Identification of 1,2,3,4,6-Penta-O-galloyl-β-d-glucopyranoside as a Glycine N-Methyltransferase Enhancer by High-Throughput Screening of Natural Products Inhibits Hepatocellular Carcinoma

Glycine N-methyltransferase (GNMT) expression is vastly downregulated in hepatocellular carcinomas (HCC). High rates of GNMT knockout mice developed HCC, while overexpression of GNMT prevented aflatoxin-induced carcinogenicity and inhibited liver cancer cell proliferation. Therefore, in this study, we aimed for the identification of a GNMT inducer for HCC therapy. We established a GNMT promoter-driven luciferase reporter assay as a drug screening platform. Screening of 324 pure compounds and 480 crude extracts from Chinese medicinal herbs resulted in the identification of Paeonia lactiflora Pall (PL) extract and the active component 1,2,3,4,6-penta-O-galloyl-β-d-glucopyranoside (PGG) as a GNMT inducer. Purified PL extract and PGG induced GNMT mRNA and protein expression in Huh7 human hepatoma cells and in xenograft tumors. PGG and PL extract had potent anti-HCC effects both in vitro and in vivo. Furthermore, PGG treatment induced apoptosis in Huh7 cells. Moreover, PGG treatment sensitized Huh7 cells to sorafenib treatment. Therefore, these results indicated that identifying a GNMT enhancer using the GNMT promoter-based assay might be a useful approach to find drugs for HCC. These data also suggested that PGG has therapeutic potential for the treatment of HCC.     

Investigation of the piroxicam/hydroxypropyl-β-cyclodextrin inclusion complexation by means of a supercritical solvent in the presence of auxiliary agents

The complexation of piroxicam and 2-hydroxypropyl-β-cyclodextrin by means of supercritical CO₂ has been investigated. The experiments were carried out by varying the temperature, pressure and contact time and introducing two different auxiliary agents: polyvinyl pyrrolidone or l-lysine.Cyclodextrins, which are widely used to solubilize a large variety of poorly soluble drugs, are often used in combination with some auxiliary agents to enhance the complexation efficiency of the conventional techniques. While many recent literature works report that supercritical carbon dioxide is a clean, non-toxic alternative to organic solvents, the use of auxiliary agents in the supercritical complexation process has been scarcely examined and still needs to be investigated.The inclusion complexes obtained in this work were analysed by means of the ‘differential solubility method’, differential scanning calorimetry and Fourier transform infrared spectroscopy. The results showed that the supercritical treatment could be successfully employed below 140-150 °C without incurring thermal degradation of the samples. While 66% inclusion efficiency could be obtained at 140 °C and 30 MPa for a mixture of piroxicam/2-hydroxypropyl-β-cyclodextrin (1:2 molar ratio), higher percentages of complexation (95% in the ternary samples with polyvinyl pyrrolidone and 89-91% in those with l-lysine) could be obtained at a lower temperature (130 °C) when auxiliary agents were employed.     

Catalysis of cleavage of di-β-naphthyl ether by electron-donating agents: an explanation for the effectiveness of phenols as promoters for coal conversion

1,3,5-Trimethoxybenzene, 1,2-dimethoxynaphthalene, and 1,4-dimethoxynaphthalene are ineffective as catalysts for the hydrogenolysis of di-β-naphthyl ether in tetralin at 450 °C. However, mixtures of these polyethers with phenol are appreciably more effective catalysts than is phenol itself. Mixtures of the dimethoxynaphthalenes with acetic acid or 1,1,1-trifluoroethanol have catalytic ability, even though the individual components are inactive. It is suggested that both electron-donating ability and acidity are factors determining catalytic activity, and a mechanism is proposed involving electron transfer from the catalyst to the protonated diaryl ether.     

β-Cyclodextrin Based Nanosponge as a Biodegradable Porous Three-Dimensional Nanocatalyst in the One-Pot Synthesis of N- Containing Organic Scaffolds

The motivation behind the present study was to develop an application of β-cyclodextrin-based nanosponges with the tiny mesh-like structure as porous three-dimensional nanocatalyst in the one-pot three component condensations of various aromatic aldehydes with activated methylene compounds such as dimedone, thiobarbituric acid, 4-hydroxycoumarin, 4-hydroxy-6-methyl-2-pyrone and nucleophiles including indole and amines. This nanosponge catalyst afforded the privileged N- containing organic scaffolds as key intermediates in pharmaceutical chemistry in very short reaction times.

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The effect of soda bagasse lignin modified by ionic liquids on properties of the urea–formaldehyde resin as a wood adhesive

The aim of this research was to investigate the influence of lignin modified by ionic liquids on physical and mechanical properties of plywood panels bonded with the urea–formaldehyde (UF) resin. For this purpose, soda bagasse lignin was modified by the 1-ethyl-3-methylimidazolium acetate ([Emim][OAc]) ionic liquid and then the various contents of unmodified and modified lignins (10, 15, and 20%) were added at pH=7 instead of second urea during the UF resin synthesis. The physicochemical properties of the prepared resins as well as the water absorption, shear strength, and formaldehyde emission of the plywood panels made with these adhesives were measured according to standard methods. According to Fourier Transform Infrared (FTIR) Spectrometry, by treatment of lignin, the C=O, C–C, and C–H bonds decrease while the content of the C–N bond dramatically increases. Based on the finding of this research, the performance of soda bagasse lignin in UF resins dramatically improves by modification by ILs; as the resins with modified lignin yielded lower formaldehyde emission and water absorption when compared to those made from unmodified lignin and commercial UF adhesives, respectively. The shear strength as well as wood failure percentages are lower for the panels produced with modified lignin than for the panels produced with UF resins alone.     

Identifying Lysophosphatidic Acid Acyltransferase β (LPAAT-β) as the Target of a Nanomolar Angiogenesis Inhibitor from a Phenotypic Screen Using the Polypharmacology Browser PPB2

By screening a focused library of kinase inhibitor analogues in a phenotypic co-culture assay for angiogenesis inhibition, we identified an aminotriazine that acts as a cytostatic nanomolar inhibitor. However, this aminotriazine was found to be completely inactive in a whole-kinome profiling assay. To decipher its mechanism of action, we used the online target prediction tool PPB2 ( http://ppb2.gdb.tools ), which suggested lysophosphatidic acid acyltransferase β (LPAAT-β) as a possible target for this aminotriazine as well as several analogues identified by structure–activity relationship profiling. LPAAT-β inhibition (IC₅₀ ≈15 nm ) was confirmed in a biochemical assay and by its effects on cell proliferation in comparison with a known LPAAT-β inhibitor. These experiments illustrate the value of target-prediction tools to guide target identification for phenotypic screening hits and significantly expand the rather limited pharmacology of LPAAT-β inhibitors.     

An Asymmetric Nanoscale SOI MOSFET by Means of a P-N Structure as Virtual Hole’s Well at the Source Side

Silicon - This paper suggests and investigates a p-n structure, which emulates as a MOSFET. In the proposed structure we utilize an L-shape contact with a proper work function over the source...     

Cellulosic CuI Nanoparticles as a Heterogeneous,Recyclable Catalyst for the Borylation of α,β-Unsaturated Acceptors in Aqueous Media

Catalysis Letters - We have demonstrated that cellulosic CuI nanoparticles could perform as an efficient heterogeneous catalyst for the synthesis of useful organoboron compounds. Desired...     

Insights into the cross-amyloid aggregation of Aβ40 and its N-terminal truncated peptide Aβ11-40 affected by epigallocatechin gallate

Inhibition of protein misfolding and aggregation is a great challenge in the field of biochemical and biopharmaceutical engineering. Alzheimer's disease (AD) is a protein-misfolding disease, and the interactions between 40-amino-acid-residue β-amyloid peptide (Aβ₄₀) and its N-terminal truncated peptide Aβ_11-40 demonstrate that Aβ_11-40 may play an important role in the pathological process of AD. However, the effect of inhibitors on Aβ_11-40 aggregation and on the cross-amyloid aggregation (co-assembly) between Aβ₄₀ and Aβ_11-40 has never been studied. Herein, coaggregation and seeding interactions between Aβ₄₀ and Aβ_11-40 as well as the effect of epigallocatechin gallate (EGCG), a small molecule inhibitor, on the cross-amyloid aggregation have been investigated by extensive analyses. It is found that Aβ_11-40 participates in the aggregation of Aβ₄₀ and leads to the formation of coaggregates that contain less β-sheet structures than pure Aβ₄₀ aggregates. The aggregation kinetics along with morphologies and secondary structures of the coaggregates are also significantly affected by the Aβ₄₀/Aβ_11-40 ratio. EGCG accelerates the nucleation of Aβ₄₀ but retards that of Aβ_11-40 by affecting their elongation and secondary nucleation processes in solution and on solid surfaces. Meanwhile, EGCG makes the conformations of the seeding-induced Aβ aggregates more compact, especially for the homologous seedings. Isothermal titration calorimetry measurement indicates that hydrophobic interactions mainly contribute to the inhibition of the two Aβ isoforms by EGCG. The findings of this research have provided new insights into Aβ aggregation and the effect of an important inhibitor and the results would benefit in the development of potent inhibitors against co-assembly of different amyloid proteins.     

Synthesis of Hydroxylated Biphenyl Derivatives Bearing an α,β-Unsaturated Ketone as a Lead Structure for the Development of Drug Candidates against Malignant Melanoma

A small collection of C₂-symmetric hydroxylated biphenyl derivatives featuring an α,β-unsaturated ketone as a lead structure was prepared, and the capacity of these compounds to act as antiproliferative agents against four human malignant melanoma cell lines was assayed. The prodrug approach was applied in order to improve the delivery of compounds into the cell by modulation of the phenolic hydroxy protecting group. The hydroxylated biphenyl structure bearing an α,β-unsaturated ketone and a phenolic-O-prenylated chain was found to facilitate the delivery of the molecule and interactions with biological targets. Four compounds showed antiproliferative activity resulting in IC₅₀ values in the range of 1.2 to 2.8 μM.     

Metabolic Activation of Dibenzo[a,l]Pyrene by Cytochrome P450 Enzymes to Stable DNA Adducts Occurs Exclusively Through the Formation of the (−)-trans−(11R, 12R)-Diol

At low doses, the carcinogenic hexacyclic hydrocarbon dibenzo[a,l]pyrene (DB[a,l]P) forms DNA adducts in human MCF-7 cells exclusively through formation of the (–)-anti?(11R, 12S)-diol (13S, 14R)-epoxide (DB[a,l]PDE) via its metabolic precursor, the (–)-(11R, 12R)-diol. The same result was obtained by exposure of V79 cells stably expressing human cytochrome P450 (P450) 1B1. Although several other metabolites such as the 7-phenol and a 11, 12-diol phenol are formed, no other DNA adducts are detectable after exposure to 0.1 μM DB[a,l]P. Exposure to 1 μM DB[a,l]P leads to the formation of low levels of (+)-syn?DB[a,l]P-DE-DNA adducts through intermediate generation of the (+)-(11S, 12S)-diol. In contrast, treatment of P450 1A1-expressing V79 cells results also in the formation of several polar DNA adducts. Incubation of the trans?8,9-diol and trans?11, 12-enantiomers of DB[a,l]P demonstrated that all polar DNA adducts detected in 1A1-expressing cells resulted from intermediate formation of the (–)-trans?11, 12-diol. Although the K-region trans?8,9-diol is metabolically converted to several diol phenols and bis?diols, this compound does not contribute to the strong DNA binding or cytotoxicity observed after exposure of P450 1A1- and 1B1-expressing cells to the parent hydrocarbon.     

Transformation of β-damascone to (+)-(S)-4-hydroxy-β-damascone by fungal strains and its evaluation as a potential insecticide against aphids Myzus persicae and lesser mealworm Alphitobius diaperinus Panzer

Microbial conversion of β-damascone (1) into 4-hydroxy-β-damascone (2) was studied. The results showed the potential of the tested biocatalysts for the regio- and enantioselective hydroxylation of substrate 1. The highest enantioselectivity was exhibited by strain Mortierella isabellina AM212. β-Damascone (1) was a relatively good deterrent towards Alphitobius diaperinus and it was behaviorally inactive to Myzus persicae. The racemic compound 2 and its (+)-(S)-enantiomer were stronger antifeedants against A. diaperinus than β-damascone (1), in the case of M. persicae only (+)-(S)-(2) exhibited the deterrent properties.     

Use of dry yeast cells as a cheap nitrogen source for lactic acid production by thermophilic Bacillus coagulans WCP10-4? ?

Dry yeast cells (DYC) were used as a cheap nitrogen source to replace expensive yeast extract (YE) for L-lactic acid production by thermophilic Bacillus coagulans. Cassava starch (200 g·L⁻¹) was converted to L-lactic acid by simultaneous saccharification and fermentation using Bacillus coagulans WCP10-4 at 50 °C in the presence of 20 g·L⁻¹ of DYC, giving 148.1 g·L⁻¹ of L-lactic acid at 27 h with a productivity of 5.5 g·L⁻¹·h⁻¹ and a yield of 92%. In contrast, 154.4 g·L⁻¹ of lactic acid was produced at 24 h with a productivity of 6.4 g·L⁻¹·h⁻¹ and a yield of 96% when equal amount of YE was used under the same conditions. Use of pre-autolyzed DYC at 50 °C for overnight slightly improved the lactic acid titer (154.5 g·L⁻¹) and productivity (7.7 g·L⁻¹·h⁻¹) but gave the same yield (96%).     

Blocking the Function of Inflammatory Cytokines and Mediators by Using IL-10 and TGF-β: A Potential Biological Immunotherapy for Intervertebral Disc Degeneration in a Beagle Model

The debilitating effects of lower back pain are a major health issue worldwide. A variety of factors contribute to this, and oftentimes intervertebral disk degeneration (IDD) is an underlying cause of this disorder. Inflammation contributes to IDD, and inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, play key roles in the pathology of IDD. Therefore, the development of treatments that inhibit the expression and/or effects of TNF-α and IL-1β in IDD patients should be a promising therapeutic approach to consider. This study characterized the potential to suppress inflammatory cytokine production in degenerative intervertebral disc (NP) cells by treatment with IL-10 and TGF-β in a canine model of IDD. IDD was induced surgically in six male beagles, and degenerative NP cells were isolated and cultured for in vitro studies on cytokine production. Cultured degenerative NP cells were divided into four experimental treatment groups: untreated control, IL-10-treated, TGF-β-treated, and IL-10- plus TGF-β-treated cells. Cultured normal NP cells served as a control group. TNF-α expression was evaluated by fluorescence activated cell sorting (FACS) analysis and enzyme-linked immunosorbent assay (ELISA); moreover, ELISA and real-time PCR were also performed to evaluate the effect of IL-10 and TGF-β on NP cell cytokine expression in vitro. Our results demonstrated that IL-10 and TGF-β treatment suppressed the expression of IL-1β and TNF-α and inhibited the development of inflammatory responses. These data suggest that IL-10 and TGF-β should be evaluated as therapeutic approaches for the treatment of lower back pain mediated by IDD.