Naa20, the catalytic subunit of NatB complex,contributes to hepatocellular carcinoma by regulating the LKB1–AMPK–mTOR axis

N-α-acetyltransferase 20 (Naa20), which is a catalytic subunit of the N-terminal acetyltransferase B (NatB) complex, has recently been reported to be implicated in hepatocellular carcinoma (HCC) progression and autophagy, but the underlying mechanism remains unclear. Here, we report that based on bioinformatic analysis of Gene Expression Omnibus and The Cancer Genome Atlas data sets, Naa20 expression is much higher in HCC tumors than in normal tissues, promoting oncogenic properties in HCC cells. Mechanistically, Naa20 inhibits the activity of AMP-activated protein kinase (AMPK) to promote the mammalian target of rapamycin signaling pathway, which contributes to cell proliferation, as well as autophagy, through its N-terminal acetyltransferase (NAT) activity. We further show that liver kinase B1 (LKB1), a major regulator of AMPK activity, can be N-terminally acetylated by NatB in vitro, but also probably by NatB and/or other members of the NAT family in vivo, which may have a negative effect on AMPK activity through downregulation of LKB1 phosphorylation at S428. Indeed, p-LKB1 (S428) and p-AMPK levels are enhanced in Naa20-deficient cells, as well as in cells expressing the nonacetylated LKB1-MPE mutant; moreover, importantly, LKB1 deficiency reverses the molecular and cellular events driven by Naa20 knockdown. Taken together, our findings suggest that N-terminal acetylation of LKB1 by Naa20 may inhibit the LKB1–AMPK signaling pathway, which contributes to tumorigenesis and autophagy in HCC.Subject terms: Cancer prevention, Tumour biomarkers     

Structure determination of fexofenadine‐α‐cyclodextrin complex by quantitative 2D ROESY analysis and molecular mechanics studies

Complexation of fexofenadine with α‐cyclodextrin in aqueous medium was studied. The stoichiometry of the resulting inclusion complex was determined by ¹H NMR titration data. 2D ROESY data provided the evidence of formation of the complex by entry of the phenyl ring into the α‐cyclodextrin cavity probably from wider opening. Determination of relative peak intensities of intermolecular cross‐peaks for the most stable complexes obtained by molecular mechanics (MM2) studies and from 2D ROESY spectral data confirmed the presence of only one complex in solution that has been fully characterized. Copyright © 2012 John Wiley & Sons, Ltd.     

The effect of tacrolimus-containing polyethylene glycol-modified maghemite nanospheres on reducing oxidative stress and accelerating the healing spinal cord injury of rats based on increasing M2 macrophages

One of the key factors in repairing spinal cord injury is reducing inflammation and oxidative stress. So, it was tried to increase the growth of neurons more rapidly by enhancing the macrophage M2 and reducing the M1 to M2 ratio by using the possible role of tacrolimus (TAC) loaded on polyethylene glycol-modified maghemite nanospheres (PEG-MNs). In this regard, after designing PEG-MNs-TAC in a three-step process and examining their properties through TEM, DLS and XRD analyses. A toxicity assay was then performed by using MTT test. To investigate the healing role of TAC on damaged tissue, a rat model was used to induce injury in vertebral T6 through physical injury. Then, rats were allocated into five groups: negative control, MNs, PEG-MNs , TAC (and PEG-MNs-TAC. Next, motor scale index, behavioral test, macrophage markers expression, concentration of IL-6, IL-2 and TNF-α, and oxidative stress on rats were analyzed. The results revealed that TAC and PEG-MNs-TAC significantly improved mobility and neuropathic tests. Furthermore, the decrease in TNF-α, IL-6, and IL-2 along with the decrease in ROS levels in the injured spinal cord were considerable in both TAC- and PEG-MNs-TAC-treated groups. Nonetheless, the PEG-MNs-TAC exposed more favorable outcomes compared to TAC. Overall, PEG-MNs-TAC could provide a new treatment for damaged spinal cord care by reducing oxidative stress and decreasing M1 to M2 ratio.     

Building up 1‐D, 2‐D,and 3‐D Polyiodide Frameworks by Finely Tuning the Size of Aryls on Ar‐S‐TTF in the Charge‐Transfer (CT) Complexes of Ar‐S‐TTFs and Iodine

The arylthio‐substituted tetrathiafulvalenes (Ar‐S‐TTFs) are electron donors having three reversible states, neutral, cation radical, and dication. The charge‐transfer (CT) between Ar‐S‐TTFs ( TTF1 — TTF3 ) and iodine (I₂) is reported herein. TTF1 — TTF3 show the CT with I₂ in the CH₂Cl₂ solution, but they are not completely converted into cation radical state. In CT complexes of TTF1 — TTF3 with I₂, the charged states of Ar‐S‐TTFs are distinct from those in solution. TTF1 is at cation radical state, and TTF2 — TTF3 are oxidized to dication. The iodine components in complexes show various structures including 1‐D chain of V‐shaped (I₅)^–, and 2‐D and 3‐D iodine networks composed of I₂ and (I₃)^–.     

The 2:1 complex of maleic acid and 1,4‐diazabicyclo[2.2.2]octane: hydrogen‐bonded sheets linked by C–H⋯O hydrogen bonds

In the title complex, 1,4‐diazo­niabi­cyclo­[2.2.2]­octane bis­(hy­drogen maleate), C₆H₁₄N₂²⁺·2C₄H₃O₄^?, the C₄H₃O₄^? and C₆H₁₄N₂²⁺ ions, derived from maleic acid and 1,4‐di­aza­bi­cyclo­[2.2.2]­octane, respectively, are disordered across a mirror plane in space group Cmc2₁, and they are linked by two nearly linear N—H?O hydrogen bonds, with N?O distances of 2.662 (3) and 2.614 (4) Å, and N—H?O angles of 173°. The crystal structure consists of sheets with reticulations of 3.3792 (4) Å in stratum and 7.3892 (8) Å in width. The sheets are linked by C—H?O hydrogen bonds.     

Cover Picture: Building up 1‐D, 2‐D,and 3‐D Polyiodide Frameworks by Finely Tuning the Size of Aryls on Ar‐S‐TTF in the Charge‐Transfer (CT) Complexes of Ar‐S‐TTFs and Iodine (Chin. J. Chem. 9/2018)

The cover picture shows The arylthio‐substituted tetrathiafulvalenes (Ar‐S‐TTFs) are electron donors having three reversible states, neutral, cation radical, and dication. The charge‐transfer (CT) between Ar‐S‐TTFs and iodine (I2) occurs in solution, whereas the Ar‐S‐TTFs are partially at cation radical state. In CT complexes of Ar‐S‐TTFs with I₂, the charged states of Ar‐S‐TTFs are distinctly increased, say, the dicationic state is observed. The iodine components in CT complexes show various structures including 1‐D polymeric chain, and 2‐D and 3‐D iodine networks. More details are discussed in the article by Shao et al. on page 845–850.

     

CH Bond Activation during and after the Reactions of a Metallacyclic Amide with Silanes: Formation of a μ‐Alkylidene Hydride Complex,Its H–D Exchange,and β‐H Abstraction by a Hydride Ligand

Metallacyclic complex [(Me₂N)₃Ta(η²‐CH₂SiMe₂NSiMe₃)] ( 3 ) undergoes C?H activation in its reaction with H₃SiPh to afford a Ta/μ‐alkylidene/hydride complex, [(Me₂N)₂{(Me₃Si)₂N}Ta(μ‐H)₂(μ‐C‐η²‐CHSiMe₂NSiMe₃)Ta(NMe₂)₂] ( 4 ). Deuterium‐labeling studies with [D₃]SiPh show H–D exchange between the Ta?D ?Ta unit and all methyl groups in [(Me₂N)₂{(Me₃Si)₂N}Ta(μ‐D)₂(μ‐C‐η²‐CHSiMe₂NSiMe₃)Ta(NMe₂)₂] ([D₂]‐ 4 ) to give the partially deuterated complex [D_n]‐ 4 . In addition, 4 undergoes β‐H abstraction between a hydride and an NMe₂ ligand and forms a new complex [(Me₂N){(Me₃Si)₂N}Ta(μ‐H)(μ‐N‐η²‐C,N‐CH₂NMe)(μ‐C‐η²‐C,N‐CHSiMe₂NSiMe₃)Ta(NMe₂)₂] ( 5 ) with a cyclometalated, η²‐imine ligand. These results indicate that there are two simultaneous processes in [D_n]‐ 4 : 1) H–D exchange through σ‐bond metathesis, and 2) H?D elimination through β‐H abstraction (to give [D_n]‐ 5 ). Both 4 and 5 have been characterized by single‐crystal X‐ray diffraction studies.     

The exchange of the fast substrate water in the S2 state of photosystem II is limited by diffusion of bulk water through channels – implications for the water oxidation mechanism

The molecular oxygen we breathe is produced from water-derived oxygen species bound to the Mn₄CaO₅ cluster in photosystem II (PSII). Present research points to the central oxo-bridge O5 as the ‘slow exchanging substrate water (W_s)’, while, in the S₂ state, the terminal water ligands W2 and W3 are both discussed as the ‘fast exchanging substrate water (W_f)’. A critical point for the assignment of W_f is whether or not its exchange with bulk water is limited by barriers in the channels leading to the Mn₄CaO₅ cluster. In this study, we measured the rates of H₂¹⁶O/H₂¹⁸O substrate water exchange in the S₂ and S₃ states of PSII core complexes from wild-type (WT) Synechocystis sp. PCC 6803, and from two mutants, D1-D61A and D1-E189Q, that are expected to alter water access via the Cl1/O4 channels and the O1 channel, respectively. We found that the exchange rates of W_f and W_s were unaffected by the E189Q mutation (O1 channel), but strongly perturbed by the D61A mutation (Cl1/O4 channel). It is concluded that all channels have restrictions limiting the isotopic equilibration of the inner water pool near the Mn₄CaO₅ cluster, and that D61 participates in one such barrier. In the D61A mutant this barrier is lowered so that W_f exchange occurs more rapidly. This finding removes the main argument against Ca-bound W3 as fast substrate water in the S₂ state, namely the indifference of the rate of W_f exchange towards Ca/Sr substitution.

Access to the oxygen-evolving complex in photosynthesis is restricted by specific barriers in the channels connecting the Mn₄CaO₅ catalyst with bulk water. Together with other recent data, this finding allows assigning the two substrate waters.     

Simultaneous determination of metoprolol and its metabolites, α‐hydroxymetoprolol and O‐desmethylmetoprolol,in human plasma by liquid chromatography with tandem mass spectrometry: Application to the pharmacokinetics of metoprolol associated with CYP2D6 genotypes

A rapid and simple LC with MS/MS method for the simultaneous determination of metoprolol and its two CYP2D6‐derived metabolites, α‐hydroxy‐ and O‐desmethylmetoprolol, in human plasma was established. Metoprolol (MET), its two metabolites, and the internal standard chlorpropamide were extracted from plasma (50 μL) using ethyl acetate. Chromatographic separation was performed on a Luna CN column with an isocratic mobile phase consisting of distilled water and methanol containing 0.1% formic acid (60:40, v/v) at a flow rate of 0.3 mL/min. The total run time was 3.0 min per sample. Mass spectrometric detection was conducted by ESI in positive ion selected‐reaction monitoring mode. The linear ranges of concentration for MET, α‐hydroxymetoprolol, and O‐desmethylmetoprolol were 2–1000, 2–500, and 2–500 ng/mL, respectively, with a lower limit of quantification of 2 ng/mL for all analytes. The coefficient of variation for the assay's precision was ≤ 13.2%, and the accuracy was 89.1–110%. All analytes were stable under various storage and handling conditions and no relevant cross‐talk and matrix effect were observed. Finally, this method was successfully applied to assess the influence of CYP2D6 genotypes on the pharmacokinetics of MET after oral administration of 100 mg to healthy Korean volunteers.     

Conformational study of Co(II), Ni(II), and Cr(III) complexes of the edta-type: Crystal structure of 1D polymeric trans(O)-Ba[Co(1,3-pddadp)] · 8H2O complex stabilized by infinite water tapes

The trans(O⁶) isomer of the Ba[Co(1,3-pddadp)] · 8H₂O complex (where 1,3-pddadp represents hexadentate 1,3-propanediamine-N,N′-diacetate-N,N′-di-3-propionate ion) has been prepared and characterized by X-ray crystallography. In the crystal structure the complex cations and anions are bridged by carboxylate oxygen atoms from the in-plane coordinated glycinate rings (G-rings) of [Co(1,3-pddadp)]²⁻ and by the barium-coordinated water molecules, thus forming 1D polymeric chains, separated by infinite water tapes hydrogen bonded to the [Co(1,3-pddadp)]²⁻ carboxylate oxygens from the out-of-plane β-alaninate rings (R-rings). Conformational analysis of the three possible geometrical isomers: trans(O⁵), trans(O⁵O⁶), and trans(O⁶) of the [Co(1,3-pddadp)]²⁻ complex, with ligand acting as hexadentate, as well as of the corresponding complexes of Ni(II) and Cr(III) has been performed using the consistent force field (CFF) method, with the parameters developed previously for edta-type complexes of chromium(III) and supplemented with new parameters for cobalt(II) and nickel(II). The energy-minimized structure of the trans(O⁵O⁶) isomer represents the global minimum for the [M(1,3-pddadp)]ⁿ⁻ (M = Co(II), Ni(II), and Cr(III)) species. The occurrence of the least energetically favored trans(O⁶) isomer in a crystal and the exceptional conformation of the axially oriented β-alaninate rings can be accounted for by the stabilizing role of the infinite tapes of planar cyclic water pentamers and hexamers which act as a “glue” to reinforce the coordination polymeric chains.     

Oxidation reactions using water, hydrogen peroxide and halogens to give pallad(IV) cyclopentane complexes PdX(C4H8 {(pz)3BH} (X = OH, Cl, Br, I). The crystal structure of the hydroxoplatinum(IV) complex Pt(OH)Me2{(pz)3BH}, formed by use of water as an oxidant

The pallada(II)cyclopentane reagent [Pd(C₄H₈{(pz)₃BH}]⁻, generated by addition of potassium tris(pyrazol-1-yl)borate to the tetramethylethylenediamine analogue, reacts with water or hydrogen peroxide to give hydroxopalladium(IV) complex Pd(OH)(C₄H₈){(pz)₃BH}. Similar oxidation reactions occur with phenyliodonium dichloride, bromine and iodine to give PdX(C₄H₈){(pz)₃BH} (X = Cl, Br, I). The hydroxoplatinum(IV) complex Pt(OH)Me₂{(pz)₃BH} has been obtaine reaction of [PtMe₂(SEt₂)]₂ with K[(pz)₃BH], followed by addition of water, and its structure determined by an X-ray diffraction study.