Novel oral SPT inhibitor CH5169356 inhibits hepatic stellate cell activation and ameliorates hepatic fibrosis in mouse models of non-alcoholic steatohepatitis (NASH).

Ceramide is a central molecule of sphingolipid metabolism and is involved in the development of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). It has already been reported that the inhibition of serine palmitoyltransferase (SPT), the rate-limiting enzyme in the sphingolipid biosynthetic pathway, has an inhibitory effect on hepatic lipidosis, but its effect on severe hepatic fibrosis is not clear. In this study, we examined whether a SPT inhibitor could suppress the activation of hepatic stellate cells (HSC) and ameliorate the progression of NASH.

Improvement of red color development on the surface of kuruma prawn Marsupenaeus japonicus under various conditions.

The degree of red color development on the surface of prawns by cooking is an important index for food quality. In this study, we tested several factors that are thought to influence the red color development to identify possible correlations with various conditions. Live kuruma prawns, Marsupenaeus japonicus, (15.

Design and synthesis of 2-amino-6-(1H,3H-benzo[de]isochromen-6-yl)-1,3,5-triazines as novel Hsp90 inhibitors.

A novel series of 2-amino-1,3,5-triazines bearing a tricyclic moiety as heat shock protein 90 (Hsp90) inhibitors is described. Molecular design was performed using X-ray cocrystal structures of the lead compound CH5015765 and natural Hsp90 inhibitor geldanamycin with Hsp90. We optimized affinity to Hsp90, in vitro cell growth inhibitory activity, water solubility, and liver microsomal stability of inhibitors and identified CH5138303.

Enantioselective synthesis of derivatives and structure-activity relationship study in the development of NA255 as a novel host-targeting anti-HCV agent.

Hepatitis C virus (HCV) infection represents a serious health-care problem. Previously we reported the identification of NA255 from our natural products library using a HCV sub-genomic replicon cell culture system. Herein, we report how the absolute stereochemistry of NA255 was determined and an enantioselective synthetic method for NA255 derivatives was developed.

Self-enhancement of hepatitis C virus replication by promotion of specific sphingolipid biosynthesis.

Lipids are key components in the viral life cycle that affect host-pathogen interactions. In this study, we investigated the effect of HCV infection on sphingolipid metabolism, especially on endogenous SM levels, and the relationship between HCV replication and endogenous SM molecular species. We demonstrated that HCV induces the expression of the genes (SGMS1 and 2) encoding human SM synthases 1 and 2.

Design and synthesis of novel macrocyclic 2-amino-6-arylpyrimidine Hsp90 inhibitors.

Macrocyclic compounds bearing a 2-amino-6-arylpyrimidine moiety were identified as potent heat shock protein 90 (Hsp90) inhibitors by modification of 2-amino-6-aryltriazine derivative (CH5015765). We employed a macrocyclic structure as a skeleton of new inhibitors to mimic the geldanamycin-Hsp90 interactions. Among the identified inhibitors, CH5164840 showed high binding affinity for N-terminal Hsp90α (K(d)=0.

Synthesis and structure-activity relationships of novel benzofuran farnesyltransferase inhibitors.

A series of benzofuran-based farnesyltransferase inhibitors have been designed and synthesized as antitumor agents. Among them, 11f showed the most potent enzyme inhibitory activity (IC(50)=1.1nM) and antitumor activity in human cancer xenografts in mice.

Trial for quality control in mercury contents by using tail muscle of full-cycle cultured bluefin tuna (Thunnus orientalis).

Substantial amounts of mercury are usually present in tuna muscle, with levels in excess of 10 times the standard safety value present in some individuals. Inspection of individual fish for mercury content would be desirable but may not be cost-effective. In this study, we tried to establish a low-cost system for checking the mercury content of tuna by using a tail muscle that is usually discarded.

[Antimicrobial susceptibility and mechanism of resistance to antibiotics for Escherichia coli O157 and verotoxin-producing E. coli isolated in northern Kyushu and Yamaguchi area].

The purpose of this study was to investigate the biochemical characteristics and antimicrobial susceptibility of Escherichia (E.) coli O157 and verotoxin-producing E. coli isolates from the Northern Kyushu Island and Yamaguchi area of Japan.

The two-component cell lysis genes holWMY and lysWMY of the Staphylococcus warneri M phage varphiWMY: cloning, sequencing, expression, and mutational analysis in Escherichia coli.

From the genome library of Staphylococcus warneri M, the two successive cell-lysis genes (holWMY and lytWMY) were cloned and characterized. The lytWMY gene encoded a protein (LysWMY), whose calculated molecular mass and pI were 54 kDa and 8.95, respectively.

Molecular properties of the two-component cell lysis system encoded by prophage phigaY of Lactobacillus gasseri JCM 1131T: cloning, sequencing, and expression in Escherichia coli.

Shotgun cloning of the Lactobacillus gasseri JCM 1131T whole DNA yielded two recombinant plasmids, p118gaY1 and p118gaY2, which directed cell lysis activity. Sequencing analysis revealed that the two plasmids carried almost identical inserted genes in following orders (truncated genes, in parentheses): in p118gaY1, (orf149)-orf92-holgaY-lysgaY-orf35-attL-(mnaAgaY1); in p118gaY2, (orfXgaY1)-orf169-orf149-orf92-holgaY-lysgaY-orf35-attP-(intgaY). The lysgaY-encoded protein (designated as LysgaY, 33.

Characterization of lytic enzyme activities of Lactobacillus gasseri with special reference to autolysis.

Lactobacillus gasseri JCM 1130 and JCM 1131(T) exhibited autolytic activity in agar containing autoclaved cells of each strain as substrate. By zymogram analysis of JCM 1131(T), two lytic bands with apparent molecular masses of 54.5 and 35 kDa, were detected.

Synthesis and biological activities of benzofuran antifungal agents targeting fungal N-myristoyltransferase.

The C-4 side chain modification of lead compound 1 has resulted in the identification of a potent and selective Candida albicans N-myristoyltransferase (CaNmt) inhibitor RO-09-4609, which exhibits antifungal activity against C. albicans in vitro. Further modification of its C-2 substituent has led to the discovery of RO-09-4879, which exhibits antifungal activity in vivo.

Design and synthesis of novel benzofurans as a new class of antifungal agents targeting fungal N-myristoyltransferase. Part 3.

A new series of acid-stable antifungal agents having strong inhibitory activity against Candida albicans N-myristoyltransferase (CaNmt) has been developed starting from acid-unstable benzofuranylmethyl aryl ether 2. The inhibitor design is based on X-ray crystallographic analysis of a CaNmt complex with aryl ether 3. Among the new inhibitors, pyridine derivative 8b and benzimidazole derivative 8k showed clear antifungal activity in a murine systemic candidiasis model.

Molecular analysis of the lysis protein Lys encoded by Lactobacillus plantarum phage phig1e.

The putative cell-lysis gene lys of Lactobacillus plantarum G1e phage phig1e encodes for a 442 amino-acids protein Lys. The N-terminal region (about 80 amino acids) of Lys consists of two discrete regions (the signal-peptide-like domain and the DE domain containing putative active sites of endolysin). To elucidate functions of the regions of Lys, mutational (random, site-directed, and/or fusion) analysis was performed.

Crystal structures of Candida albicans N-myristoyltransferase with two distinct inhibitors.

Myristoyl-CoA:protein N-myristoyltransferase (Nmt) is a monomeric enzyme that catalyzes the transfer of the fatty acid myristate from myristoyl-CoA to the N-terminal glycine residue of a variety of eukaryotic and viral proteins. Genetic and biochemical studies have established that Nmt is an attractive target for antifungal drugs. We present here crystal structures of C.

Design and synthesis of novel benzofurans as a new class of antifungal agents targeting fungal N-myristoyltransferase. Part 2.

Modification of the C-2 position of a benzofuran derivative 6 (RO-09-4609), an N-myristoyltransferase (Nmt) inhibitor, has led us to discover antifungal agents that are active in a murine systemic candidiasis model. The drug design is based on the analysis of a crystal structure of a Candida Nmt complex with 2. The optimization has been guided by various biological evaluations including a quasi in vivo assay and pharmacokinetic analysis.