Balancing Activity and Stability in Halogen-Bonding Catalysis: Iodopyridinium-Catalyzed One-Pot Synthesis of 2,3-Dihydropyridinones.

A one-pot cascade reaction for 2,3-dihydropyridinone synthesis was accomplished with 3-fluoro-2-iodo-1-methylpyridinium triflate as the halogen bond catalyst. The desired [4+2] cycloaddition products, bearing aryl, heteroaryl, alkyl, and alicyclic substituents, were successfully furnished in 28-99% yields. Mechanistic investigations proved that a strong halogen-bonding interaction forged between the iodopyridinium catalyst and imine intermediate was essential to dynamically masking the vulnerable C-I bond on the catalyst and accelerating the following aza-Diels-Alder reaction.

Fabrication, modification and application of lipid nanotubes.

The potential application of high aspect-ratio nanomaterials motivates the development of the fabrication and modification of lipid nanotubes(LNTs). To date, diverse fabricate processes and elaborate template procedures have produced suitable tubular architectures with definite dimensions and complex structures for expected functions and applications. Herein, we comprehensively summarize the fabrication of LNTs in vitro and discuss the progress made on the micro/nanomaterials fabrication using LNTs as a template, as well as the functions and possible application of a wide range of LNTs as fundamental or derivative material. In addition, the characteristics, advantages, and disadvantages of different fabrication, modification methods, and development prospects of LNTs were briefly summarized.

Drug release and magneto-calorific analysis of magnetic lipid microcapsules for potential cancer therapeutics.

Magnetic nanoparticles (MNPs) with safety, stability and excellent magneto-calorific effect are the precondition for the smart magnetic drug carriers' fabrication and controllable drug release at a specific target in clinical treatment. In this study, the drug release and magneto-calorific effect of two types of magnetic lipid microcapsules (MLMs) loading lipid-coated MNPs and uncoated MNPs respectively were compared deeply in experimental analysis and theoretical simulation. The simulation results revealed that almost same magnetic heat effect and temperature increasing exist between lipid-coated and uncoated MNPs, which was consistent with the experimental drug release results. Coating lipid on MNPs didn't affect the magnetic heat and heat transfer of the MNPs. Because of the heat transfer between MNPs and water, MLMs and water around, the temperature increasing of whole sample solution is lower than that of the MNPs themselves. Our results provide a reliable theoretical basis for the development of healthy, safe, and biocompatible drug delivery systems.

A Facile and Green Combined Strategy for Improving Photocatalytic Activity of Carbon Nitride.

We first report an efficient combined strategy that simultaneously integrates copolymerization, doping, and molecular self-assembly for the development of carbon-doping petal-like carbon nitride photocatalysts using melamine (MA), cyanuric acid (CA), and 2,4,6-triaminopyrimidine (TAP) as the starting precursors and water as the only green solvent. The morphology, textural, optical, and electronic properties of carbon nitride could be engineered by rationally manipulating the doping content of TAP. In the process of molecular self-assembly, TAP can insert the aggregate edge easily according to the results of density functional theory (DFT) calculations. The edge-termination effect of TAP made it easier for the modified carbon nitride materials to form petal-like nanosheets with porous structures and large BET surface areas. In addition, the incorporation of TAP also contributed to tuning the electronic band structures of carbon nitrides and enhancing the separation efficiency of photogenerated carriers. The as-prepared materials exhibited excellent photocatalytic activities in the degradation of tetracycline hydrochloride (TC-HCl) and rhodamine B (RhB). This work may not only offer universally powerful and stable photocatalysts for applications but also develop a new combined strategy to fabricate efficient photocatalysts in a facile and green way.

Temperature-induced structural diversity of metal-organic frameworks and their applications in selective sensing of nitrobenzene and electrocatalyzing the oxygen evolution reaction.

Structural diversities are presented in four new Co-MOFs containing 1,5-bi(imidazolyl)anthracene and different dibenzobarrelene skeletons based on dicarboxylic acid, in which MOFs 1-3 exhibit 2D networks in a 4-connected node sql topology with the point symbol of {44·62}, while MOF 4 forms a 1D chain structure. It is clearly observed that the 2D-1D structural transformation of 2-4 has been realized by temperature modulated hydrothermal synthesis procedures from 120-160 °C, suggesting the key role of temperature for constructing MOFs. In addition, obvious π-π interactions between anthracene rings can be observed in the architectures of 1-3, which may favorably stabilize their 2D supramolecular networks. More importantly, fluorescence behaviors of 1-4 have been investigated in water among various nitro-aromatic compounds (NACs) and the results show that all samples exhibit high selectivity and fine sensitivity to nitrobenzene (NB) with fluorescence quenching, which is confirmed to be the result of electron transfer from the excited state of ligands to that of NB by density functional theory. Furthermore, MOFs 1-4 have been directly employed as electrocatalysts for the oxygen evolution reaction (OER), in which MOF 4 gives the best activity towards the OER among all as-synthesized samples with an overpotential of 398 mV at a current density of 10 mA cm-2 and a low Tafel slope of 59 mV dec-1.

MicroRNA 628 suppresses migration and invasion of breast cancer stem cells through targeting SOS1.

PURPOSE: The purpose of this study is to evaluate the effects of miR-628 on migration and invasion of breast cancer stem cells (CSCs), which are essential for tumor recurrence and metastasis. MATERIALS AND METHODS: Quantitative reverse transcription-polymerase chain reaction was used to determine the expression of microRNAs and mRNAs. A subpopulation of CD44+/CD24- breast CSCs were sorted by flow cytometry. Transwell assays were used to evaluate cell migration and invasion. Luciferase reporter assays were performed to verify whether miR-628 targeted SOS Ras/Rac guanine nucleotide exchange factor 1 (SOS1). pcDNA3.1(+)-SOS1 was constructed for overexpressing SOS1 after transfection. RESULTS: Compared with primary breast cancer cells, bone metastatic breast cancer cells showed significant downregulation of miR-628. The CD44+/CD24- breast CSC subpopulations in MDA-MB-231 and MCF-7 cell lines were analyzed and sorted. Transfection with an miR-628 mimic significantly suppressed the migration and invasion of these breast CSCs by targeting SOS1, which plays an essential role in epithelial-to-mesenchymal transition. Overexpression of SOS1 rescued miR-628-mediated migration and invasion by upregulating Snail and vimentin, and downregulating E-cadherin. CONCLUSION: miR-628 suppressed migration and invasion of breast CSCs of MDA-MB-231 and MCF-7 cells by directly targeting SOS1. Enhancement of miR-628 expression might be an effective strategy for managing breast cancer metastasis.

DFT investigation on the metabolic mechanisms of theophylline by cytochrome P450 monooxygenase.

Theophylline, one of the most commonly used bronchodilators and respiratory stimulators for the treatment of acute and chronic asthmatic conditions, can cause permanent neurological damage through chronic or excessive ingestion. In this work, DFT calculation was performed to identify the metabolic mechanisms of theophylline by cytochrome P450 (CYP450) monooxygenase. Two main metabolic pathways were investigated, namely, N1- (path A) and N3- (path B) demethylations, which proceeded through N-methyl hydroxylation followed by the decomposition of the generated carbinolamine species. N-methyl hydroxylation involved a hydrogen atom transfer (HAT) mechanism, which can be generalized as the N-demethylation mechanism of xanthine derivatives. The energy gap between the low-spin double state (LS) and the high-spin quartet state (HS) was low (<1 kcal mol-1), indicating a two-state reactivity (TSR) mechanism. The generated carbinolamine species preferred to decompose through the adjacent heteroatom (O6 for path A and O2 for path B) mediated mechanism. Path B was kinetically more feasible than path A attributed to its relatively lower activation energy. 1-Methylxanthine therefore was the energetically favorable metabolite of theophylline. The observations obtained in the work were in agreement with the experimental observation, which can offer important implications for further pharmacological and clinic studies.

Electroacupuncture restores hippocampal synaptic plasticity via modulation of 5-HT receptors in a rat model of depression.

OBJECTIVE: The study aimed to determine the effect of electroacupuncture (EA) on Wistar Kyoto (WKY) depressive model rats and explore the possible mechanism of EA on hippocampal CA1 region neuronal synaptic plasticity. METHODS: The male WKY rats were randomized to three experimental groups (EA, Sham EA, and Model group, n = 8/group), and Wistar rats as the normal control group (n = 8). EA treatment was administered once daily for 3 weeks at acupuncture points Baihui (GV20) and Yintang (EX-HN3). In the Sham EA group, acupuncture needles were inserted superficially into the acupoints without electrical stimulation. On day 21, the forced swimming test (FST), open field test (OFT) and sucrose preference test (SPT) were conducted. After the behavioral tests, long-term potentiation (LTP) was evoked at Schaffer collateral-CA1 synapses in hippocampal slices in vitro by electrophysiological recording, 5-HTT, 5-HT1A and 5-HT1 B protein levels in the hippocampus CA1 region were examined by using Western blot. RESULT: EA significantly decreased immobility in FST and improved sucrose intake compared with the Sham EA and Model groups. The center time and total move time in OFT were significantly increased in the EA group compared to the Model group. Compared with those of the Sham EA and Model groups, the fEPSP slope of the EA group increased significantly, and the LTP induction was successful. EA significantly decreased 5-HTT protein expression in the hippocampus CA1 region in comparison to the Sham EA and Model groups. Additionally, EA down regulated the 5-HT1A protein expression in the hippocampus CA1 region in comparison to the Sham EA group. CONCLUSION: EA could ameliorate depressive-like behaviors by restoring hippocampus CA1 synaptic plasticity, which might be mainly mediated by regulating 5-HT receptor levels.

The Efficacy of Acupuncture for Treating Depression-Related Insomnia Compared with a Control Group: A Systematic Review and Meta-Analysis.

Objective. To evaluate the effectiveness of acupuncture as monotherapy and as an alternative therapy in treating depression-related insomnia. Data Source. Seven databases were searched starting from 1946 to March 30, 2016. Study Eligibility Criteria. Randomized-controlled trials of adult subjects (18-75 y) who had depression-related insomnia and had received acupuncture. Results. 18 randomized-controlled clinical trials (RCTs) were introduced in this meta-analysis. The findings determined that the acupuncture treatment made significant improvements in PSQI score (MD = -2.37, 95% CI -3.52 to -1.21) compared with Western medicine. Acupuncture combined with Western medicine had a better effect on improving sleep quality (MD = -2.63, 95% CI -4.40 to -0.86) compared with the treatment of Western medicine alone. There was no statistical difference (MD = -2.76, 95% CI -7.65 to 2.12) between acupuncture treatment and Western medicine towards improving the HAMD score. Acupuncture combined with Western medicine (MD = -5.46, CI -8.55 to -2.38) had more effect on improving depression degree compared with the Western medicine alone. Conclusion. This systematic review indicates that acupuncture could be an alternative therapy to medication for treating depression-related insomnia.

Theoretical study on the metabolic mechanisms of levmepromazine by cytochrome P450.

Levomepromazine, an "older" typical neuroleptic, is widely applied in psychiatry for the treatment of schizophrenia. The biotransformation of Levomepromazine remains elusive up to now, but found to result in the formation of different derivatives that may contribute to the therapeutic and/or side-effects of the parent drug. The present work aims to resolve the metabolic details of Levomepromazine catalyzed by cytochrome P450, an important heme-containing enzyme superfamily, based on DFT calculation. Two main metabolic pathways have been addressed, S-oxidation and N-demethylation. The mechanistic conclusions have revealed a stepwise transfer of two electrons mechanism in S-oxidation reaction. N-demethylation is a two-step reaction, including the rate-determining N-methyl hydroxylation which proceeds via the single electron transfer (SET) mechanism and the subsequent C-N bond fission through a water-assisted enzymatic proton-transfer process. N-demethylation is more feasible than S-oxidation due to its lower activation energy and N-desmethyllevomepromazine therefore is the most plausible metabolite of Levomepromazine. Each metabolic pathway proceeds in a spin-selective manner (SSM) mechanism, predominately via the LS state of Cpd I. Our observations are in good accordance with the experimental results, which can provide some general implications for the metabolic mechanism of Levomepromazine-like drugs. Graphical abstract The metabolic mechanisms of levmepromazine by cytochrome P450.

Efficacy and Safety of Electroacupuncture on Treating Depression Related Sleep Disorders: Study Protocol of a Randomized Controlled Trial.

Background. Depression is frequently accompanied by sleep disturbances including insomnia. Insomnia may persist even after mood symptoms have been adequately treated. Acupuncture is considered to be beneficial to adjust the state of body and mind and restore the normal sleep-awake cycle. This trial is aimed at evaluating the efficacy and safety of electroacupuncture on treating insomnia in patients with depression. Methods. We describe a protocol for a randomized, single-blinded, sham controlled trial. Ninety eligible patients will be randomly assigned to one of 3 treatment groups: treatment group (acupuncture), control A group (superficial acupuncture at sham points), and control B group (sham acupuncture). All treatment will be given 3 times per week for 8 weeks. The primary outcome is the Pittsburgh Sleep Quality Index (PSQI). The secondary outcomes are sleep parameters recorded in the Actigraphy, Hamilton Rating Scale for Depression (HAMD), and Self-Rating Depression Scale (SDS). All adverse effects will be accessed by the Treatment Emergent Symptom Scale (TESS). Outcomes will be evaluated at baseline, 4 weeks after treatment, 8 weeks after treatment, and 4 weeks of follow-up. Ethics. This trial has been approved by the Ethics Committee of Shanghai Municipal Hospital of Traditional Chinese Medicine (2015SHL-KY-21) and is registered with ChiCTR-IIR-16008058.

Enantio- and Diastereoselective Formal Hetero-Diels-Alder Reactions of Trifluoromethylated Enones Catalyzed by Chiral Primary Amines.

Enantioselective formal hetero-Diels-Alder reactions of trifluoromethylated enones and 2-amino-1,3-butadienes generated in situ from aliphatic acyclic enones and chiral primary amines are reported. The corresponding tetrahydropyran-4-ones are formed in up to 94 % yield and with up to 94 % ee. The reaction was carried out through a stepwise mechanism, including initial aminocatalytic aldol condensation of 2-amino-1,3-butadiene to the trifluoromethylated carbonyl group followed by an intramolecular oxa-Michael addition. Both NMR investigation and theoretical calculations on the transition state indicate that the protonated tertiary amine could effectively activate the carbonyl group of the trifluoromethyl ketone to promote the addition process through hydrogen-bonding interaction of N-H⋅⋅⋅F and N-H⋅⋅⋅O simultaneously, and thus provide a chiral environment for the approach of amino-1,3-butadienes to the activated trifluoromethyl ketone, resulting in high enantioselectivity.

Theoretical study on the N-demethylation mechanism of theobromine catalyzed by P450 isoenzyme 1A2.

Theobromine, a widely consumed pharmacological active substance, can cause undesirable muscle stiffness, nausea and anorexia in high doses ingestion. The main N-demethylation metabolic mechanism of theobromine catalyzed by P450 isoenzyme 1A2 (CYP1A2) has been explored in this work using the unrestricted hybrid density functional method UB3LYP in conjunction with the LACVP(Fe)/6-31G (H, C, N, O, S, Cl) basis set. Single-point calculations including empirical dispersion corrections were carried out at the higher 6-311++G** basis set. Two N-demethylation pathways were characterized, i.e., 3-N and 7-N demethylations, which involve the initial N-methyl hydroxylation to form carbinolamines and the subsequent carbinolamines decomposition to yield monomethylxanthines and formaldehydes. Our results have shown that the rate-limiting N-methyl hydroxylation occurs via a hydrogen atom transfer (HAT) mechanism, which proceeds in a spin-selective mechanism (SSM) in the gas phase. The carbinolamines generated are prone to decomposition via the contiguous heteroatom-assisted proton-transfer. Strikingly, 3-N demethylation is more favorable than 7-N demethylation due to its lower free energy barrier and 7-methylxanthine therefore is the optimum product reported for the demethylation of theobromine catalyzed by CYP1A2, which are in good agreement with the experimental observation. This work has first revealed the detail N-demethylation mechanisms of theobromine at the theoretical level. It can offer more significant information for the metabolism of purine alkaloid.

Stimulation of N--glycoside transfer in deoxythymidine glycol: mechanism of the initial step in base excision repair.

Thymine glycol (Tg), a toxic oxidative DNA lesion, is preferentially removed by endonuclease III (Endo III). To investigate the glycosylase activity of Endo III, the N--glycoside transfer mechanism in deoxythymidine glycol (dTg) is examined in this theoretical study based on the BHandHLYP/6-311++G(d,p) level of theory. Two controversial mechanisms were characterized, i.e., the displacement and endocyclic mechanisms. For each mechanism, three types of reaction models were established, including the direct reaction, local microhydration and protonated models. The calculated results indicate that (i) all three reaction models favor the displacement mechanism more than the endocyclic mechanism; (ii) the local microhydration model allows for discrete proton transfer and contributes to the reduction of activation energies, nevertheless, large activation energies are still involved; (iii) the O4'-protonated endocyclic model can efficiently promote the nucleophilic attack of lysine residue and an amino acid residue other than the nucleophilic lysine should be responsible for the opening of the sugar ring; (iv) the O2-protonated displacement model facilitates the leaving group (Tg) stabilization and therefore is the preferred mechanism for the N--glycoside transfer of dTg, whose activation energy of 17.7 kcal mol⁻¹ is in good agreement with the experimental estimate of 19.0 kcal mol⁻¹. As a result, the protonation of nucleobase plays a significant role in predicting the preferred glycosylase mechanism. Our findings can propose appropriate mechanisms for future large-scale enzymatic modeling of Endo III and provide more fundamental information about the important residues that may be included in the enzyme-catalyzed reactions.

Theoretical investigations on the thermal decomposition mechanism of 5-hydroxy-6-hydroperoxy-5,6-dihydrothymidine in water.

The main primary product of DNA oxidation by free radicals is 5-hydroxy-6- hydroperoxy-5,6-dihydrothymidine (5-OH-6-OOH-DHT), whose further degradation can yield the other mutagenic products and amplify the spectrum of DNA damage. In this study, to illustrate the thermal stability of 5-OH-6-OOH-DHT in DNA, the decomposition mechanism of 5-OH-6-OOH-DHT was identified based on the cis-(5R,6S) diastereomer. Optimized structures for all of the stationary points in the gas phase were investigated at the B3LYP/6-31+G(d,p) level of theory. Four pathways were characterized. The decomposition mechanism of 5-OH-6-OOH-DHT was proposed to involve either dehydration for paths A and B or the cleavage of a glycosidic bond for paths C and D. Moreover, to simulate the title reaction in aqueous solution, a water-mediated mechanism and cluster-continuum model, based on the SCRF/CPCM model, were taken into account. The results indicate that the most favorable reaction pathways for paths A and B both involve a sort of eight-membered ring transition structure formed by two (path A) or one (path B) auxiliary water molecules, suggesting that the thermal decomposition of 5-OH-6-OOH-DHT can be significantly facilitated by water molecules. Path A is the most feasible mechanism reported for the decomposition of 5-OH-6-OOH-DHT in the aqueous solution, which is slightly more favorable than path B. However, the unimolecular decomposition mechanisms (paths C and D) both have high-energy barriers and are largely endothermic, suggesting that the cleavage of the N-glycosidic bond via unimolecular decomposition is thermodynamically and kinetically unfavorable. These studies have shed light on the chemical properties of 5-OH-6-OOH-DHT in free radical reactions and thereby have provided new insights into the complex mechanism of oxidative DNA damage.

Molecular dynamics and density functional theory studies of substrate binding and catalysis of human brain aspartoacylase.

The active-site dynamics of human brain aspartoacylase (hASPA) complexed with its substrate (N-acetyl-L-aspartate) has been studied using a hybrid quantum mechanical/molecular mechanical (QM/MM) approach based on the self-consistent charge-density functional tight-binding (SCC-DFTB) model. The Michaelis complex, which is constructed from a recent X-ray structure of the human brain aspartoacylase with a stable tetrahedral intermediate analogue, is reproduced in 1ns molecular dynamics simulations at 300K. The simulation shows that the substrate is tightly held in the active site by a hydrogen bond network and the putative nucleophilic water molecule is reasonably close to the nucleophilic center. The catalysis is further modeled with the density functional theory (DFT) in a truncated active-site model at the B3LYP/6-31G(d) level of theory. The DFT calculations indicate the reaction proceeds via a water promoted pathway with Glu178 serving as the general base and general acid. Transition state stabilization for nucleophilic addition is achieved by formations of the weak coordination bond between the substrate carbonyl oxygen atom and the zinc ion as well as of the strong hydrogen bonds between the substrate carbonyl oxygen atom and Arg63.

Fast determination of the release degree of compound sulfamethoxazole tablets by using circulation release system combined with ultraviolet spectral net analyte signal method.

Based on ultraviolet spectral net analyte signals, this research has studied the determination of the two effective components, sulfamethoxazole (SMZ) and trimethoprim (TMP), contained in compound sulfamethoxazole tablets in acid environment. The linear ranges of SMZ and TMP were 0.48-7.84 microg/ml (the regression correlation coefficient r = 0.9981) and 0.12-1.5 microg/ml (r = 0.9986), the corresponding average recoveries were 99.5 and 101.0%, respectively, and the relative standard deviations were 1.87 and 3.60%, respectively. The method was simple, fast and accurate. A circulation release system for the determination of the tablet release degree has been built, and the on-line filtering and small-volume sampling could thus be carried out. Thanks to the combination of the circulation release system and the determination method of SMZ and TMP in acid environment, the determination of release degree for compound sulfamethoxazole tablets was fast and accurate, especially for the early time of rapid release.

Theoretical studies on the thermodynamics and kinetics of the N-glycosidic bond cleavage in deoxythymidine glycol.

The thermodynamic and kinetic properties for the nonenzymatic N-glycosidic bond cleavage in cis-(5R,6S)-5,6-dihydroxy-5,6-dihydrodeoxythymidine (deoxythymidine glycol, dTg) were studied by computational techniques. Optimized structures for all of the stationary points in the gas phase were investigated using the BHandHLYP/6-311++G(d,p) and B3LYP/6-311++G(d,p) methods. Single-point energies were determined employing the ab initio MP2 method in conjunction with the 6-311++G(d,p) basis set. For the unimolecular decomposition of dTg in the gas phase, two pathways were characterized. Subsequently, the hydrolysis of dTg by a single water molecule was investigated. Two possible pathways were considered, involving the abstraction of the C2' hydrogen followed by the attack of water on the C1'=C2' bond (SN1 pathway) and the attack of a water molecule on the C1' atom with the simultaneous cleavage of the glycosidic bond (SN2 pathway). However, both the unimolecular decomposition reaction and the hydrolysis reaction involve large energy barriers, suggesting that the role of water is not beneficial to the overall reaction and the direct involvement of a sole water molecule as a nucleophile is unlikely. This result emphasizes the important catalytic role of enzymes. In addition, the solvent effect of water on the four processes was assessed at the geometry optimization level by means of the conductor-like polarized continuum model. Single-point computation was done at the MP2/6-311++G(d,p)//BHandHLYP/6-311++G(d,p) level. The calculated results show that the presence of the solvent water substantially lowers all energy barriers. Our results give out a greater fundamental understanding of the effects of the nucleophile water and solvent water for this important biological reaction.

Chemometric classification of traditional Chinese medicines by their geographical origins using near-infrared reflectance spectra.

Some raw materials that have different places of production for the plant sources of the drugs Astragalus membranaceus and ginseng have been studied, based on their near-infrared reflectance spectra. The experimentally recorded spectra represent heavily ill-posed and highly correlative data sets. Three related methods, i.e. the Fisher linear discriminant analysis (FLDA), the ridge-type linear discriminant analysis (RLDA) and a newly proposed penalized ridge-type linear discriminant analysis (PRLDA), have been investigated. FLDA over-fits for the training objects of the two data sets to a high extent and is unstable for the predictive objects of the two data sets. RLDA shows obvious improvement in terms of over-fitting and unstability, but the stability for the predictive objects of the two data sets is too sensitive to their ridge-type penalized weights, tending to produce erroneous discrimination results. The proposed PRLDA can circumvent the two aforementioned problems with a large domain of penalized weights for correct discriminant analysis of the two data sets studied. The combination of the PRLDA method and near infrared reflectance spectroscopy can be adapted for the discrimination of the production places of plant sources of these drugs.