
Jonathan Wolf Mueller, University of Birmingham

Sulfation of Heparan and Chondroitin Sulfate Ligands Enables Cell Specific Homing of Nanoprobes.
Broad-Spectrum Virus Trapping with Heparan Sulfate-Modified DNA Origami Shells.
Heparin mimetics as potential intervention for COVID-19 and their bio-manufacturing.
Rhamnan sulfate reduces atherosclerotic plaque formation and vascular inflammation.
Transport of the pro-inflammatory chemokines CCL2 (MCP-1) and CCL5 (RANTES) across the intact mouse blood-brain barrier is inhibited by heparin and eprodisate and increased with systemic inflammation.
Sulfated endospermic nanocellulose crystals prevent the transmission of SARS-CoV-2 and HIV-1.
Steroid hormone levels in postmenopausal hysterectomised women with and without ovarian conservation: the continuous endocrine function of the ovaries.
Pharmacokinetics of Morphine Sulfate Orodispersible Tablets and Bioequivalence with Immediate-Release Oral Morphine Sulfate Formulations in Healthy Adult Subjects Under Fasting Conditions: Single-Dose Comparative Bioavailability Studies.

Chemistry. 2022 Nov 02.

Sulfation of Heparan and Chondroitin Sulfate Ligands Enables Cell Specific Homing of Nanoprobes.

Sandhya Mardhekar, Balamurugan Subramani, Prasanna Samudra, Priyadharshini Srikanth, Virendrasinh Mahida, Preeti Ravindra Bhoge, Suraj Toraskar, Nixon M Abraham, Raghavendra V Kikkeri.

  Demystifying the sulfation code of glycosaminoglycans (GAGs) to induce precise homing of nanoparticles in tumor or neuron cells influences the development of a potential drug or gene delivery system. However, GAGs, particularly heparan sulfate (HS) and chondroitin sulfate (CS), are structurally highly heterogeneous, and synthesizing well-defined HS/CS composed nanoparticles is challenging. Here, we decipher how specific sulfation patterns on HS and CS regulate receptor-mediated homing of nanoprobes in primary and secondary cells. We discovered that aggressive cancer cells such as MDA-MB-231 displayed a strong uptake of GAG-nanoprobes compared to mild or moderate aggressive cancer cells. However, there was no selectivity towards the GAG sequences, indicating the presence of more than one receptor mediated uptake. Whereas U87 cells, olfactory bulb and hippocampal primary neurons showed selective or preferential uptake of CS-E coated nanoprobes compared to other GAG-nanoprobes. Further, mechanistic studies revealed that 4,6-O-disulfated-CS nanoprobe utilized CD44 and caveolin-dependent endocytosis pathway for the uptake. These results imply new opportunities to use GAG nanoprobes in nanomedicine.

Keywords:  Carbohydrate, glycosaminoglycan, multivalency, gold nanoparticles, receptor-mediated uptake

DOI:  https://doi.org/10.1002/chem.202202622
ACS Nano. 2022 Nov 02.

Broad-Spectrum Virus Trapping with Heparan Sulfate-Modified DNA Origami Shells.

Alba Monferrer, Jessica A Kretzmann, Christian Sigl, Pia Sapelza, Anna Liedl, Barbara Wittmann, Hendrik Dietz.

  Effective broadband antiviral platforms that can act on existing viruses and viruses yet to emerge are not available, creating a need to explore treatment strategies beyond the trodden paths. Here, we report virus-encapsulating DNA origami shells that achieve broadband virus trapping properties by exploiting avidity and a widespread background affinity of viruses to heparan sulfate proteoglycans (HSPG). With a calibrated density of heparin and heparan sulfate (HS) derivatives crafted to the interior of DNA origami shells, we could encapsulate adeno, adeno-associated, chikungunya, dengue, human papilloma, noro, polio, rubella, and SARS-CoV-2 viruses or virus-like particles, in one and the same HS-functionalized shell system. Additional virus-type-specific binders were not needed for the trapping. Depending on the relative dimensions of shell to virus particles, multiple virus particles may be trapped per shell, and multiple shells can cover the surface of clusters of virus particles. The steric occlusion provided by the heparan sulfate-coated DNA origami shells can prevent viruses from further interactions with receptors, possibly including those found on cell surfaces.

Keywords:  DNA origami; antiviral; broad-spectrum; heparan sulfate; heparin; virus-like particles

DOI:  https://doi.org/10.1021/acsnano.1c11328
Synth Syst Biotechnol. 2023 Mar;8(1): 11-19

Heparin mimetics as potential intervention for COVID-19 and their bio-manufacturing.

Lan Jiang, Tianji Zhang, Hongzhong Lu, Saijuan Li, Kangjie Lv, Alex Tuffour, Lixin Zhang, Kan Ding, Jin-Ping Li, Hongmei Li, Xueting Liu.

  The COVID-19 pandemic has caused severe health problems worldwide and unprecedented decimation of the global economy. Moreover, after more than 2 years, many populations are still under pressure of infection. Thus, a broader perspective in developing antiviral strategies is still of great importance. Inspired by the observed multiple benefits of heparin in the treatment of thrombosis, the potential of low molecular weight heparin (LMWH) for the treatment of COVID-19 have been explored. Clinical applications found that LMWH decreased the level of inflammatory cytokines in COVID-19 patients, accordingly reducing lethality. Furthermore, several in vitro studies have demonstrated the important roles of heparan sulfate in SARS-CoV-2 infection and the inhibitory effects of heparin and heparin mimetics in viral infection. These clinical observations and designed studies argue for the potential to develop heparin mimetics as anti-SARS-CoV-2 drug candidates. In this review, we summarize the properties of heparin as an anticoagulant and the pharmaceutical possibilities for the treatment of virus infection, focusing on the perspectives of developing heparin mimetics via chemical synthesis, chemoenzymatic synthesis, and bioengineered production by microbial cell factories. The ultimate goal is to pave the eminent need for exploring novel compounds to treat coronavirus infection-caused diseases.

Keywords:  Bio-production; Biological activities; Biosynthesis; Heparin

DOI:  https://doi.org/10.1016/j.synbio.2022.10.002
Biomaterials. 2022 Oct 28. pii: S0142-9612(22)00505-1. [Epub ahead of print]291 121865

Rhamnan sulfate reduces atherosclerotic plaque formation and vascular inflammation.

Nikita P Patil, Almudena Gómez-Hernández, Fuming Zhang, Limary Cancel, Xu Feng, Lufeng Yan, Ke Xia, Eri Takematsu, Emily Y Yang, Victoria Le, Megan E Fisher, Agueda Gonzalez-Rodriguez, Carmelo Garcia-Monzon, James Tunnell, John Tarbell, Robert J Linhardt, Aaron B Baker.

   OBJECTIVE: While lipid-lowering drugs have become a mainstay of clinical therapy these treatments only slow the progression of the disease and can have side effects. Thus, new treatment options are needed to supplement the effects of lipid lowering therapy for treating atherosclerosis. We examined the use of an inexpensive and widely available marine polysaccharide rhamnan sulfate as an oral therapeutic for limiting vascular inflammation and atherosclerosis.
METHODS AND RESULTS: We found rhamnan sulfate enhanced the barrier function of endothelial cells, preventing the deposition of LDL and maintaining barrier function even in the presence of glycocalyx-degrading enzymes. Rhamnan sulfate was also found to bind directly to FGF-2, PDGF-BB and NF-κB subunits with high affinity. In addition, rhamnan sulfate was a potent inhibitor of NF-κB pathway activation in endothelial cells by TNF-α. We treated ApoE-/- mice with a high fat diet for 4 weeks and then an addition 9 weeks of high fat diet with or without rhamnan sulfate. Rhamnan sulfate reduced vascular inflammation and atherosclerosis in both sexes of ApoE-/- mice but had a stronger therapeutic effect in female mice. Oral consumption of rhamnan sulfate induced a significant decrease in cholesterol plasma levels in female mice but not in male mice. In addition, there was a marked reduction in inflammation for female mice in the liver and aortic root in comparison to male mice.
CONCLUSIONS: Rhamnan sulfate has beneficial effects in reducing inflammation, binding growth factors and NF-κB, enhancing endothelial barrier function and reducing atherosclerotic plaque formation in ApoE-/- mice.

Keywords:  Atherosclerosis; Inflammation; Marine polysaccharides; NF-κB pathway; Rhamnan sulfate

DOI:  https://doi.org/10.1016/j.biomaterials.2022.121865
J Pharmacol Exp Ther. 2022 Oct 30. pii: JPET-AR-2022-001380. [Epub ahead of print]

Transport of the pro-inflammatory chemokines CCL2 (MCP-1) and CCL5 (RANTES) across the intact mouse blood-brain barrier is inhibited by heparin and eprodisate and increased with systemic inflammation.

Daniel V Quaranta, Riley R Weaver, Kristen K Baumann, Takashi Fujimoto, Lindsey M Williams, Hyung Chan Kim, Aric F Logsdon, Mohamed Omer, May J Reed, William A Banks, Michelle Ann Erickson.

  One important function of the vascular blood-brain barrier (BBB) is to facilitate neuroimmune communication. The BBB fulfills this function, in part, through its ability to transport cytokines and chemokines. CCL2 (MCP-1) and CCL5 (RANTES) are pro-inflammatory chemokines that mediate neuroimmune responses to acute insults, and aspects of brain injury and neurodegenerative diseases; however, a blood-to-brain transport system has not been evaluated for either chemokine in vivo. Therefore, we determined whether CCL2 and CCL5 in blood can cross the intact BBB and enter the brain. Using CD-1 mice, we found that 125I-labeled CCL2 and CCL5 crossed the BBB, and entered the brain parenchyma. We next aimed to identify the mechanisms of 125I-CCL2 and 125I-CCL5 transport in an in-situ brain perfusion model. We found that both heparin and eprodisate inhibited brain uptake of 125I-CCL2 and 125I-CCL5 in situ, whereas antagonists of their receptors, CCR2 or CCR5 respectively, did not, suggesting that heparan sulfates at the endothelial surface mediate BBB transport. Finally, we showed that CCL2 and CCL5 transport across the BBB increased following a single injection of 0.3mg/kg lipopolysaccharide. These data demonstrate that CCL2 and CCL5 in the brain can derive, in part, from the circulation, especially during systemic inflammation. Further, binding to the BBB-associated heparan sulfate is a mechanism by which both chemokines can cross the intact BBB, highlighting a novel therapeutic target for treating neuroinflammation. Significance Statement Our work demonstrates that CCL2 and CCL5 can cross the intact BBB, and that transport is robustly increased during inflammation. These data suggest that circulating CCL2 and CCL5 can contribute to brain levels of each chemokine. We further show that the transport of both chemokines is inhibited by heparin and eprodisate, suggesting that CCL2/CCL5-heparan sulfate interactions could be therapeutically targeted to limit accumulation of these chemokines in the brain.

Keywords:  Neuroinflammation; blood-brain barrier; cytokines/chemokines; heparin

DOI:  https://doi.org/10.1124/jpet.122.001380
Res Sq. 2022 Oct 28. pii: rs.3.rs-2163527. [Epub ahead of print]

Sulfated endospermic nanocellulose crystals prevent the transmission of SARS-CoV-2 and HIV-1.

Enrique Javier Carvajal Barriga, Wendy Fitzgerald, Emilios K Dimitriadis, Leonid Margolis, R Douglas Fields.

Biomaterials with antimicrobial activity are gaining attention due to their biodegradability and efficacy in interacting with a wide range of microorganisms. A new cellulose nano-biomaterial, endospermic nanocellulose crystals (ENC) obtained from parenchymal tissue of ivory nut endosperm, has a natural capacity as a universal binder. This feature is enhanced when it is chemically functionalized, and can be exploited in the fight against microbes. We tested the ability of sulfated ENC in aqueous suspension to encapsulate viruses through a crosslinking reaction mediated by cations. 0.25% w/v ENC suspensions efficiently encapsulated spike (S) protein, preventing its interaction with ACE2 receptor. ENC was further able to encapsulate SARS-CoV-2 pseudoviruses and prevent infection of 293T-ACE2 cells. ENC also suppressed infection of MT-4 cells with HIV-1 LAI.04 . This antiviral activity of sulfated ENC is due to the irreversible interaction of ENC with viral particles mediated by crosslinking, as antiviral activity was less effective in the absence of cations. Additionally, ENC was used as a matrix to immobilize recombinant ACE2 receptors and anti-S IgG, creating molecular lures that efficiently inhibited SARS-CoV-2 infections in vitro . These results show that sulfated ENC from ivory nuts can be used as an efficient antiviral material.

DOI: https://doi.org/10.21203/rs.3.rs-2163527/v1
J Obstet Gynaecol. 2022 Nov 04. 1-4

Steroid hormone levels in postmenopausal hysterectomised women with and without ovarian conservation: the continuous endocrine function of the ovaries.

Elsa Nunes, Eugenia Gallardo, Sara Morgado-Nunes, José Fonseca-Moutinho.

  This study aims to clarify the effect of postmenopausal bilateral oophorectomy on plasma steroid hormone levels. Women who were submitted in the postmenopausal period to hysterectomy for uterine benign conditions were divided into two groups: 18 women had isolated hysterectomy and 11 had hysterectomy with bilateral salpingo-oophorectomy. In both groups serum hormone levels were quantified by solid phase extraction and gas chromatography and tandem mass spectrometry. Differences in dehydroepiandrosterone (DHEA), testosterone, androstenedione and oestradiol were determined in both groups. The analysis revealed lower steroid levels in the bilateral salpingo-oophorectomy group when compared to the isolated hysterectomy group with statistically significant differences found for DHEA (5.8 ± 3.2 vs. 9.4 ± 4.4 ng/mL; p = 0.019) and oestradiol (0.69 ± 0.4 vs. 1.48 ± 4.3 ng/mL; p = 0.007). The results are consistent with a significant endocrine activity of the postmenopausal ovary. The clinical consequences of these findings need to be clarified and postmenopausal prophylactic bilateral salpingo-oophorectomy re-evaluated.IMPACT STATEMENTWhat is already known on this subject? Although it is consensual that premenopausal prophylactic bilateral oophorectomy should not be performed because it has harmful effects on women's health, the evidence regarding the effects of postmenopausal prophylactic bilateral oophorectomy is scarce and this procedure continues to be a regular practice. Few studies have demonstrated that postmenopausal ovaries still have endocrine activity that may impact older women's health.What do the results of this study add? This is the first study to compare hormone levels of postmenopausal women based on their hysterectomy and oophorectomy status using GC-MS/MS, a highly sensitive bioanalytical assay for the measurement of steroid hormones. Previous studies relied on immunoassays and did not compare DHEA levels, which according to the intracrinology theory is a precursor for androgens and oestrogens. In this study, statistically significant lower levels of DHEA and oestradiol were found after postmenopausal bilateral salpingo-oophorectomy.What are the implications of these findings for clinical practice and/or further research? This is a pilot study that may lead to further investigation in this area to clarify the impact of the prophylactic removal of postmenopausal ovaries on older women's health and lead to changes in surgical procedures.

Keywords:  Menopause; androgens; dehydroepiandrosterone; intracrinology; oestrogens; oophorectomy

DOI:  https://doi.org/10.1080/01443615.2022.2141618
Clin Drug Investig. 2022 Nov 04.

Pharmacokinetics of Morphine Sulfate Orodispersible Tablets and Bioequivalence with Immediate-Release Oral Morphine Sulfate Formulations in Healthy Adult Subjects Under Fasting Conditions: Single-Dose Comparative Bioavailability Studies.

Nicolas Atrux-Tallau, Zulaikha Naimi, Eric-Olivier Jaudinot.

BACKGROUND AND OBJECTIVE: An orodispersible tablet (ODT) formulation of morphine sulfate has been developed to provide a novel alternative for patients with severe pain requiring opioids. This formulation has been developed in a range of doses (1-30 mg), enabling relief from severe pain to be achieved and maintained with the lowest possible morphine dose for each patient. The ODT formulation is particularly suitable for patients with swallowing difficulties.
OBJECTIVE: The aim of this study was to compare the pharmacokinetics and bioequivalence of the ODTs with reference formulations of morphine sulfate.
METHODS: Three randomized, single-dose, laboratory-blinded, phase I, crossover studies were conducted in adult healthy volunteers under fasting conditions. The pharmacokinetics of a 30 mg morphine sulfate ODT were compared with those of equivalent doses of currently marketed oral immediate-release formulations: tablets (Sevredol®), capsules (Actiskenan®), and a solution (Oramorph®). The bioequivalence of 30 mg and 10 mg doses of the ODTs and tablets was then assessed in two further studies. Subjects were asked to complete a product appreciation questionnaire for two morphine formulations (ODT and solution).
RESULTS: A total of 104 subjects were included across the three studies. The pharmacokinetics of the ODTs were assessed in 100 subjects and were found to be similar to those of the reference formulations. The time to maximum plasma concentration (Tmax) for the ODTs was 0.8 h, within the range observed for the reference formulations (0.75-1.25 h). Maximum plasma concentrations (Cmax) for the ODTs were 7.7 ± 2.7 ng/mL for the 10 mg dose and 26.1 ± 10.0 ng/mL for the 30 mg dose. These values were similar to those obtained for the 10 mg and 30 mg tablets (8.0 ± 2.9 ng/mL and 28.5 ± 11.9 ng/mL, respectively), and for the 30 mg capsule (29.9 ± 13.0 ng/mL). A higher Cmax was observed for the solution (37.9 ± 16.5 ng/mL). Plasma exposure to morphine (area under the plasma drug concentration-time curve [AUC]) after ODT administration was similar to that observed for the reference formulations: 39.8 ± 14.8 ng·h/mL and 115.5 ± 34.6 ng·h/mL for the 10 mg and 30 mg ODTs, versus 40.7 ± 13.5 ng·h/mL and 117.4 ± 31.5 ng·h/mL for the 10 mg and 30 mg tablets, and 121.8 ± 32.0 ng·h/mL and 121.0 ± 35.7 ng·h/mL for the 30 mg solution and capsule, respectively. Bioequivalence of the 30 mg and 10 mg ODTs and tablets, assessed in 83 patients across two studies, was demonstrated for both the Cmax and AUC from time zero to time t (AUC0-t). No serious or unexpected drug-related events were reported. A product appreciation questionnaire concluded that both ODTs and oral solution products were considered pleasant by most of the subjects.
CONCLUSION: The ODTs were safe, well tolerated, and showed similar pharmacokinetics to those of the reference formulations. The development of a range of doses of morphine sulfate ODTs may provide a new alternative for the oral administration of immediate-release morphine for pain management in pediatric, geriatric and adult populations with swallowing problems.

DOI: https://doi.org/10.1007/s40261-022-01214-x