Commercial Inhibitors Research Articles

Electrochemical corrosion study of La(Fe11,6-xSix1,4Mnx)H1,5 in diverse chemical environments

La-Fe-Si-based alloys represent a promising material class for magnetocaloric cooling at ambient temperatures, but contain highly oxophilic elements and are chemically sensitive, which impairs their continued operation in aqueous heat exchange media. The development of protection strategies ensuring long-term stability necessitates a comprehensive understanding of the material's corrosion characteristics. The present work focuses on a such an assessment for hydrogenated La(FeMnSi)13 containing α-Fe to enhance it's mechanical properties. Linear sweep voltammetry served as the main analytical tool and was performed in preferably buffered electrolytes with pH values reaching from moderately acidic to strongly alkaline, in the presence and absence of corrosion-enhancing species (chloride, chelators). α-Fe, La1Fe1Si1, and La(FeSi)13 were employed as reference materials to clarify the passivation pattern of the material in carbonate buffer. Specific chemical compounds with clear mechanistic impact (phosphate acting as precipitate former, hydrazine as oxygen scavenger) were tested alongside commercial corrosion inhibitors to investigate their effects. Our objective is to provide a systematic evaluation of the corrosion properties of the alloy system, building on previous investigations and taking into account its general materials chemistry.

Chemically modified MIR143-3p exhibited anti-cancer effects by impairing the KRAS network in colorectal cancer cells

Kirsten rat sarcoma virus (KRAS) mutations are frequently detected in many cancers and are major driver genes. Therefore, KRAS inhibitors have been the subject of extensive research. We developed chemically modified MIR143-3p (MIR143#12), which exhibits higher anticancer activity and nuclease resistance than other commercial inhibitors. MIR143#12 potently suppressed cell growth in colorectal and pancreatic cancer cell lines via apoptosis induced by repression of the entire rat sarcoma virus (RAS) network, which was achieved by silencing KRAS, Son of sevenless homolog 1 (SOS1), AKT, and extracellular signal-regulated kinase (ERK). We investigated the mechanistic advantages of MIR143#12 in various KRAS mutant colorectal cancer cell lines. Its effects were stronger than those of knockdown of KRAS alone in colon cancer cells because silencing of KRAS by small interfering RNA (siRNA) did not decrease the protein expression levels of AKT or ERKs. The KRAS mRNA recruitment system, called the “positive circuit” under effector signaling pathways, may contribute to insensitivity of KRAS mutant cancers to MIR143#12 and siRNAs. In an in vivo study, we newly demonstrated that MIR143#12 induced neoangiogenesis in the tumor microenvironment with growth suppression. Based on the present results, it is crucial to down-regulate not only KRAS but also the entire KRAS signaling network, which may be accomplished by MIR143#12.

Inhibitors targeting the autophosphorylation of serine/threonine kinase of Streptococcus suis show potent antimicrobial activity.

Antimicrobial resistance (AMR) is a global concern threatening public health. Developing novel antibiotics is one of the effective strategies to tackle AMR. Serine/threonine kinases (STKs) have been recently shown to play critical roles in the physiology and pathogenesis of several important bacterial pathogens which are regarded as a promising antimicrobial drug target. We previously reported the roles of STK in the regulation of bacterial cell division, metabolism, and pathogenesis in Streptococcus suis, an important zoonotic bacterial pathogen. In this study, we firstly identified the Thr167 and Ser175 residues in the activation loop of S. suis STK (ssSTK) as the kinase autophosphorylation sites. Phenotyping results demonstrated that the autophosphorylation deficient strain resembled the stk deletion strain showing essentiality for bacterial growth in minimal medium, abnormal morphology, and decreased virulence when compared with the wild-type S. suis SC19 strain. Based on these findings, we established an ssSTK inhibitor screening approach by measuring the growth of S. suis in a minimal medium and testing the autophosphorylation inhibition by measuring the consumption of ATP in an enzymatic reaction by ssSTK. A series of inhibitors against ssSTK are identified from a commercial kinase inhibitors library, including Staurosporine, K252a, AT9283, and APY29. These inhibitors showed antimicrobial activity in vitro. Moreover, by using Galleria mellonella larvae infection assay, compound APY29 displayed in vivo efficacy against S. suis infection. Additionally, it was predicted by molecular docking that these inhibitors could interact with ssSTK. Collectively, our data illustrated the essential roles of ssSTK autophosphorylation in the physiology and pathogenicity of S. suis and consider these inhibitors as promising antimicrobial lead compounds.

NF90/NFAR (nuclear factors associated with dsRNA)- a new methylation substrate of the PRMT5-WD45-RioK1 complex.

Protein-arginine methylation is a common posttranslational modification, crucial to various cellular processes, such as protein-protein interactions or binding to nucleic acids. The central enzyme of symmetric protein arginine methylation in mammals is the protein arginine methyltransferase 5 (PRMT5). While the methylation reaction itself is well understood, recruitment and differentiation among substrates remain less clear. One mechanism to regulate the diversity of PRMT5 substrate recognition is the mutual binding to the adaptor proteins pICln or RioK1. Here, we describe the specific interaction of Nuclear Factor 90 (NF90) with the PRMT5-WD45-RioK1 complex. We show for the first time that NF90 is symmetrically dimethylated by PRMT5 within the RG-rich region in its C-terminus. Since upregulation of PRMT5 is a hallmark of many cancer cells, the characterization of its dimethylation and modulation by specific commercial inhibitors in vivo presented here may contribute to a better understanding of PRMT5 function and its role in cancer.

Investigation of efficient corrosion inhibitor during acid cleaning of reverse osmosis (RO) desalination plant

Reverse osmosis (RO) technology plays a vital role in seawater desalination production, while salt scaling phenomenon is an inevitable problem during operation. Accordingly, glucuronide-substituted catechin (CG) was synthesized and developed here as an eco-friendly inhibitor for the first time, whose corrosion inhibition performances for desalination equipment alloys (i.e., carbon steel, brass, Ni-resist, and 316 L stainless steel) in 2% HCl solution were evaluated by experiments and theoretical calculations. At a concentration of 200 mg/L, CG achieved 97.81% corrosion inhibition for carbon steel, 85.91% for Ni-resist, 92.11% for brass, and 77.95% for 316 L stainless steel in weight loss experiments. The 90-hours static stability test was carried out by weight loss method, and the inhibition performance of CG was compared with that of a commercial corrosion inhibitor used in seawater desalination plant. The structural of the protective film on the metal surface was analyzed by EDX and XPS. Quantum chemical calculations based on density functional theory (DFT) and MD simulations were performed to optimize the CG molecular structure and investigate the inhibitive properties on the theoretical level, which agree well with the experimental results.

198. Lactate shuttle: a key component in osteosarcoma

<h3>BACKGROUND CONTEXT</h3> Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents and prognosis remains poor, particularly when in the spine. However, the unique metabolism of OS may allow for novel, targeted therapies. Increased glucose uptake and upregulated glycolysis in aerobic conditions are hallmarks of cancer (the"Warburg effect"). Lactate, once considered a mere byproduct of this increased glycolysis, has now proven to be a critical metabolite in most tumors, including OS. Recent work has highlighted a role for lactate transport in osteosarcoma, although whether OS cells produce or consume lactate is currently debated. Here we present data exploring the role of lactate transport in osteosarcoma by examining up and down regulation of the major lactate transporters, the monocarboxylate transporters (MCTs). <h3>PURPOSE</h3> Due to the poor prognosis of spinal osteosarcoma, identifying novel targets for cancer therapy is crucial. Here, we studied the importance of lactate as a metabolite for OS progression. Drugs specific to non-invasive biomarkers of metabolism such as lactate transporters in OS cells could help design future clinical trials. <h3>METHODS</h3> Gene expression profiles of various OS cell lines (SaOs, MNNG, HOS) in varying metabolic conditions (varying lactate and glucose concentrations) were analyzed. qPCR and immunoblotting were used to analyze expression patterns of overall MCT1 and MCT4, and surface expression of MCTs were determined using immunofluorescence microscopy. For each trial, cell proliferation was analyzed via CyQuant direct cell proliferation kit (Fischer Sci). Experiments were performed in triplicate. Conditions included combinations of low, normal, and high glucose (1, 6, and 20 mM respectively) with low, and high lactate (0.1, 1, and 5 mM respectively). All data are presented as the means ± SD where appropriate. We performed statistical analysis using Student'st-test; p less than 0.05 was considered statistically significant. <h3>RESULTS</h3> MCT1 and MCT4 were expressed in OS cell lines. MCT4 expression was upregulated in high glucose (20mM) conditions, but reduced drastically in the absence of glucose. On the other hand, MCT1 expression was not perturbed even in the absence of glucose. Conversely, MCT1, which is a bidirectional transporter of lactate, is expressed irrespective of presence of glucose. Finally, use of commercial MCT inhibitors namely AZD396, BAY8002, BAY87-2243 and Syrosingopine resulted in decreased cell survival, with simultaneous inhibition of MCT1 and MCT4 leading to the most profound effects. <h3>CONCLUSIONS</h3> The main lactate exporter, MCT4, was upregulated in high glucose conditions, indicating an increase in glycolysis to lactate with increased lactate export. Further, cells were not viable when cultured with lactate alone, unlike numerous other nontumorous tissues that uptake and use lactate as a fuel. OS cells appear to preferentially produce and export lactate, particularly if glucose is abundant, regardless of the local oxygen tension (the "Warburg effect"). Together these data suggest that lactate exportation via MCT4s is critical to osteosarcomagenesis and may serve as a unique target for spinal osteosarcomas. <h3>FDA DEVICE/DRUG STATUS</h3> AZD 3695 (Investigational/Not Approved), Syrosingopine (Not approved for this indication), BAY-8002 (Not approved for this indication)

Orexin Receptor Antagonists and Insomnia.

We review recent evidence on the use of orexin receptor antagonists (ORAs) for treating insomnia. We evaluate studies on five dual ORAs and one selective ORA. Research on suvorexant in recent years gradually focus on comorbid insomnia, while lemborexant and daridorexant were still being validated in primary insomnia. Almorexant is now mainly used as a commercial specific inhibitor of the orexin system in animal studies due to safety issues. Although filorexant has also shown a certain sleep-promoting effect, there are few clinical or experimental studies on sleep-related aspects of filorexant in recent years. As for selective ORAs, orexin receptor 2 antagonist seltorexant still has not yet reached phase 3. High-quality clinical trials in insomnia populations are needed which directly compare authorized ORAs and investigate non-approved ORAs, the use of ORAs in comorbid insomnia, and the orexin signaling system pathophysiology in insomnia.

New Developments in Inhibition of the Sweet Environment in a Variety of Corrosive Media: A Review

This paper aims to look at how pipeline steel and crude oil storage tanks resist corrosion in aqueous carbon dioxide (CO2) environments. To this aim, we have studied different inhibitors, particularly the heterocyclic inhibitor, which is used to prevent mild steel corrosion in various situations. On mild steel, the corrosion-prevention mechanism of heterocyclic inhibitors is also investigated. CO2 corrosion is the most frequent and dreaded type of corrosion in the oil and gas industry, and corrosion inhibitors are the most effective way to fight CO2 corrosion in mild steel. Nonetheless, continual exposure to pollutants and corrosion causes such as sulfur and chromate on pipeline surfaces is unavoidable. Because of their toxicity, commercial corrosion inhibitors are being used less frequently to protect the environment. As a result of the advent of "green" chemistry and fruit waste, both of which have been demonstrated to be efficient corrosion inhibitors, plant extracts have become popular. This research aims to compile a list of carbon dioxide corrosion inhibitors that have been proved to protect against this type of attack. The material on this page is relevant to the gas and oil industries, which rely on steel pipelines and crude oil tanks to transport oil and gas products. This study will also help develop better CO2 corrosion inhibitors for the gas and oil industries.

Discovery of (5-(Benzylthio)-4-(3-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-yl) Methanols as Potent Phytoene Desaturase Inhibitors through Virtual Screening and Structure Optimization.

Phytoene desaturase (PDS) is not only an important enzyme in the biosynthesis of carotenoids but also a promising target for herbicide discovery. However, in recent years, no expected PDS inhibitors with new scaffolds have been reported. Hence, a solution for developing PDS inhibitors is to search for new compounds with novel chemotypes based on the PDS protein structure. In this work, we integrated structure-based virtual screening, structure-guided optimization, and biological evaluation to discover some PDS inhibitors with novel chemotypes. It is noteworthy that the highly potent compound 1b, 1-(4-chlorophenyl)-2-((5-(hydroxymethyl)-4-(3-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-yl)thio)ethan-1-one, exhibited a broader spectrum of post-emergence herbicidal activity at 375-750 g/ha against six kinds of weeds than the commercial PDS inhibitor diflufenican. Surface plasmon resonance (SPR) assay showed that the affinity of our compound 1b (KD = 65.9 μM) to PDS is slightly weaker but at the same level as diflufenican (KD = 38.3 μM). Meanwhile, determination of the phytoene content and PDS mRNA quantification suggested that 1b could induce PDS mRNA reduction and phytoene accumulation. Moreover, 1b also caused the increase of reactive oxygen species (ROS) and the change of ROS-associated enzyme activity in albino leaves. Hence, all these results indicated the feasibility of PDS protein structure-based virtual screen and structure optimization to search for highly potent PDS inhibitors with novel chemotypes for weed control.

Dipeptides as environmentally friendly CH4 hydrate inhibitors: Experimental and computational approaches

In this study, three dipeptides (Gly-Gly, Ala-Ala, and Ala-Gly) were appraised as environmentally benign hydrate inhibitors for CH4 hydrate using both experimental and computational methods. Their kinetic inhibition performance was experimentally evaluated using a stirred high-pressure autoclave and a non-stirred high-pressure micro-differential scanning calorimeter. The experimental results demonstrated that the three dipeptides functioned well as CH4 hydrate inhibitors. Ala-Gly was found to be the most effective, and its inhibition performance was comparable to that of polyvinylcaprolactam (PVCap), a polymer-based commercial hydrate inhibitor. Snapshots, hydrate counts, F3 and F4 order parameters, displacement magnitude, mean square displacement, and radial distribution functions of each peptide-containing system were examined using molecular dynamics (MD) simulations to reveal the inhibition mechanism of dipeptides. The MD simulations showed that the N-termini of the dipeptides were the key constituents for inhibiting the CH4 hydrate, and the Ala-Gly-containing system had the strongest interaction between dipeptide molecules and CH4 hydrate. The overall results provide a better understanding of nature-derived, environmentally friendly hydrate inhibitors and offer insights into the molecular inhibition mechanism of various potential inhibitors.

Anti-Corrosion Performance of Migratory Corrosion Inhibitors on Reinforced Concrete Exposed to Varying Degrees of Chloride Erosion.

This study investigated the anti-corrosion performance of commercial amino alcohol migratory corrosion inhibitors (MCIs) on concrete that underwent varying degrees of chloride erosion. Electrochemical impedance spectroscopy (EIS), potentiodynamic polarization (PD), scanning electron microscopy, and energy dispersive spectroscopy (SEM-EDS) analyses were performed to study the anti-corrosion performance and mechanism of the MCIs on the steel bars. The results indicated that the corrosion resistance of the steel bars in concrete was significantly improved by coating with the MCIs, and the earlier the specimens were coated with the MCIs, the higher the anti-corrosion efficiency. The anti-corrosion efficiency was 55.35% when the MCIs coating was applied before chloride erosion; however, the anti-corrosion efficiency decreased to 3.40% when the MCIs coating was applied after the ninth drying–wetting cycle. The improvement in corrosion resistance of the steel bar in concrete coated with MCIs was due to the protective MCIs-molecule film that formed on the steel bar surfaces, and the oxidative dissolution of iron at the anode was effectively inhibited by the MCIs coating.

Discovery of Leishmania Druggable Serine Proteases by Activity-Based Protein Profiling.

Leishmaniasis are a group of diseases caused by parasitic protozoa of the genus Leishmania. Current treatments are limited by difficult administration, high cost, poor efficacy, toxicity, and growing resistance. New agents, with new mechanisms of action, are urgently needed to treat the disease. Although extensively studied in other organisms, serine proteases (SPs) have not been widely explored as antileishmanial drug targets. Herein, we report for the first time an activity-based protein profiling (ABPP) strategy to investigate new therapeutic targets within the SPs of the Leishmania parasites. Active-site directed fluorophosphonate probes (rhodamine and biotin-conjugated) were used for the detection and identification of active Leishmania serine hydrolases (SHs). Significant differences were observed in the SHs expression levels throughout the Leishmania life cycle and between different Leishmania species. Using iTRAQ-labelling-based quantitative proteomic mass spectrometry, we identified two targetable SPs in Leishmania mexicana: carboxypeptidase LmxM.18.0450 and prolyl oligopeptidase LmxM.36.6750. Druggability was ascertained by selective inhibition using the commercial serine protease inhibitors chymostatin, lactacystin and ZPP, which represent templates for future anti-leishmanial drug discovery programs. Collectively, the use of ABPP method complements existing genetic methods for target identification and validation in Leishmania.

Discovery of Novel Tyrosinase Inhibitors From Marine Cyanobacteria.

Tyrosinase, an important oxidase involved in the primary immune response in humans, can sometimes become problematic as it can catalyze undesirable oxidation reactions. Therefore, for decades there has been a strong pharmaceutical interest in the discovery of novel inhibitors of this enzyme. Recent studies have also indicated that tyrosinase inhibitors can potentially be used in the treatment of melanoma cancer. Over the years, many new tyrosinase inhibitors have been discovered from various natural sources; however, marine natural products (MNPs) have contributed only a small number of promising candidates. Therefore, in this study we focused on the discovery of new MNP tyrosinase inhibitors of marine cyanobacterial and algal origins. A colorimetric tyrosinase inhibitory assay was used to screen over 4,500 marine extracts against mushroom tyrosinase (A. bisporus). Our results revealed that scytonemin monomer (ScyM), a pure compound from our compound library and also the monomeric last-step precursor in the biosynthesis of the well-known cyanobacterial sunscreen pigment “scytonemin,” consistently showed the highest tyrosinase inhibitory score. Determination of the half maximal inhibitory concentration (IC50) further indicated that ScyM is more potent than the commonly used commercial inhibitor standard “kojic acid” (KA; IC50 of ScyM: 4.90 μM vs. IC50 of KA: 11.31 μM). After a scaled-up chemical synthesis of ScyM as well as its O-methyl analog (ScyM-OMe), we conducted a series of follow-up studies on their structures, inhibitory properties, and mode of inhibition. Our results supported ScyM as the second case ever of a novel tyrosinase inhibitory compound based on a marine cyanobacterial natural product. The excellent in vitro performance of ScyM makes it a promising candidate for applications such as a skin-whitening agent or an adjuvant therapy for melanoma cancer treatment.

In silico Study of Coumarins Derivatives With Potential Use in Systemic Diseases

Coumarins have been widely used in various human systemic diseases; however, their molecular action is not known in many cases. In silico studies are an option to explore the interaction of molecules with molecular targets and to obtain explanations for these biological activities. SwissTargetPrediction is an accepted tool to obtain potential biological targets for coumarin derivatives. Some carbonic anhydrases (CAs), enzymes related to the central nervous system (CNS), and estrogen receptors (ER) were evaluated vis à vis coumarins holding an electron donor (EDG) or an electron-withdrawing group (EWG). Molecular docking studies using Schrödinger carried out with some selected proteins showed that EDG and produces the best binding coupling energy (BCE) in CAs and ER. Substituents in the aromatic ring increased the BCE in targets related to CNS enzymes; EDG and EWG at positions 3 or 4 in coumarins had better activity in CAs. Also, in CAs, coumarins derivatives presented better BCE than commercial inhibitors. In ER, no competitive activity to estradiol was obtained from coumarins. All In silico results demonstrated the selective influence of the type of substitution and their position on the BCE that could permit better coumarin derivatives in protein targets implicated in human systemic diseases.

Inhibitory Effect of Commercial Inhibitor VCI 379/611 on the Corrosion Behaviour of HTCS-130 Tool Steel for Hot Work

This paper presents the results of a study of the influence of water and the commercial inhibitor VCI 379/611 on the corrosion behaviour of HTCS-130 hot work tool steel. Using the thermodynamic program Thermo-Calc, phase equilibria were determined according to the choice of calculation conditions and the known chemical composition of tool steels. From the obtained projections, it is possible to observe the secretion of individual phases at certain temperatures. To obtain insight into the corrosion resistance of steel, the following electrochemical methods were used: open circuit potential measurement; electrochemical impedance spectroscopy; and Tafel extrapolation. Metallographic tests were performed on a sample previously etched in nital to identify the microstructure of the steel. Using an optical microscope, the sample surface was analysed after each measurement. Images of the sample surface subjected to water without inhibitors indicate the occurrence of pitting corrosion. The presence of tungsten and molybdenum carbides was identified by scanning electron microscopy and energy dispersion spectroscopy. It was found that the corrosion process is more pronounced in the area of the metal base while in the areas of excreted carbides, weaker corrosion activity was observed.

Vegetable-based steel corrosion inhibitors for the protection of oilfield equipment

In this work, steel corrosion inhibitors from vegetable raw materials have been obtained to protect oilfield equipment from the corrosive action of formation waters. Extracts from the bark of "Norway spruce" and "Scots pine" were used as an inhibitor of steel corrosion. The main component of spruce and pine bark extracts with an anti-corrosion effect is tannins - a group of phenolic compounds of plant origin that have tanning properties and are capable of forming compounds with iron that are slightly soluble in water - iron tannates. The content of tannins in the extract from the bark of Norway spruce was 13.4%, in the extract from the bark of pine - 3.3 %. Corrosion tests were carried out in accordance with GOST 9.506-87 and GOST 9.502-82. The degree of protection of steel grade "Steel 20" with the addition of the spruce bark extract was 88.9 %, with the addition of pine bark extract - 74.9 %, at a dosage of 50 g/dm3. Commercial corrosion inhibitors of steel grades SNPKh-1004 and TNKhS-7 at a dosage of 1g/dm3 showed the degree of steel protection up to 92 and 90.3 %, respectively. Corrosion of steel in the formation water of oil of the Devonian sediment develops 1.5 times more intensively than in the model formation water. The best result in terms of the degree of steel protection with the addition of spruce bark extract and pine bark extract with a concentration of 50 g/dm3 was 80.0 % and 41.8 %, respectively. Thus, the corrosion resistance of the metal in accordance with GOST 9.502-82 as a result of the use of spruce bark extract as a corrosion inhibitor in the model formation water corresponds to the "stable" level, in the formation water of oil of the Devonian sediment it corresponds to the "reduced" level.Electron-microscopic measurements were carried out within the framework of the state&nbsp;task of the Federal Research Center of KazSC RAS No. AAAA-A18-118041760011-2.

Active Compounds in Zingiber officinale as Possible Redox Inhibitors of 5-Lipoxygenase Using an In Silico Approach.

5-Lipoxygenase (5-LOX) converts arachidonic acid to lipidic inflammatory mediators such as leukotrienes (LTs). In diseases such as asthma, LTs contribute to a physiopathology that could be reverted by blocking 5-LOX. Natural products with anti-inflammatory potential such as ginger have been used as nutraceuticals since ancient times. 6-Gingerol and 6-shogaol are the most abundant compounds in the ginger rhizome; they possess anti-inflammatory, antioxidant, and chemopreventive properties. In the present study, 6-gingerol and 6-shogaol structures were analyzed and compared with two commercial 5-LOX inhibitors (zileuton and atreleuton) and with other inhibitor candidates (3f, NDGA, CP 209, caffeic acid, and caffeic acid phenethyl ester (CAPE)). The pharmacokinetics and toxicological properties of 6-gingerol, 6-shogaol, and the other compounds were evaluated. Targeted molecular coupling was performed to identify the optimal catalytic pocket for 5-LOX inhibition. The results showed that 6-gingerol and 6-shogaol follow all of the recommended pharmacokinetic parameters. These compounds could be inhibitors of 5-LOX because they present specific interactions with the residues involved in molecular inhibition. The current study demonstrated the potential of 6-gingerol and 6-shogaol as anti-inflammatory agents that inhibit 5-LOX, as they present a high level of performance in the toxicological analysis and could be catabolized by the cytochrome p450 enzymatic complex; however, 6-gingerol was superior in safety compared to 6-shogaol.

Novel STAT3 Inhibitors Targeting STAT3 Dimerization by Binding to the STAT3 SH2 Domain.

Our drug discovery model has identified two novel STAT3 SH2 domain inhibitors 323–1 and 323–2 (delavatine A stereoisomers) in a series of experiments. In silico computational modeling, drug affinity responsive target stability (DARTS), and fluorescence polarization (FP) assays altogether determined that 323–1 and 323–2 directly target the STAT3 SH2 domain and inhibited both phosphorylated and non-phosphorylated STAT3 dimerization. Computational docking predicted that compound 323s bind to three subpockets of the STAT3 SH2 domain. The 323s inhibition of STAT3 dimerization was more potent than the commercial STAT3 SH2 domain inhibitor S3I-201 in the co-immunoprecipitation assay, correlating with computational docking data. The fluorescence polarization assay further confirmed that the compound 323s target the STAT3 SH2 domain by competitively abrogating the interaction between STAT3 and the SH2-binding peptide GpYLPQTV. Compared with S3I-201, the 323 compounds exhibited stronger inhibition of STAT3 and reduced the level of IL-6-stimulated phosphorylation of STAT3 (Tyr705) in LNCaP cells over the phosphorylation of STAT1 (Tyr701) induced by IFN-ɣ in PC3 cells or the phosphorylation of STAT1 (Ser727) in DU145 cells. Both compounds downregulated STAT3 target genes MCL1 and cyclin D1. Thus, the two compounds are promising lead compounds for the treatment of cancers with hyper-activated STAT3.

The Effect of Corrosion on Crude Oil Distillation Plants

The analysis of the corrosion phenomenon of the installations of the largest refinery in Romania confirmed the existence of its conditions, in the atmospheric distillation plants of crude oil, in the heat exchangers, and in the petrol and diesel hydrofining plants. However, the slightest effect of this phenomenon was found in the dome, the plates, and the exhaust pipes at the top of the distillation column, as well as in the reflux vessel of the atmospheric distillation plant. The main cause of the corrosion phenomenon and the increase in the corrosion areas of the material of the crude oil refining installations is the presence of hydrochloric acid, obtained after incorrect desalination (hydrolysis of calcium and magnesium chloride). To prevent this phenomenon, in laboratory conditions, we tested an antacid inhibitor (alkyl phenol) and a residual product (undistilled polyamine), with the role of supplementing the commercial inhibitor with a cheap product. The effectiveness of these additives was evaluated by introducing specimens made from the material taken from the refining column and from the reflux vessel into a solution of hydrochloric acid of various concentrations (5–15%). This solution was treated with the two corrosion inhibitors, the analysis of their effectiveness being performed at concentrations ranging between 0.05 and 0.2%. In addition, in this article, we deduced the equations of variation of the corrosion rate, depending on the working temperature of the refinery.

Antibody-Mediated Screening of Peptide Inhibitors for Monoamine Oxidase-B (MAO-B) from an Autodisplayed FV Library.

Inhibitors for monoamine oxidase-B (MAO-B) were screened from an FV library with a randomized complementarity-determining region 3 (CDR3) region using a monoclonal antibody against dopamine. As the first step, the FV library was expressed on the outer membrane of E. coli by site-directed mutagenesis of the randomized CDR3 region. Among the FV library, variants with a binding affinity to monoclonal antibodies against dopamine were screened and cloned. From the comparison of the binding activity of the screened clones to a control clone with a modified FV antibody (only with CDR1 and CDR2), the CDR3 regions of screened clones were determined to directly interact with the monoclonal antibody against dopamine. These CDR3 sequences were then synthesized as mimotopes (mimicking peptides) of dopamine. The inhibitory activity of two mimotopes against MAO-B was analyzed using HeLa cells overexpressing MAO-B, as well as using activated human astrocytes; their inhibitory activity was compared to that of a commercial inhibitor of MAO-B, selegiline. The inhibition efficiency of the two mimotopes (in comparison with selegiline) was estimated to be 67.2% and 69.4% in the HeLa cells and 64.4% and 58.0% in the human astrocytes. The gene expression pattern in astrocytes after treatment with the two mimotopes was also analyzed and compared with that in the human astrocytes treated with selegiline. Finally, the interaction between two mimotopes and MAO-B was analyzed using docking simulation, and the candidate regions of MAO-B for the interaction with each mimotope were explored through the docking simulation.