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Amphiphilic copolymers of comb-like poly(poly(ethylene glycol) methacrylate) (PPEGMA) with methyl methacrylate (MMA) synthesized by one-pot atom transfer radical polymerization were mixed with lithium bis (trifluoromethanesulfonyl) imide salt to formulate dry solid polymer electrolytes (DSPE) for semisolid-state Li-ion battery applications. The PEO-type side chain length (EO monomer's number) in the PEGMA macromonomer units was varied, and its influence on the mechanical and electrochemical characteristics was investigated. It was found that the copolymers, due to the presence of PMMA segments, possess viscoelastic behavior and less change in mechanical properties than a PEO homopolymer with 100 kDa molecular weight in the investigated temperature range. In contrast to the PEO homopolymer, it was found that no crystallization of the copolymers occurs in the presence of the Li-salt. Solid-state NMR and cross-polarization NMR studies revealed that no crystallization (i.e., ion-pair formation) of the Li-salt occurs in the case of the copolymer samples at ambient temperatures; thereby, no phase separation takes place, in contrast to the reference PEO homopolymer sample, which resulted in fairly good ionic conductivity of the copolymers at lower temperatures. The temperature-dependent Li-ion conductivity analyses showed that the conductivity of the copolymers falls in the 10 -6 -10 -3 S/cm range, which is typical for polyether-type DSPEs, but the much lower mass fraction of EO monomers in the copolymers provides the same ionic conductivity values than that of the PEO homopolymer. From a large-scale practical point of view, this clearly indicates reduced Li-salt usage if such copolymer matrices are used instead of PEO homopolymer. Moreover, linear sweep voltammetry (LSV) polarization measurements showed that the PPEGMA-MMA copolymer electrolytes can exhibit a 200-300 mV broader electrochemical stability window than the PEO homopolymer, which is crucial in designing high energy density semisolid-state Li-ion batteries., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Introduction: Estrogen hormones and their metabolites are implicated in the maintenance of healthy pregnancy and adequate fetal development. Abnormal levels were related to increased risk of pregnancy complications, particularly preeclampsia. Our aims were (1) to develop a methodological platform for the comprehensive assessment of estrogen metabolome in pregnancy; (2) to collect healthy reference data for relevant elements of estrogen metabolome in each trimester; (3) to assess unconjugated fractions of the estrogen metabolome, (4) to assess the dominant metabolic pathways of estrogen compounds., Methods: We enrolled healthy pregnant mothers between gestational week 5-15 (on the confirmation of pregnancy; 79 samples), gestational weeks 19-27 (70 samples), and gestational week 34-39 (54 samples). A method employing liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed to assess estrone, 17-beta-estradiol, estriol levels, and their metabolites as conjugated and unconjugated forms. Descriptive statistics were used to characterize the level of compounds in each trimester., Results: Estrone, 17-beta-estradiol and estriol levels are dramatically increasing with the advancement of pregnancy. Measured levels were in a very wide range. 17-beta-estradiol is neither glucuronated nor sulphated. To the contrary, estriol and estrone are significantly conjugated; unconjugated fraction is <15% of total hormone levels in any trimester. Regarding metabolism, 4-methoxy-estradiol and 17-epiestriol were not detected., Conclusion: We concluded that (1) the levels of estrogen compounds and metabolites increase with advancing gestational age; (2) the wide ranges of levels challenge the establishment of a healthy reference range for clinical purposes; (3) 17-beta-estradiol is not conjugated significantly; (4) 4-methylation and 17-epimerization pathways of estrogens are negligible with our LC-MS/MS method., Competing Interests: Declaration of competing interest As the corresponding author of this submitted manuscript hereby I declare that there is NO conflict of interest regarding the present study and any of co-authors., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Quantitation of protein-nanoparticle interactions is essential for the investigation of the protein corona around NPs in vivo and when using synthetic polymer nanoparticles as affinity reagents for selective protein recognition in vitro . Here, a method based on steady-state fluorescence anisotropy measurement is presented as a novel, separation-free tool for the assessment of protein-nanoparticle interactions. For this purpose, a long-lifetime luminescent Ru-complex is used for protein labelling, which exhibits low anisotropy when conjugated to the protein but displays high anisotropy when the proteins are bound to the much larger polymer nanoparticles. As a proof of concept, the interaction of lysozyme with poly( N -isopropylacrylamide- co-N-tert -butylacrylamide- co -acrylic acid) nanoparticles is studied, and fluorescence anisotropy measurements are used to establish the binding kinetics, binding isotherm and a competitive binding assay.

The type and concentration of charged groups in polymers have a key role in mucoadhesive interactions. A series of cationic poly(amino acid)s with different charge densities was designed to unravel the correlation between chemical structure and mucin-polymer interactions. Colloidal interactions between the mucin protein and synthetic polyaspartamides were tested by dynamic light scattering, zeta potential measurements and turbidimetric titration as a function of polymer-to-mucin mass ratio. The mucoadhesive interactions displayed a strongly non-linear change with polymer composition. The attractive interactions between mucin and the polyaspartamides with at least 50 % cationic groups caused increased light scattering of dispersions due to the aggregation of mucin particles upon their charge reversal. Interactions were further analysed in a thin mucin layer to model life-like situations using a quartz crystal microbalance (QCM) in flow mode. Results pointed out that the fully cationic polyaspartamide is not necessarily superior to derivatives with lower cationic group content. The maximum of adsorbed mass of polymers on mucin was experienced at medium cationic group contents. This emphasizes the relevance of cationic polyaspartamides as mucoadhesive excipients due to their multiple functionalities and the possibility of fine-tuning their interactions with mucin via straightforward chemical steps., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2023. Published by Elsevier B.V.)

Introduction: Hemoglobin A1c (HbA1c) is used to monitor glucose homeostasis and to identify risk for diabetes. As diabetic patients are frequently present with dyslipidaemia, low-grade inflammation and hyperuricemia, we tested whether HbA1c levels can be estimated having the information about lipid profile, uric acid (UA) and C-reactive protein (CRP) levels. We developed formulas to describe the association of these parameters with HbA1c levels., Methods: Data of 9599 male and 10,817 female patients, measured between 2008 and 2018, were analysed. Patients represented a general hospital patient population with overrepresentation of those with elevated HbA1c over 5.6%. The impact of gender, age, CRP, lipid profile and UA levels on HbA1c % on HbA1c levels was tested with multiple linear regression model. The magnitude of effects of individual factors was used to develop formulas to describe the association between HbA1c and other cardiometabolic parameters. With these formulas we estimated median HbA1c values in each age in both gender and compared them to measured HbA1c levels., Results: The developed formulas are as follow: HbA1c (estimated) in women = 0.752 + 0.237*log10(HDL/cholesterol) + 0.156*log10 (cholesterol) + 0.077*log10 (triglyceride) + 0.025*log10(CRP) +0.001*log10 (age) -0.026*log10(HDL/LDL) -0.063*log10 (uric acid)-0.075*log10 (LDL)-0.199*log10(HDL); HbA1c (estimated) in men = 1.146 + 0.08*log10 (triglyceride) + 0.046*log10(CRP) + 0.01*log10 (cholesterol) + 0.001*log10 (age) -0.014*log10(HDL)-0.018*log10(HDL/LDL)-0.025*log10(HDL/cholesterol) -0.068*log10 (LDL)-0.159*log10 (uric acid) Between 20 and 70 years of age, estimated HbA1c matched perfectly to measured HbA1c in., Conclusion: At population level, HbA1c levels can be estimated almost exactly based on lipid profile, CRP and uric acid levels in female patients between 20 and 70 years., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Nepafenac is a highly effective NSAID used for treating postoperative ocular inflammation and pain after cataract surgery and its advantage over conventional topical NSAIDs has been proved many times. However, Nevanac® is a suspension eye drop, which clearly lacks patient compliance causing irritation, blurred vision, foreign body sensation along with problematic dosage due to its sticky, inhomogeneous consistence. In this study, nepafenac containing eye drops were prepared using hydroxypropyl-β-cyclodextrin to ensure complete dissolution of nepafenac, sodium hyaluronate to provide mucoadhesion and adequate viscosity and a preservative-free officinal formula, Oculogutta Carbomerae containing carbomer (just like Nevanac®), therefore providing a similar base for the new formulations. According to an experimental design, 11 formulations were tested in vitro including two reference formulations by measuring their viscosity, mucoadhesion, drug release and corneal permeability. Finally, two formulations were found promising and investigated further on porcine eyes ex vivo and corneal distribution of nepafenac was determined by RAMAN mapping. The results showed that one formulation possessed better bioavailability ex vivo than Nevanac® 0.1 % suspension, while the other formulation containing only 60 % of the original dose were ex vivo equivalent with Nevanac® opening the way to nepafenac-containing eye drops with better patient compliance in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Efficient topical treatment of ocular diseases requires a prolonged residence time of drug formulations. An in situ gelling, mucoadhesive system can provide improved residence time while keeps the installation of the formulation easy and accurate due to its low initial viscosity. We synthesized a two-component, biocompatible water-based liquid formulation showing in situ gelation upon mixing. S-protected, preactivated derivatives of thiolated poly(aspartic acid) (PASP-SS-MNA) were synthesized by coupling the free thiol groups of thiolated poly(aspartic acid) (PASP-SH) with 6-mercaptonicotinic acid (MNA). The amount of protecting groups was 242, 341, and 530 µmol/g depending on the degree of thiolation of PASP. The chemical interaction between PASP-SS-MNA and mucin was proven, indicating the mucoadhesive properties. Disulfide cross-linked hydrogels were formed in situ without an oxidizing agent by mixing the aqueous solutions of PASP-SS-MNA and PASP-SH. The gelation time was controlled between 1 and 6 min, while the storage modulus was as high as 4-16 kPa depending on the composition. Swelling experiments showed that hydrogels with no residual thiol groups are stable in phosphate-buffered saline at pH = 7.4. In contrast, the presence of free thiol groups leads to the dissolution of the hydrogel with a rate depending on the excess of thiol groups. The biological safety of the polymers and MNA was confirmed on Madin-Darby Canine Kidney cell line. Furthermore, a prolonged release of ofloxacin was observed at pH = 7.4 compared to a conventional liquid formulation, supporting the potential of the developed biopolymers in ophthalmic drug delivery., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Novel poly(dithiophosphate)s (PDTPs) were successfully synthesized under mild conditions without any additive in the presence of THF or toluene diluents at 60 °C by a direct, catalyst-free reaction between the abundant phosphorus pentasulfide (P 4 S 10 ) and glycols such as ethylene glycol (EG), 1,6-hexanediol (HD) and poly(ethylene glycol) (PEG). GPC, FTIR, 1 H and 31 P NMR analyses proved the formation of macromolecules with dithiophosphate coupling groups having P=S and P-SH pendant functionalities. Surprisingly, the ring-opening of THF by the P-SH group and its pendant incorporation as a branching point occur during polymerization. This process is absent with toluene, providing conditions to obtain linear chains. 31 P NMR measurements indicate long-time partial hydrolysis and esterification, resulting in the formation of a thiophosphoric acid moiety and branching points. Copolymerization, i.e., using mixtures of EG or HD with PEG, results in polymers with broadly varying viscoelastic properties. TGA shows the lower thermal stability of PDTPs than that of PEG due to the relatively low thermal stability of the P-O-C moieties. The low T g s of these polymers, from -4 to -50 °C, and a lack of PEG crystallites were found by DSC. This polymerization process and the resulting novel PDTPs enable various new routes for polymer synthesis and application possibilities.

The perturbation of gut microbiome is a risk factor for a number of adverse conditions. Among other factors antibiotic therapy is a common culprit. We characterized the short-term alteration of gut microbiome after antibiotic therapy. Nine patients (age (median [range]): 67 [57-75 years]) were subjected to prostate biopsy. Ciprofloxacin and clindamycin, 500 mg and 150 mg, respectively, were administered twice a day; this combination therapy was started the day before and continued until 5th and 8th day, respectively, following biopsy. 16s RNA sequencing data from fecal swabs taken before antibiotic therapy and 14 days after biopsy were analysed. At phylum level, the abundance of Actinobacteria and Firmicutes decreased, while that of Bacteroides and Proteobacteria increased after antibiotic therapy. The ratio of Firmicutes:Bacteroides inversed (from 2.81 to 0.74, p = 0.035). At order level, the abundance of Bacteroidales and Veillonellales increased, while that of Clostridiales and Coriobacteriales decreased. At genus level the abundance of Bacteroides increased, while those of Roseburia, Faecalibacterium and Collinsella decreased. These findings indicate that short-term antibiotic exposure skews gut microbiome composition. The current level of knowledge does not allow to decide whether this skewness is detrimental and has any long-term effect on disease including prostate pathology., (Copyright © 2022. Published by Elsevier Ltd.)

In situ gellable polymers have potential applications as injectable formulations in drug delivery and regenerative medicine. Herein, thiolated cationic polyaspartamides were synthesised via two different approaches to correlate the side group structure with gelation properties, gel strength and drug release kinetics. Cysteamine (CEA) was used as a thiolating agent to prepare thiolated cationic polyaspartamide groups with short thiolated side groups. As a new pathway, thiolactone chemistry was integrated with cationic modification of polyaspartamides to prepare thiolated derivatives with longer, flexible side groups using N -acetyl-DL-homocysteine (NAH) thiolactone. Both types of thiolated polyaspartamides could be converted into stiff hydrogels under mild reaction conditions through oxidation-induced intermolecular disulfide formation. We confirmed that the longer side groups largely accelerated gelation and the stiffness of the resultant hydrogels was higher than that of the CEA-modified counterparts. Both the gelation time and stiffness could be adjusted by the degree of thiolation. Poly(aspartic acid) (PASP) derivatives with a controlled concentration of anionic groups were entrapped in the hydrogels during the in situ gelation. Based on the possible electrostatic interaction between the linear anionic polyelectrolytes and the cationic polymer network, we hypothesized that the release of the encapsulated material is controlled by the charge density. In accordance, fully anionic PASP was entrapped completely in the hydrogels, whereas a reduction in the number of anionic groups caused the partial release of PASP derivatives. NAH- and CEA- modified cationic polyaspartamide hydrogels showed distinct release rates, indicating the interplay between cationic and thiol functionalities in release kinetics.

The present study aimed at developing a potential in situ gellable dexamethasone (DXM) eye drop. Poly(aspartic acid) (PASP) derivatives were synthesized with dual functionality to improve the solubility of DXM, and to achieve in situ gelation. First, amine-modified β-cyclodextrin (CD) was attached to polysuccinimide (PSI), second, thiol functionalities were added by the reaction of cysteamine and succinimide rings. Finally, the PSI derivatives were hydrolysed to the corresponding PASP derivatives to get water-soluble polymers. Phase-solubility studies confirmed the complexation ability of CD-containing PASP derivatives. In situ gelation and the effect of the CD immobilization on this behaviour were characterized by rheological measurements. The solubilizing effect of CD was confirmed by kinetic solubility measurements, whereas in vitro corneal permeability assay (corneal-PAMPA) measurements were performed to determine in vitro permeability and flux values. The effect of the PASP derivatives on permeation strongly depended on chemical composition and polymer concentration., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Mucoadhesion testing at macroscopic scale needs a robust, convenient in vitro method as ex vivo methods suffer from poor reproducibility and ethical problems. Here we synthesized mucin-free poly(vinyl alcohol) (PVA) and mucin-containing PVA hydrogel substrates (Muc/PVA) to measure adhesion of polymer tablets. Freezing-thawing method was used for gelation to avoid chemical cross-linking and to preserve the functionality of mucin. The adhesion of first generation mucoadhesive polymers, poly(acrylic acid) (PAA) and hydroxypropylmethylcellulose (HPMC) was tested with outstanding reproducibility on individual batches of hydrogels and qualitative agreement with ex vivo literature data. Negatively charged PAA was less adhesive on Muc/PVA surface than on mucin-free PVA whereas HPMC as a neutral polymer displayed similar adhesion strength on both surfaces. Chitosan as a positively charged polymer showed enhanced adhesion on Muc/PVA substrate compared to mucin-free PVA. These results are corroborated by turbidimetric titration which indicated attractive electrostatic interactions between chitosan and mucin in contrast to the lack of attractive interactions for PAA and HPMC. These results prove the role of electronic theory in macroscopic mucoadhesion., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Today, graphene oxide (GO) has gained well-deserved recognition, with its applications continuing to increase. Much of the processing of GO-based devices occurs in a dispersed form, which explains the commercialization of GO suspensions. Aging of these suspensions can, however, affect the shelf life and thus their application potential. Aging of GO preparations is often acknowledged, but no longer-term systematic study has been reported on the alteration of GO suspensions. This paper investigates high-concentration (10 mg/mL) aqueous GO suspensions over a 2-year time scale. In addition to steady shear tests, the dynamic behavior of the suspensions was studied in more detail by transient shear and frequency sweep measurements. Both the viscosity and the dynamic moduli increased with age, particularly within the first year. The results of the complementary Raman spectroscopic studies indicate that the change in the rheological behavior with aging results from a slow oxidation process occurring in the highly acidic aqueous medium during the relatively long-term storage. The (over)oxidized layers peel off spontaneously or are removed by high shear stress, resulting in increased viscosity, as it was corroborated by XRD and XPS.

Enzyme replacement therapies (ERT) have been of great help over the past 30 years in the treatment of various lysosomal storage disorders, including chronic pancreatitis and its common complication, exocrine pancreatic insufficiency. Research shows that difficulties in designing such drugs can be overcome by using appropriate additives and various enzyme immobilization techniques. Cyclodextrins (CDs) can be considered as a promising additive for enzyme replacement therapies, as they are known to enhance the activity of enzymes in a complex process due to their specific binding. In this study, we investigated the formulation of lipases (from Aspergillus oryzae and Burkholderia cepacia ) paired with different cyclodextrins in poly(vinyl alcohol) (PVA) nanofibers by electrospinning technique. We examined the effect of the presence of cyclodextrins and nanoformulation on the lipase activity. The rheological and morphological characterizations of precursors and nanofibers were also performed using a viscometer as well as electron and Raman microscope. We found that by selecting the appropriate CD:lipase ratio, the activity of the investigated enzyme could be multiplied, and cyclodextrins can support the homogeneous dispersion of lipases inside the solid formula. In addition, the entrapment of lipases in PVA nanofibers led to a significant increase in activity compared to the preformulated precursor. In this way, the nanofibrous formulation of lipases combining CDs as additives can provide an efficient and sustainable possibility for designing novel solid medicines in ERT.

The dual functionalization of magnetic nanoparticles with inert (methyl) and reactive (aminopropyl) groups enables efficient immobilization of synthetic metalloporphyrins (such as 5,10,15,20-tetrakis(2,3,4,5,6-pentafluorophenyl)iron(II) porphyrin and 5,10,15,20-tetrakis-(4-sulfonatophenyl)iron(II) porphyrin) via covalent or ionic interactions. The proportion of reactive function on the surface has significant effect on the biomimetic activity of metalloporphyrins. The optimized magnetic nanocatalyst containing porphyrin was successfully applied for biomimetic oxidation of antihypertensive drug Amlodipine in batch and continuous-flow reactors as well.

In order to explore how cucurbituril hosts accommodate an N -phenyl-pyridinium derivative guest, the complexation of the solvatochromic dye, 4-(4-(dimethylamino)styryl)-1-phenylpyridinium iodide (PhSt) with , ' , δ , δ ' -tetramethyl-cucurbit[6]uril (Me 4 CB6) and cucurbit[7]uril (CB7) was investigated by absorption spectroscopic, fluorescence and NMR experiments. In aqueous solutions, PhSt forms 1:1 complexes with both cucurbiturils, the complex with CB7 has a higher stability constant ( K a = 6.0 × 10 6 M - 1 ) than the complex with Me 4 CB6 ( K a = 1.1 × 10 6 M - 1 ). As revealed by NMR experiments and confirmed by theoretical calculations, CB7 encapsulates the whole phenylpyridinium entity of the PhSt cation guest, whereas the cavity of Me 4 CB6 includes only the phenyl ring, the pyridinium ring is bound to the carbonyl rim of the host. The binding of PhSt to cucurbiturils is accompanied by a strong enhancement of the fluorescence quantum yield due to the blocking of the deactivation through a twisted intramolecular charge transfer (TICT) state. The TICT mechanism in PhSt was characterized by fluorescence experiments in polyethylene glycol (PEG) solvents of different viscosities. The PhSt-CB7 system was tested as a fluorescence indicator displacement (FID) assay, and it recognized trimethyl-lysine selectively over other lysine derivatives., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Synthetic polyaspartamides with various functional side groups including primary, secondary, tertiary amine or carboxyl groups were designed to explore the effect of chemical composition on polymer-mucin interactions. Since the molecular weight of the polymers and the degree of modification were identical for each derivative, the role of the functional groups could be evaluated. Chitosan was used as a control sample due to its strong interaction with mucin primarily through electrostatic forces. Mucoadhesive interactions of the polymers with the aqueous dispersion of commercially available porcine gastric mucin were probed on the colloid size scale using various methods including turbidimetric titration, dynamic light scattering and zeta potential measurements. Both the charge of the polymers and the type of amine groups had a pronounced effect on the interactions. The interactions were further analysed by partially screening them with either sodium chloride or urea. The results obtained allow us to classify these polymers in terms of in vitro mucoadhesive strength, which can be useful in the design of mucoadhesive formulations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Vitamin D deficiency has been linked to a higher risk of prostate cancer. We tested the hypothesis that vitamin D levels would have an impact on prostate specific antigen (PSA) levels., Methods: From our laboratory database we selected 5136 male patients with simultaneously determined vitamin D and PSA levels. Subgroups of several age cohorts with different vitamin D levels were created and PSA 95 percentile values were assessed. The independent effect of vitamin D levels and age on PSA levels was determined with logistic regression., Results: PSA levels increased with age, while no difference was identified in PSA levels in different vitamin D subgroups., Conclusion: Vitamin D levels do not have an effect on PSA. Hence, there is no need to adjust PSA reference ranges and threshold values to vitamin D levels during the process of decision making., (Copyright © 2020 International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). All rights reserved.)

Biomimetic oxidation of drugs catalyzed by metalloporphyrins can be a novel and promising way for the effective and sustainable synthesis of drug metabolites. The immobilization of 5,10,15,20-tetrakis(2,3,4,5,6-pentafluorophenyl)iron(II) porphyrin (FeTPFP) and 5,10,15,20-tetrakis-(4-sulfonatophenyl)iron(II) porphyrin (FeTSPP) via stable covalent or rapid ionic binding on aminopropyl-functionalized magnetic nanoparticles (MNPs-NH 2 ) were developed. These immobilized catalysts could be efficiently applied for the synthesis of new pharmaceutically active derivatives and liver related phase I oxidative major metabolite of an antiarrhythmic drug, amiodarone integrated in a continuous-flow magnetic chip reactor (Magnechip)., Competing Interests: The authors declare no conflict of interest.

Introduction: Recent experiments and clinical studies indicate the contribution of thyroid hormones to prostate pathology. Aim: In our retrospective analyzis of university patient population, we evaluated the association between thyroid stimulatory hormone (TSH) and prostate specific antigen (PSA). Method: From the Laboratory Information System we retrieved the data of male patients between 40 and 75 years of age who had been subjected to simultaneous TSH and PSA measurements during the last 12 years (n = 7279). The association between logTSH and logPSA levels was tested with multiple regression analysis and adjusted for age. Results: Significant associations between logPSA and logTSH and age (r = 0.297 and 0.472, respectively) were detected. PSA levels were higher in patients with TSH below (n = 405) than in those with TSH within reference range (TSH 0,35-4,95 mU/ml) (n = 6698) (PSA level: 1.118 [0.639-2.338] vs. 0.920 [0.508-1.826] ng/ml, p<0.016). Based on estimates, a 10% decrease in TSH is associated with a 0.42% increase in PSA levels in our population. This corresponds to a 42% increase in PSA levels in the same patient if he would present with 0.2 mU/ml instead of 2.0 mU/ml TSH. Conclusion: The finding that hyperthyreosis might be associated with higher PSA levels indicates that PSA reference ranges would differ in hyperthyreotic and in euthyreotic patients. Probably the PSA clinical decision limits is also recommended to be modified according to the patient's thyroid status. Orv Hetil. 2019; 160(35): 1376-1379.

The extensive metabolism of estrogen hormones, where oxidized forms, structural isomers and conjugated products appear in many tissues locally as well as in systemic circulation, is believed to be associated with a number of diseases. Targeted estrogen metabolomic studies have been largely associated with postmenopausal, malignant advert immune conditions. Although the role of estriol in maintaining pregnancy and the biological activity of estrogen metabolites is known, a relatively small number of publications have addressed the formation and transformation of these compounds during pregnancy. The aim of this study is to present in detail the formation and progression of estrogen metabolites during pregnancy and to summarize the knowledge of their role in undesirable processes occurring during gestation. Orv Hetil. 2019; 160(26): 1007-1014.

Thiolated poly(aspartic acid) is known as a good mucoadhesive polymer in aqueous ophthalmic formulations. In this paper, cyclodextrin-modified thiolated poly(aspartic acid) was synthesized for the incorporation of prednisolone, a lipophilic ophthalmic drug, in an aqueous in situ gellable mucoadhesive solution. This polymer combines the advantages of cyclodextrins and thiolated polymers. The formation of the cyclodextrin-drug complex in the gels was analyzed by X-ray powder diffraction. The ocular applicability of the polymer was characterized by means of physicochemical, rheological and drug diffusion tests. It was established that the chemical bonding of the cyclodextrin molecule did not affect the complexation of prednisolone, while the polymer solution preserved its in situ gellable and good mucoadhesive characteristics. The chemical immobilization of cyclodextrin modified the diffusion profile of prednisolone and prolonged drug release was observed. The combination of free and immobilized cyclodextrins provided the best release profile because the free complex can diffuse rapidly, while the bonded complex ensures a prolonged action., Competing Interests: The authors declare no conflict of interest.

Thiolated polymers are a promising new group of excipients, but their stability against atmospheric oxidation has not been investigated in detail, and only a few efforts have been made to improve their stability. The oxidation of the thiol groups in solutions of thiolated polymers may result in a decrease of mucoadhesion and unpredictable in situ gelation. The aims of our work were to study the stability of aqueous solutions of thiolated polymers and the effects of stabilizing agents. We investigated thiolated poly(aspartic acid) polymers stabilized with dithiothreitol, glutathione or acetylcysteine. The effects of these antioxidants on the gel structure, mucoadhesion and drug release were determined by means of scanning electron microscopy, swelling, rheology, adhesion and drug release tests. It was concluded that the stability of polymer solutions containing antioxidants is sufficient for one day. Polymers stabilized with dithiotreitol demonstrated fast swelling and drug release, but weaker mucoadhesion as compared with the other samples. Polymers stabilized with glutathione displayed the weakest cohesive properties, resulting in fast and uncontrolled drug release and moderate mucoadhesion. Acetylcysteine-stabilized polymers exhibited an optimum cross-linked structure, with free thiol groups ensuring polymer-mucin interactions, resulting in the best mucoadhesive properties., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Poly(aspartic acid) (PASP) derivatives with adjustable pH-dependent solubility were synthesized and characterized to establish the relationship between their structure and solubility in order to predict their applicability as a basic material for enteric coatings. Polysuccinimide, the precursor of PASP, was modified with short chain alkylamines, and the residual succinimide rings were subsequently opened to prepare the corresponding PASP derivatives. Study of the effect of the type and concentration of the side groups on the pH-dependent solubility of PASP showed that solubility can be adjusted by proper selection of the chemical structure. The Henderson-Hasselbalch (HH) and the extended HH equations were used to describe the pH-dependent solubility of the polymers quantitatively. The estimate provided by the HH equation is poor, but an accurate description of the pH-dependent solubility can be found with the extended HH equation. The dissolution rate of a polymer film prepared from a selected PASP derivative was determined by fluorescence marking. The film dissolved rapidly when the pH was increased above its pK a . Cellular viability tests show that PASP derivatives are non-toxic to a human cell line. These polymers are thus of great interest as starting materials for enteric coatings., Statement of Significance: Poly(amino acid) type biocompatible polymers were synthesized for future use as pharmaceutical film coatings. To this end, we tailored the pH-dependent solubility of poly(aspartic acid) (PASP). It was found that both the solubility and the pK a values of the modified PASP depended strongly on composition. Fluorescent marking was used to characterize the dissolution of a chosen PASP derivative. In acidic media only a negligible amount of the polymer dissolved, but dissolution was very fast and complete at the pH values that prevail in the small intestine. As a consequence, enteric coatings based on such PASP derivatives may be used for drug delivery in the gastrointestinal tract., (Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

A series of 14 cationic derivatives of poly(aspartic acid) i.e. cationic polyaspartamides with different (dialkylamino)alkyl and alkyl or hydroxyalkyl side groups was synthesized by nucleophilic addition on polysuccinimide. The resulting polyaspartamides have moderate amphiphilic properties. Relationships between the structure and ratio of side groups and in vitro properties of polyaspartamides, including their cytotoxic and membrane-damaging activity towards human cell lines, primary skin fibroblasts and erythrocytes, were established and discussed. Cationic polyaspartamides vary in their DNA-binding, condensing and nuclease-protecting characteristics depending on the concentration ratio of (dialkylamino)alkyl and alkyl or hydroxyalkyl side groups. Effective cell transfection was achieved upon polyaspartamide-mediated plasmid DNA delivery in serum-free medium in the presence of chloroquine. Effect of serum proteins adsorption onto polyaspartamide based polyplexes, and the role of concentration of polyplexes in culture medium in their colloidal stability and transfection process were demonstrated. Synthesized polyaspartamides are biocompatible and long-acting gene carriers, which are applied to cells after dilution and without washing, thus providing transfection level comparable to that of commercial transfection reagent., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Ocular drug delivery formulations must meet anatomical, biopharmaceutical, patient-driven and regulatory requirements. Mucoadhesive polymers can serve as a better alternative to currently available ophthalmic formulations by providing improved bioavailability. If all requirements are addressed, a polymeric formulation resembling the tear film of the eye might be the best solution. The optimum formulation must not have high osmotic activity, should provide appropriate surface tension, pH and refractive index, must be non-toxic and should be transparent and mucoadhesive. We would like to highlight the importance of in vitro polymer testing from a pharmaceutical aspect. We, therefore, carried out physical-chemical investigations to verify the suitability of certain systems for ophthalmic formulations. In this work, in situ gelling, mucoadhesive thiolated poly(aspartic acid)s were tested from ophthalmic formulation aspects. The results of preformulation measurements indicate that these polymers can be used as potential carriers in ophthalmic drug delivery.

Dry eye disease is a relatively common ocular problem, which causes eye discomfort and visual disorders leading to a decrease in the quality of life. The aim of this study was to find a possible excipient for eye drop formulations, which is able to stabilize the tear film. A cationic thiolated polyaspartamide polymer, poly[(N-mercaptoethylaspartamide)-co-(N-(N',N'-dimethylaminoethyl)aspartamide)] (ThioPASP-DME), was used as a potential vehicle. Besides satisfying the basic requirements, the chemical structure of ThioPASP-DME is similar to those of ocular mucins as it is a protein-like polymer bearing a considerable number of thiol groups. The solution of the polymer is therefore able to mimic the physiological properties of the mucins and it can interact with the mucus layer via disulphide bond formation. The resultant mucoadhesion provides a prolonged residence time and ensures protective effect for the corneal/conjunctival epithelium. ThioPASP-DME also has an antioxidant effect due to the presence of the thiol groups. The applicability of ThioPASP-DME as a potential excipient in eye drops was determined by means of ocular compatibility tests and through examinations of the interactions with the mucosal surface. The results indicate that ThioPASP-DME can serve as a potential eye drop excipient for the therapy of dry eye disease.

Chemically cross-linked poly(aspartic acid) (PASP) gels were prepared by a solid-liquid phase separation technique, cryogelation, to achieve a supermacroporous interconnected pore structure. The precursor polymer of PASP, polysuccinimide (PSI) was cross-linked below the freezing point of the solvent and the forming crystals acted as templates for the pores. Dimethyl sulfoxide was chosen as solvent instead of the more commonly used water. Thus larger temperatures could be utilized for the preparation and the drawback of increase in specific volume of water upon freezing could be eliminated. The morphology of the hydrogels was characterized by scanning electron microscopy and interconnectivity of the pores was proven by the small flow resistance of the gels. Compression tests also confirmed the interconnected porous structure and the complete re-swelling and shape recovery of the supermacroporous PASP hydrogels. The prepared hydrogels are of interest for several biomedical applications as scaffolding materials because of their cytocompatibility, controllable morphology and pH-responsive character., (Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

The ophthalmic formulations on the market suffer from poor bioavailability, and it would therefore be useful to design a new formulation which is able to prolong the residence time and reduce the administration frequency. Polymer matrices which exhibit strong mucoadhesion are promising platforms in ocular drug delivery from the aspect of improved bioavailability. In the present study, an in situ gelling, mucoadhesive drug delivery system was fabricated from thiolated poly(aspartic acid) (ThioPASP). The thiol groups of ThioPASP are able to form disulphide linkages with the mucin glycoproteins and prolong the residence time on the eye. The effects of the thiol groups on the structure, swelling behaviour and mucoadhesive character of the gel and on the drug release profile were determined. The gel structure was characterized by means of rheology. The ThioPASP gel was demonstrated by rheology, tensile test and 'wash away' measurements to display strong mucoadhesion. The drug release from the ThioPASP gel was studied on a vertical Franz diffusion cell: a burst release of sodium diclofenac occurred in the first hour, followed by sustained release of the encapsulated drug for up to 24h. The results proved the importance of the presence of the thiol groups and suggested that a ThioPASP formulation can be useful as an in situ gelling, ocular dosage form., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The bioavailability of drugs used on mucosal surfaces can be increased by the use of mucoadhesive polymers. A new type of mucoadhesive polymers is the group of thiolated polymers with thiol group containing side chains. These polymers are able to form covalent bonds (disulphide linkages) with the mucin glycoproteins. For the formulation of an ocular drug delivery system (DDS) thiolated poly(aspartic acid) polymer (ThioPASP) was used. Our aim was to determine their biocompatibility, mucoadhesion and drug release property. According to the results it can be established that the thiolated poly(aspartic acid) polymers can be a potential vehicle of an ocular drug delivery system due to their biocompatibility, good mucoadhesive property and drug release profile. Thanks to their properties controlled drug delivery can be achieved and bioavailability of the ophthalmic formulation can be increased, while the usage frequency can be decreased.

Alterations in the expression of B7 costimulatory molecules and their receptors, as well as differences in the tryptophan (TRP) catabolic pathway, may influence immunological reactivity of umbilical cord blood (UCB) compared with adult peripheral blood (APB) T lymphocytes. We determined the frequency of activated (CD11b(+)) monocytes expressing B7-1, B7-2, B7-H1, and B7-H2, and that of T cells and CD4(+) T helper cells expressing CD28, cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed death-1 receptor, and inducible costimulator of T cells in UCB and APB samples using flow cytometry. We also examined the intracellular expression of indoleamine 2,3-dioxygenase (IDO) applying flow cytometry and plasma levels of TRP, kynurenine (KYN), and kynurenic acid using high-performance liquid chromatography. The level of CTLA-4 expression on CD4 cells was higher in UCB compared with in APB, indicating that the possibility of CD28-mediated costimulation may be decreased. The level of the corresponding costimulator molecule, B7-2, was also elevated. Therefore, this inhibitory relation may function to a higher extent in UCB than in APB. The plasma KYN to TRP (K/T) ratio was 2-fold higher in UCB compared with APB. However, the capacity of UCB monocytes to produce IDO compared with APB monocytes was lower, and reverse signaling via B7-2 in UCB monocytes was found to be immature, which suggests that the observed increase in K/T ratio may be due to placental, rather than fetal, overexpression of IDO in competent cells. These factors may all contribute to the previously observed reduced reactivity of UCB T lymphocytes compared to APB T cells., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Synthesis and characterization of a pH- and redox-sensitive hydrogel of poly(aspartic acid) are reported. Reversible gelation and dissolution are achieved both in dimethylformamide and in aqueous medium via a thiol-disulphide interconversion in the side chain of the polymers. Structural changes are confirmed by Raman microscopy and rheological measurements. Injectable aqueous solutions of thiolated poly(aspartic acid) can be converted into mechanically stable gels by oxidation, which can be useful for drug encapsulation and targeted delivery. Reduction-facilitated release of an entrapped drug from disulphide cross-linked hydrogels is studied., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Aim: Our aim was to investigate the levels of hepcidin at parturition and 3 days after delivery and to relate hepcidin levels to parameters of iron homeostasis., Materials and Methods: We measured hepcidin levels with mass spectrometry in serum samples of 38 term pregnant women taken just prior to and 3 days after vaginal delivery (n = 23) or cesarean section (CS) (n = 15). Hepcidin levels were related to iron homeostasis parameters and interleukin (IL)-6 levels. Parameters measured before and after delivery were compared with the Wilcoxon test., Results: Serum iron levels (median, interquartile range) decreased (14.3, 9.6-21.1 vs. 8.9, 6.8-11.5 µmol/L, P < 0.01), while hepcidin levels increased (2.73, 2.2-3.45 vs. 10.62, 6.70-15.89 µg/L, P < 0.01) by the third day after parturition compared to those measured before delivery. IL-6 levels were comparable before and after delivery. No direct association between serum hepcidin and iron homeostasis parameters or IL-6 levels was found., Conclusions: Factors triggering hepcidin synthesis dominate 3 days after delivery. Studies are needed to assess the contribution of hepcidin to iron homeostasis during the periparturition period., (© 2011 The Authors. Journal of Obstetrics and Gynaecology Research © 2011 Japan Society of Obstetrics and Gynecology.)