The Males Absent on the First (MOF) Mediated Acetylation Alters the Protein Stability and Transcriptional Activity of YY1 in HCT116 Cells.

Yin Yang 1 (YY1) is a well-known transcription factor that controls the expression of many genes and plays an important role in the occurrence and development of various cancers. We previously found that the human males absent on the first (MOF)-containing histone acetyltransferase (HAT) complex may be involved in regulating YY1 transcriptional activity; however, the precise interaction between MOF-HAT and YY1, as well as whether the acetylation activity of MOF impacts the function of YY1, has not been reported. Here, we present evidence that the MOF-containing male-specific lethal (MSL) HAT complex regulates YY1 stability and transcriptional activity in an acetylation-dependent manner. First, the MOF/MSL HAT complex was bound to and acetylated YY1, and this acetylation further promoted the ubiquitin-proteasome degradation pathway of YY1. The MOF-mediated degradation of YY1 was mainly related to the 146-270 amino acid residues of YY1. Further research clarified that acetylation-mediated ubiquitin degradation of YY1 mainly occurred through lysine 183. A mutation at the YY1K183 site was sufficient to alter the expression level of p53-mediated downstream target genes, such as CDKN1A (encoding p21), and it also suppressed the transactivation of YY1 on CDC6. Furthermore, a YY1K183R mutant and MOF remarkably antagonized the clone-forming ability of HCT116 and SW480 cells facilitated by YY1, suggesting that the acetylation-ubiquitin mode of YY1 plays an important role in tumor cell proliferation. These data may provide new strategies for the development of therapeutic drugs for tumors with high expression of YY1.

Structurally diverse secondary metabolites from a deep-sea-derived fungus Penicillium chrysogenum SCSIO 41001 and their biological evaluation.

Five new compounds, including a cytotoxic dimeric isocoumarin, bipenicilisorin (1), a merosesquiterpenoid, yaminterritrem C (2), a citrinin dimer, penicitrinone F (3), a alkaloid, terremide D (4), and a δ-valerolacton, (E)-4-(propen-1-yl)-5,6-dihydro-2H-pyran-2-one (5), along with ten known compounds (6-15) were isolated from a deep-sea-derived fungus Penicillium chrysogenum SCSIO 41001. Their structures and absolute configurations were elucidated by NMR spectra, MS, CD, optical rotation, X-ray crystallography, and compared with literature data. Biological evaluation results revealed that 1 exhibited significant cytotoxic activities against K562, A549, and Huh-7 cell lines with IC50 values of 6.78, 6.94, and 2.59µM, respectively. Compound 3 exhibited moderate inhibitory activity against EV71 with IC50 value of 14.50µM. In addition, 13 and 14 showed specific COX-2 inhibitory activities with IC50 values of 1.09 and 1.97µM, respectively.

Gene Expression Patterns Are Altered in Athymic Mice and Metabolic Syndrome Factors Are Reduced in C57BL/6J Mice Fed High-Fat Diets Supplemented with Soy Isoflavones.

Soy isoflavones exert beneficial health effects; however, their potential to ameliorate conditions associated with the metabolic syndrome (MetS) has not been studied in detail. In vitro and in vivo models were used to determine the effect of isoflavones on lipid metabolism, inflammation, and oxidative stress. In nude mice, consumption of Novasoy (NS) increased cholesterol and lipid metabolism gene expression, including Scd-1 (27.7-fold), Cyp4a14 (35.2-fold), and Cyp4a10 (9.5-fold), and reduced anti-inflammatory genes, including Cebpd (16.4-fold). A high-fat (HF) diet containing 0.4% (w/w) NS for 10 weeks significantly reduced percent weight gain (74.6 ± 2.5 vs 68.6 ± 3.5%) and hepatic lipid accumulation (20 ± 1.2 vs 27 ± 1.5%), compared to HF alone (p < 0.05) in C57BL/6J mice. NS also increased lipid oxidation and antioxidant gene expression while decreasing inflammatory cytokines. In vitro analysis in HepG2 cells revealed that genistein dose-dependently decreases oleic acid-induced lipid accumulation. Soy isoflavones may ameliorate symptoms associated with MetS via anti-inflammatory, antioxidant, and hypolipidemic modulation.

Design and Synthesis of Dimeric Securinine Analogues with Neuritogenic Activities.

Neurite outgrowth is crucial during neuronal development and regeneration, and strategies that aim at promoting neuritogenesis are beneficial for reconstructing synaptic connections after neuronal degeneration and injury. Using a bivalent analogue strategy as a successful approach, the current study identifies a series of novel dimeric securinine analogues as potent neurite outgrowth enhancers. Compounds 13, 14, 17-19, and 21-23, with different lengths of carbon chain of N,N-dialkyl substituting diacid amide linker between two securinine molecules at C-15 position, exhibited notable positive effects on both neuronal differentiation and neurite extension of neuronal cells. Compound 14, one of the most active compounds, was used as a representative compound for mechanistic studies. Its action on neurite outgrowth was through phosphorylation/activation of multiple signaling molecules including Ca2+/calmodulin-dependent protein kinase II (CaMKII), extracellular signal-regulated kinase (ERK) and Akt. These findings collectively identify a new group of beneficial compounds for neuritogenesis, and may provide insights on drug discovery of neural repair and regeneration.

Consumption of Quercetin and Quercetin-Containing Apple and Cherry Extracts Affects Blood Glucose Concentration, Hepatic Metabolism, and Gene Expression Patterns in Obese C57BL/6J High Fat-Fed Mice.

BACKGROUND: Intake of polyphenols and polyphenol-rich fruit extracts has been shown to reduce markers of inflammation, diabetes, and hepatic complications that result from the consumption of a high-fat (HF) diet. OBJECTIVE: The objective of this study was to determine whether mice fed polyphenol-rich apple peel extract (AE), cherry extract (CE), and quercetin, a phytochemical abundant in fruits including apples and cherries, would modulate the harmful effects of adiposity on blood glucose regulation, endocrine concentrations, and hepatic metabolism in HF-fed C57BL/6J male mice. METHODS: Groups of 8-wk-old mice (n = 8 each) were fed 5 diets for 10 wk, including low-fat (LF; 10% of total energy) and HF (60% of total energy) control diets and 3 HF diets containing polyphenol-rich AE, CE, and quercetin (0.2% wt:wt). Also, an in vitro study used HepG2 cells exposed to quercetin (0-100 µmol/L) to determine whether intracellular lipid accumulation could be modulated by this phytochemical. RESULTS: Mice fed the HF control diet consumed 36% more energy, gained 14 g more body weight, and had ∼50% elevated blood glucose concentrations (all P < 0.05) than did LF-fed mice. Mice fed HF diets containing AE, CE, or quercetin became as obese as HF-fed mice, but had significantly lower blood glucose concentrations after food deprivation (-36%, -22%, -22%, respectively; P < 0.05). Concentrations of serum C-reactive protein were reduced 29% in quercetin-fed mice compared with HF-fed controls (P < 0.05). A qualitative evaluation of liver tissue sections suggested that fruit phytochemicals may reduce hepatic lipid accumulation. A quantitative analysis of lipid accumulation in HepG2 cells demonstrated a dose-dependent decrease in lipid content in cells treated with 0-100 µmol quercetin/L (P < 0.05). CONCLUSIONS: In mice, consumption of AE, CE, or quercetin appears to modulate some of the harmful effects associated with the consumption of an obesogenic HF diet. Furthermore, in a cell culture model, quercetin was shown to reduce intracellular lipid accumulation in a dose-dependent fashion.

Aligned Nanofibers from Polypyrrole/Graphene as Electrodes for Regeneration of Optic Nerve via Electrical Stimulation.

The damage of optic nerve will cause permanent visual field loss and irreversible ocular diseases, such as glaucoma. The damage of optic nerve is mainly derived from the atrophy, apoptosis or death of retinal ganglion cells (RGCs). Though some progress has been achieved on electronic retinal implants that can electrically stimulate undamaged parts of RGCs or retina to transfer signals, stimulated self-repair/regeneration of RGCs has not been realized yet. The key challenge for development of electrically stimulated regeneration of RGCs is the selection of stimulation electrodes with a sufficient safe charge injection limit (Q(inj), i.e., electrochemical capacitance). Most traditional electrodes tend to have low Q(inj) values. Herein, we synthesized polypyrrole functionalized graphene (PPy-G) via a facile but efficient polymerization-enhanced ball milling method for the first time. This technique could not only efficiently introduce electron-acceptor nitrogen to enhance capacitance, but also remain a conductive platform-the π-π conjugated carbon plane for charge transportation. PPy-G based aligned nanofibers were subsequently fabricated for guided growth and electrical stimulation (ES) of RGCs. Significantly enhanced viability, neurite outgrowth and antiaging ability of RGCs were observed after ES, suggesting possibilities for regeneration of optic nerve via ES on the suitable nanoelectrodes.

Securinega alkaloids from the fruits of Flueggea suffruticosa.

Phytochemical investigation on the fruits of Flueggea suffruticosa resulted in the isolation of three new Securinega alkaloids, secu'amamine H (1), 15ß-methoxy-14,15-dihydrosecurinine (3), and securinol E (7), as well as eight known ones (2, 4-6, and 8-11). Their structures were elucidated by means of spectroscopic techniques (1D and 2D NMR, MS, UV, and IR). The absolute configurations of the new compounds were established by single-crystal X-ray diffraction and CD analyses.

Five new acylphloroglucinol glycosides from the leaves of Eucalyptus robusta.

Five new acylphloroglucinol glycosides, robustasides A-E (1-5), together with a known one (6), were isolated from the leaves of Eucalyptus robusta. The structures were elucidated on the basis of extensive spectroscopic and spectrometric analysis and chemical evidence. The absolute configuration of 1 was further determined by quantum chemical CD calculation.

Suffrutines A and B: a pair of Z/E isomeric indolizidine alkaloids from the roots of Flueggea suffruticosa.

Suffrutines A (1) and B (2), a pair of novel photochemical Z/E isomeric indolizidine alkaloids, with a unique and highly conjugated C20 skeleton, were isolated from the roots of Flueggea suffruticosa. The structures were elucidated by extensive analysis of NMR spectra and single-crystal X-ray diffraction. The light-induced isomerization and hypothetical biogenetic pathway to 1 and 2, as well as their activity for regulating the morphology of Neuro-2a cells are also discussed.

Five new stilbene glycosides from the roots of Polygonum multiflorum.

Five new stilbene glycosides (1-5), together with six known ones, were isolated from the roots of Polygonum multiflorum. Their structures were elucidated on the basis of spectroscopic analysis and chemical evidence.

Two new euglobals from the leaves of Eucalyptus robusta.

Two new euglobals, R1 (1) and R2 (2), together with eight known euglobals (3-10) were isolated from the leaves of Eucalyptus robusta. Their structures were established by means of spectroscopic analysis and single-crystal X-ray diffraction. Euglobal R1 (1) represents a new skeleton of formyl-isovaleryl phloroglucinol-coupled ß-phellandrene.