BackgroundMicro-ribonucleic acid (miRNA)-199a-5p has been reported to be decreased in hepatocellular carcinoma (HCC) compared to normal tissue. Discoidin domain receptor-1 (DDR1) tyrosine kinase, involved in cell invasion-related signaling pathway, was predicted to be a potential target of miR-199a-5p by the use of miRNA target prediction algorithms. The aim of this study was to investigate the role of miR-199a-5p and DDR1 in HCC invasion.MethodsMature miR-199a-5p and DDR1 expression were evaluated in tumor and adjacent non-tumor liver tissues from 23 patients with HCC undergoing liver resection and five hepatoma cell lines by the use of real-time quantitative RT-PCR (qRT-PCR) analysis. The effect of aberrant miR-199a-5p expression on cell invasion was assessed in vitro using HepG2 and SNU-182 hepatoma cell lines. Luciferase reporter assay was employed to validate DDR1 as a putative miR-199a-5p target gene. Regulation of DDR1 expression by miR-199a-5p was assessed by the use qRT-PCR and western blotting analysis.ResultsA significant down-regulation of miR-199a-5p was observed in 65.2% of HCC tissues and in four of five cell lines. In contrast, DDR1 expression was significantly increased in 52.2% of HCC samples and in two of five cell lines. Increased DDR1 expression in HCC was associated with advanced tumor stage. DDR1 was shown to be a direct target of miR-199a-5p by luciferase reporter assay. Transfection of miR-199a-5p inhibited invasion of HepG2 but not SNU-182 hepatoma cells.ConclusionsDecreased expression of miR-199a-5p contributes to increased cell invasion by functional deregulation of DDR1 activity in HCC. However, the effect of miR-199a-5p on DDR1 varies among individuals and hepatoma cell lines. These findings may have significant translational relevance for development of new targeted therapies as well as prognostic prediction for patients with HCC.

Ring-opening polymerization of O-carboxyanhydrides (OCAs) can furnish polyesters with a diversity of functional groups that are traditionally hard to harvest by polymerization of lactones. Typical ring-opening catalysts are subject to unavoidable racemization of most OCA monomers, which hampers the synthesis of highly isotactic crystalline polymers. Here, we describe an effective bifunctional single-molecule organocatalysis for selective ring-opening polymerization of OCAs without epimerization. The close vicinity of both activating groups in the same molecule engenders an amplified synergetic effect and thus allows for the use of mild bases, thereby leading to minimal epimerization for polymerization. Ring-opening polymerization of manOCA monomer (OCA from mandelic acid) mediated by the bifunctional single-molecule organocatalyst yields highly isotactic poly­(mandelic acid) (PMA) with controlled molecular weights (up to 19.8 kg mol–1). Mixing of the two enantiomers of PMA generates the first example of a crystalline stereocomplex in this area, which displayed distinct T m values around 150 °C. Remarkably, the bifunctional catalysts are moisture-stable, recyclable, and easy to use, allowing sustainable and scalable synthesis of a stereoregular functional polyester.

A new cytotoxic and antiviral cyclic tetrapeptide, asperterrestide A (1), a new alkaloid, terremide C (2), and a new aromatic butenolide, aspernolide E (3), together with 10 known compounds were isolated from the fermentation broth of the marine-derived fungus Aspergillus terreus SCSGAF0162. Their structures were elucidated by spectroscopic analysis, and the absolute configuration of 1 was determined by the Mosher ester technique and analysis of the acid hydrolysates using a chiral-phase HPLC column. Compound 1 contains a rare 3-OH-N-CH3-Phe residue and showed cytotoxicity against U937 and MOLT4 human carcinoma cell lines and inhibitory effects on influenza virus strains H1N1 and H3N2.

Eight new chromones, engyodontiumones A–H (1–8), and three new phenol derivatives (9–11) together with eight known polyketides (12–19) were isolated from the deep-sea-derived fungus Engyodontium album DFFSCS021. Their structures were identified by extensive spectroscopic analysis. Compounds 8 and 16 showed significant selective cytotoxicity against human histiocytic lymphoma U937 cell line with IC50 values of 4.9 and 8.8 μM, respectively. In addition, this is the first time to report that 8, 15 and 16 had mild antibacterial activity against Escherichia coli and Bacillus subtilis, and 15 showed potent antilarval activity against barnacle Balanus amphitrite larval settlement.

Recently, a lactate racemase was discovered as a new Ni-dependent enzyme with a unique tethered NAD-like cofactor. We report the first computational study aimed at deciphering the previously unclear role of the Ni-tethered cofactor in reactions of the lactate racemase. Our calculations revealed that the cofactor increases the dehydrogenation barriers. The formation of a metastable NADH-like pyruvate intermediate and two nearby histidine bases are proposed as the key factors in the racemization reaction. Such destabilization of intermediates by the cofactor is uncommon in enzymatic catalysis. This result provides new insight into the design of a reactive metal-tethered NADH-like complex for synthetic hydrogenations.

Hetero-Diels-Alder (HDA) reaction is an important synthetic method for many natural products. An iron(III) catalyst was developed to catalyze the challenging HDA reaction of unactivated aldehydes and dienes with high selectivity. Here we report extensive densityfunctional theory (DFT) calculations and molecular dynamics simulations that show effects of iron (including its coordinate mode and/or spin state) on the dynamics of this reaction: considerably enhancing dynamically stepwise process, broadening entrance channel and narrowing exit channel from concerted asynchronous transition states. Also, our combined computational and experimental secondary KIE studies reveal unexpectedly large KIE values for the five-coordinate pathway even with considerable C-C bond forming, due to equilibrium isotope effect from the change in the metal coordination. Moreover, steric and electronic effects are computationally shown to dictate the C=O chemoselectivity for an α,β-unsaturated aldehyde, which is verified experimentally. Our mechanistic study may help design homogeneous, heterogeneous and biological catalysts for this challenging reaction.

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Many-body effects can impact on rates of energy transfer from a ‘hot’ DF solute to acetonitrile solvent.