A5003870570- Ubiquitin and proteasome pathways
- Glycosylation and Glycoproteins Research
- Advanced Glycation End Products research
- Peptidase Inhibition and Analysis
- Antibiotic Resistance in Bacteria
- Adipokines, Inflammation, and Metabolic Diseases
- Endoplasmic Reticulum Stress and Disease
- Adipose Tissue and Metabolism
- Vibrio bacteria research studies
- Tryptophan and brain disorders
- Carbohydrate Chemistry and Synthesis
- Cancer-related Molecular Pathways
- Regulation of Appetite and Obesity
- Immune Response and Inflammation
- Bacterial biofilms and quorum sensing
- Immune cells in cancer
- Stress Responses and Cortisol
- Natural Antidiabetic Agents Studies
- Cell death mechanisms and regulation
- IL-33, ST2, and ILC Pathways
- Calcium signaling and nucleotide metabolism
- Pharmacological Receptor Mechanisms and Effects
- Protein Degradation and Inhibitors
- Exercise and Physiological Responses
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Tohoku University
2024
Teikyo University
2016-2020
University of Shizuoka
2002-2014
Hokkaido University
2008
Kumamoto University
2002-2006
Supersulfides, which are defined as sulfur species with catenated atoms, increasingly being investigated in biology. We recently identified pyridoxal phosphate (PLP)-dependent biosynthesis of cysteine persulfide (CysSSH) and related supersulfides by cysteinyl-tRNA synthetase (CARS). Here, we the physiological role CysSSH budding yeast (Saccharomyces cerevisiae) generating a PLP-binding site mutation K109A CRS1 (the ortholog CARS), decreased synthesis also led to reduced chronological aging,...
Accumulation of advanced glycation end products (AGEs) on tissue proteins increases with pathogenesis diabetic complications and atherosclerosis. Here we examined the effect peroxynitrite (ONOO−) formation Nε-(carboxymethyl)lysine (CML), a major AGE-structure. When glycated human serum albumin (HSA; Amadori-modified protein) was incubated ONOO−, CML detected by both enzyme-linked immunosorbent assay high-performance liquid chromatography (HPLC) increased increasing ONOO− concentrations. also...
We investigated the numbers of planktonic and biofilm cells expression levels genes encoding efflux pumps biofilm-related proteins in 10 clinical isolates multi-drug resistant Acinetobacter baumannii (MDRA) as well its standard strain ATCC 19606 presence colistin (CST), polymyxin B (PMB), minomycin (MIN), tigecycline (TGC) at their respective sub-MICs. The number decreased all aforementioned antibiotics a dose-dependent manner. Cell also two representative MDRA strains, R2 R3, MIN TGC In...
Abstract We investigated the intracellular survival of multidrug-resistant Acinetobacter baumannii (MDRAB) clinical isolates in macrophages, after phagocytosis, to determine their virulence characteristics. After ATCC 19606 and 5 MDRAB were phagocytosed by mouse human bacterial count strains, R4 R5, increased 24 hours phagocytosis. Bacterial R1 R2, was almost equal 4 Intracellular reactive oxygen species detected macrophages phagocytosis these bacteria. Further, strains R1, R4, R5 showed...
The natural product belactosin A (1) with a trans-cyclopropane structure is useful prototype compound for developing potent proteasome (core particle, CP) inhibitors. To date, 1 and its analogues are the only CP ligands that bind to both nonprimed S1 pocket as well primed substrate binding channel; however, these molecules harbor high IC50 value of more than μM. We have performed structure–activity relationship studies, thereby elucidating unnatural cis-cyclopropane derivatives exhibit...
We investigated the expression levels of virulence factors (ompA, omp33-36 and carO) in five clinical isolates a standard ATCC 19606 strain Acinetobacter baumannii to determine their effect on characteristics isolates.The mRNA omps proinflammatory cytokines were analyzed by quantitative real-time PCR. For adherence assay, after human lung epithelial cells (A549) co-cultured with A. at 37 °C for 2 h, cell-adherent bacteria was counted. Pearson correlation analysis used compare levels, number...
Acinetobacter baumannii causes nosocomial infections due to its multidrug resistance and high environmental adaptability. Colistin is a polypeptide antibacterial agent that targets lipopolysaccharide (LPS) currently used control serious multidrug-resistant Gram-negative bacterial infections, including those caused by A. baumannii. However, may acquire colistin losing their LPS. In mouse models, LPS-deficient have attenuated virulence. Nevertheless, the mechanism through which pathogen...
The development of potent proteasome inhibitors based on the stereochemical diversity-oriented strategy using a conformationally rigid cyclopropane structure was investigated. Thus, series stereo- and regioisomeric analogs belactosin A (2), amino acid (methanoamino acid)-containing tripeptidic inhibitor, were designed, in which central part replaced with corresponding or regioisomer. Using stereoisomeric equivalents cis/trans, D/L, syn/anti diversity, previously developed by us, as key...
The pathological significance of advanced glycation end product (AGE)-modified proteins deposited in several lesions is generally accounted for by their cellular interaction via the AGE receptors and subsequent acceleration inflammatory process. In this study, we focused on two receptors-specifically, role SR-A pathogenesis diabetic nephropathy CD36 AGE-induced downregulation leptin adipocytes. terms SR-A, wild-type mice exhibited increased urinary albumin excretion, glomerular hypertrophy,...
A series of chiral 2,3- and 3,4-methanoamino acid equivalents stereochemical diversity were designed synthesized from our cyclopropane units, using a diastereoselective Grignard addition with (R)- or (S)-t-butanesulfinyl imines as the key step. These converted into proteasome inhibitor belactosin its cis-cyclopropane stereoisomer. The unnatural cis-isomer was shown to be more than twice potent inhibitor.
To develop potent covalent inhibitors, the noncovalent interactions around transition state to form bonding should be optimized because potency of inhibitor can depending on energy state. Here, we report an efficient analysis binding mode a proteasome 3a by combined use chemical approach, i.e., cyclopropylic strain-based conformational restriction, and computational docking approach. Furthermore, calculated series salinosporamide derivatives in predicted complex with simulation model...
We previously developed highly potent proteasome inhibitor 1 (IC50 = 5.7 nM) and its nonpeptide derivative 2 29 by systematic structure-activity relationship studies of the peptidic natural product belactosin A subsequent rational topology-based scaffold hopping, respectively. Their cell growth inhibitory activities, however, were only moderate 1.8 μM (1) >10 (2)). therefore planned to replace unstable β-lactone warhead with a more stable boronic acid warhead. Importantly, derivatives bind...
Rational scaffold hopping of a natural product belactosin A derivative based on the pharmacophore model constructed resulted in identification significantly simplified highly potent non-peptide derivatives.
The belactosin A analog 2a, having the unnatural cis-cyclopropane structure instead of trans-cyclopropane in A, is a much more potent proteasome inhibitor than A. However, its cell growth inhibitory effect rather lower that expected from remarkable effect, probably due to instability under cellular conditions. We hypothesized 2a was chemical and enzymatic hydrolysis strained β-lactone moiety. Thus, increase stability by modification, analogs with sterically hindered moiety and/or...
E‐series resolvins are biosynthesized from eicosapentaenoic acid during the resolution phase of acute inflammation and enhance resolution. However, role in is not yet known. Herein, we show that human polymorphonuclear neutrophils ( PMN s), resolvin E1 (RvE1) selectively enhances reactive oxygen species ROS ) generation induced by N ‐formylmethionyl‐leucyl‐phenylalanine. The RvE1‐mediated enhancement eliminated a pan‐antagonist leukotriene B4 LTB 4) receptors, LY 255283, or an NADPH oxidase...
A bstract : Previous observations by us have clarified that proteins modified advanced glycation end products (AGEs) are recognized as effective ligands CD36‐overexpressed CHO cells and undergo receptor‐mediated endocytosis. CD36, a member of the class B scavenger receptor family, also acts fatty acid transporter in adipocytes. Oxidized low‐density lipoprotein (Ox‐LDL), ligand for is known to upregulate CD36 activating peroxisome proliferator‐activated γ (PPAR‐γ) macrophages, whereas PPAR‐γ...
IDO is considered a promising therapeutic target for immunological cancer treatment. We found that the antihypertensive agent candesartan cilexetil inhibits IDO. The structural modifications provided >10-fold more potent inhibitor. Structure–activity relationship and docking studies suggested analogues uniquely bind to entrance of active site in IDO, not haem region. Analogue synthesis, kinetic analysis cellular activity are also described herein.