Synthesis of novobiocin derivatives and evaluation of their antigonococcal activity and pharmacokinetics.

Gonorrhea has become a serious problem because the number of infected people is increasing and the multi-drug resistance of the causative bacteria, Neisseria gonorrhoeae, is progressing. To develop novel drugs against resistant N. gonorrhoeae, we focused on the antibiotic novobiocin (1).

Anti-influenza Virus Activity of Methylthio-Formycin Distinct From That of T-705.

Seasonal influenza virus epidemics result in severe illness, and occasionally influenza pandemics cause significant morbidity and mortality, although vaccines and anti-influenza virus drugs are available. By screening an in-house library, we identified methylthio-formycin (SMeFM), an adenosine analog, as a potent inhibitor of influenza virus propagation. SMeFM inhibited the propagation of influenza A and B viruses (IC: 34.

Synthesis and antiviral activity of formycin derivatives with anti-influenza virus activity.

In a screening using our unique natural product library, the C-nucleoside antibiotic formycin A, which exerts strong anti-influenza virus activity, was rediscovered. Aiming to develop a new type of anti-influenza virus drug, we synthesized new derivatives of formycin and evaluated its anti-influenza virus activity. Structural modifications were focused on the base moiety and sugar portion, respectively, and >40 novel formycin derivatives were synthesized.

New anti-cancer chemicals Ertredin and its derivatives, regulate oxidative phosphorylation and glycolysis and suppress sphere formation in vitro and tumor growth in EGFRvIII-transformed cells.

Background: EGFRvIII is a mutant form of the epidermal growth factor receptor gene (EGFR) that lacks exons 2-7. The resulting protein does not bind to ligands and is constitutively activated. The expression of EGFRvIII is likely confined to various types of cancer, particularly glioblastomas.

Stereoselective Total Synthesis of KAE609 via Direct Catalytic Asymmetric Alkynylation to Ketimine.

A direct catalytic asymmetric alkynylation protocol is applied to provide the requisite enantioenriched propargylic α-tertiary amine, allowing for the stereoselective total synthesis of KAE609 (formerly NITD609 or cipargamin).

Direct catalytic asymmetric vinylogous conjugate addition of unsaturated butyrolactones to α,β-unsaturated thioamides.

Soft Lewis acid/Brønsted base cooperative catalysts have enabled direct catalytic asymmetric vinylogous conjugate addition of α,β- and β,γ-unsaturated butyrolactones to α,β-unsaturated thioamides with perfect atom economy. When using α-angelica lactone and its derivatives as pronucleophiles, as little as 0.5 mol% catalyst loading was sufficient to complete the reaction necessary to construct consecutive tri- and tetrasubstituted stereogenic centers in a highly diastereo- and enantioselective fashion.

Direct catalytic asymmetric alkynylation of ketoimines.

An efficient protocol for direct catalytic alkynylation of ketoimines is described. The simultaneous activation of a soft Lewis basic terminal alkyne and a ketoimine bearing a thiophosphinoyl group by soft Lewis acid Cu(I) is crucial for high conversion. The reaction can be rendered asymmetric with a chiral bisphosphine ligand (S,S)-Ph-BPE.

Epigenetic silencing of miR-335 and its host gene MEST in hepatocellular carcinoma.

MicroRNAs (miRNAs) are small non-coding RNAs that function as endogenous silencers of target genes. Some tumor-suppressive miRNAs are known to be epigenetically silenced by promoter DNA methylation in cancer. In the present study, we aimed to identify miRNA genes that are silenced by DNA hypermethylation in hepatocellular carcinoma (HCC).

Synthetic studies of the lichen macrolide lepranthin. Stereoselective synthesis of the diolide framework based on regioselective epoxide-opening reactions.

Stereoselective synthesis of the 16-membered diolide 27, a fully functionalized congener of lepranthin (1), is described. The requisite five asymmetric carbon centers in monomer 23 were constructed in a highly stereoselective manner by using different epoxide-opening reactions of α,β-unsaturated γ,δ-epoxy esters and epoxy alcohol derivatives as the key steps. The monomer 23 was successfully transformed into the MOM protected diolide 27 by Yamaguchi macrolactonization.

Attenuation of N-nitrosodiethylamine-induced liver fibrosis by high-molecular-weight fucoidan derived from Cladosiphon okamuranus.

Background And Aim: Liver fibrosis is closely associated with the progression of various chronic liver diseases. Fucoidan exhibits different biological properties such as anti-inflammatory, anti-oxidant and anti-fibrotic activities. The aim of this study was to determine whether oral fucoidan administration inhibits N-nitrosodiethylamine (DEN)-induced liver fibrosis.

Efficient strategy for controlling postoperative hemorrhage in total knee arthroplasty.

Purpose: The objective of the present study was to compare the intraoperative use of tranexamic acid (TNA) plus intra-articular diluted-epinephrine (DEP) with preoperative autologous blood donations and transfusions in reducing an allogeneic blood transfusion (ABT) in primary unilateral total knee arthroplasty (TKA).

Methods: Patients (n=133) treated with unilateral primary TKA were divided into three groups retrospectively: patients administered autologous blood transfusions were assigned to group A (n=51); patients administered preoperative injections of TNA and postoperative intra-articular injections of DEP were assigned to group B (n=42); and patients treated with the drain-clamp method in addition to injections of TNA and DEP were assigned to group C (n=40). The rate of avoidance of ABTs, postoperative blood loss, and complications (DVT/PE, skin problems) were examined.

Moyamoya disease presenting with an acute confusional state in an elderly patient.

Moyamoya disease is the angiographic diagnosis of a clinical syndrome showing bilateral stenosis or occlusion of the distal internal carotid arteries and their major branches with extensive parenchymal, leptomeningeal, or transdural anastomoses. The clinical features normally present as reversible ischemic neurologic deficits, sensory-motor attacks with acute hemiplegia, and motor convulsion. An acute confusional state (ACS) among hospitalized patients is a frequent and serious problem.

Evaluation of soft-tissue balance during total knee arthroplasty.

Purpose: To evaluate soft-tissue balance during versus after total knee arthroplasty (TKA).

Methods: 18 men and 75 women aged 52 to 85 (mean, 68) years who had moderate-to-severe varus deformity underwent TKAs using the Scorpio non-restrictive geometry posterior-stabilised system (Stryker Howmedica Osteonics; Allendale, [NJ], USA). All surgeries were performed by a single surgeon using the medial parapatellar approach.

Evaluation of autofluorescence colonoscopy for diagnosis of superficial colorectal neoplastic lesions.

Background And Aim: Autofluorescence (AF) imaging, which can potentially differentiate tissue types based on differences in fluorescence emission, may be useful in the diagnosis and treatment of colorectal malignancies. This study was designed to assess the potential usefulness of AF colonoscopy for evaluating superficial colorectal neoplastic lesions.

Methods: A total of 49 colorectal lesions in 43 patients were investigated.

Tissue factor pathway inhibitor 2 (TFPI2) is frequently silenced by aberrant promoter hypermethylation in gastric cancer.

Aberrant methylation of promoter CpG islands is associated with transcriptional inactivation of tumor-suppressor genes in cancer. TFPI2, a Kunitz-type serine proteinase inhibitor, has been identified as a putative tumor-suppressor gene from genome-wide screening for aberrant methylation, using a microarray combined with the methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-dCyd) in various types of tumors. We assessed the methylation status of TFPI2 and investigated its expression pattern in human primary gastric cancer (GC) tissues and in GC cell lines.

Epigenetic silencing of RELN in gastric cancer.

RELN (Reelin) is an extracellular glycoprotein that plays a critical role in neuronal migration. Here we show that the RELN gene is frequently silenced in gastric cancers (GCs) by aberrant promoter hypermethylation. Although RELN was strongly expressed in non-tumor gastric epithelia, its expression was weak, or absent, in GC cell lines and primary GC tumors.

Inhibitory effect of fucoidan on Huh7 hepatoma cells through downregulation of CXCL12.

The aim of this study is to assess whether fucoidan modulates the expression of chemokine ligand 12 (CXCL12)/chemokine receptor 4 (CXCR4) and exerts antitumor activity toward Huh7 hepatoma cells. According to 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, fucoidan inhibited the growth of Huh7 cells and HepG2 cells in a dose-dependent manner, with a 50% inhibition of cell growth (IC50) of 2.0 and 4.

Induction of type 1 interferon receptor by zinc in U937 cells.

This study aims to determine whether zinc enhances interferon (IFN)-alpha activity in U937 cells. Type 1 IFN2 receptor (IFNAR2) protein in U937 cells was measured by flow cytometry. After 24h of exposure to zinc chloride or polaprezinc (a chelate of zinc and L-carnosine) at concentrations ranging from 50 to 200 microM, histograms showing anti-IFNAR2 antibody-positive cells shifted to a higher FITC intensity.

Postoperative lateral ligamentous laxity diminishes with time after TKA in the varus knee.

For successful TKA, good soft tissue balance is one of the most important factors; however, it is unknown whether the coronal balance immediately after surgery is maintained with time. We hypothesized, if neutral mechanical alignment was achieved at the time of TKA, some degree of lateral ligamentous laxity could be accepted and the laxity would diminish with time. To confirm this hypothesis, we posed two scientific questions: (1) Does the coronal ligament balance measured immediately after TKA change with time? (2) Does the degree of preoperative varus alignment correlate with the lateral or medial ligamentous laxity observed after TKA? We measured coronal lateral or medial ligamentous laxity in 71 knees with varus deformities immediately after surgery and at 3, 6, and 12 months thereafter.

Changes of heavy metal, metallothionein and heat shock proteins in Sertoli cells induced by cadmium exposure.

In this study, we examined the levels of Cadmium (Cd), iron (Fe) and zinc (Zn), which were considered to be involved in Sertoli cell damage caused by Cd exposure. We also examined metallothionein (MT), heat shock protein 70 (Hsp70) and heme oxygenase-1 (HO-1) expressions in Sertoli cells induced by Cd exposure. Evaluation by the in-air micro-particle induced X-ray emission (PIXE) method revealed that Cd and Fe distribution was increased in the cytoplasm of Sertoli cells after Cd exposure.

The changes of heavy metal and metallothionein distribution in testis induced by cadmium exposure.

Cadmium (Cd) is known to cause various disorders in the testis, and metallothionein (MT) is known as a protein, which has a detoxification function for heavy metals. However, the changes of Fe, Cu, and Zn distribution in the testis induced by Cd exposure have not been well examined. Moreover, only a few studies have been reported on the localization of MT after Cd exposure.

Interferonbeta-induced changes in metallothionein expression and subcellular distribution of zinc in HepG2 cells.

We evaluated the changes of metallothionein induction and cellular zinc distribution in HepG2 cells by interferonbeta treatment. Immunohistochemical staining of metallothionein was observed in the cytoplasm and nuclei of hepatocytes; which was observed predominantly in the cells treated with interferon and zinc compared to those with zinc alone, interferon alone or the no-treated control. The cellular zinc level was higher in order of the interferon- and zinc-treated cells, the zinc-alone-treated cells, and the interferon-alone-treated cells.

ADAM23, a possible tumor suppressor gene, is frequently silenced in gastric cancers by homozygous deletion or aberrant promoter hypermethylation.

Array-based comparative genomic hybridization (CGH-array) has a powerful potential for high-throughput identification of genetic aberrations in cell genomes. We identified a homozygous loss of ADAM23 (2q33.3) in the course of a program to screen a panel of gastric cancer (GC) cell lines (1/32, 3.