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Not all amide bonds are created equally. The purpose of the present paper is the reinterpretation of the amide group by means of two concepts: amidicity and carbonylicity. These concepts are meant to provide a new viewpoint in defining the stability and reactivity of amides. With the help of simple quantum-chemical calculations, practicing chemists can easily predict the outcome of a desired process. The main benefit of the concepts is their simplicity. They provide intuitive, but quasi-thermodynamic data, making them a practical rule of thumb for routine use. In the current paper we demonstrate the performance of our methods to describe the chemical character of an amide bond strength and the way of its activation methods. Examples include transamidation, acyl transfer and amide reductions. Also, the method is highly capable for simple interpretation of mechanisms for biological processes, such as protein splicing and drug mechanisms. Finally, we demonstrate how these methods can provide information about photo-activation of amides, through the examples of two caged neurotransmitter derivatives. [ABSTRACT FROM AUTHOR]

In this work, the catalytic mechanism of loganic acid methyltransferase was characterized at the molecular level. This enzyme is responsible for the biosynthesis of loganin, which is a precursor for a wide range of biologically active compounds. Due to the lack of detailed knowledge about this process, the aim of this study was the analysis of the structure and activity of loganic acid methyltransferase. Using molecular dynamics (MD) simulations, the native structure of the complex was reconstructed, and the key interactions between the substrate and loganic acid methyltransferase were investigated. Subsequently, the structures obtained from the simulations were used for quantum chemical (QM) calculations. The QM calculations allowed for the exploration of the energetic aspects of the reaction and the characterization of its mechanism. The results obtained in this study suggest the existence of two patterns of interactions between loganic acid methyltransferase and the substrate. The role of residue Q38 in the binding and orientation of the substrate's carboxyl group was also demonstrated. By employing a combined MD and QM approach, the experimental reaction barrier was reproduced, and detailed insights into the enzymatic activity mechanism of loganic acid methyltransferase were revealed. [ABSTRACT FROM AUTHOR]

To successfully design and optimize the application of hydrogel matrices one has to effectively combine computational design tools with experimental methods. In this context, one of the most promising techniques is molecular modeling, which requires however accurate molecular models representing the investigated material. Although this method has been successfully used over the years for predicting the properties of polymers, its application to biopolymers, including gelatin, is limited. In this paper we provide a method for creating an atomistic representation of gelatin based on the modified FASTA codes of natural collagen. We show that the model created in this manner reproduces known experimental values of gelatin properties like density, glass-rubber transition temperature, WAXS profile and isobaric thermal expansion coefficient. We also present that molecular dynamics using the INTERFACE force field provides enough accuracy to track changes of density, fractional free volume and Hansen solubility coefficient over a narrow temperature regime (273–318 K) with 1 K accuracy. Thus we depict that using molecular dynamics one can predict properties of gelatin biopolymer as an efficient matrix for immobilization of various bioactive compounds, including enzymes. [ABSTRACT FROM AUTHOR]

Rapid and accurate discrimination of Chrysanthemum varieties is very important for producers, consumers and market regulators. The feasibility of using hyperspectral imaging combined with deep convolutional neural network (DCNN) algorithm to identify Chrysanthemum varieties was studied in this paper. Hyperspectral images in the spectral range of 874–1734 nm were collected for 11,038 samples of seven varieties. Principal component analysis (PCA) was introduced for qualitative analysis. Score images of the first five PCs were used to explore the differences between different varieties. Second derivative (2nd derivative) method was employed to select optimal wavelengths. Support vector machine (SVM), logistic regression (LR), and DCNN were used to construct discriminant models using full wavelengths and optimal wavelengths. The results showed that all models based on full wavelengths achieved better performance than those based on optimal wavelengths. DCNN based on full wavelengths obtained the best results with an accuracy close to 100% on both training set and testing set. This optimal model was utilized to visualize the classification results. The overall results indicated that hyperspectral imaging combined with DCNN was a very powerful tool for rapid and accurate discrimination of Chrysanthemum varieties. The proposed method exhibited important potential for developing an online Chrysanthemum evaluation system. [ABSTRACT FROM AUTHOR]

To highlight the importance of the spices in the Mediterranean diet, the aim of the paper was to study the essential oil compositions and to clarify the potential differences in the biological activities of the three cardamom species. In the study, we compared the phytochemical profiles and biological activities of essential oils from Elettaria cardamomum, Aframomum corrorima and Amomum subulatum. The oils were analyzed using the GC and GC/MS techniques and were mainly constituted of the oxygenated monoterpenes which represents 71.4%, 63.0%, and 51.0% of all compounds detected in E. cardamomum, A. corrorima and A. subulatum essential oils, respectively, 1,8-cineole was the main common compound between the tree tested volatile oil. The essential oils showed significant antimicrobial activity against Gram-positive and Gram-negative microorganisms tested especially the fungal strains. The Ethiopian cardamom was the most active essential oil with fungal growth inhibition zone ranging from 12.67 to 34.33 mm, MICs values ranging from 0.048 to 0.19 mg/mL, and MBCs values from 0.19 to 1.75 mg/mL. The three tested essential oils and their main component (1,8-cineole) significantly increased the production of elastase and protease production, and motility in P. aeruginosa PAO1 in a dose dependent manner. In fact, at 10 mg/mL concentration, the three essential oils showed more than 50% of inhibition of elastolytic and proteolytic activities in P. aeruginosa PAO1. The same oils inhibited also the violacein production in C. violaceum strain. It was also noticed that at high concentrations, the A. corrorima essential oil significantly inhibited the germination of radish. A thorough knowledge of the biological and safety profiles of essential oils can produce applications of economic importance. [ABSTRACT FROM AUTHOR]

Osimertinib, a new-generation inhibitor of the epidermal growth factor, has been used for the clinical treatment of advanced T790M mutation-positive tumors. In this research, an original analysis method was established for the quantification of osimertinib by ultra-performance liquid chromatography with time of flight mass spectrometry (UPLC-TOF-MS) in rat plasma. After protein precipitation with acetonitrile and sorafinib (internal standard, IS), they were chromatographed through a Waters XTerra MS C18 column. The mobile phase was acetonitrile and water (including 0.1% ammonia). The relative standard deviation (RSD) of the intra- and inter-day results ranged from 5.38 to 9.76% and from 6.02 to 9.46%, respectively, and the extraction recovery and matrix effects were calculated to range from 84.31 to 96.14% and from 91.46 to 97.18%, respectively. The results illustrated that the analysis method had sufficient specificity, accuracy and precision. Meanwhile, the UPLC-TOF-MS method for osimertinib was successfully applied into the pharmacokinetics of SD rats. [ABSTRACT FROM AUTHOR]

Quinazolin-4(3H)-ones have been prepared in one step from 2-aminobenzamides and orthoesters in the presence of acetic acid. Simple 2-aminobenzamides were easily converted to the heterocycles by refluxing in absolute ethanol with 1.5 equivalents of the orthoester and 2 equivalents of acetic acid for 12–24 h. Ring-substituted and hindered 2-aminobenzamides as well as cases incorporating an additional basic nitrogen required pressure tube conditions with 3 equivalents each of the orthoester and acetic acid in ethanol at 110 °C for 12–72 h. The reaction was tolerant towards functionality on the benzamide and a range of structures was accessible. Workup involved removal of the solvent under vacuum and either recrystallization from ethanol or trituration with ether-pentane. Several 5,6-dihydropyrimidin-4(3H)-ones were also prepared from 3-amino-2,2-dimethylpropionamide. All products were characterized by melting point, FT-IR, 1H-NMR, 13C-NMR, and HRMS. [ABSTRACT FROM AUTHOR]

Angiotensin-converting enzymes, ACE and ACE2, are two main elements in the renin–angiotensin system, with a crucial role in the regulation of blood pressure in vertebrates. Previous studies paid much attention to their physiological functions in model organisms, whereas the studies on other animals and related evolution have been sparse. Our present study performed a comprehensive genomic investigation on ace and ace2 genes in vertebrates. We successfully extracted the nucleotide sequences of ace and ace2 genes from high-quality genome assemblies of 36 representative vertebrates. After construction of their evolutionary tree, we observed that most of the phylogenetic positions are consistent with the species tree; however, certain differences appear in coelacanths and frogs, which may suggest a very slow evolutionary rate in the initial evolution of ace and ace2 in vertebrates. We further compared evolutionary rates within the entire sequences of ace and ace2, and determined that ace2 evolved slightly faster than ace. Meanwhile, we counted that the exon numbers of ace and ace2 in vertebrates are usually 25 and 18 respectively, while certain species may occur exon fusion or disruption to decrease or increase their exon numbers. Interestingly, we found three homologous regions between ace and ace2, suggesting existence of gene duplication during their evolutionary process. In summary, this report provides novel insights into vertebrate ace and ace2 genes through a series of genomic and molecular comparisons. [ABSTRACT FROM AUTHOR]

Cyclin-dependent kinase 2 (CDK2) is a potential target for treating cancer. Purine heterocycles have attracted particular attention as the scaffolds for the development of CDK2 inhibitors. To explore the interaction mechanism and the structure–activity relationship (SAR) and to design novel candidate compounds as potential CDK2 inhibitors, a systematic molecular modeling study was conducted on 35 purine derivatives as CDK2 inhibitors by combining three-dimensional quantitative SAR (3D-QSAR), virtual screening, molecular docking, and molecular dynamics (MD) simulations. The predictive CoMFA model (q2 = 0.743, r pred 2 = 0.991), the CoMSIA model (q2 = 0.808, r pred 2 = 0.990), and the Topomer CoMFA model (q2 = 0.779, r pred 2 = 0.962) were obtained. Contour maps revealed that the electrostatic, hydrophobic, hydrogen bond donor and steric fields played key roles in the QSAR models. Thirty-one novel candidate compounds with suitable predicted activity (predicted pIC50 > 8) were designed by using the results of virtual screening. Molecular docking indicated that residues Asp86, Glu81, Leu83, Lys89, Lys33, and Gln131 formed hydrogen bonds with the ligand, which affected activity of the ligand. Based on the QSAR model prediction and molecular docking, two candidate compounds, I13 and I60 (predicted pIC50 > 8, docking score > 10), with the most potential research value were further screened out. MD simulations of the corresponding complexes of these two candidate compounds further verified their stability. This study provided valuable information for the development of new potential CDK2 inhibitors. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD), a common adult-onset neurodegenerative disorder with complex pathological mechanisms, is characterized by the degeneration of dopaminergic nigrostriatal neurons. The present study demonstrated that the herbal medicines Hepad 1 and 2 protected against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity in C57BL/6 mice and SH-SY5Y cells. Hepad 1 and 2 remarkably alleviated the enhanced expression of pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-6, inducible nitric oxide synthase, cyclooxygenase-2, macrophage-1, and phosphorylated iκB-α) and apoptotic signals (Bcl-2-associated X protein, caspase-3, and poly [ADP-ribose] polymerase-1). Additionally, Hepad reduced MPTP-induced oxidative damage by increasing the expression of anti-oxidant defense enzymes (superoxide dismutase and glutathione S-transferase) and downregulating the levels of nicotinamide adenine dinucleotide phosphate oxidase 4. This study also showed that the neuroprotective effects of Hepad include anti-inflammatory, anti-apoptotic, and anti-oxidative properties, in addition to activation of the protein kinase B, extracellular-signal-regulated kinase, and c-Jun N-terminal kinase signaling pathways. Furthermore, oral administration of Hepad 1 and 2 attenuated the death of tyrosine hydroxylase-positive substantia nigra neurons that was induced by 20 mg/kg MPTP. Therefore, our results suggest that Hepad 1 and 2 are useful for treating PD and other disorders associated with neuro-inflammatory, neuro-apoptotic, and neuro-oxidative damage. [ABSTRACT FROM AUTHOR]

A high performance liquid chromatography (HPLC) method was developed for the simultaneous isolation, on a semi-preparative scale, of chavibetol and methyleugenol from the crude essential oil of P. pseudocaryophyllus leaves. The purity of the isolated compounds and their quantifications were developed using GC/FID. Chavibetol was isolated with high purity (98.7%) and mass recovery (94.6%). The mass recovery (86.4%) and purity (85.3%) of methyleugenol were lower than those of chavibetol. Both compounds were identified on the basis of spectral analysis. The results suggest that the method can provide chavibetol with high purity, mass recovery, and productivity from crude essential, which will be used in bioassays against stored insect pests. [ABSTRACT FROM AUTHOR]

Malus hupehensis belongs to the Malus genus (Rosaceae) and is an indigenous wild crabapple of China. This species has received more and more attention, due to its important medicinal, and excellent ornamental and economical, values. In this study, the whole chloroplast (cp) genome of Malus hupehensis, using a Hiseq X Ten sequencing platform, is reported. The M. hupehensis cp genome is 160,065 bp in size, containing a large single copy region (LSC) of 88,166 bp and a small single copy region (SSC) of 19,193 bp, separated by a pair of inverted repeats (IRs) of 26,353 bp. It contains 112 genes, including 78 protein-coding genes (PCGs), 30 transfer RNA genes (tRNAs), and four ribosomal RNA genes (rRNAs). The overall nucleotide composition is 36.6% CG. A total of 96 simple sequence repeats (SSRs) were identified, most of them were found to be mononucleotide repeats composed of A/T. In addition, a total of 49 long repeats were identified, including 24 forward repeats, 21 palindromic repeats, and four reverse repeats. Comparisons of the IR boundaries of nine Malus complete chloroplast genomes presented slight variations at IR/SC boundaries regions. A phylogenetic analysis, based on 26 chloroplast genomes using the maximum likelihood (ML) method, indicates that M. hupehensis clustered closer ties with M. baccata, M. micromalus, and M. prunifolia than with M. tschonoskii. The availability of the complete chloroplast genome using genomics methods is reported here and provides reliable genetic information for future exploration on the taxonomy and phylogenetic evolution of the Malus and related species. [ABSTRACT FROM AUTHOR]

Proanthocyanidins, including polymers with both low and high degrees of polymerization, are the focus of intensive research worldwide due to their high antioxidant activity, medicinal applications, and pharmacological properties. However, the nutritional value of these compounds is limited because they readily form complexes with proteins, polysaccharides, and metal ions when consumed. In this study, we examined the effects of proanthocyanidins with different degrees of polymerization on white mice. Twenty-four male white mice were randomly divided into three groups of eight mice each and fed proanthocyanidins with a low degree of polymerization or a high degree of polymerization or a distilled water control via oral gavage over a 56-day period. We examined the effects of these proanthocyanidins on digestive enzyme activity and nutrient absorption. Compared to the control group, the group fed high-polymer proanthocyanidins exhibited a significant reduction in net body mass, total food intake, food utility rate, amylase activity, protease activity, and major nutrient digestibility (p < 0.05), while the group fed low-polymerization proanthocyanidins only exhibited significant reductions in total food intake, α-amylase activity, and apparent digestibility of calcium and zinc (p < 0.05). Therefore, proanthocyanidins with a high degree of polymerization had a greater effect on digestive enzyme activity and nutrient absorption than did those with a low degree of polymerization. This study lays the foundation for elucidating the relationship between procyanidin polymerization and nutrient uptake, with the aim of reducing or eliminating the antinutritional effects of polyphenols. [ABSTRACT FROM AUTHOR]

Beyond anticoagulation, the therapeutic potential of heparin derivatives and heparan sulfate (HS) mimetics (functionally defined HS mimetics) in oncology is related to their ability to bind and modulate the function of a vast array of HS-binding proteins with pivotal roles in cancer growth and progression. The definition of structural/functional determinants and the introduction of chemical modifications enabled heparin derivatives to be identified with greatly reduced or absent anticoagulant activity, but conserved/enhanced anticancer activity. These studies paved the way for the disclosure of structural requirements for the inhibitory effects of HS mimetics on heparanase, selectins, and growth factor receptor signaling, as well as for the limitation of side effects. Actually, HS mimetics affect the tumor biological behavior via a multi-target mechanism of action based on their effects on tumor cells and various components of the tumor microenvironment. Emerging evidence indicates that immunomodulation can participate in the antitumor activity of these agents. Significant ability to enhance the antitumor effects of combination treatments with standard therapies was shown in several tumor models. While the first HS mimetics are undergoing early clinical evaluation, an improved understanding of the molecular contexts favoring the antitumor action in certain malignancies or subgroups is needed to fully exploit their potential. [ABSTRACT FROM AUTHOR]

A new synthesis of substituted acridines is achieved by palladium-catalyzed addition of terminal acetylenes between the aryl rings of bis(2-bromophenyl)amine. By including a diamine base and elevating the temperature, the reaction pathway favors the formation of acridine over a double Sonogashira reaction to form bis(tolan)amine. This method is demonstrated with several aryl-alkynes and alkyl-alkynes. [ABSTRACT FROM AUTHOR]

Inflammation is a major contributing factor to the progression of atherosclerosis. Ginsenoside Rb1 (Rb1), an active saponin of Panax notoginseng, has been found to exert beneficial effects on inflammation and oxidative stress. This study investigated the ability of Rb1 to inhibit the formation of atherosclerotic plaques and the potential mechanisms. In this study, the effects of Rb1 on the development of atherosclerosis were investigated in ApoE-/- deficient mice fed with a western diet. Mice were intragastrically administrated with Rb1 (10 mg/kg) for 8 weeks. This study is that ginsenoside Rb1 exerted an inhibitory effect on early atherosclerosis in ApoE-/- mice via decreasing body weight and food intake daily, upregulating the lipid levels of serum plasma, including those of TC, TG and LDL-C and HDL-C and reducing the atherosclerotic plaque area, suppressing inflammatory cytokines (levels of IL-1β, IL-6 and TNF-α) in the serum of ApoE-/- mice, changing the expression levels of BCL-2, BAX, cleaved caspase-3 and cleaved caspase-9 and weakening apoptosis associated with anti-inflammatory activity. Hence, all these effects against atherosclerosis were tightly associated with regulation of necrosis or apoptosis associated with anti-inflammatory activity. Additionally, the results found that ginsenoside Rb1 increased autophagy flux to inhibit apoptosis via acceleration of autophagy by promoting transformation of LC3 from type I to type II in high-fat diet-induced atherosclerosis in ApoE-/- mice. This finding, along with those of the previous study, provides evidence that Rb1 promotes the process of autophagy to protect against atherosclerosis via regulating BCL-2 family-related apoptosis. These results indicate that Rb1 exhibits therapeutic effects in atherosclerosis by reversing the imbalance between apoptosis and autophagy. [ABSTRACT FROM AUTHOR]

With the increasing interest in scarce proteins, reducing the sample volume for circular dichroism (CD) spectroscopy has become desirable. Demagnification of the incident beam size is required to reduce the sample volume for CD spectroscopy detecting transmitted light passed through the sample. In this study, the beam size was demagnified using a focal mirror, and small-capacity sample cells were developed in an attempt to reduce the sample volume. The original beam size was 6 × 6 mm2; we successfully converged it to a size of 25 × 25 μm2 using the Schwarzschild objective (SO). The new sample cell and SO allowed the required sample volume to be reduced to 1/10 (15 → 1.5 μL), when using a 15 μm path length cell. By adopting a smaller sample cell, further sample reduction could be achieved. By using the SO system, the secondary structural contents of the lysine-36 trimethylated histone H3 protein were analyzed. The trimethylation induced the increment of helix structures and decrement of unordered structures. These structural alterations may play a role in regulating cellular function(s), such as DNA damage repair processes. [ABSTRACT FROM AUTHOR]

Combination chemotherapy is a common clinical practice in cancer treatment. Here, cyclic RGD (arginylglycylaspartic acid) peptide was introduced to the surface of lipid/calcium/phosphate (LCP) asymmetric lipid layer nanoparticles for the co-delivery of paclitaxel (PTX) and gemcitabine monophosphate (GMP) (P/G-NPs). The sphere-like morphology of P/G-NPs displays a well-distributed particle size, and high entrapment efficiency and drug loading for both PTX and GMP, with a positive zeta potential. P/G-NPs were stable for up to 15 days. The cellular uptake of these cyclic RGD-modified nanoparticles was significantly higher than that of unmodified nanoparticles over 2 h incubation. Compared with the combination of free PTX and GMP (P/G-Free), P/G-NPs exhibited a longer circulation lifetime and improved absorption for PTX and GMP. Polyethylene glycol was responsible for a higher plasma concentration and a decreased apparent volume of distribution (Vz). Nanoparticles enhanced the drug accumulation in tumors compared with other major organs after 24 h. P/G-NPs nearly halted tumor growth, with little evidence of general toxicity, whereas P/G-Free had only a modest inhibitory effect at 16 mg/kg of GMP and 2.0 mg/kg of PTX. Increased levels of apoptosis within tumors were detected in P/G-NPs group by approximately 43.6% (TUNEL assay). When compared with GMP NPs, PTX NPs, and P/G-Free, P/G-NPs decreased expression of B-cell lymphoma-2 and B-cell lymphoma-extra large proteins, and increased expression of cleaved poly-ADP-ribose polymerase-1. Calreticulin expression in tumors also increased upon the co-delivery of PTX and GMP. The antitumor effect of P/G-NPs is more powerful than P/G-Free, GMP NP, or PTX NP alone, without obvious toxicity. [ABSTRACT FROM AUTHOR]

Convenient labeling of proteins is important for observing its function under physiological conditions. In tissues particularly, heptamethine cyanine dyes (Cy-7) are valuable because they absorb in the near-infrared (NIR) region (750–900 nm) where light penetration is maximal. In this work, we found Cy-7 dyes with a meso-Cl functionality covalently binding to proteins with free Cys residues under physiological conditions (aqueous environments, at near neutral pH, and 37 °C). It transpired that the meso-Cl of the dye was displaced by free thiols in protein, while nucleophilic side-chains from amino acids like Tyr, Lys, and Ser did not react. This finding shows a new possibility for convenient and selective labeling of proteins with NIR fluorescent probes. [ABSTRACT FROM AUTHOR]

In the present study, the preliminary structure and in vitro antitumor activity of three exopolysaccharides (EPSs) from Streptococcus thermophilus CH9 were investigated. Then, three purified fractions of EPS-1a, EPS-2a, and EPS-3a were obtained by chromatography using DEAE-52 cellulose and Sephadex G-100, respectively. The average molecular weight of EPS-1a, EPS-2a, and EPS-3a, were 1.80 × 106, 1.06 × 106 and 1.05 × 106. The monosaccharide composition of EPS-3a was dramatically different from the others. The EPS-1a and EPS-2a were mainly composed of mannose, in a ratio of 69.82% and 57.09%, respectively, while EPS-3a was mainly composed of glucose (63.93%), without mannose. In addition, the surface morphology observed suggested that there were protein particles on the sugar chain of EPS-3a and EPS-3a was a protein-containing polysaccharide. Furthermore, EPS-3a exhibited higher antitumor activity against human liver cancer HepG2 cells in vitro. The antitumor activity of EPS-3a in HepG2 cells was associated with cell apoptosis. HE staining and Hoechst 33342 staining showed that with the treatment of EPS-3a, HepG2 cells had typical morphological changes. Flow cytometry analysis showed that the cell cycle was arrested at G0/G1 phase. [ABSTRACT FROM AUTHOR]

Microbial solubilization applies the natural ability of a microorganism to liberate phosphorus from unavailable structures. The main mechanism recognized to be responsible for the solubilization of phosphorus is the production of different types of organic acids. Three kinds of Bacillus species and three types of raw materials (poultry bones, fish bones, and ash) were tested for solubilization. The following parameters were compared for all discussed cases: pH, specific growth rate, solubilization factor, released phosphorus concentration, and total and individual concentration of organic acids. Utilization of ash brought about the highest specific and maximum specific growth rates. A decrease in pH was observed in most of the discussed cases with the exception of fish bones. At the same time, fish bones had the highest concentration of released P2O5 and the highest total concentration of produced organic acids (gluconic, lactic, acetic, succinic, and propionic) in all discussed cases. The tested Bacillus species produced the mentioned acids with the exception of B. megaterium, where propionic acid was not present. The lactic and acetic acids were those produced in the highest amount. The kind of raw materials and type of Bacillus species used in solubilization had a strong influence on the kind of organic acids that were detected in the broth culture and its total concentration, which had a direct influence on the amount of released phosphorus. The combination of Bacillus megaterium with the fish bones at 5 g/L is proposed as the pair that gives the highest concentration of released phosphorus (483 ± 5 mg/L). [ABSTRACT FROM AUTHOR]

We previously reported that 5-[4-(4-fluorophenoxy) phenyl] methylene-3-{4-[3-(4-methylpiperazin-1-yl)propoxy]phenyl}-2-thioxo-4-thiazolidinone dihydrochloride (KSK05104) has potent, selective and metabolically stable IKKβ inhibitory activities. However, the apoptosis-inducing of KSK05104 and its underlying mechanism have not yet been elucidated in human colon cancer cells. We show that KSK05104 triggered apoptosis, as indicated by externalization of Annexin V-targeted phosphatidylserine residues in HT-29 and HCT-116 cells. KSK05104 induced the activation of caspase-8, -9, and -3, and the cleavage of poly (ADP ribose) polymerase-1 (PARP-1). KSK05104-induced apoptosis was significantly suppressed by pretreatment with z-VAD-fmk (a broad caspase inhibitor). KSK05104 also induced release of cytochrome c (Cyt c), apoptosis inducing factor (AIF), and endonuclease G (Endo G) by damaging mitochondria, resulting in caspase-dependent and -independent apoptotic cell death. KSK05104 triggered endoplasmic reticulum (ER) stress and changed the intracellular calcium level ([Ca2+]i). Interestingly, treatment with KSK05104 activated not only ER stress marker proteins including inositol-requiring enzyme 1-alpha (IRE-1α) and protein kinase RNA-like endoplasmic reticulum kinase (PERK), but also μ-calpain, and caspase-12 in a time-dependent manner. KSK05104-induced apoptosis substantially decreased in the presence of BAPTA/AM (an intracellular calcium chelator). Taken together, these results suggest that mitochondrial dysfunction and ER stress contribute to KSK05104-induced apoptosis in human colon cancer cells. [ABSTRACT FROM AUTHOR]

O6-methylguanine-DNA methyltransferase (MGMT), a unique DNA repair enzyme, can confer resistance to DNA anticancer alkylating agents that modify the O6-position of guanine. Thus, inhibition of MGMT activity in tumors has a great interest for cancer researchers because it can significantly improve the anticancer efficacy of such alkylating agents. In this study, we performed a quantitative structure activity relationship (QSAR) and classification study based on a total of 134 base analogs related to their ED50 values (50% inhibitory concentration) against MGMT. Molecular information of all compounds were described by quantum chemical descriptors and Dragon descriptors. Genetic algorithm (GA) and multiple linear regression (MLR) analysis were combined to develop QSAR models. Classification models were generated by seven machine-learning methods based on six types of molecular fingerprints. Performances of all developed models were assessed by internal and external validation techniques. The best QSAR model was obtained with Q2Loo = 0.83, R2 = 0.87, Q2ext = 0.67, and R2ext = 0.69 based on 84 compounds. The results from QSAR studies indicated topological charge indices, polarizability, ionization potential (IP), and number of primary aromatic amines are main contributors for MGMT inhibition of base analogs. For classification studies, the accuracies of 10-fold cross-validation ranged from 0.750 to 0.885 for top ten models. The range of accuracy for the external test set ranged from 0.800 to 0.880 except for PubChem-Tree model, suggesting a satisfactory predictive ability. Three models (Ext-SVM, Ext-Tree and Graph-RF) showed high and reliable predictive accuracy for both training and external test sets. In addition, several representative substructures for characterizing MGMT inhibitors were identified by information gain and substructure frequency analysis method. Our studies might be useful for further study to design and rapidly identify potential MGMT inhibitors. [ABSTRACT FROM AUTHOR]

The three-point adsorption of tripod-shaped molecules enables the formation of robust self-assembled monolayers (SAMs) on solid surfaces, where the component molecules are fixed in a strictly upright orientation. In the present study, SAMs of a rigid molecular tripod consisting of an adamantane core and three CH2SH groups were employed to arrange ferrocene on a gold surface through oligo(p-phenyleneethynylene) linkers. Cyclic voltammetry of the monolayers demonstrated high surface coverage of ferrocene, yet the molecular interaction among adjacent ferrocene units was negligible. This was because of the extended intermolecular distance caused by the bulky tripod framework. The rates of electron transfer from the ferrocene to the gold surface through different linker lengths were determined by electrochemical measurements, from which the decay factor for oligo(p-phenyleneethynylene) wire was evaluated. [ABSTRACT FROM AUTHOR]

Ischemic injuries and local hypoxia can result in osteocytes dysfunction and play a key role in the pathogenesis of avascular osteonecrosis. Conventional imaging techniques including magnetic resonance imaging (MRI) and computed tomography (CT) can reveal structural and functional changes within bony anatomy; however, characterization of osteocyte behavioral dynamics in the setting of osteonecrosis at the single cell resolution is limited. Here, we demonstrate an optical approach to study real-time osteocyte functions in vivo. Using nicotinamide adenine dinucleotide (NADH) as a biomarker for metabolic dynamics in osteocytes, we showed that NADH level within osteocytes transiently increase significantly after local ischemia through non-invasive photo-induced thrombosis of afferent arterioles followed by a steady decline. Our study presents a non-invasive optical approach to study osteocyte behavior through the modulation of local environmental conditions. Thus it provides a powerful toolkit to study cellular processes involved in bone pathologies in vivo. [ABSTRACT FROM AUTHOR]

Palm curtain was selected as carrier to immobilize Bacillus circulans ATCC 21783 to produce β-cyclodextrin (β-CD). The influence for immobilization to CGTase activity was analyzed to determine the operation stability. 83.5% cyclodextrin glycosyltransferases (CGTase) of the 1st cycle could be produced in the 7th cycle for immobilized cells, while only 28.90% CGTase was produced with free cells. When palm curtain immobilized cells were reused at the 2th cycle, enzyme activities were increased from 5003 to 5132 U/mL, which was mainly due to physical adsorption of cells on palm curtain with special concave surface structure. Furthermore, conditions for expanded culture of immobilized cells in a 5 L fermentation tank were optimized through specific rotation speed procedure (from 350 r/min to 450 r/min with step size of 50 r/min) and fixed ventilation capacity (4.5 L/min), relations between biomass, enzyme activity, pH, and oxygen dissolution was investigated, and the fermentation periods under the two conditions were both 4 h shorter. Compared with free cell, immobilized cell was more stable, effective, and had better application potential in industries. [ABSTRACT FROM AUTHOR]

Knowledge about the metal content of wine is very important, for many reasons. Depending on the element, its quantity varies in wine from ng/L to mg/L. Despite the fact that metals are not directly connected to the taste and aroma of the wine, their content should be determined and controlled, because excess is undesirable, and in some cases prohibited, due to potential toxicity. Several analytical procedures for metal determination are applied. However, due to sensitivity, low limit of detection and speed of analysis, inductively coupled plasma-mass spectrometry (ICP-MS) is one of the most frequently used techniques. The aim of this study was to reveal specific relationships between the wine samples or between the chemical variables in order to classify the wines according to their metal content by application of chemometric analysis. For metals content determination, two techniques, ICP-MS and inductively coupled plasma-optical emission spectrometry (ICP-OES), were applied. Data obtained showed that none of the wine samples surpassed the toxic levels reported for metals in the literature, thus, these wines appeared to be safe as regards the risk associated with the potentially toxic metals intake. However, specific correlations between metals and specific aspects of the wines themselves have been found. [ABSTRACT FROM AUTHOR]

The regioselective α-glucosylation of hesperetin was achieved by a transglycosylation reaction catalyzed by cyclodextrin glucanotransferase (CGTase) from Thermoanaerobacter sp. using soluble starch as glucosyl donor. By combining mass spectrometry (ESI-TOF) and 2D-NMR analysis, the main monoglucosylated derivative was fully characterized (hesperetin 7-O-α-d-glucopyranoside). In order to increase the yield of monoglucoside, several reaction parameters were optimized: Nature and percentage of cosolvent, composition of the aqueous phase, glucosyl donor, temperature, and the concentrations of hesperetin and soluble starch. Under the optimal conditions, which included the presence of 30% of bis(2-methoxyethyl) ether as cosolvent, the maximum concentration of monoglucoside was approximately 2 mM, obtained after 24 h of reaction. To our knowledge, this is the first report of direct glucosylation of hesperetin employing free enzymes instead of whole cells. [ABSTRACT FROM AUTHOR]

C118P, a phosphate prodrug of C118, which is a novel microtubule protein inhibitor, is currently under Phase I clinical development in China for treating ovarian cancer and lung cancer. The preclinical pharmacokinetics of prodrug C118P and its metabolite C118 were extensively characterized in vivo in mice, rats, and dogs and in vitro to support the further development of C118P. The preclinical tissue distribution and excretion were investigated in rats. Plasma protein binding in mice, rat, and human, and hepatic microsomal metabolic stability in mice, rat, dog, monkey, and human, were also evaluated. The (AUC0-inf) and C30s of C118P at 50 mg/kg in rats and 6 mg/kg in dogs, and the C2min of C118 at 6 mg/kg in dogs increased less than the dosage increase, suggested nonlinear pharmacokinetic occurred at high dose. As a prodrug, C118P can be quickly hydrolyzed into C118 after an intravenous administration. The unbound C118 in plasma is slightly higher than C118P. C118P can hardly penetrate the tissue, while C118 can distribute widely into tissues. In tumor-bearing nude mice, the concentration of C118 is high in lung, ovary, and tumor, with an extended half-life in tumor. C118P is a promising candidate prodrug for further clinical development. [ABSTRACT FROM AUTHOR]

CM-Str (4-(Chloromethyl)styrene) was used as a useful starting material for the construction of a series of functional monomers. Substitution of the chlorine to the corresponding azide was performed, and the reduction of the azide proceeded smoothly to afford an aminostyrene, which was used as a common precursor for the preparation of functional monomers. Condensation of the amine with a fluorophore, biotin and carbohydrate was accomplished. Among the monomers, a carbohydrate monomer was polymerized with or without acrylamide as a model polymerization to yield the corresponding water-soluble glycopolymers, and biological evaluations of the glycopolymers for a lectin, and wheat germ agglutinin (WGA), were carried out on the basis of the fluorescence change of tryptophan in the WGA. [ABSTRACT FROM AUTHOR]

An 82-residue-long chimeric peptide was synthesised by solid phase peptide synthesis (SPPS), following the Fmoc protocol. Microwave (MW) radiation-assisted synthesis was compared to standard synthesis using low loading (0.20 mmol/g) of polyethylene glycol (PEG) resin. Similar synthetic difficulties were found when the chimeric peptide was obtained via these two reaction conditions, indicating that such difficulties were inherent to the sequence and could not be resolved using MW; by contrast, the number of coupling cycles and total reaction time became reduced whilst crude yield and percentage recovery after purification were higher for MW radiation-assisted synthesis. [ABSTRACT FROM AUTHOR]

Five metabolites including two new ones, prochaetoviridin A (1) and chaetoindolin A (2), were isolated from the endophytic fungus Chaetomium globosum CDW7. Compounds 1 and 2 were characterized as an isocoumarin and an indole alkaloid derivative, respectively, with their structures elucidated by comprehensive spectroscopic analyses including high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), NMR, and circular dichroism (CD) comparison. Compounds 3–5 were identified as chaetoviridin A, chaetoglobosin R, and chaetoglobosin T, respectively. Chaetoviridin A (3) exhibited antifungal activity against Sclerotinia sclerotiorum with an EC50 value of 1.97 μg/mL. In vivo test showed that 3 displayed a protective efficacy of 64.3% against rape Sclerotinia rot at the dosage of 200 μg/mL, comparable to that of carbendazim (69.2%). [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) as a global health problem has clinical manifestations ranging from simple non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), cirrhosis, and cancer. The role of different types of fatty acids in driving the early progression of NAFL to NASH is not understood. Lipid overload causing lipotoxicity and inflammation has been considered as an essential pathogenic factor. To correlate the lipid profiles with cellular lipotoxicity, we utilized palmitic acid (C16:0)- and especially unprecedented palmitoleic acid (C16:1)-induced lipid overload HepG2 cell models coupled with lipidomic technology involving labeling with stable isotopes. C16:0 induced inflammation and cell death, whereas C16:1 induced significant lipid droplet accumulation. Moreover, inhibition of de novo sphingolipid synthesis by myriocin (Myr) aggravated C16:0 induced lipoapoptosis. Lipid profiles are different in C16:0 and C16:1-treated cells. Stable isotope-labeled lipidomics elucidates the roles of specific fatty acids that affect lipid metabolism and cause lipotoxicity or lipid droplet formation. It indicates that not only saturation or monounsaturation of fatty acids plays a role in hepatic lipotoxicity but also Myr inhibition exasperates lipoapoptosis through ceramide in-direct pathway. Using the techniques presented in this study, we can potentially investigate the mechanism of lipid metabolism and the heterogeneous development of NAFLD. [ABSTRACT FROM AUTHOR]

The aim of this study was to identify bioactive compounds from leaves of the invasive plant Xanthium spinosum and assess their phytotoxic activity. Activity-guided fractionation led to the isolation of 6 bioactive compounds: xanthatin (1), 1α,5α-epoxyxanthatin (2), 4-epiisoxanthanol (3), 4-epixanthanol (4), loliolide (5) and dehydrovomifoliol (6). Of them, compounds 2–6 were isolated from the X. spinosum for the first time. The structures of 1–6 were elucidated on the basis of extensive NMR studies and ESI-MS measurements as well as comparison with literature data. All of compounds were evaluated for their phytotoxic activity. Among them, compounds 1–4 exhibited stronger activity on 2 receiver plants compared with the other 2 compounds, with xanthatin (1) being the most potent compound, which suppressed root growth of the dicot plant Amaranthus retroflexus by 32.5%, 39.4%, 84.7% when treated xanthatin (1) at 5, 20, and 100 µg/mL, while for the monocot plant, root growth was inhibited by 14.7%, 28.0%, and 40.0%, respectively. Seedling growth was nearly completely inhibited when the concentration of xanthanolides increased to 500 µg/mL, whereas there was still some seedling growth when loliolide (5) and dehydrovomifoliol (6) were applied at the same concentration. Dehydrovomifoliol (6) did not negatively affect seedling growth of P. annua at all tested concentrations, and root length was still 42.0% of the control when the highest concentration 500 µg/mL was used. This is the first report of the phytotoxicity of 1α,5α-epoxyxanthatin (2), 4-epiisxanthanol (3) and 4-epixanthanol (4). These compounds have the potential to be utilized as natural herbicides, especially 4-epiisoxanthanol (3), which exhibited significant selective activity between the dicot and monocot plants. On the other hand, whether these bioactive substances serve as allelochemicals to facilitate the invasion success of X. spinosum needs to be further studied. [ABSTRACT FROM AUTHOR]

The article presents the results of spectroscopic studies focused on a selected compound from the 1,3,4-thiadiazole group—2-(4-fluorophenylamino)-5-(2,4-dihydroxybenzeno)-1,3,4-thia-diazole (FABT)—in a micellar system formed by Triton X-100, a non-ionic detergent. Fluorescence measurements revealed the phenomenon of dual fluorescence whose emergence is related to the particular molecular organisation of the compound, which depends both on the concentration of the detergent and, most of all, the concentration of the compound itself. Dual fluorescence of FABT in a micellar system was observed for the compound dissolved in a methanol aqueous system, i.e., an environment wherein the dual fluorescence of the compound had never been reported before. Based on the interpretation of UV-Vis electronic absorption, resonance light scattering (RLS), emission and excitation fluorescence spectra, as well as measurements of dynamic light scattering (DLS) and Principal Component Analysis (PCA), we were able to relate the occurrence of this effect to the process of molecular aggregation taking place between FABT molecules in the micellar system in question. Results of fluorescence spectra measurements and time-correlated single photon counting (TCSPC) indicate that dual fluorescence occurs at detergent concentrations necessary to form micellar systems, which in turn facilitate the process of aggregation of FABT molecules. The correlation between the observed fluorescence effects and the previous measurements performed for analogues from this group suggests the possibility of charge transfer (CT) within the range of detergent concentrations wherein the aforementioned fluorescence effects are observed. It ought to be emphasised that this type of fluorescence effects are relatively easy to induce, which predisposes this groups of fluorophores as ideal fluorescence probes in the context of biological samples. [ABSTRACT FROM AUTHOR]

Twenty-one volatile terpenes and terpenoids were found in Monomoriumchinense Santschi (Hymenoptera: Formicidae), a native Chinese ant, by using headspace solid-phase microextraction (HS-SPME) coupled with gas-phase chromatography and mass spectrometry (GC-MS), which makes this ant one of the most prolific terpene producers in insect. A sesquiterpene with unknown structure (terpene 1) was the main terpene in workers and neocembrene in queens. Terpenes and terpenoids were detected in poison, Dufour's and mandibular glands of both workers and queens. Worker ants raised on a terpene-free diet showed the same terpene profile as ants collected in the field, indicating that denovo terpene and terpenoid synthesis occurs in M. chinense. [ABSTRACT FROM AUTHOR]

Hepatic stellate cells (HSCs) are involved in the pathogenesis of liver fibrosis. Resveratrol, 3,5,4′-trihydroxystilbene, is a dietary polyphenol found in natural food products. Here, we evaluated the anti-proliferative effects of a synthetic resveratrol derivative, 3,5-diethoxy-3′-hydroxyresveratrol (DEHR), on HSCs. Flow cytometry and Western blot analyses showed that DEHR induces apoptosis through the upregulation of cleaved caspase-3 and poly (ADP-ribose) polymerase expression and reduction in the level of an anti-apoptotic protein B-cell lymphoma 2 (Bcl2). As caveolin-1 (CAV1), a competitive inhibitor of heme oxygenase 1 (HO-1), is related to apoptotic proteins in hepatic cells, we focused on the role of CAV1 in DEHR-induced apoptosis in HSCs through Western blot analyses. Our results showed that the inhibitory effect of DEHR on cell viability was stronger in HO-1 siRNA-transfected cells but weakened in CAV1 siRNA-transfected cells. Collagen concentration was significantly reduced, whereas CAV1 expression increased after treatment of a bile duct ligation injury-induced liver fibrosis model with DEHR for four weeks. We confirmed that DEHR treatment significantly reduced fibrous hyperplasia around the central veins, using hematoxylin and eosin and Sirius red staining. DEHR ameliorates liver fibrosis in vitro and in vivo, possibly through a mechanism involving CAV1. [ABSTRACT FROM AUTHOR]

As a ubiquitous molecule, melatonin plays a crucial role in tolerance to multiple stresses in plants. In the present work, we report the role of exogenous melatonin in relieving oxidative stress induced by methyl viologen (MV) in poplar (Populus alba × Populus glandulosa) leaf. Leaf discs pretreated with melatonin exhibited increased tolerance to MV-mediated oxidative stress. It was observed that melatonin pretreatment effectively reduced membrane damage and lipid oxidation as demonstrated by decreased relative electrolyte leakage and malonaldehyde content in poplar leaf discs. Exogenous melatonin also stimulated activities of antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and ascorbate peroxidase (APX), and enhanced accumulation of non-enzymatic antioxidants of AsA and GSH in leaf discs exposed to MV. In addition, pretreatment of melatonin prompted expression of genes for those antioxidant enzymes. Notably, exogenous melatonin increased expression of P5CS, a key gene for proline biosynthesis, under MV treatment. It was further observed that pretreatment with melatonin boosted activity of P5CS as well as accumulation of proline in leaf discs under MV-mediated oxidative stress. Collectively, this work provides evidence for the ameliorative effect of melatonin on MV-induced oxidative stress in poplar leaf. [ABSTRACT FROM AUTHOR]

Cyclooxygenase 2 (COX-2) is an inducible enzyme responsible for the conversion of arachidonic acid into the prostaglandins, PGG2 and PGH2. Expression of this enzyme increases in inflammation. Therefore, the development of probes for imaging COX-2 with positron emission tomography (PET) has gained interest because they could be useful for the study of inflammation in vivo, and for aiding anti-inflammatory drug development targeting COX-2. Nonetheless, effective PET radioligands are still lacking. We synthesized eleven COX-2 inhibitors based on a 2(4-methylsulfonylphenyl)pyrimidine core from which we selected three as prospective PET radioligands based on desirable factors, such as high inhibitory potency for COX-2, very low inhibitory potency for COX-1, moderate lipophilicity, and amenability to labeling with a positron-emitter. These inhibitors, namely 6-methoxy-2-(4-(methylsulfonyl)phenyl-N-(thiophen-2ylmethyl)pyrimidin-4-amine (17), the 6-fluoromethyl analogue (20), and the 6-(2-fluoroethoxy) analogue (27), were labeled in useful yields and with high molar activities by treating the 6-hydroxy analogue (26) with [11C]iodomethane, [18F]2-fluorobromoethane, and [d2-18F]fluorobromomethane, respectively. [11C]17, [18F]20, and [d2-18F]27 were readily purified with HPLC and formulated for intravenous injection. These methods allow these radioligands to be produced for comparative evaluation as PET radioligands for measuring COX-2 in healthy rhesus monkey and for assessing their abilities to detect inflammation. [ABSTRACT FROM AUTHOR]

Dendrimers are nanoscopic compounds, which are monodispersed, and they are generally considered as homogeneous. PAMAM (polyamidoamine) was introduced in 1985, by Donald A. Tomalia, as a new class of polymers, named 'starburst polymers'. This important contribution of Professor Tomalia opened a new research field involving nanotechnological approaches. From then on, many groups have been using PAMAM for diverse applications in many areas, including biomedical applications. The possibility of either linking drugs and bioactive compounds, or entrapping them into the dendrimer frame can improve many relevant biological properties, such as bioavailability, solubility, and selectivity. Directing groups to reach selective delivery in a specific organ is one of the advanced applications of PAMAM. In this review, structural and safety aspects of PAMAM and its derivatives are discussed, and some relevant applications are briefly presented. Emphasis has been given to gene delivery and targeting drugs, as advanced delivery systems using PAMAM and an incentive for its use on neglected diseases are briefly mentioned. [ABSTRACT FROM AUTHOR]

Tagetes (marigold) is native to America, and its cultivation currently extends to other countries in Africa, Asia, and Europe. Many species of this genus, such as T. minuta, T. erecta, T. patula, and T. tenuifolia, are cultivated as ornamental plants and studied for their medicinal properties on the basis of their use in folk medicine. Different parts of the Tagetes species are used as remedies to treat various health problems, including dental, stomach, intestinal, emotional, and nervous disorders, as well as muscular pain, across the world. Furthermore, these plants are studied in the field of agriculture for their fungicidal, bactericidal, and insecticidal activities. The phytochemical composition of the extracts of different Tagetes species parts are reported in this work. These compounds exhibit antioxidant, antiinflammatory, and enzyme inhibitory properties. Cultivation and the factors affecting the chemical composition of Tagetes species are also covered. In the current work, available literature on Tagetes species in traditional medicine, their application as a food preservative, and their antimicrobial activities are reviewed. [ABSTRACT FROM AUTHOR]

Leukemia, the malignancy of the hematopoietic system accounts for 10% of cancer cases with poor overall survival rate in adults; therefore, there is a high unmet medical need for the development of novel therapeutics. Eight imidazo[1,2-b]pyrazole-7-carboxamides have been tested for cytotoxic activity against five leukemia cell lines: Acute promyelocytic leukemia (HL-60), acute monocytic leukemia (THP-1), acute T-lymphoblastic leukemia (MOLT-4), biphenotypic B myelomonocytic leukemia (MV-4-11), and erythroleukemia (K-562) cells in vitro. Imidazo[1,2-b]pyrazole-7-carboxamides hampered the viability of all five leukemia cell lines with different potential. Optimization through structure activity relationship resulted in the following IC50 values for the most effective lead compound DU385: 16.54 nM, 27.24 nM, and 32.25 nM on HL-60, MOLT-4, MV-4-11 cells, respectively. Human primary fibroblasts were much less sensitive in the applied concentration range. Both monolayer or spheroid cultures of murine 4T1 and human MCF7 breast cancer cells were less sensitive to treatment with 1.5–10.8 μM IC50 values. Flow cytometry confirmed the absence of necrosis and revealed 60% late apoptotic population for MV-4-11, and 50% early apoptotic population for HL-60. MOLT-4 cells showed only about 30% of total apoptotic population. Toxicogenomic study of DU385 on the most sensitive MV-4-11 cells revealed altered expression of sixteen genes as early (6 h), midterm (12 h), and late response (24 h) genes upon treatment. Changes in ALOX5AP, TXN, and SOD1 expression suggested that DU385 causes oxidative stress, which was confirmed by depletion of cellular glutathione and mitochondrial membrane depolarization induction. Imidazo[1,2-b]pyrazole-7-carboxamides reported herein induced apoptosis in human leukemia cells at nanomolar concentrations. [ABSTRACT FROM AUTHOR]

Platycodon grandiflorum (PG) is widely used in Asia for its various beneficial effects. Although many studies were conducted to understand the molecular mechanisms of PG, it is still unclear how the combinations of multiple ingredients work together to exert its therapeutic effects. The aim of the present study was to provide a comprehensive review of the systems-level mechanisms of PG by adopting network pharmacological analysis. We constructed a compound–target–disease network for PG using experimentally validated and machine-leaning-based prediction results. Each target of the network was analyzed based on previously known pharmacological activities of PG. Gene ontology analysis revealed that the majority of targets were related to cellular and metabolic processes, responses to stimuli, and biological regulation. In pathway enrichment analyses of targets, the terms related to cancer showed the most significant enrichment and formed distinct clusters. Degree matrix analysis for target–disease associations of PG suggested the therapeutic potential of PG in various cancers including hepatocellular carcinoma, gastric cancer, prostate cancer, small-cell lung cancer, and renal cell carcinoma. We expect that network pharmacological approaches will provide an understanding of the systems-level mechanisms of medicinal herbs and further develop their therapeutic potentials. [ABSTRACT FROM AUTHOR]

Genetic studies have revealed that rare mutations and multiplications of the gene locus in α-synuclein (α-syn) are implicated in the pathogenesis of Parkinson's disease (PD). However, the pathological effects of α-syn are still obscure. The neurotoxicity of α-syn is mainly determined by its protein levels, which depend on a balance between synthesis and degradation. Therefore, verifying the possible routes contributing to the clearance of α-syn is important for PD therapy. In this study, we established stable lines overexpressing human wild-type (WT) and E46K mutant α-syn in rat PC12 cells and investigated the degradation pathways of α-syn by using a panel of inhibitors and inducers of lysosome and proteasome function. We also monitored the degradation kinetics of α-syn by using cycloheximide to block protein synthesis. Our data showed that both proteasome and chaperon-mediated autophagy (CMA) are responsible for the degradation of the WT α-syn. Meanwhile, E46K mutant α-syn is mainly degraded by the proteasome and macroautophagy pathway. Compared with the WT protein, E46K mutant α-syn turned over more slowly in PC12 cells. In addition, overexpression of E46K mutant α-syn increased vulnerability of PC12 cells to apoptosis insults when compared with WT α-syn. Our findings may verify the possible routes contributing to the degradation of the E46K mutant α-syn. [ABSTRACT FROM AUTHOR]

N- t e r t -butoxycarbonylation of amines in solution (water, organic solvents, or ionic liquids) is a common reaction for the preparation of drug molecules. To understand the reaction mechanism and the role of the solvent, quantum mechanical/molecular mechanical simulations using a polarizable multipolar force field with long–range electrostatic corrections were used to optimize the minimum energy paths (MEPs) associated with various possible reaction mechanisms employing the nudged elastic band (NEB) and the quadratic string method (QSM). The calculated reaction energies and energy barriers were compared with the corresponding gas-phase and dichloromethane results. Complementary Electron Localization Function (ELF)/NCI analyses provide insights on the critical structures along the MEP. The calculated results suggest the most likely path involves a sequential mechanism with the rate–limiting step corresponding to the nucleophilic attack of the aniline, followed by proton transfer and the release of CO 2 without the direct involvement of imidazolium cations as catalysts. [ABSTRACT FROM AUTHOR]

CO2, emitted mainly from fossil fuel combustion, is one of the major greenhouse gases. CO2 could be converted into more valuable chemical feedstocks including CO, HCOOH, HCHO, CH3OH, or CH4. To reduce CO2, catalysts were designed and their unique characteristics were utilized based on types of reaction processes, including catalytic hydrogenation, complex metal hydrides, photocatalysis, biological reduction, and electrochemical reduction. Indeed, the electroreduction method has received much consideration lately due to the simple operation, as well as environmentally friendly procedures that need to be optimized by both of the catalysts and the electrochemical process. In the past few decades, we have witnessed an explosion in development in materials science—especially in regards to the porous crystalline materials based on the strong covalent bond of the organic linkers containing light elements (Covalent organic frameworks, COFs), as well as the hybrid materials that possess organic backbones and inorganic metal-oxo clusters (Metal-organic frameworks, MOFs). Owing to the large surface area and high active site density that belong to these tailorable structures, MOFs and COFs can be applied to many practical applications, such as gas storage and separation, drug release, sensing, and catalysis. Beyond those applications, which have been abundantly studied since the 1990s, CO2 reduction catalyzed by reticular and extended structures of MOFs or COFs has been more recently turned to the next step of state-of-the-art application. In this perspective, we highlight the achievement of homogeneous catalysts used for CO2 electrochemical conversion and contrast it with the advances in new porous catalyst-based reticular chemistry. We then discuss the role of new catalytic systems designed in light of reticular chemistry in the heterogeneous-catalyzed reduction of CO2. [ABSTRACT FROM AUTHOR]

The inflammatory response mediated by microglia plays a critical role in the progression of ischemic stroke. Phosphoinositide 3-kinase gamma (PI3Kγ) has been implicated in multiple inflammatory and autoimmune diseases, making it a promising target for therapeutic intervention. The aim of this study was to evaluate the efficacy of 8e, a hydrogen sulfide (H2S) releasing derivative of 3-n-butylphthalide (NBP), on brain damage and PI3Kγ signaling following cerebral ischemia injury. 8e significantly reduced sensorimotor deficits, focal infarction, brain edema and neural apoptosis at 72 h after transient middle cerebral artery occlusion (tMCAO). The NOX2 isoform of the NADPH oxidase family is considered a major enzymatic source of superoxide. We found that the release of superoxide, together with the expression of NOX2 subunits p47phox, p-p47phox, and the upstream PI3Kγ/AKT signaling were all down-regulated by 8e, both in the penumbral region of the rat brain and in the primary cultured microglia subjected to oxygen-glucose deprivation (OGD). With the use of siRNA and pharmacological inhibitors, we further demonstrated that 8e regulates the formation of superoxide in activated microglia through the PI3Kγ/AKT/NOX2 signaling pathway and subsequently prevents neuronal death in neighboring neurons. Our experimental data indicate that 8e is a potential candidate for the treatment of ischemic stroke and PI3Kγ-mediated neuroinflammation. [ABSTRACT FROM AUTHOR]

Pancreatic lipase, a key enzyme for lipid absorption, is one of the most important targets for the treatment of obesity, while natural compounds have recently attracted much interest as potential inhibitors of this enzyme. Here, in an attempt to find new effective agents, the methanolic extract from Moricandia arvensis (L.) DC. and its sub-extracts were investigated for their potential inhibitory activity. The ability to inhibit pancreatic lipase was verified through the in vitro evaluation of the prevention of p-nitrophenyl caprylate hydrolysis. The antioxidant activity was also verified by means of DPPH and β-carotene bleaching tests. Compositional profiling revealed that flavonoid glycosides were the main specialized metabolites present in the methanolic extract from the aerial parts of the plant with kaempferol and quercetin representing the two O-glycosylated aglycones. Kaempferol-3-O-β-(2″-O-glucosyl)-rutinoside and kaempferol-3-O-a-arabinosyl-7-O-rhamnoside were the most abundant flavonols. The crude methanolic extract and the dichloromethane and ethyl acetate sub-extracts showed a strong lipase inhibitory activity, with IC50 values of 2.06 ± 0.02, 1.52 ± 0.02 and 1.31 ± 0.02 mg/mL, respectively. The best capacity to scavenge DPPH radical was detected for the ethyl acetate sub-extract (IC50 = 171.9 ± 1.0 µg/mL), which was also effective in protecting linoleic acid from peroxidation (IC50 = 35.69 ± 2.30 µg/mL). Obtained results support the hypothesis that M. arvensis can be a source of bioactive phytochemicals for the pharmacological inhibition of dietary lipids absorption. [ABSTRACT FROM AUTHOR]

Acquiring full knowledge of the reactivity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is crucial for the better understanding of the transformation and degradation of TCDD-like dioxins in the environment. To clarify the reactivity of the organic hydroperoxides toward TCDD, in this study, the reactions between the neutral/anion of the hydrogen peroxide (H2O2) and TCDD have been systematically investigated theoretically. It was found that the neutral H2O2 is relatively difficult to react with TCDD compared with its anion, exhibiting the pH dependence of the title reaction. As for the anion of H2O2, it reacts with TCDD through two reaction mechanisms, i.e., nucleophilic substitution and nucleophilic addition. For the former, the terminal O atom of HO2− nucleophilically attacks the C atom of the C-Cl bond in TCDD to form an intermediate containing an O-O bond, accompanying the dissociation of the chlorine atom. For the latter, the terminal O atom of HO2− can be easily attached to the C atom of the C-O bond in TCDD, resulting in the decomposition of C-O bond and the formation of an intermediate containing an O-O bond. For these formed intermediates in both reaction mechanisms, their O-O bonds can be homolytically cleaved to produce different radicals. In addition, the selected substitution effects including F-, Br-, and CH3- substituents on the above reactions have also been studied. Hopefully, the present results can provide new insights into the reactivity of the organic hydroperoxides toward TCDD-like environmental pollutants. [ABSTRACT FROM AUTHOR]

As new drugs for the treatment of malignant tumors, transforming growth factor-beta receptor 1 (TGFβR1) antagonists have attracted wide attention. Based on the crystal structure of TGFβR1-BMS22 complex, the pharmacophore model A02 with two hydrogen bond acceptors (HBAs) and four hydrophobic (HYD) properties was constructed. From the common features of active ligands reported in the literature, pharmacophore model B10 was also generated, which has two aromatic ring centers (RAs) and two HYD properties. The two models have high sensitivity and specificity to the training set, and they are highly consistent in spatial structure. Combining the two pharmacophore models, two novel skeleton structures with potential activity were selected by virtual screening from the DruglikeDiverse, MiniMaybridge, and ZINC Drug-Like databases. Four compounds (YXY01–YXY04) with potential anti-TGFβR1 activity were designed based on the new skeleton structures. In combination with Lipinski's rules; absorption, distribution, metabolism, excretion, and toxicity (ADMET); and, toxicological properties predicted in the study, YXY01-03 with the novel skeleton, good drug-like properties, and potential activity were finally discovered and may have higher safety relative to BMS22, which may be valuable for further research. [ABSTRACT FROM AUTHOR]