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1.
Food Res Int ; 188: 114508, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38823847

ABSTRACT

Procyanidins, which are oligomerized flavan-3-ols with a polyphenolic structure, are bioactive substances that exhibit various biological effects. However, the relationship between the degree of polymerization (DP) of procyanidins and their bioactivities remains largely unknown. In this study, the preventive effects of procyanidins with different DP (EC, PB2 and PC1) on glucose improvement and liver lipid deposition were investigated using a high-fat diet/streptozotocin-induced diabetes mouse model. The results demonstrated that all the procyanidins with different DP effectively reduced fasting blood glucose and glucose/insulin tolerance, decreased the lipid profile (total cholesterol, triglyceride, and low-density lipoprotein cholesterol content) in serum and liver tissue as well as the liver oil red staining, indicating the improvement of glucose metabolism, insulin sensitivity and hepatic lipid deposition in diabetic mice. Furthermore, the procyanidins down-regulated expression of glucose regulated 78-kDa protein (GRP78) and C/EBP homologous protein (CHOP), indicating a regulation role of endoplasmic reticulum (ER) stress. The inhibition of ER stress by tauroursodeoxycholic acid (TUDCA) treatment abolished the effects of procyanidins with different DP in PA-induced HepG2 cells, confirming that procyanidins alleviate liver hyperlipidemia through the modulation of ER stress. Molecular docking results showed that EC and PB2 could better bind GRP78 and CHOP. Collectively, our study reveals that the structure of procyanidins, particularly DP, is not directly correlated with the improvement of blood glucose and lipid deposition, while highlighting the important role of ER stress in the bioactivities of procyanidins.


Subject(s)
Blood Glucose , Diabetes Mellitus, Experimental , Diet, High-Fat , Endoplasmic Reticulum Chaperone BiP , Lipid Metabolism , Liver , Proanthocyanidins , Animals , Proanthocyanidins/pharmacology , Diet, High-Fat/adverse effects , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Male , Lipid Metabolism/drug effects , Mice , Blood Glucose/metabolism , Blood Glucose/drug effects , Liver/drug effects , Liver/metabolism , Hep G2 Cells , Humans , Polymerization , Endoplasmic Reticulum Stress/drug effects , Molecular Docking Simulation , Biflavonoids/pharmacology , Mice, Inbred C57BL , Streptozocin , Insulin Resistance , Catechin/pharmacology
2.
Food Res Int ; 188: 114503, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38823881

ABSTRACT

The aim of this work was to investigate wheat gluten protein network structure throughout the deep-frying process and evaluate its contribution to frying-induced micro- and macrostructure development. Gluten polymerization, gluten-water interactions, and molecular mobility were assessed as a function of the deep-frying time (0 - 180 s) for gluten-water model systems of differing hydration levels (40 - 60 % moisture content). Results showed that gluten protein extractability decreased considerably upon deep frying (5 s) mainly due to glutenin polymerization by disulfide covalent cross-linking. Stronger gliadin and glutenin protein-protein interactions were attributed to the formation of covalent linkages and evaporation of water interacting with protein chains. Longer deep-frying (> 60 s) resulted in progressively lower protein extractabilities, mainly due to the loss in gliadin protein extractability, which was associated with gliadin co-polymerization with glutenin by thiol-disulfide exchange reactions. The mobility of gluten polymers was substantially reduced during deep-frying (based on the lower T2 relaxation time of the proton fraction representing the non-exchanging protons of gluten) and gluten proteins gradually transitioned from the rubbery to the glassy state (based on the increased area of said protons). The sample volume during deep-frying was strongly correlated to the reduced protein extractability (r = -0.792, p < 0.001) and T2 relaxation time of non-exchanging protons of gluten proteins (r = -0.866, p < 0.001) thus demonstrating that the extent of gluten structural expansion as a result of deep-frying is dictated both by the polymerization of proteins and the reduction in their molecular mobility.


Subject(s)
Cooking , Gliadin , Glutens , Hot Temperature , Triticum , Glutens/chemistry , Triticum/chemistry , Cooking/methods , Gliadin/chemistry , Polymerization , Water/chemistry
3.
Arch Dermatol Res ; 316(7): 341, 2024 Jun 07.
Article in English | MEDLINE | ID: mdl-38847867

ABSTRACT

Topical tirbanibulin is a highly effective and well tolerated novel treatment option for actinic keratoses (AKs). This study aimed to characterize the mode of action of tirbanibulin in keratinocytes (NHEK) and cutaneous squamous cell carcinoma (cSCC) cell lines (A431, SCC-12) in vitro. Tirbanibulin significantly reduced proliferation in a dose-dependent manner in all investigated cell lines, inhibited migration, and induced G2/M-cell cycle arrest only in the cSCC cell lines analyzed, and induced apoptosis solely in A431, which showed the highest sensitivity to tirbanibulin. In general, we detected low basal expression of phosphorylated SRC in all cell lines analyzed, therefore, interference with SRC signaling does not appear to be the driving force regarding the observed effects of tirbanibulin. The most prominent tirbanibulin-mediated effect was on ß-tubulin-polymerization, which was especially impaired in A431. Additionally, tirbanibulin induced an increase of the proinflammatory cytokines IL-1α, bFGF and VEGF in A431. In conclusion, tirbanibulin mediated anti-tumor effects predominantly in A431, while healthy keratinocytes and more dedifferentiated SCC-12 were less influenced. These effects of tirbanibulin are most likely mediated via dysregulation of ß-tubulin-polymerization and may be supported by proinflammatory aspects.


Subject(s)
Apoptosis , Carcinoma, Squamous Cell , Cell Movement , Cell Proliferation , Keratinocytes , Skin Neoplasms , Tubulin , Humans , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/metabolism , Keratinocytes/drug effects , Keratinocytes/metabolism , Cell Line, Tumor , Tubulin/metabolism , Skin Neoplasms/drug therapy , Skin Neoplasms/pathology , Skin Neoplasms/metabolism , Apoptosis/drug effects , Cell Proliferation/drug effects , Cell Movement/drug effects , Antineoplastic Agents/pharmacology , Polymerization/drug effects , Keratosis, Actinic/drug therapy , Keratosis, Actinic/pathology , Keratosis, Actinic/metabolism , Signal Transduction/drug effects , Acetamides , Morpholines , Pyridines
4.
Biomacromolecules ; 25(5): 2925-2933, 2024 May 13.
Article in English | MEDLINE | ID: mdl-38691827

ABSTRACT

A "one-step" strategy has been demonstrated for the tunable synthesis of multifunctional aliphatic polycarbonates (APCs) with ethylene oxide (EO), ethylene carbonate (EC), and cyclohexene oxide (CHO) side groups by the copolymerization of 4-vinyl-1-cyclohexene diepoxide with carbon dioxide under an aminotriphenolate iron/PPNBz (PPN = bis(triphenylphosphine)-iminium, Bz = benzoate) binary catalyst. By adjusting the PPNBz-to-iron complex ratio and incorporating auxiliary solvents, the content of functional side groups can be tuned within the ranges of 53-75% for EO, 18-47% for EC, and <1-7% for CHO. The yield and molecular weight distribution of the resulting multifunctional APCs are affected by the viscosity of the polymerization system. The use of tetrahydrofuran as an auxiliary solvent enables the preparation of narrow-distribution polycarbonates at high conversion. This work presents a novel perspective for the preparation of tailorable multifunctional APCs.


Subject(s)
Carbon Dioxide , Polycarboxylate Cement , Polymerization , Carbon Dioxide/chemistry , Polycarboxylate Cement/chemistry , Epoxy Compounds/chemistry , Ethylene Oxide/chemistry , Cyclohexenes/chemistry , Catalysis , Viscosity , Dioxolanes
5.
Biomacromolecules ; 25(5): 3122-3130, 2024 May 13.
Article in English | MEDLINE | ID: mdl-38696355

ABSTRACT

Synthesis of polysaccharide-b-polypeptide block copolymers represents an attractive goal because of their promising potential in delivery applications. Inspired by recent breakthroughs in N-carboxyanhydride (NCA) ring-opening polymerization (ROP), we present an efficient approach for preparation of a dextran-based macroinitiator and the subsequent synthesis of dextran-b-polypeptides via NCA ROP. This is an original approach to creating and employing a native polysaccharide macroinitiator for block copolymer synthesis. In this strategy, regioselective (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) oxidation of the sole primary alcohol located at the C-6 position of the monosaccharide at the nonreducing end of linear dextran results in a carboxylic acid. This motif is then transformed into a tetraalkylammonium carboxylate, thereby generating the dextran macroinitiator. This macroinitiator initiates a wide range of NCA monomers and produces dextran-b-polypeptides with a degree of polymerization (DP) of the polypeptide up to 70 in a controlled manner (D < 1.3). This strategy offers several distinct advantages, including preservation of the original dextran backbone structure, relatively rapid polymerization, and moisture tolerance. The dextran-b-polypeptides exhibit interesting self-assembly behavior. Their nanostructures have been investigated by dynamic light scattering (DLS) and transmission electron microscopy (TEM), and adjustment of the structure of block copolymers allows self-assembly of spherical micelles and worm-like micelles with varied diameters and aspect ratios, revealing a range of diameters from 60 to 160 nm. Moreover, these nanostructures exhibit diverse morphologies, including spherical micelles and worm-like micelles, enabling delivery applications.


Subject(s)
Dextrans , Peptides , Polymerization , Dextrans/chemistry , Peptides/chemistry , Peptides/chemical synthesis , Polymers/chemistry , Polymers/chemical synthesis , Cyclic N-Oxides/chemistry , Anhydrides/chemistry , Polysaccharides/chemistry , Micelles
6.
Molecules ; 29(10)2024 May 08.
Article in English | MEDLINE | ID: mdl-38792062

ABSTRACT

Combretastatins isolated from the Combretum caffrum tree belong to a group of closely related stilbenes. They are colchicine binding site inhibitors which disrupt the polymerization process of microtubules in tubulins, causing mitotic arrest. In vitro and in vivo studies have proven that some combretastatins exhibit antitumor properties, and among them, combretastatin A-4 is the most active mitotic inhibitor. In this study, a series of novel combretastatin A-4 analogs containing carboxylic acid, ester, and amide moieties were synthesized and their cytotoxic activity against six tumor cell lines was determined using sulforhodamine B assay. For the most cytotoxic compounds (8 and 20), further studies were performed. These compounds were shown to induce G0/G1 cell cycle arrest in MDA and A549 cells, in a concentration-dependent manner. Moreover, in vitro tubulin polymerization assays showed that both compounds are tubulin polymerization enhancers. Additionally, computational analysis of the binding modes and binding energies of the compounds with respect to the key human tubulin isotypes was performed. We have obtained a satisfactory correlation of the binding energies with the IC50 values when weighted averages of the binding energies accounting for the abundance of tubulin isotypes in specific cancer cell lines were computed.


Subject(s)
Cell Proliferation , Drug Design , Stilbenes , Tubulin Modulators , Tubulin , Humans , Tubulin/metabolism , Tubulin/chemistry , Cell Proliferation/drug effects , Tubulin Modulators/pharmacology , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistry , Stilbenes/pharmacology , Stilbenes/chemistry , Stilbenes/chemical synthesis , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Structure-Activity Relationship , Molecular Docking Simulation , A549 Cells , Polymerization/drug effects , Drug Screening Assays, Antitumor
7.
Molecules ; 29(10)2024 May 20.
Article in English | MEDLINE | ID: mdl-38792260

ABSTRACT

(1) Background: The aim of the work is the evaluation of in vitro antiproliferative and pro-apoptotic activity of four benzimidazole derivatives containing colchicine-like and catechol-like moieties with methyl group substitution in the benzimidazole ring against highly invasive breast cancer cell line MDA-MB-231 and their related impairment of tubulin dynamics. (2) Methods: The antiproliferative activity was assessed with the MTT assay. Alterations in tubulin polymerization were evaluated with an in vitro tubulin polymerization assay and a docking analysis. (3) Results: All derivatives showed time-dependent cytotoxicity with IC50 varying from 40 to 60 µM after 48 h and between 13 and 20 µM after 72 h. Immunofluorescent and DAPI staining revealed the pro-apoptotic potential of benzimidazole derivatives and their effect on tubulin dynamics in living cells. Compound 5d prevented tubulin aggregation and blocked mitosis, highlighting the importance of the methyl group and the colchicine-like fragment. (4) Conclusions: The benzimidazole derivatives demonstrated moderate cytotoxicity towards MDA-MB-231 by retarding the initial phase of tubulin polymerization. The derivative 5d containing a colchicine-like moiety and methyl group substitution in the benzimidazole ring showed potential as an antiproliferative agent and microtubule destabilizer by facilitating faster microtubule aggregation and disrupting cellular and nuclear integrity.


Subject(s)
Antineoplastic Agents , Apoptosis , Benzimidazoles , Breast Neoplasms , Cell Proliferation , Tubulin , Humans , Tubulin/metabolism , Cell Proliferation/drug effects , Apoptosis/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Benzimidazoles/pharmacology , Benzimidazoles/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Female , Hydrazones/pharmacology , Hydrazones/chemistry , Hydrazones/chemical synthesis , Molecular Docking Simulation , Tubulin Modulators/pharmacology , Tubulin Modulators/chemistry , Structure-Activity Relationship , Polymerization , Molecular Structure
8.
Biosens Bioelectron ; 259: 116417, 2024 Sep 01.
Article in English | MEDLINE | ID: mdl-38795496

ABSTRACT

Assembling functional molecules on the surface of an enzyme electrode is the most basic technique for constructing a biosensor. However, precise control of electron transfer interface or electron mediator on the electrode surface remains a challenge, which is a key step that affects the stability and sensitivity of enzyme-based biosensors. In this study, we propose the use of controllable free radical polymerization to grow stable 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) polymer as electron mediator on enzyme surface for the first time. Through scanning electron microscopy (SEM), Raman spectroscopy, electrode surface coverage measurement, static contact angle (SCA), and a series of electrochemical methods, it has been demonstrated that the TEMPO-based enzyme electrode exhibits a uniform hydrophilic morphology and stable electrochemical performance. Furthermore, the results show that the sensor demonstrates high sensitivity for detecting glucose biomolecules in artificial sweat and serum. Attributing to the quantitative and controllable radical polymerization of TEMPO redox assembled enzyme electrode surface, the as-proposed biosensor providing a use, storage, and inter-batch sensing stability, providing a vital platform for wearable/implantable biochemical sensors.


Subject(s)
Biosensing Techniques , Cyclic N-Oxides , Electrodes , Enzymes, Immobilized , Oxidation-Reduction , Polymerization , Biosensing Techniques/methods , Cyclic N-Oxides/chemistry , Enzymes, Immobilized/chemistry , Electrochemical Techniques/methods , Glucose/analysis , Glucose/chemistry , Glucose Oxidase/chemistry , Humans , Polymers/chemistry
9.
BMC Oral Health ; 24(1): 619, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38807138

ABSTRACT

PURPOSE: The aim of this in vitro study was to evaluate the changes the rheological properties of some soft lining materials, to compare the rheological properties and viscoelastic behaviour at different temperatures. MATERIALS AND METHODS: Five soft lining materials (acrylic and silicone based) were used. the storage modulus (G'), loss modulus (G"), tan delta (tan δ) and complex viscosity (η') were chosen and for each material, measurements were repeated at 23, 33 and 37  °C, using an oscillating rheometer. All data were statistically analyzed using the Mann Whitney U test, Kruskal Wallis test and Conover's Multiple Comparison test at the significance level of 0.05. RESULTS: Soft lining materials had different viscoelastic properties and most of the materials showed different rheological behavior at 23, 33 and 37  °C. At the end of the test (t¹5), at all the temperatures, Sofreliner Tough M had the highest storage modulus values while Visco Gel had the highest loss Tan delta values. CONCLUSIONS: There were significant changes in the rheological parameters of all the materials. Also temperature affected the initial rheological properties, and polymerization reaction of all the materials, depending on temperature increase. CLINICAL IMPLICATIONS: Temperature affected the initial rheological properties, and polymerization reaction of soft denture liner materials, and clinical inferences should be drawn from such studies conducted. It can be recommended to utilize viscoelastic acrylic-based temporary soft lining materials with lower storage modulus, higher tan delta value, and high viscosity in situations where pain complaint persists and tissue stress is extremely significant, provided that they are replaced often.


Subject(s)
Acrylic Resins , Materials Testing , Rheology , Temperature , Viscosity , Acrylic Resins/chemistry , Elasticity , Denture Liners , Elastic Modulus , Dental Cavity Lining , Silicones/chemistry , Polymerization , Humans , Oscillometry
10.
Mikrochim Acta ; 191(6): 348, 2024 05 28.
Article in English | MEDLINE | ID: mdl-38805077

ABSTRACT

A novel aptamer-based sensor was developed using the signal amplification strategy of ring-opening metathesis polymerization (ROMP) and polyethyleneimine modified graphene oxide to achieve trace detection of carbendazim (CBZ). The dual identification of aptamer and antibody was used to avoid false positive results and improve the selectivity. Polyethyleneimine modified graphene oxide (GO-PEI), as a substrate material with excellent conductivity, was modified on the surface of a glassy carbon electrode (GCE) to increase the grafting amount of aptamer on the electrode surface. Moreover, a large number of cyclopentenyl ferrocene (CFc) was aggregated to form long polymer chains through ring-opening metathesis polymerization (ROMP), so as to significantly improve the detection sensitivity of the biosensor. The linear range of this sensor was 1 pg/mL-100 ng/mL with a detection limit as low as 7.80 fg/mL. The sensor exhibited excellent reproducibility and stability, and also achieved satisfactory results in actual sample detection. The design principle of such a sensor could provide innovative ideas for sensors in the detection of other types of targets.


Subject(s)
Aptamers, Nucleotide , Benzimidazoles , Biosensing Techniques , Carbamates , Electrochemical Techniques , Graphite , Limit of Detection , Polyethyleneimine , Polymerization , Graphite/chemistry , Carbamates/chemistry , Carbamates/analysis , Electrochemical Techniques/methods , Electrochemical Techniques/instrumentation , Polyethyleneimine/chemistry , Biosensing Techniques/methods , Benzimidazoles/chemistry , Aptamers, Nucleotide/chemistry , Electrodes , Reproducibility of Results
11.
Biomacromolecules ; 25(6): 3288-3301, 2024 Jun 10.
Article in English | MEDLINE | ID: mdl-38805352

ABSTRACT

Poly(2-isopropenyl-2-oxazoline) (PIPOx) represents a universal polymer platform with pendant 2-oxazoline groups, allowing the preparation of biomaterials for various biomedical applications. However, there is a lack of information on PIPOx concerning the effect of molar mass (Mn) on cytotoxicity and bioimmunological properties. Here, aqueous copper(0)-mediated reversible-deactivation radical polymerization (Cu0-RDPR) was used for the preparation of PIPOx with defined Mn and low dispersity. PIPOx of different Mn are used for the synthesis of conjugates with ibuprofen (5 mol %), the nonsteroidal anti-inflammatory drug. The release of ibuprofen at 37 °C and different pH values is monitored using high-performance liquid chromatography, where the rate of drug release increases with increasing pH and lower Mn. In vitro cytotoxicity and bioimmunological properties of PIPOx and drug conjugates are studied using 3D reconstructed tissue models of the human epidermis and intestinal epithelium. We demonstrate low cytotoxicity of PIPOx and conjugates with different Mn values on both 3D tissue models.


Subject(s)
Ibuprofen , Ibuprofen/chemistry , Ibuprofen/pharmacology , Humans , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Oxazoles/chemistry , Oxazoles/pharmacology , Polymers/chemistry , Polymers/pharmacology , Polymerization , Biocompatible Materials/chemistry , Biocompatible Materials/pharmacology
12.
Biomacromolecules ; 25(6): 3620-3627, 2024 Jun 10.
Article in English | MEDLINE | ID: mdl-38806062

ABSTRACT

Lignin is an aromatic polymer that constitutes plant cell walls. The polymerization of lignin proceeds by radical coupling, and this process requires radicalization of the phenolic end of lignin by enzymes. However, due to the steric hindrance between enzymes, lignin, and polysaccharides, the direct oxidation of the phenolic end of lignin by the enzyme would be difficult, and the details of the growth of lignin are still unknown. In this study, enzymatic dehydrogenative polymerization experiments were conducted using coniferyl alcohol (CA) and the deuterium-labeled lignin model compound (D-LM) under a noncontact condition in which horseradish peroxidase cannot directly oxidize D-LM due to separation by a dialysis membrane. Analysis of deuterium-labeled degraded compounds obtained by a combination of methylation and thioacidolysis revealed the formation of the bond between the phenolic end of D-LM and CA, suggesting that membrane-permeable, low-molecular-weight lignols functioned as a redox shuttle mediator.


Subject(s)
Lignin , Oxidation-Reduction , Polymerization , Lignin/chemistry , Lignin/metabolism , Phenols/chemistry , Phenols/metabolism , Horseradish Peroxidase/chemistry , Horseradish Peroxidase/metabolism , Molecular Weight , Phenylpropionates/chemistry , Phenylpropionates/metabolism
13.
Biosensors (Basel) ; 14(5)2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38785696

ABSTRACT

This work presents a novel approach for tailoring molecularly imprinted polymers (MIPs) with a preliminary stage of atom transfer radical polymerization (ATRP), for a more precise definition of the imprinted cavity. A well-defined copolymer of acrylamide and N,N'-methylenebisacrylamide (PAAm-co-PMBAm) was synthesized by ATRP and applied to gold electrodes with the template, followed by a crosslinking reaction. The template was removed from the polymer matrix by enzymatic/chemical action. The surface modifications were monitored via electrochemical impedance spectroscopy (EIS), having the MIP polymer as a non-conducting film designed with affinity sites for CA15-3. The resulting biosensor exhibited a linear response to CA15-3 log concentrations from 0.001 to 100 U/mL in PBS or in diluted fetal bovine serum (1000×) in PBS. Compared to the polyacrylamide (PAAm) MIP from conventional free-radical polymerization, the ATRP-based MIP extended the biosensor's dynamic linear range 10-fold, improving low concentration detection, and enhanced the signal reproducibility across units. The biosensor demonstrated good sensitivity and selectivity. Overall, the work described confirmed that the process of radical polymerization to build an MIP material influences the detection capacity for the target substance and the reproducibility among different biosensor units. Extending this approach to other cancer biomarkers, the methodology presented could open doors to a new generation of MIP-based biosensors for point-of-care disease diagnosis.


Subject(s)
Biosensing Techniques , Molecularly Imprinted Polymers , Polymerization , Molecularly Imprinted Polymers/chemistry , Molecular Imprinting , Humans , Dielectric Spectroscopy , Polymers/chemistry , Acrylamides/chemistry , Reproducibility of Results , Gold/chemistry , Acrylic Resins/chemistry
14.
Eur J Med Chem ; 272: 116497, 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38759453

ABSTRACT

A series of combretastatin A-4 (CA-4) derivatives were designed and synthesized, which contain stilbene core structure with different linker, predominantly piperazine derivatives. These compounds were evaluated for their cytotoxic activities against four cancer cell lines, HCT116, A549, AGS, and SK-MES-1. Among them, compound 13 displayed the best effectiveness with IC50 values of 0.227 µM and 0.253 µM against HCT116 and A549 cells, respectively, showing low toxicity to normal cells. Mechanistic studies showed that 13 inhibited HCT116 proliferation via arresting cell cycle at the G2/M phase through disrupting the microtubule network and inducing autophagy in HCT116 cells by regulating the expression levels of autophagy-related proteins. In addition, 13 displayed antiproliferative activities against A549 cells through blocking the cell cycle and inducing A549 cells apoptosis. Because of the poor water solubility of 13, four carbohydrate conjugates were synthesized which exhibited better water solubility. Further investigations revealed that 13 showed positive effects in vivo anticancer study with HCT116 xenograft models. These data suggest that 13 could be served as a promising lead compound for further development of anti-colon carcinoma agent.


Subject(s)
Antineoplastic Agents , Autophagy , Cell Proliferation , Drug Design , Drug Screening Assays, Antitumor , Polymerization , Stilbenes , Tubulin , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Autophagy/drug effects , Cell Proliferation/drug effects , Structure-Activity Relationship , Stilbenes/pharmacology , Stilbenes/chemistry , Stilbenes/chemical synthesis , Tubulin/metabolism , Animals , Polymerization/drug effects , Molecular Structure , HCT116 Cells , Piperazines/pharmacology , Piperazines/chemistry , Piperazines/chemical synthesis , Mice , Dose-Response Relationship, Drug , Apoptosis/drug effects , Tubulin Modulators/pharmacology , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistry , Mice, Nude , Piperazine/chemistry , Piperazine/pharmacology , Piperazine/chemical synthesis , Mice, Inbred BALB C
15.
J Chromatogr A ; 1727: 464969, 2024 Jul 19.
Article in English | MEDLINE | ID: mdl-38776606

ABSTRACT

Polymerization of 5-n-alkyl-substituted 2-norbornenes synthesized a series of polymers having the same structure of the main polymer chain, but differing in the length of the alkyl substituent (up to 14 methylene units). The obtained polymers were studied by the capillary IGC method as a stationary phase during separation of a mixture of normal hydrocarbons C6-C10. Retention data in the form of a logarithm of the retention factor lnk were correlated with the size of the sorbate (via the carbon number of the alkane ZS) and with the size of the n-alkyl substituent in the polymer chain (via the carbon number of the polymer ZP). Correlation of lnk vs. ZS turned out to be linear for all polymers, but the angle of the slope of linear dependence dlnk/dZS increases with a decrease in the carbon number of the polymer ZP. Dependency of dlnk/dZS vs. ZP is not linear and indicates an increase in the retention of sorbates by the stationary phase with a decrease in the length of the alkyl substituent in the polymer chain. The correlation of the retention of lnk analytes with the carbon number of the polymer ZP is not linear and indicates an increase in the sorbate/sorbent interaction with a decrease in the length of the alkyl substituent. Inflection points were found at both correlations with ZP in the region of ZP = 8, which indicates a possible change in the sorption mechanism or a change in the phase state of the polymer. In polymer chemistry, the phase state of a polymer is characterized by the glass transition temperature Tg, the dependence of which vs. ZP turned out to be nonlinear with an inflection point at ZP ∼11. Thus, a decrease in the length of the alkyl substituent leads to the transition of the polymer from a rubbery state to a glassy one at ZP ∼ 11, which in turn, with a further decrease in the carbon number of the polymer to ZP ∼ 8, causes a change in the sorption mechanism from bulk sorption to surface sorption. The change in the sorption mechanism is accompanied by an increase in the interaction of the sorbate with the stationary phase, which manifests itself both in an increase in the retention time of analytes and in an increase in the enthalpy and entropy of sorption. The reason for this increase can be seen in the formation of a microporous structure in 5-alkyl-substituted polynorbornenes in a glassy state.


Subject(s)
Norbornanes , Norbornanes/chemistry , Polymers/chemistry , Polymerization , Alkanes/chemistry
16.
Eur J Med Chem ; 272: 116458, 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38703557

ABSTRACT

Microtubules are recognized as one of the most vital and attractive targets in anticancer therapy. The development of novel tubulin-targeting agents with a new action mechanism is imperative. Based on the hydrophobic tagging strategy, the molecular scaffold of tirbanibulin was selected as tubulin target-binding moiety, subsequent to which a series of target compounds were rationally designed by selecting various combinations of linkers and hydrophobic tags. A set of novel molecules were synthesized and most of them exhibited potent antiproliferative activity against tumor cells in vitro. The most active compound 14b inhibited polymerization of purified recombinant tubulin and induced degradation of α- and ß-tubulin in MCF-7 cells. Notably, following treatment with compound 14b, an unexpected phenomenon of "microtubules fragmentation" was observed via immunofluorescence staining. Furthermore, compound 14b possessed antitumor activity in the 4T1 allograft models with TGI of 74.27 % without significant toxicity. In this work, we report the discovery of novel dual-mechanism tubulin-targeting agents.


Subject(s)
Antineoplastic Agents , Cell Proliferation , Drug Design , Drug Screening Assays, Antitumor , Polymerization , Tubulin Modulators , Tubulin , Humans , Tubulin/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Tubulin Modulators/pharmacology , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistry , Polymerization/drug effects , Cell Proliferation/drug effects , Structure-Activity Relationship , Molecular Structure , Animals , Dose-Response Relationship, Drug , Proteolysis/drug effects , Mice , Cell Line, Tumor , MCF-7 Cells , Female
17.
Biomacromolecules ; 25(5): 2990-3000, 2024 May 13.
Article in English | MEDLINE | ID: mdl-38696732

ABSTRACT

Recently, we reported the synthesis of a hydrophilic aldehyde-functional methacrylic polymer (Angew. Chem., 2021, 60, 12032-12037). Herein we demonstrate that such polymers can be reacted with arginine in aqueous solution to produce arginine-functional methacrylic polymers without recourse to protecting group chemistry. Careful control of the solution pH is essential to ensure regioselective imine bond formation; subsequent reductive amination leads to a hydrolytically stable amide linkage. This new protocol was used to prepare a series of arginine-functionalized diblock copolymer nanoparticles of varying size via polymerization-induced self-assembly in aqueous media. Adsorption of these cationic nanoparticles onto silica was monitored using a quartz crystal microbalance. Strong electrostatic adsorption occurred at pH 7 (Γ = 14.7 mg m-2), whereas much weaker adsorption occurred at pH 3 (Γ = 1.9 mg m-2). These findings were corroborated by electron microscopy, which indicated a surface coverage of 42% at pH 7 but only 5% at pH 3.


Subject(s)
Arginine , Nanoparticles , Nanoparticles/chemistry , Adsorption , Arginine/chemistry , Hydrogen-Ion Concentration , Polymerization , Silicon Dioxide/chemistry , Polymers/chemistry , Polymethacrylic Acids/chemistry , Polymethacrylic Acids/chemical synthesis
18.
Int J Mol Sci ; 25(10)2024 May 11.
Article in English | MEDLINE | ID: mdl-38791282

ABSTRACT

We previously found IQ motif containing GTPase activating protein (IQGAP1) to be consistently elevated in lung fibroblasts (LF) isolated from patients with scleroderma (systemic sclerosis, SSc)-associated interstitial lung disease (ILD) and reported that IQGAP1 contributed to SSc by regulating expression and organization of α-smooth muscle actin (SMA) in LF. The aim of this study was to compare the development of ILD in the presence and absence of IQGAP1. Pulmonary fibrosis was induced in IQGAP1 knockout (KO) and wild-type (WT) mice by a single-intratracheal instillation of bleomycin. Two and three weeks later, mice were euthanized and investigated. We observed that the IQGAP1 KO mouse was characterized by a reduced rate of actin polymerization with reduced accumulation of actin in the lung compared to the WT mouse. After exposure to bleomycin, the IQGAP1 KO mouse demonstrated decreased contractile activity of LF, reduced expression of SMA, TGFß, and collagen, and lowered overall fibrosis scores compared to the WT mouse. The numbers of inflammatory cells and expression of pro-inflammatory cytokines in lung tissue were not significantly different between IQGAP1 KO and WT mice. We conclude that IQGAP1 plays an important role in the development of lung fibrosis induced by bleomycin, and the absence of IQGAP1 reduces the contractile activity of lung fibroblast and bleomycin-induced pulmonary fibrosis. Thus, IQGAP1 may be a potential target for novel anti-fibrotic therapies for lung fibrosis.


Subject(s)
Actins , Bleomycin , Fibroblasts , Mice, Knockout , Pulmonary Fibrosis , ras GTPase-Activating Proteins , Animals , Bleomycin/adverse effects , ras GTPase-Activating Proteins/metabolism , ras GTPase-Activating Proteins/genetics , Actins/metabolism , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/genetics , Mice , Fibroblasts/metabolism , Fibroblasts/pathology , Lung/pathology , Lung/metabolism , Mice, Inbred C57BL , Polymerization , Disease Models, Animal
19.
Int J Mol Sci ; 25(10)2024 May 17.
Article in English | MEDLINE | ID: mdl-38791524

ABSTRACT

Actin filaments, as key components of the cytoskeleton, have aroused great interest due to their numerous functional roles in eukaryotic cells, including intracellular electrical signaling. The aim of this research is to characterize the alternating current (AC) conduction characteristics of both globular and polymerized actin and quantitatively compare their values to those theoretically predicted earlier. Actin filaments have been demonstrated to act as conducting bionanowires, forming a signaling network capable of transmitting ionic waves in cells. We performed conductivity measurements for different concentrations of actin, considering both unpolymerized and polymerized actin to identify potential differences in their electrical properties. These measurements revealed two relevant characteristics: first, the polymerized actin, arranged in filaments, has a lower impedance than its globular counterpart; second, an increase in the actin concentration leads to higher conductivities. Furthermore, from the data collected, we developed a quantitative model to represent the electrical properties of actin in a buffer solution. We hypothesize that actin filaments can be modeled as electrical resistor-inductor-capacitor (RLC) circuits, where the resistive contribution is due to the viscous ion flows along the filaments; the inductive contribution is due to the solenoidal flows along and around the helix-shaped filament and the capacitive contribution is due to the counterion layer formed around each negatively charged filament.


Subject(s)
Actin Cytoskeleton , Actins , Electric Conductivity , Actin Cytoskeleton/metabolism , Actin Cytoskeleton/chemistry , Actins/metabolism , Actins/chemistry , Animals , Polymerization
20.
Int J Mol Sci ; 25(10)2024 May 17.
Article in English | MEDLINE | ID: mdl-38791532

ABSTRACT

The development of photocurable compositions is in high demand for the manufacture of functional materials for electronics, optics, medicine, energy, etc. The properties of the final photo-cured material are primarily determined by the initial mixture, which needs to be tuned for each application. In this study we propose to use simple systems based on di(meth)acrylate, polyimide and photoinitiator for the preparation of new photo-curable compositions. It was established that a fluorinated cardo copolyimide (FCPI) based on 2,2-bis-(3,4-dicarboxydiphenyl)hexafluoropropane dianhydride, 9,9-bis-(4-aminophenyl)fluorene and 2,2-bis-(4-aminophenyl)hexafluoropropane (1.00:0.75:0.25 mol) has excellent solubility in di(met)acrylates. This made it possible to prepare solutions of FCPI in such monomers, to study the effect of FCPI on the kinetics of their photopolymerization in situ and the properties of the resulting polymers. According to the obtained data, the solutions of FCPI (23 wt.%) in 1,4-butanediol diacrylate (BDDA) and FCPI (15 wt.%) in tetraethylene glycol diacrylate were tested for the formation of the primary protective coatings of the silica optical fibers. It was found that the new coating of poly(BDDA-FCPI23%) can withstand prolonged annealing at 200 °C (72 h), which is comparable or superior to the known most thermally stable photo-curable coatings. The proposed approach can be applied to obtain other functional materials.


Subject(s)
Optical Fibers , Polymerization , Silicon Dioxide , Silicon Dioxide/chemistry , Solubility , Imides/chemistry , Temperature , Acrylates/chemistry , Polymers/chemistry , Halogenation , Photochemical Processes
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