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The abuse of antibacterial drugs imposes a selection pressure on bacteria that has driven the evolution of multidrug resistance in many pathogens. Our efforts to discover novel classes of antibiotics to combat these pathogens resulted in the discovery of amycolamicin (AMM). The absolute structure of AMM was determined by NMR spectroscopy, X-ray analysis, chemical degradation, and modification of its functional groups. AMM consists of trans-decalin, tetramic acid, two unusual sugars (amycolose and amykitanose), and dichloropyrrole carboxylic acid. The pyranose ring named as amykitanose undergoes anomerization in methanol. AMM is a potent and broad-spectrum antibiotic against Gram-positive pathogenic bacteria by inhibiting DNA gyrase and bacterial topoisomerase IV. The target of AMM has been proved to be the DNA gyrase B subunit and its binding mode to DNA gyrase is different from those of novobiocin and coumermycin, the known DNA gyrase inhibitors.

From the aerial parts of Clinopodium chinense var. parviflorum, nine new phenylpropanoids, clinopodic acids A-I (2-10), were isolated together with a known phenylpropanoid, rosmarinic acid (1). The structures of these new compounds were elucidated on the basis of spectroscopic analysis. Clinopodic acid C (4) showed MMP-2 inhibitory activity (IC(50) 3.26 microM).

Chronic fatigue is reported in more than 20% of patients examined in primary care, and this common problem affects the quality of life and work productivity.1) A large part of the chronic fatigue population meets the diagnostic criteria for chronic fatigue syndrome (CFS), which is defined by unexplained physical or mental fatigue of at least 6-month duration and a combination of nonspecific symptoms.2) Several CFS symptoms including impaired concentration, attention, and memory as well as headache suggest that the central nervous system (CNS) may be involved in CFS pathophysiology.3) Moreover, neuroimaging evidence indicates that structural and/or functional abnormalities exist in the CNS of CFS patients. For example, marked reductions in the gray matter volume are observed; 4) Cook et al. 5) found an association between subjective feelings of mental fatigue and brain responses during a fatiguing cognitive task; CFS patients always have reduced concentrations of N-acetylaspartate in the hippocampus, a putative marker of neuronal metabolism 6) ; and a 23% reduction in 5-HT 1A receptor number and affinity was found in the hippocampus of CFS patients. 7) However, neural mechanisms, especially the hippocampal substrates in CFS, are unclear in part due to the lack of a suitable animal model.In our previous study, a chronic fatigue mouse model was induced by six repeated injections of fixed killed Brucella abortus antigen solution via the tail vein every 2 weeks. 8,9) We found that brain atrophy and reduction of the hippocampal Bcl-2 and brain-derived neurotrophic factor (BDNF) mRNA expression levels were accompanied by lower spontaneous activity.8) However, the hippocampal weight was not measured in those previous studies.Resveratrol (RSV), an active component of grapevines and peanuts, is recognized as a polyphenolic activator of sirtuin 1 (Sirt1), a protein deacetylase.10) It can enhance running activity of high fat diet-fed mice two-fold by activating Sirt1. 11)Moreover, Sirt1 can protect neurons from DNA damageinduced apoptosis by downregulating p53 acetylation, an apoptotic mediator.12) RSV treatment of neural progenitor cells (NPCs) is capable of increasing differentiation and directing neurogenesis through a mechanism requiring Sirt1.13) Thus RSV may be beneficial for physical activity of our fatigue mice and even play a role in improving structural and/or functional defects of the hippocampus.We aimed to clarify the hippocampal structural and/or functional defects in this fatigue model. Another purpose of our study was to determine whether RSV intervention could improve the fatigue and reverse the abnormalities by antiapoptosis and promoting neurogenesis. MATERIALS AND METHODS Animals, Living Conditions, and Spontaneous RunningActivity Eight-week old BALB/c mice (female, 20-24 g, CLEA Japan, Tokyo, Japan) were housed singly in previously described cages 8,9) including running wheels and counters. The cages were maintained under a light-dark photoperiod (lights on from 09:00 to 17:00), and daily spontaneous ...

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Tyrosinase catalyzes the oxidation of tyrosine and certain diphenolic intermediate products to quinines, which polymerize to give rise to melanin. 1) Tyrosinase inhibitors are used in depigmentation drugs and whitening cosmetics, 2,3) whereas compounds that increase melanogenesis may protect human skin from ultraviolet irradiation damage.4) The tyrosinase metabolic pathway also seems to be involved in the antimelanoma effects of some tyrosinase analogues.2) These substances are oxidated by tyrosinase, generating reactive oquinone with cytotoxic potential.2,5) Therefore, tyrosinase may be a useful target in the fields of hyperpigmentation and cosmetic materials. 6)Flavonoids and hydroxycinnamates, major constituents of the human diet, are powerful electron-donating anti-oxidants, the catechol moiety being one of the main structural features responsible for their antioxidant activities.7,8) Several flavonoids, stilbenes and related 4-substituted resorcinols, were tested for their inhibitory activity against tyrosinase to clarify the structure-activity relationship.9)The present study was under-taken to search for tyrosinase inhibitors in the peel of Citrus fruit. It has been used not only in traditional Chinese medicines but also as a skin whitening and skin-moisturized agent in Japanese folk medicines. Citrus fruit contains several biologically active components, e.g., limonoids and their glycosides, glyceroglycolipids, alkaloids such as synephrine, and several flavonoids in a large amount. Thus, the components of the peel of Citrus fruit are expected to provide valuable material to prevent skin pigmentation. MATERIALS AND METHODS Chemicals and General MaterialsMushroom tyrosinase, l-dopa, was purchase from Nakalai Tesque (Kyoto), and kojic acid from Tokyo Kasei Co. (Tokyo). Silica gels (Wakogel C-200) were purchased from Wako Chemical, Inc., Ltd. (Kyoto). Plant materials were purchased from Uchida Wakanyaku Co. (Niigata, from China).General Procedures Melting point was determined on a Yanagimoto micromelting point apparatus and is uncorrected. A Perkin Elmer 1600 series FTIR spectrophotometer was used for the measurement of IR spectrum. Mass spectrum (MS) was taken on a JEOL DX-303 mass spectrometer. Proton nuclear magnetic resonance (NMR) spectrum was recorded with JEOL EX-270 spectrometer, and chemical shifts are given in d (ppm) with tetramethylsilane as an internal standard (s: singlet, d: doublet, dd: double doublet).Extraction and Isolation The peel of Citrus fruit (3.5 kg) was extracted twice with methanol (8 l) at room temperature. Removal of solvent in vacuo gave 952.2 g of methanol extract. The extract was dissolved in water and distributed three times between chloroform (1 l), giving a chloroform extract (31.6 g). The water-soluble residue was partitioned three times between ethyl acetate (1 l) and H 2 O (1 l). After removal of the solvent in vacuo, the ethyl acetate extract (27.3 g) was column chromatographed on silica gel (Wakogel C-200) using n-hexane and n-hexane-acetone, giving colorless needles,...

We investigated the effects of water and ethyl acetate extracts of Citrus unshiu peel (Aurantii Nobilis pericarpium) on hepatitis C virus (HCV) absorption in MOLT-4 cells (a human lymphoblastoid leukemia cell line). By reverse transcription polymerase chain reaction (RT-PCR), we showed that both the ethyl acetate layer of Citrus unshiu peel extract and fraction 7 decreased HCV absorption in MOLT-4 cells. Furthermore, we demonstrated that 3',4',5,6,7,8-hexamethoxyflavone (nobiletin) is the active ingredient that markedly inhibited HCV infection in MOLT-4 cells.

The synthesis and evaluation of antiviral activity of new furan-fused tetracyclic compounds are described. The syntheses were satisfactorily achieved on the basis of o-quinodimethane chemistry, using furan-containing benzocyclobutene derivatives as a substrate, in high generality and stereoselectivity. The various derivatives thus synthesized were examined on their inhibitory activity on virus growth using a hemagglutinin (HA) method, leading to a discovery of promising candidates for new antiviral drugs having high activity and good therapeutic index.