Neurodegeneration of mouse nigrostriatal dopaminergic system induced by repeated oral administration of rotenone is prevented by 4-phenylbutyrate, a chemical chaperone

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is primarily characterized by the degeneration of dopaminergic neurons in the nigrostriatal pathway. Previous studies have demonstrated that chronic systemic exposure of Lewis rats to rotenone produced many features of PD, and cerebral tauopathy was also detected in the case of severe weight loss. The present study was designed to assess the neurotoxicity of rotenone after daily oral administration for 28 days at several doses in C57BL/6 mice. In addition, we examined the protective effects of 4-phenylbutyrate (4-PBA) on nigral dopamine (DA) neurons in rotenone-treated mice. 4-PBA was injected intraperitoneally daily 30 min before each oral administration of rotenone. Chronic oral administration of rotenone at high doses induced specific nigrostriatal DA neurodegeneration, motor deficits and the up-regulation of alpha-synuclein in the surviving DA neurons. In contrast to the Lewis rat model, cerebral tauopathy was not detected in this mouse model. 4-PBA inhibited rotenone-induced neuronal death and decreased the protein level of alpha-synuclein. These results suggest that this rotenone mouse model may be useful for understanding the mechanism of DA neurodegeneration in PD, and that 4-PBA has a neuroprotective effect in the treatment of PD.     

Projecting the impacts of rising seawater temperatures on the distribution of seaweeds around Japan under multiple climate change scenarios

Seaweed beds play a key role in providing essential habitats and energy to coastal areas, with enhancements in productivity and biodiversity and benefits to human societies. However, the spatial extent of seaweed beds around Japan has decreased due to coastal reclamation, water quality changes, rising water temperatures, and heavy grazing by herbivores. Using monthly mean sea surface temperature (SST) data from 1960 to 2099 and SST‐based indices, we quantitatively evaluated the effects of warming seawater on the spatial extent of suitable versus unsuitable habitats for temperate seaweed Ecklonia cava, which is predominantly found in southern Japanese waters. SST data were generated using the most recent multiple climate projection models and emission scenarios (the Representative Concentration Pathways or RCPs) used in the Coupled Model Intercomparison Project phase 5 (CMIP5). In addition, grazing by Siganus fuscescens, an herbivorous fish, was evaluated under the four RCP simulations. Our results suggest that continued warming may drive a poleward shift in the distribution of E. cava, with large differences depending on the climate scenario. For the lowest emission scenario (RCP2.6), most existing E. cava populations would not be impacted by seawater warming directly but would be adversely affected by intensified year‐round grazing. For the highest emission scenario (RCP8.5), previously suitable habitats throughout coastal Japan would become untenable for E. cava by the 2090s, due to both high‐temperature stress and intensified grazing. Our projections highlight the importance of not only mitigating regional warming due to climate change, but also protecting E. cava from herbivores to conserve suitable habitats on the Japanese coast.     

IMD-4690, a Novel Specific Inhibitor for Plasminogen Activator Inhibitor-1, Reduces Allergic Airway Remodeling in a Mouse Model of Chronic Asthma via Regulating Angiogenesis and Remodeling-Related Mediators

Plasminogen activator inhibitor (PAI)-1 is the principal inhibitor of plasminogen activators, and is responsible for the degradation of fibrin and extracellular matrix. IMD-4690 is a newly synthesized inhibitor for PAI-1, whereas the effect on allergic airway inflammation and remodeling is still unclear. We examined the in vivo effects by using a chronic allergen exposure model of bronchial asthma in mice. The model was generated by an immune challenge for 8 weeks with house dust mite antigen, Dermatophagoides pteronyssinus (Dp). IMD-4690 was intraperitoneally administered during the challenge. Lung histopathology, hyperresponsiveness and the concentrations of mediators in lung homogenates were analyzed. The amount of active PAI-1 in the lungs was increased in mice treated with Dp. Administration with IMD-4690 reduced an active/total PAI-1 ratio. IMD-4690 also reduced the number of bronchial eosinophils in accordance with the decreased expressions of Th2 cytokines in the lung homogenates. Airway remodeling was inhibited by reducing subepithelial collagen deposition, smooth muscle hypertrophy, and angiogenesis. The effects of IMD-4690 were partly mediated by the regulation of TGF-β, HGF and matrix metalloproteinase. These results suggest that PAI-1 plays crucial roles in airway inflammation and remodeling, and IMD-4690, a specific PAI-1 inhibitor, may have therapeutic potential for patients with refractory asthma due to airway remodeling.     

Spectral tuning in salamander visual pigments studied with dihydroretinal chromophores.

In visual pigments, opsin proteins regulate the spectral absorption of a retinal chromophore by mechanisms that change the energy level of the excited electronic state relative to the ground state. We have studied these mechanisms by using photocurrent recording to measure the spectral sensitivities of individual red rods and red (long-wavelength-sensitive) and blue (short-wavelength-sensitive) cones of salamander before and after replacing the native 3-dehydro 11-cis retinal chromophore with retinal analogs: 11-cis retinal, 3-dehydro 9-cis retinal, 9-cis retinal, and 5,6-dihydro 9-cis retinal. The protonated Schiff's bases of analogs with unsaturated bonds in the ring had broader spectra than the same chromophores bound to opsins. Saturation of the bonds in the ring reduced the spectral bandwidths of the protonated Schiff's bases and the opsin-bound chromophores and made them similar to each other. This indicates that torsion of the ring produces spectral broadening and that torsion is limited by opsin. Saturating the 5,6 double bond in retinal reduced the perturbation of the chromophore by opsin in red and in blue cones but not in red rods. Thus an interaction between opsin and the chromophoric ring shifts the spectral maxima of the red and blue cone pigments, but not that of the red rod pigment.     

Nuclear Receptor CAR Represses TNFα-Induced Cell Death by Interacting with the Anti-Apoptotic GADD45B

Background

Phenobarbital (PB) is the most well-known among numerous non-genotoxic carcinogens that cause the development of hepatocellular carcinoma (HCC). PB activates nuclear xenobiotic receptor Constitutive Active/Androstane Receptor (CAR; NR1I3) and this activation is shown to determine PB promotion of HCC in mice. The molecular mechanism of CAR-mediated tumor promotion, however, remains elusive at the present time. Here we have identified Growth Arrest and DNA Damage-inducible 45β (GADD45B) as a novel CAR target, through which CAR represses cell death.

Methodology/Principal Findings

PB activation of nuclear xenobiotic receptor CAR is found to induce the Gadd45b gene in mouse liver throughout the development of HCC as well as in liver tumors. Given the known function of GADD45B as a factor that represses Mitogen-activated protein Kinase Kinase 7 - c-Jun N-terminal Kinase (MKK7-JNK) pathway-mediated apoptosis, we have now demonstrated that CAR interacts with GADD45B to repress Tumor Necrosis Factor α ( TNFα)-induced JNK1 phosphorylation as well as cell death. Primary hepatocytes, prepared from Car^+/+, Car^−/−, Gadd45b^+/+ and Gadd45b^−/− mice, were treated with TNFα and Actinomycin D to induce phosphorylation of JNK1 and cell death. Co-treatment with the CAR activating ligand TCPOBOP (1,4 bis[2-(3,5-dichloropyridyloxy)]benzene) has resulted in repression of both phosphorylation and cell death in the primary hepatocytes from Car^+/+ but not Car^−/−mice. Repression by TCPOBOP was not observed in those prepared from Gadd45b^−/− mice. In vitro protein-protein interaction and phosphorylation assays have revealed that CAR interacts with MKK7 and represses the MKK7-mediated phosphorylation of JNK1.

Conclusions/Significance

CAR can form a protein complex with GADD45B, through which CAR represses MKK7-mediated phosphorylation of JNK1. In addition to activating the Gadd45b gene, CAR may repress death of mouse primary hepatocytes by forming a GADD45B complex and repressing MKK7-mediated phosphorylation of JNK1. The present finding that CAR can repress cell death via its interaction with GADD45B provides an insight for further investigations into the CAR-regulated molecular mechanism by which PB promotes development of HCC.     

Identification of Nd1, a novel murine kelch family protein,involved in stabilization of actin filaments

We isolated Nd1, a novel kelch family gene that encodes two forms of proteins, Nd1-L and Nd1-S. Nd1-L contains a BTB/POZ domain in its N terminus and six kelch repeats in the C terminus. Nd1-S has the BTB/POZ domain but lacks the six kelch repeats. Nd1-L but not Nd1-S mRNA is detected ubiquitously in normal mouse tissues. Nd1-L and Nd1-S proteins can form a dimer through the BTB/POZ domain. Nd1-L colocalizes with actin filaments detected using a confocal microscope, and its kelch repeats bind to them in vitro. Overexpression of Nd1-L in NIH3T3 cells delayed cell growth by affecting the transition of cytokinesis. Furthermore, the overexpression prevented NIH3T3 cells from cell death induced by actin destabilization but not by microtubule dysfunction. These data suggest that Nd1-L functions as a stabilizer of actin filaments as an actin-binding protein and may play a role in the dynamic organization of the actin cytoskeleton.     

Nucleotidylation of Aminoglycoside Antibiotics by Bacillus brevis

Biochemical transformations of aminoglycoside antibiotics by Bacillus species were examined. Among 39 strains of 8 Bacillus species, 4 strains of B. brevis were found to inactivate several aminoglycoside antibiotics: neamine, xylostasin, butirosin A and kanamycin A.

In the presence of Mg⁺² and ATP, the cell-free extracts of B. brevis IFO 12334 catalyzed the transformation of xylostasin to its inactive form. The structure of this inactivated xylostasin was determined to be 4′-O-monoadenylylxylostain from the ¹³C-NMR spectra, and from biochemical and spectroscopic studies.     

Lectins in Immature Pods of Winged Bean,Psophocarpus tetragonolobus (L.) DC.

Lectin activity in immature pods from 30 strains of winged bean was investigated. Most of the lectin activity occurred in green shells and a small portion in immature seeds. Hemagglutinating activity of green shells was classified into four groups, according to the agglutination of trypsinized human type A, B, and O erythrocytes. Extracts from green shells of four representative strains which showed different hemagglutination patterns gave different elution profiles of lectin activity from ion exchange columns. Four types of lectin activity with different blood group specificities were apparently found in green shells.