Inhibition Capability Research Articles

Corrosion prevention of mild steel in acidic medium by 2-Pyrrolidin-1-yl-1,3-thiazole-5-carboxylic acid: Theoretical and experimental approach

The inhibition efficiency of 2-Pyrrolidin-1-yl-1,3-thiazole-5-carboxylic acid (PTCA) against mild steel (MS) corrosion was investigated in acidic solution by using quantum chemical calculations based on Density Functional Theory (DFT) method and electrochemical measurements. The electrochemical impedance spectroscopy (EIS), potentiodynamic, potential zero charge (pzc) analysis and electrochemical noise (EN) measurements at various concentrations (from 0.1 to 10 mM) and immersion times were utilized in experimental part. The surface analysis was achieved scanning electron microscope (SEM) and contact angle measurements in the absence and presence of 10 mM PTCA. According to DFT results, PTCA exhibited 3.737 eV band gap and 8.130 Debye dipole moment which were a signal of potentially convenient corrosion inhibitor properties. PTCA has a remarkable corrosion inhibition capability to mild steel, which inhibited both anodic and cathodic corrosion rates, relying on it's physically adsorption on the metal solution interface and protection ability was increased with increasing PTCA concentration. The obtained adsorption equilibrium constant was 11.11 × 103 M-1 and calculated standard free energy of adsorption was −33.03 kJ mol−1. The determined activation energy values were 55.58 kJ mol−1 and 96.86 kJ mol−1 in 0.5 M HCl in the absence and presence of 10 mM PTCA, respectively. PTCA demonstrated a strong inhibition efficiency of 98.3%, after 168 h immersion, according to the EIS results. As a consequently, we recommend that PTCA is a convenient inhibitor in 0.1 M HCl for mild steel protection against corrosion.

Experimental and theoretical evidence for effective corrosion mitigation in mild steel using novel Garcinia gummi-gutta leaf extract

PurposeSurface pretreatment of iron and its alloys to remove stains and inorganic contaminants on the metal surface undergoes dissolution by virtue of the strong acidic media thereby increasing its susceptibility to corrosion. The purpose of this study is to explore the corrosion mitigation prospects of green corrosion inhibitors on mild steel surface.Design/methodology/approachCorrosion inhibition performance of Garcinia gummi-gutta leaf extract (GGLE) was explored against mild steel in 1 M HCl solution using the weight-loss method, electrochemical impedance spectroscopy (EIS) and potentiodynamic polarization (PDP) techniques. Surface characterization was carried out to study the mechanism of inhibitor action.FindingsThe concentration of GGLE varied from 100 to 6,000 ppm and the result indicates that corrosion inhibition efficiency was amplified by raising the inhibitor concentration. The maximum inhibition efficiency was 82.2% at 6,000 ppm concentration. EIS results show the development of a protective layer of inhibitor molecule over the metal surface and PDP demonstrates that the inhibitor operates as a mixed-type inhibitor. Scanning electron microscopy and atomic force microscopy were executed to assess the surface morphology and roughness, respectively.Originality/valueTo the best of the authors’ knowledge, so far, no studies have been reported on the corrosion inhibition performance of GGLE which is rich in many bioactive components especially hydroxyl citric acid. This work encompasses the corrosion inhibition capability of GGLE against mild steel in an acidic medium.

Biocontrol of Phytophthora xcambivora on Castanea sativa: Selection of Local Trichoderma spp. Isolates for the Management of Ink Disease

Ink disease is a devastating disease of chestnut (Castanea sativa) worldwide, caused by Phytophthora species. The only management measures of this disease are chemical and agronomic interventions. This work focuses on the evaluation of the in vitro antagonistic capacity of 20 isolates of Trichoderma spp. selected in a diseased chestnut orchard in Tuscan Apennines (San Godenzo, Italy) for the biocontrol of Phytophthora xcambivora. Each Trichoderma isolate was tested to investigate pathogen inhibition capability by antagonism in dual cultures and antibiosis by secondary metabolites production (diffusible and Volatile Organic Compounds). The six most performing isolates of Trichoderma spp. were further assessed for their aptitude to synthesize chitinase, glucanase and cellulase, and to act as mycoparasite. All six selected isolates displayed the capability to control the pathogen in vitro by synergistically coupling antibiosis and mycoparasitism at different levels regardless of the species they belong to, but rather, in relation to specific features of the single genotypes. In particular, T. hamatum SG18 and T. koningiopsis SG6 displayed the most promising results in pathogen inhibition, thus further investigations are needed to confirm their in vivo efficacy.

Proposal and analysis of carbon nanotube based differential multibit through glass vias

The paper proposes glass as a potential material to advanced interposers for high-density three-dimensional (3-D) integration. On the basis of multi-bit through glass via (TGV) which comprises of TGVs filled with multi-walled carbon nanotubes (MWCNTs)/single-walled CNTs (SWCNTs) and separate conducting pads, the design of novel differential multibit-CNT TGVs (DM-TGCVs) is proposed and studied. The effective complex conductivity is formulated for accurate characterization of the high frequency behaviour of DM-TGCVs. A distributed π-type transmission line model for the modeling of DM-TGCVs is established and the frequency dependent impedance is extracted through partial element equivalent circuit (PEEC) technique. The influence of CNT filling ratio, probability of metallic fraction of CNTs, and CNTs as filler material on the resistance and inductance is also studied. Through the proposed analytical model, signal insertion loss of DM-TGCVs in the differential- and common-mode configurations is exhaustively investigated. Due to ultra-high electrical resistivity of glass (1012 − 1016 Ω-cm), signal loss in DM-TGCVs is determined by the conductor loss, which results in an improved electrical performance under differential-mode signaling than common-mode signaling approach. This phenomenon is unique to TGVs and totally different from the conventional through silicon vias, where signal loss is dominated by the dielectric loss at high frequencies. The magnitude of insertion loss (S21) for the proposed DM-TGCVs under differential-mode configuration w.r.t. differential TSVs (D-TSVs) and differential multibit CNT TSVs (DMC-TSVs) improves up to ∼ 44% and ∼22%, respectively for varying via radius. The DM-TGCVs also exhibit superior crosstalk inhibition capability and provide up to ∼89% and ∼24% improvements in crosstalk than D-TSVs and DMC-TSVs at f = 20 GHz. More importantly, DM-TGCVs provide one-third saving of the chip area compared to D-TSVs.

Mononuclear Tricoordinate Copper(I) and Silver(I) Halide Complexes of a Sterically Bulky Thiourea Ligand and a Computational Insight of Their Interaction with Human Insulin.

Reaction of two equivalents of the bulky 1,3-bis(2,6-diethylphenyl)thiourea ligand (L) with MX (being M = Cu+, Ag+; and X = Cl−, Br−, I−) in acetonitrile afforded neutral complexes of the type [MXL2] [CuClL2].2CH3CN (1a); [CuBrL2].2CH3CN (1b); [CuIL2] (1c): [AgClL2] (2a); [AgBrL2] (2b) and [AgIL2] (2c). The two aromatic groups in free ligand were found to be trans with respect to the thiourea unit, which was a reason to link the ligand molecules via intermolecular hydrogen bonding. Intramolecular hydrogen bonding was observed in all metal complexes. The copper complexes 1a and 1b are acetonitrile solvated and show not only intra- but also intermolecular hydrogen bonding between the coordinated thiourea and the solvated acetonitrile molecules. Silver complexes reported here are the first examples of structurally characterized tricoordinated thiourea-stabilized monomeric silver(I) halides. Molecular docking studies were carried out to analyze the binding modes of the metal complexes inside the active site of the human insulin (HI) protein. Analysis of the docked conformations revealed that the electrostatic and aromatic interactions of the protein N-terminal residues (i.e., Phe and His) may assist in anchoring and stabilizing the metal complexes inside the active site. According to the results of docking studies, the silver complexes exhibited the strongest inhibitory capability against the HI protein, which possesses a deactivating group, directly bonded to silver. All compounds were fully characterized by elemental analysis, NMR spectroscopy, and molecular structures of the ligand, and five out of six metal complexes were also confirmed by single-crystal X-ray diffraction.

Characterization of Inhibitory Capability on Hyperpolarization-Activated Cation Current Caused by Lutein (β,ε-Carotene-3,3'-Diol), a Dietary Xanthophyll Carotenoid.

Lutein (β,ε-carotene-3,3′-diol), a xanthophyll carotenoid, is found in high concentrations in the macula of the human retina. It has been recognized to exert potential effectiveness in antioxidative and anti-inflammatory properties. However, whether and how its modifications on varying types of plasmalemmal ionic currents occur in electrically excitable cells remain incompletely answered. The current hypothesis is that lutein produces any direct adjustments on ionic currents (e.g., hyperpolarization-activated cation current, Ih [or funny current, If]). In the present study, GH3-cell exposure to lutein resulted in a time-, state- and concentration-dependent reduction in Ih amplitude with an IC50 value of 4.1 μM. There was a hyperpolarizing shift along the voltage axis in the steady-state activation curve of Ih in the presence of this compound, despite being void of changes in the gating charge of the curve. Under continued exposure to lutein (3 μM), further addition of oxaliplatin (10 μM) or ivabradine (3 μM) could be effective at either reversing or further decreasing lutein-induced suppression of hyperpolarization-evoked Ih, respectively. The voltage-dependent anti-clockwise hysteresis of Ih responding to long-lasting inverted isosceles-triangular ramp concentration-dependently became diminished by adding this compound. However, the addition of 10 μM lutein caused a mild but significant suppression in the amplitude of erg-mediated or A-type K+ currents. Under current-clamp potential recordings, the sag potential evoked by long-lasting hyperpolarizing current stimulus was reduced under cell exposure to lutein. Altogether, findings from the current observations enabled us to reflect that during cell exposure to lutein used at pharmacologically achievable concentrations, lutein-perturbed inhibition of Ih would be an ionic mechanism underlying its changes in membrane excitability.

Antibacterial and Antifungal Potential of Berberine Isolated from Stem of Berberis aristata DC

Background: This research was conducted to evaluate berberine as an isolated bioactive compound from Berberis aristata DC for its activity against microbial infections. To examine the antibacterial activity using ethanol hot extraction procedure to verify the medicinal use of B. aristata DC in infection control and qualitatively estimate the phytochemical composition of the plant stem extract. Objective: To isolate a bioactive phytoconstituent from B. aristata DC for its antimicrobial efficacy in managing human infections. Methods: The antibacterial activity of berberine derived from the stem extract was examined against gram-ve and +ve multi-drug resistance examined by diffusion method using an agar-well isolated from the stem extract was examine by the agar-well using a 96-well microtitre plate. The minimum inhibitory concentration was calculated against each bacterium using both the microtitre plate technique and broth dilution of berberine Results: The appearance of alkaloids in the methanol extract of the stems was demonstrated. The pathogenic bacteria used were Shigella sp., Escherichia coli, including some more standard bacterial strains. These multi-drug resistant (MDR) bacteria were reported with bacterial inhibition capability when methanol was used as a solvent. In addition, the effect of berberine against Shigella sp. was the maximum inhibition zone size (1.25 cm). Ciprofloxacin 30 μg/disc served as the reference/ +ve control, whereas 10% dimethyl sulfoxide (DMSO) was the -ve control. These chosen bacteria were reported minimum inhibitory concentration (MIC) of berberine values ranging from 200 to 1000 μg/mL. Conclusions: B. aristata DC stem extract berberine showed antibacterial properties using hot methanol against all bacteria. In alternative and complementary medicine, berberine is used to treat diseases caused by many strain of bacteria.

Novel Therapeutic Strategy for Bacteria‐Contaminated Bone Defects: Reconstruction with Multi‐Biofunctional GO/Cu‐Incorporated 3D Scaffolds

AbstractLarge‐scale bone defects caused by traumatic injury or tumor resection, are accompanied by relatively high bacterial infection rates. Relevant clinical therapy encounters challenges of infection recurrence, poor vascularization, and bone destruction. Engineered substitutes endowed with multiple functions of bacterial eradication, osteoconductivity, and angiogenesis are urgently needed to address these challenges. Herein, graphene oxide/copper (GO/Cu) nanocomposite‐decorated polylactide‐co‐glycolide (PLGA)/β‐tricalcium phosphate (TCP) (P/T/GO/Cu) scaffolds are fabricated using 3D printing technology. A comprehensive evaluation of material characteristics and biological activities of these scaffolds is conducted and compared. This novel bone substitute has unique surface characteristics, and the incorporation of GO/Cu nanocomposites into the scaffolds exhibits improved antimicrobial and osteogenic potential and displays acceptable cytocompatibility. A subcutaneous implantation model in rats confirms the effective inhibition of abscess formation and inflammatory reactions, satisfactory neovascularization and tissue integration, and good biosafety of the implanted P/T/GO/Cu scaffolds. Eventually, a bacteria‐contaminated bone defect model is established in rabbits and significantly better new cancellous bone formation featuring collagen or osteoid deposition is clearly found in the defect regions implanted with P/T/GO/Cu scaffolds. Thus, this novel bone substitute with excellent bacterial inhibition, osteogenesis, and angiogenesis capabilities represents a promising strategy to satisfy the multiple demands for the repair of bacteria‐contaminated bone defects.

Ageing Effects on a Softened Bitumen by the Addition of DSA (Dodecenyl Succinic Anhydride).

The softening of aged bitumen is necessary for a successful asphalt rejuvenation in road recycling operations. Thus, this study proposes a novel and successful approach by using Dodecenyl Succinic Anhydride (DSA), a reactive surfactant with a polar head capable of reacting with some polar compounds of bitumen. On this basis, this paper analyses the softening potential and ageing inhibition capability of the addition of 3 wt.% DSA before and after the application of standard laboratory ageing methods (rolling thin film oven, RTFOT and pressure aging vessel (PAV) tests). To that end, different modified bitumens were evaluated by analysing the linear viscoelastic behaviour, viscous flow properties, thin layer chromatography, Fourier transform infrared spectroscopy (FTIR), contact angle measurements and compactibility tests. The results obtained for DSA show its greater potential to soften a model bitumen, when compared to a diluent oil, through physico-chemical processes that bring about a lowering in the polarity along with the alteration of its colloidal stability. Even though ageing processes in bitumen negatively affect its softening capacity, the developed structures still retain the ability to partially compensate for the adverse hardening effects. Furthermore, DSA addition greatly enhances the binder’s wettability on a siliceous-type aggregate and favours asphalt compaction.

Green corrosion inhibitors for drilling operation: New derivatives of fatty acid-based inhibitors in drilling fluids for 1018 carbon steel in CO2-saturated KCl environments

Corrosion of the oilfield drilling equipment can considerably affect its drilling effectiveness, service life, and operation safety as well as the surrounding environment. In this study, inhibition effects of three eco-friendly fatty acid-based inhibitors, Polyethylene glycol-2 oleamide (PEG-2 oleamide), Glycerol myristate (GM) and Glycerol linoleate (GL), in emulsion-based drilling fluids against corrosion of carbon steel were investigated. The inhibitors were characterized by Fourier transform infrared (FT-IR) spectroscopy and CHNS–O analysis. Effects of the inhibitors on corrosion of the steel were evaluated by means of electrochemical measurements of open circuit potential (OCP) and potentiodynamic polarization as well as electrochemical impedance spectroscopy (EIS). Scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS) and X-ray photoelectron spectrophotometer (XPS) were employed to study morphology and the chemical composition of surface layer adsorbed on the metal surface. The study demonstrates remarkable performance of the green inhibitors especially PEG-2 oleamide, which shows an inhibition efficiency of 99.7%. The high inhibition capability results from a formed protective layer that blocks corrosive ions to attack the steel surface. First-principles calculations and molecular dynamics simulation were performed, which reveal chemical bonding between the inhibitors and iron surface, and stronger intermolecular attraction in the adsorbed film of, e.g., PEG-2 oleamide, which renders the PEG-2 oleamide–induced film particularly durable.

Abstract 1411: Utilizing 7-azaindoles, 2,7-diazaindoles, and 1H-pyrazoles as core structures for novel cancer chemosensitizers

Abstract A quickly developing chemoresistance is the hallmark of the standard treatment failure and the poor patient prognosis. Resistance is often connected to the overexpression of the specific kinases that are involved in DNA damage response. Contrary, their inhibition could lead to augmented cancer cell sensitization to conventional approach. Among them, ataxia-telangiectasia and Rad3-related kinase (ATR), the major replication stress responder, is one of the most attractive target. Within this study our aim was to find novel chemosensitizing agents for the cancer treatment employment. Inspired by clinical candidates targeting ATR, we designed and prepared large library of 40 novel compounds utilizing 7-azaindoles, 2,7-diazaindoles, and 1H-pyrazoles as core structures. Initially, our presumption to have ATR inhibitors were confirmed by molecular dynamic study. All the compounds alone or in combination with cisplatin were screened against panel of nine cancer cell lines and one healthy cell line. The results were compared with well-known ATR inhibitor VE-821. Several compounds significantly inhibit the cell viability and some were able to potentiate cisplatin effect. From structure-activity relationship point of view, 7-azaindoles were the most cytotoxic compounds when substituted in position 3 and 5. Contrary, 2,7-diazaindoles expressed the most potent chemosensitizing capabilities. 1H-Pyrazoles were the least potent compounds within this screen. Interestingly, the status of tumor suppressor protein p53 (defect in G1) did not significantly influence chemosensitization or cytotoxic effect. Three highlighted compounds 3, 22, and 29 were selected for Broad oncology panel screening containing 104 kinases which could be potentially targeted. Only compound 29, the 2,7-diazaindole representative, showed ATR inhibitory efficacy with the IC50 around 10 µM. In contrast, the compound 22, 7-azaindole and the most cytotoxic one, expressed the multi-kinase activity with the substantial inhibitory capability against vascular endothelial growth factor receptor 3 protein (VEGFR-3). VEGFR-3 is also very attractive anticancer target with several inhibitors already approved. Finally, several compounds showed chemosensitizing potencies for temozolomide against secondary astrocytoma cell line. In overall, we showed that both, 7-azaindoles, and 2,7-diazaindoles, could be effectively utilized as novel anticancer agents. Whereas 2,7-diazaindoles could become efficient ATR inhibitors, 7-azaindoles have potential as antiangiogenics, VEGFR-3 inhibitors. Besides, both structures could be used for a glioblastoma treatment as temozolomide sensitizers. More research is currently ongoing to fully exploit potential of these compounds. Citation Format: Lukas Gorecki, Darina Muthna, Sara Merdita, Martin Andrs, Tomas Kucera, Tereza Kobrlova, Martina Rezacova, Jan Korabecny. Utilizing 7-azaindoles, 2,7-diazaindoles, and 1H-pyrazoles as core structures for novel cancer chemosensitizers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1411.

Abstract 3195: Tumor inhibitory CAFs in CNS metastases

Abstract The 2-year survival rate for patients with central nervous system (CNS) metastases (CMs) remains below 2%. With the aim to define new therapeutic options, researchers have investigated how interactions between CM cells and the surrounding tumor microenvironment (TME) support metastatic progression. As an important component of the TME, cancer associated fibroblasts (CAFs) have largely been reported as tumor supportive. But new evidence for the high heterogeneity of the CAF compartment, including in vivo studies from our lab, showed that certain CAF subpopulations could exhibit tumor inhibitory capabilities. Interestingly, recent reports revealed that CAFs showing high expression of Immunoglobulin Superfamily containing Leucin Rich Repeat (ISLR) could show tumor inhibitory capabilities in both pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC). Yet, despite the invaluable clinical potential of tumor inhibitory CAFs, the CAF compartment in the TME of CMs is still largely under described. Using CM patient tissue and CM patient-derived cell lines established in our lab, we performed single cell RNA sequencing (scRNA-seq) to define CAF subpopulations present in the TME of CMs. We identified distinct clusters characterized by differential expression of ISLR and tumor supportive CAF marker Actin Alpha 2, Smooth Muscle (ACTA2/α-SMA). CAF subpopulations were thus defined as follows: ISLRhigh/α-SMAlow, ISLRlow/α-SMAhigh, ISLRlow/α-SMAlow. Altogether, we hypothesized that ISLRhigh/α-SMAlow CAFs could act to restrain tumor progression in the TME of CMs, as opposed to potentially tumor supportive ISLRlow/α-SMAhighCAFs. ISLRhigh and ISLRlow CAFs were obtained through fluorescence-activated cell sorting (FACS) performed on one of our patient-derived CAF cell lines represented in all defined scRNA-seq clusters. ISLRhigh CAFs were validated to express lower levels of α-SMA (ISLRhigh/α-SMAlow CAFs) compared to ISLRlow cells (ISLRlow/α-SMAhigh CAFs). This mutually exclusive expression of ISLR and α-SMA in different CAF subpopulations is in accordance with recent data in PDAC and CRC and could indicate common underlying mechanisms driving the phenotype of each subpopulation. Further in vitro and in vivo experiments are currently underway in our lab to determine the tumor supportive capabilities of both ISLRhigh/α-SMAlow and ISLRlow/α-SMAhigh CAFs. Ultimately, we expect the current study to unravel the diverse and dynamic nature of CAFs in the TME of CMs, which is still largely unknown. Citation Format: Thomas Simon, David Buckley, Bodour Salhia. Tumor inhibitory CAFs in CNS metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3195.

Multi-strain probiotics show increased protection of intestinal epithelial cells against pathogens in rainbow trout (Oncorhynchus mykiss)

The use of antibiotics to treat bacterial infections in aquaculture facilities adversely affects fish and environmental health, motivating the search for alternative products such as probiotics. The present study investigated the immune modulatory effects of inoculating the intestinal epithelial cells of rainbow trout (Oncorhynchus mykiss) with the probiotic bacteria Enterococcus faecium, Pediococcus acidilactici, Lactobacillus reuteri, and Bacillus subtilis alone (single-strains) or as mixtures, which either include or exclude B. subtilis (PWBsubtilis or PWOBsubtilis, respectively). To this end, isolated intestinal epithelial cells were either incubated without probiotics or with the single- or multi-strain probiotics and then challenged with common pathogens in aquaculture. The adhesion of probiotic and pathogenic bacteria to the intestinal cells was examined by flow cytometry and confocal microscopy and the relative expression of pro- and anti-inflammatory cytokine genes was assessed through quantitative real-time PCR. Although the highest inhibition of pathogen adhesion was observed for L. reuteri alone (88%), PWOBsubtilis and PWBsubtilis inhibited 77% and 71% of pathogen attachment, respectively. Single- and multi-strain probiotics were able to elicit an immune response by activation of both pro-inflammatory and anti-inflammatory cytokines production in rainbow trout intestinal epithelial cells. This expression was generally highest for multi-strain probiotics, particularly for PWBsubtilis. The tested probiotics present different modes of action, considering their inhibition capability and immunomodulatory effects. Hence the use of multi-strain products may promote a wider range of synergies on pathogens invasion and inhibition, and immunomodulatory effects that can represent an advantage to disease outbreaks prevention in rainbow trout production.

White matter microstructure associated with the range of attentional and impulsive performance in school-aged children

IntroductionInhibition capabilities have been shown to be a strong predictor of social and educational life outcomes (Mischel & Ebbesen, 1970; Shoda et al., 1990). Inhibition capabilities have an enormous impact on attention and impulsivity (Bari & Robbins, 2013). These two executive functions are associated with numerous psychiatric disorders but are not well understood in terms of white matter (WM) connectivity (Puiu et al., 2018). Novel techniques and statistical approaches in neuroimaging bring us closer to a biologically sustained model.ObjectivesThis research aims to: 1) identify WM connections associated with attention/impulsivity performance and 2) characterize the differences in WM microstructure associated with the variation of the performance.Methods 157 children (GESTE cohort, 8-12 years, 27 Dx ADHD, 2 Dx ASD) with b=1500mm2/s, 2mm isotropic dMRI acquisitions were included. Tractography was performed with TractoFlow pipeline (Theaud et al., 2020). Dimensionality reduction of diffusion metrics yielded two components : microstructural complexity (DTI Metrics, AFD & NuFo) and axonal density (AFD_fixel) (Chamberland et al., 2019). Attention/impulsivity were evaluated with the CPT3. Multivariate linear regression was performed in python.ResultsLower microstructural complexity was associated with poorer attentional performance on regions of the parietal lobe to the occipital gyrus (P-O, p=0.044, R2=0.14, Figure 1.) and the Broadman’s area 8 to area 6 (SF8-SF6, p=0.002, R2=0.12, Figure 1.). Lower axonal density was associated with a less impulsive pattern on SF8-SF6 (p=0.001, R2=0.13, Figure 1.). Results remained significant when removing children with an ADHD or ASD diagnosis.ConclusionsWe identified underlying difference in WM microstructure that may be associated with the variation in attention/impulsivity performance in school-aged children.DisclosureNo significant relationships.

Precision medicine: Novel PI3K inhibitor as cancer treatment.

e15093 Background: Phosphoinositide 3-kinase (PI3K) is an attractive anti-cancer drug target due to its promotion of cell growth and proliferation; however, available pan-PI3K inhibitors currently lack specificity, leading to excessive drug toxicity and adverse effects. Selectide-18 is a novel PI3K inhibitor that targets PI3K’s catalytic subunit p110β, resulting in reduced viability of cancer cells. The p110β subunit is the most prominent PI3K subunit in many chemoresistant tumors. Previous research has revealed a unique 18-residue long motif within the C2 domain of p110β. This motif is not found in other catalytic subunits (p110α, p110δ, or p110γ), making it a promising drug target. Selectide-18 is a memetic peptide drug modeled after this motif and has been shown to effectively inhibit p110β binding without affecting other isoforms, separating it from currently available pan-PI3K inhibitors. While Selectide-18 has been successful in inhibiting PI3K in previous studies, it has poor cell permeability due to its large size. Previous findings have revealed functional redundancies among Selectide-18’s residues. This study aims to remove these redundancies and determine the optimal formulation of Selectide-18 through in silico analysis. Methods: An in silico protocol was developed to determine the optimal formulation of Selectide-18. By utilizing the PEP-FOLD server, 455 peptide models were created using 91 unique fragments of the Selectide-18 amino acid sequence ranging in size from 6 to 17 residues. Physical conformation of each model was compared to wild-type Selectide-18 using root-mean-square deviation data collected using PyMOL and UCSF Chimera software. Computational docking through AutoDock Vina was performed to test the binding affinity of each model to the active site of regulatory subunit p85α. The distance between each drug and the active site was measured with UCSF Chimera’s distance function. Finally, ClusPro docking of drug-bound p85α/p110β was compared to wild-type p85α/p110β, as well as non-truncated Selectide-18-bound p85α/p110β. Statistical significance was determined using a Student's t-test. Results: Select truncated models demonstrated physical confirmation (RMSD = 0.024), binding affinity (-8.74 kcal/mol), and simulated inhibitory capabilities comparable to Selectide-18. A specific group of variants comprised of 9 amino acids (9 residue_6K-14Q) had the shortest formulation without significant declines in binding affinity. Conclusions: Selectide-18 is a selective PI3K inhibitor that can be optimized by removing functionally redundant amino acids. A 9-residue variant ranging from amino acids 6Lys to 14Gln showed the most promise and will be used in future studies to reformulate Selectide-18. Being half the size of Selectide-18, this optimized drug is anticipated to have improved cell permeability without sacrificing inhibitory function.

A facile approach to fabricating graphene/waterborne epoxy coatings with dual functionalities of barrier and corrosion inhibitor

• A facile approach to fabricating C-G/WEP and S-G/WEP composite coatings with dual functionalities as barriers and corrosion inhibitors was developed. • The impedance of the C-G/WEP and S-G/WEP coatings is enhanced by more than two orders of magnitude compared with that of WEP coatings. • The presence of surfactants facilitates the dispersion of C-G and S-G nanosheets in both the solution and the composite coatings. • The surfactants endow inhibition ability of the coatings, thereby the composite coatings effectively protect the underlying Q235 steel against corrosion. • This work exemplifies a facile yet environmentally-friendly approach to preparing graphene composite coatings and may enable the large-scale production of graphene anticorrosion coatings. A facile and environmentally-friendly method is developed to prepare graphene/waterborne epoxy (WEP) composite coatings. The graphene nanosheets are produced with electrochemical-exfoliation in the solution containing surfactants, cetyl trimethyl ammonium bromide (CTAB) and sodium dodecyl sulfate (SDS). The nanosheets containing solution thus formed are subjected to a quick dialysis and then directly used as a diluent for WEP without any further treatment. This preparation method overcomes the commonly identified problems of aggregations and ‘corrosion promotion’ effect associated with graphene, and increases the impedance of the composite coatings by more than two orders of magnitude. The analysis of anticorrosion performance suggested that the presence of surfactants not only improves the dispersibility of graphene nanosheets but also endows the composite coatings with both barrier and corrosion inhibition capabilities. The strategy reported herein may pave the path to the large-scale production of graphene anticorrosion coatings.

4-Chlorophenyl-N-furfuryl-1,2,4-triazole Methylacetamides as Significant 15-Lipoxygenase Inhibitors: an Efficient Approach for Finding Lead Anti-inflammatory Compounds.

Lipoxygenases (LOXs) are a class of enzymes that catalyze the production of pro-inflammatory mediators, such as leukotrienes and lipoxins, via an arachidonic acid cascade as soon as they are released from the membrane phospholipids after tissue injury. In continuation of our efforts in search for new LOX inhibitors, a series of chlorophenyl-furfuryl-based 1,2,4-triazole derivatives were prepared and evaluated for their 15-LOX inhibitory activities. A simple precursor, 4-chlorobenzoic acid (a), was consecutively transformed into benzoate (1), hydrazide (2), semicarbazide (3), and N-furfuryl 5-(4-chlorobenzyl)-4H-1,2,4-triazole (4), which when further merged with electrophiles (6a–o) resulted in end products (7a–o). The structural elucidations of the newly synthesized compounds (7a–o) were carried out by Fourier transform infrared, 1H-, 13C NMR spectroscopy, EI-MS, and HR-EI-MS spectrometry. The inhibitive capability of compounds (7a–o) on soybean 15-LOX was performed in vitro using the chemiluminescence method. The compounds 7k, 7o, 7m, 7b, and 7i demonstrated potent activities (IC50 17.43 ± 0.38, 19.35 ± 0.71, 23.59 ± 0.68, 26.35 ± 0.62, and 27.53 ± 0.82 μM, respectively). These compounds revealed 79.5 to 98.8% cellular viability as measured by the MTT assay at 0.25 mM concentration. The structure-activity relationship (SAR) studies showed that the positions and the nature of substituents bonded to the phenyl ring are important in the determination of 15-LOX inhibitory activities. ADME, in silico, and density functional theory studies supported the evidence as yet another class of triazoles with potential lead properties in search for anti-LOX compounds with a safe gastrointestinal safety profile for various inflammatory diseases. Further work is in progress on the synthesis of more derivatives in search for anti-inflammatory agents.

Discovery of 1,6-Naphthyridin-2(1H)-one Derivatives as Novel, Potent, and Selective FGFR4 Inhibitors for the Treatment of Hepatocellular Carcinoma.

Fibroblast growth factor receptor 4 (FGFR4) has been identified as a potential target due to its transmission of the FGF19 signaling pathway, which is critical to hepatocellular carcinoma (HCC). Therefore, focusing on the specific Cys552 of FGFR4 subtype, we designed and synthesized a novel family of 1,6-naphthyridin-2(1H)-one derivatives as potent and highly selective FGFR4 inhibitors. Through detailed structural optimizations, the representative compound A34 exhibited improved FGFR4 inhibitory capability and selectivity and excellent anti-proliferative activities against FGFR4-dependent HCC cell lines. Additionally, A34 demonstrated remarkable antitumor efficacy in a Hep-3B HCC xenograft model, with favorable pharmacokinetic properties, and low risk of hERG toxicity. A34 also showed moderate inhibitory activities against the FGFR4 V550L mutant in vitro, which indicates that it has the potential as a novel anticancer agent for HCC.

Gold Nanoparticle-Decorated Drug Nanocrystals for Enhancing Anticancer Efficacy and Reversing Drug Resistance Through Chemo-/Photothermal Therapy.

Limited chemotherapeutic efficiency, drug resistance, and side effects are primary obstacles for cancer treatment. The development of co-delivery systems with synergistic treatment modes should be a promising strategy. Here, we fabricated a multifunctionalized nanocarrier with a combination of chemotherapeutic agents and gold nanoparticles (AuNPs), which could integrate chemo-photothermal therapy, thus enhancing overall anticancer efficacy, sensitizing drug-resistant cancer cells, and diminishing cancer stem cells (CSCs). To be specific, camptothecin nanocrystals (CPT NCs) were prepared as a platform, on the surface of which AuNPs were decorated and a hyaluronic acid layer acted as capping, stabilizing, targeting, and hydrophilic agents for CPT NCs, and reducing agents for AuNPs, providing a bridge connecting AuNPs to CPT. These AuNP-decorated CPT NCs exhibited good physico-chemical properties such as optimal sizes, payload, stability, and photothermal efficiency. Compared to other CPT formulations, they displayed considerably improved biocompatibility, selectivity, intracellular uptake, cytotoxicity, apoptosis induction activity, Pgp inhibitory capability, and anti-CSC activity, owing to a synergistic/cooperative effect from AuNPs, CPT, near-infrared treatment, pH/photothermal-triggered drug release, and nanoscaled structure. A mitochondrial-mediated signaling pathway is the underlying mechanism for cytotoxic and apoptotic effects from AuNP-decorated CPT NCs, in terms of mitochondrial dysfunction, intensified oxidative stress, DNA fragmentation, caspase 3 activation, upregulation of proapoptotic genes such as p53, Bax, and caspase 3, and lower levels of antiapoptotic Bcl-2.

In situ forming and biocompatible hyaluronic acid hydrogel with reactive oxygen species-scavenging activity to improve traumatic brain injury repair by suppressing oxidative stress and neuroinflammation.

The efficacy of neural repair and regeneration strategies for traumatic brain injury (TBI) treatment is greatly hampered by the harsh brain lesion microenvironment including oxidative stress and hyper-inflammatory response. Functionalized hydrogel with the capability of oxidative stress suppression and neuroinflammation inhibition will greatly contribute to the repairment of TBI. Herein, antioxidant gallic acid-grafted hyaluronic acid (HGA) was combined with hyaluronic acid-tyramine (HT) polymer to develop an injectable hydrogel by dual-enzymatically crosslinking method. The resulting HT/HGA hydrogel is biocompatible and possesses effective scavenging activity against DPPH and hydroxyl radicals. Meanwhile, this hydrogel improved cell viability and reduced intracellular reactive oxygen species (ROS) production under H2O2 insult. The in vivo study showed that in situ injection of HT/HGA hydrogel significantly reduced malondialdehyde (MDA) production and increased glutathione (GSH) expression in lesion area after treatment for 3 or 21 days, which might be associated with the activation of Nrf2/HO-1 pathway. Furthermore, this hydrogel promoted the microglia polarization to M2 (Arg1) phenotype, it also decreased the level of proinflammatory factors including TNF-α and IL-6 and increased anti-inflammatory factor expression of IL-4. Finally, blood-brain barrier (BBB) was protected, neurogenesis in hippocampus was promoted, and the motor, learning and memory ability was enhanced. Therefore, this injectable, biocompatible, and antioxidant hydrogel exhibits a huge potential for treating TBI and allows us to recognize the great value of this novel biomaterial for remodeling brain structure and function.