Search Results (19)

Zwitterionic polymer hydrogels have great application prospects in wearable electronic devices due to their antifouling and excellent biocompatibility. However, its strong hydrophilicity often leads to easy swelling and poor mechanical properties. In this study, aramid nanofiber (ANF)-reinforced zwitterionic ion hydrogels were synthesized by the one-step free radical polymerization of N-acryloyl glycinamide (NAGA), N-[Tris (hydroxymethyl) methyl] acrylamide (THMA) and sulfobetaine methacrylate (SBMA) monomers in the presence of ANFs. A large number of hydrogen bonds were formed between the amide groups of the ANFs and the amide groups of the NAGA units/the hydroxyl groups of the THMA units/the sulfonic groups of the SBMA units, which improved the internal interface force of the hydrogel. The obtained ANF-reinforced hydrogel had an anti-swelling property, and its swelling ratio and tensile strength were 25% and 170% of those of the hydrogel without the addition of ANFs. By introducing lithium chloride as an electrolyte to improve its ion conductivity and subsequently assembling it into strain sensors, it exhibited a high sensitivity (GF = 1.12), short response and recovery times (100 ms and 150 ms), and excellent cycling stability. This work provides a feasible strategy for anti-swelling wearable strain sensors. Full article

Peptides occupy a significant share of the pharmaceutical market and are among the top-200 selling drugs in the group of non-insulin drugs with analgesic, antibacterial and cardiovascular effects. The aim of this work is to develop a comprehensive analytical approach for quality control of novel synthetic peptides with non-narcotic types of analgesia and to provide docking simulations of dermorphin complex formation at the μ-opioid receptor (MOR) binding site. The materials and methods used include the pharmaceutical substance dermorphin tetrapeptide (DMTP) (tyrosyl-D-arginyl-phenylalanyl-glycinamide); Fourier transform infrared spectroscopy (FT-IR); static and dynamic laser light scattering (DLS, LALLS); scanning optical microscopy (SEM); X-ray fluorescence elements analysis; polarimetry for optical activity determining; and Spirotox method for sample biotesting. FT-IR-Spectra indicated specific amino acid chemical groups in the tetrapeptide sequence at 3300–2700 cm⁻¹, 1670 cm⁻¹. UV-absorption spectra of aqueous solutions of dermorphin tetrapeptide showed an absorption maximum at 275 nm, which is in good agreement with the presented spectrum of the bovine serum albumin (BSA) standard; the Pearson’s r of calibration line “A-C%” in 0.0125% to 0.0500% concentration range is 0.999; and the calculated specific extinction value $E_{1cm }^{1\%}$ = 18.38 ± 0.23. Of the 11 elements detected by X-rays, the elements copper (Cu) and cobalt (Co) have the highest X-ray intensity. Dispersion characteristics of dermorphin solutions were studied in the submicron and micron range. Conglomerates and druzes were detected by SEM, ranging in size from 2 µm to 100 µm. The specific optical activity index was calculated ${\left[\alpha \right]}_D^{20}$ = +36.18 ± 2.04 [°·mL·g⁻¹·dm⁻¹], according to Biot’s Law. Additionally, the orientation and conformation of the dermorphin molecule in the active binding site of the 8E0G receptor were predicted using molecular modeling, revealing that the contact area affects the key amino acid residue arginine (ARG 182). This comprehensive approach to analytical methods for qualitative and quantitative analysis of dermorphin tetrapeptide can be applied in pharmacies to enhance the understanding of its biological activity and aid in the development of regulatory documentation for a new, non-narcotic analgesic based on the dermorphin tetrapeptide. Full article

Achillea cucullata is a perennial herbaceous plant that has a long history of medical use in many cultures. The present research focuses on the biological activity and therapeutic potential of A. cucullata, namely its antibacterial and anticancer properties. While previous studies have shed light on the cytotoxic and antibacterial capabilities of Achillea cucullata aerial parts, there is still a considerable gap in knowledge concerning the anticancer potential of leaf and flower extracts. A. cucullata’s leaves and flowers were extracted using methanol. The total phenolic and flavonoid contents were evaluated. The antioxidant, cytotoxic, and antibacterial properties were evaluated against both Gram-positive and Gram-negative bacteria. The Gas Chromatography–Mass Spectrometry (GC–MS) analysis of A. cucullata leaf and flower extracts showed numerous amounts of bioactive components, including carvacrol, a TBDMS derivative; 2-Myristynoyl-glycinamide, acetylaminobenzothiazol-2-yl)-2-(adamantan-1-yl); Isolongifolol; (3E,10Z)-Oxacyclotrideca-3,10-diene-2,7-dione; and 3-Heptanone, 5-hydroxy-1,7-diphenyl. The extract has a high level of phenols and flavonoids. Cytotoxicity studies found that A. cucullata leaves and flowers had dose-dependent toxicity against MCF-7 and HepG2 cancer cell lines, with flowers being more effective. Apoptotic genes (caspase-3, 8, 9, and Bax) were upregulated in treated MCF-7 and HepG2 cells, whereas anti-apoptotic genes (Bcl-xL and Bcl-2) were reduced. Antibacterial screening revealed significant activity against both Gram-positive and Gram-negative pathogens. Overall, the research highlights the varied therapeutic potentials of A. cucullata, adding to the knowledge of plant-derived extracts in lowering disease risks. Future research should concentrate on in vivo studies to assess the effectiveness and safety of these substances. Full article

Nitrile-containing insecticides can be converted into their amide derivatives by Pseudaminobacter salicylatoxidans. N-(4-trifluoromethylnicotinoyl) glycinamide (TFNG-AM) is converted to 4-(trifluoromethyl) nicotinoyl glycine (TFNG) using nitrile hydratase/amidase. However, the amidase that catalyzes this bioconversion has not yet been fully elucidated. In this study, it was discovered that flonicamid (FLO) is degraded by P. salicylatoxidans into the acid metabolite TFNG via the intermediate TFNG-AM. A half-life of 18.7 h was observed for P. salicylatoxidans resting cells, which transformed 82.8% of the available FLO in 48 h. The resulting amide metabolite, TFNG-AM, was almost all converted to TFNG within 19 d. A novel amidase-encoding gene was cloned and overexpressed in Escherichia coli. The enzyme, PmsiA, hydrolyzed TFNG-AM to TFNG. Despite being categorized as a member of the amidase signature enzyme superfamily, PsmiA only shares 20–30% identity with the 14 previously identified members of this family, indicating that PsmiA represents a novel class of enzyme. Homology structural modeling and molecular docking analyses suggested that key residues Glu247 and Met242 may significantly impact the catalytic activity of PsmiA. This study contributes to our understanding of the biodegradation process of nitrile-containing insecticides and the relationship between the structure and function of metabolic enzymes. Full article

In this study, we report the fabrication and characterization of self-healing and shape-memorable hydrogels, the mechanical properties of which can be tuned via post-polymerization crosslinking. These hydrogels were constructed from a thermo-responsive poly(N-acryloyl glycinamide) (NAGAm) copolymer containing N-acryloyl serine methyl ester (NASMe) units (5 mol%) that were readily synthesized via conventional radical copolymerization. This transparent and free-standing hydrogel is produced via multiple hydrogen bonds between PNAGAm chains by simply dissolving the polymer in water at a high temperature (~90 °C) and then cooling it. This hydrogel exhibited moldability and self-healing properties. The post-polymerization crosslinking of the amino acid-derived vinyl copolymer network with glutaraldehyde, which acts as a crosslinker between the hydroxy groups of the NASMe units, tuned mechanical properties such as viscoelasticity and tensile strength. The optimal crosslinker concentration efficiently improved the viscoelasticity. Moreover, these hydrogels exhibited shape fixation (~60%)/memory (~100%) behavior owing to the reversible thermo-responsiveness (upper critical solution temperature-type) of the PNAGAm units. Our multifunctional hydrogel, with moldable, self-healing, mechanical tunability via post-polymerization crosslinking, and shape-memorable properties, has considerable potential for applications in engineering and biomedical materials. Full article

This article sheds light on the various scaffolds that can be used in the designing and development of novel synthetic compounds to create DPP-4 inhibitors for the treatment of type 2 diabetes mellitus (T2DM). This review highlights a variety of scaffolds with high DPP-4 inhibition activity, such as pyrazolopyrimidine, tetrahydro pyridopyrimidine, uracil-based benzoic acid and esters, triazole-based, fluorophenyl-based, glycinamide, glycolamide, β-carbonyl 1,2,4-triazole, and quinazoline motifs. The article further explains that the potential of the compounds can be increased by substituting atoms such as fluorine, chlorine, and bromine. Docking of existing drugs like sitagliptin, saxagliptin, and vildagliptin was done using Maestro 12.5, and the interaction with specific residues was studied to gain a better understanding of the active sites of DPP-4. The structural activities of the various scaffolds against DPP-4 were further illustrated by their inhibitory concentration (IC₅₀) values. Additionally, various synthesis schemes were developed to make several commercially available DPP4 inhibitors such as vildagliptin, sitagliptin and omarigliptin. In conclusion, the use of halogenated scaffolds for the development of DPP-4 inhibitors is likely to be an area of increasing interest in the future. Full article

Ascorbic acid (AA) is an essential nutrient and has great potential as a cosmeceutical that protects the health and beauty of the skin. AA is expected to attenuate photoaging and the natural aging of the skin by reducing oxidative stress caused by external and internal factors and by promoting collagen gene expression and maturation. In this review, the biochemical basis of AA associated with collagen metabolism and clinical evidence of AA in increasing dermal collagen and inhibiting skin aging were discussed. In addition, we reviewed emerging strategies that have been developed to overcome the shortcomings of AA as a cosmeceutical and achieve maximum efficacy. Because extracellular matrix proteins, such as collagen, have unique amino acid compositions, their production in cells is influenced by the availability of specific amino acids. For example, glycine residues occupy 1/3 of amino acid residues in collagen protein, and the supply of glycine can be a limiting factor for collagen synthesis. Experiments showed that glycinamide was the most effective among the various amino acids and amidated amino acids in stimulating collagen production in human dermal fibroblasts. Thus, it is possible to synergistically improve collagen synthesis by combining AA analogs and amino acid analogs that act at different stages of the collagen production process. This combination therapy would be useful for skin antiaging that requires enhanced collagen production. Full article

The rational discovery of new peptidomimetic inhibitors of the coagulation factor Xa (fXa) could help set more effective therapeutic options (to prevent atrial fibrillation). In this respect, we explored the conformational impact on the enzyme inhibition potency of the malonamide bridge, compared to the glycinamide one, as a linker connecting the P1 benzamidine anchoring moiety to the P4 aryl group of novel selective fXa inhibitors. We carried out structure–activity relationship (SAR) studies aimed at investigating para- or meta-benzamidine as the P1 basic group as well as diversely decorated aryl moieties as P4 fragments. To this end, twenty-three malonamide derivatives were synthesized and tested as inhibitors of fXa and thrombin (thr); the molecular determinants behind potency and selectivity were also studied by employing molecular docking. The malonamide linker, compared to the glycinamide one, does significantly increase anti-fXa potency and selectivity. The meta-benzamidine (P1) derivatives bearing 2′,4′-difluoro-biphenyl as the P4 moiety proved to be highly potent reversible fXa-selective inhibitors, achieving inhibition constants (K_i) in the low nanomolar range. The most active compounds were also tested against cholinesterase (ChE) isoforms (acetyl- or butyrylcholinesterase, AChE, and BChE), and some of them returned single-digit micromolar inhibition potency against AChE and/or BChE, both being drug targets for symptomatic treatment of mild-to-moderate Alzheimer’s disease. Compounds 19h and 22b were selected as selective fXa inhibitors with potential as multimodal neuroprotective agents. Full article

The purpose of this study is to present a novel strategy to enhance collagen production in cells. To identify amino acid analogs with excellent collagen production-enhancing effects, human dermal fibroblasts (HDFs) were treated with 20 kinds of amidated amino acids and 20 kinds of free amino acids, individually at 1 mM. The results showed that glycinamide enhanced collagen production (secreted collagen level) most effectively. Glycine also enhanced collagen production to a lesser degree. However, other glycine derivatives, such as N-acetyl glycine, N-acetyl glycinamide, glycine methyl ester, glycine ethyl ester, and glycyl glycine, did not show such effects. Glycinamide increased type I and III collagen protein levels without affecting COL1A1 and COL3A1 mRNA levels, whereas transforming growth factor-β1 (TGF-β1, 10 ng mL⁻¹) increased both mRNA and protein levels of collagens. Ascorbic acid (AA, 1 mM) increased COL1A1 and COL3A1 mRNA and collagen I protein levels. Unlike TGF-β1, AA and glycinamide did not increase the protein level of α-smooth muscle actin, a marker of differentiation of fibroblasts into myofibroblasts. The combination of AA and glycinamide synergistically enhanced collagen production and wound closure in HDFs to a level similar to that in cells treated with TGF-β1. AA derivatives, such as magnesium ascorbyl 3-phosphate (MAP), 3-O-ethyl ascorbic acid, ascorbyl 2-O-glucoside, and ascorbyl tetraisopalmitate, enhanced collagen production, and the mRNA and protein levels of collagens at 1 mM, and their effects were further enhanced when co-treated with glycinamide. Among AA derivatives, MAP had a similar effect to AA in enhancing wound closure, and its effect was further enhanced by glycinamide. Other AA derivatives had different effects on wound closure. This study provides a new strategy to enhance cell collagen production and wound healing using glycinamide in combination with AA. Full article

A diastereoselective synthesis of the β-anomer of glycinamide ribonucleotide (β-GAR) has been developed. The synthesis was accomplished in nine steps from D-ribose and occurred in 5% overall yield. The route provided material on the multi-milligram scale. The synthetic β-GAR formed was remarkably resistant to anomerization both in solution and as a solid. Full article

The second step in the de novo biosynthetic pathway of purine is catalyzed by PurD, which consumes an ATP molecule to produce glycinamide ribonucleotide (GAR) from glycine and phosphoribosylamine (PRA). PurD initially reacts with ATP to produce an intermediate, glycyl-phosphate, which then reacts with PRA to produce GAR. The structure of the glycyl-phosphate intermediate bound to PurD has not been determined. Therefore, the detailed reaction mechanism at the molecular level is unclear. Here, we developed a computational protocol to analyze the free-energy profile for the glycine phosphorylation process catalyzed by PurD, which examines the free-energy change along a minimum energy path based on a perturbation method combined with the quantum mechanics and molecular mechanics hybrid model. Further analysis revealed that during the formation of glycyl-phosphate, the partial atomic charge distribution within the substrate molecules was not localized according to the formal charges, but was delocalized overall, which contributed significantly to the interaction with the charged amino acid residues in the ATP-grasp domain of PurD. Full article

Prolyl hydroxylase domain-containing protein 2 (PHD2) inhibition, which stabilizes hypoxia-inducible factor (HIF)-1α and thus triggers adaptation responses to hypoxia in cells, has become an important therapeutic target. Despite the proven high potency, small-molecule PHD2 inhibitors such as IOX2 may require a nanoformulation for favorable biodistribution to reduce off-target toxicity. A liposome formulation for improving the pharmacokinetics of an encapsulated drug while allowing a targeted delivery is a viable option. This study aimed to develop an efficient loading method that can encapsulate IOX2 and other PHD2 inhibitors with similar pharmacophore features in nanosized liposomes. Driven by a transmembrane calcium acetate gradient, a nearly 100% remote loading efficiency of IOX2 into liposomes was achieved with an optimized extraliposomal solution. The electron microscopy imaging revealed that IOX2 formed nanoprecipitates inside the liposome’s interior compartments after loading. For drug efficacy, liposomal IOX2 outperformed the free drug in inducing the HIF-1α levels in cell experiments, especially when using a targeting ligand. This method also enabled two clinically used inhibitors—vadadustat and roxadustat—to be loaded into liposomes with a high encapsulation efficiency, indicating its generality to load other heterocyclic glycinamide PHD2 inhibitors. We believe that the liposome formulation of PHD2 inhibitors, particularly in conjunction with active targeting, would have therapeutic potential for treating more specifically localized disease lesions. Full article

A prospective technology for reversible enzyme complexation accompanied with its inactivation and protection followed by reactivation after a fast thermocontrolled release has been demonstrated. A thermoresponsive polymer with upper critical solution temperature, poly(N-acryloyl glycinamide) (PNAGA), which is soluble in water at elevated temperatures but phase separates at low temperatures, has been shown to bind lysozyme, chosen as a model enzyme, at a low temperature (10 °C and lower) but not at room temperature (around 25 °C). The cooling of the mixture of PNAGA and lysozyme solutions from room temperature resulted in the capturing of the protein and the formation of stable complexes; heating it back up was accompanied by dissolving the complexes and the release of the bound lysozyme. Captured by the polymer, lysozyme was inactive, but a temperature-mediated release from the complexes was accompanied by its reactivation. Complexation also partially protected lysozyme from proteolytic degradation by proteinase K, which is useful for biotechnological applications. The obtained results are relevant for important medicinal tasks associated with drug delivery such as the delivery and controlled release of enzyme-based drugs. Full article

The hydrogen bonding of water and water/salt mixtures around the proline-based tripeptide model glycyl-l-prolyl-glycinamide·HCl (GPG-NH₂) is investigated here by multi-wavelength UV resonance Raman spectroscopy (UVRR) to clarify the role of ion–peptide interactions in affecting the conformational stability of this peptide. The unique sensitivity and selectivity of the UVRR technique allow us to efficiently probe the hydrogen bond interaction between water molecules and proline residues in different solvation conditions, along with its influence on trans to cis isomerism in the hydrated tripeptide. The spectroscopic data suggest a relevant role played by the cations in altering the solvation shell at the carbonyl site of proline_., while the fluoride and chloride anions were found to promote the establishment of the strongest interactions on the $\mathrm{C}=\mathrm{O}$ site of proline. This latter effect is reflected in the greater stabilization of the trans conformers of the tripeptide in the presence of these specific ions. The molecular view provided by UVRR experiments was complemented by the results of circular dichroism (CD) measurements that show a strong structural stabilizing effect on the β-turn motif of GPG-NH₂ observed in the presence of KF as a co-solute. Full article

One-pot free-radical polymerization of N-acryloyl glycinamide in the presence of hyaluronic acid as transfer-termination agent led to new copolymers in high yields without any chemical activation of hyaluronic acid before. All the copolymers formed thermoresponsive hydrogels of the Upper Critical Solution Temperature-type in aqueous media. Gel properties and the temperature of the reversible gel ↔ sol transition depended on feed composition and copolymer concentration. Comparison with mixtures of hyaluronic acid-poly(N-acryloyl glycinamide) failed in showing the expected formation of graft copolymers conclusively because poly(N-acryloyl glycinamide) homopolymers are also thermoresponsive. Grafting and formation of comb-like copolymers were proved after degradation of inter-graft hyaluronic acid segments by hyaluronidase. Enzymatic degradation yielded poly(N-acryloyl glycinamide) with sugar residues end groups as shown by NMR. In agreement with the radical transfer mechanism, the molar mass of these released poly(N-acryloyl glycinamide) grafts depended on the feed composition. The higher the proportion of hyaluronic acid in the feed, the lower the molar mass of poly(N-acryloyl glycinamide) grafts was. Whether molar mass can be made low enough to allow kidney filtration remains to be proved in vivo. Last but not least, Prednisolone was used as model drug to show the ability of the new enzymatically degradable hydrogels to sustain progressive delivery for rather long periods of time in vitro. Full article