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Fifteen compounds were isolated from the 70% EtOH extract of leaves of Chinese hawthorn(Crataegus pinnatifida var. major) by various purification steps, and their structures were determined as 2α,3α,12β,19α,-tetrahydroxyursan-13β,28-olide(1),euscaphic acid(2), tormentic acid(3), ursolic acid(4), pomolic acid(5), corosolic acid(6), maslinic acid(7), linalyl rutinoside(8),(Z)-3-hexenyl β-D-glucoside(9),(3S, 6S)-cis-linalool-3,7-oxide-β-D-glucopyranoside(10), pisumionoside(11), icariside B6(12), byzantionoside B(13),(6R,7E,9R)-9-Hydroxy-4,7-megastigmadien-3-one 9-O-β-D-glucopyranoside(14) and(6S,7E,9R)-6,9-dihydroxy-4,7-megastigmadien-3-one 9-O-β-D-glucopyranoside(15) mainly based on the mass spectrum(MS) and nuclear magnetic resonance(NMR) spectroscopic techniques, of which compound 1 was a new pentacyclic triterpene, and compounds 2, 5, 6, 8, 10, 13 and 15 were isolated form this plant for the first time.

The histone acetyl reader bromodomain-containing protein 4 (BRD4) is an important regulator of chromatin structure and transcription, yet factors modulating its activity have remained elusive. Here we describe two complementary screens for genetic and physical interactors of BRD4, which converge on the folate pathway enzyme MTHFD1 (methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1). We show that a fraction of MTHFD1 resides in the nucleus, where it is recruited to distinct genomic loci by direct interaction with BRD4. Inhibition of either BRD4 or MTHFD1 results in similar changes in nuclear metabolite composition and gene expression; pharmacological inhibitors of the two pathways synergize to impair cancer cell viability in vitro and in vivo. Our finding that MTHFD1 and other metabolic enzymes are chromatin associated suggests a direct role for nuclear metabolism in the control of gene expression.

A phytochemical study on the leaves of Crataegus pinnatifida Bge. var. major N.E.Br. was carried out, which finally led to the isolation of nineteen phenolic compounds (1-19). The structures of all compounds were established mainly by NMR and MS spectroscopic analysis as well as the necessary ECD experimental evidence, of which compounds 1-4 (crataegunins A-D) were identified as new phenylpropanoid-substituted epicatechins. HepG2 cells were induced by oleic acid and palmitic acid to establish the model of lipid metabolism disorder. All isolated compounds were used to intervene in the model, and the contents of triglyceride (TG) and total cholesterol (TC) were detected. Compound 2 could significantly reduce the content of TG, while compounds 2 and 11 both have good activity in reducing TC content.

There is an urgent need for new antibiotics against Gram-negative pathogens that are resistant to carbapenem and third-generation cephalosporins, against which antibiotics of last resort have lost most of their efficacy. Here we describe a class of synthetic antibiotics inspired by scaffolds derived from natural products. These chimeric antibiotics contain a β-hairpin peptide macrocycle linked to the macrocycle found in the polymyxin and colistin family of natural products. They are bactericidal and have a mechanism of action that involves binding to both lipopolysaccharide and the main component (BamA) of the β-barrel folding complex (BAM) that is required for the folding and insertion of β-barrel proteins into the outer membrane of Gram-negative bacteria. Extensively optimized derivatives show potent activity against multidrug-resistant pathogens, including all of the Gram-negative members of the ESKAPE pathogens1. These derivatives also show favourable drug properties and overcome colistin resistance, both in vitro and in vivo. The lead candidate is currently in preclinical toxicology studies that—if successful—will allow progress into clinical studies that have the potential to address life-threatening infections by the Gram-negative pathogens, and thus to resolve a considerable unmet medical need. A class of chimeric synthetic antibiotics that bind to lipopolysaccharide and BamA shows potent activity against multidrug-resistant Gram-negative bacteria, with the potential to address life-threatening infections.

Phytochemical investigation of the rhizomes of Atractylodes macrocephala led to the isolation of five new sesquiterpenes, atractylmacrols A-E (1-5), as well as six known eudesmane sesquiterpenes (6-11). The structures of 1-5 were determined through interpretation of their 1D and 2D NMR spectroscopic data, as well as HREIMS values. Compounds 1-5 were evaluated for their inhibitory effects on LPS-induced nitric oxide (NO) production in RAW264.7 macrophages.

A series of analogues based on serine as lead structure were designed, and their agonist activities were evaluated at recombinant NMDA receptor subtypes (GluN1/2A–D) using two-electrode voltage-clamp (TEVC) electrophysiology. Pronounced variation in subunit-selectivity, potency, and agonist efficacy was observed in a manner that was dependent on the GluN2 subunit in the NMDA receptor. In particular, compounds 15a and 16a are potent GluN2C-specific superagonists at the GluN1 subunit with agonist efficacies of 398% and 308% compared to glycine. This study demonstrates that subunit-selectivity among glycine site NMDA receptor agonists can be achieved and suggests that glycine-site agonists can be developed as pharmacological tool compounds to study GluN2C-specific effects in NMDA receptor-mediated neurotransmission.

With the increasing resistance of many Gram-negative bacteria to existing classes of antibiotics, identifying new paradigms in antimicrobial discovery is an important research priority. Of special interest are the proteins required for the biogenesis of the asymmetric Gram-negative bacterial outer membrane (OM). Seven Lpt proteins (LptA to LptG) associate in most Gram-negative bacteria to form a macromolecular complex spanning the entire envelope, which transports lipopolysaccharide (LPS) molecules from their site of assembly at the inner membrane to the cell surface, powered by adenosine 5′-triphosphate hydrolysis in the cytoplasm. The periplasmic protein LptA comprises the protein bridge across the periplasm, which connects LptB2FGC at the inner membrane to LptD/E anchored in the OM. We show here that the naturally occurring, insect-derived antimicrobial peptide thanatin targets LptA and LptD in the network of periplasmic protein-protein interactions required to assemble the Lpt complex, leading to the inhibition of LPS transport and OM biogenesis in Escherichia coli., Science Advances, 4 (11), ISSN:2375-2548

Thanatin targets protein-protein interactions between LptA and LptD in the periplasmic bridge required for LPS transport., With the increasing resistance of many Gram-negative bacteria to existing classes of antibiotics, identifying new paradigms in antimicrobial discovery is an important research priority. Of special interest are the proteins required for the biogenesis of the asymmetric Gram-negative bacterial outer membrane (OM). Seven Lpt proteins (LptA to LptG) associate in most Gram-negative bacteria to form a macromolecular complex spanning the entire envelope, which transports lipopolysaccharide (LPS) molecules from their site of assembly at the inner membrane to the cell surface, powered by adenosine 5′-triphosphate hydrolysis in the cytoplasm. The periplasmic protein LptA comprises the protein bridge across the periplasm, which connects LptB2FGC at the inner membrane to LptD/E anchored in the OM. We show here that the naturally occurring, insect-derived antimicrobial peptide thanatin targets LptA and LptD in the network of periplasmic protein-protein interactions required to assemble the Lpt complex, leading to the inhibition of LPS transport and OM biogenesis in Escherichia coli.

C19H17IO7, triclinic, P1̅ (no. 2), a = 9.2343(19) Å, b = 10.218(2) Å, c = 10.4199(18) Å, α = 72.629(8)°, β = 74.494(7)°, γ = 86.610(9)°, V = 903.9(3) Å3, Z = 2, R gt (F) = 0.0289, wR ref (F 2 ) = 0.0670, T = 109 K.

The globus pallidus is a central nucleus in the basal ganglia motor control circuit. Morphological studies have revealed the expression of adenosine A2A receptors in the globus pallidus. To determine the modulation of adenosine A2A receptors on the activity of pallidal neurons in both normal and parkinsonian rats, in vivo electrophysiological and behavioral tests were performed in the present study. The extracellular single unit recordings showed that micro-pressure administration of adenosine A2A receptor agonist, CGS21680, regulated the pallidal firing activity. GABAergic neurotransmission was involved in CGS21680-induced modulation of pallidal neurons via a PKA pathway. Furthermore, application of two adenosine A2A receptor antagonists, KW6002 or SCH442416, mainly increased the spontaneous firing of pallidal neurons, suggesting that endogenous adenosine system modulates the activity of pallidal neurons through adenosine A2A receptors. Finally, elevated body swing test (EBST) showed that intrapallidal microinjection of adenosine A2A receptor agonist/antagonist induced ipsilateral/contralateral-biased swing, respectively. In addition, the electrophysiological and behavioral findings also revealed that activation of dopamine D2 receptors by quinpirole strengthened KW6002/SCH442416-induced excitation of pallidal activity. Co-application of quinpirole with KW6002 or SCH442416 alleviated biased swing in hemi-parkinsonian rats. Based on the present findings, we concluded that pallidal adenosine A2A receptors may be potentially useful in the treatment of Parkinson's disease.

Summary The MYC oncoprotein binds to promoter-proximal regions of virtually all transcribed genes and enhances RNA polymerase II (Pol II) function, but its precise mode of action is poorly understood. Using mass spectrometry of both MYC and Pol II complexes, we show here that MYC controls the assembly of Pol II with a small set of transcription elongation factors that includes SPT5, a subunit of the elongation factor DSIF. MYC directly binds SPT5, recruits SPT5 to promoters, and enables the CDK7-dependent transfer of SPT5 onto Pol II. Consistent with known functions of SPT5, MYC is required for fast and processive transcription elongation. Intriguingly, the high levels of MYC that are expressed in tumors sequester SPT5 into non-functional complexes, thereby decreasing the expression of growth-suppressive genes. Altogether, these results argue that MYC controls the productive assembly of processive Pol II elongation complexes and provide insight into how oncogenic levels of MYC permit uncontrolled cellular growth., Graphical Abstract, Highlights • MYC enhances productive transcription by defining the protein composition of Pol II • MYC directly binds SPT5 and hands it over to Pol II in a CDK7-dependent manner • Transfer of SPT5 increases speed and processivity of Pol II • MYC’s effects on Pol II function shape its tumor-specific gene expression profile, Baluapuri et al. report that MYC governs transition of Pol II into a transcriptionally engaged form by loading the SPT5 protein onto it. This increases Pol II processivity and productive transcription. The effect of MYC on Pol II can regulate expression of those genes, which help tumors to grow.

Three new labdane diterpenoids, calomacrins A-C (1-3), and a new diaryl butyrolactone-type lignan, calomacrol A (8), as well as four known labdane diterpenoids and six known lignans, were isolated from the twigs and leaves of Calocedrus macrolepis. Structures of the new compounds were elucidated on the basis of their spectroscopic methods, including 1D and 2D NMR techniques. Compounds 3-14 were evaluated for cytotoxicity against HL-60, SMMC-7721, A-549, MCF-7, and SW480 cell lines. (C) 2013 Elsevier B.V. All rights reserved.

A series of analogues of the (S)-2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptor agonist BnTetAMPA (5b) were synthesized and characterized pharmacologically in radioligand binding assays at native and cloned AMPA receptors and functionally by two-electrode voltage clamp electrophysiology at the four homomeric AMPA receptors expressed in Xenopus laevis oocytes. The analogues 6 and 7 exhibit very different pharmacological profiles with binding affinity preference for the subtypes GluA1 and GluA3, respectively. X-ray crystal structures of three ligands (6, 7, and 8) in complex with the agonist binding domain (ABD) of GluA2 show that they induce full domain closure despite their low agonist efficacies. Trp767 in GluA2 ABD could be an important determinant for partial agonism of this compound series at AMPA receptors, since agonist efficacy also correlated with the location of the Trp767 side chain.

Two nicotinate-containing cadmium(II) complexes were synthesized and structurally characterized. [Cd(ntb)(nic)]ClO4 · 0.5CH3OH (1) (ntb = tris(2-benzimidazolylmethyl)amine, nic = nicotinate anion) crystallized in the triclinic space group P-1 with a = 13.9979(17) A, b = 14.0344(18) A, c = 17.738(3) A and α = 104.386(10)°, β = 93.317(12)°, γ = 110.081(8)°. The central Cd(II) is coordinated by four nitrogen atoms of ntb and two oxygen atoms of nicotinate to form a distorted octahedral geometry. [Cd(tren)(nic)]BPh4 (2) (tren = tris(2-aminoethyl)amine) crystallized in the monoclinic crystal system, P21/c space group with a = 18.610(6) A, b = 10.1620(16) A, c = 20.0085(18) A and β = 111.230(11)°. The central Cd(II) is coordinated by four nitrogen atoms of tren and one oxygen atom of nicotinate to form a distorted trigonal bipyramidal geometry. A tetramer for 1 and a dimer for 2 are formed through intermolecular hydrogen-bonding.

Four new zinc(II) complexes [Zn(dien)( μ -nic)] 2 (BPh 4 ) 2 ·2CH 3 OH ( 1 ), {[Zn(dien)(isonic)]BPh 4 } n ( 2 ), [Zn(tren)(nic)]BPh 4 ( 3 ) and [Zn(tren)(isonic)]BPh 4 ( 4 ) (dien/tren = diethylenetriamine/triethylenetriamine, nic/isonic = nicotinate/isonicotinate anion) were synthesized and structurally characterized by IR, 1 H NMR and single crystal X-ray diffraction. In the zinc(II) complexes of dien, both nicotinate and isonicotinate connect the zinc(II) ions via N,O -bis-monodentate mode. Complex 1 contains a centrosymmetric dinuclear unit bridged by two nicotinate anions in anti -parallel way. Complex 2 is characterized by an infinite one-dimensional zigzag chain bridged by isonicotinate anion in an end-to-end mode. The Zn···Zn distance is 6.782 for 1 and 8.805 A for 2 . While in the complexes of tren, both 3 and 4 are mononuclear complexes with nicotinate and isonicotinate coordinated to zinc(II) ion through only one oxygen atom of their carboxylate groups. The zinc(II) ions in all of the four complexes are in a distorted trigonal bipyramidal geometry. Complex 3 forms a dinuclear unit and complex 4 forms an infinite 2D sheet structure through intermolecular H-bonds. In all of the crystal lattices, the BPh 4 - counterions act to balance the electronic charge at the same time to construct different 3D structures through noncovalent interactions such as C–H···π, N–H···π and van der Waals interactions.

Four novel nicotinato-copper(II) complexes containing polybenzimidazole and polyamine ligands were synthesized with formula [Cu2(bbma)2(nic)2](ClO4)2·CH3OH·0.5H2O (1), [Cu2(dien)2(nic)2](ClO4)2·2CH3OH (2), [Cu(ntb)(nic)]ClO4·H2O (3) and [Cu(tren)(nic)]BPh4·CH3OH·H2O (4), in which bbma is bis(benzimidazol-2-yl-methyl)amine, dien is diethylenetriamine, ntb is tris(2-benzimidazolylmethyl)amine, tren is tris(2-aminoethyl)amine and nic is nicotinate anion. All of the complexes were characterized by elemental analysis, IR and X-ray diffraction analysis. Complexes 1 and 2 contain centrosymmetric dinuclear entity with the two Cu(II) atoms bridged by two nicotinate anions in an anti-parallel mode. The Cu···Cu separation is 7.109 A for 1 and 6.979 A for 2. Complexes 3 and 4 are mononuclear with nicotinate coordinated to Cu(II) ion by the carboxylate O atom in 3 and the pyridine N atom in 4. All of the complexes exhibit abundant hydrogen bonds to form 1D chain for 1, 3, 4 and 2D network for 2. Magnetic susceptibility measurements over the 2–300 K range reveal very weak ferromagnetic interaction between the two Cu(II) ions in 1 and antiferromagnetic interaction in 2 mediated by nicotinate ligand, with J value to be 0.15 and −0.19 cm−1, respectively.

To study the chemical compositions of Eucommia ulmoides.The compounds were isolated and purified from Eucommia ulmoides by silica gel column chromatography, Sephadex LH-20, MPLC packed with MCI gel and semi-preparative HPLC. The structures of these compounds were established on the basis of spectral analyses (1H-NMR, 13C-NMR and MS).Thirteen compounds were obtained,and their structures were identified as betulin (1), syringin (2), pervoside A (3), glucosyringic acid (4), vanillic acid-beta-glucoside (5), geniposide acid (6), aucubin (7), geniposide (8), pinoresinol-4,4'-di-O-beta-D-glucopyranoside (9), syringaresinol di-O-beta-D-glucopyranoside (10), medioresinol di-O-beta-D-glucopyranoside (11), sucrose (12), and ethyl beta-glucopyranoside (13) on the basis of physical characteristics and spectral data.Compounds 3 - 5, 12 and 13 are isolated from this plant for the first itme.

[Sar9, Met(O2)11] termed Substance P (SP), is an effective and selective agonist for the neurokinin‑1 (NK‑1) receptors, which are synthetic peptides, similar in structure to SP. SP is an important neurotransmitter or neuromodulator mediated by neurokinin receptors, namely the SP receptor in the central nervous system. The excitatory effects induced by SP may be selectively inhibited by a neurokinin‑1 receptor antagonist, such as SR140333B. It has been proposed that Parkinson's disease (PD) is primarily caused by the loss of trophic peptidergic neurotransmitter, possibly SP, which may lead to the degeneration of neurons. In previous studies, 1‑methyl‑4‑phenylpyridinium (MPP+) has been frequently utilized to establish animal or cell models of PD. In the present study, to further investigate the effects of SP in PD, MPP+ was employed to investigate the promising anti‑apoptotic effects of SP, and examine the underlying mechanisms of the pathology in the MES23.5 dopaminergic cell line. The results indicated that MPP+‑triggered apoptosis was prevented by treatment with SP. SP treatment also decreased the MPP+‑triggered Ca2+ influx, caspase‑3 re‑activity, reactive oxygen species production and mitochondrial membrane potential decrease. Treatment with MPP+ also induced phosphorylation of c‑Jun N‑terminal kinase and p38 mitogen‑activated protein kinase. In addition, treatment with SP inhibited the MPP+‑triggered neurotoxicity in MES23.5 cells. However, no changes were observed in SR140333B+SP+MPP+‑treated MES23.5 cell lines. In conclusion, SP could protect the cells from MPP+‑induced cytotoxicity by inhibiting the apoptosis via NK-1 receptors.