The complete mitochondrial genome of a wood-decaying fungus Vanderbylia fraxinea (Polyporaceae, Polyporales).

Vanderbylia fraxinea (Bull.) D.A. Reid, 1973 is an important wood-inhabiting fungus that plays a significant role in nutrient recycling in most forest ecosystems. In this study, the complete mitochondrial genome of V. fraxinea was characterized through de novo assembly using Illumina sequencing data and genome annotation. The mitochondrial genome is a circular molecule of 115,473 bp with a GC content of 28.66%. It comprises a total of 62 genes. Among these, 36 are protein-coding genes including 21 free-standing open reading frames (ORFs), 24 transfer RNA genes, and two ribosomal RNA genes. Core gene set commonly found in fungal mitochondrial genomes is also present in this genome, such as the apocytochrome b (cob), three subunits of the cytochrome c oxidase (cox1, cox2, and cox3), seven subunits of the NADH dehydrogenase (nad1, nad2, nad3, nad4, nad4L, nad5, and nad6), and three subunits of the ATP synthase (atp6, atp8, and atp9), as well as ribosomal RNA subunits (rns and rnl) and a set of transfer RNA genes. Phylogenetic analysis of the protein-coding sequences from the mitochondrial genome revealed a close relationship between V. fraxinea and the Ganoderma species within the Polyporaceae family.

Discovery of N-amido-phenylsulfonamide derivatives as novel microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors.

Our previous research showed that N-carboxy-phenylsulfonyl hydrazide (scaffold A) could reduce LPS-stimulated PGE2 levels in RAW 264.7 macrophage cells by an inhibition of mPGES-1 enzyme. However, a number of scaffold A derivatives showed the drawbacks such as the formation of regioisomers and poor liver metabolic stability. In order to overcome these synthetic and metabolic problems, therefore, we decided to replace N-carboxy-phenylsulfonyl hydrazide (scaffold A) with N-carboxy-phenylsulfonamide (scaffold B) or N-amido-phenylsulfonamide frameworks (scaffold C) as a bioisosteric replacement. Among them, MPO-0186 (scaffold C) inhibited the production of PGE2 (IC50: 0.24 µM) in A549 cells via inhibition of mPGES-1 (IC50: 0.49 µM in a cell-free assay) and was found to be approximately 9- and 8-fold more potent than MK-886 as a reference inhibitor, respectively. A molecular docking study theoretically suggests that MPO-0186 could inhibit PGE2 production by blocking the PGH2 binding site of mPGES-1 enzyme. Furthermore, MPO-0186 demonstrated good liver metabolic stability and no significant inhibition observed in clinically relevant CYP isoforms except CYP2C19. This result provides a potential starting point for the development of selective and potent mPGES-1 inhibitor with a novel scaffold.

Synthesis and cytotoxic effects of 2-thio-3,4-dihydroquinazoline derivatives as novel T-type calcium channel blockers.

In our previous work, a series of 2-amino-3,4-dihydroquinazoline derivativesusing an electron acceptor group was reported to be potent T-type calcium channel blockers and exhibit strong cytotoxic effects against various cancerous cell lines. To investigate the role of the guanidine moiety in the 2-amino-3,4-dihydroquinazoline scaffold as a pharmacophore for dual biological activity, a new series of 2-thio-3,4-dihydroquniazoline derivatives using an electron donor group at the C2-position was synthesized and evaluated for T-type calcium channel blocking activity and cytotoxic effects against two human cancerous cell lines (lung cancer A549 and colon cancer HCT-116). Among them, compound 6g showed potent inhibition of Cav3.2 currents (83% inhibition) at 10 µM concentrations. The compound also exhibited IC50 values of 5.0 and 6.4 µM against A549 and HCT-116 cell lines, respectively, which are comparable to the parental lead compound KYS05090. These results indicate that the isothiourea moiety similar to the guanidine moiety of 2-amino-3,4-dihydroquinazoline derivatives may be an essential pharmacophore for the desired biological activities. Therefore, our preliminary work can provide the opportunity to expand a chemical repertoire to improve affinity and selectivity for T-type calcium channels.

KCP10043F Represses the Proliferation of Human Non-Small Cell Lung Cancer Cells by Caspase-Mediated Apoptosis via STAT3 Inactivation.

We previously reported that 4-(4-fluorobenzylcarbamoylmethyl)-3-(4-cyclohexylphenyl)-2-[3-(N,N-dimethylureido)-N'-methylpropylamino]-3,4-dihydroquinazoline (KCP10043F) can induce G1-phase arrest and synergistic cell death in combination with etoposide in lung cancer cells. Here, we investigated the underlying mechanism by which KCP10043F induces cell death in non-small cell lung cancer (NSCLC). Propidium iodide (PI) and annexin V staining revealed that KCP10043F-induced cytotoxicity was caused by apoptosis. KCP10043F induced a series of intracellular events: (1) downregulation of Bcl-2 and Bcl-xL and upregulation of Bax and cleaved Bid; (2) loss of mitochondrial membrane potential; (3) increase of cytochrome c release; (4) cleavage of procaspase-8, procaspase-9, procaspase-3, and poly (ADP-ribose) polymerase (PARP). In addition, KCP10043F exhibited potent inhibitory effects on constitutive or interleukin-6 (IL-6)-induced signal transducer and activator of transcription (STAT3) phosphorylation and STAT3-regulated genes including survivin, Mcl-1, and cyclin D1. Furthermore, STAT3 overexpression attenuated KCP10043F-induced apoptosis and the cleavage of caspase-9, caspase-3, and PARP. Docking analysis disclosed that KCP10043F could bind to a pocket in the SH2 domain of STAT3 and prevent STAT3 phosphorylation. The oral administration of KCP10043F decreased tumor growth in an A549 xenograft mouse model, as associated with the reduced phosphorylated STAT3, survivin, Mcl-1, and Bcl-2 expression and increased TUNEL staining and PARP cleavage in tumor tissues. Collectively, our data suggest that KCP10043F suppresses NSCLC cell growth through apoptosis induction via STAT3 inactivation.

Effect of fruiting body bacteria on the growth of Tricholoma matsutake and its related molds.

Tricholoma matsutake (pine mushroom, PM) is a prized mushroom in Asia due to its unique flavor and pine aroma. The fruiting body of PM forms only in its natural habitat (pine forest), and little is known regarding the natural conditions required for successful generation of the fruiting bodies in this species. Recent studies suggest that microbial interactions may be associated with the growth of PM; however, there have been few studies of the bacterial effects on PM growth. In this study, we surveyed which bacteria can directly and indirectly promote the growth of PM by using co-cultures with PM and molds associated with the fruiting body. Among 16 bacterial species isolated from the fruiting body, some species significantly influenced the mycelial growth of PM and molds. Most bacteria negatively affected PM growth and exhibited various enzyme activities, which suggests that they use the fruiting body as nutrient source. However, growth-promoting bacteria belonging to the Dietzia, Ewingella, Pseudomonas, Paenibacillus, and Rodococcus were also found. In addition, many bacteria suppressed molds, which suggests an indirect positive effect on PM as a biocontrol agent. Our results provide important insights toward a better understanding of the microbial interactions in the fruiting body of PM, and indicate that growth-promoting bacteria may be an important component in successful cultivation of PM.

Effects of Ovarian Cycle on Hemodynamic Responses during Dynamic Exercise in Sedentary Women.

This study tested the hypothesis that effects of the menstrual cycle on resting blood pressure carry over to dynamic exercise. Eleven healthy females were studied during the early (EP; low estrogen, low progesterone) and late follicular (LP; high estrogen, low progesterone) menstrual phases. Stroke volume (SV), heart rate (HR), cardiac output (CO), systolic blood pressure (SBP), diastolic blood pressure (DBP), and total vascular conductance (TVC) were assessed at rest and in response to mild and moderate cycling exercise during EP and LP. During EP, compared to LP, baseline SBP (111±1 vs. 103±2 mmHg), DBP (71±2 vs. 65±2 mmHg) and mean arterial pressure (MAP) (84±2 vs. 78±1 mmHg) were higher and TVC (47.0±1.5 vs. 54.9±4.2 ml/min/mmHg) was lower (p<0.05). During exercise, absolute values of SBP (Mild: 142±4 vs. 127±5 mmHg; Moderate: 157±4 vs. 144±5 mmHg) and MAP (Mild: 100±3 vs. 91±3 mmHg; Moderate: 110±3 vs. 101±3 mmHg) were also higher, while TVC was lower (Mild: 90.9±5.1 vs. 105.4±5.2 ml/min/mmHg; Moderate: 105.4±5.3 vs. 123.9±8.1 ml/min/mmHg) during EP (p<0.05). However, exercise-induced increases in SBP, MAP and TVC at both work intensities were similar between the two menstrual phases, even though norepinephrine concentrations were higher during LP. Results indicate that blood pressure during dynamic exercise fluctuates during the menstrual cycle. It is higher during EP than LP and appears to be due to additive effects of simultaneous increases in baseline blood pressure and reductions in baseline TVC.