Different Drug Mobilities in Hydrophobic Cavities of Host-Guest Complexes between ß-Cyclodextrin and 5-Fluorouracil at Different Stoichiometries: A Molecular Dynamics Study in Water.

Cyclodextrins (CDs) are cyclic oligosaccharides able to form noncovalent water-soluble complexes useful in many different applications for the solubilization, delivery, and greater bioavailability of hydrophobic drugs. The complexation of 5-fluorouracil (5-FU) with natural or synthetic cyclodextrins permits the solubilization of this poorly soluble anticancer drug. In this theoretical work, the complexes between ß-CD and 5-FU are investigated using molecular mechanics (MM) and molecular dynamics (MD) simulations in water. The inclusion complexes are formed thanks to the favorable intermolecular interactions between ß-CD and 5-FU. Both 1:1 and 1:2 ß-CD/5-FU stoichiometries are investigated, providing insight into their interaction geometries and stability over time in water. In the 1:2 ß-CD/5-FU complexes, the intermolecular interactions affect the drug's mobility, suggesting a two-step release mechanism: a fast release for the more exposed and hydrated drug molecule, with greater freedom of movement near the ß-CD rims, and a slow one for the less-hydrated and well-encapsulated and confined drug. MD simulations study the intermolecular interactions between drugs and specific carriers at the atomistic level, suggesting a possible release mechanism and highlighting the role of the impact of the drug concentration on the kinetics process in water. A comparison with experimental data in the literature provides further insights.

Antibacterial and Cytotoxic Silica-Polycaprolactone-Chlorogenic Acid Hybrids by Sol-Gel Route.

Organic-inorganic hybrid materials were synthesized by a sol-gel route, using silicon alkoxide together with low molecular weight polycaprolactone and caffetannic acid. The synthesized hybrids were characterized by scanning Fourier-transform infrared (FTIR) spectroscopy, and their surface morphology was acquired by scanning electron microscopy (SEM) analysis. The hybrids were investigated for their antiradical capacity using the DPPH and ABTS tests, while the Kirby-Bauer test was used to evaluate their effects on the growth of Escherichia coli and Enterococcus faecalis. Furthermore, a biologically active hydroxyapatite layer has been observed to form on the surface of intelligently synthesized materials. The MTT direct test showed that the hybrid materials are biocompatible with NIH-3T3 fibroblast cells, while they were cytotoxic towards colon, prostate, and brain tumor cell lines. These results shed new light on the suitability of the synthesized hybrids in the medical field, thus affording knowledge on the features of the bioactive silica-polycaprolactone-chlorogenic acid hybrids.

Encapsulating Calendula arvensis (Vaill.) L. Florets: UHPLC-HRMS Insights into Bioactive Compounds Preservation and Oral Bioaccessibility.

Wild edible plants, once consumed in times of famine or for health purposes, today represent an interesting dietary supplement, aimed at enriching local dishes and/or formulating healthy nutraceutical products. In fact, the broad content of different, and diversely bioactive, specialized metabolites therein suggests new scenarios of use which, in order to be as functional as possible, must maximize the bioactivity of these compounds while preserving their chemistry. In this context, based on a recent investigation on the metabolic profile of the organs of Calendula arvensis that highlighted that florets are abundant in flavonol glycosides and triterpene saponins, the freeze-drying encapsulation of their alcoholic extract (FE) into maltodextrin (MD) was investigated. FE-MD chemical composition was evaluated using Fourier Transform InfraRed spectroscopy (FTIR), while ultra-high performance liquid chromatography coupled with high-resolution tandem mass spectrometry (UHPLC-HRMS/MS) techniques were employed to unravel FE compound preservation also during in vitro simulated digestion. The establishment of H-bonds between FE compounds and MD hydroxyl groups was in line with FE-MD biocompatibility in Caco-2 cells, while in vitro digestion mostly affected structural integrity and/or diversity. Flavonol compounds underwent deglycosylation and demethylation, while deacylation, beyond oxidation, involved triterpene saponins, which massively preserve their aglycone core.

Antibacterial and Chemical Characterization of Silica-Quercetin-PEG Hybrid Materials Synthesized by Sol-Gel Route.

This paper aims to synthesize, via the sol-gel method, a biomaterial usable in the medical field. Here, the silica-PEG-quercetin system was evaluated in relation to the different concentrations of PEG (0, 6, 12, 24, 50 wt%) and quercetin (0, 5, 10, 15 wt%), respectively. In addition, Fourier Transform-Infrared spectroscopy (FT-IR), Scanning Electron Microscopy (SEM), and Kirby-Bauer analyses were performed. FT-IR was used to evaluate the hybrid formation and the influence of both PEG and Quercetin in the hybrid synthesized materials, SEM was used to evaluate the morphological properties, while the Kirby-Bauer test was used to understand the ability of the materials to inhibit the growth of the assayed bacterial strains (Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis, and Staphylococcus aureus).

Pharmacological Effects of Grifolin: Focusing on Anticancer Mechanisms.

Grifolin is a volatile compound contained in essential oils of several medicinal plants. Several studies show that this substance has been the subject of numerous pharmacological investigations, which have yielded interesting results. Grifolin demonstrated beneficial effects for health via its multiple pharmacological activities. It has anti-microbial properties against bacteria, fungi, and parasites. In addition, grifolin exhibited remarkable anti-cancer effects on different human cancer cells. The anticancer action of this molecule is related to its ability to act at cellular and molecular levels on different checkpoints controlling the signaling pathways of human cancer cell lines. Grifolin can induce apoptosis, cell cycle arrest, autophagy, and senescence in these cells. Despite its major pharmacological properties, grifolin has only been investigated in vitro and in vivo. Therefore, further investigations concerning pharmacodynamic and pharmacokinetic tests are required for any possible pharmaceutical application of this substance. Moreover, toxicological tests and other investigations involving humans as a study model are required to validate the safety and clinical applications of grifolin.

Chemical Compounds of Berry-Derived Polyphenols and Their Effects on Gut Microbiota, Inflammation, and Cancer.

Berry-derived polyphenols are bioactive compounds synthesized and secreted by several berry fruits. These polyphenols feature a diversity of chemical compounds, including phenolic acids and flavonoids. Here, we report the beneficial health effects of berry-derived polyphenols and their therapeutical application on gut-microbiota-related diseases, including inflammation and cancer. Pharmacokinetic investigations have confirmed the absorption, availability, and metabolism of berry-derived polyphenols. In vitro and in vivo tests, as well as clinical trials, showed that berry-derived polyphenols can positively modulate the gut microbiota, inhibiting inflammation and cancer development. Indeed, these compounds inhibit the growth of pathogenic bacteria and also promote beneficial bacteria. Moreover, berry-derived polyphenols exhibit therapeutic effects against different gut-microbiota-related disorders such as inflammation, cancer, and metabolic disorders. Moreover, these polyphenols can manage the inflammation via various mechanisms, in particular the inhibition of the transcriptional factor Nf-κB. Berry-derived polyphenols have also shown remarkable effects on different types of cancer, including colorectal, breast, esophageal, and prostate cancer. Moreover, certain metabolic disorders such as diabetes and atherosclerosis were also managed by berry-derived polyphenols through different mechanisms. These data showed that polyphenols from berries are a promising source of bioactive compounds capable of modulating the intestinal microbiota, and therefore managing cancer and associated metabolic diseases. However, further investigations should be carried out to determine the mechanisms of action of berry-derived polyphenol bioactive compounds to validate their safety and examinate their clinical uses.

Chlorogenic acid activates ERK1/2 and inhibits proliferation of osteosarcoma cells.

Osteosarcoma (OS) is a very aggressive metastatic pediatric and adolescent tumor. Due to its recurrent development of chemotherapy resistance, clinical outcome for OS patients remains poor. Therefore, discovering more effective anticancer agents is needed. Chlorogenic acid (CGA) is a phenolic compound contained in plant-related products that modulates many cellular functions and inhibits cell proliferation in several cancer types. However, few evidence is available in OS. Here, we investigate the effects of CGA in U2OS, Saos-2, and MG-63 OS cells. By multiple approaches, we demonstrate that CGA acts as anticancer molecule affecting the cell cycle and provoking cell growth inhibition mainly by apoptosis induction. We also provide evidence that CGA strongly activates extracellular-signal-regulated kinase1/2 (ERK1/2). Strikingly, ERK1/2 inhibitor PD98059 sensitizes the cells to CGA. Altogether, our data enforce the evidence of the anticancer activity mediated by CGA and provide the rationale for the development of innovative therapeutic strategies in OS cure.

(‒)-Cannabidiolic Acid, a Still Overlooked Bioactive Compound: An Introductory Review and Preliminary Research.

Cannabidiolic acid (CBDA) is the main phytocannabinoid in fiber and seed-oil hemp (Cannabis sativa L.) plants, but its potential health-related capabilities have been masked for years by a greater scientific interest towards its neutral derivative cannabidiol (CBD). This review aims to collect from the literature and critically discuss all the information about this molecule, starting from its biosynthesis, and focusing on its bioactivity, as an anti-inflammatory, anti-emetic, anti-convulsant, and anti-cancerogenic drug. Furthermore, in the awareness that, despite its multiple bioactive effects, currently poor efforts have been made to achieve its reliable purification, herein, we propose a relatively simple, fast, and inexpensive procedure for its recovery from pollen of industrial hemp cultivars. Spectroscopic and spectrometric techniques allowed us to unequivocally identify pure isolated CBDA and to distinguish it from the constitutional isomer tetrahydrocannabinolic acid (THCA-A).

Silica/Polyethylene Glycol Hybrid Materials Prepared by a Sol-Gel Method and Containing Chlorogenic Acid.

Chlorogenic acid (CGA) is a very common dietary polyphenolic compound. CGA is becoming very attractive due to its potential use as preventive and therapeutic agent in many diseases, including cancer. Inorganic/organic hybrid materials are gaining considerable attention in the biomedical field. The sol-gel process provides a useful way to obtain functional organic/inorganic hybrids. The aim of this study was to synthesize silica/polyethylene glycol (PEG) hybrids with different percentages of CGA by sol-gel technique and to investigate their impact on the cancer cell proliferation. Synthesized materials have been chemically characterized through the FTIR spectroscopy and their bioactivity evaluated looking by SEM at their ability to produce a hydroxyapatite layer on their surface upon incubation with simulated body fluid (SBF). Finally, their effects on cell proliferation were studied in cell lines by direct cell number counting, MTT, flow cytometry-based cell-cycle and cell death assays, and immunoblotting experiments. Notably, we found that SiO2/PEG/CGA hybrids exhibit clear antiproliferative effects in different tumor, including breast cancer and osteosarcoma, cell lines in a CGA dependent manner, but not in normal cells. Overall, our results increase the evidence of CGA as a possible anticancer agent and illustrate the potential for clinical applications of sol-gel synthesized SiO2/PEG/CGA materials.

CGRP and Visceral Pain: The Role of Sex Hormones in In Vitro Experiment.

A large number of studies have showed that women reported feeling pain more acutely than men. In support of this hypothesis, many research groups proved that in different animals model of pain the sex hormones regulate the somatic and visceral sensitivity to different noxious stimuli. Therefore, in this study, we went to evaluate if estrogen hormones by regulating the CGRP levels are implicated during the visceral pain transmission. Toward this aim, we have investigated the effect of 17ß-estradiol in regulating the synthesis and release of CGRP, as well as the expression levels of the opioid receptor of type K. In order to gain information about the potential effects of 17ß-estradiol on K-opioid receptor expression and activity, we have cultured F11 cells. Our results revealed that, when F11 cells were short-term exposed (30 min) to 17ß-estradiol, the expression of the opioid K receptor was not significantly modified. We carried out enzyme immunoassay analysis to evaluate the potential effects of short-term exposure to 17-estradiol (30 min) on the release of CGRP in F11 cells. The results obtained showed that 17ß-estradiol at the dose of 100 nM is able to induce the release of CGRP from F11 cells; whereas, a higher dose of 17ß-estradiol (200 nM) did not produce significant effects when compared to control. In conclusion, all these findings suggest that the 17ß-estradiol-regulated release of CGRP could at least in part provide a rational explanation for the difference of gender in the visceral pain sensitivity. J. Cell. Biochem. 118: 510-517, 2017. © 2016 Wiley Periodicals, Inc.

Silica/quercetin sol-gel hybrids as antioxidant dental implant materials.

The development of biomaterials with intrinsic antioxidant properties could represent a valuable strategy for preventing the onset of peri-implant diseases. In this context, quercetin, a naturally occurring flavonoid, has been entrapped at different weight percentages in a silica-based inorganic material by a sol-gel route. The establishment of hydrogen bond interactions between the flavonol and the solid matrix was ascertained by Fourier transform infrared spectroscopy. This technique also evidenced changes in the stretching frequencies of the quercetin dienonic moiety, suggesting that the formation of a secondary product occurs. Scanning electron microscopy was applied to detect the morphology of the synthesized materials. Their bioactivity was shown by the formation of a hydroxyapatite layer on sample surface soaked in a fluid that simulates the composition of human blood plasma. When the potential release of flavonol was determined by liquid chromatography coupled with ultraviolet and electrospray ionization tandem mass spectrometry techniques, the eluates displayed a retention time that was 0.5 min less than quercetin. Collision-activated dissociation mass spectrometry and untraviolet-visible spectroscopy were in accordance with the release of a quercetin derivative. The antiradical properties of the investigated systems were evaluated by DPPH and ABTS methods, whereas the 2,7-dichlorofluorescein diacetate assay highlighted their ability to inhibit the H2O2-induced intracellular production of reactive oxygen species in NIH-3T3 mouse fibroblast cells. Data obtained, along with data gathered from the MTT cytotoxicity test, revealed that the materials that entrapped the highest amount of quercetin showed notable antioxidant effectiveness.

Quantitative calculation of the role of the Na(+),K(+)-ATPase in thermogenesis.

The Na(+),K(+)-ATPase is accepted as an important source of heat generation (thermogenesis) in animals. Based on information gained on the kinetics of the enzyme's partial reactions we consider via computer simulation whether modifications to the function of the combined Na(+),K(+)-ATPase/plasma membrane complex system could lead to an increased body temperature, either through the course of evolution or during an individual's lifespan. The enzyme's kinetics must be considered because it is the rate of heat generation which determines body temperature, not simply the amount of heat per enzymatic cycle. The results obtained indicate that a decrease in thermodynamic efficiency of the Na(+),K(+)-ATPase, which could come about by Na(+) substituting for K(+) on the enzyme's extracellular face, could not account for increased thermogenesis. The only feasible mechanisms are an increase in the enzyme's expression level or an increase in its ion pumping activity. The major source of Na(+),K(+)-ATPase-related thermogenesis (72% of heat production) is found to derive from passive Na(+) diffusion into the cell, which counterbalances outward Na(+) pumping to maintain a constant Na(+) concentration gradient across the membrane. A simultaneous increase in both Na(+),K(+)-ATPase activity and the membrane's passive Na(+) permeability could promote a higher body temperature.

Alkali Activation of Metakaolin and Wollastonite: Reducing Sodium Hydroxide Use and Enhancing Gel Formation through Carbonation.

Alkali activated materials (AAMs) offer significant advantages over traditional materials like Portland cement, but require the use of strong alkaline solutions, which can have negative environmental impacts. This study investigates the synthesis of AAMs using metakaolin and wollastonite, aiming to reduce environmental impact by eliminating sodium silicate and using only sodium hydroxide as an activator. The hypothesis is that wollastonite can provide the necessary silicon for the reaction, with calcium from wollastonite potentially balancing the negative charges usually countered by sodium in the alkaline solution. This study compares raw and carbonated wollastonite (AAM-W and AAM-CW) systems, with raw materials carefully characterized and binding networks analyzed using TGA, FT-IR, and XRD. The results show that while wollastonite can reduce the amount of sodium hydroxide needed, this reduction cannot exceed 50%, as higher substitution levels lead to an insufficiently alkaline environment for the reactions. The carbonation of wollastonite enhances the availability of silicon and calcium, promoting the formation of both N-A-S-H and C-A-S-H gels.

Metakaolin-Based Geopolymers Filled with Industrial Wastes: Improvement of Physicochemical Properties through Sustainable Waste Recycling.

The increasing global demand for cement significantly impacts greenhouse gas emissions and resource consumption, necessitating sustainable alternatives. This study investigates fresh geopolymer (GP) pastes incorporating 20 wt.% of five industrial wastes-suction dust, red mud from alumina production, electro-filter dust, and extraction sludges from food supplement production and from partially stabilized industrial waste-as potential replacements for traditional cement. Consistent synthesis methods are used to prepare the geopolymers, which are characterized for their physicochemical, mechanical, and biological properties. Ionic conductivity and pH measurements together with integrity tests, thermogravimetry analysis (TGA), and leaching analysis are used to confirm the stability of the synthesized geopolymers. Fourier-transform Infrared (FT-IR) spectroscopy is used to follow geopolymerization occurrences. Results for ionic conductivity, pH, and integrity revealed that the synthesized GPs were macroscopically stable. TGA revealed that the main mass losses were ascribable to water dehydration and to water entrapped in the geopolymer networks. Only the GP filled with the powder of the red mud coming from alumina production experienced a mass loss of 23% due to a partial waste degradation. FT-IR showed a red shift in the main Si-O-(Si or Al) absorption band, indicating successful geopolymer network formations. Additionally, most of the GPs filled with the wastes exhibited higher compressive strength (37.8-58.5 MPa) compared to the control (22 MPa). Only the GP filled with the partially stabilized industrial waste had a lower mechanical strength as its structure was highly porous because of gas formation during geopolymerization reactions. Despite the high compressive strength (58.5 MPa) of the GP filled with suction dust waste, the concentration of Sb leached was 25 ppm, which limits its use. Eventually, all samples also demonstrated effective antimicrobial activity against Escherichia coli and Staphylococcus aureus due to the alkaline environment and the presence of metal cations able to react with the bacterial membranes. The findings revealed the possibility of recycling these wastes within several application fields.

Synthesis and characterizations of melamine-based epoxy resins.

A new, easy and cost-effective synthetic procedure for the preparation of thermosetting melamine-based epoxy resins is reported. By this innovative synthetic method, different kinds of resins can be obtained just by mixing the reagents in the presence of a catalyst without solvent and with mild curing conditions. Two types of resins were synthesized using melamine and a glycidyl derivative (resins I) or by adding a silane derivative (resin II). The resins were characterized by means of chemical-physical and thermal techniques. Experimental results show that all the prepared resins have a good thermal stability, but differ for their mechanical properties: resin I exhibits remarkable stiffness with a storage modulus value up to 830 MPa at room temperature, while lower storage moduli were found for resin II, indicating that the presence of silane groups could enhance the flexibility of these materials. The resins show a pot life higher than 30 min, which makes these resins good candidates for practical applications. The functionalization with silane terminations can be exploited in the formulation of hybrid organic-inorganic composite materials.

Mosses on Geopolymers: Preliminary Durability Study and Chemical Characterization of Metakaolin-Based Geopolymers Filled with Wood Ash.

Burning wood is estimated to produce about 6-10% of ash. Despite the possibility of recycling wood ash (WA), approximately 70% of the wood ash generated is landfilled, causing costs as well as environmental pollution. This study aims to recycle WA in an alternative way by inserting it as filler in geopolymeric materials. Here, metakaolin, NaOH, sodium silicate, and WA are used to realize geopolymers. Geopolymers without and with 10, 20 and 30% of WA are synthesized and characterized after 7, 14, 28 and 56 days. The article's study methods are related to geopolymers' chemical, biological and mechanical properties. The geopolymers synthesized are compact and solid. The pH and conductivity tests and the integrity and weight loss tests have demonstrated the stability of materials. The FT-IR study and boiling water test have confirmed the successful geopolymerization in all samples. The antibacterial analysis, the moss growing test and the compressive strength test have given a first idea about the durability of the materials synthesized. Furthermore, the compressive strength test result has allowed the comparison from the literature of the specimens obtained with the Portland cement (PC). The results obtained bode well for the future of this material.

Entrapment of Acridine Orange in Metakaolin-Based Geopolymer: A Feasibility Study.

Few studies have explored the immobilization of organic macromolecules within the geopolymer matrix, and some have found their chemical instability in the highly alkaline geopolymerization media. The present work reports on the feasibility of encapsulating the potentially toxic acridine orange (AO) dye in a metakaolin based geopolymer while maintaining its structural integrity. The proper structural, chemical, and mechanical stabilities of the final products were ascertained using Fourier-transform infrared (FT-IR) spectroscopy, scanning electron microscopy (SEM), X-ray diffraction (XRD), thermogravimetric (TGA/DTG), and mechanical analyses, whereas the dye integrity and its stability inside the geopolymer were investigated by the UV-Vis analysis. In addition, the antimicrobial activity was investigated. The FT-IR and XRD analyses confirmed the geopolymerization occurrence, whereas the TGA/DTG and mechanical (compressive and flexural) strength revealed that the addition of 0.31% (AO mg/ sodium silicate L) of AO to the fresh paste did not affect the thermal stability and the mechanical properties (above 6 MPa in flexural strength and above 20 MPa for compressive strength) of the hardened product. UV-Vis spectroscopy revealed that the dye did not undergo chemical degradation nor was it released from the geopolymer matrix. The results reported herein provide a useful approach for the safe removal of toxic macromolecules by means of encapsulation within the geopolymer matrix.

Thermal and Electrical Characterization of Polyester Resins Suitable for Electric Motor Insulation.

This paper undertakes the thermal and electrical characterization of three commercial unsaturated polyester imide resins (UPIR) to identify which among them could better perform the insulation function of electric motors (high-power induction motors fed by pulse-wide modulation (PWM) inverters). The process foreseen for the motor insulation using these resins is Vacuum Pressure Impregnation (VPI). The resin formulations were specially selected because they are one-component systems; hence, before the VPI process, they do not require mixing steps with external hardeners to activate the curing process. Furthermore, they are characterized by low viscosity and a thermal class higher than 180 °C and are Volatile Organic Compound (VOC)-free. Thermal investigations using Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC) techniques prove their excellent thermal resistance up to 320 °C. Moreover, impedance spectroscopy in the frequency range of 100 Hz-1 MHz was analyzed to compare the electromagnetic performance of the considered formulations. They manifest an electrical conductivity starting from 10-10 S/m, a relative permittivity around 3, and a loss tangent value lower than 0.02, which appears almost stable in the analyzed frequency range. These values confirm their usefulness as impregnating resins in secondary insulation material applications.

Antibacterial and Photocatalytic Activities of LDH-Based Sorbents of Different Compositions.

Layered double hydroxides (LDHs) play a fundamental role in the processes for the abatement of pollutants in water, with reference to heavy metal decontamination. The research on the topic is multiobjective target oriented, aiming at combining environmental remediation with the possibility of reusing a sorbent as many times as possible, turning it into a renewable resource. In this study, the antibacterial and catalytic properties of a ZnAl-SO4 LDH and its resulting product after being subjected to a Cr(VI) remediation process are compared. Both solid substrates have also been tested after undergoing a thermal annealing process. The sorbent (previously described and tested for remediation) has been investigated for its antibacterial activity in view of further surgery and drug delivery applications. Finally, its photocatalytic properties have been experimentally tested in the degradation of a model pollutant, i.e., Methyl Orange (MO), under solar-simulated light. Identifying the best recycling strategy for these materials requires an accurate knowledge of their physicochemical properties. The results show that both the antimicrobial activity and the photocatalytic performance may considerably improve after thermal annealing.

Role of MWCNTs Loading in Designing Self-Sensing and Self-Heating Structural Elements.

This work proposes nanocomposites with carbon nanotubes characterized by self-sensing and self-heating properties. Recently, a growing interest in these two properties has been found in many industrial sectors, especially in the aerospace and automotive fields. While the self-sensing function allows diagnosing the presence of micro-damage in the material thanks to the detection of residual resistance, the self-heating function is exploited to properly tune the heating performance in terms of the heating rate and final temperature values. An electrical percolation value of around 0.5% by weight of carbon nanotubes was found by electrical characterization. The AC conductivity of the nanocomposites, in the range of 100 Hz to 1 MHz, evidences that beyond a CNTs amount of 0.5% wt/wt, they are characterized by a purely resistive behavior. The self-sensing analysis displayed a gauge factor value of 4.1. The solid thermal stability up to 300 °C makes the material suitable as a heating element at high temperatures. SEM investigations and temperature maps evidence a good dispersion of the conductive filler in the epoxy matrix and, consequently, good isotropy in heat distribution. As regards the trend of electrical resistance by varying the temperature, the electro-thermal investigation has shown the presence of both Positive Temperature Coefficient (PTC) and Negative Temperature Coefficient (NTC) behaviors with a predominance of NTC as soon as the temperature becomes closer to the glass transition temperature of the epoxy resin.