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In the advanced stages of mycobacterial infections, host immune systems tend to change from a Th1-type to Th2-type immune response, resulting in the abrogation of Th1 cell- and macrophage-mediated antimicrobial host protective immunity.... more
In the advanced stages of mycobacterial infections, host immune systems tend to change from a Th1-type to Th2-type immune response, resulting in the abrogation of Th1 cell- and macrophage-mediated antimicrobial host protective immunity. Notably, this type of immune conversion is occasionally associated with the generation of. certain types of suppressor macrophage populations. During the course of infections due to pathogenic mycobacteria, the generation of macrophages which possess strong suppressor activity against host T- and B-cell functions is frequently encountered. This review describes the immunological properties of M1- and M2-type macrophages generated in hosts with certain microbial infections including mycobacteriosis and those generated in tumor-bearing animals. Particularly, this paper highlights the immunological and molecular biological characteristics of M1 and M2 macrophage populations, which are induced by mycobacterial infections
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Research Interests: Biology, Cytokines, Adolescent, Medicine, Gene expression, and 15 moreExtracellular Matrix, Cell line, Humans, Female, Gene transfer techniques, Chemokine, Cell Proliferation, Chemokines, Protein Biosynthesis, Biochemistry and cell biology, Gene expression profiling, fibroblasts, Genetic Therapy, reverse transcriptase polymerase chain reaction, and Medical biochemistry and metabolomics
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Costello syndrome is a connective tissue disorder associated with sparse, thin, and fragmented elastic fibers in tissues. In this study we demonstrated a significant decrease in the expression of tropoelastin mRNA in fibroblasts derived... more
Costello syndrome is a connective tissue disorder associated with sparse, thin, and fragmented elastic fibers in tissues. In this study we demonstrated a significant decrease in the expression of tropoelastin mRNA in fibroblasts derived from a Japanese Costello syndrome patient with impaired elastogenesis and enhanced proliferation. In contrast, there were no changes in expression of the Harvey ras (HRAS), fibrillin-1, fibulin-5, microfibril-associated glycoprotein-1 (MAGP-1), lysyl oxidase (LOX), or 67-kDa non-integrin elastin-binding protein (EBP) gene. The proliferative activity of the Costello fibroblasts was about 4-fold higher than that of the normal and pathological control ones. However, no mutations were detected in the coding region of HRAS mRNA. Transduction of the bovine tropoelastin (bTE) gene with the lentiviral vector restored the elastic fiber formation and decreased the growth rate in the Costello fibroblasts. These results strongly suggest that the defect of human tropoelastin (hTE) gene expression should induce the impaired elastogenesis and enhanced proliferation of Costello fibroblasts, and that a primary cause other than the HRAS gene mutation should contribute to the pathogenesis in the present Costello case.
Research Interests: Biochemistry, Biology, Adolescent, Medicine, Gene expression, and 15 moreHumans, Female, Animals, Lentiviral vector, Skin, Cattle, Elastin, Asian Continental Ancestry Group, Cell Proliferation, Fibulin-4, Biochemistry and cell biology, Gene Expression Regulation, fibroblasts, Medical biochemistry and metabolomics, and Connective Tissue Diseases
Research Interests: Microbiology, Medical Microbiology, Biology, Enzyme Inhibitors, Macrophages, and 11 moreMedicine, Humans, Reactive Oxygen Species, Nitric oxide, Antimicrobial, NADPH oxidase, Nitric Oxide Synthase, Antimicrobial agents, Beta Defensins, Mycobacterium avium complex, and Pharmacology and pharmaceutical sciences
Six new prenylated acylphloroglucinols, erecricins A-E (1-5) and adotogirin (6), were isolated from the roots of Hypericum erectum (Hypericaceae). Their structures were assigned on the basis of spectroscopic evidences. Erecricins A-E... more
Six new prenylated acylphloroglucinols, erecricins A-E (1-5) and adotogirin (6), were isolated from the roots of Hypericum erectum (Hypericaceae). Their structures were assigned on the basis of spectroscopic evidences. Erecricins A-E (1-5) are bicyclic prenylated acylphloroglucinols possessing a chromane or a chromene skeleton. Adotogirin (6) is a simple achylphloroglucinol with an O-geranyl moiety. Antimicrobial activities of these acylphloroglucinols were also evaluated.
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Research Interests: Microbiology, Chemistry, Biology, Macrophages, Medicine, and 8 moreCell line, Humans, Mice, Macrophage, Animals, Phagosome, Intracellular, and Phospholipase
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TB, especially multidrug-resistant TB and extensively drug-resistant TB, is an important global health concern, and the novel development of effective anti-tuberculous drugs is urgently needed. Newly elucidated, critical information on... more
TB, especially multidrug-resistant TB and extensively drug-resistant TB, is an important global health concern, and the novel development of effective anti-tuberculous drugs is urgently needed. Newly elucidated, critical information on the entire genome of Mycobacterium tuberculosis (MTB) and advances in knowledge regarding various mycobacterial virulence genes are promoting progression in the identification of genes that code for new drug targets. With this background, this review deals with the following areas: first, the future development of new anti-tuberculous drugs is discussed according to the potential pharmacological targets of MTB; and second, a review of the present development status of new anti-tuberculous drugs is conducted, particularly focusing on some promising new anti-tuberculous agents, such as nitroimidazoles, diarylquinolines and oxazolidinones.
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Research Interests: Laser, Biology, Nanoparticles, Medicine, Macromolecular X-Ray Crystallography, and 15 moreBiological Sciences, Humans, Protein Crystallization, Lasers, Animals, Proteins, Cockroaches, Electrons, In Vivo, Femtosecond, X ray diffraction, Serial Femtosecond Crystallography, CHO cells, Cricetinae, and Medical and Health Sciences
The worldwide increase in the prevalence of tuberculosis (TB), especially multidrug-resistant TB and extensively drug-resistant TB, is an important global health concern, and new effective drugs are urgently needed. Information on the... more
The worldwide increase in the prevalence of tuberculosis (TB), especially multidrug-resistant TB and extensively drug-resistant TB, is an important global health concern, and new effective drugs are urgently needed. Information on the genome of Mycobacterium tuberculosis (MTB) and various mycobacterial virulence genes is leading to the identification of genes that code for new drug targets. Mycobacterium tuberculosis (MTB) is resistant to the antimicrobial mechanisms of host macrophages and can survive and replicate in macrophages for long periods, resulting in a persistent infection. Mycobacterial virulence factors suppress macrophage bactericidal functions partly via their downregulatory effects on the host antimicrobial cytokine networks, consisting of proinflammatory, immunopotentiating, and Th1-inducing cytokines. Thus, for the development of unique drugs that exhibit antimycobacterial action through novel mechanisms, it is reasonable to search for targets among bacterial genes encoding virulence factors which interfere with the host cytokine responses protective to mycobacterial pathogens. In this review, we discuss the profiles of cytokine networks related to host resistance to mycobacteria, including the mechanisms of downregulation of host antimycobacterial immunity due to immunosuppressive cytokines, which are occasionally induced in the advanced stages of TB. We also highlight the development of antituberculous drugs based on bacterial virulence factors interfering with the host antimycobacterial cytokine network.
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Research Interests: Molecular Biology, Cancer, Biology, Japan, Medicine, and 15 moreMolecular Biology Cancer, Molecular, Humans, Female, Gastric Cancer, Male, High Performance Liquid Chromatography, Aged, Middle Aged, Carcinogenesis, Carbonic anhydrase, Liquid Chromatography, Asian Continental Ancestry Group, Adenocarcinoma, and Gastric Adenocarcinoma
The high incidence of tuberculosis (TB) in the world, especially in developing countries, the resurgence of TB in industrialized countries, and the global increase in the prevalence of Mycobacterium avium complex infections in... more
The high incidence of tuberculosis (TB) in the world, especially in developing countries, the resurgence of TB in industrialized countries, and the global increase in the prevalence of Mycobacterium avium complex infections in immunocompromised hosts have prompted the quest for novel antimycobacterial drugs. However, the development of such antimicrobial chemotherapeutics is currently making very slow progress even with using the bioinformatics-based methodology for drug design. It thus appears that devising improved administration protocols for clinical treatment against intractable mycobacterial infections using existing chemotherapeutics is more practical than awaiting the development of new antimycobacterial drugs. The potentiation of host immune responses using immunoadjunctive agents, alternatively called host-directed therapeutics (HDTs), may increase the efficacy of antimycobacterial regimens against mycobacteriosis. Particularly, the modulation of host immunity relating to macrophage antimicrobial functions may be beneficial to the immunoadjunctive therapy. This review will deal with the current status and future prospects regarding the development of HDTs useful for the clinical control of intractable mycobacterial infections.
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Picolinic acid (PA) potentiates macrophage (M) antimicrobial activity against intracellular Mycobacterium avium complex (MAC). Here, we studied the mechanisms of this phenomenon using human THP-1 Ms. First, when PA-treated MAC-infected Ms... more
Picolinic acid (PA) potentiates macrophage (M) antimicrobial activity against intracellular Mycobacterium avium complex (MAC). Here, we studied the mechanisms of this phenomenon using human THP-1 Ms. First, when PA-treated MAC-infected Ms were cultured in the presence or absence of reactive oxygen intermediate (ROI) scavengers, nitric oxide synthase (NOS) inhibitors or phospholipase A2 (PLA2) inhibitors, none of these agents blocked the activity of PA in potentiating M anti-MAC activity. Second, when PA was added to the in vitro anti-MAC bactericidal system consisting of either ROIs, reactive nitrogen intermediates (RNIs) or free fatty acid (FFA) molecules, which are the major M antimicrobial effectors, PA inhibited the activity of ROIs and conversely potentiated the activity of RNIs; PA did not affect the activity of FFAs. Third, PA reduced mRNA expression of NADPH oxidase and -defensin-1 by MAC-infected Ms, whilst neither cytosolic PLA2 nor CAP37 mRNA expression was affected. Nota...
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The high incidence of tuberculosis (TB) in the world, especially in developing countries, the resurgence of TB in industrialized countries, and the global increase in the prevalence of Mycobacterium avium complex infections in... more
The high incidence of tuberculosis (TB) in the world, especially in developing countries, the resurgence of TB in industrialized countries, and the global increase in the prevalence of Mycobacterium avium complex infections in immunocompromised hosts have prompted the quest for novel antimycobacterial drugs. However, the development of such antimicrobial chemotherapeutics is currently making very slow progress even with using the bioinformatics-based methodology for drug design. It thus appears that devising improved administration protocols for clinical treatment against intractable mycobacterial infections using existing chemotherapeutics is more practical than awaiting the development of new antimycobacterial drugs. The potentiation of host immune responses using immunoadjunctive agents, alternatively called host-directed therapeutics (HDTs), may increase the efficacy of antimycobacterial regimens against mycobacteriosis. Particularly, the modulation of host immunity relating to ...
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Six new prenylated acylphloroglucinols, erecricins A-E (1-5) and adotogirin (6), were isolated from the roots of Hypericum erectum (Hypericaceae). Their structures were assigned on the basis of spectroscopic evidences. Erecricins A-E... more
Six new prenylated acylphloroglucinols, erecricins A-E (1-5) and adotogirin (6), were isolated from the roots of Hypericum erectum (Hypericaceae). Their structures were assigned on the basis of spectroscopic evidences. Erecricins A-E (1-5) are bicyclic prenylated acylphloroglucinols possessing a chromane or a chromene skeleton. Adotogirin (6) is a simple achylphloroglucinol with an O-geranyl moiety. Antimicrobial activities of these acylphloroglucinols were also evaluated.
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Gastric adenocarcinomas comprise one of the common types of cancers in Asian countries including Japan. Comprehensive protein profiling of paired surgical specimens of primary gastric adenocarcinomas and nontumor mucosae derived from... more
Gastric adenocarcinomas comprise one of the common types of cancers in Asian countries including Japan. Comprehensive protein profiling of paired surgical specimens of primary gastric adenocarcinomas and nontumor mucosae derived from Japanese patients was carried out by means of two-dimensional gel electrophoresis (2D-EP) and liquid chromatography-electrospray ionic tandem mass spectrometry (LC-ESI-MS) to establish gastric cancer-specific proteins as putative clinical biomarkers and molecular targets for chemotherapy. Relatively common alterations in protein expression were revealed in the tumor tissues. Increases in manganese dismutase and nonhistone chromosomal protein HMG-1 (HMG-1) were observed, while decreases in carbonic anhydrases I and II, glutatione-S-transferase and foveolin precursor (gastrokine-1) (FOV), an 18-kDa stomach-specific protein with putative tumor suppressor activity, were detected. RT-PCR analysis also revealed significant down-regulation of FOV mRNA expressi...
Research Interests: Biology, Proteomics, Japan, Medicine, Molecular Biology Cancer, and 15 moreMolecular, Humans, Female, Gastric Cancer, Male, High Performance Liquid Chromatography, Aged, Middle Aged, Carbonic anhydrase, Liquid Chromatography, Protein Expression, Asian Continental Ancestry Group, Proteome, Adenocarcinoma, and Gastric Adenocarcinoma
The serendipitous discovery of the spontaneous growth of protein crystals inside cells has opened the field of crystallography to chemically unmodified samples directly available from their natural environment. On the one hand, through in... more
The serendipitous discovery of the spontaneous growth of protein crystals inside cells has opened the field of crystallography to chemically unmodified samples directly available from their natural environment. On the one hand, through in vivo crystallography, protocols for protein crystal preparation can be highly simplified, although the technique suffers from difficulties in sampling, particularly in the extraction of the crystals from the cells partly due to their small sizes. On the other hand, the extremely intense X-ray pulses emerging from X-ray free-electron laser (XFEL) sources, along with the appearance of serial femtosecond crystallography (SFX) is a milestone for radiation damage-free protein structural studies but requires micrometre-size crystals. The combination of SFX with in vivo crystallography has the potential to boost the applicability of these techniques, eventually bringing the field to the point where in vitro sample manipulations will no longer be required,...
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Research Interests: Biology, Medicine, Humans, Mutation, Skin, and 5 moreNeuraminidase, Clinical Sciences, Elastin, Base Sequence, and fibroblasts
Splenic macrophages (M(phi)s) generated in Mycobacterium intracellulare (Min)-infected mice exhibit suppressor activity against T cell mitogenesis. We examined profiles of the Min-induced generation of immunosuppressive M(phi)s... more
Splenic macrophages (M(phi)s) generated in Mycobacterium intracellulare (Min)-infected mice exhibit suppressor activity against T cell mitogenesis. We examined profiles of the Min-induced generation of immunosuppressive M(phi)s (Min-M(phi)s) in Min-susceptible BALB/c (bcg(s)) and resistant CBA/JN (bcg(r)) mice. Min infection in BALB/c mice caused a more rapid generation of the immunosuppressive M(phi)s, which expressed M(phi) markers such as CD11b and F4/80, exhibited an increased ability to generate reactive oxygen intermediates, and inhibited IL-2 receptor expression by mitogenic T cells, than did Min infection in CBA/JN mice. Thus, the bcg gene may be related to the generation of Min-M(phi)s in host mice.
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In the advanced stages of mycobacterial infections, host immune systems tend to change from a Th1-type to Th2-type immune response, resulting in the abrogation of Th1 cell- and macrophage-mediated antimicrobial host protective immunity.... more
In the advanced stages of mycobacterial infections, host immune systems tend to change from a Th1-type to Th2-type immune response, resulting in the abrogation of Th1 cell- and macrophage-mediated antimicrobial host protective immunity. Notably, this type of immune conversion is occasionally associated with the generation of. certain types of suppressor macrophage populations. During the course of infections due to pathogenic mycobacteria, the generation of macrophages which possess strong suppressor activity against host T- and B-cell functions is frequently encountered. This review describes the immunological properties of M1- and M2-type macrophages generated in hosts with certain microbial infections including mycobacteriosis and those generated in tumor-bearing animals. Particularly, this paper highlights the immunological and molecular biological characteristics of M1 and M2 macrophage populations, which are induced by mycobacterial infections
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One of the major health concerns in the world is the global increase in intractable bacterial infectious diseases due to the emergence of multi- and extensively drug-resistant bacterial pathogens as well as increase in compromised hosts... more
One of the major health concerns in the world is the global increase in intractable bacterial infectious diseases due to the emergence of multi- and extensively drug-resistant bacterial pathogens as well as increase in compromised hosts around the world. Particularly, in the case of mycobacteriosis, the high incidence of tuberculosis in developing countries, resurgence of tuberculosis in industrialized countries, and increase in the prevalence of Mycobacterium avium complex infections are important worldwide health concerns. However, the development of novel antimycobacterial drugs is currently making slow progress. Therefore, it is considered that devising improved administration protocols for clinical treatment against refractory mycobacteriosis using existing chemotherapeutics is more practical than awaiting the development of new antimycobacterial drugs. The regulation of host immune responses using immunoadjunctive agents may increase the efficacy of antimicrobial treatment aga...
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Three new naphthoquinone derivatives, rubiaquinones A-C (1-3), were isolated from the roots of Rubia yunnanensis. Rubiaquinone A (1) was a racemic naphthoquinone dimer consisting of a 1,4-dihydroxy-naphthalene and a... more
Three new naphthoquinone derivatives, rubiaquinones A-C (1-3), were isolated from the roots of Rubia yunnanensis. Rubiaquinone A (1) was a racemic naphthoquinone dimer consisting of a 1,4-dihydroxy-naphthalene and a 4-hydroxy-1,2-naphthoquinone moieties with a 2-oxo-propyl group. Rubiaquinones B (2) and C (3) were structurally unique trimeric naphthoquinones with a racemic nature possessing one chiral axis and one chiral carbon in common. The planar structures of 1-3 were assigned by detailed spectroscopic analyses, and enantiomers of 1-3 were obtained by optical resolutions. The absolute configurations of (+)-1 and (-)-1 were elucidated by interpretation of the ECD spectra with the aid of TDDFT ECD calculation, while those of enantiomers obtained from 2 and 3 were assigned by analyses of the composite ECD spectra generated by summing appropriate ECD spectra of enantiomers. Rubiaquinone A (1) exhibited antimicrobial activity against Bacillus subtilis. (C) 2017 Elsevier Ltd. All rights reserved.
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Abstract 4′-Azido- (7), 4′- C -fluoromethyl- (8) 4′- C -ethynyl- (9) and 4′- C -cyano- (10) 2′-deoxy-4′-thiocytidines have been synthesized. In this study, it was found that the isolated yield of 4′-thiouracil nucleoside 13 in a Lewis... more
Abstract 4′-Azido- (7), 4′- C -fluoromethyl- (8) 4′- C -ethynyl- (9) and 4′- C -cyano- (10) 2′-deoxy-4′-thiocytidines have been synthesized. In this study, it was found that the isolated yield of 4′-thiouracil nucleoside 13 in a Lewis acid-promoted Vorbruggen-type glycosidation utilizing 12 was better than that of the electrophilic glycosidation reaction between silylated uracil and 11. This improved result prompted us to perform the glycosidation utilizing 36 and 43 for the synthesis of 37 and 44. Introduction of the azido group was carried out by nucleophilic substitution in the 4′-benzoyloxy derivative 22a. On the other hand, 9 and 10 were synthesized by way of the chemical manipulation of the hydroxymethyl group at the 4′-position of 46. Evaluation of the antineoplastic activity of 2 and 7–10 against human B-cell (CCRF-SB) and T-cell leukemia (Molt-4) cell lines revealed that 4′-azido- (7) and 4′- C -fluoromethyl- (8) derivatives exhibited cytotoxic activity whereas no cytotoxicity was observed in the 4′- C -ethynyl- (9) and 4′- C -cyano- (10) derivatives as well as the parent compound 2. Compound 7 was also found to possess promising antiviral activity against VZV and HSV-1 without any cytotoxity against HEL host cells. It is noteworthy that 7 exhibited potent inhibitory activities against the thymidine kinase-deficient (TK − ) mutant of VZV and HSV-1.