Aldehyde reductase gene expression by lipid peroxidation end products,MDA and HNE

Membrane lipid peroxidation results in the production of a variety of aldehydic compounds that play a significant role in aging, drug toxicity and the pathogenesis of a number of human diseases, such as atherosclerosis and cancer. Increased lipid peroxidation and reduced antioxidant status may also contribute to the development of diabetic complications. This study reports that lipid peroxidation end products such as malondialdehyde (MDA) and 4-hydroxynonenal (HNE) induce aldehyde reductase (ALR) gene expression. MDA and HNE induce an increase in intracellular peroxide levels; N-Acetyl-L-cysteine (NAC) suppressed MDA- and HNE-induced ALR gene expression. These results indicate that increased levels of intracellular peroxides by MDA and HNE might be involved in the upregulation of ALR.     

Conformational restriction approach to BACE1 inhibitors II: SAR study of the isocytosine derivatives fixed with a cis-cyclopropane ring

To improve the efficacy of the conformationally restricted BACE1 inhibitors, structural modifications were investigated using two strategies: (a) modification of the terminal aromatic ring and (b) insertion of a spacer between the aromatic rings. In the latter approach, another type of inhibitor 17 bearing an ethylene spacer between two aromatic rings was found to exhibit good BACE1 inhibitory activity, while the corresponding conformationally unrestricted compound 25 showed no activity. This result revealed an interesting effect of a conformational restriction with a cyclopropane ring.     

Refeeding with a standard diet after a 48-h fast elicits an inflammatory response in the mouse liver

Unhealthy eating behaviors increase the risk of metabolic diseases, but the underlying mechanisms are not fully elucidated. Because inflammation contributes to the pathogenesis of metabolic diseases, it is important to understand the effects of unhealthy eating on the inflammatory state. The objective of our present study was to address the effects of a fasting–refeeding regime, a model of irregular eating, on the hepatic inflammatory responses in mouse. The animals were fasted for 48 h and then refed either a standard or low-carbohydrate/high-fat diet. Inflammatory gene expression in the liver was then sequentially measured for the first 17 h after initiation of refeeding. To assess the roles of dietary carbohydrates and toll-like receptor 2 (TLR2) in the refeeding-induced inflammatory changes, gene expression levels in mice refed only carbohydrates (α-corn starch and sucrose) at different doses and in TLR2-deficient mice refed a standard diet were also analyzed. Refeeding with a standard diet increased the liver expression of Tlr2, proinflammatory mediators (Cxcl10, Cxcl1, Cxcl2, Icam-1) and negative regulators of TLR-signaling (A20 and Atf3). These increases were attenuated in mice refed a low-carbohydrate/high-fat diet. Refeeding only α-corn starch and sucrose also increased the expression of these inflammatory pathway genes depending on the doses. TLR2 deficiency significantly attenuated the refeeding-induced increase in the liver expression of Cxcl10, Cxcl1, Icam-1 and A20. These findings suggest that an irregular eating behavior can elicit a liver inflammatory response, which is at least partly mediated by TLR2, and that dietary carbohydrates play critical roles in this process.     

Cold Shock of Germinating Bacillus subtilis Spores

Susceptibility of germinating spores of Bacillus subtilis to a rapid chilling was examined by viable countings. Dormant spores were quite resistant to the cold shock but the spores, immediately upon germination, lose viability almost completely by the same treatment. The presence of divalent cation, magnesium, calcium or manganese, in a buffer to which the germinating spores were suspended, markedly protected the cells from the death by the cold shock effect. When the shocked cells were incubated in the buffer containing casein acid hydrolyzate, glucose and magnesium ion for short period of time, a remarkable increase in viable counts was observed. The existence of two critical temperature zones, which were determined by the initial temperature of cell suspension, was confirmed in the cold shock of germinating spores.     

Rapid PaperMicrobial Oxygenation of Organo-metallic Bissulfides Leading to Formation of Planar Chirality and C2 Symmetry

1,2-Bis(methylthiomethyl)ferrocene (3) was oxidized by Corynebacterium equi IFO 3730 to give monosulfoxide 4 in two diastereomeric forms with (1S,2R,S_S) and (1S,2R,R_S) configurations in a ratio of 4:1, while 1,1′-bis(methylthiomethyl)ferrocene (5) was oxidized by Penicillium frequentans IFO 5692 to (R)-monosulfoxide 6 and then preferentially to (R,R)-bissulfoxide 7. Thus, the bacterial monooxygenase generated specific planar chirality in the metallocenic monosulfoxide, and the fungal enzyme formed C₂ symmetry in the bissulfoxide.     

The First and Second Dissociation Constants of Subtilisin BPN′-Plasminostreptin Complex Determined by a Polarographic Method,and the Effects of pH on Them

A polarographic method based on the Brdi?ka current (the polarographic catalytic hydrogen evolution current produced by proteins in the presence of cobalt salts) was applied to direct titration of subtilisin BPN′ (S.BPIST) with plasminostreptin (PS) at a concentration level of 10”⁸ m. The first and second dissociation constants of the S.BPN-PS complex were determined by fitting theoretical curves to the titration data, in which the multiple equilibria involving microscopically distinct forms of S.BPN-PS complex were taken into account. The intrinsic free energy change in the first binding of S.BPN′ to dimeric PS was larger than that in the second binding. The dependence of the microscopic dissociation constants of S.BPN′-PS complex on pH indicates the participation of ionizable groups of pK_a 8.0 and 9.4 in the complex formation. The repulsive effect between negatively charged molecules of S.BPN′ and PS in the complex formation at elevated pH is suggested.     

Gliclazide inhibits proliferation but stimulates differentiation of white and brown adipocytes

Gliclazide, a second-generation sulfonylurea, has anti-oxidant properties as well as hypoglycemic activities. In the present study, we investigated whether gliclazide affected proliferation and/or differentiation of HW white and HB2 brown adipocyte cell lines. Gliclazide inhibited proliferation of HW and HB2 cells in the medium containing fetal calf serum or epidermal growth factor (EGF). Gliclazide inhibited phosphorylation of EGF receptor and of extracellular signal-regulated kinase (ERK) 1/2 stimulated by EGF. Gliclazide increased lipid accumulation and peroxisome proliferator-activated receptor gamma (PPARgamma) expression in the early stage of differentiation of adipocytes. A K(ATP) channel activator, diazoxide, did not inhibit the increase of lipid accumulation by gliclazide. Furthermore, gliclazide inhibited the DNA-binding activity of PPARgamma in mature adipocytes. On the other hand, glibenclamide, other sulfonylurea, did not show these effects. These results indicate gliclazide inhibits proliferation and stimulates differentiation of adipocytes via down-regulation of the EGFR signalling. Gliclazide may have preventive and therapeutic effects on obesity, as well as on type 2 diabetes.     

Contribution of neurons to habituation to mechanical stimulation in Caenorhabditis elegans

In Caenorhabditis elegans, a light touch induces a locomotor response. Repeated touches, however, result in an attenuation of response, that is, habituation. Withdrawal responses elicited by anterior touch are controlled by anterior mechanosensory neurons (AVM and ALMs), and by four pairs of interneurons (AVA, AVB, AVD, and PVC) (Chalfie et al., 1985; White et al., 1986). To identify the neurons that participate in habituation, we ablated these neurons with a laser microbeam and investigated the resulting habituation of the operated animals. The animals lacking both left and right homologues AVDLR were habituated more rapidly than intact animals. We propose that chemical synapses at AVD play a critical role in the habituation of intact animals.